30 [AOR=1.76; 95%CI: 1.50, 2.07], being Muslim religion follower [AOR = 0.83; 95%CI: 0.73, 0.94], attending primary education [AOR=1.70; 95%CI: 1.53, 1.89], attending secondary education [AOR=3.43; 95%CI: 2.95, 3.99] and attending higher education [AOR=5.88; 95%CI: 4.66, 7.42], history of pregnancy termination [AOR=1.31; 95%CI: 1.13, 1.51], media exposure at least once a week [AOR= 1.33; 95%CI: 1.2, 1.49], internet use [AOR= 2.25; 95%CI: 1.84, 2.75], medium house hold wealth [AOR=1.17; 95%CI: 1.02, 1.34], rich house hold wealth [AOR=1.50; 95%CI:1.31, 1.72] and community level factors including high community media exposure [AOR = 1.30; 95%CI: 1.05, 1.61], high community ANC rate [AOR=1.66; 95%CI: 1.37, 2.02] and low health facility distance problem [AOR=1.49; 95%CI: 1.23, 1.81] were significantly associated with awareness of OF.\n\nConclusionThe magnitude of womens awareness of OF was very low in Ethiopia. Maternal age, religion, being educated, media exposure, being from a wealthier household, low health facility distance problem, and high community ANC rate were significantly and positively associated factors with awareness of OF.","The impact of COVID-19 on the provision of respectful maternity care: findings from a global survey of health workers\nBackgroundSignificant adjustments to the provision of maternity care in response to the COVID-19 pandemic and the direct impacts of COVID-19 can compromise the quality of maternal and newborn care.\n\nAimTo explore how the COVID-19 pandemic affected frontline health workers ability to provide respectful maternity care globally.\n\nMethodsWe conducted a global online survey of health workers to assess the provision of maternal and newborn healthcare during the COVID-19 pandemic. We collected quantitative and qualitative data between July and December 2020 and conducted a qualitative content analysis to explore open-ended responses.\n\nFindingsHealth workers (n=1,127) from 71 countries participated; and 120 participants from 33 countries provided qualitative data. The COVID-19 pandemic negatively affected the provision of respectful maternity care in multiple ways. Six central themes were identified: less family involvement, reduced emotional and physical support for women, compromised standards of care, increased exposure to medically unjustified caesarean section, and staff overwhelmed by rapidly changing guidelines and enhanced infection prevention measures. Further, respectful care provided to women and newborns with suspected or confirmed COVID-19 infection was severely affected due to health workers fear of getting infected and measures taken to minimise COVID-19 transmission.\n\nDiscussionMultidimensional and contextually-adapted actions are urgently needed to mitigate the impacts of the COVID-19 pandemic on the provision and continued promotion of respectful maternity care globally in the long-term.\n\nConclusionsThe measures taken during the COVID-19 pandemic disrupted the quality of care provided to women during labour and childbirth generally, and respectful maternity care specifically.","An AI-based quantitative home-use framework for assessing fertility and identifying novel hormone trends by recording urine hormones\nFertility testing using urinary hormones has been used to effectively improve the likelihood of pregnancy. To provide fertility scores, the existing home-use systems measure one or two hormones. However, the hormone profiles vary depending on cycle duration, fertility-related disorders, drugs and other treatments. Here, we introduce Inito, a mobile-phone connected reader that is scalable to multiple hormone tests. In this report, we assess the accuracy of the quantitative home-based fertility monitor, the Inito Fertility Monitor (IFM), and suggest using IFM as a device to monitor and analyse female hormone patterns. There were two aspects of the study: i. evaluation of the efficacy of IFM in quantifying urinary Estrone-3-glucuronide (E3G), pregnanediol glucuronide (PdG) and luteinizing hormone (LH), and ii. A retrospective study of patients hormone profiles using IFM. We observed that with all three hormones, IFM had an accurate recovery percentage and had a CV of less than 10 percent. Furthermore, in predicting the concentration of urinary hormones, IFM showed a high correlation with ELISA. Using Inito in clinical trials, we report a novel criterion for earlier confirmation of ovulation compared to existing criteria. We also present a novel hormone pattern consistent across most menstrual cycles included in the study. In conclusion, the Inito Fertility Monitor is an effective tool for calculating the urinary concentrations of E3G, PdG and LH and can also be used to provide accurate fertility scores and confirm ovulation. In addition, the sensitivity of IFM facilitates the monitoring of menstrual cycle-related hormone patterns, therefore also making it a great tool for physicians to track the hormones of their patients.","OVARIAN GRANULOSA CELLS FROM WOMEN WITH PCOS EXPRESS LOW LEVELS OF SARS-COV-2 RECEPTORS AND CO-FACTORS\nPurposeSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is global pandemic with more than 3 million deaths so far. Female reproductive tract organs express coronavirus-associated receptors and factors (SCARFs); suggesting they may be susceptible to SARS-CoV-2 infection however the susceptibility of ovary/follicle/oocyte to the same is still elusive. Co-morbidities like obesity, type-2 diabetes mellitus, cardiovascular disease etc. increase the risk of SARS-CoV-2 infection. These features are common in women with polycystic ovary syndrome (PCOS), warranting further scope to study SCARFs expression in ovary of these women.\n\nMaterials and methodsSCARFs expression in ovary and ovarian tissues of women with PCOS and healthy women was explored by analyzing publically available microarray datasets. Transcript expression of SCARFs were investigated in mural and cumulus granulosa cells (MGCs and CGCs) from control and PCOS women undergoing in vitro fertilization (IVF).\n\nResultsMicroarray data revealed that ovary expresses all genes necessary for SARS-CoV-2 infection. PCOS women mostly showed down-regulated/unchanged levels of SCARFs. MGCs and CGCs from PCOS women showed lower expression of receptors ACE2, BSG and DPP4 and protease CTSB than in controls. MGCs showed lower expression of protease CTSL in PCOS than in controls. Expression of TMPRSS2 was not detected in both cell types.\n\nConclusionsHuman ovarian follicle may be susceptible to SARS-CoV-2 infection. Lower expression of SCARFs in PCOS indicate that the risk of SARS-CoV-2 infection to the ovary may be lesser in these women than controls. This knowledge may help in safe practices at IVF settings in the current pandemic.","Placental vascular remodeling in pregnant women with COVID-19\nSevere acute respiratory syndrome coronavirus 2 has been causing the pandemic of coronavirus disease 2019 (COVID-19) that has so far resulted in over 180 million infections and nearly 4 million deaths. This respiratory virus uses angiotensin-converting enzyme 2 as a receptor to enter host cells, exhibiting a unique feature that affects various tissues in addition to the lungs. The present study reports that the placental arteries from women who gave birth to live full-term newborns while developing of COVID-19 during pregnancy exhibit severe vascular wall thickening and the occlusion of the vascular lumen. A morphometric analysis of the placental arteries stained with hematoxylin and eosin suggest a 2-fold increase in wall thickness and a 5-fold decrease in the lumen area. Immunohistochemistry with -smooth muscle actin and Massons trichrome staining showed that such placental vascular remodeling in COVID-19 is associated with smooth muscle proliferation and fibrosis. Placental vascular remodeling may represent a mechanism of the clinical problems associated with childbirth in COVID-19 patients.","Cytogenetic & Molecular analysis in Premature Ovarian Failure\nIntroductionPremature Ovarian Failure (POF) being a heterogeneous genetic disease involves the interaction of multiple genetic defects and environmental factors and has been associated with several chromosomal abnormalities, single gene mutations, and genetic polymorphisms. BMP15 is a member of the transforming growth factor {beta} (TGF-{beta}) family. BMP15 gene product (protein) have 3 domians, mature domain (c-terminal region) of BMP15 binds to receptors located on granulosa cell surface to participate in key steps regarding ovarian function, such as granulosa cell proliferation and follicle maturation, ovulation rate modulation, oocyte competence determination and regulating granulosa cell sensitivity to FSH. Single nucleotide polymorphisms (SNPs) of the BMP-15 gene are associated with POF.\n\nMaterials & Methods30 POF patients and 30 healthy age matched controls were recruited for cytogenetic and molecular analysis. 10 ml whole blood was collected for karyotyping and PCR and PCR was performed for known SNPs of BMP-15 gene (-9C>G, 538G>A, 788insTCT and 852C>T) respectively. Amplified PCR products were sequenced commercially.\n\nObservation/ResultThirty cases (mean age 30 years) and thirty healthy controls (mean age 23 years) were recruited for the study. On cytogenetic analysis 2 cases had a 45, XO chromosomal complement. One case was heterozygous for the SNP (-9C>G) and one control was homozygous for the same SNP.\n\nDiscussionThe prevalence of this SNP was about 10.7% in cases & 3.3% in healthy controls. This polymorphism in promoter region may cause altered expression of the gene and results in POF.","Estimating the effects of accelerated partner therapy (APT) on reinfection of index cases with chlamydia: a mathematical modelling study\nObjectivesThe expected effects of accelerated partner therapy (APT) on the reinfection of treated index cases by untreated partners with Chlamydia trachomatis (chlamydia) remain unclear. We analyzed data from the LUSTRUM cluster cross-over randomised controlled trial (RCT) using a mathematical model and quantified the effects of offering APT on the probability of successful partner treatment.\n\nMethodsWe extended a previously developed mathematical model to compute the probability of chlamydia reinfection of index cases by their untreated partners with chlamydia. We fitted the model to data from the RCT and estimated the probability of successful treatment of the partner of index cases using a Bayesian framework.\n\nResultsWe estimated the median probability of reinfection with chlamydia at 16.3% (50% credible interval, CrI: 12.7-20.0%) without partner treatment and 2.3% (50% CrI: 1.7-3.6%) when partner treatment is 100% successful. The observed rates of reinfection in the RCT were 6.7% (95% confidence interval, CI: 5.6-8.0%) during the control period (standard partner notification (PN)) and 4.8% (95% CI: 3.7-5.9%) during the intervention period where APT was offered in addition to standard PN. These rates correspond to a median probability of successful partner treatment of 63% (50% CrI: 47-76%) during the control period and 78% (50% CrI: 65-87%) during the intervention period.\n\nConclusionsOur study suggests that the observed reduction in reinfection with chlamydia when offering APT is consistent with a higher probability of successful partner treatment.","Feasibility of Continuous Distal Body Temperature for Passive, Early Pregnancy Detection\nThe majority of American women become aware of pregnancy ~3-7 weeks after conception, and all must seek testing to confirm their pregnant status. The delay between conception and awareness is often a time in which contraindicated behaviors take place. However, there is long standing evidence that passive, early pregnancy detection may be possible using body temperature. To address this possibility, we analyzed 30 individuals continuous distal body temperature (DBT) in the 180 days surrounding self-reported conception in comparison to self-reported pregnancy confirmation. Features of DBT nightly maxima changed rapidly following self-reported conception, reaching uniquely elevated values after a median of 5.5 {+/-} 3.5 days, whereas individuals reported a positive pregnancy test result at a median of 14.5 {+/-} 4.2 days. Together, we were able to generate a retrospective, hypothetical alert a median of 9 {+/-} 3.9 days prior to the date at which individuals received a positive pregnancy test. Continuous temperature-derived features can provide early, passive indication of pregnancy onset. We propose these features for testing and refinement in clinical settings, and for exploration in large, diverse cohorts. The development of pregnancy detection using DBT may reduce the delay from conception to awareness and increase the agency of pregnant individuals.","An approach to quantifying the interaction between behavioural and transmission clusters: the case of Hepatitis C virus infections in HIV positive men who have sex with men\nWe hypothesize that patterns of sexual behaviour play a role in the conformation of transmission networks. If that was the case, behavioural grouping might in turn correlate with transmission networks and have the potential to predict proximity in viral phylogenies. To address this hypothesis, we present an intuitive approach for quantifying interactions between clusters of sexual behaviour along a virus phylogeny. Data from the Swiss HIV Cohort Study on condom use and incident Hepatitis C virus (HCV) sequences served as proof-of-concept. A strict inclusion criteria contrasting with relatively low HCV prevalence hindered our ability to identify significant relationships. This manuscript intends to serve as guide for studies aimed at characterizing interactions between behavioural patterns and transmission networks. Large transmission networks such as those of HIV or COVID-19 are prime candidates for applying this methodological approach.","Adolescent-led sexual and reproductive health and rights research: qualitative evaluation of an innovative participatory action research project in Senegal\nParticipatory approaches are increasingly popular in public health, but remain little used to address adolescent health issues. However, adolescent participation in research has enormous potential for identifying solutions to health issues that concern them. In Senegal, a youth-led participatory action research project was implemented to evaluate the potential of the approach to address adolescent sexual and reproductive health and rights issues. A qualitative evaluation was conducted in four Senegalese communities, where teams of adolescents were trained to conduct a research project and identify solutions relevant for their communities. Observations and interviews were carried out during results dissemination meetings in each of the communities. Based on participatory action research principles and expected adolescent participation outcomes, the evaluation of the project demonstrated the potential of the approach to identify relevant solutions, while promoting positive and meaningful adolescent participation. Despite some difficulties, such as community resistance, the youth researchers were able to successfully complete their research project, while developing their confidence and self-esteem. The adolescents were convinced that they could act as agents of positive social change. This project has shown that it is possible and relevant to involve adolescents in research projects, and that this approach has significant potential in global health.","The Mediating Role of SES on the Relationship between Pregnancy History and Later Life Cognition\nObjectiveThe association of pregnancy with later life cognition is not well understood. Few studies address the potential confounding role of socioeconomic factors on this relationship. We examined whether pregnancy was associated with cognitive function in a large, population-based sample of post-menopausal women and the potential mediating effects of education level and federal income-to-poverty ratio (PIR) on this relationship.\n\nMethodsParticipants were 1,016 post-menopausal women from the National Health and Nutrition Examination Survey (NHANES). We utilized data from two study waves between years 2011-2014. Cognitive functioning was evaluated by: Digit Symbol Substitution Test (DSST), Animal Fluency (AF), Consortium to Establish a Registry for Alzheimers Disease CERAD word learning task (CERAD-WL) and CERAD delayed recall (CERAD-DR). Lifetime education level and federal income-to-poverty ratio (PIR) were examined as mediating factors. Regression models were used to examine the relationship between number of term pregnancies and incomplete pregnancies and cognitive performance.\n\nResultsA greater number of term pregnancies was related to worse performance on the DSST (p < .001), CERAD-DR (p < .007), and AF (p < .03). Conversely, greater incomplete pregnancies related to better CERAD-DR performance (p < .03). Significant associations between term pregnancies and cognitive scores were mediated by PIR but not education level.\n\nConclusionsHigher number of term pregnancies was associated with worse cognitive performance, whereas higher number of incomplete pregnancies was associated with better cognitive performance. Results indicate the necessity to consider SES factors when studying the relationship between pregnancy and cognition.","Exposing racial bias in midwifery education: a content analysis of images and text in Myles Textbook for Midwives\nObjectiveTo determine how people of different races and skin colours are represented within Myles Textbook for Midwives and whether the identified content is clinically relevant to people of all skin colours.\n\nDesignContent analysis of text and images in Myles Textbook for Midwives 17th Edition, 2020\n\nFindingsThe images overwhelmingly depict light skinned people of White European appearance. When people of colour are shown they are more likely to be positioned in prominent imagery without specific link to the chapter topic. Descriptions of skin colour in the context of clinical assessment and/or treatment often applied mostly or solely to people with light colour skin. This included text referring to serious conditions or situations associated with severe morbidity or mortality.\n\nKey conclusionsMyles Textbook for Midwives presents a light skinned White European norm and often fails to include information that is clinically relevant to the assessment and treatment of people with darker skin colours. This may lead to disparity in midwifery education and contribute to poorer outcomes for women and babies.\n\nImplications for practiceConcrete efforts are required to identify and root out racial bias at all levels of midwifery education. This needs to happen alongside addressing current lack of good quality evidence required to support practice.","Novel Investigation of SARS-CoV-2 in COVID-19 Survivors' Semen in Surabaya, Indonesia\nThe emergence and the widespread of Coronavirus disease 2019 (COVID-19) demands an accurate detection method to establish a diagnosis. Real-time polymerase chain reaction (real-time PCR) is accounted for the perfect point of reference in detecting this virus. The notion that this virus also invades the male reproductive tract requires further investigation to prove the presence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in the semen. This investigation was designed to detect SARS-CoV-2 in COVID-19 survivors semen. This study design was a cross-sectional examination and conducted between November 2020 and March 2021 in the Andrology Unit of Dr. Soetomo General Hospital and Professor Nidom Foundation, both located in the City of Surabaya, Indonesia. The sample was 34 male participants aged above 18 years old and had been confirmed COVID-19 by nasopharyngeal swab PCR test. Part of the semen was taken for real-time PCR testing with the QuantStudio 5 Applied Biosystem (AB) PCR machine and the kits utilized were the STANDARD M nCOV Real-Time Detection Kit and mBioCov-19 RT-PCR Kit. Furthermore, the mean of participants ages was 35.74 years old with 25% of them had had a history of primary infertility and 21.8% of secondary infertility. From the real-time PCR COVID-19 of the semen examination, this investigation found that 27 participants had been negatives (74.4%), six inconclusive (17.6%), and one positive (3%) of SARS CoV-2. In summary, SARS-CoV-2 could be found in the semen of COVID-19 survivors. This should be a concern for the potential impact of COVID-19 in male fertility and the possibility of transmission reproductively.","Young womens knowledge and attitudes towards cervical cancer screening at a selected higher education institution in Lesotho\nBackgroundIn Lesotho, cervical cancer is the most common female cancer and leading cause of death amongst women. In 2019, the annual number of new cancer cases was 477 and 346 women died from cancer related complications in Lesotho.\n\nAimThe aim of this study was to assess the knowledge and attitudes of young women towards cervical cancer screening at a selected higher education institution in Lesotho.\n\nMethodsA quantitative cross-sectional research design was used to collect data using an interviewer administered semi-structured questionnaire from 80 young women who were randomly selected. Permission to conduct the study was sought and granted from relevant authorities. Informed consent was sought from the respondents who were identified using codes and participated voluntarily.\n\nResultsFifty percent (n=40) of the women did not know cervical cancer screening tests, 70% (n=56) did not know about the frequency of screening, whilst 75% (n=60) knew that human papilloma virus (HPV) vaccine is be used to prevent cervical cancer. Additionally, 95% (n=76) had not screened for cervical cancer, 65% (n=52) perceived cervical cancer screening as painful, and 95% (n=76) needed more information on cervical cancer screening.\n\nConclusionsThe practice of cervical cancer screening is low and there is a high need for health education and incorporating regular cervical cancer screening in health care services to increase the uptake amongst young women. Many participants were hesitant to screen as they perceived the procedure to be painful and this suggests the need for reassurance and counselling on cervical cancer screening techniques.","Effect of COVID-19 vaccination on menstrual periods in a retrospectively recruited cohort\nSurveillance schemes are receiving increasing numbers of reports from people who have noticed a change to their period following COVID-19 vaccination. In order to investigate this, we retrospectively recruited 1273 people who have a record of their menstrual cycle and vaccination dates and used their reports to explore hypotheses about how COVID-19 vaccination and menstrual changes could be linked. In this dataset, we were unable to detect strong signals to support the idea that COVID-19 vaccination is linked to menstrual changes. However, larger, prospectively recruited studies may be able to find associations that we were not powered to detect.","Sexual Behaviours and Sexual Health Among Middle-Aged and Older Adults in Britain: A Latent Class Analysis of The Natsal-3\nObjectivesPopulation-representative studies of the sexual health of middle-aged and older adults are lacking in aging societies. This study aimed to identify latent patterns of sexual behaviours and health of people aged 45-74.\n\nMethodsWe conducted a latent class analysis of the National Attitudes and Sexual Lifestyles Survey (Natsal-3), a nationally representative survey conducted in Britain in 2011.\n\nResultsOf the 5260 respondents aged 45-74, 49% of men and 45% of women belonged to the Content Caseys class who reported good sexual health. The Infrequent Indigos (31% of men, 44% of women) were characterized by a lack of sexual activity, reported some dissatisfaction, and were more likely to have a disability. The Low-Functioning Lees (12% of men, 8% of women) reported some more disability and had issues with sexual functioning and higher levels of distress. The Multiple-Partnered Morgans (9% of men, 2% of women) were characterized by a greater number of sexual partners and several risk behaviours.\n\nConclusionsThe use of these four classes can aid in improved targeting of tailored sexual health services to improve sexual function, sexual satisfaction, reduce distress and risky behaviours among middle-aged and older adults. These services should be inclusive of the disabled community.\n\nBullet pointsO_LIAbout half of these respondents were classified as Content Caseys who reported few issues concerning their sex lives.\nC_LIO_LIOver a third who reported no recent sexual activity, the vast majority of whom are single, were classified as Infrequent Indigos.\nC_LIO_LINearly 10% were classified Low-Functioning Lees due to the greater probability of reporting sexual function issues and distress.\nC_LIO_LIThe rest were classified as Multiple Partner Morgans as a result of a high likelihood of having multiple partners and unsafe sex.\nC_LI","Willing but Unable: Physicians' Referral Knowledge as Barriers to Abortion Care\nAbortion care is a crucial part of reproductive healthcare. Nevertheless, its availability is constrained by numerous forces, including care referrals within the larger healthcare system. Using a unique study of physician faculty across multiple specialties, we examine the factors associated with doctors ability to refer patients for abortion care among those who were willing to consult in the care of a patient seeking an abortion (N=674). Even though they were willing to refer a patient for an abortion, half (53%) of the physicians did not know how and whom to make those referrals, though they care for patients who may need them. Those with the least referral knowledge had not been taught abortion care during their medical training and were in earlier stages of their career than those who had more knowledge. This research exposes another obstacle for those seeking an abortion, a barrier that would be overcome with a clear and robust referral system within and across medical specialties.","Online prescribing for sexually transmitted infections \t- what is on offer? An evaluation of internet pharmacies based in the United Kingdom\nBackgroundOnline pharmacies offer an alternative approach for patients to manage their sexual health. Our aim was to determine the type of antimicrobials sold as treatment for sexually transmitted infections (STIs) by UK internet pharmacies and if providers were adhering to national guidelines.\n\nMethodsA search engine results page (SERP) generated a list of registered UK online pharmacies offering treatment for the following infections: Chlamydia trachomatis, Neisseria gonorrhoeae, Herpes simplex and Trichomonas vaginalis. An initial audit in 2017 benchmarked each provider against the British Association of Sexual Health & HIV (BASHH guidelines. Results were fed back to each provider before re-audit in 2020. Websites selling antibiotics for non-gonococcal urethritis (NGU) and Mycoplasma genitalium were included at re-audit.\n\nResultsThere were 30 pharmacies identified in 2017 of which, five were excluded. Treatment could be obtained for Neisseria gonorrhoeae from five pharmacies without providing a culture result; three (60%) pharmacies sold BASHH approved antibiotics for Neisseria gonorrhoeae. All 25 pharmacies sold Chlamydia trachomatis treatment; 22 (88%) offered first line treatment options but no website assessed for proctitis. Herpes simplex treatment was sold on 22 websites of which, 13 (59%) offered treatment recommended by BASHH. Trichomonas vaginalis treatment was sold by four websites in line with BASHH. Results at re-audit showed an improvement in standards, although advice before, during and after treatment remained variable.\n\nDiscussionOur work has allowed us to engage with providers to improve prescribing within the UK online pharmacy industry. However, tougher regulation is needed in order to embed sustainable change for patients who choose to access treatment online."],"string":"[\n \"Unmasking Seasonal Cycles in Human Fertility: How holiday sex and fertility cycles shape birth seasonality\\nThe mechanisms of human birth seasonality have been debated for over 150 years1. In particular, the question of whether sexual activity or fertility variations drive birth seasonality has remained open and challenging to test without large-scale data on sexual activity 2,3. Analyzing data from half-a-million users worldwide collected from the female health tracking app Clue combined with birth records, we inferred that birth seasonality is primarily driven by seasonal fertility, yet increased sexual activity around holidays explains minor peaks in the birth curve. Our data came from locations in the Northern Hemisphere (UK, US, and France) and the Southern Hemisphere (Brazil). We found that fertility peaks between the autumn equinox and winter solstice in the Northern Hemisphere locations and shortly following the winter solstice in the Southern Hemisphere locations.\",\n \"Maternity waiting home Utilization and associated factors among women who gave birth in the Digelu and Tijo district of the Arsi Zone, Oromia, Ethiopia.\\nBackgroundMaternity Waiting Homes (MWHs) is an intervention designed to reduce maternal and perinatal mortality. Ethiopia has introduced the intervention before three decades however; its utilization is very low. Therefore, this study is aimed to assess MWH utilization and associated factors among women who gave birth in the last 12 months in Digelu and Tijo district Arsi Zone Oromia Region, Ethiopia.\\n\\nMethodsCommunity-based cross-sectional study was conducted in April 2019 on 530 randomly selected women. Data were collected by face-to-face interview using structured questionnaire. Descriptive statistics and logistics regressions were used to analyze the results. Adjusted odds ratio and 95% confidence interval were respectively calculated to measure strength of association and its statistical significance.The confidence interval was used to declare statistical significance in the final model.\\n\\nResultsOne hundred twenty-five (23.6%) of the respondents used maternity waiting home. Traveling time less than and equals to 60 minutes from a nearby health facility (AOR=0.16, 95% CI: 0.09, 0.27), womens decision power (AOR=1.81, 95% CI: 1.10, 2.96), not utilizing antenatal care (AOR=0.6, 95% CI: 0.37, 0.97) and delivering more than three children (AOR=0.56, 95% CI: 0.34, 0.90) were independently associated with utilizing the maternity waiting home.\\n\\nConclusionEven though the MWH was designed to reduce maternal and perinatal mortality, less than a quarter (23.6%) of women delivered in the last 12 months before the study in the Digelu and Tijo District had utilized the services. Increasing availability of the service, promoting antenatal care utilization, empowering women and evolving policy makers are recommended to enhance the current low utilization of the MWH.\",\n \"Genetic insights into the biological mechanisms governing human ovarian ageing\\nReproductive longevity is critical for fertility and impacts healthy ageing in women, yet insights into the underlying biological mechanisms and treatments to preserve it are limited. Here, we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in [~]200,000 women of European ancestry. These common alleles influence clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. Identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increase fertility and extend reproductive life in mice. Causal inference analyses using the identified genetic variants indicates that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases risks of hormone-sensitive cancers. These findings provide insight into the mechanisms governing ovarian ageing, when they act across the life-course, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.\",\n \"High prevalence of mixed and non-vaccine HPV oncogenic types and their association with higher mortality in Black women with cervical cancer\\nWe studied the incidence of HPV genotypes in mostly Black women with cervical carcinoma and correlated histopathologic tumor characteristics, immune markers and clinical data with survival. Disease-free survival (DFS) and overall survival (OS) were recorded for 60 months post-diagnosis. Fifty four of the 60 (90%) patients were Black and 36 (60%) were <55 years of age. Of the 40 patients with typeable HPV genotypes, 10 (25%) had 16/18 HPV genotypes, 30 (75%) had one of the non-16/18 HPV genotypes, and 20 (50%) had one of the 7 genotypes (35, 39, 51, 53, 56, 59 and 68) that are not included in the nonavalent vaccine. Mixed HPV infections ([≥]2 types) were found in 11/40 (27.5%) patients. Patients infected with non-16/18 genotypes, including the most common genotype, HPV 35, had significantly shorter DFS and OS. PD-L1 (p=0.003), MMR expression (p=0.01), clinical stage (p=0.048), histologic grade (p=0.015) and mixed HPV infection (p=0.026) were independent predictors of DFS. A remarkably high proportion of cervical cancer cells in our patients expressed PD-L1 which opens the possibility of the use of immune checkpoint inhibitors to treat these cancers. Exclusion of the common HPV genotypes from the vaccine exacerbates mortality from cervical cancer in underserved Black patients.\",\n \"Workplace sexual harassment in sexual and reproductive services: a preliminary cross-sectional study.\\nINTRODUCTIONSexual harassment at the workplace in health care is most prevalent in Anglo regions, although is an emerging problem globally. No research has yet focused on the prevalence of the phenomenon within the area of sexual and reproductive health care in Anglo regions. The aim of this study is therefore to measure the prevalence of sexual harassment in sexual and reproductive health care setting and compare it with other clinical areas.\\n\\nMETHODA web survey to health care workers of various NHS Trusts in the United Kingdom was carried out and a cross-sectional study was conducted to measure observed counts, expected frequencies and prevalence from a total of 90 questionnaires received.\\n\\nRESULTSThe prevalence of workplace sexual harassment within the sexual and reproductive health services is lower compared to other clinical areas.\\n\\nCONCLUSIONSWorking in sexual and reproductive services could be a protective factor for workplace sexual harassment, therefore this study originates a new line of research aiming to identify the protective factors against sexual harassment at the workplace in sexual and reproductive health and the ways they could be used to protect every health care worker from sexual harassment in the workplace.\\n\\nKEY POINTSThe prevalence of workplace sexual harassment in sexual and reproductive health services is lower compared to other clinical areas.\\n\\nWorking in sexual and reproductive services could be a protective factor for workplace sexual harassment.\",\n \"Early medical abortion by telemedicine in the United Kingdom: A cost-effectiveness analysis\\nObjectiveTo determine the potential cost savings resulting from the introduction of routine early medical abortion at home by telemedicine in the United Kingdom.\\n\\nDesignA cost-effectiveness analysis Setting: United Kingdom\\n\\nPopulationWomen in 2020 undergoing early medical abortion provided by three independent abortion providers and two NHS abortion clinics.\\n\\nMethodsComputation of the costs of each abortion procedure and of managing failed or incomplete abortion and haemorrhage requiring blood transfusion.\\n\\nOutcome measuresCost savings\\n\\nResultsOverall estimated cost savings are {pound}15.80 per abortion undertaken by independent abortion providers representing a saving to the NHS of over {pound}3 million per year. Limited data from NHS services resulted in an estimated average saving of {pound}188.84 per abortion.\\n\\nConclusionsWere telemedicine EMA to become routine, an increase in the number of women eligible for medical rather than surgical abortion, and a reduction in adverse events resulting from earlier abortion could result in significant cost-savings.\\n\\nTweetable AbstractEarly medical abortion at home using telemedicine could save the NHS {pound}3 million per year\",\n \"Factors Associated with Antenatal Care Service Utilization among Mothers with Children under five years in Sunyani Municipality, Ghana\\nBackgroundMaternal and neonatal mortality remains a public health burden around the globe most especially in developing countries. A well utilized antenatal care (ANC) is however among the identified interventions to reduce this burden of maternal and neonatal mortality rates. A lot of factors therefore predispose, enable and cause mothers to identify the need to utilize this service (ANC).\\n\\nAims/objectivesThe aim of this study was to determine factors associated with the utilization of ANC service among postpartum mothers in the Sunyani municipality.\\n\\nMethodsThis study employed descriptive cross-sectional survey design. A semi-structured questionnaire consisting of demographic profile of the respondents, their knowledge about ANC services and the level of ANC utilization. Logistic regression analysis techniques and chi-square were used for the categorical variables to examine the associations between the dependent and independent variables. Data analysis was done using the Statistical Package for Social Science software (SPSS) version 22.\\n\\nResultsMajority (87%) of postpartum mothers in the Sunyani municipality attended ANC at least once during their last pregnancy of which 95.6% had four or more visits and 77.1% initiated their ANC attendance within their first trimester. It was further observed that 97.3% of the mothers had good knowledge about ANC. Marital status and ANC knowledge were found to be significantly associated with ANC attendance. Husbands were found to be poorly involved in ANC services in the Sunyani municipality.\\n\\nConclusionMarital status and ANC knowledge predisposes most mothers to utilize ANC services. Hence, health education activities about ANC services and its importance should be channeled more to areas where ANC utilization is low.\",\n \"Prevalence of short interpregnancy interval and its associated factors among pregnant women in Debre Berhan town, Ethiopia\\nBackgroundShort inter-pregnancy interval is when the time elapsed between the dates of birth of the preceding child and the conception date of the current pregnancy is < 24 months. Despite its direct effects on the perinatal and maternal outcomes, there is a paucity of evidence on its prevalence and determinant factors, particularly in Ethiopia. Therefore, this study assessed the prevalence and associated factors of short inter-pregnancy interval among pregnant women in Debre Berhan town, Northern Ethiopia.\\n\\nMethodsA community based cross sectional study was conducted among a randomly selected 496 pregnant women in Debre Berhan town from February 9 to March 9, 2020. The data was collected by using interviewer administered questionnaire and analyzed using STATA (14.2) statistical software. To identify the predictors of short inter-pregnancy interval, multivariable binary logistic regression was fitted and findings are presented using adjusted odds ratio (AOR) with 95% confidence interval (CI).\\n\\nResultThe overall prevalence of short inter-pregnancy interval (<24 months) among pregnant women was 205 (40.9%). Being over 30 years of age at first birth (AOR=3.50; 95% CI: 2.12-6.01), non-use of modern contraceptive (AOR=2.51; 95% CI: 1.23-3.71), duration of breast feeding for less than 12 months (AOR= 2.62; 95% CI: 1.32-5.23), parity above four (AOR=0.31; 95% CI: 0.05-0.81), and unintended pregnancy (AOR= 5.42; 95% CI: 3.34-9.22) were independently associated factors with short inter-pregnancy interval.\\n\\nConclusionDespite the family planning and other public health intervention tried in the country, the prevalence of short inter-pregnancy interval in this study was high. Therefore, it implies that increasing contraceptive use and encouraging optimal breast feeding might help in the efforts made to avert the problem.\",\n \"Family Planning Performance in 113 Countries Using a New Composite Performance Index\\nIn this paper we measure family planning performance in 113 countries of the world using a composite performance index that takes into account both the met demand for family planning and the composition of the met demand. The composite performance index used in the present paper is an improvement over the existing approaches of measuring family planning performance. The analysis reveals that family planning performance varies widely across countries and it remains either poor or very poor in more than 40 per cent countries. There is no country where the performance is very high. Moreover, there are many countries where the family planning performance appears to have deteriorated over time. There are only a few countries where family planning performance has improved in recent years. The analysis calls for increased investment in family planning to meet the target set under the Sustainable Development Goals.\",\n \"Pregnancy outcomes from a restorative infertility treatment model: a single centre case series\\nBackgroundInfertility is a significant problem with multiple causes and a corresponding array of therapeutic options. In an era of increasing assisted reproductive treatments, few studies examine the role of conventional non-assisted reproductive treatments to address underlying behavioural, lifestyle and medical issues.\\n\\nAimTo assess outcomes from a conventional or non-assisted reproductive treatment approach\\n\\nMaterials and MethodsRetrospective case series of 162 couples that attended an Australian, hospital-based, multidisciplinary fertility clinic between 2005 and 2010.\\n\\nResultsThere were 58 live births for all couples giving a crude live birth rate of 35.4% over a 24-month analysis period. When adjusted by Kaplan-Meier method, a 57.4% cumulative live birth rate (CLBR) was achieved. Couples had a median 33.9 months duration of infertility and the median female age was 33.7. For the 74 couples with an unexplained infertility diagnosis, 32 achieved a live birth at a crude rate of 43.2% or 71.2% CLBR when adjusted by Kaplan-Meier method.\\n\\nConclusionsThis observational data indicates that reproductive medicine should have a personalized approach in which alternatives for immediate IVF are considered.\",\n \"Rare coding variants in five DNA damage repair genes associate with timing of natural menopause\\nThe age of menopause is associated with fertility and disease risk, and its genetic control is of great interest. We used whole-exome sequences from 119,992 women in the UK Biobank to test for associations between rare damaging variants and age at natural menopause. Rare damaging variants in three genes significantly associated with menopause: CHEK2 (p = 6.2 x 10-51) and DCLRE1A (p = 1.2 x 10-12) with later menopause and TOP3A (p = 8.8 x 10-8) with earlier menopause. Two additional genes were suggestive: RAD54L (p = 2.3 x 10-6) with later menopause and HROB (p = 2.7 x 10-6) with earlier menopause. In a follow-up analysis of repeated questionnaires in women who were initially pre-menopausal, CHEK2, TOP3A, and RAD54L genotype associated with subsequent menopause. Consistent with previous GWAS, all five genes are involved in the DNA-damage repair pathway. Phenome-wide scans across 363,977 men and women revealed that in addition to known associations with cancers and blood cell counts, rare variants in CHEK2 also associated with increased risk of uterine fibroids, polycystic ovary syndrome, and prostate hypertrophy; these associations are not shared with higher-penetrance breast cancer genes. Causal mediation analysis suggests that approximately 8% of the breast cancer risk conferred by CHEK2 pathogenic variants after menopause is mediated through delayed menopause.\",\n \"Characterisation of peri-implantation endometrial Treg and identification of an altered phenotype in recurrent pregnancy loss.\\nRecurrent Pregnancy Loss (RPL) affects 2-4% of couples, and with increasing numbers of pregnancy losses the risk of miscarrying a euploid pregnancy is increased, suggesting RPL is a pathology distinct from sporadic miscarriage that is due largely to lethal embryonic aneuploidy. There are a number of conditions associated with RPL including unspecified immune pathologies, one of the strongest candidates for dysregulation remains T regulatory cells as depletion in the very early stages of pregnancy in mice leads to pregnancy loss.\\n\\nHuman endometrial Treg and conventional CD4T cells were isolated during the peri-implantation period of the menstrual cycle in normal women. We identified an endometrial Treg transcriptomic signature and validated an enhanced regulatory phenotype compared to peripheral blood Treg. Parous women had an altered endometrial Treg transcriptome compared to nulliparity, indicating acquired immunity memory of pregnancy within the Treg population, by comparison endometrial conventional CD4T cells were not altered. We compared primary and secondary RPL to nulliparous or parous controls respectively. Both RPL subgroups displayed differentially expressed Treg gene transcriptomes compared to controls. We found increased cell surface S1PR1 and decreased TIGIT protein expression by Treg in primary RPL, confirming the presence of altered Treg in the peri-implantation RPL endometrium.\",\n \"Men and sexual and reproductive healthcare in the Nordic countries: a scoping review\\nContextMen generally seek healthcare less often than women and, other than traditional gender norms, less is known about the explanation. The aim was to identify knowledge gaps and factors influencing men regarding sexual and reproductive healthcare (SRHC) in the Nordic countries.\\n\\nMethodsWe searched PubMed and SveMed+ for peer-reviewed articles published between 2010 and 2020. The analyses identified factors influencing mens experiences of and access to SRHC.\\n\\nResultsThe majority of the 68 articles included focused on pregnancy, birth, infertility, and sexually transmitted infections including HIV. During pregnancy and childbirth, men were treated as accompanying partners rather than individuals with their own needs. The knowledge and attitudes of healthcare providers were crucial for their ability to provide SRHC and for the experiences of men. Organizational obstacles, such as women-centred SRHC and no assigned profession, hindered mens access to SRHC. Lastly, the literature rarely discussed the impact of health policies on mens access to SRHC.\\n\\nConclusionsThe identified knowledge gap indicates the necessity of the improved health and medical education of healthcare providers, as well as of health system interventions.\",\n \"Awareness of Obstetric Fistula and its Associated Factors Among Reproductive-Age Women in Ethiopia: A Multilevel Analysis Based on National Survey Data\\nObjectiveThis study aimed to determine the magnitude and associated factors of womens awareness of obstetric fistula (OF).\\n\\nMethodsThis community based crossectional study was conducted among 15,683 reproductive-aged women. A multi-level multivariable logistic regression analysis employed. A 95% CI and p-value < 0.05 were used to declare statistical significance.\\n\\nResultThe magnitude of womens awareness of OF was 38% [95%CI: 0.37, 0.39]. Individual level variables such as being in the age group 20-25 [AOR=1.17; 95%CI:1.02, 1.35], 26-30 [AOR=1.50; 95%CI: 1.27, 1.76] and >30 [AOR=1.76; 95%CI: 1.50, 2.07], being Muslim religion follower [AOR = 0.83; 95%CI: 0.73, 0.94], attending primary education [AOR=1.70; 95%CI: 1.53, 1.89], attending secondary education [AOR=3.43; 95%CI: 2.95, 3.99] and attending higher education [AOR=5.88; 95%CI: 4.66, 7.42], history of pregnancy termination [AOR=1.31; 95%CI: 1.13, 1.51], media exposure at least once a week [AOR= 1.33; 95%CI: 1.2, 1.49], internet use [AOR= 2.25; 95%CI: 1.84, 2.75], medium house hold wealth [AOR=1.17; 95%CI: 1.02, 1.34], rich house hold wealth [AOR=1.50; 95%CI:1.31, 1.72] and community level factors including high community media exposure [AOR = 1.30; 95%CI: 1.05, 1.61], high community ANC rate [AOR=1.66; 95%CI: 1.37, 2.02] and low health facility distance problem [AOR=1.49; 95%CI: 1.23, 1.81] were significantly associated with awareness of OF.\\n\\nConclusionThe magnitude of womens awareness of OF was very low in Ethiopia. Maternal age, religion, being educated, media exposure, being from a wealthier household, low health facility distance problem, and high community ANC rate were significantly and positively associated factors with awareness of OF.\",\n \"The impact of COVID-19 on the provision of respectful maternity care: findings from a global survey of health workers\\nBackgroundSignificant adjustments to the provision of maternity care in response to the COVID-19 pandemic and the direct impacts of COVID-19 can compromise the quality of maternal and newborn care.\\n\\nAimTo explore how the COVID-19 pandemic affected frontline health workers ability to provide respectful maternity care globally.\\n\\nMethodsWe conducted a global online survey of health workers to assess the provision of maternal and newborn healthcare during the COVID-19 pandemic. We collected quantitative and qualitative data between July and December 2020 and conducted a qualitative content analysis to explore open-ended responses.\\n\\nFindingsHealth workers (n=1,127) from 71 countries participated; and 120 participants from 33 countries provided qualitative data. The COVID-19 pandemic negatively affected the provision of respectful maternity care in multiple ways. Six central themes were identified: less family involvement, reduced emotional and physical support for women, compromised standards of care, increased exposure to medically unjustified caesarean section, and staff overwhelmed by rapidly changing guidelines and enhanced infection prevention measures. Further, respectful care provided to women and newborns with suspected or confirmed COVID-19 infection was severely affected due to health workers fear of getting infected and measures taken to minimise COVID-19 transmission.\\n\\nDiscussionMultidimensional and contextually-adapted actions are urgently needed to mitigate the impacts of the COVID-19 pandemic on the provision and continued promotion of respectful maternity care globally in the long-term.\\n\\nConclusionsThe measures taken during the COVID-19 pandemic disrupted the quality of care provided to women during labour and childbirth generally, and respectful maternity care specifically.\",\n \"An AI-based quantitative home-use framework for assessing fertility and identifying novel hormone trends by recording urine hormones\\nFertility testing using urinary hormones has been used to effectively improve the likelihood of pregnancy. To provide fertility scores, the existing home-use systems measure one or two hormones. However, the hormone profiles vary depending on cycle duration, fertility-related disorders, drugs and other treatments. Here, we introduce Inito, a mobile-phone connected reader that is scalable to multiple hormone tests. In this report, we assess the accuracy of the quantitative home-based fertility monitor, the Inito Fertility Monitor (IFM), and suggest using IFM as a device to monitor and analyse female hormone patterns. There were two aspects of the study: i. evaluation of the efficacy of IFM in quantifying urinary Estrone-3-glucuronide (E3G), pregnanediol glucuronide (PdG) and luteinizing hormone (LH), and ii. A retrospective study of patients hormone profiles using IFM. We observed that with all three hormones, IFM had an accurate recovery percentage and had a CV of less than 10 percent. Furthermore, in predicting the concentration of urinary hormones, IFM showed a high correlation with ELISA. Using Inito in clinical trials, we report a novel criterion for earlier confirmation of ovulation compared to existing criteria. We also present a novel hormone pattern consistent across most menstrual cycles included in the study. In conclusion, the Inito Fertility Monitor is an effective tool for calculating the urinary concentrations of E3G, PdG and LH and can also be used to provide accurate fertility scores and confirm ovulation. In addition, the sensitivity of IFM facilitates the monitoring of menstrual cycle-related hormone patterns, therefore also making it a great tool for physicians to track the hormones of their patients.\",\n \"OVARIAN GRANULOSA CELLS FROM WOMEN WITH PCOS EXPRESS LOW LEVELS OF SARS-COV-2 RECEPTORS AND CO-FACTORS\\nPurposeSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is global pandemic with more than 3 million deaths so far. Female reproductive tract organs express coronavirus-associated receptors and factors (SCARFs); suggesting they may be susceptible to SARS-CoV-2 infection however the susceptibility of ovary/follicle/oocyte to the same is still elusive. Co-morbidities like obesity, type-2 diabetes mellitus, cardiovascular disease etc. increase the risk of SARS-CoV-2 infection. These features are common in women with polycystic ovary syndrome (PCOS), warranting further scope to study SCARFs expression in ovary of these women.\\n\\nMaterials and methodsSCARFs expression in ovary and ovarian tissues of women with PCOS and healthy women was explored by analyzing publically available microarray datasets. Transcript expression of SCARFs were investigated in mural and cumulus granulosa cells (MGCs and CGCs) from control and PCOS women undergoing in vitro fertilization (IVF).\\n\\nResultsMicroarray data revealed that ovary expresses all genes necessary for SARS-CoV-2 infection. PCOS women mostly showed down-regulated/unchanged levels of SCARFs. MGCs and CGCs from PCOS women showed lower expression of receptors ACE2, BSG and DPP4 and protease CTSB than in controls. MGCs showed lower expression of protease CTSL in PCOS than in controls. Expression of TMPRSS2 was not detected in both cell types.\\n\\nConclusionsHuman ovarian follicle may be susceptible to SARS-CoV-2 infection. Lower expression of SCARFs in PCOS indicate that the risk of SARS-CoV-2 infection to the ovary may be lesser in these women than controls. This knowledge may help in safe practices at IVF settings in the current pandemic.\",\n \"Placental vascular remodeling in pregnant women with COVID-19\\nSevere acute respiratory syndrome coronavirus 2 has been causing the pandemic of coronavirus disease 2019 (COVID-19) that has so far resulted in over 180 million infections and nearly 4 million deaths. This respiratory virus uses angiotensin-converting enzyme 2 as a receptor to enter host cells, exhibiting a unique feature that affects various tissues in addition to the lungs. The present study reports that the placental arteries from women who gave birth to live full-term newborns while developing of COVID-19 during pregnancy exhibit severe vascular wall thickening and the occlusion of the vascular lumen. A morphometric analysis of the placental arteries stained with hematoxylin and eosin suggest a 2-fold increase in wall thickness and a 5-fold decrease in the lumen area. Immunohistochemistry with -smooth muscle actin and Massons trichrome staining showed that such placental vascular remodeling in COVID-19 is associated with smooth muscle proliferation and fibrosis. Placental vascular remodeling may represent a mechanism of the clinical problems associated with childbirth in COVID-19 patients.\",\n \"Cytogenetic & Molecular analysis in Premature Ovarian Failure\\nIntroductionPremature Ovarian Failure (POF) being a heterogeneous genetic disease involves the interaction of multiple genetic defects and environmental factors and has been associated with several chromosomal abnormalities, single gene mutations, and genetic polymorphisms. BMP15 is a member of the transforming growth factor {beta} (TGF-{beta}) family. BMP15 gene product (protein) have 3 domians, mature domain (c-terminal region) of BMP15 binds to receptors located on granulosa cell surface to participate in key steps regarding ovarian function, such as granulosa cell proliferation and follicle maturation, ovulation rate modulation, oocyte competence determination and regulating granulosa cell sensitivity to FSH. Single nucleotide polymorphisms (SNPs) of the BMP-15 gene are associated with POF.\\n\\nMaterials & Methods30 POF patients and 30 healthy age matched controls were recruited for cytogenetic and molecular analysis. 10 ml whole blood was collected for karyotyping and PCR and PCR was performed for known SNPs of BMP-15 gene (-9C>G, 538G>A, 788insTCT and 852C>T) respectively. Amplified PCR products were sequenced commercially.\\n\\nObservation/ResultThirty cases (mean age 30 years) and thirty healthy controls (mean age 23 years) were recruited for the study. On cytogenetic analysis 2 cases had a 45, XO chromosomal complement. One case was heterozygous for the SNP (-9C>G) and one control was homozygous for the same SNP.\\n\\nDiscussionThe prevalence of this SNP was about 10.7% in cases & 3.3% in healthy controls. This polymorphism in promoter region may cause altered expression of the gene and results in POF.\",\n \"Estimating the effects of accelerated partner therapy (APT) on reinfection of index cases with chlamydia: a mathematical modelling study\\nObjectivesThe expected effects of accelerated partner therapy (APT) on the reinfection of treated index cases by untreated partners with Chlamydia trachomatis (chlamydia) remain unclear. We analyzed data from the LUSTRUM cluster cross-over randomised controlled trial (RCT) using a mathematical model and quantified the effects of offering APT on the probability of successful partner treatment.\\n\\nMethodsWe extended a previously developed mathematical model to compute the probability of chlamydia reinfection of index cases by their untreated partners with chlamydia. We fitted the model to data from the RCT and estimated the probability of successful treatment of the partner of index cases using a Bayesian framework.\\n\\nResultsWe estimated the median probability of reinfection with chlamydia at 16.3% (50% credible interval, CrI: 12.7-20.0%) without partner treatment and 2.3% (50% CrI: 1.7-3.6%) when partner treatment is 100% successful. The observed rates of reinfection in the RCT were 6.7% (95% confidence interval, CI: 5.6-8.0%) during the control period (standard partner notification (PN)) and 4.8% (95% CI: 3.7-5.9%) during the intervention period where APT was offered in addition to standard PN. These rates correspond to a median probability of successful partner treatment of 63% (50% CrI: 47-76%) during the control period and 78% (50% CrI: 65-87%) during the intervention period.\\n\\nConclusionsOur study suggests that the observed reduction in reinfection with chlamydia when offering APT is consistent with a higher probability of successful partner treatment.\",\n \"Feasibility of Continuous Distal Body Temperature for Passive, Early Pregnancy Detection\\nThe majority of American women become aware of pregnancy ~3-7 weeks after conception, and all must seek testing to confirm their pregnant status. The delay between conception and awareness is often a time in which contraindicated behaviors take place. However, there is long standing evidence that passive, early pregnancy detection may be possible using body temperature. To address this possibility, we analyzed 30 individuals continuous distal body temperature (DBT) in the 180 days surrounding self-reported conception in comparison to self-reported pregnancy confirmation. Features of DBT nightly maxima changed rapidly following self-reported conception, reaching uniquely elevated values after a median of 5.5 {+/-} 3.5 days, whereas individuals reported a positive pregnancy test result at a median of 14.5 {+/-} 4.2 days. Together, we were able to generate a retrospective, hypothetical alert a median of 9 {+/-} 3.9 days prior to the date at which individuals received a positive pregnancy test. Continuous temperature-derived features can provide early, passive indication of pregnancy onset. We propose these features for testing and refinement in clinical settings, and for exploration in large, diverse cohorts. The development of pregnancy detection using DBT may reduce the delay from conception to awareness and increase the agency of pregnant individuals.\",\n \"An approach to quantifying the interaction between behavioural and transmission clusters: the case of Hepatitis C virus infections in HIV positive men who have sex with men\\nWe hypothesize that patterns of sexual behaviour play a role in the conformation of transmission networks. If that was the case, behavioural grouping might in turn correlate with transmission networks and have the potential to predict proximity in viral phylogenies. To address this hypothesis, we present an intuitive approach for quantifying interactions between clusters of sexual behaviour along a virus phylogeny. Data from the Swiss HIV Cohort Study on condom use and incident Hepatitis C virus (HCV) sequences served as proof-of-concept. A strict inclusion criteria contrasting with relatively low HCV prevalence hindered our ability to identify significant relationships. This manuscript intends to serve as guide for studies aimed at characterizing interactions between behavioural patterns and transmission networks. Large transmission networks such as those of HIV or COVID-19 are prime candidates for applying this methodological approach.\",\n \"Adolescent-led sexual and reproductive health and rights research: qualitative evaluation of an innovative participatory action research project in Senegal\\nParticipatory approaches are increasingly popular in public health, but remain little used to address adolescent health issues. However, adolescent participation in research has enormous potential for identifying solutions to health issues that concern them. In Senegal, a youth-led participatory action research project was implemented to evaluate the potential of the approach to address adolescent sexual and reproductive health and rights issues. A qualitative evaluation was conducted in four Senegalese communities, where teams of adolescents were trained to conduct a research project and identify solutions relevant for their communities. Observations and interviews were carried out during results dissemination meetings in each of the communities. Based on participatory action research principles and expected adolescent participation outcomes, the evaluation of the project demonstrated the potential of the approach to identify relevant solutions, while promoting positive and meaningful adolescent participation. Despite some difficulties, such as community resistance, the youth researchers were able to successfully complete their research project, while developing their confidence and self-esteem. The adolescents were convinced that they could act as agents of positive social change. This project has shown that it is possible and relevant to involve adolescents in research projects, and that this approach has significant potential in global health.\",\n \"The Mediating Role of SES on the Relationship between Pregnancy History and Later Life Cognition\\nObjectiveThe association of pregnancy with later life cognition is not well understood. Few studies address the potential confounding role of socioeconomic factors on this relationship. We examined whether pregnancy was associated with cognitive function in a large, population-based sample of post-menopausal women and the potential mediating effects of education level and federal income-to-poverty ratio (PIR) on this relationship.\\n\\nMethodsParticipants were 1,016 post-menopausal women from the National Health and Nutrition Examination Survey (NHANES). We utilized data from two study waves between years 2011-2014. Cognitive functioning was evaluated by: Digit Symbol Substitution Test (DSST), Animal Fluency (AF), Consortium to Establish a Registry for Alzheimers Disease CERAD word learning task (CERAD-WL) and CERAD delayed recall (CERAD-DR). Lifetime education level and federal income-to-poverty ratio (PIR) were examined as mediating factors. Regression models were used to examine the relationship between number of term pregnancies and incomplete pregnancies and cognitive performance.\\n\\nResultsA greater number of term pregnancies was related to worse performance on the DSST (p < .001), CERAD-DR (p < .007), and AF (p < .03). Conversely, greater incomplete pregnancies related to better CERAD-DR performance (p < .03). Significant associations between term pregnancies and cognitive scores were mediated by PIR but not education level.\\n\\nConclusionsHigher number of term pregnancies was associated with worse cognitive performance, whereas higher number of incomplete pregnancies was associated with better cognitive performance. Results indicate the necessity to consider SES factors when studying the relationship between pregnancy and cognition.\",\n \"Exposing racial bias in midwifery education: a content analysis of images and text in Myles Textbook for Midwives\\nObjectiveTo determine how people of different races and skin colours are represented within Myles Textbook for Midwives and whether the identified content is clinically relevant to people of all skin colours.\\n\\nDesignContent analysis of text and images in Myles Textbook for Midwives 17th Edition, 2020\\n\\nFindingsThe images overwhelmingly depict light skinned people of White European appearance. When people of colour are shown they are more likely to be positioned in prominent imagery without specific link to the chapter topic. Descriptions of skin colour in the context of clinical assessment and/or treatment often applied mostly or solely to people with light colour skin. This included text referring to serious conditions or situations associated with severe morbidity or mortality.\\n\\nKey conclusionsMyles Textbook for Midwives presents a light skinned White European norm and often fails to include information that is clinically relevant to the assessment and treatment of people with darker skin colours. This may lead to disparity in midwifery education and contribute to poorer outcomes for women and babies.\\n\\nImplications for practiceConcrete efforts are required to identify and root out racial bias at all levels of midwifery education. This needs to happen alongside addressing current lack of good quality evidence required to support practice.\",\n \"Novel Investigation of SARS-CoV-2 in COVID-19 Survivors' Semen in Surabaya, Indonesia\\nThe emergence and the widespread of Coronavirus disease 2019 (COVID-19) demands an accurate detection method to establish a diagnosis. Real-time polymerase chain reaction (real-time PCR) is accounted for the perfect point of reference in detecting this virus. The notion that this virus also invades the male reproductive tract requires further investigation to prove the presence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in the semen. This investigation was designed to detect SARS-CoV-2 in COVID-19 survivors semen. This study design was a cross-sectional examination and conducted between November 2020 and March 2021 in the Andrology Unit of Dr. Soetomo General Hospital and Professor Nidom Foundation, both located in the City of Surabaya, Indonesia. The sample was 34 male participants aged above 18 years old and had been confirmed COVID-19 by nasopharyngeal swab PCR test. Part of the semen was taken for real-time PCR testing with the QuantStudio 5 Applied Biosystem (AB) PCR machine and the kits utilized were the STANDARD M nCOV Real-Time Detection Kit and mBioCov-19 RT-PCR Kit. Furthermore, the mean of participants ages was 35.74 years old with 25% of them had had a history of primary infertility and 21.8% of secondary infertility. From the real-time PCR COVID-19 of the semen examination, this investigation found that 27 participants had been negatives (74.4%), six inconclusive (17.6%), and one positive (3%) of SARS CoV-2. In summary, SARS-CoV-2 could be found in the semen of COVID-19 survivors. This should be a concern for the potential impact of COVID-19 in male fertility and the possibility of transmission reproductively.\",\n \"Young womens knowledge and attitudes towards cervical cancer screening at a selected higher education institution in Lesotho\\nBackgroundIn Lesotho, cervical cancer is the most common female cancer and leading cause of death amongst women. In 2019, the annual number of new cancer cases was 477 and 346 women died from cancer related complications in Lesotho.\\n\\nAimThe aim of this study was to assess the knowledge and attitudes of young women towards cervical cancer screening at a selected higher education institution in Lesotho.\\n\\nMethodsA quantitative cross-sectional research design was used to collect data using an interviewer administered semi-structured questionnaire from 80 young women who were randomly selected. Permission to conduct the study was sought and granted from relevant authorities. Informed consent was sought from the respondents who were identified using codes and participated voluntarily.\\n\\nResultsFifty percent (n=40) of the women did not know cervical cancer screening tests, 70% (n=56) did not know about the frequency of screening, whilst 75% (n=60) knew that human papilloma virus (HPV) vaccine is be used to prevent cervical cancer. Additionally, 95% (n=76) had not screened for cervical cancer, 65% (n=52) perceived cervical cancer screening as painful, and 95% (n=76) needed more information on cervical cancer screening.\\n\\nConclusionsThe practice of cervical cancer screening is low and there is a high need for health education and incorporating regular cervical cancer screening in health care services to increase the uptake amongst young women. Many participants were hesitant to screen as they perceived the procedure to be painful and this suggests the need for reassurance and counselling on cervical cancer screening techniques.\",\n \"Effect of COVID-19 vaccination on menstrual periods in a retrospectively recruited cohort\\nSurveillance schemes are receiving increasing numbers of reports from people who have noticed a change to their period following COVID-19 vaccination. In order to investigate this, we retrospectively recruited 1273 people who have a record of their menstrual cycle and vaccination dates and used their reports to explore hypotheses about how COVID-19 vaccination and menstrual changes could be linked. In this dataset, we were unable to detect strong signals to support the idea that COVID-19 vaccination is linked to menstrual changes. However, larger, prospectively recruited studies may be able to find associations that we were not powered to detect.\",\n \"Sexual Behaviours and Sexual Health Among Middle-Aged and Older Adults in Britain: A Latent Class Analysis of The Natsal-3\\nObjectivesPopulation-representative studies of the sexual health of middle-aged and older adults are lacking in aging societies. This study aimed to identify latent patterns of sexual behaviours and health of people aged 45-74.\\n\\nMethodsWe conducted a latent class analysis of the National Attitudes and Sexual Lifestyles Survey (Natsal-3), a nationally representative survey conducted in Britain in 2011.\\n\\nResultsOf the 5260 respondents aged 45-74, 49% of men and 45% of women belonged to the Content Caseys class who reported good sexual health. The Infrequent Indigos (31% of men, 44% of women) were characterized by a lack of sexual activity, reported some dissatisfaction, and were more likely to have a disability. The Low-Functioning Lees (12% of men, 8% of women) reported some more disability and had issues with sexual functioning and higher levels of distress. The Multiple-Partnered Morgans (9% of men, 2% of women) were characterized by a greater number of sexual partners and several risk behaviours.\\n\\nConclusionsThe use of these four classes can aid in improved targeting of tailored sexual health services to improve sexual function, sexual satisfaction, reduce distress and risky behaviours among middle-aged and older adults. These services should be inclusive of the disabled community.\\n\\nBullet pointsO_LIAbout half of these respondents were classified as Content Caseys who reported few issues concerning their sex lives.\\nC_LIO_LIOver a third who reported no recent sexual activity, the vast majority of whom are single, were classified as Infrequent Indigos.\\nC_LIO_LINearly 10% were classified Low-Functioning Lees due to the greater probability of reporting sexual function issues and distress.\\nC_LIO_LIThe rest were classified as Multiple Partner Morgans as a result of a high likelihood of having multiple partners and unsafe sex.\\nC_LI\",\n \"Willing but Unable: Physicians' Referral Knowledge as Barriers to Abortion Care\\nAbortion care is a crucial part of reproductive healthcare. Nevertheless, its availability is constrained by numerous forces, including care referrals within the larger healthcare system. Using a unique study of physician faculty across multiple specialties, we examine the factors associated with doctors ability to refer patients for abortion care among those who were willing to consult in the care of a patient seeking an abortion (N=674). Even though they were willing to refer a patient for an abortion, half (53%) of the physicians did not know how and whom to make those referrals, though they care for patients who may need them. Those with the least referral knowledge had not been taught abortion care during their medical training and were in earlier stages of their career than those who had more knowledge. This research exposes another obstacle for those seeking an abortion, a barrier that would be overcome with a clear and robust referral system within and across medical specialties.\",\n \"Online prescribing for sexually transmitted infections \\t- what is on offer? An evaluation of internet pharmacies based in the United Kingdom\\nBackgroundOnline pharmacies offer an alternative approach for patients to manage their sexual health. Our aim was to determine the type of antimicrobials sold as treatment for sexually transmitted infections (STIs) by UK internet pharmacies and if providers were adhering to national guidelines.\\n\\nMethodsA search engine results page (SERP) generated a list of registered UK online pharmacies offering treatment for the following infections: Chlamydia trachomatis, Neisseria gonorrhoeae, Herpes simplex and Trichomonas vaginalis. An initial audit in 2017 benchmarked each provider against the British Association of Sexual Health & HIV (BASHH guidelines. Results were fed back to each provider before re-audit in 2020. Websites selling antibiotics for non-gonococcal urethritis (NGU) and Mycoplasma genitalium were included at re-audit.\\n\\nResultsThere were 30 pharmacies identified in 2017 of which, five were excluded. Treatment could be obtained for Neisseria gonorrhoeae from five pharmacies without providing a culture result; three (60%) pharmacies sold BASHH approved antibiotics for Neisseria gonorrhoeae. All 25 pharmacies sold Chlamydia trachomatis treatment; 22 (88%) offered first line treatment options but no website assessed for proctitis. Herpes simplex treatment was sold on 22 websites of which, 13 (59%) offered treatment recommended by BASHH. Trichomonas vaginalis treatment was sold by four websites in line with BASHH. Results at re-audit showed an improvement in standards, although advice before, during and after treatment remained variable.\\n\\nDiscussionOur work has allowed us to engage with providers to improve prescribing within the UK online pharmacy industry. However, tougher regulation is needed in order to embed sustainable change for patients who choose to access treatment online.\"\n]","isConversational":false},"negative":{"kind":"list like","value":["Aerosol decontamination and spatial separation using a free-space LED-based UV-C light curtain\nBackgroundThe SARS-CoV-2 pandemic demonstrated the vulnerability of our societies to aerosol transmitted pathogens. With no less than 260mio known cases and > 5mio deaths, SARS-CoV-2 is a global catastrophe leading to human and economic losses unprecedented in recent history. Thus, effective methods to limit the spread of aerosol transmitted pathogens are needed. Universal masking and curfew laws are effective but no permanent solution.\n\nMethodsA mass producible LED light source emitting homogeneous parallel UV-C light was used as a \"light-barrier\" to block the spread of infectious aerosols. In an aerosol test channel, Gram-negative and Gram-positive bacteria as well as coronavirus were nebulized and inactivation rates were determined.\n\nFindingsWith air speeds of 0.1 m s-1 an exposure time of 1 s in the UV-C light is obtained. Reduction in CFU for E. coli was >3log10 and for S. aureus [~]2.8log10. Plug-forming-units of the murine coronavirus (Mouse Hepatitis Virus, MHV) were reduced by about 3log10.\n\nInterpretationThe concept of a UV-C light barrier to ward off infectious aerosols if feasible and possible with a light element as described here. Coupled with sensor based activation/deactivation, such a technology could greatly reduce the transmission rates of aerosol transmitted pathogens while not disturbing natural human behaviour. This is an interesting technology allowing a \"new normal\" in societies after/with SARS-CoV-2.","Elevated plasma Complement Factor H Regulating Protein 5 is associated with venous thromboembolism and COVID-19 severity\nVenous thromboembolism (VTE), comprising both deep vein thrombosis (DVT) and pulmonary embolism (PE) is a common, multi-causal disease with potentially serious short- and long-term complications. In clinical practice, there is a need for improved plasma biomarker-based tools for VTE diagnosis and risk prediction. We used multiplex proteomics profiling to screen plasma from patients with suspected acute VTE, and a case-control study of patients followed up after ending anticoagulant treatment for a first VTE. With replication in 5 independent studies, together totalling 1137 patients and 1272 controls, we identify Complement Factor H Related Protein (CFHR5), a regulator of the alternative pathway of complement activation, as a novel VTE associated plasma biomarker. Using GWAS analysis of 2967 individuals we identified a genome-wide significant pQTL signal on chr1q31.3 associated with CFHR5 levels. We showed that higher CFHR5 levels are associated with increased thrombin generation in patient plasma and that recombinant CFHR5 enhances platelet activation in vitro. Thrombotic complications are a frequent feature of COVID-19; in hospitalised patients we found CFHR5 levels at baseline were associated with short-time prognosis of disease severity, defined as maximum level of respiratory support needed during hospital stay. Our results indicate a clinically important role for regulation of the alternative pathway of complement activation in the pathogenesis of VTE and pulmonary complications in acute COVID-19. Thus, CFHR5 is a potential diagnostic and/or risk predictive plasma biomarker reflecting underlying pathology in VTE and acute COVID-19.","Human genetic factors associated with pneumonia susceptibility, a cue for COVID-19 mortality\nThe risk for community acquired pneumonia (CAP) is partially driven by genetics. To identify the CAP-associated genetic risk loci, we performed a meta-analysis of clinically diagnosed CAP (3,310 individuals) with 2,655 healthy controls. The findings revealed CYP1A1 variants (rs2606345, rs4646903, rs1048943) associated with pneumonia. We observed rs2606345 [G vs T; OR=1.49(1.29-1.69); p=0.0001; I2= 15.5%], and rs1048943 [T vs G; OR= 1.31(0.90-1.71); p=0.002; I2=19.3%] as risk markers and rs4646903 [T vs C; OR= 0.79(0.62-0.96); p=0.03; I2=0%] as a protective marker for susceptibility to CAP, when compared with healthy controls. Our meta-analysis showed the presence of CYP1A1 SNP alleles contributing significant risk toward pneumonia susceptibility. Interestingly, we observed a striking difference of allele frequency for rs2606345 (CYP1A1) among Europeans, Africans and Asians which may provide a possible link for observed variations in death due to coronavirus disease 2019 (COVID-19), a viral pneumonia. We report, for the first time, a significant positive correlation for the risk allele (T or A) of rs2606345, with a higher COVID-19 mortality rate worldwide and within a genetically heterogeneous nation like India. Mechanistically, the risk allele A (rs2606345) is associated with lower expression of CYP1A1 and presumably leads to reduced capacity for xenobiotic detoxification. We note that ambient air pollution, a powerful inducer of CYP1A1 gene expression, is globally associated with lower, not higher mortality, as would normally be predicted. In conclusion, we find that CYP1A1 alleles are associated with CAP mortality, presumably via altered xenobiotic metabolism. We speculate that gene-environment interactions governing CYP1A1 expression may influence COVID-19 mortality.","The bidirectional causal effects of brain morphology across the life course and risk of Alzheimers disease: A cross-cohort comparison and Mendelian randomization meta-analysis\nNeuropathological changes associated with Alzheimers disease (AD) can occur decades before clinical symptoms. We investigated whether neurodevelopment and/or neurodegeneration affects the risk of AD, through reducing structural brain reserve and/or accelerating brain atrophy, respectively. We used bidirectional two-sample Mendelian randomization to estimate the effects of genetic liability to AD on global and regional cortical thickness, total intracranial volume, volume of subcortical structures and cerebral white matter in 36,842 participants aged eight to 81 years across five independent cohorts, and the effects of global and regional cortical thickness and subcortical volumes on AD risk in 94,337 participants. Our findings show that AD risk alleles have an age-dependent effect on a range of cortical and subcortical brain measures that starts in mid-life, in non-clinical populations. Evidence for such effects across childhood and young adulthood is weak. We also found little evidence to suggest brain morphology alters AD risk. Thus, genetic liability to AD is likely to alter mechanisms and/or rates of neurodegeneration, rather than reduce structural brain reserve.","How does migratory status affect non-communicable disease risk in a global context? A systematic review.\nChallenges pertaining to the study of migrant health have been reported in medical and sociological literature. A literature review was thus conducted to gauge what research currently holds about the risk of non-communicable disease within migrant populations globally. The search strategy is outlined; CASP checklists were used to critically appraise articles, and the relevant data was synthesised and analysed. The research identifies several overarching quantitative themes regarding risk patterns. Recommendations are made.","RBDAct: Home screening of REM sleep behaviour disorder based on wrist actigraphy in Parkinson's patients\nBackgroundREM sleep behaviour disorder (RBD) is a disabling, often overlooked sleep disorder affecting up to 70% of patients with Parkinsons disease. Identifying and treating RBD is critical to prevent severe sleep-related injuries, both to patients and bedpartners. Current diagnosis relies on nocturnal video-polysomnography, which is an expensive and cumbersome exam requiring specific clinical expertise.\n\nObjectivesTo design, optimise, and validate a novel home-screening tool, termed RBDAct, that automatically identifies RBD in Parkinsons patients based on wrist actigraphy only.\n\nMethodsTwenty-six Parkinsons patients underwent two-week home wrist actigraphy worn on their more affected arm, followed by two non-consecutive in-lab evaluations. Patients were classified as RBD versus non-RBD based on dream enactment history and video-polysomnography. We characterised patients movement patterns during sleep using raw tri-axial accelerometer signals from wrist actigraphy. Machine learning classification algorithms were then trained to discriminate between patients with or without RBD using actigraphic features that described patients movements. Classification performance was quantified with respect to clinical diagnosis, separately for in-lab and at-home recordings.\n\nResultsClassification performance from in-lab actigraphic data reached an accuracy of 92.9{+/-}8.16% (sensitivity 94.9{+/-}7.4%, specificity 92.7{+/-}13.8%). When tested on home recordings, accuracy rose to 100% over the two-week window. Features showed robustness across tests and conditions.\n\nConclusionsRBDAct provides reliable predictions of RBD in Parkinsons patients based on home wrist actigraphy only. These results open new perspectives for faster, cheaper and more regular screening of sleep disorders, both for routine clinical practice and for clinical trials.","Improving Machine Learning Prediction of ADHD Using Gene Set Polygenic Risk Scores and Risk Scores from Genetically Correlated Phenotypes\nBackgroundPolygenic risk scores (PRSs), which sum the effects of SNPs throughout the genome to measure risk afforded by common genetic variants, have improved our ability to estimate disorder risk for Attention-Deficit/Hyperactivity Disorder (ADHD) but the accuracy of risk prediction is rarely investigated.\n\nMethodsWith the goal of improving risk prediction, we performed gene set analysis of GWAS data to select gene sets associated with ADHD within a training subset. For each selected gene set, we generated gene set polygenic risk scores (gsPRSs), which sum the effects of SNPs for each selected gene set. We created gsPRS for ADHD and for phenotypes having a high genetic correlation with ADHD. These gsPRS were added to the standard PRS as input to machine learning models predicting ADHD. We used feature importance scores to select gsPRS for a final model and to generate a ranking of the most consistently predictive gsPRS.\n\nResultsFor a test subset that had not been used for training or validation, a random forest (RF) model using PRSs from ADHD and genetically correlated phenotypes and an optimized group of 20 gsPRS had an area under the receiving operating characteristic curve (AUC) of 0.72 (95% CI: 0.70 - 0.74). This AUC was a statistically significant improvement over logistic regression models and RF models using only PRS from ADHD and genetically correlated phenotypes.\n\nConclusionsSumming risk at the gene set level and incorporating genetic risk from disorders with high genetic correlations with ADHD improved the accuracy of predicting ADHD. Learning curves suggest that additional improvements would be expected with larger study sizes. Our study suggests that better accounting of genetic risk and the genetic context of allelic differences results in more predictive models.","Remote patient monitoring to interrupt chains of respiratory infections in outpatient care - a case-control study during the 2020/21 infection season\nAim of the studyThe aim of the study was to investigate satisfaction, saving of time and the possible reduction of patient visits to practices that use Remote Patient Monitoring (RPM) during treatment compared to usual care.\n\nMethodsIn a case-control study between October 2020 and May 2021, the participating practices were randomized into three groups (two different RPM systems, one control). The doctors were required to enroll patients with acute respiratory infection [≥] 18 years who have a web-enabled device. After a three-month study phase, the doctors were asked to describe the treatment of their patients via online survey. The patients were also questioned. The analysis was carried out descriptively and with group comparisons.\n\nResults51 practices with 121 patients were included. Overall, the results show a positive assessment of digital care on the patient side. As for the doctors, handling and integration of the systems into consisting practice processes seem to be a challenge. Further, the number of patient visits to the practice was not reduced by using the systems and the doctors did not save time, but the relationship to the patients was intensified.\n\nConclusionEven if there were no indications for more efficiency by using the RPM systems, the doctors see great potential to intensify the interaction between doctor and patient. In particular, more intensive contact with patients with chronic diseases (e. g. COPD, long-COVID) could be of long-term interest and importance for doctors in outpatient care.\n\nTrial RegistrationDRKS00023553","Evaluating the utility of high-resolution proximity metrics in predicting the spread of COVID-19\nAO_SCPLOWBSTRACTC_SCPLOWHigh resolution mobility datasets have become increasingly available in the past few years and have enabled detailed models for infectious disease spread including those for COVID-19. However, there are open questions on how such a mobility data can be used effectively within epidemic models and for which tasks they are best suited. In this paper, we extract a number of graph-based proximity metrics from high resolution cellphone trace data from X-Mode and use it to study COVID-19 epidemic spread in 50 land grant university counties in the US. We present an approach to estimate the effect of mobility on cases by fitting an ODE based model and performing multivariate linear regression to explain the estimated time varying transmissibility. We find that, while mobility plays a significant role, the contribution is heterogeneous across the counties, as exemplified by a subsequent correlation analysis. We subsequently evaluate the metrics utility for case surge prediction defined as a supervised classification problem, and show that the learnt model can predict surges with 95% accuracy and 87% F1-score.","Breakthrough infection with SARS-CoV-2 and its predictors among healthcare workers in a medical college and hospital complex in Delhi, India\nIntroductionThe study objective was to determine the breakthrough infection rate of Covid-19 (SARS-CoV-2) infection in those vaccinated with either BBV152 or AZD1222 (ChAdOx1-S) vaccine among healthcare workers (HCWs).\n\nMethodsA cross-sectional analysis was conducted a medical college and hospital complex in Delhi, India through telephonic interviews among HCWs who had received at-least one dose of a Covid-19 vaccine during January to March 2021. Breakthrough infections were operationally defined as occurrence of Covid-19 infection [≥]14 days after administration of two doses of either Covid-19 vaccine.\n\nResultsWe enrolled 325 HCWs with mean (SD) age of 29.1 (9.9) years including 211 (64.9%) males. Two seventy nine (85.8%) HCWs were fully vaccinated while 46 (14.2%) were partially vaccinated. There were 168 (51.7%) BBV152 and 157 (48.3%) AZD1222 (ChAdOx1-S) recipients.\n\nA total of 37 (11.3%, 95% C.I. 8.3, 15.3) breakthrough infections were observed in the HCWs. The median (IQR) time until incidence of Covid-19 breakthrough infection since receiving second dose of either Covid-19 vaccine was 47 (28.5, 55) days. Additionally, 20 (6.1%) non-breakthrough Covid-19 infections were recorded in the HCWs post vaccination with either a single dose of a Covid-19 vaccine or both doses but prior to a period of 14 days since administration of the second dose.\n\nMost breakthrough infection cases (94.4%) were mild and did not require supplemental oxygen therapy. HCWs without a history of natural Covid-19 infection and recovery prior to vaccination were 3.8 times more at risk to contract a Covid-19 infection or reinfection in spite of vaccination with at-least one dose of either Covid-19 vaccine.\n\nConclusionNearly one in nine HCWs experienced a Covid-19 breakthrough infection in the present study.","Addressing Extreme Imbalance for Detecting Medications Mentioned in Twitter User Timelines\nTweets mentioning medications are valuable for efforts in digital epidemiology to supplement traditional methods of monitoring public health. A major obstacle, however, is to differentiate them from the large majority of tweets on other topics posted in a users timeline: solving the infamous needle in a haystack problem. While deep learning models have significantly improved classification, their performance and inference processing time remain low on extremely imbalanced corpora where the tweets of interest are less than 1% of all tweets. In this study, we empirically evaluate under-sampling, fine-tuning, and filtering heuristics to train such classifiers. Using a corpus of 212 Twitter timelines (181,607 tweets with only 0.2% tweets mentioning a medication), our results show that combining these heuristics is necessary to impact the classifiers performance. In our intrinsic evaluation, a classifier based on a lexicon and a BERT-base neural network achieved a 0.838 F1-score, a score similar to the ones of the best existing classifier, but it processed the corpus 28 times faster - a positive result, since processing speed is still a roadblock to deploying classifiers on large cohorts of Twitter users needed for pharmacovigilance. In our extrinsic evaluation, our classifier helped a labeler to extract the spans of medications more accurately and achieved a 0.76 Strict F1-score. To the best of our knowledge, this is the first evaluation of medications extraction in Twitter timelines and it establishes the first benchmark for future studies.","A more compact photoacoustic imaging system to detect periodontitis\nPhotoacoustic imaging has shown value in periodontal disease, but the large size of conventional photoacoustic transducers prevents imaging of more posterior teeth, i.e., molars. Here, we report a clinical \"hockey stick\"-style transducer repurposed for photoacoustic (PA) via an integrated fiber bundle. The shape of the hockey stick transducer facilitates imaging of the 1st pre-molars in contrast to conventional photoacoustic transducer designs. This tool was then deployed for photoacoustic imaging of periodontal disease and the periodontal pocket via a food-grade contrast agent (cuttlefish ink). We characterized the resolution and imaging range and then validated the system with a swine model and human subjects. We could image four additional teeth per quadrant with the smaller design versus a commercial photoacoustic transducer. Three raters evaluated the performance of the hockey stick transducer. The measurements between the probing and the PA methods were blinded, but the outcomes were highly correlated. We showed a bias of [~]0.3 mm for the imaging-based technique versus conventional probing. In addition, the inter-reliability was over 0.60 for three different raters of varying experience suggesting that this approach to evaluating dental health is teachable and reproducible. Finally, we demonstrated the utility in a human subject and can image teeth much more posterior in the mouth than with conventional photoacoustic transducers.","SARS-CoV-2 Testing Strategies for Outbreak Mitigation in Vaccinated Populations\nAlthough COVID-19 vaccines are globally available, waning immunity and emerging vaccine-evasive variants of concern have hindered the international response as COVID-19 cases continue to rise. Mitigating COVID-19 requires testing to identify and isolate infectious individuals. We developed a stochastic compartmentalized model to simulate SARS-CoV-2 spread in the United States and India using Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) assays, rapid antigen tests, and vaccinations. We detail the optimal testing frequency and coverage in the US and India to mitigate an emerging outbreak even in a vaccinated population: overall, maximizing frequency is more important, but high coverage remains necessary when there is sustained transmission. We show that a resource-limited vaccination strategy still requires high-frequency testing and is 16.50% more effective in India than the United States. Tailoring testing strategies to transmission settings can help effectively reduce cases more than if a uniform approach is employed without regard to differences in location.","Epigenetic aging and perceived psychological stress in old age\nAdverse effects of psychological stress on physical and mental health, especially in older age, are well documented. How perceived stress relates to the epigenetic clock measure, DNA methylation age acceleration (DNAmAA), is less well understood and existing studies reported inconsistent results.\n\nDNAmAA was estimated from five epigenetic clocks (7-CpG, Horvaths, Hannums, PhenoAge and GrimAge DNAmAA). Cohens Perceived Stress Scale (PSS) was used as marker of psychological stress.\n\nWe analyzed data from 1,100 Berlin Aging Study II (BASE-II) participants assessed as part of the GendAge study (mean age = 75.6 years, SD = 3.8 years, 52.1% women).\n\nIn a first step, we replicated well-established associations of perceived stress with morbidity, frailty, and symptoms of depression in the BASE-II cohort studied here. In a second step, we did not find any statistically significant association of perceived stress with any of the five epigenetic clocks in multiple linear regression analyses that adjusted for covariates.\n\nAlthough the body of literature suggests an association between higher DNAmAA and stress or trauma during early childhood, the current study found no evidence for an association of perception of stress with DNAmAA in older people. We discuss possible reasons for the lack of associations and highlight directions for future research.","Aberrant naive CD4+ T Cell differentiation in systemic juvenile idiopathic arthritis is committed to B cell help\nObjectiveSystemic juvenile idiopathic arthritis (sJIA) features characteristics of autoinflammation and autoimmunity, culminating in chronic arthritis. Previous work indicated decreased IFN{gamma}-expression by T helper (Th) cells in sJIA. Here, we hypothesized this to result from aberrant or incomplete Th cell polarization.\n\nMethodsCells or sera were obtained from healthy controls (HC, n=26) and sJIA patients (n=61). Isolated naive Th cells were cultured under Th1, Th17, and T follicular or T peripheral helper (Tf/ph) polarizing conditions and were partly co-cultured with allogenic memory B cells. Surface marker, transcription factor, and/or cytokine expression in peripheral or polarized Th cells or sera as well as B cellular plasma blast generation were studied by flow cytometry, multiplexed bead array assays, ELISA and retrospective RNA profiling analyses.\n\nResultsSJIA naive Th cell differentiation towards Th1 resulted in low IFN{gamma} and Eomesodermin expression. Instead, developing sJIA Th1 cells revealed elevated IL-21 release that negatively correlated with cellular IFN{gamma} and Eomesodermin expression. Both In vitro and ex vivo, IL-21 together with PD-1, ICOS and CXCR5 expression indicated naive sJIA Th cell differentiation to rather polarize towards a Tf/ph phenotype. Retrospective analysis of whole blood RNA sequencing data demonstrated sJIA-specific overexpression of Bcl-6 as respective master transcription factor. Compared to controls, in vitro generated sJIA Tf/ph cells promoted enhanced B cellular plasma-blast generation.\n\nConclusionIn sJIA pathogenesis skewing of sJIA naive Th cell differentiation towards a Tf/ph phenotype may represent an echo of autoimmunity, which could shed light on the mechanisms driving the progression towards chronic destructive arthritis.","Beyond well-mixed: a simple probabilistic model of airborne disease transmission in indoor spaces\nWe develop a simple model for assessing risk of airborne disease transmission that accounts for non-uniform mixing in indoor spaces and is compatible with existing epidemiological models. A database containing 174 high-resolution simulations of airflow in classrooms, lecture halls, and buses is generated and used to quantify the spatial distribution of expiratory droplet nuclei for a wide range of ventilation rates, exposure times, and room configurations. Imperfect mixing due to obstructions, buoyancy, and turbulent dispersion results in concentration fields with significant variance. The spatial non-uniformity is found to be accurately described by a shifted lognormal distribution. A well-mixed mass balance model is used to predict the mean, and the standard deviation is parameterized based on ventilation rate and room geometry. When employed in a dose-response function risk model, infection probability can be estimated considering spatial heterogeneity that contributes to both short- and long-range transmission.","Using time use diaries to track changing behavior across successive stages of COVID-19 social restrictions\nHow did people change their behavior over the different phases of the UK COVID-19 restrictions, and how did these changes affect their risk of being exposed to infection? Time use diary surveys are unique in providing a complete chronicle of daily behavior; 24-hour continuous records of the populations activities, their social context and their location. We present results from four such surveys, collected in real time from representative UK samples, both before, and at three points over the course of the current pandemic. Comparing across the four waves, we find evidence of substantial changes in the UK populations behavior relating to activities, locations and social context. We assign different levels of risk to combinations of activities, locations and copresence, to compare risk-related behavior across successive lockdowns. We find evidence that during the second lockdown (November 2020) there was an increase in high-risk behaviors relative to the first (starting March 2020). This increase is shown to be associated with more paid work time in the workplace. At a time when capacity is still limited both in respect of immunization and track-trace technology, governments must continue to rely on changes in peoples daily behaviors to contain the spread of COVID-19 and similar viruses. Time use diary information of this type, collected in real time across the course of the COVID-19 pandemic, can provide policy-makers with information to assess and quantify changes in daily behaviors, and the impact they are likely to have on overall behavioral-associated risks.","Assessing genetic overlap and causality between blood plasma proteins and Alzheimer's Disease\nBackground Blood plasma proteins are modifiable and have been associated with Alzheimers disease (AD), but understanding which proteins are on the causal pathway remains challenging.\n\nObjectiveInvestigate the genetic overlap between candidate proteins and AD using polygenic risk scores (PRS) and interrogate their causal relationship using bi-directional Mendelian Randomization (MR).\n\nMethodsFollowing a literature review, 31 proteins were selected for PRS analysis. PRS were constructed for prioritised proteins with and without the apolipoprotein E region (APOE+/- PRS) and tested for association with AD status across three cohorts (n=6244). An AD PRS was also tested for association with protein levels in one cohort (n=410). Proteins showing association with AD were taken forward for MR.\n\nResultsFor APOE e3, apolipoprotein B-100, and C-reactive protein (CRP), protein APOE+ PRS were associated with AD below Bonferroni significance (pBonf, p-value <0.00017). No protein APOE-PRS or AD PRS (APOE+/-) passed pBonf. However, vitamin D-binding protein (protein PRS APOE-, p-value=0.009) and insulin-like growth factor-binding protein 2 (AD APOE- PRS p-value=0.025, protein APOE-PRS p-value=0.045) displayed suggestive signals and were selected for MR. In bi-directional MR, none of the 5 proteins demonstrated a causal association (p-value<0.05) in either direction.\n\nConclusionApolipoproteins and CRP PRS are associated with AD and provide a genetic signal linked to a specific, modifiable risk factor. Whilst evidence of causality was limited, this study was conducted in a moderate sample size and provides a framework for larger samples with greater statistical power.","Characterizing the performance of a DIY air filter\nAir filtration serves to reduce concentrations of particles in indoor environments. Most standalone, also referred to as portable or in-room, air filtration systems use HEPA filters, and cost generally scales with the clean air delivery rate. A \"do-it-yourself\" lower-cost alternative, known as the Corsi-Rosenthal Box, that uses MERV-13 filters coupled with a box fan has been recently proposed, but lacks systematic performance characterization. We have characterized the performance of a five-panel Corsi-Rosenthal air filter. Measurements of size-resolved and overall decay rates of aerosol particles larger than 0.5 microns emitted into rooms of varying size with and without the air filter allowed for determination of the apparent clean air delivery rate--both as a function of size and integrated across particle sizes. The measurements made in the different rooms produced similar results, demonstrating the robustness of the method used. The size-integrated apparent clean air delivery rate increases with fan speed, from about 600 to 850 ft3 min-1 (1019 to 1444 m3 h-1). Overall, our results demonstrate that the Corsi-Rosenthal filter efficiently reduces suspended particle concentrations in indoor environments.\n\nOne Sentence SummaryA DIY air cleaner can effectively reduce aerosols in indoor spaces.","Pediatric Nemaline Myopathy: A systematic review using individual patient data\nContextNemaline myopathy (NM) is a skeletal muscle disease that affects 1 in 50,000 live births.\n\nObjectiveDevelop a narrative synthesis of the findings of a systematic review of the latest case descriptions of patients with nemaline myopathy.\n\nData SourcesA systematic search of MEDLINE, Embase, CINAHL, Web of Science, and Scopus was performed using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines using the keywords pediatric, child, nemaline myopathy, nemaline rod, rod myopathy.\n\nStudy SelectionCase studies focused on pediatric NM and published in English between January 1, 2010 and December 31, 2020 in order to represent the most recent findings.\n\nData ExtractionInformation was collected about the age of first signs, earliest presenting neuromuscular signs and symptoms, systems affected, progression, death, pathological description, and genetic changes.\n\nResultsOf a total of 385 records, 55 case reports or series were reviewed, covering 101 pediatric patients from 23 countries. We review varying presentations in children ranging in severity despite being caused by the same mutation, in addition to current and future clinical considerations relevant to the care of patients with nemaline myopathy.\n\nLimitationsThe results are limited by findings shared in the literature, which varied in their detail and sometimes lacked histological or genetic results. Trends and correlations may be altered by information available.\n\nConclusionsThis review synthesizes genetic, histopathologic, and disease presentation findings from pediatric nemaline myopathy case reports. These data strengthen our understanding of the wide spectrum of disease seen in nemaline myopathy. Future studies are needed to identify the underlying molecular mechanism of pathology, to improve diagnostics, and to develop better methods to improve quality of life for these patients.","Impact of reproduction number on multiwave spreading dynamics of COVID-19 with temporary immunity : a mathematical model\nCOVID-19 is caused by a hitherto nonexistent pathogen, hence the immune response to the disease is currently unknown. Studies conducted over the past few weeks have found that the antibody titre levels in the blood plasma of infected patients decrease over time, as is common for acute viral infections. Fully documented reinfection cases from Hong Kong, India, Belgium and USA, as well as credible to anecdotal evidence of second-time cases from other countries, bring into sharp focus the question of what profile the epidemic trajectories may take if immunity were really to be temporary in a significant fraction of the population. Here we use mathematical modeling to answer this question, constructing a novel delay differential equation model which is tailored to accommodate different kinds of immune response. We consider two immune responses here : (a) where a recovered case becomes completely susceptible after a given time interval following infection and (b) where a first-time recovered case becomes susceptible to a lower virulence infection after a given time interval following recovery, and becomes permanently immunized by a second infection. We find possible solutions exhibiting large number of waves of disease in the first situation and two to three waves in the second situation. Interestingly however, these multiple wave solutions are manifest only for some intermediate values of the reproduction number R, which is governed by public health intervention measures. For sufficiently low as well as sufficiently high R, we find conventional single-wave solutions despite the short-lived immunity. Our results cast insight into the potential spreading dynamics of the disease and might also be useful for analysing the spread after a vaccine is invented, and mass vaccination programs initiated.","Vaccine effectiveness of BNT162b2 against Omicron and Delta outcomes in adolescents\nIntroductionData on vaccine effectiveness (VE) against Omicron in adolescents are limited. We estimated 2-dose and 3-dose VE against Omicron and Delta in adolescents aged 12-17 years in Ontario, Canada.\n\nMethodsWe conducted a test-negative design study among SARS-CoV-2-tested adolescents aged 12-17 years between November 22, 2021 (date of first Omicron detection) and March 6, 2022; we assessed Delta outcomes prior to January 2, 2022. We used multivariable logistic regression to compare the odds of vaccination in cases to symptomatic test-negative controls and calculated VE as 1-adjusted odds ratio.\n\nResultsVE was lower against symptomatic Omicron infection than against Delta and decreased more rapidly over time, from 51% (95%CI, 38-61%) in the 7-59 days following a second dose to 29% (95%CI, 17-38%) after 180 days, compared to 97% (95%CI, 94-99%) and 90% (95%CI, 79-95%) for the same intervals against symptomatic Delta infection. Overall, 2-dose VE against severe outcomes caused by Omicron was 85% (95%CI, 74-91%) [≥]7 days following a second dose and estimates were similar over time. VE against symptomatic Omicron infection was 62% (95%CI, 49-72%) [≥]7 days following a third dose.\n\nDiscussionTwo-dose VE against symptomatic Omicron infection wanes over time in adolescents. While lower than observed against Delta, protection against severe outcomes appears to be maintained over time. A third dose substantially improves protection against Omicron infection, but 3-dose VE is only moderate at approximately 60% in the early period following vaccination and the duration of this protection is unknown.","Nowcasting food insecurity on a global scale\nLack of regular physical or economic access to safe, nutritious and sufficient food is a critical issue affecting millions of people world-wide. Estimating how many and where these people are is of fundamental importance for governments and humanitarian organizations to take informed and timely decisions on relevant policies and programmes. In this study, we propose a machine learning approach to predict the prevalence of people with insufficient food consumption and of people using crisis or above crisis food-based coping when primary data is not available. Making use of a unique global data set, we show that the proposed models can explain up to 78% of the variation in insufficient food consumption and crisis or above food-based coping levels. We also show that the proposed models can be used to nowcast the food security situation in near-real time and propose a method to identify which variables are driving the changes observed in predicted trends, which is key to make predictions serviceable to decision makers.","CD56brightCD16- NATURAL KILLER CELLS ARE IN HIGHER COUNTS IN THE UMBILICAL CORD BLOOD THAN IN THE PERIPHERAL BLOOD\nUmbilical cord blood (UCB) is an alternative source for hematopoietic stem cells allogeneic hematopoietic stem cell transplantation in the absence of compatible donor. UCB transplantation has a lower incidence of chronic graft versus host disease (GvHD) but is associated with slower engraftment and slower immune reconstitution as compared to other sources. Dendritic cells (DC) and Natural Killer cells (NK) play a central role in the development of GVHD, the graft versus leukemia (GvL) effect, and in the control of infectious complications. We quantified by multiparametric flow cytometry monocytes, lymphocytes, NK cells, and DC, including their subsets, in UCB samples from 54 healthy newborns and peripheral blood (PB) from 25 healthy adult volunteers. In the UCB samples, there were higher counts of CD56brightCD16-NK cells (median 0.024x109/L), as compared to the PB samples (0.012x109/L, P<0.0001), CD56dimCD16bright NK cells (median 0.446x109/L vs. 0.259x109/L for PB samples, P= 0.001), and plasmacytoid dendritic cells (pDC, median 0.008x109/L for UCB samples vs. 0.006x109/L for PB samples, P= 0.03). Moreover, non-classical monocytes counts were lower in UCB than in PB (median 0.024x109/L vs. 0.051 x109/L, respectively, P< 0.0001). In conclusion, there were higher counts of NK cells and pDC, and lower counts of non-classical monocytes in UCB than in PB from healthy individuals. These findings might explain the lower incidence and severity of chronic GVHD although maintaining the GVL effect in UCB transplants recipients as compared to other stem cell sources.\n\nHighlightsO_LICD56brightCD16- NK cells are more frequent in UCB than in PB.\nC_LIO_LIPlasmacytoid dendritic cells are more frequent in UCB than in PB.\nC_LIO_LINon-classical monocytes are more frequent in PB than in UCB.\nC_LI","Inflammatory Bowel Disease Risk Variants Are Associated with an Increased Risk of Skin Cancer\nBackground and AimsInflammatory bowel disease is associated with an increased risk of skin cancer. The aims of this study were to determine whether genomic variants associated with IBD susceptibility are also associated with skin cancer susceptibility and if such risk is augmented by the use of immune-suppressive therapy.\n\nMethodsThe discovery cohort included participants in the UK Biobank (n=408,381). The validation cohort included participants in the Michigan Genomics Initiative (n=51,405). The primary outcome of interest was skin cancer, sub-grouped into non-melanoma (NMSC) and melanoma skin cancers (MSC). Multivariable logistic regression was performed to identify genomic predictors of skin malignancy. Validated SNPs were evaluated for effect modification by immune-suppressive medication.\n\nResultsThe discovery cohort included 11,079 cases of NMSC and 2,054 cases of MSC. The validation cohort included 7,334 cases of NMSC and 3,304 cases of MSC. Thirty variants were associated with risk of NMSC in the discovery cohort, of which six replicated in the validation cohort [Increased risk: rs7773324-A (DUSP22; IRF4), rs2476601-G (PTPN22), rs1847472-C (BACH2), rs72810983-A (CPEB4); Decreased risk: rs6088765-G (PROCR; MMP24), rs11229555-G (ZFP91-CNTF; GLYAT)]. Twelve variants were associated with risk of MSC in the discovery cohort, of which three replicated in the validation cohort (Increased risk: rs61839660-T (IL2RA); Decreased risk: rs17391694-C (GIPC2; MGC27382), rs6088765-G (PROCR; MMP24)]. No effect modification was observed.\n\nConclusionThe results of this study highlight shared genetic susceptibility across IBD and skin cancer, with increased risk of NMSC in those who carry risk variants in IRF4, PTPN22, CPEB4, and BACH2 and increased risk of MSC in those who carry a risk variant in IL2RA.","Disrupted network segregation of the default mode network in autism spectrum disorder\nBackgroundChanges in the brains default mode network (DMN) in the resting state are closely related to autism spectrum disorder (ASD). Module segmentation can effectively elucidate the neural mechanism of ASD and explore the intra- and internetwork connections by means of the participation coefficient (PC).\n\nMethodsResting-state fMRI data from 269 ASD patients and 340 healthy controls (HCs) were used in the current study. The PC of brain network modules was calculated and compared between ASD subjects and HCs. In addition, we further explored the features according to different age groups and different subtypes of ASD. Intra- and internetwork differences were further calculated to find the potential mechanism underlying the results.\n\nResultsASD subjects showed significantly higher PC of the DMN than HC subjects. This difference was caused by lower intramodule connections within the DMN and higher internetwork connections between the DMN and networks. When the subjects were split into age groups, the results were verified in the 7-12 and 12-18 age groups but not in the adult group (18-25). When the subjects were divided according to different subtypes of ASD, the results were also observed in the classic autism and pervasive developmental disorder groups, but not in the Asperger disorder group. In addition, compared with the HC group, the ASD group showed significantly increased intranetwork connections between the DMN and the frontoparietal network.\n\nConclusionsLess developed network segregation in the DMN could be a valid biomarker for ASD, and this feature was validated with different measures. The current results provide new insights into the neural underpinnings of ASD and provide targets for potential interventions using brain modulation and behavioural training.","A scoping review exploring the impact of digital systems on processes and outcomes in the care management of acute kidney injury and progress towards establishing learning healthcare systems\nBackgroundDigital systems have long been used to improve the quality and safety of care when managing Acute Kidney Injury (AKI). The availability of digitised clinical data can also turn organisations and their networks into Learning Healthcare Systems (LHSs) if used across all levels of health and care. This review explores the impact of digital systems on AKI patient care to gauge progress towards establishing LHSs and to identify existing gaps in the research.\n\nMethodEmbase, PubMed, Medline, Cochrane, Scopus and Web of Science databases were searched. Studies of real-time or near real-time digital AKI management systems which reported process and outcome measures were included.\n\nResultsThematic analysis of 43 studies showed that most interventions used real-time serum creatinine (SCr) levels to trigger responses to enable risk prediction, early recognition of AKI or harm prevention by individual clinicians (micro level) or specialist teams (meso level). Interventions at system (macro level) were rare. There was limited evidence of change in outcomes.\n\nConclusionWhilst the benefits of real time digital clinical data at micro level for AKI management have been evident for some time, their application at meso and macro levels is emergent therefore limiting progress towards establishing LHSs. Lack of progress is due to digital maturity, system design, human factors and policy levers. Future approaches need to harness the potential of interoperability and data analytic advances and include multiple stakeholder perspectives to overcome these factors.","When thinking you are better leads to feeling worse: Self-other asymmetries in prosocial behavior and increased anxiety during the Covid-19 pandemic\nThinking one is better than peers is generally associated with positive psychological outcomes like increased self-esteem and resilience. However, this tendency may be problematic in the context of collective action problems, wherein individuals are reliant on others prosocial behaviors to achieve larger goals. We examined this question in the context of the Covid-19 pandemic, and recruited participants (n = 1022) from a university community in Spring 2020. We found evidence for a self-peer asymmetry, such that participants reported that they were doing more to stop the spread of the disease and were more prosocially motivated than peers. Actual peer reports indicated that these were overestimations. This self-enhancement tendency comes with a cost: the perceived self-peer asymmetry mediated the relationship between Covid-specific worry and general anxiety during the early lockdown period. This indicates that while believing one is doing more than others may be maladaptive in collective action problems.","Tenofovir Disoproxil Fumarate and severity of COVID-19 in people with HIV infection\nBackgroundEffective, safe, and affordable antivirals are needed for COVID-19. Tenofovir has not been studied in randomized trials despite evidence consistent with its effectiveness against COVID-19.\n\nMethodsWe studied HIV-positive individuals on antiretroviral therapy (ART) in 2020 at 69 HIV clinics in Spain. We collected data on sociodemographics, ART, CD4-cell count, HIV-RNA viral load, comorbidities and the following outcomes: laboratory-confirmed SARS-CoV-2 infection, COVID-19 hospitalization, intensive care unit (ICU) admission and death. We compared the 48-week risks for individuals receiving tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), tenofovir alafenamide (TAF)/ FTC, abacavir (ABC)/lamivudine (3TC), and other regimes. All estimates were adjusted for clinical and sociodemographic characteristics via inverse probability weighting.\n\nResultsOf 51,558 eligible individuals, 39.6% were on TAF/FTC, 11.9% on TDF/FTC, 26.6% on ABC/3TC, 21.8% on other regimes. There were 2,402 documented SARS-CoV-2 infections (425 hospitalizations, 45 ICU admissions, 37 deaths). Compared with TAF/FTC, the estimated risk ratios (RR) (95% CI) of hospitalization were 0.66 (0.43, 0.91) for TDF/FTC and 1.29 (1.02, 1.58) for ABC/3TC, the RRs of ICU admission were 0.28 (0.11, 0.90) for TDF/FTC and 1.39 (0.70, 2.80) for ABC/3TC, and the RRs of death were 0.37 (0.23, 1.90) for TDF/FTC and 2.02 (0.88-6.12) for ABC/3TC. The corresponding RRs of hospitalization for TDF/FTC were 0.49 (0.24, 0.81) in individuals [≥]50 years and 1.15 (0.59, 1.93) in younger individuals.\n\nConclusionOur findings suggest that, compared with other antiretrovirals, TDF/FTC lowers COVID-19 severity among HIV-positive individuals with virological control. This protective effect may be restricted to individuals aged 50 years and older.","Physicians' Reactions to COVID-19: The Results of an International Internet Survey\nObjectivesPhysicians across the world have been disproportionately affected by the COVID-19 pandemic. This study was designed and conducted to assess the emotional, cognitive, and behavioural reactions of physicians to the initial phase of the COVID-19 pandemic.\n\nMaterials and methodsAn online survey questionnaire using the google forms platform was constructed by the authors. The items in the questionnaire were based on clinical experience, relevant literature review and discussion with peers. A list of issues that were deemed as essential components of the experience of the pandemic relevant to physicians was arrived at. Thereafter these issues were operationalized into question form and hosted on the google forms platform. The link to this questionnaire was circulated by the authors among their peer groups in the month of April 2020.\n\nResultsWe received 295 responses and 3 were unusable. Most of the responses were from India, the United States of America, Australia, Canada and the United Kingdom. About 60% of the respondents identified themselves as frontline and had a decade of clinical experience. Most respondents reported being anxious due to the pandemic and also observed the same in their peers and families. A majority also observed changes in behaviour in self and others and advanced a variety of reasons and concerns. A sense of duty was the most commonly employed coping mechanism.\n\nConclusionPhysicians are not immune from information and misinformation, or cues in the environment. Behavioural choices are not always predicted by knowledge but by a combination of knowledge, emotional state, personality and environment. Healthcare settings need to be ready for emergencies and should focus on reducing uncertainty in physicians. These factors may also be gainfully used in the mental health promotion of physicians in COVID-19 care roles.","How to decide which COVID-19 patient with myocardial infarction to send to the Cath Lab? - A case series of COVID-19 patients with myocardial infarction\nINTRODUCTIONThe Coronavirus pandemic has hit the world with its vast contagiousness, high morbidity, and mortality. Apart from the direct damage to the lung tissue, the corona virus infection is able to predispose patients to thrombotic disease, thus causing cerebral or coronary incidents.\n\nAIMSThe aim of this study was to find a clinical or laboratory parameter, that would help in distinguishing between COVID-19 patients with myocardial infarction (MI), who have an infarct-related artery (IRA) and therefore, require immediate revascularization, and those, who have no IRA.\n\nMETHODSThis was a single-center, observational study of 10 consecutive patients with COVID-19, who were admitted with confirmed MI.\n\nRESULTSIn our study group the mean age was 67.5 {+/-} 8.3 years, half of the patients were female; all of them had arterial hypertension; 8 patients (80%) had dyslipidemy; 4 (40%) had diabetes. 30% of the patients with MI did not have an IRA, and did not require pPCI. Patients with MI and IRA had significantly higher hsTrI values (48.9 {+/-} 43.2 vs 0.6 {+/-} 0.7, p=0.007) and exclusively typical chest pain 100% vs 0%, p=0.007), compared to patients with MI without an IRA. The ECG changes had only marginal statistical significance. Our results suggest that using a higher cut-off value for hsTrI (>7.5 times upper reference range) increases the specificity and positive predictive value for diagnosing a MI with the presence of IRA and need for pPCI, to 100%\n\nCONCLUSIONIn our analysis we confirm that a higher cut-off value for hsTrI helps distinguish between COVID patients with MI, who have IRA and therefore, require immediate revascularization, compared to those, who have no IRA.","Altered Cerebral Blood Flow in Older Adults with Alzheimer's Disease: A Systematic Review\nThe prevalence of Alzheimers disease is projected to reach 13 million in the U.S. by 2050. Although major efforts have been made to avoid this outcome, so far there are no treatments that can stop or reverse the progressive cognitive decline that defines Alzheimers disease. The utilization of preventative treatment before significant cognitive decline has occurred may ultimately be the solution, necessitating a reliable biomarker of preclinical/prodromal disease stages to determine which older adults are most at risk. Quantitative cerebral blood flow is a promising potential early biomarker for Alzheimers disease, but the spatiotemporal patterns of altered cerebral blood flow in Alzheimers disease are not fully understood. The current systematic review compiles the findings of 29 original studies that compared quantitative cerebral blood flow in older adults with mild cognitive impairment or Alzheimers disease to that of cognitively normal older adults and/or assessed the relationship between cerebral blood flow and objective cognitive function. Individuals with Alzheimers disease had relatively decreased cerebral blood flow in all brain regions investigated, especially the temporoparietal and posterior cingulate, while individuals with mild cognitive impairment had less consistent results, with relatively increased cerebral blood flow reported in the temporal lobe and thalamus. Most papers reported a positive correlation between cerebral blood flow and cognitive function. This review highlights the need for more studies comparing cerebral blood flow between cognitively normal individuals and those with mild cognitive impairment, as well as the importance of including potential confounding factors in these analyses.","Machine Learning based COVID-19 Diagnosis from Blood Tests with Robustness to Domain Shifts\nWe investigate machine learning models that identify COVID-19 positive patients and estimate the mortality risk based on routinely acquired blood tests in a hospital setting. However, during pandemics or new outbreaks, disease and testing characteristics change, thus we face domain shifts. Domain shifts can be caused, e.g., by changes in the disease prevalence (spreading or tested population), by refined RT-PCR testing procedures (taking samples, laboratory), or by virus mutations. Therefore, machine learning models for diagnosing COVID-19 or other diseases may not be reliable and degrade in performance over time. To countermand this effect, we propose methods that first identify domain shifts and then reverse their negative effects on the model performance. Frequent re-training and reassessment, as well as stronger weighting of more recent samples, keeps model performance and credibility at a high level over time. Our diagnosis models are constructed and tested on large-scale data sets, steadily adapt to observed domain shifts, and maintain high ROC AUC values along pandemics.","Clinical Burkholderia pseudomallei isolates from Queensland carry diverse bimABm genes that are associated with central nervous system disease and are phylogenomically distinct from other Australian strains\nBurkholderia pseudomallei is an environmental gram-negative bacterium that causes the disease melioidosis and is endemic in many countries of the Asia-Pacific region. In Australia, the mortality rate remains high at approximately 10%. The bacterium is almost exclusively found in the endemic region, which spans the Northern Territory, Western Australia and North Queensland. However, Queensland infections remain understudied compared to those of the Northern Territory. This pilot study aimed to assess the prevalence of central nervous system disease associated variant bimABm, identify circulating antimicrobial resistance mutations and genetically distinct strains from Queensland, via comparative genomics. From 76 clinical isolates, we identified the bimABm variant in 20 (26.3%) isolates and in 9 (45%) of the isolates with documented central nervous system infection (n=18). Explorative analysis suggests a significant association between isolates carrying the bimABm variant and central nervous system disease (OR 2.8, 95% CI 1.3-6.0, P=0.009) compared with isolates carrying the wildtype bimABp, with the possibility of additional driving factors. Furthermore, 50% of isolates were identified as novel multi-locus sequence types (STs), while the bimABm variant was more commonly identified in isolates with novel sequence STs, compared to those of previously described STs. Additionally, mutations associated with acquired antimicrobial resistance were only identified in 14.5% of all genomes. The findings of this research have provided clinically relevant genomic data of B. pseudomallei in Queensland and suggest that the bimABm variant may enable risk stratification for the development CNS complications and be a potential therapeutic target.","Opioid Use Stigmatization and Destigmatization in Healthcare Professional Social Media\nStigmatization of opioid use constitutes a significant barrier to addressing the opioid crisis. Increasing use of social media by healthcare professionals provides an opportunity to foster destigmatization. However, little is known about stigmatization and destigmatization within healthcare professional social media communities. Accordingly, this study investigates the use of stigmatizing and destigmatizing language in three such communities: Medical Twitter, Public Health Twitter, and Epidemiology Twitter. Using a dataset of 2,319 tweets discussing opioids and associated with these Twitter communities, we analyzed each tweet for evidence of stigmatizing or destigmatizing language based on guidance from the National Institute on Drug Abuse. The results indicate that overall use of both stigmatizing and destigmatizing language is currently low across communities compared to the overall volume of opioid-related content. Additionally, there are measurable changes in stigmatizing and destigmatizing language on quarterly bases between 2012 and 2020. During this time, Public Health Twitter has seen a quarterly 19% reduction in rates of stigmatizing (IRR = 0.81, 95% CI 0.67 to 0.97), and all communities have experienced a quarterly 57% increase in destigmatizing language (IRR = 1.57, 95% CI: 1.33 to 1.85). This study also reveals that tweets containing stigmatizing and destigmatizing language receive minimal user engagement (measured by likes, retweets, quote tweets, and comments). While the longitudinal findings on increasing use of destigmatizing language are promising, they also indicate a need for increased efforts to encourage broader use of destigmatizing language. Leveraging the social learning potentials of Twitter offers one promising pathway for future initiatives.","Superiority of serum NFL in predicting Multiple Sclerosis severity\nObjectiveSerum neurofilament light chain (sNFL) is becoming an important biomarker of neuroaxonal injury. While sNFL correlates with cerebrospinal fluid NFL (cNFL), 40-60% of variance remains unexplained. Assuming that for diseases of the central nervous system (CNS), such as multiple sclerosis (MS), the cNFL better reflects CNS injury, our goal was to develop and validate adjustment of sNFL for relevant confounders, to strengthen cNFL-sNFL correlations.\n\nMethodsWe used 1,378 matched cNFL-sNFL pairs divided into training and validation cohort with matching data on 11 confounders, neuroexam, and magnetic resonance imaging (MRI). The effect of confounders on cNFL-sNFL relationship was tested using multiple linear regression (MLR) model. Propensity score matching was used to identify effect of spinal cord damage on sNFL levels.\n\nResultsIn the training cohort (n=898) we correlated 11 confounders with the residuals from cNFL-sNFL linear regression. Four non-overlapping confounders explaining highest proportion of variance (12%: age, 8.7%: blood urea nitrogen, 3%: alkaline phosphatase, and 3.9%: weight) were used in MLR model. The model strengthened the cNFL-sNFL correlation from R2 = 0.52 to 0.64 in the independent validation cohort and strengthened correlation of adjusted sNFL with number of contrast-enhancing lesions (from R2 0.11 to 0.18). However, only sNFL, but not cNFL correlated with MS severity outcomes. Using propensity score matching, we demonstrated that subjects with proportionally higher sNFL to cNFL levels have significantly higher clinical and radiological evidence of spinal cord injury.\n\nInterpretationSuperiority of sNFL likely resides in the release of NFL from axons of lower motor or dorsal ganglia neurons directly to blood.","Performance in Fundamentals of Laparoscopic Surgery (FLS): Does it Reflect Global Rating Scales in Objective Structured Assessment of Technical Skills (OSATS) in Porcine Laparoscopic Surgery?\nBackgroundTo correlate the utility of Fundamentals of Laparoscopic Surgery (FLS) manual skills program with the Objective Structured Assessment of Technical Skills (OSATS) global rating scale in evaluating operative performance.\n\nMaterials and MethodsThe Asian Urological Surgery Training and Educational Group (AUSTEG) Laparoscopic Upper Tract Surgery Course (LUTSC) implemented and validated the FLS program for its usage in laparoscopic surgical training. Delegates basic laparoscopic skills were assessed using three different training models (Peg Transfer, Precision Cutting and Intra-corporeal Suturing). They also performed live porcine laparoscopic surgery at the same workshop. Live surgery skills were assessed by blinded faculty using the OSATS rating scale.\n\nResultsFrom 2016 to 2019, a total of 81 certified urologists participated in the course, with a median of 5 years experience post residency. Although differences in task timings did not reach statistical significance, those with more surgical experience were visibly faster at completing the peg transfer and intra-corporeal suturing FLS tasks. However, they took longer to complete the precision cutting task than participants with less experience. Overall OSATS scores correlated weakly with all three FLS tasks (Peg Transfer Time: R = -0.331, R2 = 0.110; Precision Cutting Time: R = - 0.240, R2 = 0.058; Suturing with Intra-corporeal Knot Time: R = -0.451, R2 = 0.203).\n\nConclusionFLS task parameters did not correlate strongly with OSATS globing rating scale performance. Although the FLS task models demonstrated strong validity, it is important to assimilate the inconsistencies when benchmarking technical proficiency against real-life operative competence, as evaluated by FLS and OSATS respectively.","Genetic support of a causal relationship between Iron status and atrial fibrillation: a Mendelian randomization study\nBackgroundAtrial fibrillation is the most common arrhythmia disease.Animal and observational studies have found a link between iron status and atrial fibrillation. However, the causal relationship between iron status and the risk of atrial fibrillation may be biased by confounding and reverse causality.The purpose of this investigation was to use Mendelian randomization (MR) analysis, which has been widely appied to estimate the causal effect,to reveal whether systemic iron status was causally related to atrial fibrillation.\n\nMethodsSingle nucleotide polymorphisms (SNPs) strongly associated (P < 5x10-8) with four biomarkers of systemic iron status were obtained from a genome-wide association study involving 48,972 subjects conducted by the Genetics of Iron Status consortium.\n\nSummary-level data for the genetic associations with atrial fibrillation were acquired from AFGen (Atrial Fibrillation Genetics) consortium study(including 65,446 atrial fibrillation cases and 522,744 controls). We used a two-sample MR analysis to obtain a causal estimate, and further verified credibility through sensitivity analysis.\n\nResultsGenetically instrumented serum iron [OR:1.09;95%; confidence interval (CI)1.02-1.16; p=0.01], ferritin [OR:1.16;95%CI:1.02-1.33; p=0.02], and transferrin saturation [OR:1.05;95%CI:1.01-1.11; p=0.01] had positive effects on atrial fibrillation. Genetically instrumented transferrin levels [OR:0.90;95%CI:0.86-0.97; p=0.006] was an inverse correlation with atrial fibrillation.\n\nConclusionIn conclusion,our results strongly elucidated a causal link between genetically determined higher iron status and increased the risk of atrial fibrillation.This provided new ideas for clinical prevention and treatment of atrial fibrillation.","A comparison of health care use after severe COVID-19, respiratory syncytial virus, and influenza in children\nBackgroundWe aimed to explore whether children in hospital care with COVID-19 have increased post-discharge health care use when compared to children in hospital care with 1) RSV infection, and 2) other RTIs.\n\nMethodsIn 34,214 children aged 1 month to 5 years who were registered with one or more hospital contacts with COVID-19 (N=128), RSV infection (N=4,009) or other RTIs (upper- and lower unspecified RTI as well as influenza) (N=34,457) (January 1st, 2017 to September 20th, 2021), we used a pre-post study design to investigate the individual all-cause primary and specialist health care use from 12 weeks prior to hospital admission, to 12 weeks after hospital discharge, stratified on infants (1-12 months) and toddlers (1-5 years).\n\nFindingsWe found a slight increase in primary health care use in the first four weeks after discharge for children aged 1-12 months with COVID-19 when compared to children with RSV infection (0.064 percentage points, 95% CI 0.02-0.126, 0.52% relative increase). For children aged 1-5 years, COVID-19 discharge was associated with a 1-4 weeks increase in primary health care use when compared to children with RSV infection (0.068 percentage points, 95% CI 0.022-0.144, 0.53% relative increase) and other RTI (0.046 percentage points, 95% CI 0.002-0.091, 0.45% relative increase). For children aged 1-12 months in hospital care with COVID-19, we found a similar-magnitude-increase in post-discharge inpatient specialist care use, which lasted for 12 weeks.\n\nInterpretationOur findings imply no severe impact on health care use after hospitalization with COVID-19 compared to hospitalization with RSV infection or other RTIs. The etiological mechanisms for potentially worse post-hospitalization complaints or health-seeking behavior for COVID-19 than for other RTIs in children should be further explored.","A SARS-CoV-2 negative antigen rapid diagnostic in RT-qPCR positive samples correlates with a low likelihood of infectious viruses in the nasopharynx.\nSARS-CoV-2 transmission occurs even among fully vaccinated individuals; thus, prompt identification of infected patients is central to control viral circulation. Antigen rapid diagnostic tests (Ag-RDT) are highly specific, but sensitivity is variable.Discordant RT-qPCR vs Ag-RDT results are reported, raising the question of whether negative Ag-RDT in positive RT-qPCR samples could imply the absence of infectious viruses. To study the relationship between a negative Ag-RDT results with virological, molecular, and serological parameters, we selected a cross sectional and a follow-up dataset and analyzed virus culture, subgenomic RNA quantification, and sequencing to determine infectious viruses and mutations. We demonstrated that a positive SARS-CoV-2 Ag-RDT result correlates with the presence of infectious virus in nasopharyngeal samples. A decrease in sgRNA detection together with an expected increase in detectable anti-S and anti-N IgGs was verified in negative Ag-RDT / positive RT-qPCR samples. The data clearly demonstrates the less likelihood of a negative Ag-RDT sample to harbor infectious SARS-CoV-2 and consequently with a lower transmissible potential.","Data-driven estimate of SARS-CoV-2 herd immunity threshold in populations with individual contact pattern variations\nThe development of efficacious vaccines has made it possible to envision mass vaccination programs aimed at suppressing SARS-CoV-2 transmission around the world. Here we use a data-driven age-structured multilayer representation of the population of 34 countries to estimate the disease induced immunity threshold, accounting for the contact variability across individuals. We show that the herd immunization threshold of random (un-prioritized) mass vaccination programs is generally larger than the disease induced immunity threshold. We use the model to test two additional vaccine prioritization strategies, transmission-focused and age-based, in which individuals are inoculated either according to their behavior (number of contacts) or infection fatality risk, respectively. Our results show that in the case of a sterilizing vaccine the behavioral strategy achieves herd-immunity at a coverage comparable to the disease-induced immunity threshold, but it appears to have inferior performance in averting deaths than the risk vaccination strategy. The presented results have potential use in defining the effects that the heterogeneity of social mixing and contact patterns has on herd immunity levels and the deployment of vaccine prioritization strategies.","Neighborhood Disadvantage and Active, Disabled and Total Life Expectancy Among Community-living Older Persons\nBackgroundNeighborhood disadvantage is a novel social determinant of health that could adversely affect the functional well-being and longevity of older persons. We evaluated whether estimates of active, disabled and total life expectancy differ on the basis of neighborhood disadvantage after accounting for individual-level socioeconomic characteristics and other prognostic factors.\n\nMethodsWe used data on 754 community-living older persons from South Central Connecticut, who completed monthly assessments of disability from 1998 to 2020. Scores on the area deprivation index were dichotomized at the 80th state percentile to distinguish neighborhoods that were disadvantaged (81-100) from those that were not (1-80).\n\nResultsWithin 5-year age increments from 70 to 90, active and total life expectancy were consistently lower in participants from neighborhoods that were disadvantaged versus not disadvantaged, and these differences persisted and remained statistically significant after adjustment for individual-level race/ethnicity, education, income, and other prognostic factors. At age 70, adjusted estimates (95% CI) for active and total life expectancy (in years) were 12.3 (11.5-13.1) and 15.0 (13.8-16.1) in the disadvantaged group and 14.2 (13.5-14.7) and 16.7 (15.9-17.5) in the non-disadvantaged group. At each age, participants from disadvantaged neighborhoods spent a greater percentage of their projected remaining life disabled, relative to those from non-disadvantaged neighborhoods, with adjusted values (SE) ranging from 17.7 (0.8) vs. 15.3 (0.5) at age 70 to 55.0 (1.7) vs. 48.1 (1.3) at age 90.\n\nConclusionsLiving in a disadvantaged neighborhood is associated with lower active and total life expectancy and a greater percentage of projected remaining life disabled.","Unifying diagnostic criteria for gestational diabetes mellitus\nAIMSDisagreement about the appropriate criteria for the diagnosis of gestational diabetes mellitus (GDM) persists. This study examines an alternative approach which combines information from all time-points on the glucose tolerance test (GTT) into a single index and expands the GDM spectrum into four categories using data from three geographically and ethnically distinct populations.\n\nMETHODSA retrospective observational study design was used. Data from Wisconsin, USA (723 women) was used in derivation of the criterion and data from Doha, Qatar (1284 women) and Cape Town, South Africa (220 women) for confirmation. Pregnant women without pre-existing diabetes with a GTT done between 23 and 30 weeks gestation were included. A novel index was derived from the GTT termed the weighted average glucose (wAG). This was categorized into four pre-defined groups (henceforth National Priorities Research Program (NPRP) criterion); i) normal gestational glycemia (NGG), ii) impaired gestational glycemia (IGG), iii) GDM and iv) high risk GDM (hGDM).\n\nRESULTSIn the Doha cohort, compared to the NGG group, the odds of large for gestational age babies increased 1.33 fold (P=0.432), 2.86 fold (P<0.001) and 3.35 fold (P<0.001) in the IGG, GDM and hGDM groups respectively. The odds of pregnancy induced hypertension increased 2.10 fold (P=0.024) in GDM & hGDM groups compared to the IGG and NGG groups. In the Cape Town cohort, a third of women in the GDM group and two-thirds in the hGDM group progressed to T2DM at 5 years.\n\nCONCLUSIONSThe NPRP categorization identifies four distinct risk clusters of glycemia in pregnancy which may aid better decision making in routine management, avoid potential over-diagnosis of women at lower risk of complications and assist with diabetes prevention in women at high-risk after an index pregnancy with GDM.","Optimizing SARS-CoV-2 vaccination strategies in France: Results from a stochastic agent-based model\nThe COVID-19 pandemic is a major global societal, economic and health threat. The availability of COVID-19 vaccines has raised hopes for a decline in the pandemic. We built upon a stochastic agent-based microsimulation model of the COVID-19 epidemic in France. We examined the potential impact of different vaccination strategies, defined according to the age, medical conditions, and expected vaccination acceptance of the target non-immunized adult population, on disease cumulative incidence, mortality, and number of hospital admissions. Specifically, we examined whether these vaccination strategies would allow to lift all non-pharmacological interventions (NPIs), based on a sufficiently low cumulative mortality and number of hospital admissions. While vaccinating the full adult non-immunized population, if performed immediately, would be highly effective in reducing incidence, mortality and hospital-bed occupancy, and would allow discontinuing all NPIs, this strategy would require a large number of vaccine doses. Vaccinating only adults at higher risk for severe SARS-CoV-2 infection, i.e. those aged over 65 years or with medical conditions, would be insufficient to lift NPIs. Immediately vaccinating only adults aged over 45 years, or only adults aged over 55 years with mandatory vaccination of those aged over 65 years, would enable lifting all NPIs with a substantially lower number of vaccine doses, particularly with the latter vaccination strategy. Benefits of these strategies would be markedly reduced if the vaccination was delayed, was less effective than expected on virus transmission or in preventing COVID-19 among older adults, or was not widely accepted.","Selective tweeting of COVID-19 articles: Does title or abstract positivity influence dissemination?\nBackgroundPrevious research has shown that articles may be cited more frequently on the basis of title or abstract positivity. Whether a similar selective sharing practice exists on Twitter is not well understood. The objective of this study was to assess if COVID-19 articles with positive titles or abstracts were tweeted more frequently than those with non-positive titles or abstracts.\n\nMethodsCOVID-19 related articles published between January 1st and April 14th, 2020 were extracted from the LitCovid database and all articles were screened for eligibility. Titles and abstracts were classified using a list of positive and negative words from a previous study. A negative binomial regression analysis controlling for confounding variables (2018 impact factor, open access status, continent of the corresponding author, and topic) was performed to obtain regression coefficients, with the p values obtained by likelihood ratio testing.\n\nResultsA total of 3752 COVID-19 articles were included. Of the included studies, 44 titles and 112 abstracts were positive; 1 title and 7 abstracts were negative; and 3707 titles and 627 abstracts were neutral. Articles with positive titles had a lower tweet rate relative to articles with non-positive titles, with a regression coefficient of -1.10 (P < .001), while the positivity of the abstract did not impact tweet rate (P = .2218).\n\nConclusionCOVID-19 articles with non-positive titles are preferentially tweeted, while abstract positivity does not influence tweet rate.","An integrated genome and phenome-wide association study approach to understanding Alzheimer's disease predisposition\nBackgroundGenome-wide association studies (GWAS) have identified common, heritable alleles that increase late-onset Alzheimers disease (LOAD) risk. We recently published an analytic approach to integrate GWAS and phenome-wide association study (PheWAS) data, enabling identification of candidate traits and trait-associated variants impacting disease risk, and apply it here to LOAD.\n\nMethodsPheWAS was performed for 23 known LOAD-associated single nucleotide polymorphisms (SNPs) and 4:1 matched control SNPs using UK Biobank data. Traits enriched for association with LOAD SNPs were ascertained and used to identify trait-associated candidate SNPs to be tested for association with LOAD risk (17,008 cases; 37,154 controls).\n\nResultsLOAD-associated SNPs were significantly enriched for associations with 6/778 queried traits, including three platelet traits. The strongest enrichment was for platelet distribution width (PDW) (P=1.2x10-5), but no consistent direction of effect was observed between increased PDW and LOAD susceptibility across variants or in Mendelian randomization analysis. Of 384 PDW-associated SNPs identified by prior GWAS, 36 were nominally associated with LOAD risk and 5 survived false-discovery rate correction for multiple testing. Associations confirmed known LOAD risk loci near PICALM, CD2AP, SPI1, and NDUFAF6, and identified a novel risk locus in the epidermal growth factor receptor (EGFR) gene.\n\nConclusionsThrough integration of GWAS and PheWAS data, we identify substantial pleiotropy between genetic determinants of LOAD and of platelet morphology, and for the first time implicate EGFR - a mediator of {beta}-amyloid toxicity - in Alzheimers disease susceptibility.","SARS-CoV-2 infections in infants in Haiti 2020-2021; evidence from a serological cohort\nBetween February 2019 and March 2021, 388 dried blood spot samples were obtained from 257 children <30 months of age who were part of a longitudinal maternal/infant cohort in Haiti. Among the children followed, 16.7% became seropositive; sampling date was the only covariate associated with the hazard of seroconversion.","Liquid-biopsy transcriptomic profiling uncovers molecular mediators of resistance to androgen receptor signaling inhibition in lethal prostate cancer\nAndrogen receptor signaling inhibitors (ARSi) are a mainstay for patients with metastatic castration-resistant prostate cancer (mCRPC). However, patient response is heterogeneous and the molecular underpinnings of ARSi resistance are not well elucidated. Here we performed transcriptome analysis of circulating tumor cells (CTCs) and peripheral blood mononuclear cells (PBMC) in the context of a prospective clinical trial of men with mCRPC treated with abiraterone (Abi) or enzalutamide (Enza). CTC RNA-sequencing identified that RB loss and enhanced E2F signaling along with BRCA loss transcriptional networks were associated with intrinsic ARSi resistance, while an inflammatory response signature was significantly associated with acquired resistance. Transcriptomic analysis of matching PBMCs identified enrichment of inflammasome gene signatures indicative of activated innate immunity at progression, with concurrent downregulation of T and NK cells. Importantly, CTC gene signatures had a significant positive association with circulating immune macroenvironment (CIME) signatures. Taken together, these data demonstrate that liquid biopsy transcriptomics can identify molecular pathways associated with clinical ARSi resistance paving the way for treatment optimization in patients with mCRPC.","Regional Variation in COVID-19 Scarce Resource Allocation Protocols\nBackgroundScarce resource allocation policies vary across the United States. Little is known about regional variation in hospital-level resource allocation protocols and variation in their application.\n\nObjectiveTo evaluate how scarce resource allocation policies throughout the Chicagoland area vary and whether there are differences in policy application within and amongst hospitals.\n\nDesignTwo cross-sectional surveys.\n\nSettingChicagoland hospitals.\n\nParticipantsRepresentatives from Chicagoland hospitals and triage officers at these hospitals.\n\nMeasurementsSurvey responses and categorical variables are described by frequency of occurrence. Intra- and interhospital variation in ranking of hypothetical patients was assessed using Kappa coefficients.\n\nResultsEight Chicago area hospitals responded to the survey assessing scarce resource allocation protocols. For hospitals willing to describe their specific ventilator allocation protocol (n=7), the initial scoring system varied with most utilizing the sequential organ failure assessment (SOFA) score (86%) and medical comorbidities (57%). A majority gave priority to pre-defined groups in their initial scoring system (86%), all discussed withdrawal of mechanical ventilation for adult patients (100%), and a minority had exclusion criteria (43%). Forty-nine triage officers from nine hospitals responded to the second survey. Triage officer rankings of hypothetical patients had slight agreement amongst all hospitals (Kappa 0.158) and fair agreement within two hospitals with the most respondents (Kappa 0.21 and 0.25). Almost half of triage officer respondents reported using tiebreakers to rank patients (N=23/49, 47%).\n\nConclusionAlthough most Chicago area hospitals surveyed created guidelines for resource allocation during the COVID-19 pandemic, these guidelines and application of these protocols by triage officers varied significantly.\n\nFunding SourceNone.","A whole system approach to increasing childrens physical activity in a multi-ethnic UK city: a process evaluation protocol\nBackgroundEngaging in regular physical activity requires continued complex decision-making in varied and dynamic individual, social and structural contexts. Widespread shortfalls of physical activity interventions suggests the complex underlying mechanisms of change are not yet fully understood. More insightful process evaluations are needed to design and implement more effective approaches. This paper describes the protocol for a process evaluation of the JU:MP programme, a whole systems approach to increasing physical activity in children and young people aged 5-14 years in North Bradford, UK.\n\nMethodsThis process evaluation, underpinned by realist philosophy, aims to understand the development and implementation of the JU:MP programme and the mechanisms by which JU:MP influences physical activity in children and young people. It also aims to explore behaviour change across wider policy, strategy and neighbourhood systems. A mixed method data collection approach will include semi-structured interview, observation, documentary analysis, surveys, and participatory evaluation methods including reflections and ripple effect mapping.\n\nDiscussionNot only is this an innovative approach to process evaluation but it will also feed into iterative programme development to generate evidence-based practice and deliver practice-based evidence. This paper advances knowledge regarding the development of process evaluations for evaluating systems interventions, and emphasises the importance of process evaluation.","SARS-CoV-2 screening in patients in need of urgent inpatient treatment in the Emergency Department (ED) by digitally integrated point-of-care PCR: A clinical cohort study\nPatients in need of urgent inpatient treatment were recruited prospectively. A rapid point of care PCR test (POC-PCR; Liat(R)) for SARS-CoV2 was conducted in the ED and a second PCR-test from the same swab was ordered in the central laboratory (CL-PCR). POC-PCR analyzers were digitally integrated in the laboratory information system.\n\nOverall, 160 ED patients were included. A valid POC-PCR-test result was available in 96.3% (n=154) of patients. N=16 patients tested positive for SARS-CoV-2 (10.0%). The POC PCR test results were available within 102 minutes (median, IQR: 56-211), which was significantly earlier compared to the CL PCR (811 minutes; IQR: 533-1289, p < 0.001). The diagnostic accuracy of the POC-PCR test was 100%. The implementation and digital LIS integration was successfully done. Staff satisfaction with the POC process was high.\n\nThe POC-PCR testing in the emergency department is feasible and shows a very high diagnostic performance.\n\nTrial registration: DRKS00019207","Financial and Non-financial Conflicts of Interest Among the Japanese Government Advisory Board Members Concerning Coronavirus Disease 2019\nObjectivesThis study aimed to assess the extent of conflicts of interest among the Japanese government COVID-19 advisory board members and elucidate the accuracy of conflicts of interest (COI) disclosure and management strategies.\n\nMethodsUsing the payment data from all 79 pharmaceutical companies in Japan between 2017 and 2018 and direct research grants from the Japanese government between 2019 and 2020, we evaluated the extent of financial and non-financial COI among all 20 Japanese government COVID-19 advisory board members.\n\nResultsJapanese government COVID-19 advisory board members were predominantly male (75.0%) and physicians (50.0%). Between 2019 and 2020, two members (10.0%) received a total of $819,244 in government research funding. Another five members (25.0%) received $419,725 in payments, including $223,183 in personal fees, from 28 pharmaceutical companies between 2017 and 2018. The average value of the pharmaceutical payments was $20,986 (standard deviation: $81,762). Further, neither the Ministry of Health, Labor, and Welfare nor the Japanese Cabinet Secretariat disclosed financial or non-financial COI with industry. Further, the government and had no policies for managing COI among advisory board members.\n\nConclusionsThis study found that the Japanese government COVID-19 advisory board had financial and non-financial COI with pharmaceutical companies and the government. Further, there were no rigorous COI management strategies for the COVID-19 advisory board members. Any government must ensure the independence of scientific advisory boards by implementing more rigorous and transparent management strategies that require the declaration and public disclosure of all COI.","Implementation of Mercury Biomonitoring in German Adults using Dried Blood Spot Sampling in Combination with Direct Mercury Analysis\nVenous blood is a preferred matrix for the determination of total mercury (Hg) in human biomonitoring but has some drawbacks such as the requirement for an uninterrupted cold chain for transport and storage and the need of medical personnel for sample collection. Therefore, we tested and implemented a simpler and less expensive method for measuring Hg in human blood using dried blood spots (DBS). For method development, we investigated the influence of different storage conditions (temperature, storage vessel, time) on DBS samples. For method validation, we compared DBS and venous blood and investigated whether DBS sampling is suitable for measuring Hg in the general population in countries with low Hg exposure such as Germany. Based on our results, we found that pre-cleaned glass tubes were most suitable for storage of DBS samples, as this allowed the samples to remain stable for at least four weeks even at high temperatures (40{degrees}C). When comparing venous blood and DBS, a very good correlation (r=0.95, p<0.01) and high precision of DBS (mean relative standard deviation 8.2% vs. 7.2% in venous blood samples) were observed. Comparing the recoveries of both matrices in different concentration ranges, the scattering of the recoveries decreases with increasing Hg concentration. The same applies to the mean recoveries. Overall, we found comparable results for DBS and whole blood using direct Hg analysis. Furthermore, we demonstrated that DBS are suitable for Hg biomonitoring in the general population in Germany and improved the storage conditions for the DBS.","Environment-wide association study (EWAS) on cardiometabolic traits: A systematic assessment of the association of lifestyle variables on a longitudinal setting\nThe present study aims to assess the over-time association of [~]300 lifestyle exposures with nine cardiometabolic traits with the ultimate aim of identifying exposures/exposure groups that could inform lifestyle interventions aiming at controlling cardiometabolic diseases. The analyses were undertaken in a longitudinal sample comprising >31000 adults living in northern Sweden. Linear mixed models were used to assess the average associations of lifestyle exposures and linear regression models were used to test association with 10-year change of the cardiometabolic traits. Physical activity and General Health were the exposure categories containing the highest number of tentative signals in analyses assessing the average association of lifestyle variables, while Tobacco use was the top-category for the 10-year change association analyses. Thirteen modifiable variables showed a consistent average association among the majority of cardiometabolic traits. These variables belonged to four main groups: i) Smoking, ii) Diet (secoisolariciresinol intake and brewed coffee), iii) Leisure time physical activity and iv) a group of variables more specific to the Swedish lifestyle (snuff status, hunting/fishing during leisure time and boiled coffee). Interestingly, sweet drinks, fish intake and salt content, all lifestyle exposures frequently mentioned in public health recommendations were not broadly associated with the analysed cardiometabolic traits.","Repeated introductions and intensive community transmission fueled a mumps virus outbreak in Washington State\nIn 2016/2017, Washington State experienced a mumps outbreak despite high childhood vaccination rates, with cases more frequently detected among school-aged children and members of the Marshallese community. We sequenced 166 mumps virus genomes collected during outbreaks in Washington and other US states, and apply phylodynamic approaches to trace mumps introductions and transmission within Washington. We uncover that mumps was introduced into Washington at least 13 times, primarily from Arkansas, sparking multiple co-circulating transmission chains. Neither vaccination status nor age were strong determinants of transmission. Instead, the outbreak in Washington was overwhelmingly sustained by transmission within the Marshallese community. Our findings underscore the utility of genomic data to clarify epidemiologic factors driving transmission, and pinpoint contact networks as critical determinants of mumps transmission. These results imply that contact structures and historic disparities may leave populations at increased risk for respiratory virus disease even when a vaccine is effective and widely used.","Mitigating the identity and health threat of COVID-19: Perspectives of Middle-Class South Asians living in the UK\nThe recognition and representation of BAME community as \"high risk\" of Covid-19 in the UK presents both a health and an identity threat to this ethnic group. This study employed thematic analysis to explore response to these threats as related by a sample of thirteen middle class members of the South Asian community. This work advances both health and identity psychological theory by recognising the affinity between expressions of health efficacy and identity. Our findings identify South Asian intragroup stigmatisation and commonalities that have implications for the promotion of health behaviour and health communications for minority groups.","Presence of Major Depressive Disorder influences both neuropsychiatric symptoms and the cognitive profile in Mild Cognitive impairment and Alzheimers disease\nObjectivesThe impact of depression, as quantified with specific tests, and neuropsychiatric symptoms (NPS) on mnesic and executive performance has been documented previously. However, the depression can be also diagnosed as Major Depressive Disorder (MDD) based on the DSM-V. We aimed to determine how MDD influences NPS and cognitive performance in Alzheimers disease (AD), Mild Cognitive Impairment (MCI) and Healthy Controls (CH).\n\nParticipants647 HC, 291 patients with MCI and 208 patients with AD were extracted from the National Alzheimers Coordinating Center database.\n\nMeasurementsDuring their inclusion in the cohort, each patient was assessed by a physician to distinguish those with a diagnosis of MDD from those without MDD. Patients were assessed with the NeuroPsychiatric Inventory and a comprehensive cognitive assessment. We performed logistic regression and a MANCOVA models respectively with NPS and cognitive performance as variables of interest and MDD as fixed factors within each group. The MANCOVA was controlled for the effects of age, sex, and education.\n\nResultsOur results exhibited that: MDD was associated with and predicted psychotic, affective and behavioral NPS in MCI, and affective/behavioral NPS in CH and AD; MCI with MDD had lower performance of selective attention and mental flexibility whereas AD with MDD had better working memory performance, than those without MDD.\n\nConclusionsMDD was mainly associated with higher prevalence of NPS in CH and both level of cognitive decline. This suggest that early treatment of MDD could reduce essentially neuropsychiatric symptomatology and caregiver mental burden.","Association between benzodiazepine receptor agonist use and increased mortality among patients hospitalized for COVID-19: results from an observational study\nObjectiveTo examine the association between benzodiazepine receptor agonist (BZRA) use and mortality in patients hospitalized for COVID-19.\n\nMethodsWe conducted an observational multicenter retrospective cohort study at AP-HP Greater Paris University hospitals. The sample involved 14,381 adult patients hospitalized for COVID-19. 686 (4.8%) inpatients received a BZRA within at the time of hospital admission at a mean daily diazepam-equivalent dose of 19.7 mg (SD=25.4). The study baseline was the date of hospital admission and the primary endpoint was death. We compared this endpoint between patients who received BZRAs and those who did not in time-to-event analyses adjusted for patient characteristics (such as age, sex, obesity and comorbidity) and other medications. The primary analysis was a Cox regression model with inverse probability weighting (IPW).\n\nResultsOver a mean follow-up of 14.5 days (SD=18.1), the primary endpoint occurred in 186 patients (27.1%) who received a BZRA and in 1,134 patients (8.3%) who did not. There was a significant association between BZRA use and increased mortality both in the crude analysis (HR=3.20; 95% CI=2.74-3.74; p<0.01) and in the primary IPW analysis (HR=1.61; 95% CI=1.31-1.98, p<0.01), with a significant dose-dependent relationship (HR=1.55; 95% CI=1.08-2.22; p=0.02). This association remained significant in multiple sensitivity analyses.\n\nConclusionsBZRA use was associated with increased mortality among patients hospitalized for COVID-19 with a dose-dependent relationship, suggesting a potential benefit of decreasing dose or tapering off these medications when possible in these patients.","A Design Thinking Approach to Enhance Interprofessional Education Between Technology and Medicine for Innovative Elder Pain Care.\nBackgroundDesign thinking (DT) describes three stages in the design thinking cycle: 1) inspiration, which embodies the initial problem or opportunity; 2) ideation, which encompasses the development and refinement of ideas; and 3) implementation, which involves the introduction and application of the derived solution.\n\nMethodThe prospective educational program evaluation July 2020 - December 2020. A 150 min interactive workshop regarding developing innovative elder pain care. Medical students will be grouping into four medical students: 1 technological student. Then they will be assigned to match with a technology student. The interprofessional education design thinking activity consists of three parts; a brief introduction, the brainstorming process to identified pain points by persona and user journey to generate the idea, and the prototype presentation.\n\nResultsForty sixth-year medical students and twelve technological students participated. 58% of medical students and 95% of technological students perceived DT as very helpful for their careers. However, only 30% of medical students and 60% of technological students were inspired to develop actual prototypes after the course. Nearly all of the students responded they comfortable with this interdisciplinary project-based style. Still, the time of the workshop is too limited, and among those responding with no interest pursue the project gave a reason that they lack time after rotating to other courses.\n\nConclusionMost medical students and technological students perceived DT as beneficial for their career and displayed satisfy in this co-project style. However, finding matched schedule of two disciplines made long-term interpersonal education challenging.","Prospective validation of host transcriptomic biomarkers for pulmonary tuberculosis by real-time PCR\nWe tested performance of host-blood transcriptomic tuberculosis (TB) signatures for active case-finding. Among 20,207 HIV-uninfected and 963 HIV-infected adults screened; 2,923 and 861 were enrolled from five South African communities. Eight signatures were measured by microfluidic RT-qPCR and participants were microbiologically-investigated for pulmonary TB at baseline, and actively surveilled for incident disease through 15 months. Diagnostic AUCs for 61 HIV-uninfected (weighted-prevalence 1.1%) and 10 HIV-infected (prevalence 1.2%) prevalent TB cases for the 8 signatures were 0.63-0.79 and 0.65-0.88, respectively. Thereafter, 24 HIV-uninfected and 9 HIV-infected participants progressed to incident TB (1.1 and 1.0 per 100 person-years, respectively). Prognostic AUCs through 15-months follow-up were 0.49-0.66 and 0.54-0.81, respectively. Prognostic performance for incident TB occurring within 6-12 months in HIV-negative participants was higher for all signatures. None of the signatures met WHO Target Product Profile criteria for a triage test to diagnose asymptomatic TB; most signatures met the criteria for symptomatic TB. Prognostic accuracy of most signatures for incident TB within six months of testing met the criteria for an incipient TB test.","Spotlight on the dark figure: Exhibiting dynamics in the case detection ratio of COVID-19 infections in Germany\nThe case detection ratio of COVID-19 infections varies over time due to changing testing capacities, modified testing strategies and also, apparently, due to the dynamics in the number of infected itself. In this paper we investigate these dynamics by jointly looking at the reported number of detected COVID-19 infections with non-fatal and fatal outcomes in different age groups in Germany. We propose a statistical approach that allows us to spotlight the case detection ratio and quantify its changes over time. With this we can adjust the case counts reported at different time points so that they become comparable. Moreover we can explore the temporal development of the real number of infections, shedding light on the dark number. The results show that the case detection ratio has increased and, depending on the age group, is four to six times higher at the beginning of the second wave compared to what it was at the peak of the first wave. The true number of infection in Germany in October was considerably lower as during the peak of the first wave, where only a small fraction of COVID-19 infections were detected. Our modelling approach also allows quantifying the effects of different testing strategies on the case detection ratio. The analysis of the dynamics in the case detection rate and in the true infection figures enables a clearer picture of the course of the COVID-19 pandemic.","Transmission blocking activity of low dose tafenoquine in healthy volunteers experimentally infected with Plasmodium falciparum\nBackgroundBlocking the transmission of parasites from humans to mosquitoes is a key component of malaria control. Tafenoquine exhibits activity against all stages of the malaria parasite and may have utility as a transmission blocking agent. We aimed to characterize the transmission blocking activity of low dose tafenoquine.\n\nMethodsHealthy adults were inoculated with P. falciparum 3D7-infected erythrocytes on day 0. Piperaquine was administered on days 9 and 11 to clear asexual parasitemia while allowing gametocyte development. A single 50 mg oral dose of tafenoquine was administered on day 25. Transmission was determined by enriched membrane feeding assays pre-dose and at 1, 4 and 7 days post-dose. Artemether-lumefantrine was administered following the final assay. Outcomes were the reduction in mosquito infection and gametocytemia post-tafenoquine, and safety parameters.\n\nResultsSix participants were enrolled, and all were infective to mosquitoes pre-tafenoquine, with a median 86% (range: 22-98) of mosquitoes positive for oocysts and 57% (range: 4-92) positive for sporozoites. By day 4 post-tafenoquine, the oocyst and sporozoite positivity rate had reduced by a median 35% (IQR: 16-46) and 52% (IQR: 40-62), respectively, and by day 7, 81% (IQR 36-92) and 77% (IQR 52-98), respectively. The decline in gametocyte density post-tafenoquine was not significant. No significant participant safety concerns were identified.\n\nConclusionLow dose tafenoquine reduces P. falciparum transmission to mosquitoes, with a delay in effect.\n\nTrial registrationAustralian New Zealand Clinical Trials Registry (ACTRN12620000995976).\n\nFundingQIMR Berghofer Medical Research Institute.","A Systematic Review of Datasets to Research the Effect of Policy and Place on Immigrant Health\nState and local immigrant policies--which regulate immigrants rights and access to services and material resources--shape self-rated health and health care access for Hispanic/Latino immigrants. However, due to data limitations, we know little about their impacts on non-Hispanic immigrants or on objective measures of health. To help researchers address these gaps, this systematic review creates a comprehensive resource indexing nationally-representative US datasets that can be used to measure the effects of policy and place on immigrant health. Following PRISMA guidelines, I searched ICPSR and federal data repositories for nationally-representative, population-based, longitudinal or repeated cross-sectional datasets that included health/health care access, race/ethnicity, and state or county of residence. I extracted information about race, ethnicity, migration, language, and geocodes in each dataset for each year, 2005-2021. Data searches (final search December 2021) identified 54 datasets, many of which have never been used to study the effects of policies on immigrant health. These data sources have unexploited potential to advance this literature. For example, longitudinal data sources will allow researchers to examine the effects of policies on the same individuals over time, while datasets with detailed measures of race/ethnicity and migration can be used to distinguish which immigrants are most impacted.","Hypothesis-free detection of gene-interaction effects on biomarker concentration in UK Biobank using variance prioritisation\nBlood biomarkers include disease intervention targets that may interact with genetic and environmental factors resulting in subgroups of individuals who respond differently to treatment. Such interactions may be observed in genetic effects on trait variance. Variance prioritisation is an approach to identify genetic loci with interaction effects by estimating their association with trait variance, even where the modifier is unknown or unmeasured. Here, we develop and evaluate a regression-based Brown-Forsythe test and variance effect estimate to detect such interactions. We provide scalable open-source software (varGWAS) for genome-wide association analysis of SNP-variance effects (https://github.com/MRCIEU/varGWAS) and apply our software to 30 blood biomarkers in UK Biobank. We find 468 variance quantitative trait loci across 24 biomarkers and follow up findings to detect 82 gene-environment and six gene-gene interactions independent of strong scale or phantom effects. Our results replicate existing findings and identify novel epistatic effects of TREH rs12225548 x FUT2 rs281379 and TREH rs12225548 x ABO rs635634 on alkaline phosphatase and ZNF827 rs4835265 x NEDD4L rs4503880 on gamma glutamyltransferase. These data could be used to discover possible subgroup effects for a given biomarker during preclinical drug development.","Fear among Syrians: a Proposed Cutoff Score and Validation of the Arabic Fear of COVID-19 Scale- A National Survey\nCOVID-19 pandemic has led to psychological health issues one of which is fear. This study validates the Arabic version of the fear of COVID-19 scale and suggests a new cutoff score to measure fear of COVID-19 among the Syrian Population. A total of 3989 participants filled an online survey consisting of socio-demographic information, the fear of COVID-19 scale, the patient health questionnaire 9-item, and the generalized anxiety disorder 7-item. Receiver operating characteristic analysis was used to define cutoff scores for the fear of COVID-19 scale in relation to generalized anxiety disorder 7-item and the patient health questionnaire 9-item. The Cronbach value of the Arabic fear of COVID-19 scale was 0.896, revealing good stability and internal consistency. The inter-item correlations were between [0.420 - 0.868] and the corrected item-total correlations were between [0.614 - 0.768]. A cutoff point of 17.5 was deduced from analysis. According to the deduced cutoff point, 2111(52.9%) were classified as cases with extreme fear. This cutoff score deduced from this study can be used for screening purposes to identify individuals that may be most vulnerable towards developing extreme fear of COVID-19. Therefore, early preventive and supportive measures can then be delivered.","Polygenic risk score and statin relative risk reduction for primary prevention in a real-world population\nAbstractsO_ST_ABSBackgroundC_ST_ABSRandomized-controlled trials demonstrate that high coronary heart disease (CHD) polygenic risk score modifies statin CHD relative risk reduction, but it is unknown if the association extends to statin users undergoing routine care.\n\nObjectivesThe primary objective was to determine how statin effectiveness is modified by CHD polygenic risk score in a real-world cohort of primary prevention participants.\n\nMethodsWe determined polygenic risk scores in participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. Cox regression models were used to compare the risk of the cardiovascular outcomes between statin users and matched nonusers.\n\nResultsThe hazard ratio (HR) for statin effectiveness on incident myocardial infarction was similar within 10-year atherosclerotic cardiovascular disease (ASCVD) risk score groups at 0.65 (95% confidence interval [CI] 0.39-1.08; P=0.10), 0.65 (95% CI 0.56-0.77; P=2.1E-7), and 0.67 (95% CI 0.57-0.80; P=4.3E-6) for borderline, intermediate, and high ASCVD groups, respectively. In contrast, statin effectiveness by polygenic risk was largest in the high polygenic risk score group (HR 0.62, 95% CI 0.50-0.77; P=1.4E-5), intermediate in the intermediate polygenic risk score group (HR 0.70, 95% CI 0.61-0.80; P=5.7E-7), and smallest in the low polygenic risk score group (HR 0.86, 95% CI 0.65-1.16; P=0.33). ASCVD risk and statin LDL-C lowering did not differ across polygenic risk score groups.\n\nConclusionsIn primary prevention patients undergoing routine care, CHD polygenic risk modified statin relative risk reduction of incident myocardial infarction independent of statin LDL-C lowering. Our findings extend prior work by identifying a subset of patients with attenuated clinical benefit from statins.","Topographic volume-standardization atlas of the human brain\nObjectiveSpecific anatomical patterns are seen in various diseases affecting the brain. Clinical studies on the topography of pathologies are often limited by the absence of a normalization of the prevalence of pathologies to the relative volume of the affected anatomical structures. A comprehensive reference on the relative volumes of clinically relevant anatomical structures serving for such a normalization, is currently lacking.\n\nMethodsThe analyses are based on anatomical high-resolution three-dimensional T1-weighted magnetic resonance imaging data of 30 healthy Caucasian volunteers, including 14 females (mean age 37.79 years, SD 13.04) and 16 males (mean age 38.31 years, SD 16.91). Semi-automated anatomical segmentation was used, guided by a neuroanatomical parcellation algorithm differentiating 96 structures. Relative volumes were derived by normalizing parenchymal structures to the total individual encephalic volume and ventricular segments to the total individual ventricular volume.\n\nResultsThe present investigation provides the absolute and relative volumes of 96 anatomical parcellation units of the human encephalon. A larger absolute volume in males than in females is found for almost all parcellation units. While parenchymal structures display a trend towards decreasing volumes with increasing age, a significant inverse effect is seen with the ventricular system. The variances in volumes as well as the effects of gender and age are given for each structure before and after normalization.\n\nConclusionThe provided atlas constitutes an anatomically detailed and comprehensive analysis of the absolute and relative volumes of the human encephalic structures using a clinically oriented parcellation algorithm. It is intended to serve as a reference for volume-standardization in clinical studies on the topographic prevalence of pathologies.","Prediction and predictor elucidation of the onset of metabolic syndrome among young workers using machine learning techniques: A nationwide study in Japan\nObjectivesPredictive models for the onset of metabolic syndrome (MS) among people in their 30s are scarce. This study aimed to construct a highly accurate model to predict MS onset by age 40 years and to identify the important predictors of MS onset using health checkup data of Japanese company employees aged 30 and 35.\n\nMethodsThe study included 6,048 Japanese employees aged 40 years who had undergone periodic health examinations over 10 years. We developed prediction models for MS onset using machine learning methods including the random forest and logistic regression, and evaluated the models using the receiver operating characteristics and precision-recall curves. For the random forest models, the variable importance of each explanatory variable was calculated to identify important predictors of MS onset.\n\nResultsThe random forest had higher predictive power than logistic regression in all models, although the differences were non-significant. Regarding important predictors, diastolic blood pressure was the most important predictor of MS onset for men aged 30 and 35 years, while body mass index was the most important predictor for women aged 30 and 35 years.\n\nConclusionsWe created a machine learning model to predict MS onset at age 40 with high accuracy from health examination data obtained at ages 30 or 35. Sex differences in important predictors of MS onset was shown by the variable importance indices of the random forest. Applying our model in routine healthcare management should provide early and appropriate health interventions to prevent MS onset in young people.","Incorporating the mutational landscape of SARS-COV-2 variants and case-dependent vaccination rates into epidemic models\nCoronavirus Disease (COVID-19), which began as a small outbreak in Wuhan, China in December 2019, became a global pandemic within months due to its high transmissibility. In the absence of pharmaceutical treatment, various non-pharmaceutical interventions (NPIs) to contain the spread of COVID-19 brought the entire world to a halt. After almost a year of seemingly returning to normalcy with the worlds quickest vaccine development, the emergence of more infectious and vaccine resistant coronavirus variants is bringing the situation back to where it was a year ago. In the light of this new situation, we conducted a study to portray the possible scenarios based on the three key factors : impact of interventions (pharmaceutical and NPIs), vaccination rate, and vaccine efficacy. In our study, we assessed two of the most crucial factors, transmissibility and vaccination rate, in order to reduce the spreading of COVID-19 in a simple but effective manner. In order to incorporate the time-varying mutational landscape of COVID-19 variants, we estimated a weighted transmissibility composed of the proportion of existing strains that naturally vary over time. Additionally, we consider time varying vaccination rates based on the number of daily new cases. Our method for calculating the vaccination rate from past active cases is an effective approach in forecasting probable future scenarios as it actively tracks peoples attitudes toward immunization as active cases change. Our simulations show that if a large number of individuals cannot be vaccinated by ensuring high efficacy in a short period of time, adopting NPIs is the best approach to manage disease transmission with the emergence of new vaccine breakthrough and more infectious variants.","The reliability of two prospective cortical biomarkers for pain: EEG peak alpha frequency and TMS corticomotor excitability\nMany pain biomarkers fail to move from discovery to clinical application, attributed to poor reliability and feasible classifications of at-risk individuals. Preliminary evidence has shown that higher pain sensitivity is associated with slow peak alpha frequency (PAF) and depression of corticomotor excitability (CME). The present study evaluated the reliability of these measures, specifically whether, over several days of pain, a) PAF remains stable and b) individuals show two stable and distinct CME responses: facilitation and depression. Seventy-five healthy participants were given an injection of nerve growth factor (NGF) into the right masseter muscle on Day 0 and Day 2, inducing sustained pain. Electroencephalography (EEG) to assess PAF and transcranial magnetic stimulation (TMS) to assess CME were recorded on Day 0, Day 2 and Day 5. PAF reliability was in the excellent range even without standard pre-processing and [~]2 minutes recording length. Moreover, two distinct and stable CME responses were demonstrated: facilitation and depression. These findings support the notion that PAF is a stable trait characteristic, with reliability unaffected by pain, and excellent reliability achievable with minimal pre-processing and [~]2 minutes recording, making it a readily translatable biomarker. Furthermore, the study showed novel evidence of two stable corticomotor adaptations to sustained pain. Overall, the study provides support for the reliability of PAF and CME as prospective cortical biomarkers.","Effects of medical school on mental health and sleep habits\nBACKGROUND and OBJECTIVESThis study aims to define changes in anxiety and depression among medical students while evaluating the association of sleep habits and other risk factors, including exercise habits and a diagnosis of chronic disease. The effect of the COVID-19 pandemic was also evaluated.\n\nDESIGNA cohort of first- and second-year medical students was evaluated longitudinally using survey methods to quantify changes from pre-medical school and summer break to each semester in medical school throughout years one and two.\n\nMETHODSData was analyzed using Generalized Linear Mixed Models (GLMMs) on the numeric responses of General Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and Pittsburg Sleep Quality Index. Additional assessments evaluated exercise habits, chronic disease, and impact of COVID-19 Pandemic.\n\nRESULTSDepression, anxiety, and sleep habits displayed a cyclical change that was associated with the academic cycle. The COVID-19 pandemic was never significant. Medical students who had a chronic disease diagnosis had increased severity. Exercise did not play a role.\n\nCONCLUSIONThe main driver for depression, anxiety, and poor sleep quality was the academic cycle, while the COVID-19 pandemic did not have an impact on mental health.","The Reliability and Validity of the Hebrew Patient Health Questionnaire (PHQ-9) in the General Population\nObjectiveTo assess the psychometric properties of the Hebrew version of the Patient Health Questionnaire (PHQ-9) in the general population.\n\nMethodsUsing an online survey, we assessed test-retest reliability with a two-week time interval. A total of 118 participants enrolled in the study, of whom 103 completed the survey twice. Each participant filled out the PHQ-9 and the 12-Item Short Form Survey (SF-12). Our statistical analysis includes Cronbachs alpha, Intraclass Correlation Coefficient (ICC2,1), Spearmans rank correlation coefficient, Standard Error of Measurement (SEM), and Minimal Detectable Change (MDC).\n\nResultsInternal consistency of the Hebrew version of the PHQ-9 ranged from =0.79-0.83. The test-retest reliability of the questionnaire is good (ICC2,1= 0.81), and it is moderately and negatively correlated to the mental component of the SF-12 (Spearman {rho}= -0.57, p< .05). The SEM of the PHQ-9 is 1.83 points, and the MDC was found to be 5 points.\n\nConclusionThe Hebrew version of the PHQ-9 is valid and reliable for screening self-reported depressive symptoms online in the general Hebrew-speaking population.","Proactive COVID-19 testing in a partially vaccinated population\nDuring the initial stages of the COVID-19 pandemic, many workplaces and universities implemented institution-wide proactive testing programs of all individuals, ir-respective of symptoms. These measures have proven effective in mitigating outbreaks. As a greater fraction of the population becomes vaccinated, we need to understand what continued benefit, if any, proactive testing can contribute. Here, we address this problem with two distinct modeling approaches: a simple analytical model and a more simulation using the SEIRS+ platform. Both models indicate that proactive testing remains useful until a threshold level of vaccination is reached. This threshold depends on the transmissibility of the virus and the scope of other control measures in place. If a community is able to reach the threshold level of vaccination, testing can cease. Otherwise, continued testing will be an important component of disease control. Because it is usually difficult or impossible to precisely estimate key parameters such as the basic reproduction number for a specific workplace or other setting, our results are more useful for understanding general trends than for making precise quantitative predictions.","The genetic architecture of human infectious diseases and pathogen-induced cellular phenotypes\nHere, we develop a genetics-anchored framework to decipher mechanisms of infectious disease (ID) risk and infer causal effect on potential complications. We perform transcriptome-wide association studies (TWAS) of 35 ID traits in 27,615 individuals in a broad collection of human tissues, identifying 70 gene-level associations with 26 ID traits, with replication in two large-scale biobanks. A phenome-scale scan and Mendelian Randomization of the 70 gene-level associations across 197 traits proposes a molecular basis for known complications of the ID traits. This rich resource of host genetic associations with pathogen cultures and 16S-rRNA-based microbiome variation provides a platform to investigate host-pathogen interactions. To identify relevant cellular processes, we develop a TWAS repository of 79 pathogen-exposure induced cellular phenotypes. Our study will facilitate mechanistic insights into the role of host genetic variation on ID risk and pathophysiology, with important implications for our molecular understanding of severe phenotypic outcomes.","Association between Systemic Lupus Erythematosus and Coronary Heart Disease: a retrospective case-control analysis and Mendelian Randomization Study\nObjectivesTo appraise the causal effect of systemic lupus erythematosus (SLE) for risk of Coronary heart disease (CHD).\n\nMethodsWe selected single nucleotide polymorphisms (SNPs) associated with SLE as instrumental variables (IVs) from three independent genome-wide association studies (GWAS), the three largest to date for SLE of European ancestry. Then we conducted two-sample Mendelian randomization (2SMR) analyses to estimate the effects of IVs on the odds of CHD and traditional coronary risk factors (including high LDL cholesterol levels, low HDL cholesterol levels, Apolipoprotein A-I, Apolipoprotein B, diabetes mellitus, and hypertension). Additionally, we searched for common risk loci between SLE and premature coronary atherosclerosis. Furthermore, we retrospectively reviewed the lipid profile of treatment-naive SLE patients and age-matched healthy controls.\n\nResultsGenetically predicted SLE did not increase the odds of CHD. Nevertheless, we found mild causal relationships between SLE and decreased HDL cholesterol levels, and between SLE and decreased apolipoprotein A-I. There was one common risk locus (rs597808) between SLE and premature coronary atherosclerosis at a genome-wide significance level (P<5 x 10-8). Retrospective analysis showed decreased HDL-cholesterol (0.98{+/-}0.516mmol/L vs. 1.46{+/-}0.307mmol/L in female, 0.76{+/-}0.199mmol/L vs. 1.19{+/-}0.257mmol/L in male; both P<0.001) and apolipoprotein A-I (1.06{+/-}0.314g/L vs. 1.37{+/-}0.205g/L in female, 0.87{+/-}0.174g/L vs. 1.24{+/-}0.200g/L in male; both P<0.001) in naive SLE patients.\n\nConclusionSLE may accelerate coronary atherosclerosis in young patients by reducing HDL cholesterol and apolipoprotein A-I intrinsically, but it seems not to play a predominant role in CHD development in old patients.","Addressing selection bias in the UK Biobank neurological imaging cohort\nThe UK Biobank is a national prospective study of half a million participants between the ages of 40 and 69 at the time of recruitment between 2006 and 2010, established to facilitate research on diseases of aging. The imaging cohort is a subset of UK Biobank participants who have agreed to undergo extensive additional imaging assessments. However, Fry et al. (2017) finds evidence of \"healthy volunteer bias\" in the UK Biobank - participants are less likely to smoke, be obese, consume alcohol daily than the target population of UK adults. Here we examine selection bias in the UK Biobank imaging cohort. We address two common misconceptions: first, that study size can compensate for bias in data collection, and second that selection bias does not affect estimates of associations, which are the primary interest of the UK Biobank. We introduce inverse probability weighting (IPW) as an approach commonly used in survey research that can be used to address selection bias in volunteer health studies like the UK Biobank. We discuss 6 such methods - five existing and one novel -, assess relative performance in simulation studies, and apply them to the UK Biobank imaging cohort. We find that our novel method, BART for predicting the probability of selection combined with raking, performs well relative to existing methods, and helps alleviate selection bias in the UK Biobank imaging cohort.","Metacognitive insight into cognitive performance in pre and early-stage Huntington's disease\nObjectivesInsight is an important predictor of quality of life in Huntingtons disease and other neurodegenerative conditions. However, estimating insight with traditional methods such as questionnaires is challenging and subject to limitations. This cross-sectional study experimentally quantified metacognitive insight into cognitive performance in Huntingtons disease gene-carriers.\n\nMethodsWe dissociated perceptual decision-making performance and metacognitive insight into performance in healthy controls (n=29), premanifest (n=19) and early-manifest (n=10) Huntingtons disease gene-carriers. Insight was operationalised as the degree to which a participants confidence in their performance was informative of their actual performance (metacognitive efficiency) and estimated using a computational model (HMeta-d).\n\nResultsWe found that pre and early-manifest Huntingtons disease gene-carriers were impaired in making perceptual decisions compared to controls. Gene-carriers required more evidence in favour of the correct choice to achieve similar performance and perceptual impairments were increased in those with manifest disease. Surprisingly, despite marked perceptual impairments, Huntingtons disease gene-carriers retained metacognitive insight into their perceptual performance. This was the case after controlling for confounding variables and regardless of disease stage.\n\nConclusionWe report for the first time a dissociation between impaired cognition and intact metacognition (trial-by-trial insight) in the early-stages of a neurodegenerative disease. This unexpected finding contrasts with the prevailing assumption that cognitive deficits are associated with impaired insight. Future studies should investigate how intact metacognitive insight could be used by some early Huntingtons disease gene-carriers to positively impact their quality of life.","Longitudinal DNA Methylation Profiling of the Rectal Mucosa Identifies Cell-specific Signatures of Disease Status, Severity and Clinical Outcomes in Ulcerative Colitis\nIn peripheral blood, DNA methylation (DNAm) patterns in inflammatory bowel disease patients reflect inflammatory status rather than disease status. Here, we studied DNAm in diseased rectal mucosa from ulcerative colitis (UC) patients, conducting a cell-type-specific EWAS in epithelial, immune and fibroblast cells to understand DNAm changes across disease states, course, and clinical outcomes. At diagnosis, rectal mucosa in UC exhibited a lower proportion of epithelial cells and fibroblasts, and higher proportion of immune cells, along with 3504, 910, and 2279 altered DNAm sites as detected in our cell-specific EWAS, respectively. While treatment had significant effects on DNAm of immune cells, its effects on fibroblasts and epithelial cells were attenuated. Those requiring colectomy exhibited cell composition and DNAm patterns at follow-up more like disease onset than patients who did not require colectomy. Collectively DNAm and gene expression analysis suggest that targeting epithelial genes involved in barrier function may improve clinical outcomes.","ADVANCED AUTOLOGOUS LOWER DERMAL SLING TECHNIQUE FOR IMMEDIATE BREAST RECONSTRUCTION SURGERY IN SMALL AND NON-PTOTIC BREASTS\nBackgroundBreast reconstruction with an autologous lower dermal sling (ALDS) is an established one-stage procedure in patients with moderate to large ptotic breasts. However, this technique is difficult to perform in small and non/minimally ptotic breasts. We describe our experiences from a single institution about a novel Advanced Autologous Lower Dermal Sling (A-ALDS) technique for reconstruction in small breasts.\n\nMethodsWe performed one stage nipple/skin sparing mastectomies in 61 patients with immediate reconstruction either by conventional immediate breast reconstruction surgery or A-ALDS technique.\n\nResultsMean age of study patients was 46.9 years. We observed significantly better cosmetic score and lower immediate complication rate vis-a-vis skin necrosis, implant loss with the A-ALDS technique (i.e., nil versus 3 in Conventional Immediate Breast Reconstruction Surgery - IBRS). 40 patients completed 12 months follow-up. The PROMs-Patient Reported Outcomes Measures (Breast-Q) revealed good to excellent scores for satisfaction with breast, cosmetic outcome and psychosocial well-being in patients operated with both these techniques. However, sexual well-being was significantly better in the A-ALDS group.\n\nConclusionThe A-ALDS is a novel, cost-effective and safe technique for immediate one stage implant-based reconstruction for small breasts. It provides a dermal barrier flap and hence, ensures less complications, excellent cosmetic results and patient satisfaction.","HIV testing uptake according to opt-in, opt-out or risk-based testing approaches: a systematic review and meta-analysis\nPurpose of reviewImproving HIV testing uptake is essential to ending the HIV pandemic. HIV testing approaches can be opt-in, opt-out or risk-based. This systematic review examines and compares the uptake of HIV testing in opt-in, opt-out and risk-based testing approaches.\n\nRecent findingsThere remains missed opportunities for HIV testing in a variety of settings using different approaches: opt-in (a person actively accepts to be tested for HIV), opt-out (a person is informed that HIV testing is routine/standard of care, and they actively decline if they do not wish to be tested for HIV) or risk-based (using risk-based screening tools to focus testing on certain individuals or sub-populations at greater risk of HIV). It is not clear how the approach could impact HIV test uptake when adjusted for other factors (e.g. rapid testing, country-income level, test setting and population tested).\n\nSummaryWe searched four databases for studies reporting on HIV test uptake. In total, 18,238 records were screened, and 150 studies were included in the review. Most studies described an opt-in approach (87 estimates), followed by opt-out (76) and risk-based (19). Opt-out testing was associated with 64.3% test uptake (I2=99.9%), opt-in testing with 59.8% (I2=99.9%), and risk-based testing with 54.4% (I2=99.9%). When adjusted for settings that offered rapid testing, country income level, setting and population tested, opt-out testing had a significantly higher uptake (+12% (95% confidence intervals: 3-21), p=0.007) than opt-in testing. We also found that emergency department patients and hospital outpatients had significantly lower HIV test uptake than other populations.","Analysis of communities of countries with similar dynamics of the COVID-19 pandemic evolution\nThis work addresses the spread of the coronavirus through a non-parametric approach, with the aim of identifying communities of countries based on how similar their evolution of the disease is. The analysis focuses on the number of daily new COVID-19 cases per ten thousand people during a period covering at least 250 days after the confirmation of the tenth case. Dynamic analysis is performed by constructing Minimal Spanning Trees (MST) and identifying groups of similarity in contagions evolution in 95 time windows of a 150-day amplitude that moves one day at a time. The number of times countries belonged to a similar performance group in constructed time windows was the intensity measure considered. Groups composition is not stable, indicating that the COVID-19 evolution needs to be treated as a dynamic problem in the context of complex systems. Three communities were identified by applying the Louvain algorithm. Identified communities analysis according to each countrys socioeconomic characteristics and variables related to the disease sheds light on whether there is any suggested course of action. Even when strong testing and tracing cases policies may be related with a more stable dynamic of the disease, results indicate that communities are conformed by countries with diverse characteristics. The best option to counteract the harmful effects of a pandemic may be having strong health systems in place,with contingent capacity to deal with unforeseen events and available resources capable of a rapid expansion of its capacity.","Covid-19 infection and attributable mortality in UK Long Term Care Facilities: Cohort study using active surveillance and electronic records (March-June 2020)\nBackgroundEpidemiological data on COVID-19 infection in care homes are scarce. We analysed data from a large provider of long-term care for older people to investigate infection and mortality during the first wave of the pandemic.\n\nMethodsCohort study of 179 UK care homes with 9,339 residents and 11,604 staff.We used manager-reported daily tallies to estimate the incidence of suspected and confirmed infection and mortality in staff and residents. Individual-level electronic health records from 8,713 residents were used to model risk factors for confirmed infection, mortality, and estimate attributable mortality.\n\nResults2,075/9,339 residents developed COVID-19 symptoms (22.2% [95% confidence interval: 21.4%; 23.1%]), while 951 residents (10.2% [9.6%; 10.8%]) and 585 staff (5.0% [4.7%; 5.5%]) had laboratory-confirmed infections. The incidence of confirmed infection was 152.6 [143.1; 162.6] and 62.3 [57.3; 67.5] per 100,000 person-days in residents and staff respectively. 121/179 (67.6%) care homes had at least one COVID-19 infection or COVID-19-related death. Lower staffing ratios and higher occupancy rates were independent risk factors for infection.\n\n217/607 residents with confirmed infection died (case-fatality rate: 35.7% [31.9%; 39.7%]). Mortality in residents with no direct evidence of infection was two-fold higher in care homes with outbreaks versus those without (adjusted HR 2.2 [1.8; 2.6]).\n\nConclusionsFindings suggest many deaths occurred in people who were infected with COVID-19, but not tested. Higher occupancy and lower staffing levels were independently associated with risks of infection. Protecting staff and residents from infection requires regular testing for COVID-19 and fundamental changes to staffing and care home occupancy.","Indoor Air Quality Intervention in Schools; Effectiveness of a Portable HEPA Filter Deployment in Five Schools Impacted by Roadway and Aircraft Pollution Sources\nThe Healthy Air, Healthy Schools Study was established in January 2020 to better understand the impact of ultrafine particles (UFP) on indoor air quality in communities surrounding Seattle-Tacoma (Sea-Tac) International Airport. The study team took multipollutant measurements indoor and outdoor air pollution at five participating school locations to infiltration indoors. The schools participating in this project were located within a 7-mile radius of Sea-Tac Airport and within 0.5 miles of an active flight path. Based on experimental measures in an unoccupied classroom, infiltration rates of a) Ultrafine particles of aircraft origin b) Ultrafine particles of traffic origin and c) Wildfire smoke or other outdoor pollutants were characterized before and after the introduction of a classroom based portable HEPA filter intervention. The portable HEPA cleaners were an effective short-term intervention to improve the air quality in classroom environments, reducing the ultrafine particles to approximately 1/10th of that measured outside. Before the HEPA filter deployment, approximately one-half of all outdoor UFPs were measured indoors. This study is unique in focusing on UFP in school settings and demonstrating through multivariate methods that the UFP measured in the classroom space is primarily of outdoor origin. Although existing research suggests that improvements to indoor air quality in homes can significantly improve asthma outcomes, further research is necessary to establish the benefit to student health and academic performance of improved air quality in schools.","Association of polycyclic aromatic hydrocarbons in moss with blood biomarker among nearby residents in Portland, Oregon\nPolycyclic aromatic hydrocarbons (PAHs) are a component of air pollutants that are costly to measure using traditional air-quality monitoring methods. We used an epiphytic bio-indicator (moss genus: Orthotrichum) to cost-effectively evaluate atmospheric deposition of PAHs in Portland, Oregon in May 2013. However, it is unclear if measurements derived from these bioindicators are good proxies for human exposure. To address this question, we simultaneously, measured PAH-DNA adducts in blood samples of non-smokers residing close to the sites of moss measurements. We accounted for individual determinants of PAH uptake that are not related to environmental air quality through questionnaires, e.g., wood fires, consumption of barbecued and fried meats. Correlation and linear regression (to control for confounders from the lifestyle factors) evaluated the associations. We did not observe evidence of an association between PAH levels in moss and PAH-DNA adducts in blood of nearby residents, but higher level of adduct were evident in those who used wood fire in their houses in the last 48 hours. It remains to be determined whether bio-indicators in moss can be used for human health risk assessment.\n\nHighlightsO_LIConcentration of PAH in moss do not relate to DNA adducts of PAH in blood of nearby residents in our sample.\nC_LIO_LIContent of moss may not be suitable for assessing exposure to PAH among humans.\nC_LI","Prevalence of Salivary IgA Reacting with SARS-CoV-2 among Japanese People Unexposed to the Virus\nWhile the COVID-19 pandemic caused by SARS-CoV-2 has posed a threat to public health as the number of cases and COVID-19-related deaths are increasing worldwide, the incidence of the virus infection are extremely low in Japan compared with many other countries. To explore the reason for this strange phenomenon, we hypothesized the high prevalence of \"natural\" secretory IgA in saliva as mucosal IgA reacting with SARS-CoV-2, and thus surveyed the positivity for, as well as levels of, such reactive salivary IgA in a cohort of Japanese people of a wide range of age. The major findings were that 95/180 (52.78 %) of overall individuals who had not been exposed to SARS-CoV-2 were positive for salivary IgA with the levels ranging from 0.002 to 3.272 ng/ml, and that there may be a negative trend in positivity for salivary IgA according to age. These results suggest a role of mucosal IgA in host defense against SARS-CoV-2 infection.\n\nOne Sentence Summary\"Natural\" secretory immunoglobulin A autoantibodies may play a role in mucosal defense against SARS-CoV-2.","The Understanding persistent Pain Where it ResiDes study of low back pain cohort profile\nBackgroundDespite chronic low back pain (LBP) being considered a biopsychosocial condition for diagnosis and management, few studies have investigated neurophysiological or neurobiological risk factors thought to underpin the transition from acute to chronic LBP. The aim of this cohort profile is to describe the methodology, compare baseline characteristics between acute LBP participants and pain-free controls, and compare LBP participants with or without completed follow-up.\n\nMethods120 individuals experiencing acute LBP and 57 pain-free controls were recruited to participate in the Understanding Persistent Pain Where it Resides (UPWaRD) study. Screening was conducted via email and phone. Neurobiological, psychological, and sociodemographic data were collected at baseline, three- and six-months. LBP status was assessed using the numerical rating scale and Roland-Morris disability questionnaire at three and six-month follow-up.\n\nResults95 participants (79%) provided outcome data at three-month follow-up and 96 participants (80%) at six-months. Participants who did not complete follow-up at three- and six-months within the UPWaRD LBP cohort had higher psychological distress, higher pain interference, higher levels of moderate physical activity, and reported occupational difficulties due to pain (P = <0.05). Compared to controls, LBP participants in the UPWaRD cohort were older, had a higher BMI, a higher prevalence of comorbidities and higher medication usage. Higher depression, anxiety and stress, lower pain self-efficacy and higher pain catastrophizing during acute LBP were correlated with higher six-month pain and disability (P = < 0.01).\n\nConclusionsThis cohort profile reports baseline characteristics of the UPWaRD LBP and pain-free control cohort.","Clonal chromosomal mosaicism and loss of chromosome Y in men are risk factors for SARS-CoV-2 vulnerability in the elderly\nThe ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) has an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome events (CME) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (CME and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, CME and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people.","Compartment-specific total RNA profile of Hippocampal and Cortical cells from Mesial Temporal Lobe Epilepsy tissue\nMesial temporal lobe epilepsy (mTLE) is a chronic neurological disease characterized by recurrent seizures. The pathogenic mechanisms underlying mTLE involve defects in post-transcriptional regulation of gene expression. So far, transcriptome profiles from epileptic tissue have been generated using whole cells, thereby lacking information on RNA localization and function at a subcellular level. In line with this, we have previously observed by in situ hybridization that a few microRNAs (miRNAs) display subcellular mis-localization with aberrant enrichment in the nucleus in human hippocampal mTLE tissue samples (Kan et al., 2012). To further investigate the possible mechanisms leading to the mis-localization of miRNAs, we set out to understand the compartment-specific total RNA (coding and non-coding) profile of human mTLE tissue samples. For this, we have successfully established a protocol to isolate cytoplasmic and nuclear compartments from human hippocampal tissue. After confirming the purity of the isolated cell compartments, we performed total RNA-sequencing (RNA-seq) on five resected hippocampal (HC) mTLE (no hippocampal sclerosis (non-HS)) samples and five HC postmortem control samples. Similarly, six neo-cortical (Cx) tissue samples from mTLE non-HS and HS International League Against Epilepsy (ILAE) Type 1, or mTLE+HS, samples were compared with six Cx postmortem controls. Our dataset provides a comprehensive overview of compartment-specific transcriptomic profiles of pharmacoresistant mTLE patient HC and Cx tissue, which in further studies can be used to investigate disease mechanisms.","Postoperative morbidity after liver resection- A Systemic review, meta-analysis, and metaregression of factors affecting them.\nAim of the studyThis systemic review and meta-analysis aimed to analyze post-operative morbidity after liver resection, and also study various factors associated with mortality via metaregression analysis.\n\nMaterial and MethodsPubMed, Cochrane Library, Embase, google scholar, web of science with keywords like liver resection\"; \"mortality\";\" hepatectomy\". Weighted percentage post-operative morbidities were analyzed. Meta-analysis and meta-regression were done by the DerSimonian-Liard random effect model. Heterogeneity was assessed using the Higgins I2 test. Publication bias was assessed using a funnel plot. Funnel plot asymmetry was evaluated by Eggers test. Morbidity was defined as any postoperative morbidity mentioned.\n\nResultsA total of 46 studies was included in the final analysis. Total 45771 patients underwent liver resections. 16111 patients experienced complications during the postoperative period. Weighted post-operative morbidity was 30.2% (95 % C.I. 24.8-35.7%). Heterogeneity was high with I2 99.46% and p-value <0.01. On univariate analysis, major liver resections were significantly associated with heterogeneity. (p=0.024). However, residual heterogeneity was still high with I2 98.62%, p<0.001. So, multifactor metaregression analysis major hepatectomy (p<0.001), Open hepatectomy (p=0.001), cirrhotic liver (p=0.002), age (p<0.001), blood loss (p<0.001), and colorectal metastasis (p<0.001) independently associated with postoperative morbidity. Residual heterogeneity was moderate I2= 39.9% and nonsignificant p=0.189.\n\nConclusionLiver resection is associated with high postoperative morbidity and various factors like major hepatectomy, Open hepatectomy, cirrhotic liver, blood loss, and colorectal metastasis were associated with morbidity and responsible for heterogeneity across the studies.","Analyzing human knockouts to validate GPR151 as a therapeutic target for reduction of body mass index\nNovel drug targets for sustained reduction in body mass index (BMI) are needed to curb the epidemic of obesity, which affects 650 million individuals worldwide and is a causal driver of cardiovascular and metabolic disease and mortality. Previous studies reported that the Arg95Ter nonsense variant of GPR151, an orphan G protein-coupled receptor, is associated with reduced BMI and reduced risk of Type 2 Diabetes (T2D). Here, we follow up on GPR151 with the Pakistan Genome Resource (PGR), which is one of the largest exome biobanks of human homozygous loss-of-function carriers (knockouts) in the world. Among PGR participants, we identify 3 GPR151 putative loss-of-function (plof) variants (Arg95Ter, Tyr99Ter, and Phe175LeufsTer7) with a cumulative allele frequency of 2.2% and present at homozygosity. We confirm these alleles in vitro as loss-of-function. We test if GPR151 plof is associated with BMI, T2D, or other metabolic traits. GPR151 deficiency in complete human knockouts is not associated with a clinically significant difference in BMI. Moreover, loss of GPR151 confers a nominally significant increase in risk of T2D (odds ratio = 1.2, p value = 0.03). Relative to wild-type mice, Gpr151-/- animals exhibit no difference in body weight on normal chow, and higher body weight on a high-fat diet, consistent with the findings in humans. Together, our findings indicate that GPR151 antagonism is not a compelling therapeutic approach for obesity.","Examining the Association between the COVID-19 Pandemic and Self-Harm Death Counts in Four Canadian Provinces\nGovernments implemented lockdowns and other physical distancing measures to stop the spread of SARS-CoV-2 (COVID-19). Resulting unemployment, income loss, poverty, and social isolation, coupled with daily reports of dire news about the COVID-19 pandemic, could serve as catalysts for increased self-harm deaths (SHD). This ecological study examined whether observed SHD counts were higher than predicted SHD counts during the pandemic period in the Canadian provinces of Alberta, British Columbia, Ontario, and Quebec. The study also explored whether SHD counts during the pandemic were affected by lockdown severity (measured using the lockdown stringency index [LSI]) and COVID-19 case numbers. We utilized publicly available SHD data from January 2018 through November 2020, and employed AutoRegressive Integrated Moving Average (ARIMA) modelling, to predict SHD during the COVID-19 period (March 21 to November 28, 2020). We used Poisson and negative binomial regression to assess ecological associations between the LSI and COVID-19 case numbers, controlling for seasonality, and SHD counts during the COVID-19 period. On average, observed SHD counts were lower than predicted counts during this period (p < 0.05 [except Alberta]). Additionally, LSI and COVID-19 case numbers were not statistically significantly associated with SHD counts.","P. acnes qPCR-based antibiotics resistance assay (ACQUIRE) reveals widespread macrolide resistance in acne patients and can eliminate macrolide misuse in acne treatment\nBackgroundMacrolides have been widely used to treat moderate-to-severe acne for more than 50 years. However, prevalent antibiotic resistance of Propionibacterium acnes, along with the absence of clinically available resistance tests, has made macrolide misuse a frequent occurrence, with serious consequences.\n\nObjectiveWe developed P. acnes qPCR-based antibiotics resistance assay (ACQUIRE) to enable fast and accurate detection of P. acnes macrolide resistance in clinical settings, representing an opportunity to administer antibiotics more wisely and improve the quality of care.\n\nMethodsA cross-sectional observational study was conducted to probe into the macrolide resistance of P. acnes in acne patients.\n\nResultsThe high sensitivity of ACQUIRE enabled us to reveal a much higher P. acnes 23S rDNA point mutation rate (52%) and thus a higher macrolide resistance (75.5%) compared to previous reports. Carriage of ermX gene was discovered on 472 (53%) subjects, which concurs with previous studies.\n\nConclusionMacrolide resistance of P. acnes is much higher than previously reported.","Machine learning approaches for electronic health records phenotyping: A methodical review\nObjectiveAccurate and rapid methods for phenotyping are a prerequisite to realizing the potential of electronic health records (EHRs) data for clinical and translational research. This study reviews the literature on machine learning (ML) approaches for phenotyping with respect to the phenotypes considered, the data sources and methods used, and the contributions within the wider context of EHR-based research.\n\nMaterials and MethodsWe searched for relevant articles in PubMed and Web of Science published between January 1, 2018 and April 14, 2022. After screening, we collected data on 52 variables across 106 selected articles.\n\nResultsML-based methods were developed for 156 unique phenotypes, primarily using EHR data from a single institution or health system. 72 of 106 articles leveraged unstructured data in clinical notes. In terms of methodology, supervised learning is the most prevalent ML paradigm (n = 64, 60.4%), with half of the articles employing deep learning. Semi-supervised and weakly-supervised approaches were applied to reduce the burden of obtaining gold-standard labeled data (n = 21, 19.8%), while unsupervised learning was used for phenotype discovery (n = 20, 18.9%). Federated learning has been applied to develop algorithms across multiple institutions while preserving data privacy (n = 2, 1.9%).\n\nDiscussionWhile the use of ML for phenotyping is growing, most articles applied traditional supervised ML to characterize the presence of common, chronic conditions.\n\nConclusionContinued research in ML-based methods is warranted, with particular attention to the development of advanced methods for complex phenotypes and standards for reporting and evaluating phenotyping algorithms.","Financial Meltdown in Swing Hospitals during the COVID-19 Outbreak\nHospitals in Japan have complete autonomy in deciding whether to admit COVID-19 patients, similar to that of the US. Taking this into account, we estimated the effect of admitting COVID-19 patients on hospital profits, using instrumental variable (IV) regression. Using IVs related to government intervention enabled us to not only estimate the effect of admitting COVID-19 patients among \"swing hospitals,\" where both options (to admit or to not admit COVID-19 patients) could potentially be realized but to also evaluate the effect of government intervention on such hospitals. Our empirical results revealed that monthly profits per bed decreased by approximately JPY 600,000 ({approx} USD 6,000) among swing hospitals, which is 15 times the average monthly profits in 2019. This overwhelming financial damage indicates that it would be costly for swing hospitals to treat COVID-19 patients because of their low suitability for admitting such patients. Given the implications of our main results, we propose an alternative strategy to handling surges in patients with new infectious diseases.","JIA patient T cells differentiate into Th1, Th17 and Th1.17 effector cells under Th1 polarizing conditions\nObjectiveT helper cells develop into discrete Th1, Th2 or Th17 lineages that selectively express IFN{gamma}, IL-4/IL-5/IL-13, or IL-17, respectively and actively silence signature cytokines expressed by opposing lineages. Our objective was to compare Th1, Th2 and Th17 polarization in cell culture models using JIA patient samples.\n\nMethodsPeripheral blood mononuclear cells were isolated from JIA or healthy prepubescent children. T cell naive and memory phenotypes were assessed by flow cytometry. T cell proliferation was measured using a fluorescence-based assay. Th cell cultures were generated in vitro and IFN{gamma}, IL-17, and TNF measured by ELISA and flow cytometry.\n\nResultsJIA Th1 cells produced increased IFN{gamma} and inappropriately produced IL-17. JIA Th17 cells produced increased IL-17. JIA Th1 cell cultures develop dual producers of IFN{gamma} and IL-17, which are Th1.17 cells. JIA Th1 cultures expressed elevated levels of both T-bet and ROR{gamma}T. RNA sequencing confirmed activation of immune responses and inappropriate activation of IL-17 signaling pathways in Th1 cultures. A subset of JIA patient samples was disproportionally responsible for the enhanced IFN{gamma} and IL-17 phenotype and Th1.17 phenotype.\n\nConclusionsThis study reveals that JIA patient uncommitted T cell precursors, but not healthy children, inappropriately develop into inflammatory effector Th1.17 and Th17 cells under Th1 polarizing conditions.\n\nRheumatology key messagesO_LITh1 differentiation of JIA PBMCs generates high IFN{gamma}, IL-17, and dual IFN{gamma}-IL-17 producing cells.\nC_LIO_LIJIA Th1 differentiation increases master transcription factor expression for Tbet and ROR{gamma}T.\nC_LIO_LIEnhanced JIA Th1 IFN{gamma} and IL-17 production occurs in a subset of JIA patients.\nC_LI","Association between Functional Inhibitors of Acid Sphingomyelinase and Reduced Risk of Intubation or Death in Individuals Hospitalized for Severe COVID-19: results from an observational multicenter study\nSeveral medications commonly used for a number of medical conditions share a property of functional inhibition of acid sphingomyelinase (ASM), or FIASMA. Preclinical and clinical evidence suggest that the (ASM)/ceramide system may be central to SARS-CoV-2 infection. We examined the potential usefulness of FIASMA use among patients hospitalized for severe COVID-19 in an observational multicenter retrospective study conducted at Greater Paris University hospitals. Of 2,846 adult patients hospitalized for severe COVID-19, 277 (9.7%) were taking a FIASMA medication at the time of their hospital admission. The primary endpoint was a composite of intubation and/or death. We compared this endpoint between patients taking vs. not taking a FIASMA medication in time-to-event analyses adjusted for sociodemographic characteristics and medical comorbidities. The primary analysis was a Cox regression model with inverse probability weighting (IPW). Over a mean follow-up of 9.2 days (SD=12.5), the primary endpoint occurred in 104 patients (37.5%) who were taking a FIASMA medication, and 1,060 patients (41.4%) who were not. Taking a FIASMA medication was associated with reduced likelihood of intubation or death in both crude (HR=0.71; 95%CI=0.58-0.87; p<0.001) and the primary IPW (HR=0.58; 95%CI=0.46-0.72; p<0.001) analyses. This association remained significant in multiple sensitivity analyses and was not specific to one FIASMA class or medication. These results show the potential importance of the ASM/ceramide system as a treatment target in COVID-19. Double-blind controlled randomized clinical trials of these medications for COVID-19 are needed.","Open label phase I/II clinical trial and predicted efficacy of SARS-CoV-2 RBD protein vaccines SOBERANA 02 and SOBERANA Plus in children\nObjectivesTo evaluate heterologous scheme in children 3-18 y/o using two SARS-CoV-2 r-RBD protein vaccines.\n\nMethodsA phase I/II open-label, adaptive and multicenter trial evaluated the safety and immunogenicity of two doses of SOBERANA02 and a heterologous third dose of SOBERANA Plus in 350 children 3-18 y/o in Havana Cuba. Primary outcomes were safety (in phase I) and safety/immunogenicity (in phase II) measured by anti-RBD IgG ELISA, molecular and live-virus neutralization tests and specific T-cells response. An immunobridging and prediction of efficacy were additional analysis.\n\nResultsLocal pain was the unique adverse event with >10% frequency, none was serious or severe. Two doses of SOBERANA 02 elicited humoral immune response similar to natural infection; the third dose increased significantly the response in all children, similar to that achieved in vaccinated young adults and higher than in convalescents children. The neutralizing titer was evaluated in a participants subset: all had neutralizing antibodies vs. alpha and delta; 97.9% vs. beta. GMT was 173.8 (CI 95% 131.7; 229.5) vs. alpha, 142 (CI 95% 101.3; 198.9) vs. delta and 24.8 (CI 95% 16.8; 36.6) vs. beta. An efficacy over 90% was estimated.\n\nConclusionHeterologous scheme was safe and immunogenic in children 3-18 y/o. Trial registry: https://rpcec.sld.cu/trials/RPCEC00000374","Validation of the short Mood and Feelings Questionnaire in young adulthood\nBackgroundDepression often onsets in adolescence and is associated with recurrence in adulthood. There is a need to identify and monitor depression symptoms across adolescence and into young adulthood. The short Mood and Feelings Questionnaire (sMFQ) is commonly used to measure depression symptoms in adolescence but has yet to be validated in young adulthood. This study aimed to (1) examine whether the sMFQ is a valid assessment of depression in young adults, and (2) identify cut-points that best capture a DSM-5 diagnosis of depression at age 25.\n\nMethodsThe sample included young people who took part in the Avon Longitudinal Study of Parents and Children (ALSPAC) at age 25 (n=4098). Receiver Operating Characteristic analyses were used to examine how well the self-rated sMFQ discriminates between cases and non-cases of DSM-5 Major Depressive Disorder (MDD) classified using the self-rated Development and Well Being Assessment. Sensitivity and specificity values were used to identify cut-points on the sMFQ.\n\nResultsThe sMFQ had high accuracy for discriminating MDD cases from non-cases at age 25. The commonly used cut-point in adolescence ([≥]12) performed well at this age, best balancing sensitivity and specificity. However, a lower cut-point ([≥]10) may be appropriate in some contexts, e.g. for screening, when sensitivity is favoured over specificity.\n\nLimitationsALSPAC is a longitudinal population cohort that suffers from non-random attrition.\n\nConclusionsThe sMFQ is a valid measure of depression in young adults in the general population. It can be used to screen for and monitor depression across adolescence and early adulthood.","Effective connectivity during faces processing in major depression: Distinguishing markers of pathology, risk, and resilience\nBackgroundAberrant brain connectivity during emotional processing, especially within the fronto-limbic pathway, is one of the hallmarks of major depressive disorder (MDD). However, a lack of systematic approaches in previous studies made it difficult to determine whether a specific alteration in brain connectivity reflects a cause, correlate, or effect of the disorder. The current study aimed to investigate neural mechanisms that correspond to disease, risk and resilience in major depression during implicit processing of emotion cues.\n\nMethodsForty-eight patients with MDD, 49 first-degree relatives of patients with MDD and 103 healthy controls performed a face-matching task during functional magnetic resonance imaging. We used dynamic causal modelling to estimate task-dependent effective connectivity at the subject level. Parametric empirical Bayes was then performed to quantify group differences in effective connectivity.\n\nResultsDepressive pathology was associated with decreased effective connectivity from the left amygdala and left dorsolateral prefrontal cortex to the right fusiform gyrus, whereas familial risk for depression corresponded to decreased connectivity from the right orbitofrontal cortex to the left insula and from the left orbitofrontal cortex to the right fusiform gyrus. Resilience for depression was related to increased connectivity from the anterior cingulate cortex to the left dorsolateral prefrontal cortex.\n\nConclusionsOur results suggest that the depressive state alters top-down control of higher visual regions during the processing of emotional faces, whereas increased connectivity within the cognitive control network promotes resilience to depression.","Mitochondrial genome copy number measured by DNA sequencing in human blood is strongly associated with metabolic traits via cell-type composition differences\nMitochondrial genome copy number (MT-CN) varies among humans and across tissues and is highly heritable, but its causes and consequences are not well understood. When measured by bulk DNA sequencing in blood, MT-CN may reflect a combination of the number of mitochondria per cell and cell type composition. Here, we studied MT-CN variation in blood-derived DNA from 19,184 Finnish individuals using a combination of genome (N = 4,163) and exome sequencing (N = 19,034) data as well as imputed genotypes (N = 17,718). We identified two loci significantly associated with MT-CN variation: a common variant at the MYB-HBS1L locus (P = 1.6x10-8), which has previously been associated with numerous hematological parameters; and a burden of rare variants in the TMBIM1 gene (P = 3.0x10-8), which has been reported to protect against non-alcoholic fatty liver disease. We also found that MT-CN is strongly associated with insulin levels (P = 2.0x10-21) and other metabolic syndrome (metS) related traits. Using a Mendelian randomization framework, we show evidence that MT-CN measured in blood is causally related to insulin levels. We then applied an MT-CN polygenic risk score (PRS) derived from Finnish data to the UK Biobank, where the association between the PRS and metS traits was replicated. Adjusting for cell counts largely eliminated these signals, suggesting that MT-CN affects metS via cell type composition. These results suggest that measurements of MT-CN in blood-derived DNA partially reflect differences in cell-type composition and that these differences are causally linked to insulin and related traits.","Heterogeneous Mental Health Development During the COVID-19 Pandemic in the United Kingdom\nThe COVID-19 pandemic and the mitigation measures by governments have upended the economic and social lives of many, leading to widespread psychological distress. We explore heterogeneity in trajectories of psychological distress during the pandemic in the United Kingdom and relate this heterogeneity to socio-demographic and health factors. We analyze nine waves of longitudinal, nationally representative survey data from the UK Household Longitudinal Study (N =15,914), covering the period from early 2020 to mid-2021. First, latent class mixture modelling (LCCM) is used to identify trajectories of psychological distress. Second, associations of the trajectories with covariates are tested with multinomial logistic regressions. We find four different trajectories of distress: continuously low, temporarily elevated, repeatedly elevated, and continuously elevated distress. Nearly two fifths of the population experienced severely elevated risks of distress during the pandemic. Long-term distress was highest among younger people, women, people living without a partner, those who had no work or lost income, and those with previous health conditions or COVID-19 symptoms. Given the threat of persistent stress on health, policy measures should be sensitized to the unintended yet far-reaching consequences of non-pharmaceutical interventions.","Social connectedness as a determinant of mental health: A scoping review\nPublic health and epidemiologic research have established that social connectedness promotes overall health. Yet there have been no recent reviews of findings from research examining social connectedness as a determinant of mental health. The goal of this review was to evaluate recent longitudinal research probing the effects of social connectedness on depression and anxiety symptoms and diagnoses in the general population. A scoping review was performed of PubMed and PsychInfo databases from January 2015 to December 2020 following PRISMA-ScR guidelines using a defined search strategy. The search yielded 56 articles representing 52 unique studies. In research with other than pregnant women, 84% (16 of 19) studies reported that social support benefited symptoms of depression with the remaining 16% (3 of 19) reporting minimal or no evidence that lower levels of social support predict depression at follow-up. In research with pregnant women, 80% (21 of 26 studies) found that low social support increased postpartum depressive symptoms. Among 3 of 4 studies that focused on loneliness, feeling lonely at baseline was related to adverse outcomes at follow-up including higher risks of major depressive disorder, depressive symptom severity, generalized anxiety disorder, and lower levels of physical activity. In 5 of 7 reports, smaller social network size predicted depressive symptoms or disorder at follow-up. In summary, most recent relevant longitudinal studies have demonstrated that social support protects adults in the general population from depressive symptoms and disorders. The results, which were largely consistent across settings, exposure measures, and populations, support efforts to improve clinical detection of high-risk patients, including adults with low social support and elevated loneliness.","Evaluation of chest X-Ray with automated interpretation algorithms for mass tuberculosis screening in prisons.\nRationaleThe World Health Organization (WHO) recommends systematic tuberculosis (TB) screening in prisons. Evidence is lacking for accurate and scalable screening approaches in this setting.\n\nObjectivesTo assess the diagnostic accuracy of artificial intelligence-based chest x-ray interpretation algorithms for TB screening in prisons.\n\nMethodsProspective TB screening study in three prisons in Brazil from October 2017 to December 2019. We administered a standardized questionnaire, performed chest x-ray in a mobile unit, and collected sputum for confirmatory testing using Xpert MTB/RIF and culture. We evaluated x-ray images using three algorithms (CAD4TB version 6, LunitTB and qXR) and compared their diagnostic accuracy. We utilized multivariable logistic regression to assess the effect of demographic and clinical characteristics on algorithm accuracy. Finally, we investigated the relationship between abnormality scores and Xpert semi-quantitative results.\n\nMeasurements and Main ResultsAmong 2,075 incarcerated individuals, 259 (12.5%) had confirmed TB. All three algorithms performed similarly overall with AUCs of 0.87-0.91. At 90% sensitivity, only LunitTB and qXR met the WHO Target Product Profile requirements for a triage test, with specificity of 84% and 74%, respectively. All algorithms had variable performance by age, prior TB, smoking, and presence of TB symptoms. LunitTB was the most robust to this heterogeneity, but nonetheless failed to meet the TPP for individuals with previous TB. Abnormality scores of all three algorithms were significantly correlated with sputum bacillary load.\n\nConclusionsAutomated x-ray interpretation algorithms can be an effective triage tool for TB screening in prisons. However, their specificity is insufficient in individuals with previous TB.","Inter-population differences of allele frequency and regulome tagging are associated with the heterogeneity of loci identified by cross-ancestry genome-wide association studies\nTo provide novel insight regarding the inter-population diversity of loci associated with complex traits, we integrated genome-wide data from UK Biobank (UKB) and 1,000 Genomes Project (1KG) data representative of the genetic diversity among worldwide populations. We investigated genome-wide data of 4,359 traits from 361,194 UKB participants of European descent. Using 1KG data, we explored the allele frequency differences and linkage disequilibrium (LD) structure of UKB genome-wide significant (GWS) loci across worldwide populations. Functional annotation data were used to identify regulatory elements and evaluate the tagging properties of GWS variants. No significant difference was observed in allele frequency between UKB and 1KG GBR (British in England and Scotland). Considering other population groups, we identified genome-wide significant alleles with frequencies different from what expected by chance: UKB vs. 1KG Europeans without GBR (rs74945666; allele=T [0.908 vs. 0.03], standing height pGWAS=1.48x10-17), UKB vs. 1KG African (rs556562; allele=A [0.942 vs. 0.083], platelet count pGWAS=4.84x10-15), UKB vs. 1KG Admixed Americans (rs1812378; allele=T [0.931 vs. 0.089], standing height pGWAS=4.23x10-12), UKB vs. 1KG East Asian (rs55881864; allele=T [0.911 vs. 0.001], monocyte count pGWAS=7.29x10-13), and UKB vs. South Asian (rs74945666; allele=T [0.908 vs. 0.061], standing height pGWAS=1.48x10-17). LD-structure analysis and computational prediction showed differences in how these alleles tag functional elements across human populations. In conclusion, the human diversity of certain GWS loci appear to be affected by local adaptation while in other cases the associations may be biased by residual population stratification.","Genome-wide association study of liking of physical activity in the UK Biobank\nA lack of physical activity (PA) is one of the most pressing health issues facing society today. Our individual propensity for PA is partly influenced by genetic factors. Stated liking of various PA behaviors may capture additional dimensions of PA behavior that are not captured by other measures, and contribute to our understanding of the genetics of PA behavior. Here, in over 157,000 individuals from the UK Biobank, we sought to complement and extend previous findings on the genetics of PA behavior by performing genome-wide association studies of self-reported liking of several PA-related behaviors plus an additional derived trait of overall PA-liking. We identified a total of 19 unique genome-wide significant loci across all traits, only four of which overlap with loci previously identified for PA behavior. The PA-liking traits were genetically correlated with self-reported (rg: 0.38 - 0.80) and accelerometry-derived (rg: 0.26 - 0.49) PA measures, and with a wide range of health-related traits and dietary behaviors. Replication in the Netherlands Twin Register (NTR; n>7,300) and the TwinsUK (n>1,300) study revealed directionally consistent associations. Polygenic risk scores (PRS) were then trained in UKB for each PA-liking trait and for self-reported PA behavior. The PA-liking PRS significantly predicted the same liking trait in NTR. The PRS for liking of going to the gym predicted PA behavior in NTR (r2 = 0.40%) nearly as well as the one constructed based on self-reported PA behavior (r2 = 0.42%). Combining the two PRS into a single model increased the r2 to 0.59%, suggesting that although these PRS correlate with each other, they are also capturing distinct dimensions of PA behavior. In conclusion, we have identified the first loci associated with PA-liking, and extended and refined our understanding of the genetic basis of PA behavior.","Indexing Cerebrovascular Health Using Near-infrared Spectroscopy\nNear-infrared spectroscopy (NiRS) is a relatively new technology of brain imaging with its potential in the assessment of cerebrovascular health only recently discovered. Encouraging early results suggest that NiRS can be used as an inexpensive and portable cerebrovascular health tracking device using a recently proposed pulse relaxation function (PReFx). In this paper, we propose a new NiRS timing index, TINiRS, of cerebrovascular health. TINiRS is a novel use of the NiRS technology. TINiRS is motivated by the previously proved relationship of the timing of the reflected wave with vascular resistance and compliance in the context of pressure waveforms. We correlated both TINiRS and PReFx against age, a non-exercise cardiorespiratory fitness (CRF) index, and two existing indices of cerebrovascular health, namely Transcranial Doppler (TCD) augmentation index, AITCD, and magnetic resonance imaging (MRI) blood flow pulsatility index, PIMRI. The TINiRS correlations with Age, CRF, PIMRI and AITCD all are significant, i.e., r = 0.53 (p = 0.002), r = -0.44 (p = 0.011), r = 0.45 (p = 0.012) and r = 0.46 (p = 0.010), respectively. PReFx, however, did not have significant correlations with any of the vascular health factors. The proposed timing index is a reliable indicator of cerebrovascular aging factors in the NiRS waveform.","Irremediable psychiatric suffering in the context of medical assistance in dying: a qualitative study\nBackgroundEstablishing irremediability is a central challenge in determining the appropriateness of medical assistance in dying (MAID) for patients with a psychiatric disorder. The objective of this study is to learn how experienced psychiatrists define irremediable psychiatric suffering (IPS) in the context of MAID and what challenges they face while establishing IPS.\n\nMethodsIn a qualitative study, we performed 11 in-depth interviews with psychiatrists who have experience assessing IPS in the context of MAID.\n\nResultsAlthough determining IPS is, essentially, a prospective assessment, psychiatrists mostly rely on retrospective dimensions, such as the history of failed treatments, when defining IPS. When establishing IPS, psychiatrists face diagnosis and treatment challenges. The main challenge regarding diagnosis is that patients requesting MAID are often diagnosed with more than one psychiatric disorder. Important treatment related challenges are: assessing the quality of past treatments, establishing the limits of approaches that aim to alter the patients perception, and managing treatment fatigue and treatment refusal.\n\nInterpretationIPS is mostly defined in terms of failed past treatments. Challenges regarding diagnosis and treatment complicate the process of establishing IPS. The finding that most patients are diagnosed with more than one psychiatric disorder calls for a critical appraisal of the due diligence procedure for MAID. In response to the challenges related to treatment, intersubjective clinical criteria for IPS in the context of MAID should be developed. Also, further investigation of the concept of treatment fatigue in psychiatry may provide insight into why patients requesting MAID.\n\nRegistrationthis study was preregistered under osf.io/2jrnd.","Population-split-based risk assessment model of venous thromboembolism in Chinese medical inpatients\nAbstractsO_ST_ABSObjectiveC_ST_ABSInpatients with high risk of venous thromboembolism (VTE) usually face serious threats to their health and economic conditions. Many studies using machine learning (ML) models to predict VTE risk neglected an important statistical phenomenon, fuzzy feature, and achieved inferior results. Considering the effect of fuzzy feature, our study aims to develop a VTE risk assessment model suitable for Chinese medical inpatients.\n\nMaterials and MethodsInpatients in the medical department of Peking Union Medical College Hospital (PUMCH) from January 2014 to June 2016 were collected. A new ML VTE risk assessment model was built through population splitting. First patients were classified into different groups based on values of VTE risk factors, then trustless groups were filtered out, and finally ML models were built on training data in unit of groups. Predictive performances of our method, five traditional ML models, and the Padua model were compared.\n\nResultsThe fuzzy feature was verified on the whole dataset. Compared with the Padua model, the proposed model showed higher sensitivities and specificities on training data, and higher specificities and similar sensitivities on test data. Standard deviations of predictive validity of five ML models were larger than the proposed model.\n\nDiscussionThe proposed model was the only one which showed advantages on both sensitivity and specificity over Padua model. Its robustness was better than traditional ML models.\n\nConclusionThis study built a population-split-based ML model of VTE for Chinese medical inpatients and it may help clinicians stratify VTE risk and guide prevention more efficiently.","A cross-sectional study of psychosocial factors and sickness presenteeism in Japanese workers during the COVID-19 pandemic\nBackgroundWe examined the association between socioeconomic and health status, and lifestyle and sickness presenteeism among Japanese workers during the COVID-19 epidemic.\n\nMethodsA cross-sectional study using an Internet-monitor survey was conducted in December, 2020 in Japan. Of 33,302 survey participants, we analyzed 27,036 participants (13,814 men and 13,222 women) who reported experience with sickness presenteeism.\n\nResultsThe odds ratio (OR) of sickness presenteeism associated with unmarried versus married status was 1.15. Respective figures for other variables were 1.11 for manual laboring work compared to desk work; 1.79 and 2.29 for loss of employment at the time the pandemic began and continuation of unemployment compared to maintaining employment during the pandemic; and 3.34 for a feeling of financial instability compared to stability.\n\nConclusionThe issue of sickness presenteeism has become more prominent under the COVID-19 epidemic.","Occupational versus community risk of SARS-CoV-2 infection among employees of a long-term care facility: an observational study\nObjectivesWe investigated the relative contribution of occupational (vs. community) exposure for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among employees of a university-affiliated long-term care facility (LTCF), during the 1st pandemic wave in Switzerland (March to June 2020).\n\nMethodsWe performed a nested analysis of a seroprevalence study among all volunteering LTCF staff to determine community and nosocomial risk factors for SARS-CoV-2 seropositivity using modified Poison regression. We also combined epidemiological and genetic sequencing data from a coronavirus disease 2019 (COVID-19) outbreak investigation in a LTCF ward to infer transmission dynamics and acquisition routes of SARS-CoV-2, and evaluated strain relatedness using a maximum likelihood phylogenetic tree.\n\nResultsAmong 285 LTCF employees, 176 participated in the seroprevalence study, of whom 30 (17%) were seropositive for SARS-CoV-2. Most (141/176, 80%) were healthcare workers (HCWs). Risk factors for seropositivity included exposure to a COVID-19 inpatient (adjusted prevalence ratio [aPR] 2.6; 95%CI 0.9-8.1) and community contact with a COVID-19 case (aPR 1.7; 95%CI 0.8-3.5). Among 18 employees included in the outbreak investigation, the outbreak reconstruction suggests 4 likely importation events by HCWs with secondary transmissions to other HCWs and patients.\n\nConclusionsThese two complementary epidemiologic and molecular approaches suggest a substantial contribution of both occupational and community exposures to COVID-19 risk among HCWs in LTCFs. These data may help to better assess the importance of occupational health hazards and related legal implications during the COVID-19 pandemic.","Airway management, procedural data, and mortality records of patients undergoing surgery for mucormycosis associated with coronavirus disease (COVID-19)\nIn India, the second wave of coronavirus disease (COVID -19) was associated with a distinct surge in cases of invasive fungal infection with mucormycosis. This disease was seen typically in the sinonasal form in COVID-19 patients. Uncontrolled diabetes, steroid use in COVID-19 treatment, etc. were some of the postulated risk factors for the association of COVID 19 and Mucormycosis. The management plan of these cases included surgical debridement, systemic antifungal therapy, sugar control, and management of antifungal related systemic adverse effects. In this retrospective case record review, we aimed to evaluate the airway management plan, demographics, and overall outcomes in patients undergoing surgical resection for COVID-19 associated mucormycosis. Forty-one (71.9 %) patients had a diagnosis of sino-nasal mucormycosis, fourteen (24.6%) had a diagnosis of rhino-orbital mucormycosis, and 2 patients (3.5%) were diagnosed with palatal mucormycosis. Total 44 (77.19 %) patients had co-morbidities. The most common co-morbidity was Diabetes Mellitus 42 (73.6%), followed by hypertension 21 (36.84%) and Acute kidney injury 14 (28.07%). We used the intubation difficulty scale score to assess intubating conditions. Intubation was easy to slightly difficult in 53 out of 57 patients. In our study, mortality occurred in 7 (12.28 %) patients. The median mortality time was 60 (range, 27-74) days. The median time to hospital discharge was 53.5 (range,10-85) days. Managing COVID-19 on its own is challenging and additional mucormycosis can lead to increased morbidity and mortality. Despite challenges and risks, timely and meticulous interventions can reduce complications.","Associations between antipsychotic use, substance use and relapse risks in patients with schizophrenia - real-world evidence from two national cohorts\nBackgroundResearch on the effectiveness of pharmacotherapies for schizophrenia-substance use disorder comorbidity (Sch-SUD) is very sparse and non-existent on the prevention of the development of substance use disorders (SUD) in patients with schizophrenia.\n\nAimsTo compare the real-world effectiveness of antipsychotics in schizophrenia in decreasing risks of: 1) development of an initial SUD; and 2) psychiatric hospitalization and hospitalization due to SUD among patients with SUD.\n\nMethodsTwo independent national cohorts including all persons diagnosed with schizophrenia (N=45,476) were followed up for 22 (Finland: 1996-2017) and 11 years (Sweden: 2006-2016). Risks of developing SUD were calculated with between-individual models, and risks of psychiatric and SUD hospitalization with within-individual models using Cox regression and adjusted Hazard Ratios (aHRs) when using vs. not using certain antipsychotics.\n\nResultsFor schizophrenia patients without SUDs, clozapine use (aHR 0.20, 95%CI 0.16-0.24, p<0.001, in Finland; 0.35, 0.24-0.50, p<0.001, in Sweden) was associated with lowest risks of developing an initial SUD in both countries. Antipsychotic polytherapy was associated with second lowest risk (0.54, 0.44-0.66) in Sweden, and third lowest risk (0.47, 0.42-0.53) in Finland. Risks of psychiatric hospitalization and hospitalization due to SUD were lowest during use of clozapine, antipsychotic polytherapy, and long-acting injectables in both countries. Results were consistent across both countries.\n\nConclusionClozapine and antipsychotic polytherapy are most strongly associated with reduced chances of developing SUDs among patients with schizophrenia and with lower relapse rates among patients with both diagnoses.","Estimating the asymptomatic proportion of SARS-CoV-2 infection in the general population: Analysis of a nationwide serosurvey in the Netherlands\nBackgroundThe proportion of SARS-CoV-2 positive persons who are asymptomatic - and whether this proportion is age-dependent - are still open research questions. Because an unknown proportion of reported symptoms among SARS-CoV-2 positives will be attributable to another infection or affliction, the observed, or crude proportion without symptoms may underestimate the proportion of persons without symptoms that are caused by SARS-CoV-2 infection.\n\nMethodsBased on a large population-based serological study comprising test results on seropositivity and self-reported symptom history conducted in April/May 2020 in the Netherlands (n=3147), we estimated the proportion of reported symptoms among those persons infected with SARS-CoV-2 that is attributable to this infection, where the set of relevant symptoms fulfills the ECDC case definition of COVID-19, using inferential methods for the attributable risk (AR). Generalised additive regression modelling was used to estimate the age-dependent relative risk (RR) of reported symptoms, and the AR and asymptomatic proportion (AP) were calculated from the fitted RR.\n\nResultsUsing age-aggregated data, the estimated AP was 70% (95% CI: 65-77%). The estimated AP decreased with age, from 80% (95% CI: 67-100%) for the <20 years age-group, to 55% (95% CI: 48-68%) for the 70+ years age-group.\n\nConclusionWhereas the crude AP represents a lower bound for the proportion of persons infected with SARS-CoV-2 without COVID-19 symptoms, the AP as estimated via an attributable risk approach represents an upper bound. Age-specific AP estimates can inform the implementation of public health actions such as targetted virological testing and therefore enhance containment strategies.","High Brain-Derived Neurotrophic Factor (BDNF) and Negative Psychological Flexibility associate with Early Fatigue Syndrome in healthy females\nBackgroundRecent studies showed that enhancing psychological flexibility could improve fatigue interference. Brain-Derived Neurotrophic Factor (BDNF), Heart Rate Variability (HRV), and Cortisol were proposed to involve biomarkers in psychological flexibility. Our study aims to explore the association of fatigue with psychological flexibility and related biomarkers.\n\nMethodA cross-sectional study gathered data from a baseline characteristic mindful volunteer. Each participant was self-evaluated with the questionnaire of fatigue and psychological flexibility. The participants were evaluated potential biomarkers related to psychological flexibility including HRV, serum cortisol, and BDNF within one week after responding to the questionnaire.\n\nResultsThe 47 healthy females including 22 nurses and 25 occupational therapy students, mean age 29.70 {+/-} 12.55 years. The prevalence of fatigue is 38.30%. The multivariate analysis showed the independent factors associated with fatigue including negative psychological flexibility (OR 1.31, p=0.03) and high BDNF (OR 1.33, p=0.05).\n\nConclusionOur study found that psychological flexibility and high BDNF was independent factors associate with fatigue. This result provide insight that intervention that increase either psychological flexibility may prevent fatigue symptoms. The high BDNF may reflex the adaptive response of fatigue person and may be potential biomarkers for detecting early fatigue conditions.","Butyrate and related epigenetic changes link Parkinson's disease to inflammatory bowel disease and depressive symptoms\nBackgroundThe gut microbiome and its metabolites can impact brain health and are altered in Parkinsons disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. Here, we investigate whether the changes in the gut microbiome and associated metabolites are linked to PD symptoms and epigenetic markers in leucocytes and neurons.\n\nMethodsStool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified the genome-wide DNA methylation by targeted bisulfite sequencing.\n\nResultsWe show that lower fecal butyrate and reduced Roseburia, Romboutsia, and Prevotella counts are linked to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA (mDNA) regions in PD overlap with those altered in gastrointestinal, autoimmune, and psychiatric diseases.\n\nConclusionsDecreased levels of bacterially produced butyrate are linked to epigenetic changes in leucocytes and neurons from PD patients, and to the severity of their depressive symptoms. PD shares common butyrate-dependent epigenetic changes with certain gastrointestinal and psychiatric disorders, which could be relevant for their epidemiological linkage.","Grandparental Childcare During the Pandemic and Effects on Mental Health: Evidence From England\nObjectivesPolicies aiming at reducing rates of hospitalisation and death from COVID-19 encouraged older people to reduce physical interactions. For grandparents in England, this meant that provision of care for grandchildren was allowed only under very limited circumstances. Evidence also suggests that reduced face-to-face interactions took a toll on mental health during the pandemic. This study aims to investigate whether changes in grandchild care provision during the pandemic impacted grandparents mental health.\n\nMethodsUsing pre-pandemic data from Wave 9 (2018/19) and the second Covid-19 sub-study (November/December 2020) of the English Longitudinal Study of Ageing, we first describe changes in grandparenting since the start of the pandemic to then investigate, using regression models, associations between changes in grandparenting and mental health (depression, quality of life, life satisfaction) during the pandemic, while controlling for pre-pandemic levels of the outcome variables. Results: About 10% of grandparents stopped altogether to look after grandchildren during the pandemic, with 22% reporting an overall decrease in the amount of grandchild care provided and 20% an increase or similar levels. Compared to grandparents who mostly maintained unchanged their grandchild care provision, those who stopped altogether and those who mostly reduced the amount of grandchild care provided were more likely to report poorer mental health, even accounting for pre-pandemic health.\n\nDiscussionWhile measures to limit physical contact and shield older people were necessary to reduce the spread of COVID-19, policymakers should acknowledge potential adverse consequences for mental health among grandparents who experienced changes in their roles as grandchild caregivers.","Factors affecting use of speech testing in adult audiology\nObjectiveTo investigate the factors affecting the use speech testing in adult audiology services\n\nDesignA mixed-methods cross-sectional questionnaire study\n\nStudy SampleA UK sample (n=306) of hearing healthcare professionals (HHPs) from the public (64%) and private sector (36%) completed the survey\n\nResultsIn the UK, speech testing practice varied significantly between health sector. Speech testing was carried out during the audiology assessment by 68% of private sector HHPs and 5% of those from the public sector. During the hearing aid intervention stage speech testing was carried out by 40% and 8% of HHPs from the private and public sector, respectively. Recognised benefits of speech testing included: 1) providing patients with relatable assessment information, 2) guiding hearing aid fitting, 3) supporting a diagnostic test battery. A lack of clinical time was a key barrier to uptake.\n\nConclusionUse of speech testing varies in adult audiology. Results from the present study found the percentage of UK HHPs making use of speech tests was low compared to other countries. HHPs recognised different benefits of speech testing in audiology practice but the barriers limiting uptake were often driven by factors derived from decision makers rather than clinical rationale. Privately funded HHPs used speech tests more frequently than those working in the public sector where time and resources are under greater pressure and governed by guidance that does not include a recommendation for speech testing. Therefore, the inclusion of speech testing in national clinical guidelines could increase the consistency of use.","Brain Structure in Acutely Underweight and Partially Weight-Restored Individuals with Anorexia Nervosa - A Coordinated Analysis by the ENIGMA Eating Disorders Working Group\nThe pattern of structural brain abnormalities in anorexia nervosa (AN) is still not well understood. While several studies report substantial deficits in grey matter volume and cortical thickness in acutely underweight patients, others find no differences, or even increases in patients compared with healthy controls. Recent weight regain before scanning may explain some of this heterogeneity across studies. To clarify the extent, magnitude, and dependencies of grey matter changes in AN, we conducted a prospective, coordinated meta-analysis of multicenter neuroimaging data. We analyzed T1-weighted structural MRI scans assessed with standardized methods from 685 female AN patients and 963 female healthy controls across 22 sites worldwide. In addition to a case-control comparison, we conducted a three-group analysis comparing healthy controls to acutely underweight AN patients (n = 466), and to those in treatment and partially weight-restored (n = 251). In AN, reductions in cortical thickness, subcortical volumes, and, to a lesser extent, cortical surface area, were sizable (Cohens d up to 0.95), widespread and co-localized with hub regions. Highlighting the effects of undernutrition, these deficits associated with lower BMI in the AN sample and were less pronounced in partially weight-restored patients. Notably, the effect sizes observed for cortical thickness deficits in acute AN are the largest of any psychiatric disorder investigated in the ENIGMA consortium to date. These results confirm the importance of considering weight loss and renutrition in biomedical research on AN and underscore the importance of treatment engagement to prevent potentially long-lasting structural brain changes in this population.","Autoantibodies Detected in MIS-C Patients due to Administration of Intravenous Immunoglobulin\nThe autoantibody profile associated with known autoimmune diseases in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that adults with COVID-19 had a moderate prevalence of autoantibodies against the lung antigen KCNRG, and SLE-associated Smith autoantigen. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute insulin-dependent diabetes. While autoantibodies associated with SLE/Sjogrens syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring in vivo decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Together these findings demonstrate that administration of high-dose IVIG is responsible for the detection of several autoantibodies in MIS-C and KD. Further studies are needed to investigate autoantibody production in MIS-C patients, independently from IVIG administration.","Title: Length of hospital stay and risk of intensive care admission and in-hospital death among COVID-19 patients in Norway: a register-based cohort study comparing patients fully vaccinated with an mRNA vaccine to unvaccinated patients\nObjectivesWith most of the Norwegian population vaccinated against COVID-19, an increasing number and proportion of COVID-19 related hospitalisations are occurring among vaccinated patients. We estimated the length of stay (LoS) in hospital and an intensive care unit (ICU), and risk of admission to ICU and in-hospital death among COVID-19 patients [≥]18 years who had been fully vaccinated with an mRNA vaccine, compared to unvaccinated patients.\n\nMethodsUsing national registry data, we conducted a cohort study on SARS-CoV-2 positive patients hospitalised in Norway between 1 February and 30 November 2021, with COVID-19 as the main cause of hospitalisation. We ran Cox proportional hazards models to analyse differences in our outcomes. Explanatory variables included vaccination status, age, sex, county of residence, regional health authority, date of admission, country of birth, virus variant and underlying risk factors.\n\nResultsWe included 3,203 patients, of whom 716 (22%) were fully vaccinated (at least two doses or one dose and previous SARS-CoV-2 infection). Fully vaccinated patients had a shorter overall LoS in hospital (aHR for discharge: 1.61, 95%CI: 1.24-2.08), shorter LoS without ICU (aHR: 1.27, 95%CI: 1.07-1.52), and lower risk of ICU admission (aHR: 0.50, 95%CI: 0.37-0.69) compared to unvaccinated patients. We observed no difference in the LoS in ICU, nor risk of in-hospital death between fully vaccinated and unvaccinated patients.\n\nConclusionsFully vaccinated patients hospitalised with COVID-19 in Norway have a shorter LoS and lower risk of ICU admission than unvaccinated patients. These findings can support patient management and ongoing capacity planning in hospitals."],"string":"[\n \"Aerosol decontamination and spatial separation using a free-space LED-based UV-C light curtain\\nBackgroundThe SARS-CoV-2 pandemic demonstrated the vulnerability of our societies to aerosol transmitted pathogens. With no less than 260mio known cases and > 5mio deaths, SARS-CoV-2 is a global catastrophe leading to human and economic losses unprecedented in recent history. Thus, effective methods to limit the spread of aerosol transmitted pathogens are needed. Universal masking and curfew laws are effective but no permanent solution.\\n\\nMethodsA mass producible LED light source emitting homogeneous parallel UV-C light was used as a \\\"light-barrier\\\" to block the spread of infectious aerosols. In an aerosol test channel, Gram-negative and Gram-positive bacteria as well as coronavirus were nebulized and inactivation rates were determined.\\n\\nFindingsWith air speeds of 0.1 m s-1 an exposure time of 1 s in the UV-C light is obtained. Reduction in CFU for E. coli was >3log10 and for S. aureus [~]2.8log10. Plug-forming-units of the murine coronavirus (Mouse Hepatitis Virus, MHV) were reduced by about 3log10.\\n\\nInterpretationThe concept of a UV-C light barrier to ward off infectious aerosols if feasible and possible with a light element as described here. Coupled with sensor based activation/deactivation, such a technology could greatly reduce the transmission rates of aerosol transmitted pathogens while not disturbing natural human behaviour. This is an interesting technology allowing a \\\"new normal\\\" in societies after/with SARS-CoV-2.\",\n \"Elevated plasma Complement Factor H Regulating Protein 5 is associated with venous thromboembolism and COVID-19 severity\\nVenous thromboembolism (VTE), comprising both deep vein thrombosis (DVT) and pulmonary embolism (PE) is a common, multi-causal disease with potentially serious short- and long-term complications. In clinical practice, there is a need for improved plasma biomarker-based tools for VTE diagnosis and risk prediction. We used multiplex proteomics profiling to screen plasma from patients with suspected acute VTE, and a case-control study of patients followed up after ending anticoagulant treatment for a first VTE. With replication in 5 independent studies, together totalling 1137 patients and 1272 controls, we identify Complement Factor H Related Protein (CFHR5), a regulator of the alternative pathway of complement activation, as a novel VTE associated plasma biomarker. Using GWAS analysis of 2967 individuals we identified a genome-wide significant pQTL signal on chr1q31.3 associated with CFHR5 levels. We showed that higher CFHR5 levels are associated with increased thrombin generation in patient plasma and that recombinant CFHR5 enhances platelet activation in vitro. Thrombotic complications are a frequent feature of COVID-19; in hospitalised patients we found CFHR5 levels at baseline were associated with short-time prognosis of disease severity, defined as maximum level of respiratory support needed during hospital stay. Our results indicate a clinically important role for regulation of the alternative pathway of complement activation in the pathogenesis of VTE and pulmonary complications in acute COVID-19. Thus, CFHR5 is a potential diagnostic and/or risk predictive plasma biomarker reflecting underlying pathology in VTE and acute COVID-19.\",\n \"Human genetic factors associated with pneumonia susceptibility, a cue for COVID-19 mortality\\nThe risk for community acquired pneumonia (CAP) is partially driven by genetics. To identify the CAP-associated genetic risk loci, we performed a meta-analysis of clinically diagnosed CAP (3,310 individuals) with 2,655 healthy controls. The findings revealed CYP1A1 variants (rs2606345, rs4646903, rs1048943) associated with pneumonia. We observed rs2606345 [G vs T; OR=1.49(1.29-1.69); p=0.0001; I2= 15.5%], and rs1048943 [T vs G; OR= 1.31(0.90-1.71); p=0.002; I2=19.3%] as risk markers and rs4646903 [T vs C; OR= 0.79(0.62-0.96); p=0.03; I2=0%] as a protective marker for susceptibility to CAP, when compared with healthy controls. Our meta-analysis showed the presence of CYP1A1 SNP alleles contributing significant risk toward pneumonia susceptibility. Interestingly, we observed a striking difference of allele frequency for rs2606345 (CYP1A1) among Europeans, Africans and Asians which may provide a possible link for observed variations in death due to coronavirus disease 2019 (COVID-19), a viral pneumonia. We report, for the first time, a significant positive correlation for the risk allele (T or A) of rs2606345, with a higher COVID-19 mortality rate worldwide and within a genetically heterogeneous nation like India. Mechanistically, the risk allele A (rs2606345) is associated with lower expression of CYP1A1 and presumably leads to reduced capacity for xenobiotic detoxification. We note that ambient air pollution, a powerful inducer of CYP1A1 gene expression, is globally associated with lower, not higher mortality, as would normally be predicted. In conclusion, we find that CYP1A1 alleles are associated with CAP mortality, presumably via altered xenobiotic metabolism. We speculate that gene-environment interactions governing CYP1A1 expression may influence COVID-19 mortality.\",\n \"The bidirectional causal effects of brain morphology across the life course and risk of Alzheimers disease: A cross-cohort comparison and Mendelian randomization meta-analysis\\nNeuropathological changes associated with Alzheimers disease (AD) can occur decades before clinical symptoms. We investigated whether neurodevelopment and/or neurodegeneration affects the risk of AD, through reducing structural brain reserve and/or accelerating brain atrophy, respectively. We used bidirectional two-sample Mendelian randomization to estimate the effects of genetic liability to AD on global and regional cortical thickness, total intracranial volume, volume of subcortical structures and cerebral white matter in 36,842 participants aged eight to 81 years across five independent cohorts, and the effects of global and regional cortical thickness and subcortical volumes on AD risk in 94,337 participants. Our findings show that AD risk alleles have an age-dependent effect on a range of cortical and subcortical brain measures that starts in mid-life, in non-clinical populations. Evidence for such effects across childhood and young adulthood is weak. We also found little evidence to suggest brain morphology alters AD risk. Thus, genetic liability to AD is likely to alter mechanisms and/or rates of neurodegeneration, rather than reduce structural brain reserve.\",\n \"How does migratory status affect non-communicable disease risk in a global context? A systematic review.\\nChallenges pertaining to the study of migrant health have been reported in medical and sociological literature. A literature review was thus conducted to gauge what research currently holds about the risk of non-communicable disease within migrant populations globally. The search strategy is outlined; CASP checklists were used to critically appraise articles, and the relevant data was synthesised and analysed. The research identifies several overarching quantitative themes regarding risk patterns. Recommendations are made.\",\n \"RBDAct: Home screening of REM sleep behaviour disorder based on wrist actigraphy in Parkinson's patients\\nBackgroundREM sleep behaviour disorder (RBD) is a disabling, often overlooked sleep disorder affecting up to 70% of patients with Parkinsons disease. Identifying and treating RBD is critical to prevent severe sleep-related injuries, both to patients and bedpartners. Current diagnosis relies on nocturnal video-polysomnography, which is an expensive and cumbersome exam requiring specific clinical expertise.\\n\\nObjectivesTo design, optimise, and validate a novel home-screening tool, termed RBDAct, that automatically identifies RBD in Parkinsons patients based on wrist actigraphy only.\\n\\nMethodsTwenty-six Parkinsons patients underwent two-week home wrist actigraphy worn on their more affected arm, followed by two non-consecutive in-lab evaluations. Patients were classified as RBD versus non-RBD based on dream enactment history and video-polysomnography. We characterised patients movement patterns during sleep using raw tri-axial accelerometer signals from wrist actigraphy. Machine learning classification algorithms were then trained to discriminate between patients with or without RBD using actigraphic features that described patients movements. Classification performance was quantified with respect to clinical diagnosis, separately for in-lab and at-home recordings.\\n\\nResultsClassification performance from in-lab actigraphic data reached an accuracy of 92.9{+/-}8.16% (sensitivity 94.9{+/-}7.4%, specificity 92.7{+/-}13.8%). When tested on home recordings, accuracy rose to 100% over the two-week window. Features showed robustness across tests and conditions.\\n\\nConclusionsRBDAct provides reliable predictions of RBD in Parkinsons patients based on home wrist actigraphy only. These results open new perspectives for faster, cheaper and more regular screening of sleep disorders, both for routine clinical practice and for clinical trials.\",\n \"Improving Machine Learning Prediction of ADHD Using Gene Set Polygenic Risk Scores and Risk Scores from Genetically Correlated Phenotypes\\nBackgroundPolygenic risk scores (PRSs), which sum the effects of SNPs throughout the genome to measure risk afforded by common genetic variants, have improved our ability to estimate disorder risk for Attention-Deficit/Hyperactivity Disorder (ADHD) but the accuracy of risk prediction is rarely investigated.\\n\\nMethodsWith the goal of improving risk prediction, we performed gene set analysis of GWAS data to select gene sets associated with ADHD within a training subset. For each selected gene set, we generated gene set polygenic risk scores (gsPRSs), which sum the effects of SNPs for each selected gene set. We created gsPRS for ADHD and for phenotypes having a high genetic correlation with ADHD. These gsPRS were added to the standard PRS as input to machine learning models predicting ADHD. We used feature importance scores to select gsPRS for a final model and to generate a ranking of the most consistently predictive gsPRS.\\n\\nResultsFor a test subset that had not been used for training or validation, a random forest (RF) model using PRSs from ADHD and genetically correlated phenotypes and an optimized group of 20 gsPRS had an area under the receiving operating characteristic curve (AUC) of 0.72 (95% CI: 0.70 - 0.74). This AUC was a statistically significant improvement over logistic regression models and RF models using only PRS from ADHD and genetically correlated phenotypes.\\n\\nConclusionsSumming risk at the gene set level and incorporating genetic risk from disorders with high genetic correlations with ADHD improved the accuracy of predicting ADHD. Learning curves suggest that additional improvements would be expected with larger study sizes. Our study suggests that better accounting of genetic risk and the genetic context of allelic differences results in more predictive models.\",\n \"Remote patient monitoring to interrupt chains of respiratory infections in outpatient care - a case-control study during the 2020/21 infection season\\nAim of the studyThe aim of the study was to investigate satisfaction, saving of time and the possible reduction of patient visits to practices that use Remote Patient Monitoring (RPM) during treatment compared to usual care.\\n\\nMethodsIn a case-control study between October 2020 and May 2021, the participating practices were randomized into three groups (two different RPM systems, one control). The doctors were required to enroll patients with acute respiratory infection [≥] 18 years who have a web-enabled device. After a three-month study phase, the doctors were asked to describe the treatment of their patients via online survey. The patients were also questioned. The analysis was carried out descriptively and with group comparisons.\\n\\nResults51 practices with 121 patients were included. Overall, the results show a positive assessment of digital care on the patient side. As for the doctors, handling and integration of the systems into consisting practice processes seem to be a challenge. Further, the number of patient visits to the practice was not reduced by using the systems and the doctors did not save time, but the relationship to the patients was intensified.\\n\\nConclusionEven if there were no indications for more efficiency by using the RPM systems, the doctors see great potential to intensify the interaction between doctor and patient. In particular, more intensive contact with patients with chronic diseases (e. g. COPD, long-COVID) could be of long-term interest and importance for doctors in outpatient care.\\n\\nTrial RegistrationDRKS00023553\",\n \"Evaluating the utility of high-resolution proximity metrics in predicting the spread of COVID-19\\nAO_SCPLOWBSTRACTC_SCPLOWHigh resolution mobility datasets have become increasingly available in the past few years and have enabled detailed models for infectious disease spread including those for COVID-19. However, there are open questions on how such a mobility data can be used effectively within epidemic models and for which tasks they are best suited. In this paper, we extract a number of graph-based proximity metrics from high resolution cellphone trace data from X-Mode and use it to study COVID-19 epidemic spread in 50 land grant university counties in the US. We present an approach to estimate the effect of mobility on cases by fitting an ODE based model and performing multivariate linear regression to explain the estimated time varying transmissibility. We find that, while mobility plays a significant role, the contribution is heterogeneous across the counties, as exemplified by a subsequent correlation analysis. We subsequently evaluate the metrics utility for case surge prediction defined as a supervised classification problem, and show that the learnt model can predict surges with 95% accuracy and 87% F1-score.\",\n \"Breakthrough infection with SARS-CoV-2 and its predictors among healthcare workers in a medical college and hospital complex in Delhi, India\\nIntroductionThe study objective was to determine the breakthrough infection rate of Covid-19 (SARS-CoV-2) infection in those vaccinated with either BBV152 or AZD1222 (ChAdOx1-S) vaccine among healthcare workers (HCWs).\\n\\nMethodsA cross-sectional analysis was conducted a medical college and hospital complex in Delhi, India through telephonic interviews among HCWs who had received at-least one dose of a Covid-19 vaccine during January to March 2021. Breakthrough infections were operationally defined as occurrence of Covid-19 infection [≥]14 days after administration of two doses of either Covid-19 vaccine.\\n\\nResultsWe enrolled 325 HCWs with mean (SD) age of 29.1 (9.9) years including 211 (64.9%) males. Two seventy nine (85.8%) HCWs were fully vaccinated while 46 (14.2%) were partially vaccinated. There were 168 (51.7%) BBV152 and 157 (48.3%) AZD1222 (ChAdOx1-S) recipients.\\n\\nA total of 37 (11.3%, 95% C.I. 8.3, 15.3) breakthrough infections were observed in the HCWs. The median (IQR) time until incidence of Covid-19 breakthrough infection since receiving second dose of either Covid-19 vaccine was 47 (28.5, 55) days. Additionally, 20 (6.1%) non-breakthrough Covid-19 infections were recorded in the HCWs post vaccination with either a single dose of a Covid-19 vaccine or both doses but prior to a period of 14 days since administration of the second dose.\\n\\nMost breakthrough infection cases (94.4%) were mild and did not require supplemental oxygen therapy. HCWs without a history of natural Covid-19 infection and recovery prior to vaccination were 3.8 times more at risk to contract a Covid-19 infection or reinfection in spite of vaccination with at-least one dose of either Covid-19 vaccine.\\n\\nConclusionNearly one in nine HCWs experienced a Covid-19 breakthrough infection in the present study.\",\n \"Addressing Extreme Imbalance for Detecting Medications Mentioned in Twitter User Timelines\\nTweets mentioning medications are valuable for efforts in digital epidemiology to supplement traditional methods of monitoring public health. A major obstacle, however, is to differentiate them from the large majority of tweets on other topics posted in a users timeline: solving the infamous needle in a haystack problem. While deep learning models have significantly improved classification, their performance and inference processing time remain low on extremely imbalanced corpora where the tweets of interest are less than 1% of all tweets. In this study, we empirically evaluate under-sampling, fine-tuning, and filtering heuristics to train such classifiers. Using a corpus of 212 Twitter timelines (181,607 tweets with only 0.2% tweets mentioning a medication), our results show that combining these heuristics is necessary to impact the classifiers performance. In our intrinsic evaluation, a classifier based on a lexicon and a BERT-base neural network achieved a 0.838 F1-score, a score similar to the ones of the best existing classifier, but it processed the corpus 28 times faster - a positive result, since processing speed is still a roadblock to deploying classifiers on large cohorts of Twitter users needed for pharmacovigilance. In our extrinsic evaluation, our classifier helped a labeler to extract the spans of medications more accurately and achieved a 0.76 Strict F1-score. To the best of our knowledge, this is the first evaluation of medications extraction in Twitter timelines and it establishes the first benchmark for future studies.\",\n \"A more compact photoacoustic imaging system to detect periodontitis\\nPhotoacoustic imaging has shown value in periodontal disease, but the large size of conventional photoacoustic transducers prevents imaging of more posterior teeth, i.e., molars. Here, we report a clinical \\\"hockey stick\\\"-style transducer repurposed for photoacoustic (PA) via an integrated fiber bundle. The shape of the hockey stick transducer facilitates imaging of the 1st pre-molars in contrast to conventional photoacoustic transducer designs. This tool was then deployed for photoacoustic imaging of periodontal disease and the periodontal pocket via a food-grade contrast agent (cuttlefish ink). We characterized the resolution and imaging range and then validated the system with a swine model and human subjects. We could image four additional teeth per quadrant with the smaller design versus a commercial photoacoustic transducer. Three raters evaluated the performance of the hockey stick transducer. The measurements between the probing and the PA methods were blinded, but the outcomes were highly correlated. We showed a bias of [~]0.3 mm for the imaging-based technique versus conventional probing. In addition, the inter-reliability was over 0.60 for three different raters of varying experience suggesting that this approach to evaluating dental health is teachable and reproducible. Finally, we demonstrated the utility in a human subject and can image teeth much more posterior in the mouth than with conventional photoacoustic transducers.\",\n \"SARS-CoV-2 Testing Strategies for Outbreak Mitigation in Vaccinated Populations\\nAlthough COVID-19 vaccines are globally available, waning immunity and emerging vaccine-evasive variants of concern have hindered the international response as COVID-19 cases continue to rise. Mitigating COVID-19 requires testing to identify and isolate infectious individuals. We developed a stochastic compartmentalized model to simulate SARS-CoV-2 spread in the United States and India using Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) assays, rapid antigen tests, and vaccinations. We detail the optimal testing frequency and coverage in the US and India to mitigate an emerging outbreak even in a vaccinated population: overall, maximizing frequency is more important, but high coverage remains necessary when there is sustained transmission. We show that a resource-limited vaccination strategy still requires high-frequency testing and is 16.50% more effective in India than the United States. Tailoring testing strategies to transmission settings can help effectively reduce cases more than if a uniform approach is employed without regard to differences in location.\",\n \"Epigenetic aging and perceived psychological stress in old age\\nAdverse effects of psychological stress on physical and mental health, especially in older age, are well documented. How perceived stress relates to the epigenetic clock measure, DNA methylation age acceleration (DNAmAA), is less well understood and existing studies reported inconsistent results.\\n\\nDNAmAA was estimated from five epigenetic clocks (7-CpG, Horvaths, Hannums, PhenoAge and GrimAge DNAmAA). Cohens Perceived Stress Scale (PSS) was used as marker of psychological stress.\\n\\nWe analyzed data from 1,100 Berlin Aging Study II (BASE-II) participants assessed as part of the GendAge study (mean age = 75.6 years, SD = 3.8 years, 52.1% women).\\n\\nIn a first step, we replicated well-established associations of perceived stress with morbidity, frailty, and symptoms of depression in the BASE-II cohort studied here. In a second step, we did not find any statistically significant association of perceived stress with any of the five epigenetic clocks in multiple linear regression analyses that adjusted for covariates.\\n\\nAlthough the body of literature suggests an association between higher DNAmAA and stress or trauma during early childhood, the current study found no evidence for an association of perception of stress with DNAmAA in older people. We discuss possible reasons for the lack of associations and highlight directions for future research.\",\n \"Aberrant naive CD4+ T Cell differentiation in systemic juvenile idiopathic arthritis is committed to B cell help\\nObjectiveSystemic juvenile idiopathic arthritis (sJIA) features characteristics of autoinflammation and autoimmunity, culminating in chronic arthritis. Previous work indicated decreased IFN{gamma}-expression by T helper (Th) cells in sJIA. Here, we hypothesized this to result from aberrant or incomplete Th cell polarization.\\n\\nMethodsCells or sera were obtained from healthy controls (HC, n=26) and sJIA patients (n=61). Isolated naive Th cells were cultured under Th1, Th17, and T follicular or T peripheral helper (Tf/ph) polarizing conditions and were partly co-cultured with allogenic memory B cells. Surface marker, transcription factor, and/or cytokine expression in peripheral or polarized Th cells or sera as well as B cellular plasma blast generation were studied by flow cytometry, multiplexed bead array assays, ELISA and retrospective RNA profiling analyses.\\n\\nResultsSJIA naive Th cell differentiation towards Th1 resulted in low IFN{gamma} and Eomesodermin expression. Instead, developing sJIA Th1 cells revealed elevated IL-21 release that negatively correlated with cellular IFN{gamma} and Eomesodermin expression. Both In vitro and ex vivo, IL-21 together with PD-1, ICOS and CXCR5 expression indicated naive sJIA Th cell differentiation to rather polarize towards a Tf/ph phenotype. Retrospective analysis of whole blood RNA sequencing data demonstrated sJIA-specific overexpression of Bcl-6 as respective master transcription factor. Compared to controls, in vitro generated sJIA Tf/ph cells promoted enhanced B cellular plasma-blast generation.\\n\\nConclusionIn sJIA pathogenesis skewing of sJIA naive Th cell differentiation towards a Tf/ph phenotype may represent an echo of autoimmunity, which could shed light on the mechanisms driving the progression towards chronic destructive arthritis.\",\n \"Beyond well-mixed: a simple probabilistic model of airborne disease transmission in indoor spaces\\nWe develop a simple model for assessing risk of airborne disease transmission that accounts for non-uniform mixing in indoor spaces and is compatible with existing epidemiological models. A database containing 174 high-resolution simulations of airflow in classrooms, lecture halls, and buses is generated and used to quantify the spatial distribution of expiratory droplet nuclei for a wide range of ventilation rates, exposure times, and room configurations. Imperfect mixing due to obstructions, buoyancy, and turbulent dispersion results in concentration fields with significant variance. The spatial non-uniformity is found to be accurately described by a shifted lognormal distribution. A well-mixed mass balance model is used to predict the mean, and the standard deviation is parameterized based on ventilation rate and room geometry. When employed in a dose-response function risk model, infection probability can be estimated considering spatial heterogeneity that contributes to both short- and long-range transmission.\",\n \"Using time use diaries to track changing behavior across successive stages of COVID-19 social restrictions\\nHow did people change their behavior over the different phases of the UK COVID-19 restrictions, and how did these changes affect their risk of being exposed to infection? Time use diary surveys are unique in providing a complete chronicle of daily behavior; 24-hour continuous records of the populations activities, their social context and their location. We present results from four such surveys, collected in real time from representative UK samples, both before, and at three points over the course of the current pandemic. Comparing across the four waves, we find evidence of substantial changes in the UK populations behavior relating to activities, locations and social context. We assign different levels of risk to combinations of activities, locations and copresence, to compare risk-related behavior across successive lockdowns. We find evidence that during the second lockdown (November 2020) there was an increase in high-risk behaviors relative to the first (starting March 2020). This increase is shown to be associated with more paid work time in the workplace. At a time when capacity is still limited both in respect of immunization and track-trace technology, governments must continue to rely on changes in peoples daily behaviors to contain the spread of COVID-19 and similar viruses. Time use diary information of this type, collected in real time across the course of the COVID-19 pandemic, can provide policy-makers with information to assess and quantify changes in daily behaviors, and the impact they are likely to have on overall behavioral-associated risks.\",\n \"Assessing genetic overlap and causality between blood plasma proteins and Alzheimer's Disease\\nBackground Blood plasma proteins are modifiable and have been associated with Alzheimers disease (AD), but understanding which proteins are on the causal pathway remains challenging.\\n\\nObjectiveInvestigate the genetic overlap between candidate proteins and AD using polygenic risk scores (PRS) and interrogate their causal relationship using bi-directional Mendelian Randomization (MR).\\n\\nMethodsFollowing a literature review, 31 proteins were selected for PRS analysis. PRS were constructed for prioritised proteins with and without the apolipoprotein E region (APOE+/- PRS) and tested for association with AD status across three cohorts (n=6244). An AD PRS was also tested for association with protein levels in one cohort (n=410). Proteins showing association with AD were taken forward for MR.\\n\\nResultsFor APOE e3, apolipoprotein B-100, and C-reactive protein (CRP), protein APOE+ PRS were associated with AD below Bonferroni significance (pBonf, p-value <0.00017). No protein APOE-PRS or AD PRS (APOE+/-) passed pBonf. However, vitamin D-binding protein (protein PRS APOE-, p-value=0.009) and insulin-like growth factor-binding protein 2 (AD APOE- PRS p-value=0.025, protein APOE-PRS p-value=0.045) displayed suggestive signals and were selected for MR. In bi-directional MR, none of the 5 proteins demonstrated a causal association (p-value<0.05) in either direction.\\n\\nConclusionApolipoproteins and CRP PRS are associated with AD and provide a genetic signal linked to a specific, modifiable risk factor. Whilst evidence of causality was limited, this study was conducted in a moderate sample size and provides a framework for larger samples with greater statistical power.\",\n \"Characterizing the performance of a DIY air filter\\nAir filtration serves to reduce concentrations of particles in indoor environments. Most standalone, also referred to as portable or in-room, air filtration systems use HEPA filters, and cost generally scales with the clean air delivery rate. A \\\"do-it-yourself\\\" lower-cost alternative, known as the Corsi-Rosenthal Box, that uses MERV-13 filters coupled with a box fan has been recently proposed, but lacks systematic performance characterization. We have characterized the performance of a five-panel Corsi-Rosenthal air filter. Measurements of size-resolved and overall decay rates of aerosol particles larger than 0.5 microns emitted into rooms of varying size with and without the air filter allowed for determination of the apparent clean air delivery rate--both as a function of size and integrated across particle sizes. The measurements made in the different rooms produced similar results, demonstrating the robustness of the method used. The size-integrated apparent clean air delivery rate increases with fan speed, from about 600 to 850 ft3 min-1 (1019 to 1444 m3 h-1). Overall, our results demonstrate that the Corsi-Rosenthal filter efficiently reduces suspended particle concentrations in indoor environments.\\n\\nOne Sentence SummaryA DIY air cleaner can effectively reduce aerosols in indoor spaces.\",\n \"Pediatric Nemaline Myopathy: A systematic review using individual patient data\\nContextNemaline myopathy (NM) is a skeletal muscle disease that affects 1 in 50,000 live births.\\n\\nObjectiveDevelop a narrative synthesis of the findings of a systematic review of the latest case descriptions of patients with nemaline myopathy.\\n\\nData SourcesA systematic search of MEDLINE, Embase, CINAHL, Web of Science, and Scopus was performed using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines using the keywords pediatric, child, nemaline myopathy, nemaline rod, rod myopathy.\\n\\nStudy SelectionCase studies focused on pediatric NM and published in English between January 1, 2010 and December 31, 2020 in order to represent the most recent findings.\\n\\nData ExtractionInformation was collected about the age of first signs, earliest presenting neuromuscular signs and symptoms, systems affected, progression, death, pathological description, and genetic changes.\\n\\nResultsOf a total of 385 records, 55 case reports or series were reviewed, covering 101 pediatric patients from 23 countries. We review varying presentations in children ranging in severity despite being caused by the same mutation, in addition to current and future clinical considerations relevant to the care of patients with nemaline myopathy.\\n\\nLimitationsThe results are limited by findings shared in the literature, which varied in their detail and sometimes lacked histological or genetic results. Trends and correlations may be altered by information available.\\n\\nConclusionsThis review synthesizes genetic, histopathologic, and disease presentation findings from pediatric nemaline myopathy case reports. These data strengthen our understanding of the wide spectrum of disease seen in nemaline myopathy. Future studies are needed to identify the underlying molecular mechanism of pathology, to improve diagnostics, and to develop better methods to improve quality of life for these patients.\",\n \"Impact of reproduction number on multiwave spreading dynamics of COVID-19 with temporary immunity : a mathematical model\\nCOVID-19 is caused by a hitherto nonexistent pathogen, hence the immune response to the disease is currently unknown. Studies conducted over the past few weeks have found that the antibody titre levels in the blood plasma of infected patients decrease over time, as is common for acute viral infections. Fully documented reinfection cases from Hong Kong, India, Belgium and USA, as well as credible to anecdotal evidence of second-time cases from other countries, bring into sharp focus the question of what profile the epidemic trajectories may take if immunity were really to be temporary in a significant fraction of the population. Here we use mathematical modeling to answer this question, constructing a novel delay differential equation model which is tailored to accommodate different kinds of immune response. We consider two immune responses here : (a) where a recovered case becomes completely susceptible after a given time interval following infection and (b) where a first-time recovered case becomes susceptible to a lower virulence infection after a given time interval following recovery, and becomes permanently immunized by a second infection. We find possible solutions exhibiting large number of waves of disease in the first situation and two to three waves in the second situation. Interestingly however, these multiple wave solutions are manifest only for some intermediate values of the reproduction number R, which is governed by public health intervention measures. For sufficiently low as well as sufficiently high R, we find conventional single-wave solutions despite the short-lived immunity. Our results cast insight into the potential spreading dynamics of the disease and might also be useful for analysing the spread after a vaccine is invented, and mass vaccination programs initiated.\",\n \"Vaccine effectiveness of BNT162b2 against Omicron and Delta outcomes in adolescents\\nIntroductionData on vaccine effectiveness (VE) against Omicron in adolescents are limited. We estimated 2-dose and 3-dose VE against Omicron and Delta in adolescents aged 12-17 years in Ontario, Canada.\\n\\nMethodsWe conducted a test-negative design study among SARS-CoV-2-tested adolescents aged 12-17 years between November 22, 2021 (date of first Omicron detection) and March 6, 2022; we assessed Delta outcomes prior to January 2, 2022. We used multivariable logistic regression to compare the odds of vaccination in cases to symptomatic test-negative controls and calculated VE as 1-adjusted odds ratio.\\n\\nResultsVE was lower against symptomatic Omicron infection than against Delta and decreased more rapidly over time, from 51% (95%CI, 38-61%) in the 7-59 days following a second dose to 29% (95%CI, 17-38%) after 180 days, compared to 97% (95%CI, 94-99%) and 90% (95%CI, 79-95%) for the same intervals against symptomatic Delta infection. Overall, 2-dose VE against severe outcomes caused by Omicron was 85% (95%CI, 74-91%) [≥]7 days following a second dose and estimates were similar over time. VE against symptomatic Omicron infection was 62% (95%CI, 49-72%) [≥]7 days following a third dose.\\n\\nDiscussionTwo-dose VE against symptomatic Omicron infection wanes over time in adolescents. While lower than observed against Delta, protection against severe outcomes appears to be maintained over time. A third dose substantially improves protection against Omicron infection, but 3-dose VE is only moderate at approximately 60% in the early period following vaccination and the duration of this protection is unknown.\",\n \"Nowcasting food insecurity on a global scale\\nLack of regular physical or economic access to safe, nutritious and sufficient food is a critical issue affecting millions of people world-wide. Estimating how many and where these people are is of fundamental importance for governments and humanitarian organizations to take informed and timely decisions on relevant policies and programmes. In this study, we propose a machine learning approach to predict the prevalence of people with insufficient food consumption and of people using crisis or above crisis food-based coping when primary data is not available. Making use of a unique global data set, we show that the proposed models can explain up to 78% of the variation in insufficient food consumption and crisis or above food-based coping levels. We also show that the proposed models can be used to nowcast the food security situation in near-real time and propose a method to identify which variables are driving the changes observed in predicted trends, which is key to make predictions serviceable to decision makers.\",\n \"CD56brightCD16- NATURAL KILLER CELLS ARE IN HIGHER COUNTS IN THE UMBILICAL CORD BLOOD THAN IN THE PERIPHERAL BLOOD\\nUmbilical cord blood (UCB) is an alternative source for hematopoietic stem cells allogeneic hematopoietic stem cell transplantation in the absence of compatible donor. UCB transplantation has a lower incidence of chronic graft versus host disease (GvHD) but is associated with slower engraftment and slower immune reconstitution as compared to other sources. Dendritic cells (DC) and Natural Killer cells (NK) play a central role in the development of GVHD, the graft versus leukemia (GvL) effect, and in the control of infectious complications. We quantified by multiparametric flow cytometry monocytes, lymphocytes, NK cells, and DC, including their subsets, in UCB samples from 54 healthy newborns and peripheral blood (PB) from 25 healthy adult volunteers. In the UCB samples, there were higher counts of CD56brightCD16-NK cells (median 0.024x109/L), as compared to the PB samples (0.012x109/L, P<0.0001), CD56dimCD16bright NK cells (median 0.446x109/L vs. 0.259x109/L for PB samples, P= 0.001), and plasmacytoid dendritic cells (pDC, median 0.008x109/L for UCB samples vs. 0.006x109/L for PB samples, P= 0.03). Moreover, non-classical monocytes counts were lower in UCB than in PB (median 0.024x109/L vs. 0.051 x109/L, respectively, P< 0.0001). In conclusion, there were higher counts of NK cells and pDC, and lower counts of non-classical monocytes in UCB than in PB from healthy individuals. These findings might explain the lower incidence and severity of chronic GVHD although maintaining the GVL effect in UCB transplants recipients as compared to other stem cell sources.\\n\\nHighlightsO_LICD56brightCD16- NK cells are more frequent in UCB than in PB.\\nC_LIO_LIPlasmacytoid dendritic cells are more frequent in UCB than in PB.\\nC_LIO_LINon-classical monocytes are more frequent in PB than in UCB.\\nC_LI\",\n \"Inflammatory Bowel Disease Risk Variants Are Associated with an Increased Risk of Skin Cancer\\nBackground and AimsInflammatory bowel disease is associated with an increased risk of skin cancer. The aims of this study were to determine whether genomic variants associated with IBD susceptibility are also associated with skin cancer susceptibility and if such risk is augmented by the use of immune-suppressive therapy.\\n\\nMethodsThe discovery cohort included participants in the UK Biobank (n=408,381). The validation cohort included participants in the Michigan Genomics Initiative (n=51,405). The primary outcome of interest was skin cancer, sub-grouped into non-melanoma (NMSC) and melanoma skin cancers (MSC). Multivariable logistic regression was performed to identify genomic predictors of skin malignancy. Validated SNPs were evaluated for effect modification by immune-suppressive medication.\\n\\nResultsThe discovery cohort included 11,079 cases of NMSC and 2,054 cases of MSC. The validation cohort included 7,334 cases of NMSC and 3,304 cases of MSC. Thirty variants were associated with risk of NMSC in the discovery cohort, of which six replicated in the validation cohort [Increased risk: rs7773324-A (DUSP22; IRF4), rs2476601-G (PTPN22), rs1847472-C (BACH2), rs72810983-A (CPEB4); Decreased risk: rs6088765-G (PROCR; MMP24), rs11229555-G (ZFP91-CNTF; GLYAT)]. Twelve variants were associated with risk of MSC in the discovery cohort, of which three replicated in the validation cohort (Increased risk: rs61839660-T (IL2RA); Decreased risk: rs17391694-C (GIPC2; MGC27382), rs6088765-G (PROCR; MMP24)]. No effect modification was observed.\\n\\nConclusionThe results of this study highlight shared genetic susceptibility across IBD and skin cancer, with increased risk of NMSC in those who carry risk variants in IRF4, PTPN22, CPEB4, and BACH2 and increased risk of MSC in those who carry a risk variant in IL2RA.\",\n \"Disrupted network segregation of the default mode network in autism spectrum disorder\\nBackgroundChanges in the brains default mode network (DMN) in the resting state are closely related to autism spectrum disorder (ASD). Module segmentation can effectively elucidate the neural mechanism of ASD and explore the intra- and internetwork connections by means of the participation coefficient (PC).\\n\\nMethodsResting-state fMRI data from 269 ASD patients and 340 healthy controls (HCs) were used in the current study. The PC of brain network modules was calculated and compared between ASD subjects and HCs. In addition, we further explored the features according to different age groups and different subtypes of ASD. Intra- and internetwork differences were further calculated to find the potential mechanism underlying the results.\\n\\nResultsASD subjects showed significantly higher PC of the DMN than HC subjects. This difference was caused by lower intramodule connections within the DMN and higher internetwork connections between the DMN and networks. When the subjects were split into age groups, the results were verified in the 7-12 and 12-18 age groups but not in the adult group (18-25). When the subjects were divided according to different subtypes of ASD, the results were also observed in the classic autism and pervasive developmental disorder groups, but not in the Asperger disorder group. In addition, compared with the HC group, the ASD group showed significantly increased intranetwork connections between the DMN and the frontoparietal network.\\n\\nConclusionsLess developed network segregation in the DMN could be a valid biomarker for ASD, and this feature was validated with different measures. The current results provide new insights into the neural underpinnings of ASD and provide targets for potential interventions using brain modulation and behavioural training.\",\n \"A scoping review exploring the impact of digital systems on processes and outcomes in the care management of acute kidney injury and progress towards establishing learning healthcare systems\\nBackgroundDigital systems have long been used to improve the quality and safety of care when managing Acute Kidney Injury (AKI). The availability of digitised clinical data can also turn organisations and their networks into Learning Healthcare Systems (LHSs) if used across all levels of health and care. This review explores the impact of digital systems on AKI patient care to gauge progress towards establishing LHSs and to identify existing gaps in the research.\\n\\nMethodEmbase, PubMed, Medline, Cochrane, Scopus and Web of Science databases were searched. Studies of real-time or near real-time digital AKI management systems which reported process and outcome measures were included.\\n\\nResultsThematic analysis of 43 studies showed that most interventions used real-time serum creatinine (SCr) levels to trigger responses to enable risk prediction, early recognition of AKI or harm prevention by individual clinicians (micro level) or specialist teams (meso level). Interventions at system (macro level) were rare. There was limited evidence of change in outcomes.\\n\\nConclusionWhilst the benefits of real time digital clinical data at micro level for AKI management have been evident for some time, their application at meso and macro levels is emergent therefore limiting progress towards establishing LHSs. Lack of progress is due to digital maturity, system design, human factors and policy levers. Future approaches need to harness the potential of interoperability and data analytic advances and include multiple stakeholder perspectives to overcome these factors.\",\n \"When thinking you are better leads to feeling worse: Self-other asymmetries in prosocial behavior and increased anxiety during the Covid-19 pandemic\\nThinking one is better than peers is generally associated with positive psychological outcomes like increased self-esteem and resilience. However, this tendency may be problematic in the context of collective action problems, wherein individuals are reliant on others prosocial behaviors to achieve larger goals. We examined this question in the context of the Covid-19 pandemic, and recruited participants (n = 1022) from a university community in Spring 2020. We found evidence for a self-peer asymmetry, such that participants reported that they were doing more to stop the spread of the disease and were more prosocially motivated than peers. Actual peer reports indicated that these were overestimations. This self-enhancement tendency comes with a cost: the perceived self-peer asymmetry mediated the relationship between Covid-specific worry and general anxiety during the early lockdown period. This indicates that while believing one is doing more than others may be maladaptive in collective action problems.\",\n \"Tenofovir Disoproxil Fumarate and severity of COVID-19 in people with HIV infection\\nBackgroundEffective, safe, and affordable antivirals are needed for COVID-19. Tenofovir has not been studied in randomized trials despite evidence consistent with its effectiveness against COVID-19.\\n\\nMethodsWe studied HIV-positive individuals on antiretroviral therapy (ART) in 2020 at 69 HIV clinics in Spain. We collected data on sociodemographics, ART, CD4-cell count, HIV-RNA viral load, comorbidities and the following outcomes: laboratory-confirmed SARS-CoV-2 infection, COVID-19 hospitalization, intensive care unit (ICU) admission and death. We compared the 48-week risks for individuals receiving tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), tenofovir alafenamide (TAF)/ FTC, abacavir (ABC)/lamivudine (3TC), and other regimes. All estimates were adjusted for clinical and sociodemographic characteristics via inverse probability weighting.\\n\\nResultsOf 51,558 eligible individuals, 39.6% were on TAF/FTC, 11.9% on TDF/FTC, 26.6% on ABC/3TC, 21.8% on other regimes. There were 2,402 documented SARS-CoV-2 infections (425 hospitalizations, 45 ICU admissions, 37 deaths). Compared with TAF/FTC, the estimated risk ratios (RR) (95% CI) of hospitalization were 0.66 (0.43, 0.91) for TDF/FTC and 1.29 (1.02, 1.58) for ABC/3TC, the RRs of ICU admission were 0.28 (0.11, 0.90) for TDF/FTC and 1.39 (0.70, 2.80) for ABC/3TC, and the RRs of death were 0.37 (0.23, 1.90) for TDF/FTC and 2.02 (0.88-6.12) for ABC/3TC. The corresponding RRs of hospitalization for TDF/FTC were 0.49 (0.24, 0.81) in individuals [≥]50 years and 1.15 (0.59, 1.93) in younger individuals.\\n\\nConclusionOur findings suggest that, compared with other antiretrovirals, TDF/FTC lowers COVID-19 severity among HIV-positive individuals with virological control. This protective effect may be restricted to individuals aged 50 years and older.\",\n \"Physicians' Reactions to COVID-19: The Results of an International Internet Survey\\nObjectivesPhysicians across the world have been disproportionately affected by the COVID-19 pandemic. This study was designed and conducted to assess the emotional, cognitive, and behavioural reactions of physicians to the initial phase of the COVID-19 pandemic.\\n\\nMaterials and methodsAn online survey questionnaire using the google forms platform was constructed by the authors. The items in the questionnaire were based on clinical experience, relevant literature review and discussion with peers. A list of issues that were deemed as essential components of the experience of the pandemic relevant to physicians was arrived at. Thereafter these issues were operationalized into question form and hosted on the google forms platform. The link to this questionnaire was circulated by the authors among their peer groups in the month of April 2020.\\n\\nResultsWe received 295 responses and 3 were unusable. Most of the responses were from India, the United States of America, Australia, Canada and the United Kingdom. About 60% of the respondents identified themselves as frontline and had a decade of clinical experience. Most respondents reported being anxious due to the pandemic and also observed the same in their peers and families. A majority also observed changes in behaviour in self and others and advanced a variety of reasons and concerns. A sense of duty was the most commonly employed coping mechanism.\\n\\nConclusionPhysicians are not immune from information and misinformation, or cues in the environment. Behavioural choices are not always predicted by knowledge but by a combination of knowledge, emotional state, personality and environment. Healthcare settings need to be ready for emergencies and should focus on reducing uncertainty in physicians. These factors may also be gainfully used in the mental health promotion of physicians in COVID-19 care roles.\",\n \"How to decide which COVID-19 patient with myocardial infarction to send to the Cath Lab? - A case series of COVID-19 patients with myocardial infarction\\nINTRODUCTIONThe Coronavirus pandemic has hit the world with its vast contagiousness, high morbidity, and mortality. Apart from the direct damage to the lung tissue, the corona virus infection is able to predispose patients to thrombotic disease, thus causing cerebral or coronary incidents.\\n\\nAIMSThe aim of this study was to find a clinical or laboratory parameter, that would help in distinguishing between COVID-19 patients with myocardial infarction (MI), who have an infarct-related artery (IRA) and therefore, require immediate revascularization, and those, who have no IRA.\\n\\nMETHODSThis was a single-center, observational study of 10 consecutive patients with COVID-19, who were admitted with confirmed MI.\\n\\nRESULTSIn our study group the mean age was 67.5 {+/-} 8.3 years, half of the patients were female; all of them had arterial hypertension; 8 patients (80%) had dyslipidemy; 4 (40%) had diabetes. 30% of the patients with MI did not have an IRA, and did not require pPCI. Patients with MI and IRA had significantly higher hsTrI values (48.9 {+/-} 43.2 vs 0.6 {+/-} 0.7, p=0.007) and exclusively typical chest pain 100% vs 0%, p=0.007), compared to patients with MI without an IRA. The ECG changes had only marginal statistical significance. Our results suggest that using a higher cut-off value for hsTrI (>7.5 times upper reference range) increases the specificity and positive predictive value for diagnosing a MI with the presence of IRA and need for pPCI, to 100%\\n\\nCONCLUSIONIn our analysis we confirm that a higher cut-off value for hsTrI helps distinguish between COVID patients with MI, who have IRA and therefore, require immediate revascularization, compared to those, who have no IRA.\",\n \"Altered Cerebral Blood Flow in Older Adults with Alzheimer's Disease: A Systematic Review\\nThe prevalence of Alzheimers disease is projected to reach 13 million in the U.S. by 2050. Although major efforts have been made to avoid this outcome, so far there are no treatments that can stop or reverse the progressive cognitive decline that defines Alzheimers disease. The utilization of preventative treatment before significant cognitive decline has occurred may ultimately be the solution, necessitating a reliable biomarker of preclinical/prodromal disease stages to determine which older adults are most at risk. Quantitative cerebral blood flow is a promising potential early biomarker for Alzheimers disease, but the spatiotemporal patterns of altered cerebral blood flow in Alzheimers disease are not fully understood. The current systematic review compiles the findings of 29 original studies that compared quantitative cerebral blood flow in older adults with mild cognitive impairment or Alzheimers disease to that of cognitively normal older adults and/or assessed the relationship between cerebral blood flow and objective cognitive function. Individuals with Alzheimers disease had relatively decreased cerebral blood flow in all brain regions investigated, especially the temporoparietal and posterior cingulate, while individuals with mild cognitive impairment had less consistent results, with relatively increased cerebral blood flow reported in the temporal lobe and thalamus. Most papers reported a positive correlation between cerebral blood flow and cognitive function. This review highlights the need for more studies comparing cerebral blood flow between cognitively normal individuals and those with mild cognitive impairment, as well as the importance of including potential confounding factors in these analyses.\",\n \"Machine Learning based COVID-19 Diagnosis from Blood Tests with Robustness to Domain Shifts\\nWe investigate machine learning models that identify COVID-19 positive patients and estimate the mortality risk based on routinely acquired blood tests in a hospital setting. However, during pandemics or new outbreaks, disease and testing characteristics change, thus we face domain shifts. Domain shifts can be caused, e.g., by changes in the disease prevalence (spreading or tested population), by refined RT-PCR testing procedures (taking samples, laboratory), or by virus mutations. Therefore, machine learning models for diagnosing COVID-19 or other diseases may not be reliable and degrade in performance over time. To countermand this effect, we propose methods that first identify domain shifts and then reverse their negative effects on the model performance. Frequent re-training and reassessment, as well as stronger weighting of more recent samples, keeps model performance and credibility at a high level over time. Our diagnosis models are constructed and tested on large-scale data sets, steadily adapt to observed domain shifts, and maintain high ROC AUC values along pandemics.\",\n \"Clinical Burkholderia pseudomallei isolates from Queensland carry diverse bimABm genes that are associated with central nervous system disease and are phylogenomically distinct from other Australian strains\\nBurkholderia pseudomallei is an environmental gram-negative bacterium that causes the disease melioidosis and is endemic in many countries of the Asia-Pacific region. In Australia, the mortality rate remains high at approximately 10%. The bacterium is almost exclusively found in the endemic region, which spans the Northern Territory, Western Australia and North Queensland. However, Queensland infections remain understudied compared to those of the Northern Territory. This pilot study aimed to assess the prevalence of central nervous system disease associated variant bimABm, identify circulating antimicrobial resistance mutations and genetically distinct strains from Queensland, via comparative genomics. From 76 clinical isolates, we identified the bimABm variant in 20 (26.3%) isolates and in 9 (45%) of the isolates with documented central nervous system infection (n=18). Explorative analysis suggests a significant association between isolates carrying the bimABm variant and central nervous system disease (OR 2.8, 95% CI 1.3-6.0, P=0.009) compared with isolates carrying the wildtype bimABp, with the possibility of additional driving factors. Furthermore, 50% of isolates were identified as novel multi-locus sequence types (STs), while the bimABm variant was more commonly identified in isolates with novel sequence STs, compared to those of previously described STs. Additionally, mutations associated with acquired antimicrobial resistance were only identified in 14.5% of all genomes. The findings of this research have provided clinically relevant genomic data of B. pseudomallei in Queensland and suggest that the bimABm variant may enable risk stratification for the development CNS complications and be a potential therapeutic target.\",\n \"Opioid Use Stigmatization and Destigmatization in Healthcare Professional Social Media\\nStigmatization of opioid use constitutes a significant barrier to addressing the opioid crisis. Increasing use of social media by healthcare professionals provides an opportunity to foster destigmatization. However, little is known about stigmatization and destigmatization within healthcare professional social media communities. Accordingly, this study investigates the use of stigmatizing and destigmatizing language in three such communities: Medical Twitter, Public Health Twitter, and Epidemiology Twitter. Using a dataset of 2,319 tweets discussing opioids and associated with these Twitter communities, we analyzed each tweet for evidence of stigmatizing or destigmatizing language based on guidance from the National Institute on Drug Abuse. The results indicate that overall use of both stigmatizing and destigmatizing language is currently low across communities compared to the overall volume of opioid-related content. Additionally, there are measurable changes in stigmatizing and destigmatizing language on quarterly bases between 2012 and 2020. During this time, Public Health Twitter has seen a quarterly 19% reduction in rates of stigmatizing (IRR = 0.81, 95% CI 0.67 to 0.97), and all communities have experienced a quarterly 57% increase in destigmatizing language (IRR = 1.57, 95% CI: 1.33 to 1.85). This study also reveals that tweets containing stigmatizing and destigmatizing language receive minimal user engagement (measured by likes, retweets, quote tweets, and comments). While the longitudinal findings on increasing use of destigmatizing language are promising, they also indicate a need for increased efforts to encourage broader use of destigmatizing language. Leveraging the social learning potentials of Twitter offers one promising pathway for future initiatives.\",\n \"Superiority of serum NFL in predicting Multiple Sclerosis severity\\nObjectiveSerum neurofilament light chain (sNFL) is becoming an important biomarker of neuroaxonal injury. While sNFL correlates with cerebrospinal fluid NFL (cNFL), 40-60% of variance remains unexplained. Assuming that for diseases of the central nervous system (CNS), such as multiple sclerosis (MS), the cNFL better reflects CNS injury, our goal was to develop and validate adjustment of sNFL for relevant confounders, to strengthen cNFL-sNFL correlations.\\n\\nMethodsWe used 1,378 matched cNFL-sNFL pairs divided into training and validation cohort with matching data on 11 confounders, neuroexam, and magnetic resonance imaging (MRI). The effect of confounders on cNFL-sNFL relationship was tested using multiple linear regression (MLR) model. Propensity score matching was used to identify effect of spinal cord damage on sNFL levels.\\n\\nResultsIn the training cohort (n=898) we correlated 11 confounders with the residuals from cNFL-sNFL linear regression. Four non-overlapping confounders explaining highest proportion of variance (12%: age, 8.7%: blood urea nitrogen, 3%: alkaline phosphatase, and 3.9%: weight) were used in MLR model. The model strengthened the cNFL-sNFL correlation from R2 = 0.52 to 0.64 in the independent validation cohort and strengthened correlation of adjusted sNFL with number of contrast-enhancing lesions (from R2 0.11 to 0.18). However, only sNFL, but not cNFL correlated with MS severity outcomes. Using propensity score matching, we demonstrated that subjects with proportionally higher sNFL to cNFL levels have significantly higher clinical and radiological evidence of spinal cord injury.\\n\\nInterpretationSuperiority of sNFL likely resides in the release of NFL from axons of lower motor or dorsal ganglia neurons directly to blood.\",\n \"Performance in Fundamentals of Laparoscopic Surgery (FLS): Does it Reflect Global Rating Scales in Objective Structured Assessment of Technical Skills (OSATS) in Porcine Laparoscopic Surgery?\\nBackgroundTo correlate the utility of Fundamentals of Laparoscopic Surgery (FLS) manual skills program with the Objective Structured Assessment of Technical Skills (OSATS) global rating scale in evaluating operative performance.\\n\\nMaterials and MethodsThe Asian Urological Surgery Training and Educational Group (AUSTEG) Laparoscopic Upper Tract Surgery Course (LUTSC) implemented and validated the FLS program for its usage in laparoscopic surgical training. Delegates basic laparoscopic skills were assessed using three different training models (Peg Transfer, Precision Cutting and Intra-corporeal Suturing). They also performed live porcine laparoscopic surgery at the same workshop. Live surgery skills were assessed by blinded faculty using the OSATS rating scale.\\n\\nResultsFrom 2016 to 2019, a total of 81 certified urologists participated in the course, with a median of 5 years experience post residency. Although differences in task timings did not reach statistical significance, those with more surgical experience were visibly faster at completing the peg transfer and intra-corporeal suturing FLS tasks. However, they took longer to complete the precision cutting task than participants with less experience. Overall OSATS scores correlated weakly with all three FLS tasks (Peg Transfer Time: R = -0.331, R2 = 0.110; Precision Cutting Time: R = - 0.240, R2 = 0.058; Suturing with Intra-corporeal Knot Time: R = -0.451, R2 = 0.203).\\n\\nConclusionFLS task parameters did not correlate strongly with OSATS globing rating scale performance. Although the FLS task models demonstrated strong validity, it is important to assimilate the inconsistencies when benchmarking technical proficiency against real-life operative competence, as evaluated by FLS and OSATS respectively.\",\n \"Genetic support of a causal relationship between Iron status and atrial fibrillation: a Mendelian randomization study\\nBackgroundAtrial fibrillation is the most common arrhythmia disease.Animal and observational studies have found a link between iron status and atrial fibrillation. However, the causal relationship between iron status and the risk of atrial fibrillation may be biased by confounding and reverse causality.The purpose of this investigation was to use Mendelian randomization (MR) analysis, which has been widely appied to estimate the causal effect,to reveal whether systemic iron status was causally related to atrial fibrillation.\\n\\nMethodsSingle nucleotide polymorphisms (SNPs) strongly associated (P < 5x10-8) with four biomarkers of systemic iron status were obtained from a genome-wide association study involving 48,972 subjects conducted by the Genetics of Iron Status consortium.\\n\\nSummary-level data for the genetic associations with atrial fibrillation were acquired from AFGen (Atrial Fibrillation Genetics) consortium study(including 65,446 atrial fibrillation cases and 522,744 controls). We used a two-sample MR analysis to obtain a causal estimate, and further verified credibility through sensitivity analysis.\\n\\nResultsGenetically instrumented serum iron [OR:1.09;95%; confidence interval (CI)1.02-1.16; p=0.01], ferritin [OR:1.16;95%CI:1.02-1.33; p=0.02], and transferrin saturation [OR:1.05;95%CI:1.01-1.11; p=0.01] had positive effects on atrial fibrillation. Genetically instrumented transferrin levels [OR:0.90;95%CI:0.86-0.97; p=0.006] was an inverse correlation with atrial fibrillation.\\n\\nConclusionIn conclusion,our results strongly elucidated a causal link between genetically determined higher iron status and increased the risk of atrial fibrillation.This provided new ideas for clinical prevention and treatment of atrial fibrillation.\",\n \"A comparison of health care use after severe COVID-19, respiratory syncytial virus, and influenza in children\\nBackgroundWe aimed to explore whether children in hospital care with COVID-19 have increased post-discharge health care use when compared to children in hospital care with 1) RSV infection, and 2) other RTIs.\\n\\nMethodsIn 34,214 children aged 1 month to 5 years who were registered with one or more hospital contacts with COVID-19 (N=128), RSV infection (N=4,009) or other RTIs (upper- and lower unspecified RTI as well as influenza) (N=34,457) (January 1st, 2017 to September 20th, 2021), we used a pre-post study design to investigate the individual all-cause primary and specialist health care use from 12 weeks prior to hospital admission, to 12 weeks after hospital discharge, stratified on infants (1-12 months) and toddlers (1-5 years).\\n\\nFindingsWe found a slight increase in primary health care use in the first four weeks after discharge for children aged 1-12 months with COVID-19 when compared to children with RSV infection (0.064 percentage points, 95% CI 0.02-0.126, 0.52% relative increase). For children aged 1-5 years, COVID-19 discharge was associated with a 1-4 weeks increase in primary health care use when compared to children with RSV infection (0.068 percentage points, 95% CI 0.022-0.144, 0.53% relative increase) and other RTI (0.046 percentage points, 95% CI 0.002-0.091, 0.45% relative increase). For children aged 1-12 months in hospital care with COVID-19, we found a similar-magnitude-increase in post-discharge inpatient specialist care use, which lasted for 12 weeks.\\n\\nInterpretationOur findings imply no severe impact on health care use after hospitalization with COVID-19 compared to hospitalization with RSV infection or other RTIs. The etiological mechanisms for potentially worse post-hospitalization complaints or health-seeking behavior for COVID-19 than for other RTIs in children should be further explored.\",\n \"A SARS-CoV-2 negative antigen rapid diagnostic in RT-qPCR positive samples correlates with a low likelihood of infectious viruses in the nasopharynx.\\nSARS-CoV-2 transmission occurs even among fully vaccinated individuals; thus, prompt identification of infected patients is central to control viral circulation. Antigen rapid diagnostic tests (Ag-RDT) are highly specific, but sensitivity is variable.Discordant RT-qPCR vs Ag-RDT results are reported, raising the question of whether negative Ag-RDT in positive RT-qPCR samples could imply the absence of infectious viruses. To study the relationship between a negative Ag-RDT results with virological, molecular, and serological parameters, we selected a cross sectional and a follow-up dataset and analyzed virus culture, subgenomic RNA quantification, and sequencing to determine infectious viruses and mutations. We demonstrated that a positive SARS-CoV-2 Ag-RDT result correlates with the presence of infectious virus in nasopharyngeal samples. A decrease in sgRNA detection together with an expected increase in detectable anti-S and anti-N IgGs was verified in negative Ag-RDT / positive RT-qPCR samples. The data clearly demonstrates the less likelihood of a negative Ag-RDT sample to harbor infectious SARS-CoV-2 and consequently with a lower transmissible potential.\",\n \"Data-driven estimate of SARS-CoV-2 herd immunity threshold in populations with individual contact pattern variations\\nThe development of efficacious vaccines has made it possible to envision mass vaccination programs aimed at suppressing SARS-CoV-2 transmission around the world. Here we use a data-driven age-structured multilayer representation of the population of 34 countries to estimate the disease induced immunity threshold, accounting for the contact variability across individuals. We show that the herd immunization threshold of random (un-prioritized) mass vaccination programs is generally larger than the disease induced immunity threshold. We use the model to test two additional vaccine prioritization strategies, transmission-focused and age-based, in which individuals are inoculated either according to their behavior (number of contacts) or infection fatality risk, respectively. Our results show that in the case of a sterilizing vaccine the behavioral strategy achieves herd-immunity at a coverage comparable to the disease-induced immunity threshold, but it appears to have inferior performance in averting deaths than the risk vaccination strategy. The presented results have potential use in defining the effects that the heterogeneity of social mixing and contact patterns has on herd immunity levels and the deployment of vaccine prioritization strategies.\",\n \"Neighborhood Disadvantage and Active, Disabled and Total Life Expectancy Among Community-living Older Persons\\nBackgroundNeighborhood disadvantage is a novel social determinant of health that could adversely affect the functional well-being and longevity of older persons. We evaluated whether estimates of active, disabled and total life expectancy differ on the basis of neighborhood disadvantage after accounting for individual-level socioeconomic characteristics and other prognostic factors.\\n\\nMethodsWe used data on 754 community-living older persons from South Central Connecticut, who completed monthly assessments of disability from 1998 to 2020. Scores on the area deprivation index were dichotomized at the 80th state percentile to distinguish neighborhoods that were disadvantaged (81-100) from those that were not (1-80).\\n\\nResultsWithin 5-year age increments from 70 to 90, active and total life expectancy were consistently lower in participants from neighborhoods that were disadvantaged versus not disadvantaged, and these differences persisted and remained statistically significant after adjustment for individual-level race/ethnicity, education, income, and other prognostic factors. At age 70, adjusted estimates (95% CI) for active and total life expectancy (in years) were 12.3 (11.5-13.1) and 15.0 (13.8-16.1) in the disadvantaged group and 14.2 (13.5-14.7) and 16.7 (15.9-17.5) in the non-disadvantaged group. At each age, participants from disadvantaged neighborhoods spent a greater percentage of their projected remaining life disabled, relative to those from non-disadvantaged neighborhoods, with adjusted values (SE) ranging from 17.7 (0.8) vs. 15.3 (0.5) at age 70 to 55.0 (1.7) vs. 48.1 (1.3) at age 90.\\n\\nConclusionsLiving in a disadvantaged neighborhood is associated with lower active and total life expectancy and a greater percentage of projected remaining life disabled.\",\n \"Unifying diagnostic criteria for gestational diabetes mellitus\\nAIMSDisagreement about the appropriate criteria for the diagnosis of gestational diabetes mellitus (GDM) persists. This study examines an alternative approach which combines information from all time-points on the glucose tolerance test (GTT) into a single index and expands the GDM spectrum into four categories using data from three geographically and ethnically distinct populations.\\n\\nMETHODSA retrospective observational study design was used. Data from Wisconsin, USA (723 women) was used in derivation of the criterion and data from Doha, Qatar (1284 women) and Cape Town, South Africa (220 women) for confirmation. Pregnant women without pre-existing diabetes with a GTT done between 23 and 30 weeks gestation were included. A novel index was derived from the GTT termed the weighted average glucose (wAG). This was categorized into four pre-defined groups (henceforth National Priorities Research Program (NPRP) criterion); i) normal gestational glycemia (NGG), ii) impaired gestational glycemia (IGG), iii) GDM and iv) high risk GDM (hGDM).\\n\\nRESULTSIn the Doha cohort, compared to the NGG group, the odds of large for gestational age babies increased 1.33 fold (P=0.432), 2.86 fold (P<0.001) and 3.35 fold (P<0.001) in the IGG, GDM and hGDM groups respectively. The odds of pregnancy induced hypertension increased 2.10 fold (P=0.024) in GDM & hGDM groups compared to the IGG and NGG groups. In the Cape Town cohort, a third of women in the GDM group and two-thirds in the hGDM group progressed to T2DM at 5 years.\\n\\nCONCLUSIONSThe NPRP categorization identifies four distinct risk clusters of glycemia in pregnancy which may aid better decision making in routine management, avoid potential over-diagnosis of women at lower risk of complications and assist with diabetes prevention in women at high-risk after an index pregnancy with GDM.\",\n \"Optimizing SARS-CoV-2 vaccination strategies in France: Results from a stochastic agent-based model\\nThe COVID-19 pandemic is a major global societal, economic and health threat. The availability of COVID-19 vaccines has raised hopes for a decline in the pandemic. We built upon a stochastic agent-based microsimulation model of the COVID-19 epidemic in France. We examined the potential impact of different vaccination strategies, defined according to the age, medical conditions, and expected vaccination acceptance of the target non-immunized adult population, on disease cumulative incidence, mortality, and number of hospital admissions. Specifically, we examined whether these vaccination strategies would allow to lift all non-pharmacological interventions (NPIs), based on a sufficiently low cumulative mortality and number of hospital admissions. While vaccinating the full adult non-immunized population, if performed immediately, would be highly effective in reducing incidence, mortality and hospital-bed occupancy, and would allow discontinuing all NPIs, this strategy would require a large number of vaccine doses. Vaccinating only adults at higher risk for severe SARS-CoV-2 infection, i.e. those aged over 65 years or with medical conditions, would be insufficient to lift NPIs. Immediately vaccinating only adults aged over 45 years, or only adults aged over 55 years with mandatory vaccination of those aged over 65 years, would enable lifting all NPIs with a substantially lower number of vaccine doses, particularly with the latter vaccination strategy. Benefits of these strategies would be markedly reduced if the vaccination was delayed, was less effective than expected on virus transmission or in preventing COVID-19 among older adults, or was not widely accepted.\",\n \"Selective tweeting of COVID-19 articles: Does title or abstract positivity influence dissemination?\\nBackgroundPrevious research has shown that articles may be cited more frequently on the basis of title or abstract positivity. Whether a similar selective sharing practice exists on Twitter is not well understood. The objective of this study was to assess if COVID-19 articles with positive titles or abstracts were tweeted more frequently than those with non-positive titles or abstracts.\\n\\nMethodsCOVID-19 related articles published between January 1st and April 14th, 2020 were extracted from the LitCovid database and all articles were screened for eligibility. Titles and abstracts were classified using a list of positive and negative words from a previous study. A negative binomial regression analysis controlling for confounding variables (2018 impact factor, open access status, continent of the corresponding author, and topic) was performed to obtain regression coefficients, with the p values obtained by likelihood ratio testing.\\n\\nResultsA total of 3752 COVID-19 articles were included. Of the included studies, 44 titles and 112 abstracts were positive; 1 title and 7 abstracts were negative; and 3707 titles and 627 abstracts were neutral. Articles with positive titles had a lower tweet rate relative to articles with non-positive titles, with a regression coefficient of -1.10 (P < .001), while the positivity of the abstract did not impact tweet rate (P = .2218).\\n\\nConclusionCOVID-19 articles with non-positive titles are preferentially tweeted, while abstract positivity does not influence tweet rate.\",\n \"An integrated genome and phenome-wide association study approach to understanding Alzheimer's disease predisposition\\nBackgroundGenome-wide association studies (GWAS) have identified common, heritable alleles that increase late-onset Alzheimers disease (LOAD) risk. We recently published an analytic approach to integrate GWAS and phenome-wide association study (PheWAS) data, enabling identification of candidate traits and trait-associated variants impacting disease risk, and apply it here to LOAD.\\n\\nMethodsPheWAS was performed for 23 known LOAD-associated single nucleotide polymorphisms (SNPs) and 4:1 matched control SNPs using UK Biobank data. Traits enriched for association with LOAD SNPs were ascertained and used to identify trait-associated candidate SNPs to be tested for association with LOAD risk (17,008 cases; 37,154 controls).\\n\\nResultsLOAD-associated SNPs were significantly enriched for associations with 6/778 queried traits, including three platelet traits. The strongest enrichment was for platelet distribution width (PDW) (P=1.2x10-5), but no consistent direction of effect was observed between increased PDW and LOAD susceptibility across variants or in Mendelian randomization analysis. Of 384 PDW-associated SNPs identified by prior GWAS, 36 were nominally associated with LOAD risk and 5 survived false-discovery rate correction for multiple testing. Associations confirmed known LOAD risk loci near PICALM, CD2AP, SPI1, and NDUFAF6, and identified a novel risk locus in the epidermal growth factor receptor (EGFR) gene.\\n\\nConclusionsThrough integration of GWAS and PheWAS data, we identify substantial pleiotropy between genetic determinants of LOAD and of platelet morphology, and for the first time implicate EGFR - a mediator of {beta}-amyloid toxicity - in Alzheimers disease susceptibility.\",\n \"SARS-CoV-2 infections in infants in Haiti 2020-2021; evidence from a serological cohort\\nBetween February 2019 and March 2021, 388 dried blood spot samples were obtained from 257 children <30 months of age who were part of a longitudinal maternal/infant cohort in Haiti. Among the children followed, 16.7% became seropositive; sampling date was the only covariate associated with the hazard of seroconversion.\",\n \"Liquid-biopsy transcriptomic profiling uncovers molecular mediators of resistance to androgen receptor signaling inhibition in lethal prostate cancer\\nAndrogen receptor signaling inhibitors (ARSi) are a mainstay for patients with metastatic castration-resistant prostate cancer (mCRPC). However, patient response is heterogeneous and the molecular underpinnings of ARSi resistance are not well elucidated. Here we performed transcriptome analysis of circulating tumor cells (CTCs) and peripheral blood mononuclear cells (PBMC) in the context of a prospective clinical trial of men with mCRPC treated with abiraterone (Abi) or enzalutamide (Enza). CTC RNA-sequencing identified that RB loss and enhanced E2F signaling along with BRCA loss transcriptional networks were associated with intrinsic ARSi resistance, while an inflammatory response signature was significantly associated with acquired resistance. Transcriptomic analysis of matching PBMCs identified enrichment of inflammasome gene signatures indicative of activated innate immunity at progression, with concurrent downregulation of T and NK cells. Importantly, CTC gene signatures had a significant positive association with circulating immune macroenvironment (CIME) signatures. Taken together, these data demonstrate that liquid biopsy transcriptomics can identify molecular pathways associated with clinical ARSi resistance paving the way for treatment optimization in patients with mCRPC.\",\n \"Regional Variation in COVID-19 Scarce Resource Allocation Protocols\\nBackgroundScarce resource allocation policies vary across the United States. Little is known about regional variation in hospital-level resource allocation protocols and variation in their application.\\n\\nObjectiveTo evaluate how scarce resource allocation policies throughout the Chicagoland area vary and whether there are differences in policy application within and amongst hospitals.\\n\\nDesignTwo cross-sectional surveys.\\n\\nSettingChicagoland hospitals.\\n\\nParticipantsRepresentatives from Chicagoland hospitals and triage officers at these hospitals.\\n\\nMeasurementsSurvey responses and categorical variables are described by frequency of occurrence. Intra- and interhospital variation in ranking of hypothetical patients was assessed using Kappa coefficients.\\n\\nResultsEight Chicago area hospitals responded to the survey assessing scarce resource allocation protocols. For hospitals willing to describe their specific ventilator allocation protocol (n=7), the initial scoring system varied with most utilizing the sequential organ failure assessment (SOFA) score (86%) and medical comorbidities (57%). A majority gave priority to pre-defined groups in their initial scoring system (86%), all discussed withdrawal of mechanical ventilation for adult patients (100%), and a minority had exclusion criteria (43%). Forty-nine triage officers from nine hospitals responded to the second survey. Triage officer rankings of hypothetical patients had slight agreement amongst all hospitals (Kappa 0.158) and fair agreement within two hospitals with the most respondents (Kappa 0.21 and 0.25). Almost half of triage officer respondents reported using tiebreakers to rank patients (N=23/49, 47%).\\n\\nConclusionAlthough most Chicago area hospitals surveyed created guidelines for resource allocation during the COVID-19 pandemic, these guidelines and application of these protocols by triage officers varied significantly.\\n\\nFunding SourceNone.\",\n \"A whole system approach to increasing childrens physical activity in a multi-ethnic UK city: a process evaluation protocol\\nBackgroundEngaging in regular physical activity requires continued complex decision-making in varied and dynamic individual, social and structural contexts. Widespread shortfalls of physical activity interventions suggests the complex underlying mechanisms of change are not yet fully understood. More insightful process evaluations are needed to design and implement more effective approaches. This paper describes the protocol for a process evaluation of the JU:MP programme, a whole systems approach to increasing physical activity in children and young people aged 5-14 years in North Bradford, UK.\\n\\nMethodsThis process evaluation, underpinned by realist philosophy, aims to understand the development and implementation of the JU:MP programme and the mechanisms by which JU:MP influences physical activity in children and young people. It also aims to explore behaviour change across wider policy, strategy and neighbourhood systems. A mixed method data collection approach will include semi-structured interview, observation, documentary analysis, surveys, and participatory evaluation methods including reflections and ripple effect mapping.\\n\\nDiscussionNot only is this an innovative approach to process evaluation but it will also feed into iterative programme development to generate evidence-based practice and deliver practice-based evidence. This paper advances knowledge regarding the development of process evaluations for evaluating systems interventions, and emphasises the importance of process evaluation.\",\n \"SARS-CoV-2 screening in patients in need of urgent inpatient treatment in the Emergency Department (ED) by digitally integrated point-of-care PCR: A clinical cohort study\\nPatients in need of urgent inpatient treatment were recruited prospectively. A rapid point of care PCR test (POC-PCR; Liat(R)) for SARS-CoV2 was conducted in the ED and a second PCR-test from the same swab was ordered in the central laboratory (CL-PCR). POC-PCR analyzers were digitally integrated in the laboratory information system.\\n\\nOverall, 160 ED patients were included. A valid POC-PCR-test result was available in 96.3% (n=154) of patients. N=16 patients tested positive for SARS-CoV-2 (10.0%). The POC PCR test results were available within 102 minutes (median, IQR: 56-211), which was significantly earlier compared to the CL PCR (811 minutes; IQR: 533-1289, p < 0.001). The diagnostic accuracy of the POC-PCR test was 100%. The implementation and digital LIS integration was successfully done. Staff satisfaction with the POC process was high.\\n\\nThe POC-PCR testing in the emergency department is feasible and shows a very high diagnostic performance.\\n\\nTrial registration: DRKS00019207\",\n \"Financial and Non-financial Conflicts of Interest Among the Japanese Government Advisory Board Members Concerning Coronavirus Disease 2019\\nObjectivesThis study aimed to assess the extent of conflicts of interest among the Japanese government COVID-19 advisory board members and elucidate the accuracy of conflicts of interest (COI) disclosure and management strategies.\\n\\nMethodsUsing the payment data from all 79 pharmaceutical companies in Japan between 2017 and 2018 and direct research grants from the Japanese government between 2019 and 2020, we evaluated the extent of financial and non-financial COI among all 20 Japanese government COVID-19 advisory board members.\\n\\nResultsJapanese government COVID-19 advisory board members were predominantly male (75.0%) and physicians (50.0%). Between 2019 and 2020, two members (10.0%) received a total of $819,244 in government research funding. Another five members (25.0%) received $419,725 in payments, including $223,183 in personal fees, from 28 pharmaceutical companies between 2017 and 2018. The average value of the pharmaceutical payments was $20,986 (standard deviation: $81,762). Further, neither the Ministry of Health, Labor, and Welfare nor the Japanese Cabinet Secretariat disclosed financial or non-financial COI with industry. Further, the government and had no policies for managing COI among advisory board members.\\n\\nConclusionsThis study found that the Japanese government COVID-19 advisory board had financial and non-financial COI with pharmaceutical companies and the government. Further, there were no rigorous COI management strategies for the COVID-19 advisory board members. Any government must ensure the independence of scientific advisory boards by implementing more rigorous and transparent management strategies that require the declaration and public disclosure of all COI.\",\n \"Implementation of Mercury Biomonitoring in German Adults using Dried Blood Spot Sampling in Combination with Direct Mercury Analysis\\nVenous blood is a preferred matrix for the determination of total mercury (Hg) in human biomonitoring but has some drawbacks such as the requirement for an uninterrupted cold chain for transport and storage and the need of medical personnel for sample collection. Therefore, we tested and implemented a simpler and less expensive method for measuring Hg in human blood using dried blood spots (DBS). For method development, we investigated the influence of different storage conditions (temperature, storage vessel, time) on DBS samples. For method validation, we compared DBS and venous blood and investigated whether DBS sampling is suitable for measuring Hg in the general population in countries with low Hg exposure such as Germany. Based on our results, we found that pre-cleaned glass tubes were most suitable for storage of DBS samples, as this allowed the samples to remain stable for at least four weeks even at high temperatures (40{degrees}C). When comparing venous blood and DBS, a very good correlation (r=0.95, p<0.01) and high precision of DBS (mean relative standard deviation 8.2% vs. 7.2% in venous blood samples) were observed. Comparing the recoveries of both matrices in different concentration ranges, the scattering of the recoveries decreases with increasing Hg concentration. The same applies to the mean recoveries. Overall, we found comparable results for DBS and whole blood using direct Hg analysis. Furthermore, we demonstrated that DBS are suitable for Hg biomonitoring in the general population in Germany and improved the storage conditions for the DBS.\",\n \"Environment-wide association study (EWAS) on cardiometabolic traits: A systematic assessment of the association of lifestyle variables on a longitudinal setting\\nThe present study aims to assess the over-time association of [~]300 lifestyle exposures with nine cardiometabolic traits with the ultimate aim of identifying exposures/exposure groups that could inform lifestyle interventions aiming at controlling cardiometabolic diseases. The analyses were undertaken in a longitudinal sample comprising >31000 adults living in northern Sweden. Linear mixed models were used to assess the average associations of lifestyle exposures and linear regression models were used to test association with 10-year change of the cardiometabolic traits. Physical activity and General Health were the exposure categories containing the highest number of tentative signals in analyses assessing the average association of lifestyle variables, while Tobacco use was the top-category for the 10-year change association analyses. Thirteen modifiable variables showed a consistent average association among the majority of cardiometabolic traits. These variables belonged to four main groups: i) Smoking, ii) Diet (secoisolariciresinol intake and brewed coffee), iii) Leisure time physical activity and iv) a group of variables more specific to the Swedish lifestyle (snuff status, hunting/fishing during leisure time and boiled coffee). Interestingly, sweet drinks, fish intake and salt content, all lifestyle exposures frequently mentioned in public health recommendations were not broadly associated with the analysed cardiometabolic traits.\",\n \"Repeated introductions and intensive community transmission fueled a mumps virus outbreak in Washington State\\nIn 2016/2017, Washington State experienced a mumps outbreak despite high childhood vaccination rates, with cases more frequently detected among school-aged children and members of the Marshallese community. We sequenced 166 mumps virus genomes collected during outbreaks in Washington and other US states, and apply phylodynamic approaches to trace mumps introductions and transmission within Washington. We uncover that mumps was introduced into Washington at least 13 times, primarily from Arkansas, sparking multiple co-circulating transmission chains. Neither vaccination status nor age were strong determinants of transmission. Instead, the outbreak in Washington was overwhelmingly sustained by transmission within the Marshallese community. Our findings underscore the utility of genomic data to clarify epidemiologic factors driving transmission, and pinpoint contact networks as critical determinants of mumps transmission. These results imply that contact structures and historic disparities may leave populations at increased risk for respiratory virus disease even when a vaccine is effective and widely used.\",\n \"Mitigating the identity and health threat of COVID-19: Perspectives of Middle-Class South Asians living in the UK\\nThe recognition and representation of BAME community as \\\"high risk\\\" of Covid-19 in the UK presents both a health and an identity threat to this ethnic group. This study employed thematic analysis to explore response to these threats as related by a sample of thirteen middle class members of the South Asian community. This work advances both health and identity psychological theory by recognising the affinity between expressions of health efficacy and identity. Our findings identify South Asian intragroup stigmatisation and commonalities that have implications for the promotion of health behaviour and health communications for minority groups.\",\n \"Presence of Major Depressive Disorder influences both neuropsychiatric symptoms and the cognitive profile in Mild Cognitive impairment and Alzheimers disease\\nObjectivesThe impact of depression, as quantified with specific tests, and neuropsychiatric symptoms (NPS) on mnesic and executive performance has been documented previously. However, the depression can be also diagnosed as Major Depressive Disorder (MDD) based on the DSM-V. We aimed to determine how MDD influences NPS and cognitive performance in Alzheimers disease (AD), Mild Cognitive Impairment (MCI) and Healthy Controls (CH).\\n\\nParticipants647 HC, 291 patients with MCI and 208 patients with AD were extracted from the National Alzheimers Coordinating Center database.\\n\\nMeasurementsDuring their inclusion in the cohort, each patient was assessed by a physician to distinguish those with a diagnosis of MDD from those without MDD. Patients were assessed with the NeuroPsychiatric Inventory and a comprehensive cognitive assessment. We performed logistic regression and a MANCOVA models respectively with NPS and cognitive performance as variables of interest and MDD as fixed factors within each group. The MANCOVA was controlled for the effects of age, sex, and education.\\n\\nResultsOur results exhibited that: MDD was associated with and predicted psychotic, affective and behavioral NPS in MCI, and affective/behavioral NPS in CH and AD; MCI with MDD had lower performance of selective attention and mental flexibility whereas AD with MDD had better working memory performance, than those without MDD.\\n\\nConclusionsMDD was mainly associated with higher prevalence of NPS in CH and both level of cognitive decline. This suggest that early treatment of MDD could reduce essentially neuropsychiatric symptomatology and caregiver mental burden.\",\n \"Association between benzodiazepine receptor agonist use and increased mortality among patients hospitalized for COVID-19: results from an observational study\\nObjectiveTo examine the association between benzodiazepine receptor agonist (BZRA) use and mortality in patients hospitalized for COVID-19.\\n\\nMethodsWe conducted an observational multicenter retrospective cohort study at AP-HP Greater Paris University hospitals. The sample involved 14,381 adult patients hospitalized for COVID-19. 686 (4.8%) inpatients received a BZRA within at the time of hospital admission at a mean daily diazepam-equivalent dose of 19.7 mg (SD=25.4). The study baseline was the date of hospital admission and the primary endpoint was death. We compared this endpoint between patients who received BZRAs and those who did not in time-to-event analyses adjusted for patient characteristics (such as age, sex, obesity and comorbidity) and other medications. The primary analysis was a Cox regression model with inverse probability weighting (IPW).\\n\\nResultsOver a mean follow-up of 14.5 days (SD=18.1), the primary endpoint occurred in 186 patients (27.1%) who received a BZRA and in 1,134 patients (8.3%) who did not. There was a significant association between BZRA use and increased mortality both in the crude analysis (HR=3.20; 95% CI=2.74-3.74; p<0.01) and in the primary IPW analysis (HR=1.61; 95% CI=1.31-1.98, p<0.01), with a significant dose-dependent relationship (HR=1.55; 95% CI=1.08-2.22; p=0.02). This association remained significant in multiple sensitivity analyses.\\n\\nConclusionsBZRA use was associated with increased mortality among patients hospitalized for COVID-19 with a dose-dependent relationship, suggesting a potential benefit of decreasing dose or tapering off these medications when possible in these patients.\",\n \"A Design Thinking Approach to Enhance Interprofessional Education Between Technology and Medicine for Innovative Elder Pain Care.\\nBackgroundDesign thinking (DT) describes three stages in the design thinking cycle: 1) inspiration, which embodies the initial problem or opportunity; 2) ideation, which encompasses the development and refinement of ideas; and 3) implementation, which involves the introduction and application of the derived solution.\\n\\nMethodThe prospective educational program evaluation July 2020 - December 2020. A 150 min interactive workshop regarding developing innovative elder pain care. Medical students will be grouping into four medical students: 1 technological student. Then they will be assigned to match with a technology student. The interprofessional education design thinking activity consists of three parts; a brief introduction, the brainstorming process to identified pain points by persona and user journey to generate the idea, and the prototype presentation.\\n\\nResultsForty sixth-year medical students and twelve technological students participated. 58% of medical students and 95% of technological students perceived DT as very helpful for their careers. However, only 30% of medical students and 60% of technological students were inspired to develop actual prototypes after the course. Nearly all of the students responded they comfortable with this interdisciplinary project-based style. Still, the time of the workshop is too limited, and among those responding with no interest pursue the project gave a reason that they lack time after rotating to other courses.\\n\\nConclusionMost medical students and technological students perceived DT as beneficial for their career and displayed satisfy in this co-project style. However, finding matched schedule of two disciplines made long-term interpersonal education challenging.\",\n \"Prospective validation of host transcriptomic biomarkers for pulmonary tuberculosis by real-time PCR\\nWe tested performance of host-blood transcriptomic tuberculosis (TB) signatures for active case-finding. Among 20,207 HIV-uninfected and 963 HIV-infected adults screened; 2,923 and 861 were enrolled from five South African communities. Eight signatures were measured by microfluidic RT-qPCR and participants were microbiologically-investigated for pulmonary TB at baseline, and actively surveilled for incident disease through 15 months. Diagnostic AUCs for 61 HIV-uninfected (weighted-prevalence 1.1%) and 10 HIV-infected (prevalence 1.2%) prevalent TB cases for the 8 signatures were 0.63-0.79 and 0.65-0.88, respectively. Thereafter, 24 HIV-uninfected and 9 HIV-infected participants progressed to incident TB (1.1 and 1.0 per 100 person-years, respectively). Prognostic AUCs through 15-months follow-up were 0.49-0.66 and 0.54-0.81, respectively. Prognostic performance for incident TB occurring within 6-12 months in HIV-negative participants was higher for all signatures. None of the signatures met WHO Target Product Profile criteria for a triage test to diagnose asymptomatic TB; most signatures met the criteria for symptomatic TB. Prognostic accuracy of most signatures for incident TB within six months of testing met the criteria for an incipient TB test.\",\n \"Spotlight on the dark figure: Exhibiting dynamics in the case detection ratio of COVID-19 infections in Germany\\nThe case detection ratio of COVID-19 infections varies over time due to changing testing capacities, modified testing strategies and also, apparently, due to the dynamics in the number of infected itself. In this paper we investigate these dynamics by jointly looking at the reported number of detected COVID-19 infections with non-fatal and fatal outcomes in different age groups in Germany. We propose a statistical approach that allows us to spotlight the case detection ratio and quantify its changes over time. With this we can adjust the case counts reported at different time points so that they become comparable. Moreover we can explore the temporal development of the real number of infections, shedding light on the dark number. The results show that the case detection ratio has increased and, depending on the age group, is four to six times higher at the beginning of the second wave compared to what it was at the peak of the first wave. The true number of infection in Germany in October was considerably lower as during the peak of the first wave, where only a small fraction of COVID-19 infections were detected. Our modelling approach also allows quantifying the effects of different testing strategies on the case detection ratio. The analysis of the dynamics in the case detection rate and in the true infection figures enables a clearer picture of the course of the COVID-19 pandemic.\",\n \"Transmission blocking activity of low dose tafenoquine in healthy volunteers experimentally infected with Plasmodium falciparum\\nBackgroundBlocking the transmission of parasites from humans to mosquitoes is a key component of malaria control. Tafenoquine exhibits activity against all stages of the malaria parasite and may have utility as a transmission blocking agent. We aimed to characterize the transmission blocking activity of low dose tafenoquine.\\n\\nMethodsHealthy adults were inoculated with P. falciparum 3D7-infected erythrocytes on day 0. Piperaquine was administered on days 9 and 11 to clear asexual parasitemia while allowing gametocyte development. A single 50 mg oral dose of tafenoquine was administered on day 25. Transmission was determined by enriched membrane feeding assays pre-dose and at 1, 4 and 7 days post-dose. Artemether-lumefantrine was administered following the final assay. Outcomes were the reduction in mosquito infection and gametocytemia post-tafenoquine, and safety parameters.\\n\\nResultsSix participants were enrolled, and all were infective to mosquitoes pre-tafenoquine, with a median 86% (range: 22-98) of mosquitoes positive for oocysts and 57% (range: 4-92) positive for sporozoites. By day 4 post-tafenoquine, the oocyst and sporozoite positivity rate had reduced by a median 35% (IQR: 16-46) and 52% (IQR: 40-62), respectively, and by day 7, 81% (IQR 36-92) and 77% (IQR 52-98), respectively. The decline in gametocyte density post-tafenoquine was not significant. No significant participant safety concerns were identified.\\n\\nConclusionLow dose tafenoquine reduces P. falciparum transmission to mosquitoes, with a delay in effect.\\n\\nTrial registrationAustralian New Zealand Clinical Trials Registry (ACTRN12620000995976).\\n\\nFundingQIMR Berghofer Medical Research Institute.\",\n \"A Systematic Review of Datasets to Research the Effect of Policy and Place on Immigrant Health\\nState and local immigrant policies--which regulate immigrants rights and access to services and material resources--shape self-rated health and health care access for Hispanic/Latino immigrants. However, due to data limitations, we know little about their impacts on non-Hispanic immigrants or on objective measures of health. To help researchers address these gaps, this systematic review creates a comprehensive resource indexing nationally-representative US datasets that can be used to measure the effects of policy and place on immigrant health. Following PRISMA guidelines, I searched ICPSR and federal data repositories for nationally-representative, population-based, longitudinal or repeated cross-sectional datasets that included health/health care access, race/ethnicity, and state or county of residence. I extracted information about race, ethnicity, migration, language, and geocodes in each dataset for each year, 2005-2021. Data searches (final search December 2021) identified 54 datasets, many of which have never been used to study the effects of policies on immigrant health. These data sources have unexploited potential to advance this literature. For example, longitudinal data sources will allow researchers to examine the effects of policies on the same individuals over time, while datasets with detailed measures of race/ethnicity and migration can be used to distinguish which immigrants are most impacted.\",\n \"Hypothesis-free detection of gene-interaction effects on biomarker concentration in UK Biobank using variance prioritisation\\nBlood biomarkers include disease intervention targets that may interact with genetic and environmental factors resulting in subgroups of individuals who respond differently to treatment. Such interactions may be observed in genetic effects on trait variance. Variance prioritisation is an approach to identify genetic loci with interaction effects by estimating their association with trait variance, even where the modifier is unknown or unmeasured. Here, we develop and evaluate a regression-based Brown-Forsythe test and variance effect estimate to detect such interactions. We provide scalable open-source software (varGWAS) for genome-wide association analysis of SNP-variance effects (https://github.com/MRCIEU/varGWAS) and apply our software to 30 blood biomarkers in UK Biobank. We find 468 variance quantitative trait loci across 24 biomarkers and follow up findings to detect 82 gene-environment and six gene-gene interactions independent of strong scale or phantom effects. Our results replicate existing findings and identify novel epistatic effects of TREH rs12225548 x FUT2 rs281379 and TREH rs12225548 x ABO rs635634 on alkaline phosphatase and ZNF827 rs4835265 x NEDD4L rs4503880 on gamma glutamyltransferase. These data could be used to discover possible subgroup effects for a given biomarker during preclinical drug development.\",\n \"Fear among Syrians: a Proposed Cutoff Score and Validation of the Arabic Fear of COVID-19 Scale- A National Survey\\nCOVID-19 pandemic has led to psychological health issues one of which is fear. This study validates the Arabic version of the fear of COVID-19 scale and suggests a new cutoff score to measure fear of COVID-19 among the Syrian Population. A total of 3989 participants filled an online survey consisting of socio-demographic information, the fear of COVID-19 scale, the patient health questionnaire 9-item, and the generalized anxiety disorder 7-item. Receiver operating characteristic analysis was used to define cutoff scores for the fear of COVID-19 scale in relation to generalized anxiety disorder 7-item and the patient health questionnaire 9-item. The Cronbach value of the Arabic fear of COVID-19 scale was 0.896, revealing good stability and internal consistency. The inter-item correlations were between [0.420 - 0.868] and the corrected item-total correlations were between [0.614 - 0.768]. A cutoff point of 17.5 was deduced from analysis. According to the deduced cutoff point, 2111(52.9%) were classified as cases with extreme fear. This cutoff score deduced from this study can be used for screening purposes to identify individuals that may be most vulnerable towards developing extreme fear of COVID-19. Therefore, early preventive and supportive measures can then be delivered.\",\n \"Polygenic risk score and statin relative risk reduction for primary prevention in a real-world population\\nAbstractsO_ST_ABSBackgroundC_ST_ABSRandomized-controlled trials demonstrate that high coronary heart disease (CHD) polygenic risk score modifies statin CHD relative risk reduction, but it is unknown if the association extends to statin users undergoing routine care.\\n\\nObjectivesThe primary objective was to determine how statin effectiveness is modified by CHD polygenic risk score in a real-world cohort of primary prevention participants.\\n\\nMethodsWe determined polygenic risk scores in participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. Cox regression models were used to compare the risk of the cardiovascular outcomes between statin users and matched nonusers.\\n\\nResultsThe hazard ratio (HR) for statin effectiveness on incident myocardial infarction was similar within 10-year atherosclerotic cardiovascular disease (ASCVD) risk score groups at 0.65 (95% confidence interval [CI] 0.39-1.08; P=0.10), 0.65 (95% CI 0.56-0.77; P=2.1E-7), and 0.67 (95% CI 0.57-0.80; P=4.3E-6) for borderline, intermediate, and high ASCVD groups, respectively. In contrast, statin effectiveness by polygenic risk was largest in the high polygenic risk score group (HR 0.62, 95% CI 0.50-0.77; P=1.4E-5), intermediate in the intermediate polygenic risk score group (HR 0.70, 95% CI 0.61-0.80; P=5.7E-7), and smallest in the low polygenic risk score group (HR 0.86, 95% CI 0.65-1.16; P=0.33). ASCVD risk and statin LDL-C lowering did not differ across polygenic risk score groups.\\n\\nConclusionsIn primary prevention patients undergoing routine care, CHD polygenic risk modified statin relative risk reduction of incident myocardial infarction independent of statin LDL-C lowering. Our findings extend prior work by identifying a subset of patients with attenuated clinical benefit from statins.\",\n \"Topographic volume-standardization atlas of the human brain\\nObjectiveSpecific anatomical patterns are seen in various diseases affecting the brain. Clinical studies on the topography of pathologies are often limited by the absence of a normalization of the prevalence of pathologies to the relative volume of the affected anatomical structures. A comprehensive reference on the relative volumes of clinically relevant anatomical structures serving for such a normalization, is currently lacking.\\n\\nMethodsThe analyses are based on anatomical high-resolution three-dimensional T1-weighted magnetic resonance imaging data of 30 healthy Caucasian volunteers, including 14 females (mean age 37.79 years, SD 13.04) and 16 males (mean age 38.31 years, SD 16.91). Semi-automated anatomical segmentation was used, guided by a neuroanatomical parcellation algorithm differentiating 96 structures. Relative volumes were derived by normalizing parenchymal structures to the total individual encephalic volume and ventricular segments to the total individual ventricular volume.\\n\\nResultsThe present investigation provides the absolute and relative volumes of 96 anatomical parcellation units of the human encephalon. A larger absolute volume in males than in females is found for almost all parcellation units. While parenchymal structures display a trend towards decreasing volumes with increasing age, a significant inverse effect is seen with the ventricular system. The variances in volumes as well as the effects of gender and age are given for each structure before and after normalization.\\n\\nConclusionThe provided atlas constitutes an anatomically detailed and comprehensive analysis of the absolute and relative volumes of the human encephalic structures using a clinically oriented parcellation algorithm. It is intended to serve as a reference for volume-standardization in clinical studies on the topographic prevalence of pathologies.\",\n \"Prediction and predictor elucidation of the onset of metabolic syndrome among young workers using machine learning techniques: A nationwide study in Japan\\nObjectivesPredictive models for the onset of metabolic syndrome (MS) among people in their 30s are scarce. This study aimed to construct a highly accurate model to predict MS onset by age 40 years and to identify the important predictors of MS onset using health checkup data of Japanese company employees aged 30 and 35.\\n\\nMethodsThe study included 6,048 Japanese employees aged 40 years who had undergone periodic health examinations over 10 years. We developed prediction models for MS onset using machine learning methods including the random forest and logistic regression, and evaluated the models using the receiver operating characteristics and precision-recall curves. For the random forest models, the variable importance of each explanatory variable was calculated to identify important predictors of MS onset.\\n\\nResultsThe random forest had higher predictive power than logistic regression in all models, although the differences were non-significant. Regarding important predictors, diastolic blood pressure was the most important predictor of MS onset for men aged 30 and 35 years, while body mass index was the most important predictor for women aged 30 and 35 years.\\n\\nConclusionsWe created a machine learning model to predict MS onset at age 40 with high accuracy from health examination data obtained at ages 30 or 35. Sex differences in important predictors of MS onset was shown by the variable importance indices of the random forest. Applying our model in routine healthcare management should provide early and appropriate health interventions to prevent MS onset in young people.\",\n \"Incorporating the mutational landscape of SARS-COV-2 variants and case-dependent vaccination rates into epidemic models\\nCoronavirus Disease (COVID-19), which began as a small outbreak in Wuhan, China in December 2019, became a global pandemic within months due to its high transmissibility. In the absence of pharmaceutical treatment, various non-pharmaceutical interventions (NPIs) to contain the spread of COVID-19 brought the entire world to a halt. After almost a year of seemingly returning to normalcy with the worlds quickest vaccine development, the emergence of more infectious and vaccine resistant coronavirus variants is bringing the situation back to where it was a year ago. In the light of this new situation, we conducted a study to portray the possible scenarios based on the three key factors : impact of interventions (pharmaceutical and NPIs), vaccination rate, and vaccine efficacy. In our study, we assessed two of the most crucial factors, transmissibility and vaccination rate, in order to reduce the spreading of COVID-19 in a simple but effective manner. In order to incorporate the time-varying mutational landscape of COVID-19 variants, we estimated a weighted transmissibility composed of the proportion of existing strains that naturally vary over time. Additionally, we consider time varying vaccination rates based on the number of daily new cases. Our method for calculating the vaccination rate from past active cases is an effective approach in forecasting probable future scenarios as it actively tracks peoples attitudes toward immunization as active cases change. Our simulations show that if a large number of individuals cannot be vaccinated by ensuring high efficacy in a short period of time, adopting NPIs is the best approach to manage disease transmission with the emergence of new vaccine breakthrough and more infectious variants.\",\n \"The reliability of two prospective cortical biomarkers for pain: EEG peak alpha frequency and TMS corticomotor excitability\\nMany pain biomarkers fail to move from discovery to clinical application, attributed to poor reliability and feasible classifications of at-risk individuals. Preliminary evidence has shown that higher pain sensitivity is associated with slow peak alpha frequency (PAF) and depression of corticomotor excitability (CME). The present study evaluated the reliability of these measures, specifically whether, over several days of pain, a) PAF remains stable and b) individuals show two stable and distinct CME responses: facilitation and depression. Seventy-five healthy participants were given an injection of nerve growth factor (NGF) into the right masseter muscle on Day 0 and Day 2, inducing sustained pain. Electroencephalography (EEG) to assess PAF and transcranial magnetic stimulation (TMS) to assess CME were recorded on Day 0, Day 2 and Day 5. PAF reliability was in the excellent range even without standard pre-processing and [~]2 minutes recording length. Moreover, two distinct and stable CME responses were demonstrated: facilitation and depression. These findings support the notion that PAF is a stable trait characteristic, with reliability unaffected by pain, and excellent reliability achievable with minimal pre-processing and [~]2 minutes recording, making it a readily translatable biomarker. Furthermore, the study showed novel evidence of two stable corticomotor adaptations to sustained pain. Overall, the study provides support for the reliability of PAF and CME as prospective cortical biomarkers.\",\n \"Effects of medical school on mental health and sleep habits\\nBACKGROUND and OBJECTIVESThis study aims to define changes in anxiety and depression among medical students while evaluating the association of sleep habits and other risk factors, including exercise habits and a diagnosis of chronic disease. The effect of the COVID-19 pandemic was also evaluated.\\n\\nDESIGNA cohort of first- and second-year medical students was evaluated longitudinally using survey methods to quantify changes from pre-medical school and summer break to each semester in medical school throughout years one and two.\\n\\nMETHODSData was analyzed using Generalized Linear Mixed Models (GLMMs) on the numeric responses of General Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and Pittsburg Sleep Quality Index. Additional assessments evaluated exercise habits, chronic disease, and impact of COVID-19 Pandemic.\\n\\nRESULTSDepression, anxiety, and sleep habits displayed a cyclical change that was associated with the academic cycle. The COVID-19 pandemic was never significant. Medical students who had a chronic disease diagnosis had increased severity. Exercise did not play a role.\\n\\nCONCLUSIONThe main driver for depression, anxiety, and poor sleep quality was the academic cycle, while the COVID-19 pandemic did not have an impact on mental health.\",\n \"The Reliability and Validity of the Hebrew Patient Health Questionnaire (PHQ-9) in the General Population\\nObjectiveTo assess the psychometric properties of the Hebrew version of the Patient Health Questionnaire (PHQ-9) in the general population.\\n\\nMethodsUsing an online survey, we assessed test-retest reliability with a two-week time interval. A total of 118 participants enrolled in the study, of whom 103 completed the survey twice. Each participant filled out the PHQ-9 and the 12-Item Short Form Survey (SF-12). Our statistical analysis includes Cronbachs alpha, Intraclass Correlation Coefficient (ICC2,1), Spearmans rank correlation coefficient, Standard Error of Measurement (SEM), and Minimal Detectable Change (MDC).\\n\\nResultsInternal consistency of the Hebrew version of the PHQ-9 ranged from =0.79-0.83. The test-retest reliability of the questionnaire is good (ICC2,1= 0.81), and it is moderately and negatively correlated to the mental component of the SF-12 (Spearman {rho}= -0.57, p< .05). The SEM of the PHQ-9 is 1.83 points, and the MDC was found to be 5 points.\\n\\nConclusionThe Hebrew version of the PHQ-9 is valid and reliable for screening self-reported depressive symptoms online in the general Hebrew-speaking population.\",\n \"Proactive COVID-19 testing in a partially vaccinated population\\nDuring the initial stages of the COVID-19 pandemic, many workplaces and universities implemented institution-wide proactive testing programs of all individuals, ir-respective of symptoms. These measures have proven effective in mitigating outbreaks. As a greater fraction of the population becomes vaccinated, we need to understand what continued benefit, if any, proactive testing can contribute. Here, we address this problem with two distinct modeling approaches: a simple analytical model and a more simulation using the SEIRS+ platform. Both models indicate that proactive testing remains useful until a threshold level of vaccination is reached. This threshold depends on the transmissibility of the virus and the scope of other control measures in place. If a community is able to reach the threshold level of vaccination, testing can cease. Otherwise, continued testing will be an important component of disease control. Because it is usually difficult or impossible to precisely estimate key parameters such as the basic reproduction number for a specific workplace or other setting, our results are more useful for understanding general trends than for making precise quantitative predictions.\",\n \"The genetic architecture of human infectious diseases and pathogen-induced cellular phenotypes\\nHere, we develop a genetics-anchored framework to decipher mechanisms of infectious disease (ID) risk and infer causal effect on potential complications. We perform transcriptome-wide association studies (TWAS) of 35 ID traits in 27,615 individuals in a broad collection of human tissues, identifying 70 gene-level associations with 26 ID traits, with replication in two large-scale biobanks. A phenome-scale scan and Mendelian Randomization of the 70 gene-level associations across 197 traits proposes a molecular basis for known complications of the ID traits. This rich resource of host genetic associations with pathogen cultures and 16S-rRNA-based microbiome variation provides a platform to investigate host-pathogen interactions. To identify relevant cellular processes, we develop a TWAS repository of 79 pathogen-exposure induced cellular phenotypes. Our study will facilitate mechanistic insights into the role of host genetic variation on ID risk and pathophysiology, with important implications for our molecular understanding of severe phenotypic outcomes.\",\n \"Association between Systemic Lupus Erythematosus and Coronary Heart Disease: a retrospective case-control analysis and Mendelian Randomization Study\\nObjectivesTo appraise the causal effect of systemic lupus erythematosus (SLE) for risk of Coronary heart disease (CHD).\\n\\nMethodsWe selected single nucleotide polymorphisms (SNPs) associated with SLE as instrumental variables (IVs) from three independent genome-wide association studies (GWAS), the three largest to date for SLE of European ancestry. Then we conducted two-sample Mendelian randomization (2SMR) analyses to estimate the effects of IVs on the odds of CHD and traditional coronary risk factors (including high LDL cholesterol levels, low HDL cholesterol levels, Apolipoprotein A-I, Apolipoprotein B, diabetes mellitus, and hypertension). Additionally, we searched for common risk loci between SLE and premature coronary atherosclerosis. Furthermore, we retrospectively reviewed the lipid profile of treatment-naive SLE patients and age-matched healthy controls.\\n\\nResultsGenetically predicted SLE did not increase the odds of CHD. Nevertheless, we found mild causal relationships between SLE and decreased HDL cholesterol levels, and between SLE and decreased apolipoprotein A-I. There was one common risk locus (rs597808) between SLE and premature coronary atherosclerosis at a genome-wide significance level (P<5 x 10-8). Retrospective analysis showed decreased HDL-cholesterol (0.98{+/-}0.516mmol/L vs. 1.46{+/-}0.307mmol/L in female, 0.76{+/-}0.199mmol/L vs. 1.19{+/-}0.257mmol/L in male; both P<0.001) and apolipoprotein A-I (1.06{+/-}0.314g/L vs. 1.37{+/-}0.205g/L in female, 0.87{+/-}0.174g/L vs. 1.24{+/-}0.200g/L in male; both P<0.001) in naive SLE patients.\\n\\nConclusionSLE may accelerate coronary atherosclerosis in young patients by reducing HDL cholesterol and apolipoprotein A-I intrinsically, but it seems not to play a predominant role in CHD development in old patients.\",\n \"Addressing selection bias in the UK Biobank neurological imaging cohort\\nThe UK Biobank is a national prospective study of half a million participants between the ages of 40 and 69 at the time of recruitment between 2006 and 2010, established to facilitate research on diseases of aging. The imaging cohort is a subset of UK Biobank participants who have agreed to undergo extensive additional imaging assessments. However, Fry et al. (2017) finds evidence of \\\"healthy volunteer bias\\\" in the UK Biobank - participants are less likely to smoke, be obese, consume alcohol daily than the target population of UK adults. Here we examine selection bias in the UK Biobank imaging cohort. We address two common misconceptions: first, that study size can compensate for bias in data collection, and second that selection bias does not affect estimates of associations, which are the primary interest of the UK Biobank. We introduce inverse probability weighting (IPW) as an approach commonly used in survey research that can be used to address selection bias in volunteer health studies like the UK Biobank. We discuss 6 such methods - five existing and one novel -, assess relative performance in simulation studies, and apply them to the UK Biobank imaging cohort. We find that our novel method, BART for predicting the probability of selection combined with raking, performs well relative to existing methods, and helps alleviate selection bias in the UK Biobank imaging cohort.\",\n \"Metacognitive insight into cognitive performance in pre and early-stage Huntington's disease\\nObjectivesInsight is an important predictor of quality of life in Huntingtons disease and other neurodegenerative conditions. However, estimating insight with traditional methods such as questionnaires is challenging and subject to limitations. This cross-sectional study experimentally quantified metacognitive insight into cognitive performance in Huntingtons disease gene-carriers.\\n\\nMethodsWe dissociated perceptual decision-making performance and metacognitive insight into performance in healthy controls (n=29), premanifest (n=19) and early-manifest (n=10) Huntingtons disease gene-carriers. Insight was operationalised as the degree to which a participants confidence in their performance was informative of their actual performance (metacognitive efficiency) and estimated using a computational model (HMeta-d).\\n\\nResultsWe found that pre and early-manifest Huntingtons disease gene-carriers were impaired in making perceptual decisions compared to controls. Gene-carriers required more evidence in favour of the correct choice to achieve similar performance and perceptual impairments were increased in those with manifest disease. Surprisingly, despite marked perceptual impairments, Huntingtons disease gene-carriers retained metacognitive insight into their perceptual performance. This was the case after controlling for confounding variables and regardless of disease stage.\\n\\nConclusionWe report for the first time a dissociation between impaired cognition and intact metacognition (trial-by-trial insight) in the early-stages of a neurodegenerative disease. This unexpected finding contrasts with the prevailing assumption that cognitive deficits are associated with impaired insight. Future studies should investigate how intact metacognitive insight could be used by some early Huntingtons disease gene-carriers to positively impact their quality of life.\",\n \"Longitudinal DNA Methylation Profiling of the Rectal Mucosa Identifies Cell-specific Signatures of Disease Status, Severity and Clinical Outcomes in Ulcerative Colitis\\nIn peripheral blood, DNA methylation (DNAm) patterns in inflammatory bowel disease patients reflect inflammatory status rather than disease status. Here, we studied DNAm in diseased rectal mucosa from ulcerative colitis (UC) patients, conducting a cell-type-specific EWAS in epithelial, immune and fibroblast cells to understand DNAm changes across disease states, course, and clinical outcomes. At diagnosis, rectal mucosa in UC exhibited a lower proportion of epithelial cells and fibroblasts, and higher proportion of immune cells, along with 3504, 910, and 2279 altered DNAm sites as detected in our cell-specific EWAS, respectively. While treatment had significant effects on DNAm of immune cells, its effects on fibroblasts and epithelial cells were attenuated. Those requiring colectomy exhibited cell composition and DNAm patterns at follow-up more like disease onset than patients who did not require colectomy. Collectively DNAm and gene expression analysis suggest that targeting epithelial genes involved in barrier function may improve clinical outcomes.\",\n \"ADVANCED AUTOLOGOUS LOWER DERMAL SLING TECHNIQUE FOR IMMEDIATE BREAST RECONSTRUCTION SURGERY IN SMALL AND NON-PTOTIC BREASTS\\nBackgroundBreast reconstruction with an autologous lower dermal sling (ALDS) is an established one-stage procedure in patients with moderate to large ptotic breasts. However, this technique is difficult to perform in small and non/minimally ptotic breasts. We describe our experiences from a single institution about a novel Advanced Autologous Lower Dermal Sling (A-ALDS) technique for reconstruction in small breasts.\\n\\nMethodsWe performed one stage nipple/skin sparing mastectomies in 61 patients with immediate reconstruction either by conventional immediate breast reconstruction surgery or A-ALDS technique.\\n\\nResultsMean age of study patients was 46.9 years. We observed significantly better cosmetic score and lower immediate complication rate vis-a-vis skin necrosis, implant loss with the A-ALDS technique (i.e., nil versus 3 in Conventional Immediate Breast Reconstruction Surgery - IBRS). 40 patients completed 12 months follow-up. The PROMs-Patient Reported Outcomes Measures (Breast-Q) revealed good to excellent scores for satisfaction with breast, cosmetic outcome and psychosocial well-being in patients operated with both these techniques. However, sexual well-being was significantly better in the A-ALDS group.\\n\\nConclusionThe A-ALDS is a novel, cost-effective and safe technique for immediate one stage implant-based reconstruction for small breasts. It provides a dermal barrier flap and hence, ensures less complications, excellent cosmetic results and patient satisfaction.\",\n \"HIV testing uptake according to opt-in, opt-out or risk-based testing approaches: a systematic review and meta-analysis\\nPurpose of reviewImproving HIV testing uptake is essential to ending the HIV pandemic. HIV testing approaches can be opt-in, opt-out or risk-based. This systematic review examines and compares the uptake of HIV testing in opt-in, opt-out and risk-based testing approaches.\\n\\nRecent findingsThere remains missed opportunities for HIV testing in a variety of settings using different approaches: opt-in (a person actively accepts to be tested for HIV), opt-out (a person is informed that HIV testing is routine/standard of care, and they actively decline if they do not wish to be tested for HIV) or risk-based (using risk-based screening tools to focus testing on certain individuals or sub-populations at greater risk of HIV). It is not clear how the approach could impact HIV test uptake when adjusted for other factors (e.g. rapid testing, country-income level, test setting and population tested).\\n\\nSummaryWe searched four databases for studies reporting on HIV test uptake. In total, 18,238 records were screened, and 150 studies were included in the review. Most studies described an opt-in approach (87 estimates), followed by opt-out (76) and risk-based (19). Opt-out testing was associated with 64.3% test uptake (I2=99.9%), opt-in testing with 59.8% (I2=99.9%), and risk-based testing with 54.4% (I2=99.9%). When adjusted for settings that offered rapid testing, country income level, setting and population tested, opt-out testing had a significantly higher uptake (+12% (95% confidence intervals: 3-21), p=0.007) than opt-in testing. We also found that emergency department patients and hospital outpatients had significantly lower HIV test uptake than other populations.\",\n \"Analysis of communities of countries with similar dynamics of the COVID-19 pandemic evolution\\nThis work addresses the spread of the coronavirus through a non-parametric approach, with the aim of identifying communities of countries based on how similar their evolution of the disease is. The analysis focuses on the number of daily new COVID-19 cases per ten thousand people during a period covering at least 250 days after the confirmation of the tenth case. Dynamic analysis is performed by constructing Minimal Spanning Trees (MST) and identifying groups of similarity in contagions evolution in 95 time windows of a 150-day amplitude that moves one day at a time. The number of times countries belonged to a similar performance group in constructed time windows was the intensity measure considered. Groups composition is not stable, indicating that the COVID-19 evolution needs to be treated as a dynamic problem in the context of complex systems. Three communities were identified by applying the Louvain algorithm. Identified communities analysis according to each countrys socioeconomic characteristics and variables related to the disease sheds light on whether there is any suggested course of action. Even when strong testing and tracing cases policies may be related with a more stable dynamic of the disease, results indicate that communities are conformed by countries with diverse characteristics. The best option to counteract the harmful effects of a pandemic may be having strong health systems in place,with contingent capacity to deal with unforeseen events and available resources capable of a rapid expansion of its capacity.\",\n \"Covid-19 infection and attributable mortality in UK Long Term Care Facilities: Cohort study using active surveillance and electronic records (March-June 2020)\\nBackgroundEpidemiological data on COVID-19 infection in care homes are scarce. We analysed data from a large provider of long-term care for older people to investigate infection and mortality during the first wave of the pandemic.\\n\\nMethodsCohort study of 179 UK care homes with 9,339 residents and 11,604 staff.We used manager-reported daily tallies to estimate the incidence of suspected and confirmed infection and mortality in staff and residents. Individual-level electronic health records from 8,713 residents were used to model risk factors for confirmed infection, mortality, and estimate attributable mortality.\\n\\nResults2,075/9,339 residents developed COVID-19 symptoms (22.2% [95% confidence interval: 21.4%; 23.1%]), while 951 residents (10.2% [9.6%; 10.8%]) and 585 staff (5.0% [4.7%; 5.5%]) had laboratory-confirmed infections. The incidence of confirmed infection was 152.6 [143.1; 162.6] and 62.3 [57.3; 67.5] per 100,000 person-days in residents and staff respectively. 121/179 (67.6%) care homes had at least one COVID-19 infection or COVID-19-related death. Lower staffing ratios and higher occupancy rates were independent risk factors for infection.\\n\\n217/607 residents with confirmed infection died (case-fatality rate: 35.7% [31.9%; 39.7%]). Mortality in residents with no direct evidence of infection was two-fold higher in care homes with outbreaks versus those without (adjusted HR 2.2 [1.8; 2.6]).\\n\\nConclusionsFindings suggest many deaths occurred in people who were infected with COVID-19, but not tested. Higher occupancy and lower staffing levels were independently associated with risks of infection. Protecting staff and residents from infection requires regular testing for COVID-19 and fundamental changes to staffing and care home occupancy.\",\n \"Indoor Air Quality Intervention in Schools; Effectiveness of a Portable HEPA Filter Deployment in Five Schools Impacted by Roadway and Aircraft Pollution Sources\\nThe Healthy Air, Healthy Schools Study was established in January 2020 to better understand the impact of ultrafine particles (UFP) on indoor air quality in communities surrounding Seattle-Tacoma (Sea-Tac) International Airport. The study team took multipollutant measurements indoor and outdoor air pollution at five participating school locations to infiltration indoors. The schools participating in this project were located within a 7-mile radius of Sea-Tac Airport and within 0.5 miles of an active flight path. Based on experimental measures in an unoccupied classroom, infiltration rates of a) Ultrafine particles of aircraft origin b) Ultrafine particles of traffic origin and c) Wildfire smoke or other outdoor pollutants were characterized before and after the introduction of a classroom based portable HEPA filter intervention. The portable HEPA cleaners were an effective short-term intervention to improve the air quality in classroom environments, reducing the ultrafine particles to approximately 1/10th of that measured outside. Before the HEPA filter deployment, approximately one-half of all outdoor UFPs were measured indoors. This study is unique in focusing on UFP in school settings and demonstrating through multivariate methods that the UFP measured in the classroom space is primarily of outdoor origin. Although existing research suggests that improvements to indoor air quality in homes can significantly improve asthma outcomes, further research is necessary to establish the benefit to student health and academic performance of improved air quality in schools.\",\n \"Association of polycyclic aromatic hydrocarbons in moss with blood biomarker among nearby residents in Portland, Oregon\\nPolycyclic aromatic hydrocarbons (PAHs) are a component of air pollutants that are costly to measure using traditional air-quality monitoring methods. We used an epiphytic bio-indicator (moss genus: Orthotrichum) to cost-effectively evaluate atmospheric deposition of PAHs in Portland, Oregon in May 2013. However, it is unclear if measurements derived from these bioindicators are good proxies for human exposure. To address this question, we simultaneously, measured PAH-DNA adducts in blood samples of non-smokers residing close to the sites of moss measurements. We accounted for individual determinants of PAH uptake that are not related to environmental air quality through questionnaires, e.g., wood fires, consumption of barbecued and fried meats. Correlation and linear regression (to control for confounders from the lifestyle factors) evaluated the associations. We did not observe evidence of an association between PAH levels in moss and PAH-DNA adducts in blood of nearby residents, but higher level of adduct were evident in those who used wood fire in their houses in the last 48 hours. It remains to be determined whether bio-indicators in moss can be used for human health risk assessment.\\n\\nHighlightsO_LIConcentration of PAH in moss do not relate to DNA adducts of PAH in blood of nearby residents in our sample.\\nC_LIO_LIContent of moss may not be suitable for assessing exposure to PAH among humans.\\nC_LI\",\n \"Prevalence of Salivary IgA Reacting with SARS-CoV-2 among Japanese People Unexposed to the Virus\\nWhile the COVID-19 pandemic caused by SARS-CoV-2 has posed a threat to public health as the number of cases and COVID-19-related deaths are increasing worldwide, the incidence of the virus infection are extremely low in Japan compared with many other countries. To explore the reason for this strange phenomenon, we hypothesized the high prevalence of \\\"natural\\\" secretory IgA in saliva as mucosal IgA reacting with SARS-CoV-2, and thus surveyed the positivity for, as well as levels of, such reactive salivary IgA in a cohort of Japanese people of a wide range of age. The major findings were that 95/180 (52.78 %) of overall individuals who had not been exposed to SARS-CoV-2 were positive for salivary IgA with the levels ranging from 0.002 to 3.272 ng/ml, and that there may be a negative trend in positivity for salivary IgA according to age. These results suggest a role of mucosal IgA in host defense against SARS-CoV-2 infection.\\n\\nOne Sentence Summary\\\"Natural\\\" secretory immunoglobulin A autoantibodies may play a role in mucosal defense against SARS-CoV-2.\",\n \"The Understanding persistent Pain Where it ResiDes study of low back pain cohort profile\\nBackgroundDespite chronic low back pain (LBP) being considered a biopsychosocial condition for diagnosis and management, few studies have investigated neurophysiological or neurobiological risk factors thought to underpin the transition from acute to chronic LBP. The aim of this cohort profile is to describe the methodology, compare baseline characteristics between acute LBP participants and pain-free controls, and compare LBP participants with or without completed follow-up.\\n\\nMethods120 individuals experiencing acute LBP and 57 pain-free controls were recruited to participate in the Understanding Persistent Pain Where it Resides (UPWaRD) study. Screening was conducted via email and phone. Neurobiological, psychological, and sociodemographic data were collected at baseline, three- and six-months. LBP status was assessed using the numerical rating scale and Roland-Morris disability questionnaire at three and six-month follow-up.\\n\\nResults95 participants (79%) provided outcome data at three-month follow-up and 96 participants (80%) at six-months. Participants who did not complete follow-up at three- and six-months within the UPWaRD LBP cohort had higher psychological distress, higher pain interference, higher levels of moderate physical activity, and reported occupational difficulties due to pain (P = <0.05). Compared to controls, LBP participants in the UPWaRD cohort were older, had a higher BMI, a higher prevalence of comorbidities and higher medication usage. Higher depression, anxiety and stress, lower pain self-efficacy and higher pain catastrophizing during acute LBP were correlated with higher six-month pain and disability (P = < 0.01).\\n\\nConclusionsThis cohort profile reports baseline characteristics of the UPWaRD LBP and pain-free control cohort.\",\n \"Clonal chromosomal mosaicism and loss of chromosome Y in men are risk factors for SARS-CoV-2 vulnerability in the elderly\\nThe ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) has an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome events (CME) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (CME and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, CME and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people.\",\n \"Compartment-specific total RNA profile of Hippocampal and Cortical cells from Mesial Temporal Lobe Epilepsy tissue\\nMesial temporal lobe epilepsy (mTLE) is a chronic neurological disease characterized by recurrent seizures. The pathogenic mechanisms underlying mTLE involve defects in post-transcriptional regulation of gene expression. So far, transcriptome profiles from epileptic tissue have been generated using whole cells, thereby lacking information on RNA localization and function at a subcellular level. In line with this, we have previously observed by in situ hybridization that a few microRNAs (miRNAs) display subcellular mis-localization with aberrant enrichment in the nucleus in human hippocampal mTLE tissue samples (Kan et al., 2012). To further investigate the possible mechanisms leading to the mis-localization of miRNAs, we set out to understand the compartment-specific total RNA (coding and non-coding) profile of human mTLE tissue samples. For this, we have successfully established a protocol to isolate cytoplasmic and nuclear compartments from human hippocampal tissue. After confirming the purity of the isolated cell compartments, we performed total RNA-sequencing (RNA-seq) on five resected hippocampal (HC) mTLE (no hippocampal sclerosis (non-HS)) samples and five HC postmortem control samples. Similarly, six neo-cortical (Cx) tissue samples from mTLE non-HS and HS International League Against Epilepsy (ILAE) Type 1, or mTLE+HS, samples were compared with six Cx postmortem controls. Our dataset provides a comprehensive overview of compartment-specific transcriptomic profiles of pharmacoresistant mTLE patient HC and Cx tissue, which in further studies can be used to investigate disease mechanisms.\",\n \"Postoperative morbidity after liver resection- A Systemic review, meta-analysis, and metaregression of factors affecting them.\\nAim of the studyThis systemic review and meta-analysis aimed to analyze post-operative morbidity after liver resection, and also study various factors associated with mortality via metaregression analysis.\\n\\nMaterial and MethodsPubMed, Cochrane Library, Embase, google scholar, web of science with keywords like liver resection\\\"; \\\"mortality\\\";\\\" hepatectomy\\\". Weighted percentage post-operative morbidities were analyzed. Meta-analysis and meta-regression were done by the DerSimonian-Liard random effect model. Heterogeneity was assessed using the Higgins I2 test. Publication bias was assessed using a funnel plot. Funnel plot asymmetry was evaluated by Eggers test. Morbidity was defined as any postoperative morbidity mentioned.\\n\\nResultsA total of 46 studies was included in the final analysis. Total 45771 patients underwent liver resections. 16111 patients experienced complications during the postoperative period. Weighted post-operative morbidity was 30.2% (95 % C.I. 24.8-35.7%). Heterogeneity was high with I2 99.46% and p-value <0.01. On univariate analysis, major liver resections were significantly associated with heterogeneity. (p=0.024). However, residual heterogeneity was still high with I2 98.62%, p<0.001. So, multifactor metaregression analysis major hepatectomy (p<0.001), Open hepatectomy (p=0.001), cirrhotic liver (p=0.002), age (p<0.001), blood loss (p<0.001), and colorectal metastasis (p<0.001) independently associated with postoperative morbidity. Residual heterogeneity was moderate I2= 39.9% and nonsignificant p=0.189.\\n\\nConclusionLiver resection is associated with high postoperative morbidity and various factors like major hepatectomy, Open hepatectomy, cirrhotic liver, blood loss, and colorectal metastasis were associated with morbidity and responsible for heterogeneity across the studies.\",\n \"Analyzing human knockouts to validate GPR151 as a therapeutic target for reduction of body mass index\\nNovel drug targets for sustained reduction in body mass index (BMI) are needed to curb the epidemic of obesity, which affects 650 million individuals worldwide and is a causal driver of cardiovascular and metabolic disease and mortality. Previous studies reported that the Arg95Ter nonsense variant of GPR151, an orphan G protein-coupled receptor, is associated with reduced BMI and reduced risk of Type 2 Diabetes (T2D). Here, we follow up on GPR151 with the Pakistan Genome Resource (PGR), which is one of the largest exome biobanks of human homozygous loss-of-function carriers (knockouts) in the world. Among PGR participants, we identify 3 GPR151 putative loss-of-function (plof) variants (Arg95Ter, Tyr99Ter, and Phe175LeufsTer7) with a cumulative allele frequency of 2.2% and present at homozygosity. We confirm these alleles in vitro as loss-of-function. We test if GPR151 plof is associated with BMI, T2D, or other metabolic traits. GPR151 deficiency in complete human knockouts is not associated with a clinically significant difference in BMI. Moreover, loss of GPR151 confers a nominally significant increase in risk of T2D (odds ratio = 1.2, p value = 0.03). Relative to wild-type mice, Gpr151-/- animals exhibit no difference in body weight on normal chow, and higher body weight on a high-fat diet, consistent with the findings in humans. Together, our findings indicate that GPR151 antagonism is not a compelling therapeutic approach for obesity.\",\n \"Examining the Association between the COVID-19 Pandemic and Self-Harm Death Counts in Four Canadian Provinces\\nGovernments implemented lockdowns and other physical distancing measures to stop the spread of SARS-CoV-2 (COVID-19). Resulting unemployment, income loss, poverty, and social isolation, coupled with daily reports of dire news about the COVID-19 pandemic, could serve as catalysts for increased self-harm deaths (SHD). This ecological study examined whether observed SHD counts were higher than predicted SHD counts during the pandemic period in the Canadian provinces of Alberta, British Columbia, Ontario, and Quebec. The study also explored whether SHD counts during the pandemic were affected by lockdown severity (measured using the lockdown stringency index [LSI]) and COVID-19 case numbers. We utilized publicly available SHD data from January 2018 through November 2020, and employed AutoRegressive Integrated Moving Average (ARIMA) modelling, to predict SHD during the COVID-19 period (March 21 to November 28, 2020). We used Poisson and negative binomial regression to assess ecological associations between the LSI and COVID-19 case numbers, controlling for seasonality, and SHD counts during the COVID-19 period. On average, observed SHD counts were lower than predicted counts during this period (p < 0.05 [except Alberta]). Additionally, LSI and COVID-19 case numbers were not statistically significantly associated with SHD counts.\",\n \"P. acnes qPCR-based antibiotics resistance assay (ACQUIRE) reveals widespread macrolide resistance in acne patients and can eliminate macrolide misuse in acne treatment\\nBackgroundMacrolides have been widely used to treat moderate-to-severe acne for more than 50 years. However, prevalent antibiotic resistance of Propionibacterium acnes, along with the absence of clinically available resistance tests, has made macrolide misuse a frequent occurrence, with serious consequences.\\n\\nObjectiveWe developed P. acnes qPCR-based antibiotics resistance assay (ACQUIRE) to enable fast and accurate detection of P. acnes macrolide resistance in clinical settings, representing an opportunity to administer antibiotics more wisely and improve the quality of care.\\n\\nMethodsA cross-sectional observational study was conducted to probe into the macrolide resistance of P. acnes in acne patients.\\n\\nResultsThe high sensitivity of ACQUIRE enabled us to reveal a much higher P. acnes 23S rDNA point mutation rate (52%) and thus a higher macrolide resistance (75.5%) compared to previous reports. Carriage of ermX gene was discovered on 472 (53%) subjects, which concurs with previous studies.\\n\\nConclusionMacrolide resistance of P. acnes is much higher than previously reported.\",\n \"Machine learning approaches for electronic health records phenotyping: A methodical review\\nObjectiveAccurate and rapid methods for phenotyping are a prerequisite to realizing the potential of electronic health records (EHRs) data for clinical and translational research. This study reviews the literature on machine learning (ML) approaches for phenotyping with respect to the phenotypes considered, the data sources and methods used, and the contributions within the wider context of EHR-based research.\\n\\nMaterials and MethodsWe searched for relevant articles in PubMed and Web of Science published between January 1, 2018 and April 14, 2022. After screening, we collected data on 52 variables across 106 selected articles.\\n\\nResultsML-based methods were developed for 156 unique phenotypes, primarily using EHR data from a single institution or health system. 72 of 106 articles leveraged unstructured data in clinical notes. In terms of methodology, supervised learning is the most prevalent ML paradigm (n = 64, 60.4%), with half of the articles employing deep learning. Semi-supervised and weakly-supervised approaches were applied to reduce the burden of obtaining gold-standard labeled data (n = 21, 19.8%), while unsupervised learning was used for phenotype discovery (n = 20, 18.9%). Federated learning has been applied to develop algorithms across multiple institutions while preserving data privacy (n = 2, 1.9%).\\n\\nDiscussionWhile the use of ML for phenotyping is growing, most articles applied traditional supervised ML to characterize the presence of common, chronic conditions.\\n\\nConclusionContinued research in ML-based methods is warranted, with particular attention to the development of advanced methods for complex phenotypes and standards for reporting and evaluating phenotyping algorithms.\",\n \"Financial Meltdown in Swing Hospitals during the COVID-19 Outbreak\\nHospitals in Japan have complete autonomy in deciding whether to admit COVID-19 patients, similar to that of the US. Taking this into account, we estimated the effect of admitting COVID-19 patients on hospital profits, using instrumental variable (IV) regression. Using IVs related to government intervention enabled us to not only estimate the effect of admitting COVID-19 patients among \\\"swing hospitals,\\\" where both options (to admit or to not admit COVID-19 patients) could potentially be realized but to also evaluate the effect of government intervention on such hospitals. Our empirical results revealed that monthly profits per bed decreased by approximately JPY 600,000 ({approx} USD 6,000) among swing hospitals, which is 15 times the average monthly profits in 2019. This overwhelming financial damage indicates that it would be costly for swing hospitals to treat COVID-19 patients because of their low suitability for admitting such patients. Given the implications of our main results, we propose an alternative strategy to handling surges in patients with new infectious diseases.\",\n \"JIA patient T cells differentiate into Th1, Th17 and Th1.17 effector cells under Th1 polarizing conditions\\nObjectiveT helper cells develop into discrete Th1, Th2 or Th17 lineages that selectively express IFN{gamma}, IL-4/IL-5/IL-13, or IL-17, respectively and actively silence signature cytokines expressed by opposing lineages. Our objective was to compare Th1, Th2 and Th17 polarization in cell culture models using JIA patient samples.\\n\\nMethodsPeripheral blood mononuclear cells were isolated from JIA or healthy prepubescent children. T cell naive and memory phenotypes were assessed by flow cytometry. T cell proliferation was measured using a fluorescence-based assay. Th cell cultures were generated in vitro and IFN{gamma}, IL-17, and TNF measured by ELISA and flow cytometry.\\n\\nResultsJIA Th1 cells produced increased IFN{gamma} and inappropriately produced IL-17. JIA Th17 cells produced increased IL-17. JIA Th1 cell cultures develop dual producers of IFN{gamma} and IL-17, which are Th1.17 cells. JIA Th1 cultures expressed elevated levels of both T-bet and ROR{gamma}T. RNA sequencing confirmed activation of immune responses and inappropriate activation of IL-17 signaling pathways in Th1 cultures. A subset of JIA patient samples was disproportionally responsible for the enhanced IFN{gamma} and IL-17 phenotype and Th1.17 phenotype.\\n\\nConclusionsThis study reveals that JIA patient uncommitted T cell precursors, but not healthy children, inappropriately develop into inflammatory effector Th1.17 and Th17 cells under Th1 polarizing conditions.\\n\\nRheumatology key messagesO_LITh1 differentiation of JIA PBMCs generates high IFN{gamma}, IL-17, and dual IFN{gamma}-IL-17 producing cells.\\nC_LIO_LIJIA Th1 differentiation increases master transcription factor expression for Tbet and ROR{gamma}T.\\nC_LIO_LIEnhanced JIA Th1 IFN{gamma} and IL-17 production occurs in a subset of JIA patients.\\nC_LI\",\n \"Association between Functional Inhibitors of Acid Sphingomyelinase and Reduced Risk of Intubation or Death in Individuals Hospitalized for Severe COVID-19: results from an observational multicenter study\\nSeveral medications commonly used for a number of medical conditions share a property of functional inhibition of acid sphingomyelinase (ASM), or FIASMA. Preclinical and clinical evidence suggest that the (ASM)/ceramide system may be central to SARS-CoV-2 infection. We examined the potential usefulness of FIASMA use among patients hospitalized for severe COVID-19 in an observational multicenter retrospective study conducted at Greater Paris University hospitals. Of 2,846 adult patients hospitalized for severe COVID-19, 277 (9.7%) were taking a FIASMA medication at the time of their hospital admission. The primary endpoint was a composite of intubation and/or death. We compared this endpoint between patients taking vs. not taking a FIASMA medication in time-to-event analyses adjusted for sociodemographic characteristics and medical comorbidities. The primary analysis was a Cox regression model with inverse probability weighting (IPW). Over a mean follow-up of 9.2 days (SD=12.5), the primary endpoint occurred in 104 patients (37.5%) who were taking a FIASMA medication, and 1,060 patients (41.4%) who were not. Taking a FIASMA medication was associated with reduced likelihood of intubation or death in both crude (HR=0.71; 95%CI=0.58-0.87; p<0.001) and the primary IPW (HR=0.58; 95%CI=0.46-0.72; p<0.001) analyses. This association remained significant in multiple sensitivity analyses and was not specific to one FIASMA class or medication. These results show the potential importance of the ASM/ceramide system as a treatment target in COVID-19. Double-blind controlled randomized clinical trials of these medications for COVID-19 are needed.\",\n \"Open label phase I/II clinical trial and predicted efficacy of SARS-CoV-2 RBD protein vaccines SOBERANA 02 and SOBERANA Plus in children\\nObjectivesTo evaluate heterologous scheme in children 3-18 y/o using two SARS-CoV-2 r-RBD protein vaccines.\\n\\nMethodsA phase I/II open-label, adaptive and multicenter trial evaluated the safety and immunogenicity of two doses of SOBERANA02 and a heterologous third dose of SOBERANA Plus in 350 children 3-18 y/o in Havana Cuba. Primary outcomes were safety (in phase I) and safety/immunogenicity (in phase II) measured by anti-RBD IgG ELISA, molecular and live-virus neutralization tests and specific T-cells response. An immunobridging and prediction of efficacy were additional analysis.\\n\\nResultsLocal pain was the unique adverse event with >10% frequency, none was serious or severe. Two doses of SOBERANA 02 elicited humoral immune response similar to natural infection; the third dose increased significantly the response in all children, similar to that achieved in vaccinated young adults and higher than in convalescents children. The neutralizing titer was evaluated in a participants subset: all had neutralizing antibodies vs. alpha and delta; 97.9% vs. beta. GMT was 173.8 (CI 95% 131.7; 229.5) vs. alpha, 142 (CI 95% 101.3; 198.9) vs. delta and 24.8 (CI 95% 16.8; 36.6) vs. beta. An efficacy over 90% was estimated.\\n\\nConclusionHeterologous scheme was safe and immunogenic in children 3-18 y/o. Trial registry: https://rpcec.sld.cu/trials/RPCEC00000374\",\n \"Validation of the short Mood and Feelings Questionnaire in young adulthood\\nBackgroundDepression often onsets in adolescence and is associated with recurrence in adulthood. There is a need to identify and monitor depression symptoms across adolescence and into young adulthood. The short Mood and Feelings Questionnaire (sMFQ) is commonly used to measure depression symptoms in adolescence but has yet to be validated in young adulthood. This study aimed to (1) examine whether the sMFQ is a valid assessment of depression in young adults, and (2) identify cut-points that best capture a DSM-5 diagnosis of depression at age 25.\\n\\nMethodsThe sample included young people who took part in the Avon Longitudinal Study of Parents and Children (ALSPAC) at age 25 (n=4098). Receiver Operating Characteristic analyses were used to examine how well the self-rated sMFQ discriminates between cases and non-cases of DSM-5 Major Depressive Disorder (MDD) classified using the self-rated Development and Well Being Assessment. Sensitivity and specificity values were used to identify cut-points on the sMFQ.\\n\\nResultsThe sMFQ had high accuracy for discriminating MDD cases from non-cases at age 25. The commonly used cut-point in adolescence ([≥]12) performed well at this age, best balancing sensitivity and specificity. However, a lower cut-point ([≥]10) may be appropriate in some contexts, e.g. for screening, when sensitivity is favoured over specificity.\\n\\nLimitationsALSPAC is a longitudinal population cohort that suffers from non-random attrition.\\n\\nConclusionsThe sMFQ is a valid measure of depression in young adults in the general population. It can be used to screen for and monitor depression across adolescence and early adulthood.\",\n \"Effective connectivity during faces processing in major depression: Distinguishing markers of pathology, risk, and resilience\\nBackgroundAberrant brain connectivity during emotional processing, especially within the fronto-limbic pathway, is one of the hallmarks of major depressive disorder (MDD). However, a lack of systematic approaches in previous studies made it difficult to determine whether a specific alteration in brain connectivity reflects a cause, correlate, or effect of the disorder. The current study aimed to investigate neural mechanisms that correspond to disease, risk and resilience in major depression during implicit processing of emotion cues.\\n\\nMethodsForty-eight patients with MDD, 49 first-degree relatives of patients with MDD and 103 healthy controls performed a face-matching task during functional magnetic resonance imaging. We used dynamic causal modelling to estimate task-dependent effective connectivity at the subject level. Parametric empirical Bayes was then performed to quantify group differences in effective connectivity.\\n\\nResultsDepressive pathology was associated with decreased effective connectivity from the left amygdala and left dorsolateral prefrontal cortex to the right fusiform gyrus, whereas familial risk for depression corresponded to decreased connectivity from the right orbitofrontal cortex to the left insula and from the left orbitofrontal cortex to the right fusiform gyrus. Resilience for depression was related to increased connectivity from the anterior cingulate cortex to the left dorsolateral prefrontal cortex.\\n\\nConclusionsOur results suggest that the depressive state alters top-down control of higher visual regions during the processing of emotional faces, whereas increased connectivity within the cognitive control network promotes resilience to depression.\",\n \"Mitochondrial genome copy number measured by DNA sequencing in human blood is strongly associated with metabolic traits via cell-type composition differences\\nMitochondrial genome copy number (MT-CN) varies among humans and across tissues and is highly heritable, but its causes and consequences are not well understood. When measured by bulk DNA sequencing in blood, MT-CN may reflect a combination of the number of mitochondria per cell and cell type composition. Here, we studied MT-CN variation in blood-derived DNA from 19,184 Finnish individuals using a combination of genome (N = 4,163) and exome sequencing (N = 19,034) data as well as imputed genotypes (N = 17,718). We identified two loci significantly associated with MT-CN variation: a common variant at the MYB-HBS1L locus (P = 1.6x10-8), which has previously been associated with numerous hematological parameters; and a burden of rare variants in the TMBIM1 gene (P = 3.0x10-8), which has been reported to protect against non-alcoholic fatty liver disease. We also found that MT-CN is strongly associated with insulin levels (P = 2.0x10-21) and other metabolic syndrome (metS) related traits. Using a Mendelian randomization framework, we show evidence that MT-CN measured in blood is causally related to insulin levels. We then applied an MT-CN polygenic risk score (PRS) derived from Finnish data to the UK Biobank, where the association between the PRS and metS traits was replicated. Adjusting for cell counts largely eliminated these signals, suggesting that MT-CN affects metS via cell type composition. These results suggest that measurements of MT-CN in blood-derived DNA partially reflect differences in cell-type composition and that these differences are causally linked to insulin and related traits.\",\n \"Heterogeneous Mental Health Development During the COVID-19 Pandemic in the United Kingdom\\nThe COVID-19 pandemic and the mitigation measures by governments have upended the economic and social lives of many, leading to widespread psychological distress. We explore heterogeneity in trajectories of psychological distress during the pandemic in the United Kingdom and relate this heterogeneity to socio-demographic and health factors. We analyze nine waves of longitudinal, nationally representative survey data from the UK Household Longitudinal Study (N =15,914), covering the period from early 2020 to mid-2021. First, latent class mixture modelling (LCCM) is used to identify trajectories of psychological distress. Second, associations of the trajectories with covariates are tested with multinomial logistic regressions. We find four different trajectories of distress: continuously low, temporarily elevated, repeatedly elevated, and continuously elevated distress. Nearly two fifths of the population experienced severely elevated risks of distress during the pandemic. Long-term distress was highest among younger people, women, people living without a partner, those who had no work or lost income, and those with previous health conditions or COVID-19 symptoms. Given the threat of persistent stress on health, policy measures should be sensitized to the unintended yet far-reaching consequences of non-pharmaceutical interventions.\",\n \"Social connectedness as a determinant of mental health: A scoping review\\nPublic health and epidemiologic research have established that social connectedness promotes overall health. Yet there have been no recent reviews of findings from research examining social connectedness as a determinant of mental health. The goal of this review was to evaluate recent longitudinal research probing the effects of social connectedness on depression and anxiety symptoms and diagnoses in the general population. A scoping review was performed of PubMed and PsychInfo databases from January 2015 to December 2020 following PRISMA-ScR guidelines using a defined search strategy. The search yielded 56 articles representing 52 unique studies. In research with other than pregnant women, 84% (16 of 19) studies reported that social support benefited symptoms of depression with the remaining 16% (3 of 19) reporting minimal or no evidence that lower levels of social support predict depression at follow-up. In research with pregnant women, 80% (21 of 26 studies) found that low social support increased postpartum depressive symptoms. Among 3 of 4 studies that focused on loneliness, feeling lonely at baseline was related to adverse outcomes at follow-up including higher risks of major depressive disorder, depressive symptom severity, generalized anxiety disorder, and lower levels of physical activity. In 5 of 7 reports, smaller social network size predicted depressive symptoms or disorder at follow-up. In summary, most recent relevant longitudinal studies have demonstrated that social support protects adults in the general population from depressive symptoms and disorders. The results, which were largely consistent across settings, exposure measures, and populations, support efforts to improve clinical detection of high-risk patients, including adults with low social support and elevated loneliness.\",\n \"Evaluation of chest X-Ray with automated interpretation algorithms for mass tuberculosis screening in prisons.\\nRationaleThe World Health Organization (WHO) recommends systematic tuberculosis (TB) screening in prisons. Evidence is lacking for accurate and scalable screening approaches in this setting.\\n\\nObjectivesTo assess the diagnostic accuracy of artificial intelligence-based chest x-ray interpretation algorithms for TB screening in prisons.\\n\\nMethodsProspective TB screening study in three prisons in Brazil from October 2017 to December 2019. We administered a standardized questionnaire, performed chest x-ray in a mobile unit, and collected sputum for confirmatory testing using Xpert MTB/RIF and culture. We evaluated x-ray images using three algorithms (CAD4TB version 6, LunitTB and qXR) and compared their diagnostic accuracy. We utilized multivariable logistic regression to assess the effect of demographic and clinical characteristics on algorithm accuracy. Finally, we investigated the relationship between abnormality scores and Xpert semi-quantitative results.\\n\\nMeasurements and Main ResultsAmong 2,075 incarcerated individuals, 259 (12.5%) had confirmed TB. All three algorithms performed similarly overall with AUCs of 0.87-0.91. At 90% sensitivity, only LunitTB and qXR met the WHO Target Product Profile requirements for a triage test, with specificity of 84% and 74%, respectively. All algorithms had variable performance by age, prior TB, smoking, and presence of TB symptoms. LunitTB was the most robust to this heterogeneity, but nonetheless failed to meet the TPP for individuals with previous TB. Abnormality scores of all three algorithms were significantly correlated with sputum bacillary load.\\n\\nConclusionsAutomated x-ray interpretation algorithms can be an effective triage tool for TB screening in prisons. However, their specificity is insufficient in individuals with previous TB.\",\n \"Inter-population differences of allele frequency and regulome tagging are associated with the heterogeneity of loci identified by cross-ancestry genome-wide association studies\\nTo provide novel insight regarding the inter-population diversity of loci associated with complex traits, we integrated genome-wide data from UK Biobank (UKB) and 1,000 Genomes Project (1KG) data representative of the genetic diversity among worldwide populations. We investigated genome-wide data of 4,359 traits from 361,194 UKB participants of European descent. Using 1KG data, we explored the allele frequency differences and linkage disequilibrium (LD) structure of UKB genome-wide significant (GWS) loci across worldwide populations. Functional annotation data were used to identify regulatory elements and evaluate the tagging properties of GWS variants. No significant difference was observed in allele frequency between UKB and 1KG GBR (British in England and Scotland). Considering other population groups, we identified genome-wide significant alleles with frequencies different from what expected by chance: UKB vs. 1KG Europeans without GBR (rs74945666; allele=T [0.908 vs. 0.03], standing height pGWAS=1.48x10-17), UKB vs. 1KG African (rs556562; allele=A [0.942 vs. 0.083], platelet count pGWAS=4.84x10-15), UKB vs. 1KG Admixed Americans (rs1812378; allele=T [0.931 vs. 0.089], standing height pGWAS=4.23x10-12), UKB vs. 1KG East Asian (rs55881864; allele=T [0.911 vs. 0.001], monocyte count pGWAS=7.29x10-13), and UKB vs. South Asian (rs74945666; allele=T [0.908 vs. 0.061], standing height pGWAS=1.48x10-17). LD-structure analysis and computational prediction showed differences in how these alleles tag functional elements across human populations. In conclusion, the human diversity of certain GWS loci appear to be affected by local adaptation while in other cases the associations may be biased by residual population stratification.\",\n \"Genome-wide association study of liking of physical activity in the UK Biobank\\nA lack of physical activity (PA) is one of the most pressing health issues facing society today. Our individual propensity for PA is partly influenced by genetic factors. Stated liking of various PA behaviors may capture additional dimensions of PA behavior that are not captured by other measures, and contribute to our understanding of the genetics of PA behavior. Here, in over 157,000 individuals from the UK Biobank, we sought to complement and extend previous findings on the genetics of PA behavior by performing genome-wide association studies of self-reported liking of several PA-related behaviors plus an additional derived trait of overall PA-liking. We identified a total of 19 unique genome-wide significant loci across all traits, only four of which overlap with loci previously identified for PA behavior. The PA-liking traits were genetically correlated with self-reported (rg: 0.38 - 0.80) and accelerometry-derived (rg: 0.26 - 0.49) PA measures, and with a wide range of health-related traits and dietary behaviors. Replication in the Netherlands Twin Register (NTR; n>7,300) and the TwinsUK (n>1,300) study revealed directionally consistent associations. Polygenic risk scores (PRS) were then trained in UKB for each PA-liking trait and for self-reported PA behavior. The PA-liking PRS significantly predicted the same liking trait in NTR. The PRS for liking of going to the gym predicted PA behavior in NTR (r2 = 0.40%) nearly as well as the one constructed based on self-reported PA behavior (r2 = 0.42%). Combining the two PRS into a single model increased the r2 to 0.59%, suggesting that although these PRS correlate with each other, they are also capturing distinct dimensions of PA behavior. In conclusion, we have identified the first loci associated with PA-liking, and extended and refined our understanding of the genetic basis of PA behavior.\",\n \"Indexing Cerebrovascular Health Using Near-infrared Spectroscopy\\nNear-infrared spectroscopy (NiRS) is a relatively new technology of brain imaging with its potential in the assessment of cerebrovascular health only recently discovered. Encouraging early results suggest that NiRS can be used as an inexpensive and portable cerebrovascular health tracking device using a recently proposed pulse relaxation function (PReFx). In this paper, we propose a new NiRS timing index, TINiRS, of cerebrovascular health. TINiRS is a novel use of the NiRS technology. TINiRS is motivated by the previously proved relationship of the timing of the reflected wave with vascular resistance and compliance in the context of pressure waveforms. We correlated both TINiRS and PReFx against age, a non-exercise cardiorespiratory fitness (CRF) index, and two existing indices of cerebrovascular health, namely Transcranial Doppler (TCD) augmentation index, AITCD, and magnetic resonance imaging (MRI) blood flow pulsatility index, PIMRI. The TINiRS correlations with Age, CRF, PIMRI and AITCD all are significant, i.e., r = 0.53 (p = 0.002), r = -0.44 (p = 0.011), r = 0.45 (p = 0.012) and r = 0.46 (p = 0.010), respectively. PReFx, however, did not have significant correlations with any of the vascular health factors. The proposed timing index is a reliable indicator of cerebrovascular aging factors in the NiRS waveform.\",\n \"Irremediable psychiatric suffering in the context of medical assistance in dying: a qualitative study\\nBackgroundEstablishing irremediability is a central challenge in determining the appropriateness of medical assistance in dying (MAID) for patients with a psychiatric disorder. The objective of this study is to learn how experienced psychiatrists define irremediable psychiatric suffering (IPS) in the context of MAID and what challenges they face while establishing IPS.\\n\\nMethodsIn a qualitative study, we performed 11 in-depth interviews with psychiatrists who have experience assessing IPS in the context of MAID.\\n\\nResultsAlthough determining IPS is, essentially, a prospective assessment, psychiatrists mostly rely on retrospective dimensions, such as the history of failed treatments, when defining IPS. When establishing IPS, psychiatrists face diagnosis and treatment challenges. The main challenge regarding diagnosis is that patients requesting MAID are often diagnosed with more than one psychiatric disorder. Important treatment related challenges are: assessing the quality of past treatments, establishing the limits of approaches that aim to alter the patients perception, and managing treatment fatigue and treatment refusal.\\n\\nInterpretationIPS is mostly defined in terms of failed past treatments. Challenges regarding diagnosis and treatment complicate the process of establishing IPS. The finding that most patients are diagnosed with more than one psychiatric disorder calls for a critical appraisal of the due diligence procedure for MAID. In response to the challenges related to treatment, intersubjective clinical criteria for IPS in the context of MAID should be developed. Also, further investigation of the concept of treatment fatigue in psychiatry may provide insight into why patients requesting MAID.\\n\\nRegistrationthis study was preregistered under osf.io/2jrnd.\",\n \"Population-split-based risk assessment model of venous thromboembolism in Chinese medical inpatients\\nAbstractsO_ST_ABSObjectiveC_ST_ABSInpatients with high risk of venous thromboembolism (VTE) usually face serious threats to their health and economic conditions. Many studies using machine learning (ML) models to predict VTE risk neglected an important statistical phenomenon, fuzzy feature, and achieved inferior results. Considering the effect of fuzzy feature, our study aims to develop a VTE risk assessment model suitable for Chinese medical inpatients.\\n\\nMaterials and MethodsInpatients in the medical department of Peking Union Medical College Hospital (PUMCH) from January 2014 to June 2016 were collected. A new ML VTE risk assessment model was built through population splitting. First patients were classified into different groups based on values of VTE risk factors, then trustless groups were filtered out, and finally ML models were built on training data in unit of groups. Predictive performances of our method, five traditional ML models, and the Padua model were compared.\\n\\nResultsThe fuzzy feature was verified on the whole dataset. Compared with the Padua model, the proposed model showed higher sensitivities and specificities on training data, and higher specificities and similar sensitivities on test data. Standard deviations of predictive validity of five ML models were larger than the proposed model.\\n\\nDiscussionThe proposed model was the only one which showed advantages on both sensitivity and specificity over Padua model. Its robustness was better than traditional ML models.\\n\\nConclusionThis study built a population-split-based ML model of VTE for Chinese medical inpatients and it may help clinicians stratify VTE risk and guide prevention more efficiently.\",\n \"A cross-sectional study of psychosocial factors and sickness presenteeism in Japanese workers during the COVID-19 pandemic\\nBackgroundWe examined the association between socioeconomic and health status, and lifestyle and sickness presenteeism among Japanese workers during the COVID-19 epidemic.\\n\\nMethodsA cross-sectional study using an Internet-monitor survey was conducted in December, 2020 in Japan. Of 33,302 survey participants, we analyzed 27,036 participants (13,814 men and 13,222 women) who reported experience with sickness presenteeism.\\n\\nResultsThe odds ratio (OR) of sickness presenteeism associated with unmarried versus married status was 1.15. Respective figures for other variables were 1.11 for manual laboring work compared to desk work; 1.79 and 2.29 for loss of employment at the time the pandemic began and continuation of unemployment compared to maintaining employment during the pandemic; and 3.34 for a feeling of financial instability compared to stability.\\n\\nConclusionThe issue of sickness presenteeism has become more prominent under the COVID-19 epidemic.\",\n \"Occupational versus community risk of SARS-CoV-2 infection among employees of a long-term care facility: an observational study\\nObjectivesWe investigated the relative contribution of occupational (vs. community) exposure for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among employees of a university-affiliated long-term care facility (LTCF), during the 1st pandemic wave in Switzerland (March to June 2020).\\n\\nMethodsWe performed a nested analysis of a seroprevalence study among all volunteering LTCF staff to determine community and nosocomial risk factors for SARS-CoV-2 seropositivity using modified Poison regression. We also combined epidemiological and genetic sequencing data from a coronavirus disease 2019 (COVID-19) outbreak investigation in a LTCF ward to infer transmission dynamics and acquisition routes of SARS-CoV-2, and evaluated strain relatedness using a maximum likelihood phylogenetic tree.\\n\\nResultsAmong 285 LTCF employees, 176 participated in the seroprevalence study, of whom 30 (17%) were seropositive for SARS-CoV-2. Most (141/176, 80%) were healthcare workers (HCWs). Risk factors for seropositivity included exposure to a COVID-19 inpatient (adjusted prevalence ratio [aPR] 2.6; 95%CI 0.9-8.1) and community contact with a COVID-19 case (aPR 1.7; 95%CI 0.8-3.5). Among 18 employees included in the outbreak investigation, the outbreak reconstruction suggests 4 likely importation events by HCWs with secondary transmissions to other HCWs and patients.\\n\\nConclusionsThese two complementary epidemiologic and molecular approaches suggest a substantial contribution of both occupational and community exposures to COVID-19 risk among HCWs in LTCFs. These data may help to better assess the importance of occupational health hazards and related legal implications during the COVID-19 pandemic.\",\n \"Airway management, procedural data, and mortality records of patients undergoing surgery for mucormycosis associated with coronavirus disease (COVID-19)\\nIn India, the second wave of coronavirus disease (COVID -19) was associated with a distinct surge in cases of invasive fungal infection with mucormycosis. This disease was seen typically in the sinonasal form in COVID-19 patients. Uncontrolled diabetes, steroid use in COVID-19 treatment, etc. were some of the postulated risk factors for the association of COVID 19 and Mucormycosis. The management plan of these cases included surgical debridement, systemic antifungal therapy, sugar control, and management of antifungal related systemic adverse effects. In this retrospective case record review, we aimed to evaluate the airway management plan, demographics, and overall outcomes in patients undergoing surgical resection for COVID-19 associated mucormycosis. Forty-one (71.9 %) patients had a diagnosis of sino-nasal mucormycosis, fourteen (24.6%) had a diagnosis of rhino-orbital mucormycosis, and 2 patients (3.5%) were diagnosed with palatal mucormycosis. Total 44 (77.19 %) patients had co-morbidities. The most common co-morbidity was Diabetes Mellitus 42 (73.6%), followed by hypertension 21 (36.84%) and Acute kidney injury 14 (28.07%). We used the intubation difficulty scale score to assess intubating conditions. Intubation was easy to slightly difficult in 53 out of 57 patients. In our study, mortality occurred in 7 (12.28 %) patients. The median mortality time was 60 (range, 27-74) days. The median time to hospital discharge was 53.5 (range,10-85) days. Managing COVID-19 on its own is challenging and additional mucormycosis can lead to increased morbidity and mortality. Despite challenges and risks, timely and meticulous interventions can reduce complications.\",\n \"Associations between antipsychotic use, substance use and relapse risks in patients with schizophrenia - real-world evidence from two national cohorts\\nBackgroundResearch on the effectiveness of pharmacotherapies for schizophrenia-substance use disorder comorbidity (Sch-SUD) is very sparse and non-existent on the prevention of the development of substance use disorders (SUD) in patients with schizophrenia.\\n\\nAimsTo compare the real-world effectiveness of antipsychotics in schizophrenia in decreasing risks of: 1) development of an initial SUD; and 2) psychiatric hospitalization and hospitalization due to SUD among patients with SUD.\\n\\nMethodsTwo independent national cohorts including all persons diagnosed with schizophrenia (N=45,476) were followed up for 22 (Finland: 1996-2017) and 11 years (Sweden: 2006-2016). Risks of developing SUD were calculated with between-individual models, and risks of psychiatric and SUD hospitalization with within-individual models using Cox regression and adjusted Hazard Ratios (aHRs) when using vs. not using certain antipsychotics.\\n\\nResultsFor schizophrenia patients without SUDs, clozapine use (aHR 0.20, 95%CI 0.16-0.24, p<0.001, in Finland; 0.35, 0.24-0.50, p<0.001, in Sweden) was associated with lowest risks of developing an initial SUD in both countries. Antipsychotic polytherapy was associated with second lowest risk (0.54, 0.44-0.66) in Sweden, and third lowest risk (0.47, 0.42-0.53) in Finland. Risks of psychiatric hospitalization and hospitalization due to SUD were lowest during use of clozapine, antipsychotic polytherapy, and long-acting injectables in both countries. Results were consistent across both countries.\\n\\nConclusionClozapine and antipsychotic polytherapy are most strongly associated with reduced chances of developing SUDs among patients with schizophrenia and with lower relapse rates among patients with both diagnoses.\",\n \"Estimating the asymptomatic proportion of SARS-CoV-2 infection in the general population: Analysis of a nationwide serosurvey in the Netherlands\\nBackgroundThe proportion of SARS-CoV-2 positive persons who are asymptomatic - and whether this proportion is age-dependent - are still open research questions. Because an unknown proportion of reported symptoms among SARS-CoV-2 positives will be attributable to another infection or affliction, the observed, or crude proportion without symptoms may underestimate the proportion of persons without symptoms that are caused by SARS-CoV-2 infection.\\n\\nMethodsBased on a large population-based serological study comprising test results on seropositivity and self-reported symptom history conducted in April/May 2020 in the Netherlands (n=3147), we estimated the proportion of reported symptoms among those persons infected with SARS-CoV-2 that is attributable to this infection, where the set of relevant symptoms fulfills the ECDC case definition of COVID-19, using inferential methods for the attributable risk (AR). Generalised additive regression modelling was used to estimate the age-dependent relative risk (RR) of reported symptoms, and the AR and asymptomatic proportion (AP) were calculated from the fitted RR.\\n\\nResultsUsing age-aggregated data, the estimated AP was 70% (95% CI: 65-77%). The estimated AP decreased with age, from 80% (95% CI: 67-100%) for the <20 years age-group, to 55% (95% CI: 48-68%) for the 70+ years age-group.\\n\\nConclusionWhereas the crude AP represents a lower bound for the proportion of persons infected with SARS-CoV-2 without COVID-19 symptoms, the AP as estimated via an attributable risk approach represents an upper bound. Age-specific AP estimates can inform the implementation of public health actions such as targetted virological testing and therefore enhance containment strategies.\",\n \"High Brain-Derived Neurotrophic Factor (BDNF) and Negative Psychological Flexibility associate with Early Fatigue Syndrome in healthy females\\nBackgroundRecent studies showed that enhancing psychological flexibility could improve fatigue interference. Brain-Derived Neurotrophic Factor (BDNF), Heart Rate Variability (HRV), and Cortisol were proposed to involve biomarkers in psychological flexibility. Our study aims to explore the association of fatigue with psychological flexibility and related biomarkers.\\n\\nMethodA cross-sectional study gathered data from a baseline characteristic mindful volunteer. Each participant was self-evaluated with the questionnaire of fatigue and psychological flexibility. The participants were evaluated potential biomarkers related to psychological flexibility including HRV, serum cortisol, and BDNF within one week after responding to the questionnaire.\\n\\nResultsThe 47 healthy females including 22 nurses and 25 occupational therapy students, mean age 29.70 {+/-} 12.55 years. The prevalence of fatigue is 38.30%. The multivariate analysis showed the independent factors associated with fatigue including negative psychological flexibility (OR 1.31, p=0.03) and high BDNF (OR 1.33, p=0.05).\\n\\nConclusionOur study found that psychological flexibility and high BDNF was independent factors associate with fatigue. This result provide insight that intervention that increase either psychological flexibility may prevent fatigue symptoms. The high BDNF may reflex the adaptive response of fatigue person and may be potential biomarkers for detecting early fatigue conditions.\",\n \"Butyrate and related epigenetic changes link Parkinson's disease to inflammatory bowel disease and depressive symptoms\\nBackgroundThe gut microbiome and its metabolites can impact brain health and are altered in Parkinsons disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. Here, we investigate whether the changes in the gut microbiome and associated metabolites are linked to PD symptoms and epigenetic markers in leucocytes and neurons.\\n\\nMethodsStool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified the genome-wide DNA methylation by targeted bisulfite sequencing.\\n\\nResultsWe show that lower fecal butyrate and reduced Roseburia, Romboutsia, and Prevotella counts are linked to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA (mDNA) regions in PD overlap with those altered in gastrointestinal, autoimmune, and psychiatric diseases.\\n\\nConclusionsDecreased levels of bacterially produced butyrate are linked to epigenetic changes in leucocytes and neurons from PD patients, and to the severity of their depressive symptoms. PD shares common butyrate-dependent epigenetic changes with certain gastrointestinal and psychiatric disorders, which could be relevant for their epidemiological linkage.\",\n \"Grandparental Childcare During the Pandemic and Effects on Mental Health: Evidence From England\\nObjectivesPolicies aiming at reducing rates of hospitalisation and death from COVID-19 encouraged older people to reduce physical interactions. For grandparents in England, this meant that provision of care for grandchildren was allowed only under very limited circumstances. Evidence also suggests that reduced face-to-face interactions took a toll on mental health during the pandemic. This study aims to investigate whether changes in grandchild care provision during the pandemic impacted grandparents mental health.\\n\\nMethodsUsing pre-pandemic data from Wave 9 (2018/19) and the second Covid-19 sub-study (November/December 2020) of the English Longitudinal Study of Ageing, we first describe changes in grandparenting since the start of the pandemic to then investigate, using regression models, associations between changes in grandparenting and mental health (depression, quality of life, life satisfaction) during the pandemic, while controlling for pre-pandemic levels of the outcome variables. Results: About 10% of grandparents stopped altogether to look after grandchildren during the pandemic, with 22% reporting an overall decrease in the amount of grandchild care provided and 20% an increase or similar levels. Compared to grandparents who mostly maintained unchanged their grandchild care provision, those who stopped altogether and those who mostly reduced the amount of grandchild care provided were more likely to report poorer mental health, even accounting for pre-pandemic health.\\n\\nDiscussionWhile measures to limit physical contact and shield older people were necessary to reduce the spread of COVID-19, policymakers should acknowledge potential adverse consequences for mental health among grandparents who experienced changes in their roles as grandchild caregivers.\",\n \"Factors affecting use of speech testing in adult audiology\\nObjectiveTo investigate the factors affecting the use speech testing in adult audiology services\\n\\nDesignA mixed-methods cross-sectional questionnaire study\\n\\nStudy SampleA UK sample (n=306) of hearing healthcare professionals (HHPs) from the public (64%) and private sector (36%) completed the survey\\n\\nResultsIn the UK, speech testing practice varied significantly between health sector. Speech testing was carried out during the audiology assessment by 68% of private sector HHPs and 5% of those from the public sector. During the hearing aid intervention stage speech testing was carried out by 40% and 8% of HHPs from the private and public sector, respectively. Recognised benefits of speech testing included: 1) providing patients with relatable assessment information, 2) guiding hearing aid fitting, 3) supporting a diagnostic test battery. A lack of clinical time was a key barrier to uptake.\\n\\nConclusionUse of speech testing varies in adult audiology. Results from the present study found the percentage of UK HHPs making use of speech tests was low compared to other countries. HHPs recognised different benefits of speech testing in audiology practice but the barriers limiting uptake were often driven by factors derived from decision makers rather than clinical rationale. Privately funded HHPs used speech tests more frequently than those working in the public sector where time and resources are under greater pressure and governed by guidance that does not include a recommendation for speech testing. Therefore, the inclusion of speech testing in national clinical guidelines could increase the consistency of use.\",\n \"Brain Structure in Acutely Underweight and Partially Weight-Restored Individuals with Anorexia Nervosa - A Coordinated Analysis by the ENIGMA Eating Disorders Working Group\\nThe pattern of structural brain abnormalities in anorexia nervosa (AN) is still not well understood. While several studies report substantial deficits in grey matter volume and cortical thickness in acutely underweight patients, others find no differences, or even increases in patients compared with healthy controls. Recent weight regain before scanning may explain some of this heterogeneity across studies. To clarify the extent, magnitude, and dependencies of grey matter changes in AN, we conducted a prospective, coordinated meta-analysis of multicenter neuroimaging data. We analyzed T1-weighted structural MRI scans assessed with standardized methods from 685 female AN patients and 963 female healthy controls across 22 sites worldwide. In addition to a case-control comparison, we conducted a three-group analysis comparing healthy controls to acutely underweight AN patients (n = 466), and to those in treatment and partially weight-restored (n = 251). In AN, reductions in cortical thickness, subcortical volumes, and, to a lesser extent, cortical surface area, were sizable (Cohens d up to 0.95), widespread and co-localized with hub regions. Highlighting the effects of undernutrition, these deficits associated with lower BMI in the AN sample and were less pronounced in partially weight-restored patients. Notably, the effect sizes observed for cortical thickness deficits in acute AN are the largest of any psychiatric disorder investigated in the ENIGMA consortium to date. These results confirm the importance of considering weight loss and renutrition in biomedical research on AN and underscore the importance of treatment engagement to prevent potentially long-lasting structural brain changes in this population.\",\n \"Autoantibodies Detected in MIS-C Patients due to Administration of Intravenous Immunoglobulin\\nThe autoantibody profile associated with known autoimmune diseases in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that adults with COVID-19 had a moderate prevalence of autoantibodies against the lung antigen KCNRG, and SLE-associated Smith autoantigen. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute insulin-dependent diabetes. While autoantibodies associated with SLE/Sjogrens syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring in vivo decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Together these findings demonstrate that administration of high-dose IVIG is responsible for the detection of several autoantibodies in MIS-C and KD. Further studies are needed to investigate autoantibody production in MIS-C patients, independently from IVIG administration.\",\n \"Title: Length of hospital stay and risk of intensive care admission and in-hospital death among COVID-19 patients in Norway: a register-based cohort study comparing patients fully vaccinated with an mRNA vaccine to unvaccinated patients\\nObjectivesWith most of the Norwegian population vaccinated against COVID-19, an increasing number and proportion of COVID-19 related hospitalisations are occurring among vaccinated patients. We estimated the length of stay (LoS) in hospital and an intensive care unit (ICU), and risk of admission to ICU and in-hospital death among COVID-19 patients [≥]18 years who had been fully vaccinated with an mRNA vaccine, compared to unvaccinated patients.\\n\\nMethodsUsing national registry data, we conducted a cohort study on SARS-CoV-2 positive patients hospitalised in Norway between 1 February and 30 November 2021, with COVID-19 as the main cause of hospitalisation. We ran Cox proportional hazards models to analyse differences in our outcomes. Explanatory variables included vaccination status, age, sex, county of residence, regional health authority, date of admission, country of birth, virus variant and underlying risk factors.\\n\\nResultsWe included 3,203 patients, of whom 716 (22%) were fully vaccinated (at least two doses or one dose and previous SARS-CoV-2 infection). Fully vaccinated patients had a shorter overall LoS in hospital (aHR for discharge: 1.61, 95%CI: 1.24-2.08), shorter LoS without ICU (aHR: 1.27, 95%CI: 1.07-1.52), and lower risk of ICU admission (aHR: 0.50, 95%CI: 0.37-0.69) compared to unvaccinated patients. We observed no difference in the LoS in ICU, nor risk of in-hospital death between fully vaccinated and unvaccinated patients.\\n\\nConclusionsFully vaccinated patients hospitalised with COVID-19 in Norway have a shorter LoS and lower risk of ICU admission than unvaccinated patients. These findings can support patient management and ongoing capacity planning in hospitals.\"\n]","isConversational":false},"cluster":{"kind":"number","value":7,"string":"7"}}},{"rowIdx":222,"cells":{"query":{"kind":"string","value":"Variability in physical inactivity responses of university students during COVID-19 pandemic: A monitoring of daily step counts using a smartphone application\nThis study investigated the changes in physical inactivity of university students during the COVID-19 pandemic, with reference to their academic calendar. We used the daily step counts recorded by a smartphone application (iPhone Health App) from April 2020 to January 2021 (287 days) for 603 students. The data for 287 days were divided into five periods based on their academic calendar. The median value of daily step counts across each period was calculated. A k-means clustering analysis was performed to classify the 603 participants into subgroups to demonstrate the variability in the physical inactivity responses. The median daily step counts, with a 7-days moving average, dramatically decreased from 5,000 to 2,000 steps/day in early April. It remained at a lower level (less than 2,000 steps/day) during the first semester, then increased to more than 5,000 steps/day at the start of summer vacation. The clustering analysis demonstrated the variability in physical inactivity responses. Independent of the academic calendar, many inactive students did not recover their original daily step counts after its dramatic decrement. Consequently, promoting physical activity is recommended for inactive university students over the course of the whole semester."},"positive":{"kind":"list like","value":["Transgender Swimmer in College Athletics\nThere is current scientific and legal controversy about sports competition eligibility regulations for transgender athletes. To better understand and contextualize the effect of androgen-suppression treatment on swimming performance, we compared the gender-related differences in performance of a transgender swimmer who competed in both the male and female NCAA (collegiate) categories to the sex-related differences in performance of world and national class swimmers. These data demonstrate that the gender-related differences in middle distance freestyle performances of a transgender woman are smaller than the observed sex-related differences in performance of top athletes. Our analysis may be useful as a framework for regulators considering participation guidelines which promote fair competition for all athletes, whether cisgender or transgender.\n\nOne-Sentence SummaryRecent outstanding performances by a transgender woman swimmer are faster than predictions based on historic sex-related differences in swimming performance.","An experimental feasibility study evaluating the adequacy of sportswear-type wearables for recording physical exercise intensity\nSportswear-type wearables with integrated inertial sensors and electrocardiogram (ECG) electrodes, have been developed. We examined the feasibility of using sportswear-type wearables to evaluate exercise intensity within a controlled laboratory setting. Six male college athletes were asked to wear a sportswear-type wearable while performing a treadmill test that reached up to 20 km/h. The magnitude of the filtered tri-axial acceleration signal, recorded by the inertial sensor, was used to calculate the acceleration index. The R-R intervals of ECG were used to determine heart rate; the external validity of the heart rate was then evaluated according to oxygen uptake, which is the gold standard physiological exercise intensity. Single regression analyses between treadmill speed and the acceleration index in each participant showed that the slope of the regression line was significantly greater than zero with a high coefficient of determination (walking, 0.95; jogging, 0.96; running, 0.90). Another single regression analyses between heart rate and oxygen uptake showed that the slope of the regression line was significantly greater than zero, with a high coefficient of determination (0.96). Together, these results indicate that sportswear-type wearables are a feasible technology for evaluating physical and physiological exercise intensity across a wide range of physical activities and sport performances.","COVID-19 vaccination status is associated with physical activity in German-speaking countries: the COR-PHYS-Q cohort study\nBackgroundTo examine the association between COVID-19 vaccination status and physical activity (PA), sporting behavior, as well as barriers to PA in adults in Switzerland, Germany, and Austria.\n\nMethodsA total of 1516 adults provided complete responses to our online questionnaire sent out in August 2021. Information about self-reported PA categories, sporting behavior, barriers to PA, and COVID-19 vaccination status were gathered. Main analyses were done using multiple linear regression adjusted for relevant parameters.\n\nResultsWe found a significant association of vaccination status with total PA (p = .011), vigorous PA (p = .015), and moderate PA (p = .001) but not transport-related PA or sedentary time. Unvaccinated adults tended to have more total and vigorous PA than those vaccinated once (ratios of geometric means: 1.34 and 1.60, respectively) or twice (1.22 and 1.09, respectively). Yet, not sufficient evidence was available to confirm this. There was no between-group difference in the contribution of leisure time, work-related, or transport-related PA to total PA. Vaccination status was not associated with sporting behavior except for jogging as the primary intensive type of sports. Finally, there were no significant differences in any of the COVID-19 specific barriers to PA between groups.\n\nConclusionOur data showed that vaccination status is associated with PA even in summer, where the number of COVID-19 cases was low and the severity of safety measures was mild. These findings may enhance future research and improve/extend COVID-19-specific PA guidelines.","The Psychosocial Benefits of Sport Participation During COVID-19 Are Only Partially Explained by Increased Physical Activity\nThe purpose of this study was to determine whether physical activity (PA) increases were responsible for the improvements in mental health and quality of life (QOL) seen among adolescents who returned to sport during the COVID-19 pandemic.Adolescent athletes were asked to complete a survey in October 2020 regarding demographic information, whether they had returned to sport participation (no [DNP], yes [PLY]), school instruction type (virtual, in-person, hybrid), anxiety, depression, QOL, and PA. Anxiety, depression, QOL and PA were compared between PLY and DNP using least squares means from linear models adjusted for age, gender, and instruction type. Mediation analysis assessed whether the relationship between sport status and anxiety, depression, and QOL was mediated by PA. 171 athletes had returned to play, while 388 had not. PLY athletes had significantly lower anxiety (3.6{+/-}0.4 v 8.2{+/-}0.6, p<0.001) and depression (4.2{+/-}0.4 v 7.3{+/-}0.6, p<0.001), and significantly higher QOL (88.1{+/-}1.0 v 80.2{+/-}1.4, p<0.001) and PA (24.0{+/-}0.5 v 16.3{+/-}0.7, p<0.001). PA explained a significant, but relatively small portion of the difference in depression (22.1%, p=0.02) and QOL (16.0%, p=0.048) between PLY and DNP athletes, but did not explain the difference in anxiety (6.6%, p=0.20). Increased PA is only responsible for a small portion of the improvements in depression and QOL among athletes who returned to sports and unrelated to improvements in anxiety. This suggests that the majority of the mental health benefits of sport participation for adolescents during the COVID-19 pandemic are independent of, and in addition to, the benefits of increased PA.","The Chinese Assessment of physical literacy: Based on Grounded Theory Paradigm for children in grades 3-6\nThe aim of this study is to construct and validate \"physical literacy self-assessment questionnaire\"(PLAQ)for Chinese students in grades 3-6. This study uses qualitative and quantitative methods to construct evaluation indicators of PL and determine the weights of each indicator. The 60 items of original PLAQ was based on literature review and interviews,and administered to 1179 primary students graded 3-6 in China. Exploratory factor analysis(EFA)and confirmatory factor analysis(CFA) are used to optimize the structure and verify the reliability and validity of the questionnaire. The model of PLAQ is composed of 4 first-level indicators, 10 second-level indicators and 35 third-level indicators. The results of EFA and CFA resulted in a 44-items, 4-factor questionnaire. EFA item loadings ranged from 0.558 to 0.896,and Cronbachs alpha ranged from 0.818 to 0.892. The results of CFA show that the constructed model fits well, and PLAQ has good convergent validity and discriminative validity. The PLAQ appeared to be reliable and valid that can be used as an assessment tool for students in grades 3-6. PLAQ can be used as a guide for the development of PL. Additionally, PLAQ gives us a shared understanding about what PL is and how it can be developed by Chinese children. However, studies on the accuracy and generalizability of the PLAQ should be conducted to improve it in the future.","Ready for Impact? A validity and feasibility study of instrumented mouthguards (iMGs)\nObjectivesDetermine the validity and feasibility of current Instrumented mouthguards (iMGs) and associated systems.\n\nMethodsPhase 1; Four iMG systems (Football Research Inc [FRI], HitIQ, ORB, Prevent) were compared against dummy headform laboratory criterion standards (25, 50, 75, 100 g). Phase 2; Four iMG systems were evaluated for on-field validity of iMG-triggered events against video-verification to determine true-positives, false-positives and false-negatives (20 {+/-} 9 player matches per iMG). Phase 3; Four iMG systems were evaluated by eighteen rugby players, for perceptions of fit, comfort and function. Phase 4; Three iMG systems (FRI, HitIQ, Prevent) were evaluated for practical feasibility (system usability scale; SUS) by four practitioners.\n\nResultsPhase 1; Total concordance correlation coefficient was 98.3%, 95.3%, 42.5% and 97.9% for FRI, HitIQ, ORB and Prevent. Phase 2; Different on-field kinematics were observed between iMGs. Positive predictive values were 0.98, 0.90, 0.53 and 0.94 for FRI, HitIQ, ORB and Prevent. Sensitivity values were 0.51, 0.40, 0.71 and 0.75 for FRI, HitIQ, ORB and Prevent. Phase 3; player perceptions of fit, comfort and function were 77%, 6/10, 55% for FRI, 88%, 8/10, 61% for HitIQ, 65%, 5/10, 43% for ORB, and 85%, 8/10, 67% for Prevent. Phase 4; SUS was 51.3-50.6/100, 71.3-78.8/100, and 83.8-80.0/100 for FRI, HitIQ, and Prevent.\n\nConclusionThis study shows that differences between current iMG systems exist. Sporting organisations can use these findings to ensure accurate head acceleration event data are obtained and system adoption is optimized, to support player welfare initiatives directly related to long-term brain health.","The Acute Effects of Physical Exercise Breaks on Cognitive Function During Prolonged Sitting: A First Quantitative Evidence\nPurposeThis systematic review and meta-analysis aims to investigate the cognitive benefits of breaking up prolonged sitting (PS) by acute physical exercises (PE).\n\nMethodsA systematic literature search was performed in six electronic databases (PubMed, Scopus, Web of Science, PsycINFO, SPORTDiscus, and Cochrane Library) to identify cross-over studies with a pre-posttest design that examined the effects of PE breaks during 3 to 5 h of prolonged sitting on cognitive performance. A meta-analysis was performed using a random effects model, with subgroup analyses investigating dose-response effects and differences between cognitive domains. Additionally, study quality was rated using the PEDro scale.\n\nResultsThirteen randomized controlled trials (RCTs) with a total of 295 participants (171 female and 124 male) were included in this systematic review. Thereof, nine studies were included in our meta-analysis. We observed that during PS, PE breaks did not improve overall cognitive performance (Hedges g=-0.043[-0.158,0.073]). There was no between-study heterogeneity indicated. This is further supported by the subgroup analyses showing no differences in effect sizes between cognitive domains and different exercise intensities.\n\nConclusionsOur findings suggest that interrupting PS by PE breaks neither improved, nor impaired cognitive performance. Consequently, PE breaks during PS allows to integrate regular physical activity in daily routines (i.e., through PE breaks) without compromising the performance of cognitively demanding tasks.","VALIDATION OF AN INSTRUMENTED MOUTHGUARD\nThe purpose of this study was to determine the validity of an raw and filtered acceleration time-series data from an instrumented mouthguard system against an anthropometric testing device. Testing was conducted in a laboratory using a standard impact protocol utilising the head-form of reference system and the mouthguard system. Testing occurred at 5 impact locations: facemask, front, oblique, side and back, and at four velocities (3.6, 5.5, 7.4, and 9.3 m/s) to attain a total of 55 impacts. A 160 Hz Low-pass 4th order Butterworth filter was applied to the time-series data, and was reported as raw and filtered. Peak linear acceleration, peak rotational velocity and peak rotational acceleration was statistically compared to the reference measurement system. Total concordance correlation coefficient was 90.7% and 96.9%, for raw and filtered data set. Raw and filtered had intraclass correlation coefficients of 0.85 and 0.95 for peak linear acceleration, 0.99 and 0.99 for peak rotational velocity and 0.94 and 0.95 peak rotational acceleration respectively. The instrumented mouthguard displayed high accuracy when measuring head impact kinematics in a laboratory setting. The results presented in this study provide the basis on which the instrumented mouthguard can be further developed for deployment and application within sport quantify head impact collision dynamics in order to optimise performance and brain health.","A qualitative examination of the factors affecting the adoption of injury focused wearable technologies in recreational runners\nPurposeUnderstanding users perceived usefulness and ease of use of technologies will influence their adoption and sustained use. The objectives of this study were to determine the metrics deemed important by runners for monitoring running-related injury (RRI) risk, and identify the barriers and facilitators to their use of injury focused wearable technologies.\n\nMethodsA qualitative focus group study was undertaken. Nine semi-structured focus groups with male (n=13) and female (n=14) recreational runners took place. Focus groups were audio and video recorded, and transcribed verbatim. Transcripts were thematically analysed. A critical friend approach was taken to data coding, and multiple methods of trustworthiness were executed.\n\nResultsExcessive loading and inadequate recovery were deemed the most important risk factors to monitor for RRI risk. Other important factors included training activities, injury status and history, and running technique. The location and attachment method of a wearable device and the design of a smartphone application were identified as important barriers and facilitators, with receiving useful injury-related feedback identified as a further facilitator.\n\nConclusionsOvertraining, training-related and individual- related risk factors are essential metrics that need to be monitored for RRI risk. RRI apps should include the metrics deemed important by runners, once there is supporting evidence- based research. The difficulty and/or ease of use of a device, and receiving useful feedback will influence the adoption of injury focused running technologies. There is a clear willingness from recreational runners to adopt injury focused wearable technologies whilst running.","Oral injury in Kendo players: a cross-sectional survey\nThis study evaluated the risk of oral injury in Kendo. We hypothesized that Kendo players in Japan may experience oral injury due to the use of face protector for kendo (men) with inaccurate measurements or wearing it incorrectly. The survey included 400 kendo players (male, 276; female, 174) and covered four areas: the relationship between the characteristics, percentage of oral injury, temporomandibular disorder (TMD), and use of men. Based on the who experience of oral injury, participants were classified into trauma and non-trauma groups. Those who suffered oral injury were 179 (44.8 %; males, n=118; females, n=61). In the past month, 32 (8.2%) Kendo players reported that their matches/training were affected by dental/oral problems. For TMD, 50 participants had a total score >8.5 from four screening questions. For 289 (72.3%) participants, the men they are currently wearing fit well. Of those that reported that their men do not fit properly, 48 (12.0%) felt that their men were too large, and 14 (3.5%) felt that their men were too small. Years of experience and clenching of ones jaws during an offensive Kendo movement significantly contributed to oral injury. Clenching ones jaws during a defensive Kendo move, current men fit, sleep bruxism, and morning symptoms from sleep bruxism significantly contributed to TMD. Men with an accurate sizing allows proper field of vision, eliminating head shifting inside men during strikes and movements. This suggests that vision can be secured by adjusting the ties on men, chin movement, and the way one looks through the men. Since Kendo equipment is originally a Japanese craft, it has high artistry. Thus, properly worn Kendo equipment brings higher functionality and esthetic appeal.","The acute effects of knee extension exercises with different contraction durations on the subsequent maximal knee extension torque for athletes with different strength levels\nIndividuals with high fatigue resistance against a high-intensity conditioning activity (CA) may be able to avoid experiencing significant fatigue and enhance their voluntary performance. We examined whether the optimal contraction duration of dynamic knee extension exercises to maximize subsequent voluntary performance varies depending on the strength level of an individual. The study participants were 22 male American college football players. Initially, all participants performed a 10-s maximal isometric knee extension exercise and were classified as stronger individuals (n = 8) and weaker individuals (n = 8) based on their relative muscle strength. Each group then performed three types of dynamic CA with different contraction durations (6 s [6-CA], 12 s [12-CA], and 18 s [18-CA]) in random order. To observe the time-course changes in post-activation potentiation and performance enhancement, the twitch torques induced by electrical stimulation and isokinetic knee extension torques at 180{degrees}/s were recorded before and after each CA. The twitch torque increased at 10 s (29.5% {+/-} 9.3%) and 1 min (18.5% {+/-} 6.8%) after 6-CA for the stronger individuals (p < 0.05). However, no post-activation potentiation was induced in the weaker individuals in either protocol. Voluntary performance increased at 4 (7.0% {+/-} 4.5%) and 7 (8.2% {+/-} 4.3%) min after 18-CA for stronger individuals (p < 0.05). However, there was no post-activation performance enhancement in either protocol for weaker individuals. Thus, CA with a relatively long contraction duration was optimal to maximize the subsequent voluntary performance for stronger individuals. It remains unknown whether CAs performed with relatively short or long contraction durations were optimal for weaker individuals.","Effects of vitamin D deficiency on blood lipids and bone metabolism: a large cross- sectional study\nPurposeTo investigate the relationship between serum HDL-C and spinal bone mineral density (BMD) under different serum 25-hydroxyvitamin D (25 (OH) D) levels in adults over 40 years old and to explore its mechanism.\n\nMethodsParticipants over the age of 40 with data on HDL-C, 25 (OH) D, spinal BMD, and other variables in NHANES 2007-2010 were included in the final analysis. A weighted multiple linear regression model was used to evaluate the association between serum HDL-C and spinal BMD in different gender, ages and serum 25 (OH) D levels.\n\nResultsA total of 3599 subjects aged [≥] 40 years old were included in this study. Univariate analysis of the complete correction model showed a negative correlation between serum HDL-C and spinal BMD. In the two subgroups of serum 25(OH)D, we found that the higher the serum HDL-C in the female with serum 25 (OH) D < 75nmol/L aged 40-59 years old, the lower the total spinal BMD, and a similar relationship was found in the lumbar spine (L1-L4). However, no similar relationship was found in all populations with serum 25 (OH) D [≥] 75nmol/L and males with serum 25 (OH) D < 75nmol/L.\n\nConclusionAmong Americans over the age of 40, the increase of serum HDL-C is related to decreased BMD of spine only in women aged 40-59 years with vitamin D insufficiency or deficiency.\n\nAuthor summaryWe performed a cross-sectional study using the National Health Examination and Nutrition Survey (NHANES) data. We found that increased serum high-density lipoprotein cholesterol (HDL-C) during vitamin D deficiency is a potential risk factor for osteopenia or osteoporosis in middle-aged and elderly American women.","Acute exercise induces natural killer cell mobilization but not infiltration into prostate cancer tissue in humans\nThe mobilization and activation of natural killer (NK) cells have been proposed as key mechanisms promoting anti oncogenic effects of physical exercise. Although mouse models have proven that physical exercise recruits NK cells to tumor tissue and inhibits tumor growth, this preclinical finding has not been transferred to the clinical setting yet. In this first-in-human study, we found that physical exercise mobilizes and redistributes NK cells, especially those with a cytotoxic phenotype, in line with preclinical models. However, physical exercise did not increase NK cell tumor infiltrates. Future studies should carefully distinguish between acute and chronic exercise modalities and should be encouraged to investigate more immune responsive tumor entities.","Reduced motor unit discharge rates in gastrocnemius lateralis, but not in gastrocnemius medialis or soleus, in runners with Achilles tendinopathy\nObjectivesDeficits in muscle performance could be a consequence of a reduced ability of a motor neuron to increase the rate in which it discharges. This study aimed to investigate motor unit (MU) discharge properties of each Triceps surae muscle (TS), and TS torque steadiness during submaximal intensities in runners with Achilles tendinopathy (AT).\n\nMethodsWe recruited runners with (n=12) and without (n=13) mid-portion AT. MU discharge rate was analysed for each of the TS muscles, using High-Density surface electromyography during 10 and 20% isometric plantar flexor contractions.\n\nResultsMU mean discharge rate was lower in the Gastrocnemius lateralis (GL) in AT compared to controls. In AT, GL MU mean discharge rate did not increase as torque increased from 10% peak torque, 8.24pps (95%CI: 7.08 to 9.41) to 20%, 8.52pps (7.41 to 9.63, p=0.540); however, in controls, MU discharge rate increased as torque increased from 10%, 8.39pps (7.25 to 9.53) to 20%, 10.07pps (8.89 to 11.25, p<0.001). There were no between-group difference in Gastrocnemius medialis (GM) or Soleus (SOL) MU discharge rates. We found no between-groups differences in coefficient of variation of MU discharge rate in any of the TS muscles nor in TS torque steadiness.\n\nConclusionOur data demonstrates that runners with AT may have a reduced neural drive to GL, failing to increase MU discharge rate to adjust for the increase in torque demand. Further research is needed to understand how interventions focusing on increasing neural drive to GL would affect muscle function in runners with AT."],"string":"[\n \"Transgender Swimmer in College Athletics\\nThere is current scientific and legal controversy about sports competition eligibility regulations for transgender athletes. To better understand and contextualize the effect of androgen-suppression treatment on swimming performance, we compared the gender-related differences in performance of a transgender swimmer who competed in both the male and female NCAA (collegiate) categories to the sex-related differences in performance of world and national class swimmers. These data demonstrate that the gender-related differences in middle distance freestyle performances of a transgender woman are smaller than the observed sex-related differences in performance of top athletes. Our analysis may be useful as a framework for regulators considering participation guidelines which promote fair competition for all athletes, whether cisgender or transgender.\\n\\nOne-Sentence SummaryRecent outstanding performances by a transgender woman swimmer are faster than predictions based on historic sex-related differences in swimming performance.\",\n \"An experimental feasibility study evaluating the adequacy of sportswear-type wearables for recording physical exercise intensity\\nSportswear-type wearables with integrated inertial sensors and electrocardiogram (ECG) electrodes, have been developed. We examined the feasibility of using sportswear-type wearables to evaluate exercise intensity within a controlled laboratory setting. Six male college athletes were asked to wear a sportswear-type wearable while performing a treadmill test that reached up to 20 km/h. The magnitude of the filtered tri-axial acceleration signal, recorded by the inertial sensor, was used to calculate the acceleration index. The R-R intervals of ECG were used to determine heart rate; the external validity of the heart rate was then evaluated according to oxygen uptake, which is the gold standard physiological exercise intensity. Single regression analyses between treadmill speed and the acceleration index in each participant showed that the slope of the regression line was significantly greater than zero with a high coefficient of determination (walking, 0.95; jogging, 0.96; running, 0.90). Another single regression analyses between heart rate and oxygen uptake showed that the slope of the regression line was significantly greater than zero, with a high coefficient of determination (0.96). Together, these results indicate that sportswear-type wearables are a feasible technology for evaluating physical and physiological exercise intensity across a wide range of physical activities and sport performances.\",\n \"COVID-19 vaccination status is associated with physical activity in German-speaking countries: the COR-PHYS-Q cohort study\\nBackgroundTo examine the association between COVID-19 vaccination status and physical activity (PA), sporting behavior, as well as barriers to PA in adults in Switzerland, Germany, and Austria.\\n\\nMethodsA total of 1516 adults provided complete responses to our online questionnaire sent out in August 2021. Information about self-reported PA categories, sporting behavior, barriers to PA, and COVID-19 vaccination status were gathered. Main analyses were done using multiple linear regression adjusted for relevant parameters.\\n\\nResultsWe found a significant association of vaccination status with total PA (p = .011), vigorous PA (p = .015), and moderate PA (p = .001) but not transport-related PA or sedentary time. Unvaccinated adults tended to have more total and vigorous PA than those vaccinated once (ratios of geometric means: 1.34 and 1.60, respectively) or twice (1.22 and 1.09, respectively). Yet, not sufficient evidence was available to confirm this. There was no between-group difference in the contribution of leisure time, work-related, or transport-related PA to total PA. Vaccination status was not associated with sporting behavior except for jogging as the primary intensive type of sports. Finally, there were no significant differences in any of the COVID-19 specific barriers to PA between groups.\\n\\nConclusionOur data showed that vaccination status is associated with PA even in summer, where the number of COVID-19 cases was low and the severity of safety measures was mild. These findings may enhance future research and improve/extend COVID-19-specific PA guidelines.\",\n \"The Psychosocial Benefits of Sport Participation During COVID-19 Are Only Partially Explained by Increased Physical Activity\\nThe purpose of this study was to determine whether physical activity (PA) increases were responsible for the improvements in mental health and quality of life (QOL) seen among adolescents who returned to sport during the COVID-19 pandemic.Adolescent athletes were asked to complete a survey in October 2020 regarding demographic information, whether they had returned to sport participation (no [DNP], yes [PLY]), school instruction type (virtual, in-person, hybrid), anxiety, depression, QOL, and PA. Anxiety, depression, QOL and PA were compared between PLY and DNP using least squares means from linear models adjusted for age, gender, and instruction type. Mediation analysis assessed whether the relationship between sport status and anxiety, depression, and QOL was mediated by PA. 171 athletes had returned to play, while 388 had not. PLY athletes had significantly lower anxiety (3.6{+/-}0.4 v 8.2{+/-}0.6, p<0.001) and depression (4.2{+/-}0.4 v 7.3{+/-}0.6, p<0.001), and significantly higher QOL (88.1{+/-}1.0 v 80.2{+/-}1.4, p<0.001) and PA (24.0{+/-}0.5 v 16.3{+/-}0.7, p<0.001). PA explained a significant, but relatively small portion of the difference in depression (22.1%, p=0.02) and QOL (16.0%, p=0.048) between PLY and DNP athletes, but did not explain the difference in anxiety (6.6%, p=0.20). Increased PA is only responsible for a small portion of the improvements in depression and QOL among athletes who returned to sports and unrelated to improvements in anxiety. This suggests that the majority of the mental health benefits of sport participation for adolescents during the COVID-19 pandemic are independent of, and in addition to, the benefits of increased PA.\",\n \"The Chinese Assessment of physical literacy: Based on Grounded Theory Paradigm for children in grades 3-6\\nThe aim of this study is to construct and validate \\\"physical literacy self-assessment questionnaire\\\"(PLAQ)for Chinese students in grades 3-6. This study uses qualitative and quantitative methods to construct evaluation indicators of PL and determine the weights of each indicator. The 60 items of original PLAQ was based on literature review and interviews,and administered to 1179 primary students graded 3-6 in China. Exploratory factor analysis(EFA)and confirmatory factor analysis(CFA) are used to optimize the structure and verify the reliability and validity of the questionnaire. The model of PLAQ is composed of 4 first-level indicators, 10 second-level indicators and 35 third-level indicators. The results of EFA and CFA resulted in a 44-items, 4-factor questionnaire. EFA item loadings ranged from 0.558 to 0.896,and Cronbachs alpha ranged from 0.818 to 0.892. The results of CFA show that the constructed model fits well, and PLAQ has good convergent validity and discriminative validity. The PLAQ appeared to be reliable and valid that can be used as an assessment tool for students in grades 3-6. PLAQ can be used as a guide for the development of PL. Additionally, PLAQ gives us a shared understanding about what PL is and how it can be developed by Chinese children. However, studies on the accuracy and generalizability of the PLAQ should be conducted to improve it in the future.\",\n \"Ready for Impact? A validity and feasibility study of instrumented mouthguards (iMGs)\\nObjectivesDetermine the validity and feasibility of current Instrumented mouthguards (iMGs) and associated systems.\\n\\nMethodsPhase 1; Four iMG systems (Football Research Inc [FRI], HitIQ, ORB, Prevent) were compared against dummy headform laboratory criterion standards (25, 50, 75, 100 g). Phase 2; Four iMG systems were evaluated for on-field validity of iMG-triggered events against video-verification to determine true-positives, false-positives and false-negatives (20 {+/-} 9 player matches per iMG). Phase 3; Four iMG systems were evaluated by eighteen rugby players, for perceptions of fit, comfort and function. Phase 4; Three iMG systems (FRI, HitIQ, Prevent) were evaluated for practical feasibility (system usability scale; SUS) by four practitioners.\\n\\nResultsPhase 1; Total concordance correlation coefficient was 98.3%, 95.3%, 42.5% and 97.9% for FRI, HitIQ, ORB and Prevent. Phase 2; Different on-field kinematics were observed between iMGs. Positive predictive values were 0.98, 0.90, 0.53 and 0.94 for FRI, HitIQ, ORB and Prevent. Sensitivity values were 0.51, 0.40, 0.71 and 0.75 for FRI, HitIQ, ORB and Prevent. Phase 3; player perceptions of fit, comfort and function were 77%, 6/10, 55% for FRI, 88%, 8/10, 61% for HitIQ, 65%, 5/10, 43% for ORB, and 85%, 8/10, 67% for Prevent. Phase 4; SUS was 51.3-50.6/100, 71.3-78.8/100, and 83.8-80.0/100 for FRI, HitIQ, and Prevent.\\n\\nConclusionThis study shows that differences between current iMG systems exist. Sporting organisations can use these findings to ensure accurate head acceleration event data are obtained and system adoption is optimized, to support player welfare initiatives directly related to long-term brain health.\",\n \"The Acute Effects of Physical Exercise Breaks on Cognitive Function During Prolonged Sitting: A First Quantitative Evidence\\nPurposeThis systematic review and meta-analysis aims to investigate the cognitive benefits of breaking up prolonged sitting (PS) by acute physical exercises (PE).\\n\\nMethodsA systematic literature search was performed in six electronic databases (PubMed, Scopus, Web of Science, PsycINFO, SPORTDiscus, and Cochrane Library) to identify cross-over studies with a pre-posttest design that examined the effects of PE breaks during 3 to 5 h of prolonged sitting on cognitive performance. A meta-analysis was performed using a random effects model, with subgroup analyses investigating dose-response effects and differences between cognitive domains. Additionally, study quality was rated using the PEDro scale.\\n\\nResultsThirteen randomized controlled trials (RCTs) with a total of 295 participants (171 female and 124 male) were included in this systematic review. Thereof, nine studies were included in our meta-analysis. We observed that during PS, PE breaks did not improve overall cognitive performance (Hedges g=-0.043[-0.158,0.073]). There was no between-study heterogeneity indicated. This is further supported by the subgroup analyses showing no differences in effect sizes between cognitive domains and different exercise intensities.\\n\\nConclusionsOur findings suggest that interrupting PS by PE breaks neither improved, nor impaired cognitive performance. Consequently, PE breaks during PS allows to integrate regular physical activity in daily routines (i.e., through PE breaks) without compromising the performance of cognitively demanding tasks.\",\n \"VALIDATION OF AN INSTRUMENTED MOUTHGUARD\\nThe purpose of this study was to determine the validity of an raw and filtered acceleration time-series data from an instrumented mouthguard system against an anthropometric testing device. Testing was conducted in a laboratory using a standard impact protocol utilising the head-form of reference system and the mouthguard system. Testing occurred at 5 impact locations: facemask, front, oblique, side and back, and at four velocities (3.6, 5.5, 7.4, and 9.3 m/s) to attain a total of 55 impacts. A 160 Hz Low-pass 4th order Butterworth filter was applied to the time-series data, and was reported as raw and filtered. Peak linear acceleration, peak rotational velocity and peak rotational acceleration was statistically compared to the reference measurement system. Total concordance correlation coefficient was 90.7% and 96.9%, for raw and filtered data set. Raw and filtered had intraclass correlation coefficients of 0.85 and 0.95 for peak linear acceleration, 0.99 and 0.99 for peak rotational velocity and 0.94 and 0.95 peak rotational acceleration respectively. The instrumented mouthguard displayed high accuracy when measuring head impact kinematics in a laboratory setting. The results presented in this study provide the basis on which the instrumented mouthguard can be further developed for deployment and application within sport quantify head impact collision dynamics in order to optimise performance and brain health.\",\n \"A qualitative examination of the factors affecting the adoption of injury focused wearable technologies in recreational runners\\nPurposeUnderstanding users perceived usefulness and ease of use of technologies will influence their adoption and sustained use. The objectives of this study were to determine the metrics deemed important by runners for monitoring running-related injury (RRI) risk, and identify the barriers and facilitators to their use of injury focused wearable technologies.\\n\\nMethodsA qualitative focus group study was undertaken. Nine semi-structured focus groups with male (n=13) and female (n=14) recreational runners took place. Focus groups were audio and video recorded, and transcribed verbatim. Transcripts were thematically analysed. A critical friend approach was taken to data coding, and multiple methods of trustworthiness were executed.\\n\\nResultsExcessive loading and inadequate recovery were deemed the most important risk factors to monitor for RRI risk. Other important factors included training activities, injury status and history, and running technique. The location and attachment method of a wearable device and the design of a smartphone application were identified as important barriers and facilitators, with receiving useful injury-related feedback identified as a further facilitator.\\n\\nConclusionsOvertraining, training-related and individual- related risk factors are essential metrics that need to be monitored for RRI risk. RRI apps should include the metrics deemed important by runners, once there is supporting evidence- based research. The difficulty and/or ease of use of a device, and receiving useful feedback will influence the adoption of injury focused running technologies. There is a clear willingness from recreational runners to adopt injury focused wearable technologies whilst running.\",\n \"Oral injury in Kendo players: a cross-sectional survey\\nThis study evaluated the risk of oral injury in Kendo. We hypothesized that Kendo players in Japan may experience oral injury due to the use of face protector for kendo (men) with inaccurate measurements or wearing it incorrectly. The survey included 400 kendo players (male, 276; female, 174) and covered four areas: the relationship between the characteristics, percentage of oral injury, temporomandibular disorder (TMD), and use of men. Based on the who experience of oral injury, participants were classified into trauma and non-trauma groups. Those who suffered oral injury were 179 (44.8 %; males, n=118; females, n=61). In the past month, 32 (8.2%) Kendo players reported that their matches/training were affected by dental/oral problems. For TMD, 50 participants had a total score >8.5 from four screening questions. For 289 (72.3%) participants, the men they are currently wearing fit well. Of those that reported that their men do not fit properly, 48 (12.0%) felt that their men were too large, and 14 (3.5%) felt that their men were too small. Years of experience and clenching of ones jaws during an offensive Kendo movement significantly contributed to oral injury. Clenching ones jaws during a defensive Kendo move, current men fit, sleep bruxism, and morning symptoms from sleep bruxism significantly contributed to TMD. Men with an accurate sizing allows proper field of vision, eliminating head shifting inside men during strikes and movements. This suggests that vision can be secured by adjusting the ties on men, chin movement, and the way one looks through the men. Since Kendo equipment is originally a Japanese craft, it has high artistry. Thus, properly worn Kendo equipment brings higher functionality and esthetic appeal.\",\n \"The acute effects of knee extension exercises with different contraction durations on the subsequent maximal knee extension torque for athletes with different strength levels\\nIndividuals with high fatigue resistance against a high-intensity conditioning activity (CA) may be able to avoid experiencing significant fatigue and enhance their voluntary performance. We examined whether the optimal contraction duration of dynamic knee extension exercises to maximize subsequent voluntary performance varies depending on the strength level of an individual. The study participants were 22 male American college football players. Initially, all participants performed a 10-s maximal isometric knee extension exercise and were classified as stronger individuals (n = 8) and weaker individuals (n = 8) based on their relative muscle strength. Each group then performed three types of dynamic CA with different contraction durations (6 s [6-CA], 12 s [12-CA], and 18 s [18-CA]) in random order. To observe the time-course changes in post-activation potentiation and performance enhancement, the twitch torques induced by electrical stimulation and isokinetic knee extension torques at 180{degrees}/s were recorded before and after each CA. The twitch torque increased at 10 s (29.5% {+/-} 9.3%) and 1 min (18.5% {+/-} 6.8%) after 6-CA for the stronger individuals (p < 0.05). However, no post-activation potentiation was induced in the weaker individuals in either protocol. Voluntary performance increased at 4 (7.0% {+/-} 4.5%) and 7 (8.2% {+/-} 4.3%) min after 18-CA for stronger individuals (p < 0.05). However, there was no post-activation performance enhancement in either protocol for weaker individuals. Thus, CA with a relatively long contraction duration was optimal to maximize the subsequent voluntary performance for stronger individuals. It remains unknown whether CAs performed with relatively short or long contraction durations were optimal for weaker individuals.\",\n \"Effects of vitamin D deficiency on blood lipids and bone metabolism: a large cross- sectional study\\nPurposeTo investigate the relationship between serum HDL-C and spinal bone mineral density (BMD) under different serum 25-hydroxyvitamin D (25 (OH) D) levels in adults over 40 years old and to explore its mechanism.\\n\\nMethodsParticipants over the age of 40 with data on HDL-C, 25 (OH) D, spinal BMD, and other variables in NHANES 2007-2010 were included in the final analysis. A weighted multiple linear regression model was used to evaluate the association between serum HDL-C and spinal BMD in different gender, ages and serum 25 (OH) D levels.\\n\\nResultsA total of 3599 subjects aged [≥] 40 years old were included in this study. Univariate analysis of the complete correction model showed a negative correlation between serum HDL-C and spinal BMD. In the two subgroups of serum 25(OH)D, we found that the higher the serum HDL-C in the female with serum 25 (OH) D < 75nmol/L aged 40-59 years old, the lower the total spinal BMD, and a similar relationship was found in the lumbar spine (L1-L4). However, no similar relationship was found in all populations with serum 25 (OH) D [≥] 75nmol/L and males with serum 25 (OH) D < 75nmol/L.\\n\\nConclusionAmong Americans over the age of 40, the increase of serum HDL-C is related to decreased BMD of spine only in women aged 40-59 years with vitamin D insufficiency or deficiency.\\n\\nAuthor summaryWe performed a cross-sectional study using the National Health Examination and Nutrition Survey (NHANES) data. We found that increased serum high-density lipoprotein cholesterol (HDL-C) during vitamin D deficiency is a potential risk factor for osteopenia or osteoporosis in middle-aged and elderly American women.\",\n \"Acute exercise induces natural killer cell mobilization but not infiltration into prostate cancer tissue in humans\\nThe mobilization and activation of natural killer (NK) cells have been proposed as key mechanisms promoting anti oncogenic effects of physical exercise. Although mouse models have proven that physical exercise recruits NK cells to tumor tissue and inhibits tumor growth, this preclinical finding has not been transferred to the clinical setting yet. In this first-in-human study, we found that physical exercise mobilizes and redistributes NK cells, especially those with a cytotoxic phenotype, in line with preclinical models. However, physical exercise did not increase NK cell tumor infiltrates. Future studies should carefully distinguish between acute and chronic exercise modalities and should be encouraged to investigate more immune responsive tumor entities.\",\n \"Reduced motor unit discharge rates in gastrocnemius lateralis, but not in gastrocnemius medialis or soleus, in runners with Achilles tendinopathy\\nObjectivesDeficits in muscle performance could be a consequence of a reduced ability of a motor neuron to increase the rate in which it discharges. This study aimed to investigate motor unit (MU) discharge properties of each Triceps surae muscle (TS), and TS torque steadiness during submaximal intensities in runners with Achilles tendinopathy (AT).\\n\\nMethodsWe recruited runners with (n=12) and without (n=13) mid-portion AT. MU discharge rate was analysed for each of the TS muscles, using High-Density surface electromyography during 10 and 20% isometric plantar flexor contractions.\\n\\nResultsMU mean discharge rate was lower in the Gastrocnemius lateralis (GL) in AT compared to controls. In AT, GL MU mean discharge rate did not increase as torque increased from 10% peak torque, 8.24pps (95%CI: 7.08 to 9.41) to 20%, 8.52pps (7.41 to 9.63, p=0.540); however, in controls, MU discharge rate increased as torque increased from 10%, 8.39pps (7.25 to 9.53) to 20%, 10.07pps (8.89 to 11.25, p<0.001). There were no between-group difference in Gastrocnemius medialis (GM) or Soleus (SOL) MU discharge rates. We found no between-groups differences in coefficient of variation of MU discharge rate in any of the TS muscles nor in TS torque steadiness.\\n\\nConclusionOur data demonstrates that runners with AT may have a reduced neural drive to GL, failing to increase MU discharge rate to adjust for the increase in torque demand. Further research is needed to understand how interventions focusing on increasing neural drive to GL would affect muscle function in runners with AT.\"\n]","isConversational":false},"negative":{"kind":"list like","value":["Using DeepLabCut for tracking body landmarks in videos of children with dyskinetic cerebral palsy: a working methodology\nMarkerless motion tracking is a promising technique to capture human movements and postures. It could be a clinically feasible tool to objectively assess movement disorders within severe dyskinetic cerebral palsy (CP). Here, we aim to evaluate tracking accuracy on clinically recorded video data.\n\nMethod94 video recordings of 33 participants (dyskinetic CP, 8-23 years; GMFCS IV-V, i.e. non-ambulatory) from a previous clinical trial were used. Twenty-second clips were cut during lying down as this is a postion for this group of children and young adults allows to freely move. Video image resolution was 0.4 cm per pixel. Tracking was performed in DeepLabCut. We evaluated a model that was pre-trained on a human healthy adult data set with an increasing number of manually labeled frames (0, 1, 2, 6, 10, 15 and 20 frames per video). To assess generalizability, we used 80% of videos for the model development and evaluated the generalizability of the model using the remaining 20%. For evaluation the mean absolute error (MAE) between DeepLabCuts prediction of the position of body points and manual labels was calculated.\n\nResultsUsing just the pre-trained adult human model yielded a MAE of 121 pixels. An MAE of 4.5 pixels (about 1.5 cm) could be achieved by adding 15-20 manual labels. When applied to unseen video clips (i.e. generalization set), the MAE was 33 pixels with a dedicated model trained on 20 frames per videos.\n\nConclusionAccuracy of tracking with a standard pre-trained model is insufficiently to automatically assess movement disorders in dyskinetic CP. However, manually adding labels improves the model performance substantially. In addition, the methodology proposed within our study is applicable to check the accuracy of DeepLabCut application within other clinical data set.","A Solution to the Kermack and McKendrick Integro-Differential Equations\nIn this manuscript, we derive a closed form solution to the full Kermack and McKendrick integro-differential equations (Kermack and McKendrick 1927) which we call the KMES. The KMES can be cast in the form of a step function response to the input of new infections; and that response is the time series of the total infections. We demonstrate the veracity of the KMES using independent data from the Covid 19 pandemic and derive many previously unknown and useful analytical expressions for diagnosing and managing an epidemic. These include new expressions for the viral load, the final size, the effective reproduction number, and the time to the peak in infections.\n\nSince the publication of Kermack and McKendricks seminal paper (1927), thousands of authors have utilized the Susceptible, Infected, and Recovered (SIR) approximations; expressions which are putatively derived from the integro-differential equations, to model epidemic dynamics. Implicit in the use of the SIR approximation are the beliefs that there is no closed form solution to the more complex integro-differential equations, that the approximation adequately reproduces the dynamics of the integro-differential equations, and that herd immunity always exists. However, as we explicate in this manuscript, the KMES demonstrates that the SIR models are not adequate representations of the integro-differential equations, and herd immunity is not guaranteed. Our conclusion is that the KMES obsoletes the need for the SIR approximations; and provides a new level of understanding of epidemic dynamics.","Deep learning to estimate gestational age from blind ultrasound sweeps of the gravid abdomen\nBackgroundUltrasound is indispensable to gestational age estimation, and thus to quality obstetric care, yet high equipment cost and need for trained sonographers limit its use in low-resource settings.\n\nMethodsFrom September 2018 through June 2021, we recruited 4,695 pregnant volunteers in North Carolina and Zambia and obtained blind ultrasound sweeps (cineloops) of the gravid abdomen alongside standard fetal biometry. We trained a neural network to estimate gestational age from the sweeps and, in three test sets, assessed performance of the model and biometry against previously established gestational age.\n\nResultsIn our main test set, model mean absolute error (MAE) was 3.9 days (standard error [SE] 0.12) vs. 4.7 days (SE 0.15) for biometry (difference -0.8 days; 95% CI -1.1, -0.5; p<0.001). Results were similar in North Carolina (difference -0.6 days, 95% CI -0.9, -0.2) and Zambia (-1.0 days, 95% CI -1.5, -0.5). Findings were supported in the test set of women who conceived by in vitro fertilization (model MAE 2.8 days [SE 0.28] vs. 3.6 days [SE 0.53] for biometry; difference -0.8 days, 95% CI -1.7, 0.2), and in the set of women from whom sweeps were collected by untrained users with low-cost, battery-powered devices (model MAE 4.9 days [SE 0.29] vs. 5.4 days [SE 0.28] for biometry; difference -0.6, 95% CI -1.3, 0.1).\n\nConclusionsOur model estimated gestational age more accurately from blindly obtained ultrasound sweeps than did trained sonographers performing fetal biometry. These results presage a future where all pregnant people - not just those in rich countries - can access the diagnostic benefits of sonography.","Increasing trends in mental health problems among Chinese young adolescents: results from repeated cross-sectional data in Changsha 2016-2020\nThis study performed a repeated cross-sectional analysis to explore possible trends in mental health problems among Chinese adolescents during 2016 to 2020. A total of 2837 seventh-grade students from Changsha city were surveyed in three waves in 2016, 2019 and 2020. The results showed that obsessive-compulsive tendencies, interpersonal sensitivity, depression, anxiety, academic stress and emotional disturbance problems were significantly increased in surveyed adolescents during 2016 to 2020. Moreover, positive rates of most of these problems were higher in females than males, and were significantly increased in only females. These results highlight the importance of focusing on mental health among Chinese adolescents, especially girls.","A Machine Learning Approach to Identifying Delirium from Electronic Health Records\nBackgroundDespite the well-known impact of delirium on long-term clinical outcomes, identification of delirium in electronic health records (EHR) remains difficult due to inadequate assessment or documentation of delirium. The purpose of this research is to present a classification model that identifies delirium using retrospective EHR data. The classification model would support the additional identification of delirium cases otherwise undocumented during routine practice.\n\nMethodsDelirium was confirmed with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Age, sex, Elixhauser comorbidity index, drug exposures, and diagnoses were used as features to train the logistic regression and multi-layer perceptron models. The clinical notes from the EHR were parsed to supplement the features that were not recorded in the structured data. The model performance was evaluated with a 5-fold cross-validation area under the receiver operating characteristic curve (AUC).\n\nResultsSeventy-six patients (17 cases and 59 controls) with at least one CAM-ICU evaluation result during ICU stay from January 30, 2018 to February 20, 2018 were included in the model. The multi-layer perceptron model achieved the best performance in identifying delirium; mean AUC of 0.967 {+/-} 0.019. The mean positive predictive value (PPV), mean negative predicted value (NPV), mean sensitivity, and mean specificity of the MLP model were 0.9, 0.88, 0.56, and 0.95, respectively.\n\nConclusionA simple classification model showed a mean AUC over 0.95. This model promises to identify delirium cases with EHR data, thereby enable a sustainable infrastructure to build a retrospective cohort of delirium in the ICU. The cohort would be useful for the evaluation of long-term sequelae of delirium in ICU.","Brain Injury in COVID-19 is Associated with Autoinflammation and Autoimmunity\nCOVID-19 has been associated with many neurological complications including stroke, delirium and encephalitis. Furthermore, many individuals experience a protracted post-viral syndrome which is dominated by neuropsychiatric symptoms, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of severe COVID-19 more broadly.\n\nWe sought to investigate the dynamics of, and relationship between, serum markers of brain injury (neurofilament light [NfL], Glial Fibrillary Acidic Protein [GFAP] and total Tau) and markers of dysregulated host response including measures of autoinflammation (proinflammatory cytokines) and autoimmunity. Brain injury biomarkers were measured using the Quanterix Simoa HDx platform, cytokine profiling by Luminex (R&D) and autoantibodies by a custom protein microarray.\n\nDuring hospitalisation, patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependant manner, and there was evidence of ongoing active brain injury at follow-up 4 months later. Raised NfL and GFAP were associated with both elevations of pro-inflammatory cytokines and the presence of autoantibodies; autoantibodies were commonly seen against lung surfactant proteins as well as brain proteins such as myelin associated glycoprotein, but reactivity was seen to a large number of different antigens.\n\nFurthermore, a distinct process characterised by elevation of serum total Tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses in the same manner as NfL and GFAP.","Transferability of Psychological Interventions from Disaster-Exposed Employees to Healthcare Workers Working during the COVID-19 Pandemic\nBackgroundThe COVID-19 Pandemic had a significant negative impact on the mental health of healthcare workers. Evidence-based interventions that could be used to mitigate this impact are lacking in the literature. This review aims to evaluate psychological interventions used for employees following previous disasters and assess the transferability of these interventions to a healthcare setting during the COVID-19 pandemic.\n\nMethodsIntervention information from a previously published systematic review of the literature published up to 2015 was extracted, and an additional search of studies published from 2015-2020 was conducted. Studies were assessed for transferability using a checklist derived from the PIET-T process model.\n\nResultsInterventions from eighteen studies were assessed for transferability (including three studies identified in an updated literature search). Interventions established as most transferable included resilience training, meditation/mindfulness interventions, and cognitive behavioural therapy. Psychological debriefing was transferable but as it is contrary to current recommendations is not deemed appropriate for adoption.\n\nImplicationsSeveral existing interventions have the potential to be utilised within the COVID-19 context/pandemic. More research needs to be undertaken in this area to assess these interventions upon transfer.","A territory-wide study of arrhythmogenic right ventricular cardiomyopathy patients from Hong Kong\nBackgroundArrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a hereditary disease characterized by fibrofatty infiltration of the right ventricular myocardium that predisposes affected patients to malignant ventricular arrhythmias, dual-chamber cardiac failure and sudden cardiac death (SCD). The present study aims to investigate the risk of detrimental cardiovascular events in an Asian population of ARVC/D patients, including the incidence of malignant ventricular arrhythmias, new-onset heart failure with reduced ejection fraction (HFrEF), as well as long-term mortality.\n\nMethods and ResultsThis was a territory-wide retrospective cohort study of patients diagnosed with ARVC/D between 1997 and 2019 in Hong Kong. This study consisted of 109 ARVC/D patients (median age: 61 [46-71] years; 58% male). Of these, 51 and 24 patients developed incident VT/VF and new-onset HFrEF, respectively. Five patients underwent cardiac transplantation, and 14 died during follow-up. Multivariable Cox regression identified prolonged QRS duration as a predictor of VT/VF (p < 0.05). Female gender, prolonged QTc duration, the presence of epsilon waves and T-wave inversion (TWI) in any lead except aVR/V1 predicted new-onset HFrEF (P < 0.05. The presence of epsilon waves, in addition to the parameters of prolonged QRS duration and worsening ejection fraction predicted all-cause mortality (p<0.05). Clinical scores were developed to predict incident VT/VF, new-onset HFrEF and all-cause mortality, and all were significantly improved by machine learning techniques.\n\nConclusionClinical and electrocardiographic parameters are important for assessing prognosis in ARVC/D patients and should in turn be used in tandem to aid risk stratification in the hospital setting.","A very simple model to account for the rapid rise of the British variant of SARS-CoV-2 in several countries and the world\nSince its first detection in the UK in September 2020, a highly contagious version of the coronavirus, called the British variant or B.1.1.7 SARS-CoV-2 virus lineage, is rapidly spreading across several countries and becoming the dominant strain in the outbreak.\n\nHere it is shown that a very simple evolutionary model, when including the latest available data from March 2021, can fit the observed change in frequency of B.1.1.7 for several countries, regions of countries and the whole world with a single parameter which is almost universal.","Loss of recognition of SARS-CoV-2 B.1.351 variant spike epitopes but overall preservation of T cell immunity\nSARS-CoV-2 variants have emerged that escape neutralization and potentially impact vaccine efficacy. T cell responses play a role in protection from reinfection and severe disease, but the potential for spike mutations to affect T cell immunity is poorly studied. We assessed both neutralizing antibody and T cell responses in 44 South African COVID-19 patients infected either with B.1.351, now dominant in South Africa, or infected prior to its emergence ( first wave), to provide an overall measure of immune evasion. We show for the first time that robust spike-specific CD4 and CD8 T cell responses were detectable in B.1.351-infected patients, similar to first wave patients. Using peptides spanning only the B.1.351 mutated regions, we identified CD4 T cell responses targeting the wild type peptides in 12/22 (54.5%) first wave patients, all of whom failed to recognize corresponding B.1.351-mutated peptides (p=0.0005). However, responses to the mutated regions formed only a small proportion (15.7%) of the overall CD4 response, and few patients (3/44) mounted CD8 responses that targeted the mutated regions. First wave patients showed a 12.7 fold reduction in plasma neutralization of B.1.351. This study shows that despite loss of recognition of immunodominant CD4 epitope(s), overall CD4 and CD8 T cell responses to B.1.351 are preserved. These observations may explain why, despite substantial loss of neutralizing antibody activity against B.1.351, several vaccines have retained the ability to protect against severe COVID-19 disease.\n\nOne Sentence SummaryT cell immunity to SARS-CoV-2 B.1.351 is preserved despite some loss of variant epitope recognition by CD4 T cells.","COVID-19 and Herpes Simplex Virus Infection: A Cross-Sectional Study\nBackgroundDespite being variable and poorly characterized, the reported cutaneous manifestations of COVID-19 are of increasing concern.\n\nAim of the StudyThis study aimed to assess the prevalence and possible association between COVID-19 and herpes simplex virus (HSV) infection.\n\nPatients and methodsA 9-item questionnaire was sent to 120 PCR-confirmed COVID-19 patients with a response rate of 66.67%. This cross-sectional observational study included 80 patients with mild to moderate COVID-19 infection who did not require hospitalization or steroid therapy.\n\nResultsOne or more HSV infections were observed in 28 patients (35%) with COVID-19 infection, including 10 males (35.7%) and 18 females (64.29%). Of the 28 patients, fever was reported in 17 patients (75%) during COVID-19. Most of the respondents (78%) described a single HSV reactivation, 14.29% had 2 attacks, and 7.14% experienced 3 attacks. Compared to previous non-COVID-19 related HSV reactivation, the COVID-19 related attacks were more severe in 12 patients (42.85%), equally severe in 5 patients (17.85%) and less severe in 1 patient (3.57%). Interestingly, 10 patients (35.71%) developed an initial symptomatic HSV attack during COVID-19 infection.\n\nConclusionsThis study demonstrated a possible association between COVID-19 infection and primary HSV infection and/or reactivation. The COVID-19 direct neuronal effect in addition to COVID-19 related psychological stress, fever and immunological dysregulation could play a potential role.","Individual cardiorespiratory fitness exercise prescription in elderly based on BP neural network.\nCardiorespiratory fitness (CRF) declines as age increases in elderly. An individualized CRF exercise prescription can maintain the CRF level and delay aging process. Traditional exercise prescriptions are general and lack of individualization. In this paper, a new study based on back-propagation (BP) neural network, is investigated to predict the individualized CRF exercise prescriptions for elderly by correlate variables (age, sex, BMI, VO2max initial value, improvement etc.). The raw data are split to two parts, 90% for training the machine and the remaining 10% for testing the performance. Based on a database with 2078 people, the exercise prescription prediction models MAE, RMSE and R2 are1.5206,1.4383 and 0.9944. 26 female subjects aged 60-79 years are recruited to test the models validity. The VO2maxs expected improvement was set at 10%. Based on the basic information of these elder women, we get personalized exercise prescription (frequency, intensity, time and volume) of each subject. All of them finished their own exercise intervention. The results show that the post VO2max was significantly different from the pre VO2max and improved by 10.1%, and a total of 20 subjects(74.1%) improved within one standard deviation and 25 subjects(92.6%)improved within 1.96 times standard deviations. Our study shows that a high degree of accuracy in exercise suggestions for elderly was achieved by applying the BP neural network model.","Intermittent calorie restriction alters T cell subsets and metabolic markers in people with multiple sclerosis\nBackgroundIntermittent fasting or calorie restriction (CR) diets provide anti-inflammatory and neuroprotective advantages in models of multiple sclerosis (MS); data in humans are sparse.\n\nMethodsWe conducted a randomized-controlled feeding study of different CR diets in 36 people with MS over 8 weeks. Patients were randomized to receive either: a daily CR diet (22% reduction in calories, 7 days/week), an intermittent CR diet (75% reduction, 2 days/week; 100%, 5 days/week), or a weight-stable diet (100%, 7 days/week). Untargeted metabolomics was performed on plasma samples at weeks 0, 4 and 8 at Metabolon Inc (Durham, NC). Flow cytometry of cryopreserved peripheral blood mononuclear cells at weeks 0 and 8 were used to identify CD4+ and CD8+ T cell subsets including effector memory, central memory, and naive cells.\n\nResults31 (86%) completed the trial. Over time, individuals randomized to intermittent CR had significant reductions in CD4+CM -4.87%; 95%CI: -8.59%, -1.15%; p=0.01), CD4+EM (-3.82%; 95%CI: -7.44, - 0.21; p=0.04), and CD8+EM (-6.96%; 95%CI: -11.96, -1.97; p=0.006) with proportional increases in naive subsets (CD4+Naive: 5.81%; 95%CI: -0.01, 11.63%; p=0.05; CD8+Naive: 10.11%; 95%CI: 3.30, 16.92%; p=0.006). No changes were observed for daily CR or weight-stable diets. Larger within-person changes in lysophospholipid and lysoplasmalogen metabolites in intermittent CR were associated with larger reductions in memory T cell subsets and larger increases in naive T cell subsets.\n\nConclusionsIn people with MS, an intermittent CR diet was associated with reduction in memory T cell subsets. The observed changes may be mediated by changes in specific classes of lipid metabolites.\n\nTrial RegistrationThis study is registered on Clinicaltrials.gov with identifier NCT02647502.\n\nFundingNational MS Society, NIH, Johns Hopkins Catalyst Award","Effectiveness of quarantine and testing to prevent COVID-19 transmission from arriving travelers\nObjectiveTo assess the efficacy of policies designed to reduce the risk of international travelers importing SARS-CoV-2 into a country.\n\nMethodWe developed a simulation model and compared mandatory quarantine, testing, and combined quarantine and testing. We assessed the sensitivity of policy effectiveness to the timing of testing, compliance with quarantine and isolation, and other factors.\n\nResultsIn the base scenario, a 2-day quarantine reduced more risk than testing alone. The effectiveness of a 5-day quarantine requirement with perfect compliance was similar to a 14-day quarantine with moderate compliance. Testing 72h before arrival reduced less than 10% of in-country transmission risk across all scenarios. The addition of testing to quarantine added value for shorter quarantine lengths, when testing compliance was enforced, and when testing was performed near the end of quarantine.\n\nConclusionsQuarantine is more effective at preventing SARS-CoV-2 transmission from arriving travelers than testing alone, but testing combined with quarantine can add value if longer quarantine requirements are infeasible. Enforcing compliance with quarantine and isolation is critical. Requiring a negative test up to 72h before arrival may have limited effectiveness.","Brain cortical changes are related to inflammatory biomarkers in hospitalized SARS-CoV-2 patients with neurological symptoms\nIncreasing evidence shows that the brain is a target of SARS-CoV-2. However, the consequences of the virus on the cortical regions of hospitalized patients are currently unknown. The purpose of this study was to assess brain cortical gray matter volume (GMV), thickness (Th), and surface area (SA) characteristics in SARS-CoV-2 hospitalized patients with a wide range of neurological symptoms and their association with clinical indicators of inflammatory processes. A total of 33 patients were selected from a prospective, multicenter, cross-sectional study during the ongoing pandemic (August 2020-April 2021) at Basel University Hospital. Retrospectively biobank healthy controls with the same image protocol served as controls group. For each anatomical T1w MPRAGE image, the Th and GMV segmentation were performed with the FreeSurfer-5.0. Cortical measures were compared between groups using a linear regression model. The covariates were age, gender, age*gender, MRI magnetic field strength, and total intracranial volume/mean Th/Total SA. The association between cortical features and laboratory variables was assessed using partial correlation adjusting for the same covariates. P-values were adjusted using false discovery rate (FDR). Our findings revealed a lower cortical gray matter volume in orbitofrontal and cingulate regions in patients compared to controls. The orbitofrontal grey matter volume was negatively associated with protein levels, CSF-blood/albumin ratio and CSF EN-RAGE level. CSF EN-RAGE and CSF/Blood-albumin ratio, which are neuroinflammatory biomarkers, were associated with cortical alterations in gray matter volume and thickness in frontal, orbitofrontal, and temporal regions. Our data suggest that viral-triggered inflammation leads to increased neurotoxic damage in some cortical areas.","The relation between COVID-19 vaccinations and public governance to improve preparedness of next pandemic impacts and crisis management: a global study\nThe goal of this study is to analyze the relationship between COVID-19 vaccinations and public governance performing a global analysis of more than 110 countries worldwide. Methodology applies the Independent Samples T-Test that compares the means of two independent groups (countries with high/low level of vaccinations) to determine whether there is statistical evidence that the associated population means of indicators of public governance are significantly different. Findings suggest that high levels of governance can support a better function of health systems in the rollout of vaccinations to cope with COVID-19 pandemic crisis. This study may assist long-run policy of governments to improve good governance and health systems of countries in order to reinforce the preparedness to face next pandemic threats and in general future crisis management in society.","The genetic risk for COVID-19 severity is associated with defective innate immune responses\nRecent genome-wide association studies (GWASs) of COVID-19 patients of European ancestry have identified genetic loci significantly associated with disease severity (1). Here, we employed the detailed clinical, immunological and multi-omics dataset of the Human Functional Genomics Projects (HFGP) to explore the physiological significance of the host genetic variants that influence susceptibility to severe COVID-19. A genomics investigation intersected with functional characterization of individuals with high genetic risk for severe COVID-19 susceptibility identified several major patterns: i. a large impact of genetically determined innate immune responses in COVID-19, with increased susceptibility for severe disease in individuals with defective monocyte-derived cytokine production; ii. genetic susceptibility related to ABO blood groups is probably mediated through the von Willebrand factor (VWF) and endothelial dysfunction. We further validated these identified associations at transcript and protein levels by using independent disease cohorts. These insights allow a physiological understanding of genetic susceptibility to severe COVID-19, and indicate pathways that could be targeted for prevention and therapy.\n\nOne Sentence summaryIn this study, we explore the physiological significance of the genetic variants associated with COVID-19 severity using detailed clinical, immunological and multi-omics data from large cohorts. Our findings allow a physiological understanding of genetic susceptibility to severe COVID-19, and indicate pathways that could be targeted for prevention and therapy.","Seasonality in living kidney donation in the United States from 1995-2019\nFor nearly two decades, the annual number of US living kidney donors has been characterized by worrying patterns of decline and no factors have been identified to explain and reverse these patterns. Evidence suggests that there is seasonality in living kidney donation; herein we investigate whether potentially modifiable social, economic, and structural issues might explain this seasonality. Using donor-registry data from the Scientific Registry of Transplant Recipients, we described this seasonality in living kidney donation and used Poisson regression stratified by both donor-recipient biological relationship and estimated household income tertile to quantify these trends. In every decade from 1980-2020, there was a summer-only surge in living kidney donations (13%-25% for biologically related donors and 10%-17% for unrelated donors). This summer-only surge was evident for the months of June, July, and August when compared with January for each given year and statistically significant in some groups (range of incidence rate ratio [IRR] for related donors: 1.05-1.34; IRR for unrelated donors: 1.08-1.19). We observed this summer-only surge across all three income tertiles ($73,544+, $52,635- $73,544, and <$52,635) and regardless of donor-recipient relationship. Seasonal variation in donation is associated with structural factors, which may serve as potential targets for interventions to increase donation.","Prognosis of Acute Ischaemic Stroke in Cancer Patients: A National Inpatient Sample Study\nBackground and PurposeWhilst cancer is a risk factor for acute ischaemic stroke (AIS), its impact on AIS prognosis between metastatic and non-metastatic (MC and NMC) disease is poorly understood. Furthermore, the receipt of intravenous thrombolysis (IVT) and endovascular thrombectomy (ET) and their outcomes is poorly researched.\n\nMethodsAIS admissions from the National Inpatient Sample (NIS) were included (October 2015-December 2017). Multivariable logistic regressions adjusting for a wide range of confounders analysed the relationship between NMC and MC and AIS in-hospital outcomes (mortality, prolonged hospitalisation >4 days and routine home discharge). Interaction terms with IVT and ET were also computed to explore their impact amongst cancer patients.\n\nResults221,249 records representative of 1,106,045 admissions were included. There were 38,855 (3.51%) patients with co-morbid cancers: NMC=53.78% and MC=46.22%. NMC was associated with 23% increased odds of in-hospital mortality (odds ratio (95% confidence interval) = 1.23 (1.07-1.42)), which was mainly driven by pancreatic and respiratory cancers. This association was entirely offset by both IVT and ET. MC was associated with 2-fold increased odds of in-hospital mortality (2.16 (1.90-2.45)), which was mainly driven by respiratory, pancreatic and colorectal cancers. This association was only offset by ET. Both NMC and MC were significantly associated with prolonged hospitalisation and decreased odds of routine discharge.\n\nConclusionsCancer patients are at higher odds of acute adverse outcomes after AIS and warrant robust primary prevention. IVT and ET improve these outcomes and should thus be offered routinely unless otherwise contraindicated in this group of stroke patients.","40Hz sensory stimulation induces gamma entrainment and affects brain structure, sleep and cognition in patients with Alzheimer's dementia\nNon-invasive Gamma ENtrainment Using Sensory stimuli (GENUS) at 40Hz reduced Alzheimers disease (AD) pathology, prevented cerebral atrophy and improved performance during behavioral testing in mouse models of AD. We report data from a safety study (NCT04042922) and a randomized, placebo-controlled trial in participants with probable mild AD dementia after 3 months of one-hour daily 40Hz light and sound GENUS (NCT04055376) to assess safety, compliance, entrainment and possible effects on brain structure, function, sleep and cognitive function. GENUS was well-tolerated and compliance was high in both groups. Electroencephalography recordings show that our GENUS device safely and effectively induced 40Hz entrainment in cognitively normal subjects and participants with mild AD. After 3 months of daily stimulation, participants with mild AD in the 40Hz GENUS group showed less ventricular enlargement and stabilization of the hippocampal size compared to the control group. Functional connectivity increased in both the default mode network and the medial visual network after 3 months of stimulation. Circadian rhythmicity also improved with GENUS. Compared to controls, the active group performed better on the face-name association delayed recall test. These results suggest that 40Hz GENUS can be used safely at home daily and shows favorable outcomes on cognitive function, daily rhythms, and structural and functional MRI biomarkers of AD-related degeneration. These results support further evaluation of GENUS in larger and longer clinical trials to evaluate its potential as a disease modifying therapeutic for Alzheimers disease.","Validation of the RT-LAMP assay in a large cohort of nasopharyngeal swab samples shows that it is a useful screening method for detecting SARS-CoV-2 and its VOC variants\nThe COVID-19 pandemic is challenging the global supply chain and equipment needed for mass testing with RT-qPCR, the gold standard for SARS-CoV-2 diagnosis. Here, we propose the RT-LAMP assay as an additional strategy for rapid virus diagnosis. However, its validation as a diagnostic method remains uncertain. In this work, we validated the RT-LAMP assay in 1,266 nasopharyngeal swab samples with confirmed diagnosis by CDC 2019-nCoV RT-qPCR. Our cohort was divided, the first (n=984) was used to evaluate two sets of oligonucleotides (S1 and S3) and the second (n=281) to determine whether RT-LAMP could detect samples with several types of variants. This assay can identify positive samples by color change or fluorescence within 40 minutes and shows high concordance with RT-qPCR in samples with CT [≤]35. Also, S1 and S3 are able to detect SARS-CoV-2 with a sensitivity of 68.4% and 65.8%, and a specificity of 98.9% and 97.1%, respectively. Furthermore, RT-LAMP assay identified 279 sequenced samples as positive (99.3% sensitivity) corresponding to the Alpha, Beta, Gamma, Delta, Epsilon, Iota, Kappa, Lambda, Mu and Omicron variants. In conclusion, RT-LAMP is able to identify SARS-CoV-2 with good sensitivity and excellent specificity, including all VOC, VOI, VUM and FMV variants.","Preservation of neutralizing antibody function in COVID-19 convalescent plasma treated using a riboflavin and ultraviolet light-based pathogen reduction technology\nBackground and ObjectiveConvalescent plasma (CP) has been embraced as a safe therapeutic option for coronavirus disease 2019 (COVID-19) while other treatments are developed. However, transfusion-transmitted disease is a risk, particularly in regions with high endemic prevalence of transfusion-transmissible diseases. Pathogen reduction can mitigate this risk; thus, the objective of this study was to evaluate the effect of riboflavin and ultraviolet light (R+UV) pathogen reduction technology on the functional properties of CCP.\n\nMaterials and MethodsCCP units (n = 6) from recovered COVID-19 research donors were treated with R+UV. Pre- and post-treatment samples were tested for coagulation factor and immunoglobulin retention. Antibody binding to spike protein receptor binding domain (RBD), S1, and S2 epitopes of SARS-CoV-2 was assessed by ELISA.\n\nNeutralizing antibody (nAb) function was assessed by pseudovirus reporter viral particle neutralization (RVPN) assay and plaque reduction neutralization test (PRNT).\n\nResultsMean retention of coagulation factors was [≥] 70% while retention of immunoglobulins was 100%. Starting nAb titers were low, but PRNT50 titers did not differ between pre- and post-treatment samples. No statistically significant differences were detected in levels of IgG (P [≥] 0.3665) and IgM (P [≥] 0.1208) antibodies to RBD, S1, and S2 proteins before and after treatment.\n\nConclusionR+UV PRT effects on coagulation factors were similar to previous reports, but no significant effects were observed on immunoglobulin concentration and antibody function. SARS-CoV-2 nAb function in COVID-19 convalescent plasma is conserved following R+UV PRT treatment.","Vaccine Rollout Strategies: The Case for Vaccinating Essential Workers Early\nIn planning for upcoming mass vaccinations against COVID-19, many jurisdictions have proposed using primarily age-based rollout strategies, where the oldest are vaccinated first and the youngest last. In the wake of growing evidence that approved vaccines are effective at preventing not only adverse outcomes, but also infection (and hence transmission of SARS-CoV-2), we propose that such age-based rollouts are both less equitable and less effective than strategies that prioritize essential workers. We demonstrate that strategies that target essential workers earlier consistently outperform those that do not, and that prioritizing essential work-ers provides a significant level of indirect protection for older adults. This conclusion holds across numerous outcomes, including cases, hospitalizations, Long COVID, deaths and net monetary benefit, and over a range of possible values for the efficacy of vaccination against infection. Our analysis focuses on regimes where the pandemic continues to be controlled with distancing and other measures as vaccination proceeds, and where the vaccination strategy is expected to last for over the coming 6-8 months -- for example British Columbia, Canada. In such a setting with a total population of 5M, vaccinating essential workers sooner is expected to prevent over 200,000 infections, over 600 deaths, and to produce a net monetary benefit of over $500M.","Passively Sensing SARS-CoV-2 RNA in Public Transit Buses\nAffordably tracking the transmission of respiratory infectious diseases in urban transport infrastructures can inform individuals about potential exposure to diseases and guide public policymakers to prepare timely responses based on geographical transmission in different areas in the city. Towards that end, we designed and tested a method to detect SARS-CoV-2 RNA in the air filters of public buses, revealing that air filters could be used as passive fabric sensors for the detection of viral presence. We placed and retrieved filters in the existing HVAC systems of public buses to test for the presence of trapped SARS-CoV-2 RNA using phenol-chloroform extraction and RT-qPCR. SARS-CoV-2 RNA was detected in 14% (5/37) of public bus filters tested in Seattle, Washington, from August 2020 to March 2021. These results indicate that this sensing system is feasible and that, if scaled, this method could provide a unique lens into the geographically relevant transmission of SARS-CoV-2 through public transit rider vectors, pooling samples of riders over time in a passive manner without installing any additional systems on transit vehicles.\n\nSynopsisPassive sensing of viral presence on urban transit infrastructure is proven, with forward-looking benefits for tracking pandemic spread.","A general model for the demographic signatures of the transition from pandemic emergence to endemicity\nAnticipating the medium- and long-term trajectory of pathogen emergence has acquired new urgency given the ongoing COVID-19 pandemic. For many human pathogens the burden of disease depends on age and prior exposure. Understanding the intersection between human population demography and transmission dynamics is therefore critical. Here, we develop a realistic age-structured (RAS) mathematical model that integrates demography, social mixing and immunity to establish the suite of possible scenarios of future age-incidence and burden of mortality. With respect to COVID-19, we identify a plausible transition in the age-structure of risks once the disease reaches seasonal endemism, whether assuming long-lasting or brief protective immunity, and across a range of assumptions of relative severity of primary versus subsequent reinfections. We train the model using diverse real-world demographies and age-structured social mixing patterns to bound expectations for changing age-incidence and disease burden. The mathematical framework is flexible and can help tailoring mitigation strategies countries worldwide with varying demographies and social mixing patterns.\n\nOne Sentence SummaryA shift of COVID-19 risks to younger age-classes in future endemic circulation.","Negative impact of COVID-19 associated health system shutdown on patients diagnosed with colorectal cancer: a retrospective study from a large tertiary center in Ontario, Canada.\nBackgroundIn March 2020, a directive to halt all elective and non-urgent procedures was issued in Ontario, Canada because of COVID-19. The directive caused a temporary slowdown of screening programs including surveillance colonoscopies for colorectal cancer (CRC). Our goal was to determine if there was a difference in patient and tumour characteristics between CRC patients treated surgically prior to the COVID-19 directive compared to CRC patients treated after the slowdown.\n\nMethodsCRC resections collected within the Champlain catchment area of eastern Ontario in the six months prior to COVID-19 (August 1, 2019-January 31, 2020) were compared to CRC resections collected in the six months post-COVID-19 slowdown (August 1, 2020-January 31, 2021). Clinical (e.g. gender, patient age, tumour site, clinical presentation) and pathological (tumour size, tumour stage, nodal stage, lymphovascular invasion) features were evaluated using chi square tests, T-tests and Mann-Whitney tests where appropriate.\n\nResults343 CRC specimens were identified (175 pre-COVID-19, 168 post-COVID-19 slowdown). CRC patients treated surgically post-COVID-19 slowdown had larger tumours (44 mm vs. 35 mm; p = 0.0048) and were more likely to have presented emergently (24% vs .10%; p < 0.001). While there was a trend towards higher tumour stage, nodal stage, and clinical stage, these differences did not reach statistical significance. Other demographic and pathologic variables including patient gender, age, and tumour site were similar between the two cohorts.\n\nInterpretationThe COVID-19 slowdown resulted in a shift in the severity of disease experienced by CRC patients in Ontario. Pandemic planning in the future should consider the long-term consequences to cancer diagnosis and management.","How to coordinate vaccination and social distancing to mitigate SARS-CoV-2 outbreaks\nMost countries have started vaccinating people against COVID-19. However, due to limited production capacities and logistical challenges it will take months/years until herd immunity is achieved. Therefore, vaccination and social distancing have to be coordinated. In this paper, we provide some insight on this topic using optimization-based control on an age-differentiated compartmental model. For real-life decision making, we investigate the impact of the planning horizon on the optimal vaccination/social distancing strategy. We find that in order to reduce social distancing in the long run, without overburdening the healthcare system, it is essential to vaccinate the people with the highest contact rates first. That is also the case if the objective is to minimize fatalities provided that the social distancing measures are sufficiently strict. However, for short-term planning it is optimal to focus on the high-risk group.","High performances of a novel antigen detection test on nasopharyngeal specimens for SARS-CoV-2 infection diagnosis: a prospective study\nIntroductionThe SARS-CoV-2 pandemic has become a major public health issue worldwide. Developing and evaluating rapid and easy-to-perform diagnostic tests is an absolute priority. The current study was designed to assess diagnostic performances of an antigen-based rapid detection test (COVID-VIRO(R)) in a real-life setting.\n\nMethodsTwo nasopharyngeal specimens of symptomatic or asymptomatic adult patients hospitalized in the Infectious Diseases Department or voluntarily accessing the COVID-19 Screening Department of the Regional Hospital of Orleans, France, were concurrently collected. COVID VIRO(R) diagnostic specificity and sensitivity were assessed in comparison to real-time reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) results. A subset of patients underwent an additional oropharyngeal and/or a saliva swab for rapid testing.\n\nResults121 patients already having a confirmed infection and 127 patients having no evidence of recent or ongoing infection were enrolled, for a total of 248 couple of nasopharyngeal swab specimens. Overall COVID-VIRO(R) sensitivity was 96.7% (IC: 93.5%-99.9%). In asymptomatic patients, symptomatic patients having symptoms for more than 4 days and those having a RT-qPCR Cycle threshold value [≥]32, sensitivity was of 100%, 95.8% and 91.9% respectively. The concordance between RT-qPCR and COVID VIRO(R) rapid test was 100% for the 127 patients with no SARS-CoV-2 infection.\n\nConclusionCOVID-VIRO(R) test had 100% specificity and above 95% sensitivity, better than WHO recommendations (specificity [≥]97-100%, sensitivity [≥]80%). These rapid tests are particularly interesting for large-scale screening in Emergency Department, low resource settings and airports.","COVID19, Consumption and Inequality: A Systematic Analysis of Rural Population of India\nBackgroundCOVID19 pandemic has had major impact on consumption levels and inequality within India. Government policy interventions have targeted poor households for cash and food transfers. It is important, however, to study the impact of the pandemic on consumption levels of non-poor in India, and in particular the middle class. In this paper, we aim to quantify the changes in consumption levels and inequality over time, across all groups of rural households in India.\n\nMethodsWe analyze three rounds of COVID 19-related shock surveys between May and September 2020. These surveys cover rural households of six large states in India and are representative of more than 442 million (52% of Indias rural population).\n\nFindingsIn the early phase of the pandemic, it was the bottom 40% of households that experienced the most severe decline in consumption. But as the pandemic deepened, consumption declined across all classes of households. Besides the poorest, it was particularly severe for the middle class (defined as 40%-80%). We also measure consumption inequality over time and find that the Gini coefficient of consumption distribution increased significantly.\n\nInterpretationIn addition to focusing on poor households, policy responses to alleviate peoples sufferings would have to consider a more comprehensive boost to consumption and compensate for the reduced consumption among middle class families as well.\n\nFundingNone.","Diminishing immune responses against variants of concern in dialysis patients four months after SARS-CoV-2 mRNA vaccination\nPatients undergoing chronic hemodialysis were among the first to receive SARS-CoV-2 vaccinations due to their increased risk for severe COVID-19 disease and high case fatality rates. To date, there have been minimal longitudinal studies in hemodialysis patients to ascertain whether protection offered by vaccination is long-lasting. To assess how surrogates for protection changed over time, we examined both the humoral and cellular response in a previously reported cohort of at-risk hemodialysis patients and healthy donors, four months after their second dose of Pfizer BNT162b2. Compared to three weeks post-second vaccination, both cellular and humoral responses against the original SARS-CoV-2 isolate as well as variants of concern were significantly reduced, with some dialyzed individuals having no B- or T-cell response. Our data strongly support the need for a third booster in hemodialysis patients and potentially other at-risk individuals.","Trends in medical and surgical admission length of stay by race/ethnicity and socioeconomic status: a time series analysis\nLength of stay, a metric of hospital efficiency, differs by race/ethnicity and socioeconomic status (SES). Longer LOS is associated with adverse health outcomes. We assessed differences in average adjusted length of stay (aALOS) over time by race/ethnicity, and SES stratified by discharge destination (home or non-home). Using the 2009-2014 State Inpatient Datasets from three states, we examined trends in aALOS differences by race/ethnicity, and SES (defined first vs fourth quartile of median income by zip code) controlling for patient, disease and hospital characteristics. For those discharged home, racial/ethnic and SES aALOS differences remained stable. Notably, for those discharged to non-home destinations, Black vs White, and low vs high SES aALOS differences increased significantly from 2009 to 2013, more sharply after Q3 2011, the Affordable Care Acts (ACA) introduction. Further research to understand the ACAs policy impact on hospital efficiencies, and relationship to racial/ethnic and SES differences in LOS is warranted.","Pre-immunity: the Schrodinger's cat of immunology\nEarly 2020, catastrophic consequences of COVID-19 was predicted in the do-nothing scenario, based on mathematical models for epidemiology. As data began to emerge, several scientists noted that growth did not seem exponential, as the models predicted, leading to speculations of pre-existing immunity or immunological dark matter to explain this pattern. On the other hand, reports of choir-rehearsals infecting most members seemed to refute this, and the topic remained inconclusive. We provide a mathematical theory in which both observations are true; on a population level, pre-immunity exists, on an individual level, it doesnt. This theory demonstrates that established formulas relating e.g. R0 and the herd-immunity threshold are wrong. We derive new mathematical formulas, which applies to any virus whose transmission dynamics is associated with large individual variability in susceptibility to the infection. Contrary to great variability in infectivity, which we show has no bearing on the mathematical modeling, variability in susceptibility actually manifests itself as pre-immunity on a macroscopic scale, thus making pre-immunity a necessity for accurate mathematical modeling.","Saliva-based detection of COVID-19 infection in a real-world setting using reagent-free Raman spectroscopy and machine learning\nSignificanceThe primary method of COVID-19 detection is reverse transcription polymerase chain reaction (RT-PCR) testing. PCR test sensitivity may decrease as more variants of concern arise.\n\nAimWe aimed to develop a reagent-free way to detect COVID-19 in a real-world setting with minimal constraints on sample acquisition.\n\nApproachWe present a workflow for collecting, preparing and imaging dried saliva supernatant droplets using a non-invasive, label-free technique - Raman spectroscopy - to detect changes in the molecular profile of saliva associated with COVID-19 infection.\n\nResultsUsing machine learning and droplet segmentation, amongst all confounding factors, we discriminated between COVID-positive and negative individuals yielding receiver operating coefficient (ROC) curves with an area under curve (AUC) of 0.8 in both males (79% sensitivity, 75% specificity) and females (84% sensitivity, 64% specificity). Taking the sex of the saliva donor into account increased the AUC by 5%.\n\nConclusionThese findings may pave the way for new rapid Raman spectroscopic screening tools for COVID-19 and other infectious diseases.","COVID-19 vaccine uptake, predictors of vaccination, and self-reported barriers to vaccination among primary school teachers in Poland\nIt has been proposed that teachers, like healthcare workers, constitute a strategic target for COVID-19 vaccine programs as immunization is a key element in protecting both them and their pupils. The present study examined vaccine uptake among primary-school teachers and sought to identify factors associated with it. A sample was recruited from 553 Polish primary schools, and data were collected at two time points: December 2020 and March 2021. Associations between vaccine uptake among teachers and their attitudes toward COVID-19 vaccination were assessed through multivariate logistic regression. 6152 participants completed both baseline and follow-up surveys. Of these, 4502 (73.2%) reported their intention at baseline to receive a COVID-19 vaccination, if available; at follow-up, 3894 (86.5%) of the same 4502 reported having received the vaccination. A significant association was revealed between vaccine uptake and perceived severity, self-efficacy, and social norms. The principal driver for vaccine acceptance was the wish to avoid contracting the disease. Conversely, the principal driver for vaccine refusal was concern about side effects and safety. A strong association exists between intention to receive the COVID-19 vaccine and actual uptake. Future COVID-19 immunization programs may benefit from a stronger understanding of the factors associated with vaccine uptake among this cohort.","Cytokine release syndrome-like serum responses after COVID-19 vaccination are frequent but clinically inapparent in cancer patients under immune checkpoint therapy\nCancer patients frequently receive immune checkpoint therapies (ICT) which may modulate immune responses to COVID-19 vaccines. Recently, cytokine release syndrome (CRS) was observed in a cancer patient who received the BTN162b2 vaccine under ICT. Here, we analyzed adverse events (AEs) in patients of various solid tumor types undergoing (n=64) or not undergoing (n=26) COVID-19 vaccination under ICT as an exploratory endpoint of a prospectively planned cohort study. We did not observe clinically relevant CRS after vaccination (95% CI [0,0.056]). Short term (<4 weeks) serious AEs were rare (12.5%) and overall AEs under ICT were comparable to unvaccinated patients. Despite the absence of CRS symptoms, we observed a pairwise-correlated set of CRS-associated cytokines upregulated in 42% of patients after vaccination and ICT (>1.5fold). Hence, clinically meaningful CRS appears to be rare in cancer patients under ICT and elevated serum cytokine levels are common but not sufficient to establish CRS diagnosis.","Incorporating Vaccination into Compartment Models for Infectious Diseases\nThe standard way of incorporating vaccination into a compartment model for an infectious disease is as a spontaneous transition process that applies to the entire susceptible class. The large degree of COVID-19 vaccine refusal and initial limitations of supply and distribution require reconsideration of this standard treatment. In this paper, we address these issues for models on endemic and epidemic time scales. On an endemic time scale, we partition the susceptible class into prevaccinated and unprotected subclasses and show that vaccine refusal has a significant impact on endemic behavior, particularly for diseases where immunity is short-lived. On an epidemic time scale, we develop a supply-limited Holling type 3 vaccination model and show that it is an excellent fit to vaccination data. We also extend the Holling model to a COVID-19 scenario in which the population is divided into two risk classes, with the high-risk class being prioritized for vaccination. For both cases with and without stratification by risk, we see significant differences in epidemiological outcomes between the Holling vaccination model and naive models. Finally, we use the new model to explore implications for public health policies in future pandemics.","Actionable absolute risk prediction of atherosclerotic cardiovascular disease: a behavior-management approach based on data from 464,547 UK Biobank participants\nCardiovascular diseases (CVDs) are the primary cause of all global death. Timely and accurate identification of people at risk of developing an atherosclerotic CVD and its sequelae, via risk prediction model, is a central pillar of preventive cardiology. However, currently available models only consider a limited set of risk factors and outcomes, do not focus on providing actionable advice to individuals based on their holistic medical state and lifestyle, are often not interpretable, were built with small cohort sizes or are based on lifestyle data from the 1960s, e.g. the Framingham model. The risk of developing atherosclerotic CVDs is heavily lifestyle dependent, potentially making a high percentage of occurrences preventable. Providing actionable and accurate risk prediction tools to the public could assist in atherosclerotic CVD prevention. We developed a benchmarking pipeline to find the best set of data preprocessing and algorithms to predict absolute 10-year atherosclerotic CVD risk. Based on the data of 464,547 UK Biobank participants without atherosclerotic CVD at baseline, we used a comprehensive set of 203 consolidated risk factors associated with atherosclerosis and its sequelae (e.g. heart failure).\n\nOur two best performing absolute atherosclerotic risk prediction models provided higher performance than Framingham and QRisk3. Using a subset of 25 risk factors identified with feature selection, our reduced model achieves similar performance while being less complex. Further, it is interpretable, actionable and highly generalizable. The model could be incorporated into clinical practice and could allow continuous personalized predictions with automated intervention suggestions.","Early detection of patients with narcotic use disorder using a modified MEDD score based on the analysis of real-world prescription patterns\nBackgroundAddiction to prescription narcotics is a global issue, and detection of individuals with a narcotic use disorder (NUD) at an early stage can help prevent narcotics misuse and abuse. We developed a novel index to detect early NUD based on a real-world prescription pattern analysis in a large hospital.\n\nMethodsWe analyzed narcotic prescriptions of 221 887 patients prescribed by 8737 doctors from July 2000 to June 2018. For the early detection of patients who could potentially progress to developing NUD after a long history of narcotic prescription, a weighted morphine equivalent daily dose (wt-MEDD) score was developed based on the number of prescription dates on which the actual MEDD was higher than the intended MEDD. Performance of the wt-MEDD scoring system in detecting patients diagnosed with NUD by doctors was compared with that of other NUD high risk indexes such as the MEDD scoring system, number of days on prescribed narcotics, the frequency/duration of prescription, narcotics prescription across multiple doctors, and the number of early refills of narcotics.\n\nResultsA wt-MEDD score cut-off value of 10.5 could detect all outliers, as well as patients diagnosed with NUD with 100% sensitivity and 99.6% specificity. The wt-MEDD score showed the highest sensitivity and specificity in identifying NUD among all indexes. Further, combining the wt-MEDD score with other NUD high risk indexes improved the prediction performance.\n\nConclusionWe developed a novel index to distinguish patients with vulnerable use patterns of narcotics. The wt-MEDD score showed excellent performance in detecting early NUD.","Evaluating Digital Device Technology in Alzheimer's Disease via Artificial Intelligence\nThe use of digital technologies may help to diagnose Alzheimers Disease (AD) at the pre-symptomatic stage. However, before implementation into clinical practice, digital measures (DMs) need to be evaluated for their diagnostic benefit compared to established questionnaire-based assessments, such as the Mini-Mental State Examination (MMSE) for cognition and Functional Activity Questionnaire (FAQ) for daily functioning. Moreover, the quantitative and qualitative relationship of DMs to these well understood scores needs to be clarified to aid interpretation. In this work we analyzed data from 148 subjects, 58 cognitively normal and 90 at different stages of the disease, which had performed a smartphone based virtual reality game to assess cognitive function. In addition, we used clinical data from Alzheimers Disease Neuroimaging Initiative (ADNI). We employed an Artificial Intelligence (AI) based approach to elucidate the relationship of DMs to questionnaire-based cognition and functional activity scores. In addition, we used Machine Learning (ML) and statistical methods to assess the diagnostic benefit of DMs compared to questionnaire-based scores. We found non-trivial relationships between DMs, MMSE, and FAQ which can be visualized as a complex network. DMs, in particular those reflecting scores of individual tasks in the virtual reality game, showed a better ability to discriminate between different stages of the disease than questionnaire-based methods. Our results indicate that DMs have the potential to act as a crucial measure in the early diagnosis and staging of AD.","UK Health Care Workers' Experiences of Major System Change in Elective Surgery during the COVID-19 Pandemic: Reflections on Rapid Service Adaptation\nBackgroundThe COVID-19 pandemic disrupted the delivery of elective surgery in the UK. The majority of planned surgery was cancelled or postponed in March 2020 for the duration of the first wave of the pandemic. We investigated the experiences of staff responsible for delivering rapid changes to surgical services during the first wave of the pandemic in the UK, with the aim of developing lessons for future major systems change.\n\nMethodsUsing a rapid qualitative study design, we conducted 25 interviews with frontline surgical staff during the first wave of the pandemic. We also carried out a policy review of the guidance developed for those delivering surgical services in pandemic conditions. We used framework analysis to organise and interpret findings.\n\nResultsStaff discussed positive and negative experiences of rapid service organisation. Clinician-led decision making, the flexibility of individual staff and teams, and the opportunity to innovate service design were all seen as positive contributors to success in service adaptation. The negative aspects of rapid change were inconsistent guidance from national government and medical bodies, top-down decisions about when to cancel and restart surgery, the challenges of delivering emergency surgical care safely and the complexity of prioritising surgical cases when services re-started.\n\nConclusionSuccess in the rapid reorganisation of elective surgical services can be attributed to the flexibility and adaptability of staff. However, there was an absence of involvement of staff in wider system-level pandemic decision-making and competing guidance from national bodies. Involving staff in decisions about the organisation and delivery of major systems change is essential for the sustainability of change processes.","Healthcare workers' mental health and wellbeing during the COVID-19 pandemic: Longitudinal analysis of interview and social media data\nThe COVID-19 pandemic has shed light on the fractures of healthcare systems around the world, particularly in relation to the healthcare workforce. Frontline staff, in particular, have been exposed to unprecedented strain and delivering care during the pandemic has impacted their safety, mental health and wellbeing. The aim of this paper was to explore the experiences of HCWs delivering care in the UK during the COVID-19 pandemic to understand their wellbeing needs, experiences and strategies used to maintain wellbeing (at individual and organizational levels). We analysed 94 telephone interviews with HCWs and 2000 tweets about HCWs mental health taking place during the first year of the COVID-19 pandemic. Results were grouped under six themes: redeployment; wellbeing support and coping strategies; mental health effects; organisational support; social network and public support. These findings demonstrate a need for open conversations, where staffs wellbeing needs and strategies can be shared and encouraged, rather than implementing solely top-down psychological interventions. At the macro level, findings also highlighted the impact on HCWs wellbeing of public and government support, as well as the need for ensuring protection through PPE, testing, and/or vaccines for frontline workers.","Large-scale social media language analysis reveals emotions and behaviours associated with nonmedical prescription drug use\nNonmedical use of prescription drugs (NMPDU) is a global health concern. The extent of, behaviors and emotions associated with, and reasons for NMPDU are not well-captured through traditional instruments such as surveys, prescribing databases and insurance claims. Therefore, this study analyses [~]130 million public posts from 87,718 Twitter users in terms of expressed emotions, sentiments, concerns, and potential reasons for NMPDU via natural language processing. Our results show that users in the NMPDU group express more negative emotions and less positive emotions, more concerns about family, the past and body, and less concerns related to work, leisure, home, money, religion, health and achievement, compared to a control group (i.e., users who never reported NMPDU). NMPDU posts tend to be highly polarized, indicating potential emotional triggers. Gender-specific analysis shows that female users in the NMPDU group express more content related to positive emotions, anticipation, sadness, joy, concerns about family, friends, home, health and the past, and less about anger, compared to males. The findings of the study can enrich our understanding of NMPDU.","Urinary sodium excretion is not associated with the incidence of end-stage kidney disease and kidney-related death: results from the UK Biobank\nBackgroundSodium reduction lowers blood pressure and albuminuria, indicating a hypothesized but yet-to-be proven association between sodium intake and kidney-related endpoints.\n\nObjectivesWe aimed to investigate the associations of 24-h urinary sodium excretion, reflecting daily sodium intake, with kidney-related outcomes.\n\nMethodsProspective cohort of 444,086 middle- to early late-aged participants from the UK Biobank. The primary outcome was a composite of incident end-stage kidney disease (ESKD) and death due to a kidney-related cause, each of which was separately examined as a secondary outcome. Death due to a non-kidney related cause prior to ESKD was considered a competing event.\n\nResultsThe mean 24-h urinary sodium excretion estimated from spot urinary biomarkers was 3.3 g. During a median follow-up of 11.8 years, 1,256 composite events occurred. Multivariable-adjusted cause-specific hazards models showed that, with every 1-g increment in 24-h urinary sodium excretion, hazard ratios (95% confidence intervals) were 1.03 (0.91-1.16), 1.08 (0.88-1.32), and 1.01 (0.88-1.16) for the composite outcome, incident ESKD, and kidney-related death, respectively. Similar null results were observed when the exposure was treated as binary (<2 g/d vs. [≥]2 g/d) or multicategorical (quartiles). Nonlinear associations were not detected with restricted cubic splines. The findings also held constant in prespecified sensitivity and subgroup analyses.\n\nConclusionsEstimated 24-h urinary sodium excretion was not linearly or nonlinearly associated with the incidence of ESKD or death due to kidney-related causes. Our findings did not support the hypothesized notion that sodium intake should be reduced to prevent kidney-related endpoints at the population level.","Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a fourplex real-time quantitative reverse transcription-PCR assays.\nThe early diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is required to identify and isolate contagious patients to prevent further transmission of the coronavirus disease 2019 (COVID-19). In this study, we present a multitarget real-time TaqMan reverse transcription PCR (rRT-PCR) assay for the quantitative detection of SARS-CoV-2 and some of its circulating variants harboring mutations that give SARS-CoV-2 a selective advantage. Seven different primer-probe sets that included probes containing locked nucleic acid (LNA) nucleotides were designed to amplify specific wild-type and mutant sequences in Orf1ab, Envelope (E), Spike (S), and Nucleocapsid (N) genes. Furthermore, a newly developed primer-probe set targeted human {beta}2-microglobulin (B2M) as a highly sensitive internal control for RT efficacy. All singleplex and fourplex assays detected [≤] 14 copies/reaction of quantified synthetic RNA transcripts, with a linear amplification range of 9 logarithmic orders. Primer-probe sets for detection of SARS-CoV-2 exhibited no false-positive amplifications with other common respiratory pathogens, including human coronaviruses NL63, 229E, OC43, and HKU-1. Given the emergence of SARS-CoV-2 variants and their rapid spread in some populations, fourplex rRT-PCR assay containing four primer-probe sets represents a reliable approach to detect multiple viral target sequences containing typical mutations of SARS-CoV-2 variants in a single reaction, allowing quicker detection of circulating relevant variants.","Patients with CLL have similar high risk of death upon the omicron variant of COVID-19 as previously during the pandemic.\nPrevious studies have shown that patients with chronic lymphocytic leukemia (CLL) and coronavirus disease 2019 (COVID-19) have high mortality rates. The omicron variant has been reported to give milder disease in the general population, but outcomes of infections with the omicron variant among immunocompromised patients have not previously been reported. In a population-based cohort we assessed rates of hospitalizations, ICU-admissions, and 30-day all-cause mortality among all patients with CLL from Eastern Denmark testing positive for severe adult respiratory syndrome coronavirus 2 (SARS-CoV-2) in time periods before and after dominance of the omicron variant. Rates of hospitalizations and ICU-admissions declined significantly, whereas 30-day mortality remained as high as 23% in the period with dominance of the omicron sublineage BA.2 variant. Thus, patients with CLL in general and in particular those above 70 years of age with one or more comorbidities should be considered for closer monitoring and pre-emptive antiviral therapy upon a positive SARS-CoV-2 test.\n\nKey pointsO_LIThe omicron variant of COVID-19 leads to high fatality rates in CLL, despite milder disease in the background population\nC_LIO_LIPatients with CLL who test positive for SARS-CoV-2 in the era of the omicron variant should be considered for pre-emptive antiviral therapy\nC_LI\n\nExplanation of noveltyThe omicron variant has been reported to give milder disease in the general population, but outcomes of infections with the omicron variant among immunocompromised patients have not previously been reported. These population-based data on outcome for patients with CLL upon infection with the omicron variant of SARS-CoV-2 warrants closer monitoring and pre-emptive antiviral therapy upon a positive SARS-CoV-2 test for patients with CLL.","sMAdCAM:IL-6 (sMIL Index): A novel signature associated with COVID-19 disease progression and development of anti-SARS-CoV-2 antibodies\nRecent studies positing the gut as a sanctuary site for viral persistence in SARS-CoV-2 infection highlight the importance of assimilating profiles of systemic as well as gut inflammatory mediators to understand the pathology of COVID-19. Also, the role of these markers in governing virus specific immunity following infection remains largely unexplored. A cohort (n=84) of SARS-C0V-2 infected individuals included a group of in-patients (n=60) at various stages of disease progression together with convalescent individuals (n=24) recruited between April and June 2020 from Mumbai, India. Follow-up of 35 in-patients at day 7 post diagnosis was carried out. Th1/Th2/Th17 cytokines along with soluble MAdCAM (sMAdCAM) levels in plasma were measured. Also, anti-viral humoral response as measured by rapid antibody test (IgG, IgM), Chemiluminescent Immunoassay (IgG) and antibodies binding to SARS-CoV-2 proteins were measured by Surface Plasmon Resonance (SPR) from plasma.IL-6 and sMAdCAM levels among in-patients inversely correlated with one another. When expressed as a novel integrated marker -sMIL index (sMAdCAM/IL-6 ratio), these levels were incrementally and significantly higher in various disease states with convalescents exhibiting the highest values. Importantly, sMAdCAM levels as well as sMIL index (fold change) correlated with peak association rates of receptor binding domain and fold change in binding to spike respectively as measured by SPR. Our results highlight key systemic and gutassociated parameters that need to be monitored and investigated further to optimally guide therapeutic and prophylactic interventions for COVID-19.","Monocyte, Neutrophil and Whole Blood Transcriptome Dynamics Following Ischemic Stroke\nBackgroundAfter ischemic stroke (IS), peripheral leukocytes infiltrate the damaged region and modulate the response to injury. Peripheral blood cells display distinctive gene expression signatures post IS and these transcriptional programs reflect changes in immune responses to IS. Dissecting the temporal dynamics of gene expression after IS improves our understanding of immune and clotting responses at the molecular and cellular level that are involved in acute brain injury and may assist with time-targeted, cell-specific therapy.\n\nMethodsThe transcriptomic profiles from peripheral monocytes, neutrophils, and whole blood from 38 ischemic stroke patients and 18 controls were analyzed with RNAseq as a function of time and etiology after stroke. Differential expression analyses were performed at 0-24 h, 24-48 h, and >48 h following stroke.\n\nResultsUnique patterns of temporal gene expression and pathways were distinguished for monocytes, neutrophils and whole blood with enrichment of interleukin signaling pathways for different timepoints and stroke etiologies. Compared to control subjects, gene expression was generally up-regulated in neutrophils and generally down- regulated in monocytes over all times for cardioembolic, large vessel and small vessel strokes. Self-Organizing Maps identified gene clusters with similar trajectories of gene expression over time for different stroke causes and sample types. Weighted Gene Co- expression Network Analyses identified modules of co-expressed genes that significantly varied with time after stroke and included hub genes of immunoglobulin genes in whole blood.\n\nConclusionsAltogether, the identified genes and pathways are critical for understanding how the immune and clotting systems change over time after stroke. This study identifies potential time- and cell-specific biomarkers and treatment targets.","Whole genome sequencing identifies multiple loci for critical illness caused by COVID-19\nCritical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care1 or hospitalisation2;3;4 following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study recruits critically-ill cases and compares their genomes with population controls in order to find underlying disease mechanisms.\n\nHere, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identify 15 new independent associations with critical COVID-19, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease.\n\nWe show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.","Design and evaluation of mobile monitoring campaigns for air pollution exposure assessment in epidemiologic cohorts\nMobile monitoring campaigns to estimate long-term air pollution levels are becoming increasingly common. Still, many campaigns have not conducted temporally-balanced sampling, and few have looked at the implications of such study designs for epidemiologic exposure assessment. We carried out a simulation study of fixed-site air quality monitors to better understand how different mobile monitoring designs involving short-term stationary measurements at fixed locations impact the resulting exposure surfaces. We used Monte Carlo resampling to simulate three archetypal monitoring designs using oxides of nitrogen (NOx) monitoring data from 69 regulatory sites in California: a year-around Balanced Design that sampled during all seasons of the year, days of the week, and all or various hours of the day; a temporally reduced Rush Hours Design; and a temporally reduced Business Hours Design. We evaluated the performance of each designs land use regression prediction model. The Balanced Design consistently yielded the most accurate annual averages; while the reduced Rush Hours and Business Hours Designs generally produced more biased results. A temporally-balanced sampling design is crucial for mobile monitoring campaigns aiming to assess accurate long-term exposure in epidemiologic cohorts.\n\nSynopsisAir pollution mobile monitoring campaigns rarely conduct temporally balanced sampling. We show that this results in biased annual average exposure estimates.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC=\"FIGDIR/small/21255641v2_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (26K):\norg.highwire.dtl.DTLVardef@126c8ddorg.highwire.dtl.DTLVardef@14d52e5org.highwire.dtl.DTLVardef@17d390dorg.highwire.dtl.DTLVardef@2cc3d1_HPS_FORMAT_FIGEXP M_FIG C_FIG","COVID-19 vaccine uptake among older people in relation to sociodemographic factors: cohort results from southern Sweden\nThe aim of this cohort study was to investigate sociodemographic determinants of COVID-19 vaccine uptake in the 70+ age group in Sk[a]ne county, Sweden (n = 216 243 at baseline). Uptake of the first dose was high (91.9%) overall, but markedly lower (75.3%) among persons born outside the Nordic countries. Vaccine uptake was generally satisfactory among native Swedes also in areas with lower socioeconomic status, but dropped substantially among non-Nordic born in those areas. The identified clusters of unvaccinated older people, mainly representing ethnic minorities in disadvantaged areas, warrants intensified efforts regarding tailored communication, easier vaccine access and local engagement.\n\nKey pointsO_LICOVID-19 vaccine uptake in the 70+ age group in Sk[a]ne county, Sweden, was high (91.9%) overall, but markedly lower (75.3%) within the group born outside the Nordic countries\nC_LIO_LIInverse associations between indicators of neighbourhood deprivation and vaccine uptake were observed, which lowered the uptake among persons born outside the Nordic countries further\nC_LIO_LIThe identified clusters of unvaccinated older people, mainly representing ethnic minorities in disadvantaged areas, warrants intensified efforts regarding tailored communication, easier vaccine access and local engagement\nC_LI","EVALUATION OF THE PANBIO SARS-COV-2 RAPID ANTIGEN DETECTION TEST IN THE BAHAMAS\nIdentification and isolation of persons infected with SARS-COV-2 are key mitigation strategies in the current pandemic, and rapid antigen detection tests (RADTs) offer the promise of decreased turnaround time to diagnosis when compared with gold standard RT-PCR testing. We evaluated the analytical performance of the Abbott(R) Panbio RADT on nasopharyngeal samples stored at the Ministry of Health National Reference Lab in Nassau, Bahamas. The Panbio demonstrated a test sensitivity of 94% and a specificity of 100% on 50 PCR negative samples and 50 samples presumed to be infectious based on having PCR cycle threshold values below 30. Additionally, in our examination of operator results there was low interpersonal variation (1%) among three blind operators and significant correlation between sample Ct value and perceived signal strength on the RADT device. However, three PCR positive samples below Ct 30 were misdiagnosed by RADT, including one sample with Ct value less than 20. These results support the use of the Panbio in symptomatic persons to detect active SARS-COV-2 infections, with the caveat that RADT-negative samples should be confirmed by RT-PCR.","Controlling the pandemic during the SARS-CoV-2 vaccination rollout: a modeling study\nThere is a consensus that mass vaccination against SARS-CoV-2 will ultimately end the COVID-19 pandemic. However, it is not clear when and which control measures can be relaxed during the rollout of vaccination programmes. We investigate relaxation scenarios using an age-structured transmission model that has been fitted to age-specific seroprevalence data, hospital admissions, and projected vaccination coverage for Portugal. Our analyses suggest that the pressing need to restart socioeconomic activities could lead to new pandemic waves, and that substantial control efforts prove necessary throughout 2021. Using knowledge on control measures introduced in 2020, we anticipate that relaxing measures completely or to the extent as in autumn 2020 could launch a wave starting in April 2021. Additional waves could be prevented altogether if measures are relaxed as in summer 2020 or in a step-wise manner throughout 2021. We discuss at which point control of COVID-19 would be achieved for each scenario.","All Models Are Useful: Bayesian Ensembling for Robust High Resolution COVID-19 Forecasting\nTimely, high-resolution forecasts of infectious disease incidence are useful for policy makers in deciding intervention measures and estimating healthcare resource burden. In this paper, we consider the task of forecasting COVID-19 confirmed cases at the county level for the United States. Although multiple methods have been explored for this task, their performance has varied across space and time due to noisy data and the inherent dynamic nature of the pandemic. We present a forecasting pipeline which incorporates probabilistic forecasts from multiple statistical, machine learning and mechanistic methods through a Bayesian ensembling scheme, and has been operational for nearly 6 months serving local, state and federal policymakers in the United States. While showing that the Bayesian ensemble is at least as good as the individual methods, we also show that each individual method contributes significantly for different spatial regions and time points. We compare our models performance with other similar models being integrated into CDC-initiated COVID-19 Forecast Hub, and show better performance at longer forecast horizons. Finally, we also describe how such forecasts are used to increase lead time for training mechanistic scenario projections. Our work demonstrates that such a real-time high resolution forecasting pipeline can be developed by integrating multiple methods within a performance-based ensemble to support pandemic response.\n\nACM Reference FormatAniruddha Adiga, Lijing Wang, Benjamin Hurt, Akhil Peddireddy, Przemys-law Porebski,, Srinivasan Venkatramanan, Bryan Lewis, Madhav Marathe. 2021. All Models Are Useful: Bayesian Ensembling for Robust High Resolution COVID-19 Forecasting. In Proceedings of ACM Conference (Conference17). ACM, New York, NY, USA, 9 pages. https://doi.org/10.1145/nnnnnnn.nnnnnnn","Impacts of COVID-19 public measures on country-level trade flows: Global panel regression analysis\nAs of 10 July 2021, there have been over 186 million cases of COVID-19 and more than four million died as a result of this disease. The COVID-19 outbreak has also contributed to tremendous global decline in trade flows. The rapid spread of COVID-19 and the measures implemented by governments to contain the pandemic have had serious consequences for the worlds economies. While the pandemic has affected the international movement of people, goods and services, there is still limited systematic research regarding the possible associations between the COVID-19 measures on countries international trade flows. To fill this gap, we conducted regression analysis based on country level time series data from the United Nations and World Bank datasets. The results of the random effects panel regression models show that, the country import and export values are positively affected by health-related policies, while there is a negative association between stringency measures and import and export values. More specifically, school closing, stay-at-home requirements, and testing policy measures were found to have significant negative effects on countries trade values. In contrast, facial covering policies were found to have significant positive effects on countries import, export and total trade values.","Measuring the digital divide among people with Severe Mental Ill Health using the Essential Digital Skills framework.\nAimsAmidst the vast digitalisation of health and other services during the pandemic, people with no digital skills are at risk for digital exclusion. This risk might not abide by the end of the pandemic. This paper seeks to understand whether people with severe mental ill health (SMI) have the necessary digital skills to adapt to these changes and avoid digital exclusion.\n\nMethods249 adults with SMI across England completed a survey online or offline. They provided information on their digital skills based on the Essential Digital Skills (EDS) framework, sociodemographic information, and digital access. This is the first time the EDS is benchmarked in people with SMI.\n\nResults42.2% had no Foundation Skills and 46.2% lacked skills for daily life (lacking Foundation or Life Skills). 23.0% of those working lacked skills for professional life (lacking Foundation or Work Skills). The most commonly missing skills were handling passwords and using the device settings (Foundation Skills) and online problem solving (Skills for Life). People were interested in learning more about approximately half of the skills they did not have. People were more likely to lack Foundation Skills if they were older, not in employment, had a psychosis-spectrum disorder, or had no Internet access at home.\n\nConclusionA significant portion of people with SMI lacked Foundation Skills in this objective and benchmarked survey. This points to a high risk for digital exclusion and the need for focused policy and tailored health sector support, to ensure people retain access to key services and develop digital skills and confidence. To our knowledge this is the first time this has been described using the Essential Digital Skills (EDS) framework. Services, including the NHS, need to be aware and mitigate the risks.","Environment-wide association study (EWAS) on cardiometabolic traits: A systematic assessment of the association of lifestyle variables on a longitudinal setting\nThe present study aims to assess the over-time association of [~]300 lifestyle exposures with nine cardiometabolic traits with the ultimate aim of identifying exposures/exposure groups that could inform lifestyle interventions aiming at controlling cardiometabolic diseases. The analyses were undertaken in a longitudinal sample comprising >31000 adults living in northern Sweden. Linear mixed models were used to assess the average associations of lifestyle exposures and linear regression models were used to test association with 10-year change of the cardiometabolic traits. Physical activity and General Health were the exposure categories containing the highest number of tentative signals in analyses assessing the average association of lifestyle variables, while Tobacco use was the top-category for the 10-year change association analyses. Thirteen modifiable variables showed a consistent average association among the majority of cardiometabolic traits. These variables belonged to four main groups: i) Smoking, ii) Diet (secoisolariciresinol intake and brewed coffee), iii) Leisure time physical activity and iv) a group of variables more specific to the Swedish lifestyle (snuff status, hunting/fishing during leisure time and boiled coffee). Interestingly, sweet drinks, fish intake and salt content, all lifestyle exposures frequently mentioned in public health recommendations were not broadly associated with the analysed cardiometabolic traits.","A mathematical model to estimate percentage secondary infections from margin of error of diagnostic sensitivity: Useful tool for regulatory agencies to assess the risk of propagation due to false negative outcome of diagnostics\nFalse negative outcome of a diagnosis is one the major reasons for the dissemination of the diseases with high risk of propagation. Diagnostic sensitivity and the margin of error determine the false negative outcome of the diagnosis. A mathematical model had been developed to estimate the mean % secondary infections based on the margin of error of diagnostic sensitivity, % prevalence and R0 value. This model recommends a diagnostic test with diagnostic sensitivity [≥] 96% and at least 92% lower bound limit of the 95% CI or [≤] 4% margin of error for a highly infectious diseases like COVID-19 to curb the secondary transmission of the infection due to false negative cases. Positive relationship was found between mean % secondary infection and margin of error of sensitivity suggesting greater the margin of error of a diagnostic test sensitivity, higher the number of secondary infections in a population due to false negative cases. Negative correlation was found between number of COVID-19 test kits (>90% sensitivity) with regulatory approval and margin of error (R= -0.92, p=0.023) suggesting lesser the margin of error of a diagnostic test, higher the chances of getting approved by the regulatory agencies. However, there are no specific regulatory standards available for margin of error of the diagnostic sensitivity of COVID-19 diagnostic tests. Highly infectious disease such as COVID-19, certainly need specific regulatory standards on margin of error or 95% CI of the diagnostic sensitivity to curb the dissemination of the disease due to false negative cases and our model can be used to set the standards such as sensitivity, margin of error or lower bound limit of 95% CI.","Association between COVID-19 Outcomes and Mask Mandates, Adherence, and Attitudes\nWe extend previous studies on the impact of masks on COVID-19 outcomes by investigating an unprecedented breadth and depth of health outcomes, geographical resolutions, types of mask mandates, early versus later waves and controlling for other government interventions, mobility testing rate and weather. We show that mask mandates are associated with a statistically significant decrease in new cases (-3.55 per 100K), deaths (-0.13 per 100K), and the proportion of hospital admissions (-2.38 percentage points) up to 40 days after the introduction of mask mandates both at the state and county level. These effects are large, corresponding to 14% of the highest recorded number of cases, 13% of deaths, and 7% of admission proportion. We also find that mask mandates are linked to a 23.4 percentage point increase in mask adherence in four diverse states. Lastly, using a large novel survey dataset of almost half a million people in 68 countries, we introduce the novel results that community mask adherence and community attitudes towards masks are associated with a reduction in COVID-19 cases and deaths. Our results have policy implications for reinforcing the need to maintain and encourage mask-wearing by the public, especially in light of some states starting to remove their mask mandates.","Prevalence and clinical profile of SARS-CoV-2 infection among farmworkers in Monterey County, California: June-November, 2020\nAs essential personnel, United States farmworkers have continued working in-person throughout the COVID-19 pandemic. We undertook prospective surveillance of SARS-CoV-2 infection and antibody prevalence among farmworkers in Californias Salinas Valley from 15 June to 30 November, 2020. Over this period, we observed 22.1% (1514/6864) positivity for current SARS-CoV-2 by nucleic acid detection among farmworkers tested at federally-qualified migrant and community health clinics, as compared to 17.2% (1255/7305) among other adults from the same communities (risk ratio, 1.29; 95% confidence interval, 1.20-1.37). In a nested study enrolling 1,115 farmworkers, prevalence of current infection was 27.7% among farmworkers reporting [≥]1 potential COVID-19 symptom, and 7.2% among farmworkers without symptoms (adjusted odds ratio 4.17; 2.86-6.09). Prevalence of anti-SARS-CoV-2 IgG antibodies increased from 10.5% (6.0-18.4%) between 16 July-31 August to 21.2% (16.6-27.4%) between 1-30 November. The high observed prevalence of infection among farmworkers underscores the need for vaccination and other preventive interventions.","Using mobile health technology to assess childhood autism in low-resource community settings in India : an innovation to address the detection gap\nAutism Spectrum Disorders, hereafter referred to as autism, emerge early and persist throughout life, contributing significantly to global years lived with disability. Typically, an autism diagnosis depends on clinical assessments by highly trained professionals. This high resource demand poses a challenge in resource-limited areas where skilled personnel are scarce and awareness of neurodevelopmental disorder symptoms is low. We have developed and tested a novel app, START, that can be administered by non-specialists to assess several domains of the autistic phenotype (social, sensory, motor functioning) through direct observation and parent report. N=131 children (2-7 years old; 48 autistic, 43 intellectually disabled, and 40 typically developing) from low-resource settings in the Delhi-NCR region, India were assessed using START in home settings by non-specialist health workers. We observed a consistent pattern of differences between typically and atypically developing children in all three domains assessed. The two groups of children with neurodevelopmental disorders manifested lower social preference, higher sensory sensitivity, and lower fine-motor accuracy compared to their typically developing counterparts. Parent-report further distinguished autistic from non-autistic children. Machine-learning analysis combining all START-derived measures demonstrated 78% classification accuracy for the three groups (ASD, ID, TD). Qualitative analysis of the interviews with health workers and families (N= 15) of the participants suggest high acceptability and feasibility of the app. These results provide proof of principle for START, and demonstrate the potential of a scalable, mobile tool for assessing neurodevelopmental disorders in low-resource settings.","Pilot study on the use of low molecular weight heparins in the prevention of thromboembolic disease during pregnancy and puerperium.\nA pregnant woman is 4 to 5 times more likely to suffer a thromboembolic event than a non-pregnant woman. Furthermore, an increase in these episodes has been observed in women infected with SARS-CoV-2. Consequently, the prophylactic prescription of low-molecular-weight heparins (LMWH) in pregnant women is undergoing an increase that has not been evaluated yet. The aim of this study was to determine the prevalence of LMWH prescription in pregnant women at the Hospital Universitario Puerta de Hierro Majadahonda (HUPHM), according to their level of risk and its variation due to SARS-CoV-2 infection. To answer this question, a retrospective cohort of 113 women who gave birth during the month of February at the HUPHM was designed. The level of individual risk of thromboembolism, according to the Royal College guidelines (37a), was calculated with an interview to complete a questionnaire and the analysis of their clinical records. 53.6% of the women were prescribed LMWH as indicated in the guidelines. This high prevalence is explained by the high age of the pregnant women (over 35 years), the wave of the omicron variant (December 2021) and a high rate of cesarean sections (25%). On the other hand, the percentage of patients with COVID-19 was 17.6% but only 53% of them had received LMWH. In conclusion, LMWH is a very common prescription in obstetrics, mostly during puerperium, and has become even more relevant due to the COVID-19 pandemic","Genetic risk prediction of COVID-19 susceptibility and severity in the Indian population\nHost genetic variants can determine the susceptibility to COVID-19 infection and severity as noted in a recent Genome-wide Association Study (GWAS) by Pairo-Castineira et al.1. Given the prominent genetic differences in Indian sub-populations as well as differential prevalence of COVID-19, here, we deploy the previous study and compute genetic risk scores in different Indian sub-populations that may predict the severity of COVID-19 outcomes in them. We computed polygenic risk scores (PRSs) in different Indian sub-populations with the top 100 single-nucleotide polymorphisms (SNPs) with a p-value cutoff of 10-6 derived from the previous GWAS summary statistics1. We selected SNPs overlapping with the Indian Genome Variation Consortium (IGVC) and with similar frequencies in the Indian population. For each population, median PRS was calculated, and a correlation analysis was performed to test the association of these genetic risk scores with COVID-19 mortality. We found a varying distribution of PRS in Indian sub-populations. Correlation analysis indicates a positive linear association between PRS and COVID-19 deaths. This was not observed with non-risk alleles in Indian sub-populations. Our analyses suggest that Indian sub-populations differ with respect to the genetic risk for developing COVID-19 mediated critical illness. Combining PRSs with other observed risk-factors in a Bayesian framework can provide a better prediction model for ascertaining high COVID-19 risk groups. This has a potential utility in the design of more effective vaccine disbursal schemes.","Dynamic Prediction of SARS-CoV-2 RT-PCR status on Chest Radiographs using Deep Learning Enabled Radiogenomics\nReverse Transcription-Polymerase Chain Reaction (RT-PCR) is the gold standard for diagnosis of SARS-CoV-2 infection, but requires specialized equipment and reagents and suffers from long turnaround times. While valuable, chest imaging currently only detects COVID-19 pneumonia, but if it can predict actual RT-PCR SARS-CoV-2 status is unknown. Radiogenomics may provide an effective and accurate RT-PCR-based surrogate. We describe a deep learning radiogenomics (DLR) model (RadGen) that predicts a patient's RT-PCR SARS-CoV-2 status solely from their frontal chest radiograph (CXR).","Impact of SARS-CoV-2 vaccination on systemic immune responses in people living with HIV\nThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and an ongoing global pandemic. Despite the development of vaccines, which protect healthy people from severe and life-threatening COVID-19, the immunological responses of people with secondary immunodeficiencies to SARS-CoV-2 mRNA vaccines are currently not well understood. Human Immunodeficiency Virus (HIV), causing acquired immunodeficiency syndrome (AIDS), targets CD4+ T helper (Th) cells that orchestrate the immune response. Anti-retroviral therapy suppresses HIV burden and restores Th cell numbers. Here, we investigated the humoral and cellular immune responses elicited by the BTN162b2 vaccine in a cohort of people living with HIV (PLWH), who receive anti-retroviral therapy. While antibody responses in PLWH increased progressively after the first and second vaccination compared to baseline, they were reduced compared to HIV negative study participants (controls). CD8+ T cells exhibited a general activated phenotype and increased effector and effector memory compartments. In contrast, CD4+ Th cell responses exhibited a vaccination-dependent increase and were comparable between PLWH and controls. In line with their reduced humoral response, the correlation between neutralizing antibodies and the CD4+ T cell response was decreased in PLWH compared to healthy controls. Interestingly, CD4+ T cell activation negatively correlated with the CD4 to CD8 ratio, indicating that low CD4 T cell numbers do not necessarily interfere with cellular immune responses. Taken together, our data demonstrate that COVID-19 mRNA vaccination in PLWH results in potent cellular immune responses, but the reduced antibody responses suggest that booster vaccination might be required for preventing disease.","Genetics of symptom remission in outpatients with COVID-19\nWe conducted a genome-wide association study of time to remission of COVID-19 symptoms in 1723 outpatients with at least one risk factor for disease severity from the COLCORONA clinical trial. We found a significant association at 5p13.3 (rs1173773; P = 4.94 x 10-8) near the natriuretic peptide receptor 3 gene (NPR3). By day 15 of the study, 44%, 54% and 59% of participants with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. In 851 participants not treated with colchicine (placebo), there was a significant association at 9q33.1 (rs62575331; P = 2.95 x 10-8) in interaction with colchicine (P = 1.19 x 10-5) without impact on risk of hospitalisations, highlighting a possibly shared mechanistic pathway. By day 15 of the study, 46%, 62% and 64% of those with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. The findings need to be replicated and could contribute to the biological understanding of COVID-19 symptom remission.","Clinical implementation of a machine learning system to detect deteriorating patients reduces time to response and intervention\nIntroductionAcute physiological deterioration is a major contributor to in-hospital morbidity and mortality. Early detection and intervention of deteriorating patients is key to improving patient outcomes. Prior research has demonstrated the effectiveness of Early Warning Systems and other algorithmic approaches in automatically identifying these patients from passively monitoring vital signs.\n\nMethodsIn this work, we conduct a prospective pilot study of clinical deployment of the Mayo Clinic Bedside Patient Rescue (BPR) system using an escalating alerting logic enabled by machine learning. Among four units where the BPR system was deployed, time to response and time to intervention for deteriorating patients were significantly reduced relative to matched control units.\n\nResultsIn pilot units, time to response decreased by 35.4% (from 63.2 minutes to 40.8 minutes) and time to intervention decreased by 48.5% (from 106.3 minutes to 55.9 minutes). No significant differences were observed in counterbalance metrics of mortality, ICU transfer rate, and Rapid Response Team activation rate. Furthermore, the automated alerting system was well-received by clinicians participating in the pilot study, as assessed by survey.\n\nDiscussionThese results demonstrate a successful clinical deployment of a practice-changing machine learning alert system with demonstrable impact on improving patient care.","Resolutive results with oral corticosteroids for patients with COVID-19 in pulmonary inflammatory phase. Successful outpatient experience during the collapse of Belem do Para Health System - Brazil.\nIn the face of new diseases, medicine needs to reinvent itself in order to contain and control epidemics, such as the one we have recently faced, COVID-19, a disease with a wide spectrum of clinical severity. A new moment has been established, since the application of well known, effective and safe medications for other diseases, has shown high success rates in the treatment of COVID-19. Thereunto, studies with early intervention are needed, which can change the unfavorable outcome of patients. In this article, we report the successful experience using an oral strategy during the collapse of Belem do Para Health System, Brazil. Two hundred and ten patients were diagnosed with respiratory failure due to COVID-19, with no option of hospital treatment due to lack of beds and resources. These patients were then started on therapeutic regimen consisting of prednisolone, enoxaparin and macrolides associated and followed in outpatient facilities. Two hundred and eight patients had excellent therapeutic response and there were only two fatalities. These results push research boundaries, valuing outpatient treatment with early use of prednisolone in the initial pulmonary phase, preventing severe COVID-19 pneumonitis. Adoption of the proposed treatment intends to reduce the need for hospitalization, as well as lethality, with social robust benefits and incalculable economic savings since involves the use of accessible, safe and not expensive medications.","Immune response to third SARS-CoV-2 vaccination in seronegative kidney transplant recipients: possible improvement by mycophenolate mofetil reduction\nBackgroundModification of vaccination strategies is needed to improve the immune response to SARS-CoV-2 vaccination in kidney transplant recipients (KTRs).\n\nMethodsThis multicenter observational study aimed to determine antibody kinetics among 60 seropositive KTRs and analyzed the effects of the third vaccination against SARS-CoV-2 in 174 previously seronegative KTRs. We investigated whether mycophenolate mofetil (MMF) dose reduction by 25-50% prior the third vaccination influences vaccination success.\n\nResults18 of 60 (30%) seropositive KTRs became seronegative in the serological assay within six months. Loss of antibodies was predicted by low initial antibody levels ([≤]206.8 BAU/ml), older age, and impaired graft function. A third vaccination in previously seronegative KTRs induced seroconversion in 56 of 174 (32.1%) KTRs with median antibody levels 119 (76-353) BAU/ml and median neutralizing capacity titer of 1:10 (0- 1:40). Multivariate logistic regression revealed that initial antibody levels (OR 1.39, 95% CI 1.09-1.76), graft function (OR 0.05, 95% CI 0.01-0.39), time after transplantation (OR 1.04, 95% CI 1.02-1.07) and MMF trough levels (OR 0.43, 95% CI 0.21-0.88) correlated with seroconversion, p<0.05. After controlling for these confounders, the effect of MMF dose reduction was calculated using propensity score matching. KTRs in the MMF reduction group had significantly lower MMF serum concentrations prior to the third vaccination and were more likely to develop antibody levels [≥]35.2 BAU/ml than their matched KTRs (p=0.02).\n\nConclusionsTemporary reduction in MMF dose might be a promising approach to improve the immune response in KTRs.","Electronic health record enabled track and trace inan urban hospital network: implications for infectionprevention and control\nHealthcare-associated infections represent one of the most significant challenges for modern medicine as they can significantly impact patientslives. Carbapenemase-producing Enterobacteriaceae (CPE) pose the greatest clinical threat, given the high levels of resistance to carbapenems, which are considered as agents of last resort against life-threatening infections. Understanding patterns of CPE infection spreading in hospitals is paramount to design effective infection control protocols to mitigate the presence of CPE in hospitals. We used patient electronic health records from three urban hospitals to: i) track microbiologically confirmed carbapenemase producing Escherichia coli (CP-Ec) carriers and ii) trace the patients they shared place and time with until their identification. We show that yearly contact networks in each hospital consistently exhibit a core-periphery structure, highlighting the presence of a core set of wards where most carrier-contact interactions occured before being distributed to peripheral wards. We also identified functional communities of wards from the general patient movement network. The contact networks projected onto the general patient movement community structure showed a comprehensive coverage of the hospital. Our findings highlight that infections such as CP-Ec infections can reach virtually all parts of hospitals through first-level contacts.","High throughput sequencing based detection of SARS-CoV-2 prevailing in wastewater of Pune, West India\nGiven a large number of SARS-CoV-2 infected individuals, clinical detection has proved challenging. The wastewater-based epidemiological paradigm would cover the clinically escaped asymptomatic individuals owing to the faecal shedding of the virus. We hypothesised using wastewater as a valuable resource for analysing SARS-CoV-2 mutations circulating in the wastewater of Pune region (Maharashtra; India), one of the most affected during the covid-19 pandemic. We conducted a case study in open wastewater drains from December 2020-March 2021 to assess the presence of SARS-CoV-2 nucleic acid and further detect mutations using ARTIC protocol of MinION sequencing. The analysis revealed 108 mutations across six samples categorised into 40 types of mutations. We report the occurrence of mutations associated with B.1.617 lineage in March-2021 samples, simultaneously also reported as a Variant of Concern (VoC) responsible for the rapid increase in infections. The study also revealed four mutations; S:N801, S:C480R, NSP14:C279F and NSP3:L550del not currently reported from wastewater or clinical data in India but reported in the world. Further, a novel mutation NSP13:G206F mapping to NSP13 region was observed from wastewater. Notably, S:P1140del mutation was observed in December 2020 samples while it was reported in February 2021 from clinical data, indicating the instrumentality of wastewater data in early detection. This is the first study in India to conclude that wastewater-based epidemiology to identify mutations associated with SARS-CoV-2 virus from wastewater as an early warning indicator system.","Using rapid (point-of-care) tests for COVID-19: A decision analysis comparing the expected benefit of two screening strategies\nBackgroundRapid tests for COVID-19 could be used to augment the otherwise limited laboratory-based testing capacity, but there are concerns that their utility may be compromised by their limited accuracy. The objective of this article is to compare the expected benefit (EB) of two screening strategies, one with rapid tests (SwRT) and another one without rapid tests [Formula].\n\nMethodsWe performed a decision analysis, with the overall EB defined as the proportion of correctly identified individuals minus the proportion of incorrectly identified individuals. Accordingly, the SwRT strategy will be deemed a better screening strategy if its lesser EB for COVID-19 free individuals is more than compensated by its greater EB for COVID-19 individuals. Otherwise, it will not.\n\nResultsAs expected, the EB for COVID-19 individuals was greater for the SwRT strategy, with a far superior ability to rule out the presence of COVID-19. In fact, under the scenario of interest (i.e., 8000 ID Now rapid tests in addition to 28185 lab-based RT-PCR tests), it identified almost 16% more COVID-19 individuals than the [Formula] strategy. In addition, the EB for COVID-19 free individuals was the same for both strategies, with a perfect ability at ruling in the presence of COVID-19.\n\nConclusionThe SwRT strategy identified more COVID-19 individuals and this gain was not obtained at the detriment of COVID-19 free individuals who were equally well identified by both strategies. Hence, the SwRT strategy is a better screening strategy for COVID-19. It represents an opportunity to curtail the spread of SARS-CoV-2 that we may not afford to miss with new more contagious variants becoming more and more common in Canada.","Correlates of COVID-19 vaccine acceptance, hesitancy and refusal among employees of a safety net California county health system with an early and aggressive vaccination program: Results from a cross-sectional survey\nInformation on vaccine acceptance among healthcare workers is needed as health professionals provide front line care to COVID-19 patients. We developed and implemented an anonymous internet-based cross-sectional survey with direct solicitation among employees of a safety net health system. Items queried demographic and health-related characteristics, experience with and knowledge of COVID-19, and determinants of decisions to vaccinate. COVID-19 vaccine acceptance groups (acceptors, hesitant, refusers) were defined; an adapted version of the WHO vaccine hesitancy scale was included. The survey demonstrated good reliability (Cronbachs alpha = 0.92 for vaccine hesitancy scale; 0.93 for determinants). General linear and logistic regression methods examined factors which were univariately associated with vaccine hesitancy and vaccine acceptance, respectively. Multivariable models were constructed with stepwise model-building procedures. Race/ethnicity, marital status, job classification, immunocompromised status, flu vaccination and childhood vaccination opinions independently predicted hesitancy scale scores. Gender, education, job classification and BMI independently predicted acceptance, hesitancy and refusal groups. Among hesitant employees, uncertainty was reflected in reports of motivating factors influencing their indecision. Despite a strong employee-support environment and job protection, respondents reported physical and mental health effects. Appreciation of varied reasons for refusing vaccination should lead to culturally sensitive interventions to increase vaccination rates in healthcare workers.","Revisiting the diagnostic criteria for emergence from the minimally conscious state: An empirical investigation\nObjectiveTo determine whether consistent command-following (CCF) should be added to the diagnostic criteria for emergence from the minimally conscious state (MCS)\n\nDesignRetrospective cohort study\n\nSettingInpatient rehabilitation hospital\n\nParticipantsPatients with severe acquired brain injury and disorders of consciousness (DoC) admitted to a specialized rehabilitation program\n\nMain Outcome MeasureDifference between time to recovery of CCF and time to recovery of functional object use [FOU] or functional communication [FC] (the two existing criteria for emergence from MCS) as measured by the Coma Recovery Scale - Revised [CRS-R]).\n\nResultsOf 214 patients (median [interquartile range] age: 53 [34, 66] years, male: 134 (62.6%), traumatic etiology: 115 (53.7%), admission CRS-R total score: 10 [7, 13]) admitted to rehabilitation without CCF, FO, or FC, 162 (75.7%) recovered CCF and FOU or FC during the eight-week observation period. On average, recovery of CCF, FOU, and FC was observed within one day of one another, approximately 46 [38.25, 58] days post-injury. One hundred and sixteen patients (71.6%) recovered FOU or FC prior to or at the same time as CCF.\n\nConclusionsIn patients recovering from DoC, CCF reemerges around the same time as FOU and FC. This finding likely reflects the shared dependency of these behaviors on cognitive procecess (e.g., language comprehension, attention, motor control) that are essential for effective interpersonal interaction and social participation. Our results support the addition of CCF to the existing diagnostic criteria for emergence from MCS.","Identifying patients at high risk of inappropriate drug dosing in periods with renal dysfunction\nIntroductionDosing of renally cleared drugs in patients with kidney failure often deviates from clinical guidelines but little is known about what is predictive of receiving inappropriate doses.\n\nMethods and materialsWe combined data from the Danish National Patient Register and in-hospital data on drug administrations and estimated glomerular filtration rates for admissions between 1 October 2009 and 1 June 2016, from a pool of about 2.9 million persons. We trained artificial neural network and linear logistic ridge regression models to predict the risk of five outcomes (>0, [≥]1, [≥]2, [≥]3 and [≥]5 inappropriate doses daily) with index set 24 hours after admission. We used time-series validation for evaluating discrimination, calibration, clinical utility and explanations.\n\nResultsOf 52,451 admissions included, 42,250 (81%) were used for model development. The median age was 77 years; 50% of admissions were of women. [≥]5 drugs were used between admission start and index in 23,124 admissions (44%); the most common drug classes were analgesics, systemic antibacterials, diuretics, antithrombotics, and antacids. The neural network models had better discriminative power (all AUROCs between 0.77 and 0.81) and were better calibrated than their linear counterparts. The main prediction drivers were use of anti-inflammatory, antidiabetic and anti-Parkisons drugs as well as having a diagnosis of chronic kidney failure. Sex and age affected predictions but slightly.\n\nConclusionOur models can flag patients at high risk of receiving at least one inappropriate dose daily in a controlled in-silico setting. A prospective clinical study may confirm this holds in real-life settings and translates into benefits in hard endpoints.","A comprehensive evaluation methodology for the publicly accessible AI services for medical diagnostics\nOnline AI in telemedicine for radiology became widely available and valuable in the pandemic, particularly for chest CT analysis. On the other hand, the potentially harmful consequences of such services inappropriate usage cannot be neglected. Thus, a suitable methodology for quality assurance and quality control has to be established.\n\nA studys purpose was to develop and test an original methodology for a complex evaluation of open-access AI services in teleradiology. The approach included assessing the user experience, accessibility, safety, and diagnostic accuracy on the independent reference dataset. The methodology was applied to assess seven AI services for the detection of COVID-19 on a CT scan. A comparative analysis of this assessment is presented in this work. The analysis allowed us to draw conclusions about AI services quality and their value for different users - patients, physicians, and healthcare data scientists. The originality of the findings, timeliness, and interdisciplinary approach make this quality assurance methodology of particular interest for further application and spreading.\n\nHighlightsO_LIThe availability of diagnostic procedures increases each year with a corresponding increase of low-impact workload.\nC_LIO_LIDuring pandemics, medical AI services have become valuable in reducing the workload on healthcare professionals.\nC_LIO_LIQuality assurance for AI in healthcare requires an interdisciplinary approach - medicine, IT, and data science collaboration.\nC_LIO_LISuggested methodology of AI quality assurance suits different target users groups, such as the general public, physicians, and data scientists.\nC_LI","Projecting the transition of COVID-19 burden towards the young population while vaccines are rolled out: a modelling study\nObjectivesSARS-CoV-2 infection causes most cases of severe illness and fatality in older age groups. In China, over 99% of individuals aged [>=]12 years have been fully vaccinated against COVID-19 (albeit with vaccines developed against historical lineages), while 65.0% children aged 3-11 years have been vaccinated their first doses (as of November 12, 2021). Here, we aimed to assess whether, in this vaccination landscape, the importation of Delta variant infections could shift the COVID-19 burden from adults to children.\n\nMethodsWe developed an age-structured susceptible-infectious-removed model of SARS-CoV-2 transmission dynamics to simulate epidemics triggered by the importation of Delta variant infections and project the age-specific incidence of SARS-CoV-2 infections, cases, hospitalisations, intensive care unit (ICU) admissions, and deaths.\n\nResultsIn the context of the vaccination programme targeting individuals aged [≥]12 years (as it was the case until mid-October 2021), and in the absence of non-pharmaceutical interventions, the importation of Delta variant infections could have led to widespread transmission and substantial disease burden in mainland China, even with vaccination coverage as high as 97% across the eligible age groups. Extending the vaccination roll-out to include children aged 3-11 years (as it was the case since the end of October 2021) is estimated to dramatically decrease the burden of symptomatic infections and hospitalisations within this age group (54% and 81%, respectively, when considering a vaccination coverage of 99%), but would have a low impact on protecting infants (aged 0-2 years).\n\nConclusionsOur findings highlight the importance of including children among the target population and the need to strengthen vaccination efforts by increasing vaccine effectiveness.","Face Masks, Public Policies and Slowing the Spread of COVID-19: Evidence from Canada\nWe estimate the impact of indoor face mask mandates and other non-pharmaceutical interventions (NPI) on COVID-19 case growth in Canada. Mask mandate introduction was staggered from mid-June to mid-August 2020 in the 34 public health regions in Ontario, Canadas largest province by population. Using this variation, we find that mask mandates are associated with a 22 percent weekly reduction in new COVID-19 cases, relative to the trend in absence of mandate. Province-level data provide corroborating evidence. We control for mobility behaviour using Google geo-location data and for lagged case totals and case growth as information variables. Our analysis of additional survey data shows that mask mandates led to an increase of about 27 percentage points in self-reported mask wearing in public. Counterfactual policy simulations suggest that adopting a nationwide mask mandate in June could have reduced the total number of diagnosed COVID-19 cases in Canada by over 50,000 over the period July-November 2020. Jointly, our results indicate that mandating mask wearing in indoor public places can be a powerful policy tool to slow the spread of COVID-19.\n\nJEL codesI18, I12, C23","Forecasting COVID-19 cases: A comparative analysis between Recurrent and Convolutional Neural Networks\nWhen the entire world is waiting restlessly for a safe and effective COVID-19 vaccine that could soon become a reality, numerous countries around the globe are grappling with unprecedented surges of new COVID-19 cases. As the number of new cases is skyrocketing, pandemic fatigue and public apathy towards different intervention strategies are posing new challenges to the government officials to combat the pandemic. Henceforth, it is indispensable for the government officials to understand the future dynamics of COVID-19 flawlessly in order to develop strategic preparedness and resilient response planning. In light of the above circumstances, probable future outbreak scenarios in Brazil, Russia and the United kingdom have been sketched in this study with the help of four deep learning models: long short term memory (LSTM), gated recurrent unit (GRU), convolutional neural network (CNN) and multivariate convolutional neural network (MCNN). In our analysis, CNN algorithm has outperformed other deep learning models in terms of validation accuracy and forecasting consistency. It has been unearthed in our study that CNN can provide robust long term forecasting results in time series analysis due to its capability of essential features learning, distortion invariance and temporal dependence learning. However, the prediction accuracy of LSTM algorithm has been found to be poor as it tries to discover seasonality and periodic intervals from any time series dataset, which were absent in our studied countries. Our study has highlighted the promising validation of using convolutional neural networks instead of recurrent neural networks when it comes to forecasting with very few features and less amount of historical data.","Professionals' views on the mental health problems and vulnerability of children and young people during the early phase of the COVID-19 pandemic\nThe COVID-19 pandemic caused major disruptions to everyday life for children and young people. The aim of this study was to examine professionals views on the mental health problems and vulnerabilities of children and young people during the early phase of the COVID-19 pandemic. We conducted a secondary analysis of an online survey completed by mental health professionals in the UK between 22 April 2020 and 12 May 2020. The final sample was N = 601 professionals who at least partly worked with children and young people. Quantitative and qualitative survey data showed that professionals were concerned about young people experiencing economic disadvantage and young people from minority ethnic groups, as pre-existing social inequalities resulted in increased risk of infection and reduced access to physical and mental health care. Professionals were concerned about young people with little family support and young people at risk of relapse or deterioration in mental health, reporting the exacerbation of pre-existing mental health difficulties and challenging behaviours. Further research, involving young people as researchers, is needed to explore the continued impact for children and young people, and their families, including in comparison to their experiences before the pandemic.","metaCOVID: An R-Shiny application for living meta-analyses of COVID-19 trials\n\"Living\" evidence synthesis is of primary interest for decision-makers to overcome the COVID-19 pandemic. The COVID-NMA provides open-access living meta-analyses assessing different therapeutic and preventive interventions. Data are posted on a platform (https://covid-nma.com/) and analyses are updated every week. However, guideline developers and other stakeholders also need to investigate the data and perform their own analyses. This requires resources, time, statistical expertise, and software knowledge. To assist them, we created the \"metaCOVID\" application which, based on automation processes, facilitates the fast exploration of the data and the conduct of analyses tailored to end-users needs. metaCOVID has been created in R and is freely available as an R-Shiny application. The application conducts living meta-analyses for every outcome. Several options are available for subgroup and sensitivity analyses. The results are presented in downloadable forest plots. metaCOVID is freely available from https://covid-nma.com/metacovid/ and the source code from https://github.com/TEvrenoglou/metaCovid.","Predicting vaccine hesitancy from area-level indicators: A machine learning approach\nVaccine hesitancy (VH) might represent a serious threat to the next COVID-19 mass immunization campaign. We use machine-learning algorithms to predict communities at a high risk of VH relying on area-level indicators easily available to policymakers. We illustrate our approach on data from child immunization campaigns for seven non-mandatory vaccines carried out in 6408 Italian municipalities in 2016. A battery of machine learning models is compared in terms of area under the Receiver Operating Characteristics (ROC) curve. We find that the Random Forest algorithm best predicts areas with a high risk of VH improving the unpredictable baseline level by 24% in terms of accuracy. Among the area-level indicators, the proportion of waste recycling and the employment rate are found to be the most powerful predictors of high VH. This can support policy makers to target area-level provaccine awareness campaigns.","Occupational exposures and mitigation strategies among homeless shelter workers at risk of COVID-19\nObjectiveTo describe the work environment and COVID-19 mitigation measures for homeless shelter workers and assess occupational risk factors for COVID-19 infection\n\nMethodsBetween June 9-August 10, 2020, we conducted a self-administered survey among homeless shelter workers in Washington, Massachusetts, Utah, Maryland, and Georgia. We calculated frequencies for work environment, personal protective equipment use, and SARS-CoV-2 testing history. We used generalized linear models to produce unadjusted prevalence ratios (PR) to assess risk factors for SARS-CoV-2 infection.\n\nResultsOf the 106 respondents, 43.4% reported frequent close contact with clients; 75% were worried about work-related SARS-CoV-2 infections; 15% reported testing positive. Close contact with clients was associated with testing positive for SARS-CoV-2 (PR 3.97, 95%CI 1.06, 14.93).\n\nConclusionsHomeless shelter workers may be at higher risk of being infected with SARS-CoV-2 during the course of their work. Protecting these critical essential workers by implementing mitigation measures and prioritizing for COVID-19 vaccination, is imperative during the pandemic.","Coronavirus GenBrowser for monitoring the transmission and evolution of SARS-CoV-2\nGenomic epidemiology is important to study the COVID-19 pandemic and more than two million SARS-CoV-2 genomic sequences were deposited into public databases. However, the exponential increase of sequences invokes unprecedented bioinformatic challenges. Here, we present the Coronavirus GenBrowser (CGB) based on a highly efficient analysis framework and a movie maker strategy. In total, 1,002,739 high quality genomic sequences with the transmission-related metadata were analyzed and visualized. The size of the core data file is only 12.20 MB, efficient for clean data sharing. Quick visualization modules and rich interactive operations are provided to explore the annotated SARS-CoV-2 evolutionary tree. CGB binary nomenclature is proposed to name each internal lineage. The pre-analyzed data can be filtered out according to the user-defined criteria to explore the transmission of SARS-CoV-2. Different evolutionary analyses can also be easily performed, such as the detection of accelerated evolution and on-going positive selection. Moreover, the 75 genomic spots conserved in SARS-CoV-2 but non-conserved in other coronaviruses were identified, which may indicate the functional elements specifically important for SARS-CoV-2. The CGB not only enables users who have no programming skills to analyze millions of genomic sequences, but also offers a panoramic vision of the transmission and evolution of SARS-CoV-2.","Effectiveness of the EPA-based 'Toolbox Family Medicine' on students' learning satisfaction: study protocol for a controlled trial\nBackgroundFamily practices constitute an important learning environment for medical students. However, teaching situations markedly vary between practices, and students frequently find rotations underwhelming. Especially, students active participation in patient care varies profoundly, although it has a significant impact on students interest in primary care careers. To standardize and improve learning situations in practices, we developed the so-called Toolbox Family Medicine (TFM) using the concept of entrustable professional activities. It provides standardized learning content appropriate for students levels and allows teaching adaptable to actual practice conditions.\n\nMethodsUsing a controlled trial with a waiting list control arm, we will evaluate the effectiveness of the toolbox on students learning satisfaction. A total of 94 students will be allocated 1:1 to intervention and control practices. The teaching concept Toolbox Family Medicine (TFM) comprises a didactic workshop for supervising physicians and a toolbox with practice-specific tasks for medical students. The primary outcome is students overall satisfaction with their learning progress after the rotation. Secondary outcomes include the kind and number of tasks performed, the entrusted level per task, the feasibility of implementing the toolbox in actual practice settings, and students motivation to pursue a career in primary care.\n\nDiscussionWe assume an improvement in learning satisfaction with the intervention. The study will begin with the next practice rotations.\n\nAdministrative information\n\nO_TBL View this table:\norg.highwire.dtl.DTLVardef@1854ffborg.highwire.dtl.DTLVardef@1460a5eorg.highwire.dtl.DTLVardef@152d543org.highwire.dtl.DTLVardef@12f4f85org.highwire.dtl.DTLVardef@10dcc59_HPS_FORMAT_FIGEXP M_TBL C_TBL","Syncope and COVID-19 disease - a systematic review.\nBackgroundSyncope is not a common manifestation of COVID-19, but it may occur in this context and it can be the presenting symptom in some cases. Although several mechanisms may explain the pathophysiology behind COVID-19 related syncope, a valid relationship has not been established yet. In this systematic review, we aimed to examine the current incidence of syncope in COVID-19 patients and to explore different patterns observed in this setting.\n\nMethodsA systematic review across PubMed, ISI Web of Knowledge and SCOPUS was performed, according to PRISMA guidelines, in order to identify all relevant articles regarding both COVID-19 and syncope.\n\nResultsWe identified 81 publications, of which 62 were excluded. The cumulative incidence of syncope and pre-syncope across the selected studies was 7.1% (256/3584 patients). Unspecified syncope was the most common type (76.2% of the reported episodes), followed by reflex syncope (18.1% of the cases). Orthostatic hypotension was responsible for 3.6% of the cases and syncope of presumable cardiac cause accounted for 2.0%. Arterial hypertension was present in 64.7% of the patients and either angiotensin receptor blockers or angiotensin converting enzyme inhibitors were used by 39.5% of hypertensive patients with syncope.\n\nConclusionSyncope, although not considered a typical symptom of the COVID-19 disease, can be associated with it, particularly in early stages. Different types of syncope were seen in this context, each with different implications requiring distinct approaches. A careful reevaluation of blood pressure whenever a patient develops COVID-19 is suggested, including reassessment of antihypertensive therapy.","Development and validation of a length- and habitus-based method of total body weight estimation for critically ill adults requiring urgent weight-based medical intervention\nBackgroundErroneous weight estimation during the management of emergency presentations in adults may contribute to patient harm and poor outcomes. Patients can often not be weighed during emergencies and a weight estimation is required to facilitate weight-based therapies. Many existing methods of weight estimation are either unacceptably inaccurate or very difficult to use during the provision of emergency care.\n\nMethodsThe weight estimation system developed in this study was based on and modified from the PAWPER XL-MAC method, a paediatric weight estimation system that uses recumbent length and mid-arm circumference (MAC) to predict total body weight. This model was validated in the 2015 - 2018 National Health and Nutrition Examination Survey (NHANES) datasets. The primary outcome measure was to achieve >95% of estimations within 20% of measured weight (P20>95%).\n\nResultsThe modified PAWPER XL-MAC model achieved a P20 of 96.0% and a P10 of 71.3% in the validation dataset (N=11520). This accuracy (P20>95%) was maintained in both sexes, all ages, all ethnic groups, all lengths and in all habitus-types, except for the subgroup of severely obese individuals.\n\nConclusionsThe modified PAWPER XL-MAC model proved to be a very accurate method of weight estimation. It is more accurate than most other published reports of existing methods of weight estimation, except for patients own estimations. It therefore could have a role in facilitating emergency drug dose calculations, if prospective studies bear out the accuracy found in this study.","PBPK-led guidance for cystic fibrosis patients taking elexacaftor-tezacaftor-ivacaftor with nirmatrelvir-ritonavir for the treatment of COVID-19\nBackgroundCystic fibrosis transmembrane conductance regulator (CFTR) modulating therapies including elexacaftor, tezacaftor, and ivacaftor (ETI) are primarily eliminated through cytochrome P450 (CYP) 3A-mediated metabolism. This creates a therapeutic challenge to the treatment of COVID-19 with nirmatrelvir-ritonavir in people with cystic fibrosis (pwCF) due to the potential for significant drug-drug interactions (DDI). However, pwCF are more at risk of serious illness following COVID-19 infection and hence it is important to manage the DDI risk and provide treatment options.\n\nMethodsCYP3A-mediated DDI of ETI was evaluated using a physiologically based pharmacokinetic (PBPK) modeling approach. Modeling was performed incorporating physiological information and drug dependent parameters of ETI to predict the effect of ritonavir (the CYP3A4 inhibiting component of the combination) on pharmacokinetics of ETI. The ETI models were verified using independent clinical pharmacokinetic and DDI data of ETI with a range of CYP3A modulators.\n\nResultsWhen ritonavir was administered on day 1 through 5, the predicted AUC ratio of ivacaftor (the most sensitive CYP3A substrate) on day 6 was 9.31, indicating that its metabolism was strongly inhibited. Based on the predicted DDI, the dose of ETI should be reduced when co-administered with nirmatrelvir-ritonavir to elexacaftor 200mg-tezacaftor 100mg-ivacaftor 150mg on days 1 and 5, with resumption of full dose ETI on day 9, considering the residual inhibitory effect of ritonavir as a mechanism-based inhibitor.\n\nConclusionsCoadministration of nirmatrelvir-ritonavir requires a significant reduction in the ETI dosing frequency with delayed resumption of full dose due to the mechanism-based inhibition with ritonavir.","Leaders gender and the fight against COVID-19: investigation, replication, and a possible explanation\nObjectivesTo investigate the alleged relationship between leaders gender and COVID-19 related cases and deaths in different countries across the globe.\n\nStudy designThe relationship between leaders gender and percent of women in parliament to COVID-19 cases and death per million was investigated in three time points (10 months) across 180 countries, controlling for possible covariates.\n\nMethodsThree different types of analyses were run: (1) Six basic t-tests; (2) Two repeated-measure ANOVA tests analyzing change over time; (3) Six stepwise regression analyses for both leaders gender and the percentage of women in parliament.\n\nResultsOur findings suggest that, contrary to some research and popular media headlines, and in-line with recent academic research, leadership gender is not a significant factor in explaining the variation between countries in the fight against the COVID-19 pandemic.\n\nConclusionsWe suggest that this alleged relationship may stem from an illusory correlation. We argue that the uncertainty, stress, and anxiety that prevail in these times of global pandemic may be the breeding ground for judgmental biases of this sort.","Change in Symptoms and Immune Response in People with Post-Acute Sequelae of SARS-Cov-2 Infection (PASC) After SARS-Cov-2 Vaccination\nAs more people are vaccinated against SARS-CoV-2, many of those already infected are still suffering from Post-Acute Sequelae (PASC). Although there is no current treatment for PASC, reports from patients that the vaccine itself improves, and in some reports, worsens, PASC symptoms may lead to a deeper understanding of the causes of PASC symptoms and viable treatments. As such, we are conducting a study that measures the changes in PASC symptoms after vaccination. We are collecting baseline self-report and biospecimens for immune assays and then are following up with participants to collect the same data at 2-weeks, 6-weeks, and 12-weeks post-vaccination (first dose). Immune assays using blood specimens will include B-cell, T-cell, and myeloid cell panels; evaluation of T-cell responsiveness to SARS-CoV-2 peptides and antigen specific response; autoantibody screening (of IgG, IgM, and IgA antibodies that attack human proteins); and TCR sequencing and antigen mapping of CD8+ T-cells. Mucosal immunity will be measured using saliva specimens. The study aims to provide answers for people with PASC, especially regarding the causes of their symptoms and how the vaccine may affect them, and clues for PASC treatment.","Impact of the World Inflammatory Bowel Disease Day and Crohn's & Colitis Awareness Week on Population Interest between 2016 and 2020: Google Trends Analysis\nBackgroundMore than 6 million people are affected by inflammatory bowel disease (IBD) globally. World IBD Day (WID; May 19) and Crohns and Colitis Awareness Week (CCAW; December 1-7) occur yearly as national health observances to raise public awareness of IBD, but their effects are unclear.\n\nMethodsThis study evaluates the impact of WID and CCAW on the public awareness of IBD in the United States (US) and worldwide from 2016 to 2020 using the relative search volume (RSV) of \"IBD,\" \"Ulcerative colitis,\" and \"Crohns disease\" in Google Trends (GT). To identify significant timepoints of trend changes (joinpoints), we performed Joinpoint regression analysis.\n\nResultsNo joinpoints were noted around the time of WID or CCAW during the study period in the search results of the US. Worldwide, joinpoints were noted around WID in 2020 with the search for \"IBD\" and around CAAW in 2017 and 2019 to search for \"ulcerative colitis.\" However, the extents of trend changes were modest without statistically significant increases.\n\nConclusionsWID and CCAD may not have worked as expected to raise public awareness of IBD. Additional measures are necessary to help raise awareness of IBD related to the health observances.\n\nSummaryWorld IBD Day and Crohns and Colitis Awareness Week are key health observances related to IBD. These observances, however, might not have been effective in raising public awareness of IBD in the US and worldwide, according to Google Trends analysis.","Diminished neutralization responses towards SARS-CoV-2 Omicron VoC after mRNA or vector-based COVID-19 vaccinations\nSARS-CoV-2 variants accumulating immune escape mutations provide a significant risk to vaccine-induced protection. The novel variant of concern (VoC) Omicron (B.1.1.529) has the largest number of amino acid alterations in its Spike protein to date. Thus, it may efficiently escape recognition by neutralizing antibodies, allowing breakthrough infections in convalescent and vaccinated individuals. We analyzed neutralization activity of sera from individuals after vaccination with all mRNA-, vector- or heterologous immunization schemes currently available in Europe by in vitro neutralization assay at peak response towards SARS-CoV-2 B.1, Omicron, Beta and Delta pseudotypes and also provide longitudinal follow-up data from BNT162b2 vaccinees. All vaccines apart from Ad26.CoV2.S showed high levels of responder rates (93-100%) towards SARS-CoV-2 wild-type, but some reductions in neutralizing Beta and Delta VoC pseudotypes. The novel Omicron variant had the biggest impact, both in terms of response rates and neutralization titers. Only mRNA-1273 showed a 100% response rate to Omicron and induced the highest level of neutralizing antibody titers, followed by heterologous prime-boost approaches. Homologous BNT162b2 vaccination or vector-based AZD1222 or Ad26.CoV2.S performed less well with peak responder rates of 33%, 50% and 9%, respectively. However, Omicron responder rates in BNT162b2 recipients were maintained in our six month longitudinal follow-up indicating that individuals with cross-protection against Omicron maintain it over time. Overall, our data strongly argues for urgent booster doses in individuals who were previously vaccinated with BNT162b2, or a vector-based immunization scheme.","Impulse dispersion of aerosols during playing wind instruments\nMusical activities especially singing and playing wind instruments have been singled out as potentially high-risk activities for transmission of SARS CoV-2, because of a higher rate of aerosol production and emission. Playing wind instruments can produce condensation water, droplets of saliva, and aerosol particles, which hover and convectional spread in the environmental air and can be potentially infectious.\n\nThe aim of this study is to investigate the primary impulse dispersion of aerosols during playing different wind instruments in comparison to breathing and speaking. Nine professional musicians (3 trumpeters, 3 cross flutists and 3 clarinetists) of the Bavarian Symphony Orchestra performed the main theme of Ludwig van Beethoven s 9th symphony, 4th movement in different pitches and loudness. Thereby, the inhaled air volume was marked with small aerosol particles produced with a commercial e-cigarette. The expelled aerosol cloud was recorded by cameras from different perspectives. Afterwards, the dimensions and dynamics of the aerosol cloud was measured by segmenting the video footage at every time point.\n\nOverall, the cross flutes produced the largest dispersion at the end of task of up to maximum distances of 1.88 m in front direction. Thereby it was observed an expulsion of aerosol in different directions: upwards and downwards at the mouthpiece, at the end of the instrument and along the cross flute at the key plane. In comparison, the maximum impulse dispersion generated by the trumpets and clarinets were lower in frontal and lateral direction (1.2 m and 1.0 m in front-direction). The expulsion to the sides was also lower. Consequently, a distance of 3 m to the front and to the sides of 2 m for the cross flutes in an orchestral formation is proposed, for trumpets and clarinets a safety distance of 2 m to the front and 1.5 m between instrumentalists are recommendable.","Brain connectivity and motor improvements after ballet intervention in multiple sclerosis: pilot\nBackground and PurposeA pilot study to determine feasibility of detecting changes in structural connectivity (SC) and resting-state functional connectivity (RSFC) occur alongside motor improvements after participation in the Targeted Ballet Program (TBP) in adults with relapsing-remitting multiple sclerosis (RRMS).\n\nMethodsFive participants (four female) with RRMS between the ages of 38-64 with the following characteristics at baseline: Expanded Disability Status Scale 2.0-6.0, International Cooperative Ataxia Rating Scale (ICARS) > 7, Symbol-Digit Modality Test > 22, and no relapses or initiation of medications indicated to affect mobility within the past 30 days. Participants were asked to complete 12 weeks (one hour, twice per week) of the TBP. Magnetic resonance imaging data was collected pre- and post-intervention for SC and RSFC network analysis.\n\nResultsIncreases in two RRMS-related graph theoretical measures (mean strength and mean clustering coefficient) for RSFC (p < 0.05) are detectable alongside significant reduction in ataxia (ICARS: p = 0.01012, Smoothness Index: p = 0.04995), and increase in balance (Mini-BESTest: p = 0.01474) following participation in the well-tolerated TBP.\n\nDiscussion and ConclusionsSignificant increases in mean strength and mean clustering coefficient of RSFC suggest functional neurological improvements after participation in the TBP. The relationship between these network changes and clinical improvements in balance and amelioration of ataxia after participation in the TBP requires a larger randomized-controlled clinical trial of the TBP in persons with RRMS.","Preserved T cell responses to SARS-CoV-2 in anti-CD20 treated multiple sclerosis.\nObjectiveTo analyze humoral and cellular immune responses to SARS-CoV-2 vaccinations and infections in anti-CD20 treated patients with multiple sclerosis (pwMS).\n\nMethods181 pwMS on anti-CD20 therapy and 41 pwMS who began anti-CD20 therapy were included in a prospective, observational, single-center cohort study between March 2020 and August 2021. 51 pwMS under anti-CD20 treatment, 14 anti-CD20 therapy-naive pwMS and 19 healthy controls (HC) were vaccinated twice against SARS-CoV-2. We measured SARS-CoV-2 spike protein (full-length, S1 domain and receptor binding domain) immunoglobulin (Ig)G and S1 IgA and virus neutralizing capacity and avidity of SARS-CoV-2 antibodies. SARS-CoV-2 specific T cells were determined by interferon-{gamma} release assays.\n\nResultsFollowing two SARS-CoV-2 vaccinations, levels of IgG and IgA antibodies to SARS-CoV-2 spike protein as well as neutralizing capacity and avidity of SARS-CoV-2 IgG were lower in anti-CD20 treated pwMS than in anti-CD20 therapy-naive pwMS and in HC (p<0.003 for all pairwise comparisons). However, in all anti-CD20 treated pwMS vaccinated twice (n=26) or infected with SARS-CoV-2 (n=2), in whom SARS-CoV-2 specific T cells could be measured, SARS-CoV-2 specific T cells were detectable, at levels similar to those of twice-vaccinated anti-CD20 therapy-naive pwMS (n=7) and HC (n=19). SARS-CoV-2 S1 IgG levels (r=0.42, p=0.002), antibody avidity (r=0.7, p<0.001) and neutralizing capacity (r=0.44, p=0.03) increased with time between anti-CD20 infusion and second vaccination. Based on detection of SARS-CoV-2 antibodies, SARS-CoV-2 infections occurred in 4/175 (2.3%) anti-CD20 treated pwMS, all of whom recovered fully.\n\nInterpretationThese findings should inform treatment decisions and SARS-CoV-2 vaccination management in pwMS.","Clustering ICU patients with sepsis based on the patterns of their circulating biomarkers: a secondary analysis of the CAPTAIN prospective multicenter cohort study.\nBackgroundAlthough sepsis is a life-threatening condition, its heterogeneous presentation likely explains the negative results of most trials on adjunctive therapy. This study in patients with sepsis aimed to identify subgroups with similar immune profiles and their clinical and outcome correlates.\n\nMethodsA secondary analysis used data of a prospective multicenter cohort that included patients with early assessment of sepsis. They were described using Predisposition, Insult, Response, Organ failure sepsis (PIRO) staging system. Thirty-eight circulating biomarkers (27 proteins, 11 mRNAs) were assessed at sepsis diagnosis, and their patterns were determined through principal component analysis (PCA). Hierarchical clustering was used to group the patients and k-means algorithm was applied to assess the internal validity of the clusters.\n\nResultsTwo hundred and three patients were assessed, of median age 64.5 [52.0-77.0] years and SAPS2 score 55 [49-61] points. Five main patterns of biomarkers and six clusters of patients (including 42%, 21%, 17%, 9%, 5% and 5% of the patients) were evidenced. Clusters were distinguished according to the certainty of the causal infection, inflammation, use of organ support, pro- and anti-inflammatory activity, and adaptive profile markers.\n\nConclusionsIn this cohort of patients with suspected sepsis, we individualized clusters which may be described with criteria used to stage sepsis. As these clusters are based on the patterns of circulating biomarkers, whether they might help to predict treatment responsiveness should be addressed in further studies.\n\nTrial registrationThe CAPTAIN study was registered on clinicaltrials.gov on June 22, 2011, # NCT01378169.","Validation of a Novel IoT and AI based Point-of-Care Testing Laboratory: Analytical Accuracy and Clinical Agreement\nPoint-of-care testing (POCT) offers several advantages over traditional laboratory testing. Offering less invasive testing with a faster turnaround time is not enough if not associated with an acceptable level of accuracy. Here, we show the analytical validation behind the multi-analyte POCT immunochromatography analyser, Hilab Flow (HiF). Analyses from 4,518 clinical samples were compared to College of American Pathologists accredited laboratories for ten quantitative and thirteen qualitative exams. Compatibility between methods was evaluated in terms of association/correlation and clinical agreement. Strong correlation/ concordance was observed between quantitative (CHOL, HDL-c, TG, HbA1c, Glycemia, 25-Hydroxy Vitamin D, TSH, Uric Acid, Creatinine, Urea) and qualitative methods (COVID-19 IgG/ IgM, Beta-hCG, Syphilis, Anti-HBsAg, Zika IgG/ IgM, Influenza A/B, HIV, HCV, HBsAg, Dengue NS1, COVID-19 Ag, Dengue IgG/ IgM, PSA). Approval criteria was obtaining a kappa agreement > 0.8 or a Pearson correlation > 0.9 depending on the exam. Overall percentage agreement was greater than 95% for all exams, indicating a good clinical agreement to gold-standard laboratory-based tests. Results indicate all exams are suitable for POCT and present a reliable performance. Data support the analyser is a useful tool to aid decision-making at the clinical setting, with potential to contribute with healthcare solutions in diagnostic medicine worldwide.","Using conditional inference to quantify interaction effects of socio-demographic covariates of US COVID-19 vaccine hesitancy\nCOVID-19 vaccine hesitancy has become a major issue in the U.S. as vaccine supply has outstripped demand and vaccination rates slow down. At least one recent global survey has sought to study the covariates of vaccine acceptance, but an inferential model that makes simultaneous use of several socio-demographic variables has been lacking. In this article, we present such a model using US-based survey data collected by Gallup. Our study agrees with the global survey results in some respects, but is also found to exhibit significant differences. For example, women and people aged between 25-54 were found to be more vaccine hesitant. Our conditional inference tree model suggests that trust in government, age and ethnicity are the most important covariates for predicting vaccine hesitancy, and can interact in ways that make them useful for communication-based outreach, especially if conjoined with census data. In particular, we found that the most vaccine hesitant individuals were those who identified as Black Republicans with a high school (or lower) education and lower income levels, who were involuntarily unemployed and trusted in the Trump administration.","Decreased Immune Response to COVID-19 mRNA Vaccine in Patients with Inflammatory Bowel Diseases Treated with Anti TNFα\nBackgroundPatients with inflammatory bowel diseases (IBD), specifically those treated with anti-tumor necrosis factor (TNF) biologics are at high risk for vaccine preventable infections. Their ability to mount adequate vaccine responses is unclear.\n\nAimto assess immune responses to mRNA-COVID-19 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared to healthy controls (HC).\n\nMethodsProspective, controlled, multi-center Israeli study. Subjects enrolled received two BNT162b2 (Pfizer/BioNTech) doses. Anti-spike (S) antibodies levels and functional activity, anti-TNF levels and adverse events (AEs) were detected longitudinaly.\n\nResultsOverall 258 subjects: 185 IBD (67 treated with anti-TNF), and 73 HC. After the first vaccine dose all HC were seropositive, while some patients with IBD, regardless of treatment, remained seronegative. After the second dose all subjects were seropositive, however anti-S levels were significantly lower in anti-TNF treated compared to untreated patients, and HC (p<0.001; p<0.001, respectively). Neutralizing and inhibitory functions were both lower in anti-TNF treated compared to untreated patients, and HC (p<0.03; p<0.0001, respectively). Anti-TNF drug levels and vaccine responses did not affect anti-S levels. Infection rate ([~]2%) and AEs were comparable in all groups. IBD activity did not change in response to BNT162b2.\n\nConclusionsIn this prospective study in patients with IBD stratified according to treatment all patients mounted an immune response to two doses of BNT162b2. However, its magnitude was significantly lower in patients treated with anti-TNF, regardless of administration timing and drug levels. Vaccine was safe. As vaccine immune response longevity in this group may be limited, vaccine booster dose should be considered.","Quarantine, relaxation and mutation explaining the CoViD-19 epidemic in Sao Paulo State (Brazil)\nBackgroundThe continuous SARS-CoV-2 transmission in several countries could contribute to the mutations appearance. The circulation of more virulent variants may increase the number of severe CoViD-19 needing hospital care and fatalities hugely.\n\nMethodsThe partial quarantine in Sao Paulo State and further relaxation associated with the mutations are explained by a mathematical model based on the CoViD-19 natural history encompassing the age-dependent fatality. The model parameters were fitted considering the observed data from Sao Paulo State.\n\nResultsThe partial quarantine was explained by the less virulent SARS-CoV-2 transmission, but the relaxation alone could not explain the epidemic observed in Sao Paulo State. However, more virulent variants plus the transmission among isolated individuals explained the increased CoViD-19 fatalities.\n\nConclusionsThe model described the CoViD-19 epidemic in Sao Paulo State by considering the partial quarantine, relaxation and mutations. The model provided a potential epidemiological scenario in the absence of mass vaccination.","Gender differences in housework and childcare among Japanese workers during the COVID-19 pandemic.\nObjectivesAlthough gender stereotypes regarding paid work and unpaid work are changing, most wives are responsible for taking care of the family and home in Japan. It is unclear how time spent on housework and childcare has changed between working men and women during the COVID-19 pandemic in Japan. The purpose of this study is to investigate how working men and womens responsibilities for housework and childcare changed during the COVID-19 pandemic in Japan depending on occupation, job type, and the number of employees in the workplace.\n\nMethodsA cross-sectional analysis (N=14,454) was conducted using data from an internet monitoring study (CORoNa Work Project), which was conducted in December 2020. A multilevel logistic model with nested prefectures of residence was conducted to estimate the odds ratio (OR) for change in time devoted to housework and childcare among men and women adjusting for age, household income, frequency of telecommuting, presence of spouse who work, occupation, job type, the number of employees in the workplace, and the incidence rate of COVID-19 by prefecture.\n\nResultsRegardless of occupation related factors, more women than men reported increased time spent on housework and childcare. Furthermore, women were significantly more likely to experience an increase in time spent on those activities than men (housework: OR 1.97, 95% CI [1.75, 2.21], p < 0.001; childcare: OR 1.66, 95% CI [1.37, 2.02], p < 0.001).\n\nConclusionsThe time spent by women on housework and childcare increased significantly compared to men during the COVID-19 pandemic in Japan.","Development and validation of a modified Cambridge Multimorbidity Score for use with internationally recognized electronic health record clinical terms (SNOMED CT)\nBackgroundPeople with multiple health conditions are more likely to have poorer health outcomes and greater care and service needs; a reliable measure of multimorbidity would inform management strategies and resource allocation. This study aims to develop and validate a modified version of the Cambridge Multimorbidity Score in an extended age range, using clinical terms which are routinely used in electronic health records across the world (SNOMED CT).\n\nMethods and FindingsWe curated new variables describing 37 health conditions and modelled the associations between these and 1-year mortality risk using the Cox proportional hazard model in a development dataset (n=300,000). We then developed two simplified models - a 20-condition model as per the original Cambridge Multimorbidity Score, and a variable reduction model using backward elimination with Akaike information criterion as the stopping criterion. The results were compared and validated for 1-year mortality in a synchronous validation dataset (n=150,000), and for 1-year and 5-year mortality in an asynchronous validation dataset (n=150,000).\n\nOur final variable reduction model retained 21 conditions, and the conditions mostly overlapped with those in the 20-condition model. The model performed similarly to the 37- and 20-condition models, showing high discrimination and good calibration following recalibration.\n\nConclusionsThis modified version of the Cambridge Multimorbidity Score allows reliable estimation using clinical terms which can be applied internationally across multiple healthcare settings.","The rapid reemergence of seasonal respiratory viruses in Houston, Texas, after relaxing COVID-19 restrictions\nBrief abstractImplementation of measures to limit the spread of the SARS-CoV-2 virus at the start of the COVID-19 pandemic resulted in a rapid decrease in all other respiratory pathogens. As COVID-19 containment measures were relaxed, the first non-COVID respiratory viruses to return to prepandemic levels were members of the rhinovirus/enterovirus, followed by the rapid return of seasonal coronaviruses, parainfluenza, and respiratory syncytial virus after the complete removal of COVID-19 precautions at the state level, including an end to mask mandates. Inasmuch as COVID-19 has dominated the landscape of respiratory infections since early 2020, it is important for clinicians to recognize the return of non-COVID respiratory pathogens may be rapid and significant when COVID-19 containment measures are removed.","Deep-sequence phylogenetics to quantify patterns of HIV transmission in the context of a universal testing and treatment trial -- BCPP/ Ya Tsie trial\nMathematical models predict that community-wide access to HIV testing-and-treatment can rapidly and substantially reduce new HIV infections. Yet several large universal test-and-treat HIV prevention trials in high-prevalence epidemics demonstrated variable reduction in population-level incidence. To elucidate patterns of HIV spread in universal test-and-treat trials we quantified the contribution of geographic-location, gender, age and randomized-HIV- intervention to HIV transmissions in the 30-community Ya Tsie trial in Botswana (estimated trial population: 175,664). Deep-sequence phylogenetic analysis revealed that most inferred HIV transmissions within the trial occurred within the same or between neighboring communities, and between similarly-aged partners. Transmissions into intervention communities from control communities were more common than the reverse post-baseline (30% [12.2 - 56.7] versus 3% [0.1 - 27.3]) than at baseline (7% [1.5 - 25.3] versus 5% [0.9 - 22.9]) compatible with a benefit from treatment-as-prevention. Our findings suggest that population mobility patterns are fundamental to HIV transmission dynamics and to the impact of HIV control strategies.","Preexisting diabetes and COVID-associated hyperglycaemia in patients with COVID-19 pneumonia\nAO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSAimC_ST_ABSThe aim of the current study was to compare clinical characteristics, laboratory findings and major outcomes of patients hospitalized for COVID-19 pneumonia with COVID-associated hyperglycaemia or preexisting diabetes.\n\nMethodsA cohort of 176 adult patients with a diagnosis of pre-existing diabetes (n=112) or COVID-associated hyperglycaemia (n=55) was studied. Clinical outcomes and laboratory findings were analysed according to the presence of the two conditions. The time to viral clearance was assessed during the follow-up after hospital discharge.\n\nResultPatients with COVID-associated hyperglycaemia had lower BMI, significantly less comorbidities and higher levels of inflammatory markers and indicators of multi-organ injury than those with preexisting diabetes. No differences between preexisting diabetes and COVID-associated hyperglycaemia were evident for symptoms at admission, humoral response against SARS-CoV-2 or autoantibodies to glutamic acid decarboxylase or interferon alpha-4. COVID-associated hyperglycaemia was independently associated with the risk of adverse clinical outcome defined as ICU admission or death (HR 2.11, 95% CI 1.34-3.31; p=0.001), even after adjustment for age, sex and other selected variables associated with COVID-19 severity. Furthermore, we documented a negative association (HR 0.661, 95% CI 0.43-1.02; p=0.063) between COVID-associated hyperglycaemia and the time to swab negativization.\n\nConclusionsThe recognition of hyperglycaemia as a specific clinical entity associated with COVID-19 pneumonia is relevant for early and appropriate patient management and close monitoring for the progression of disease severity.","Up-regulated tumor intrinsic growth potential and decreased immune function orchestrate the evolution of lung adenocarcinoma\nIntroductionLung adenocarcinoma is the most common pathological subtype of lung cancer. Precursors of lung adenocarcinoma, namely adenocarcinoma in situ and minimally invasive adenocarcinoma, have a superb 5-year survival rate after surgical resection. A deeper understanding of the key genetic changes driving the progression of lung adenocarcinoma is needed.\n\nMethodsIn this study, we performed whole-exome sequencing and RNA-sequencing on surgically resected 24 AIS, 74 MIA, 99 LUAD specimens and their adjacent paired normal tissues. Radiological, clinical, and pathological characteristics were recorded. Gene expression patterns were identified to find key pathways driving the progression of lung adenocarcinoma. Furthermore, genomic alterations and differential expression analyses were performed to compare tumors with different radiological manifestations. Finally, a progressive index was developed to quantitatively measure the level of imbalance between tumor intrinsic growth potential and immune microenvironment.\n\nResults12 patterns of gene expression were identified. Pathways associated with tumor growth and metastasis were found to be up-regulated as tumors progressed, while pathways associated with immune function were found to be down-regulated. Deconvolution of RNA-seq data also showed a decrease of CD8+ T cells and an increase of Tregs as the tumors progressed. Furthermore, tumors with more solid components on CT scan had a higher mutation frequency of tumor suppressor genes, higher tumor mutation burden and higher frequency of somatic copy number alterations. Finally, tumor progressive index demonstrated an increasing trend with the progression of lung adenocarcinoma.\n\nDiscussionOur results reveal the imbalance of tumor intrinsic factors and immune function orchestrate the progression of lung adenocarcinoma.","Geographically-targeted COVID-19 vaccination is more equitable and averts more deaths than age-based thresholds alone\nCOVID-19 mortality increases dramatically with age and is also substantially higher among Black, Indigenous, and People of Color (BIPOC) populations in the United States. These two facts introduce tradeoffs because BIPOC populations are younger than white populations. In analyses of California and Minnesota--demographically divergent states--we show that COVID vaccination schedules based solely on age benefit the older white populations at the expense of younger BIPOC populations with higher risk of death from COVID-19. We find that strategies that prioritize high-risk geographic areas for vaccination at all ages better target mortality risk than age-based strategies alone, although they do not always perform as well as direct prioritization of high-risk racial/ethnic groups.\n\nOne-sentence summaryAge-based COVID-19 vaccination prioritizes white people above higher-risk others; geographic prioritization improves equity.","Machine Learning Based Prediction of COVID-19 Mortality Suggests Repositioning of Anticancer Drug for Treating Severe Cases\nDespite available vaccinations COVID-19 case numbers around the world are still growing, and effective medications against severe cases are lacking. In this work, we developed a machine learning model which predicts mortality for COVID-19 patients using data from the multi-center Lean European Open Survey on SARS-CoV-2-infected patients (LEOSS) observational study (>100 active sites in Europe, primarily in Germany), resulting into an AUC of almost 80%. We showed that molecular mechanisms related to dementia, one of the relevant predictors in our model, intersect with those associated to COVID-19. Most notably, among these molecules was tyrosine kinase 2 (TYK2), a protein that has been patented as drug target in Alzheimers Disease but also genetically associated with severe COVID-19 outcomes. We experimentally verified that anti-cancer drugs Sorafenib and Regorafenib showed a clear anti-cytopathic effect in Caco2 and VERO-E6 cells and can thus be regarded as potential treatments against COVID-19. Altogether, our work demonstrates that interpretation of machine learning based risk models can point towards drug targets and new treatment options, which are strongly needed for COVID-19.","Genomic Surveillance of SARS-CoV-2 in Erie County, New York\nEarly in the SAR-CoV-2 pandemic, we established a whole genome sequencing pipeline to assess lineages circulating in Western New York. Initial sequences revealed entry into the region via Europe, similar to observations in New York City. However, as the pandemic progressed and variants of concern emerged, we observed distinct patterns in lineages relative to NYC. Notably, B.1.427 became dominant in Western New York, before it was displaced by B.1.1.7. Our hierarchical cluster analysis of B.1.1.7 lineages, which by May 2021 made up [~] 80% of all cases, indicated both multiple introductions and community spread. Our work highlights the importance of widespread, regional surveillance of SARS-CoV-2 across the United States.","Multi-Analyte Liquid Biopsies for Molecular Pathway Guided Personalized Treatment Selection in Advanced Refractory Cancers: A Clinical Utility Pilot Study\nPurposeThe selection of safe and efficacious anticancer regimens for treatment of broadly refractory patients with metastatic cancers remains a clinical challenge. Such patients are often fatigued by toxicities of prior failed treatments and may have no further viable standard of care treatment options. Liquid Biopsy-based multi-analyte profiling in peripheral blood can identify a majority of drug targets that can guide the selection of efficacious combination regimens.\n\nPatients and MethodsLIQUID IMPACT was a pilot clinical study where patients with advanced refractory cancers received combination anticancer treatment regimens based on multi-analyte liquid biopsy (MLB) profiling of circulating tumor biomarkers; this study design was based on the findings of prior feasibility analysis to determine the abundance of targetable variants in blood specimens from 1299 real-world cases of advanced refractory cancers.\n\nResultsAmong the 29 patients in the intent to treat (ITT) cohort of the trial, 26 were finally evaluable as per study criteria out of whom 12 patients showed Partial Response (PR) indicating an Objective Response Rate (ORR) of 46.2% and 11 patients showed Stable Disease (SD) indicating the Disease Control Rate (DCR) to be 88.5%. The median Progression-Free Survival (mPFS) and median Overall Survival (mOS) were 4.3 months (95% CI: 3.0 - 5.6 months) and 8.8 months (95% CI: 7.0 - 10.7 months), respectively. Toxicities were manageable and there were no treatment-related deaths.\n\nConclusionThe study findings suggest that MLB could be used to assist treatment selection in heavily pretreated patients with advanced refractory cancers.","COVID-19 vaccine hesitancy in diverse groups in the UK - is the driver economic or cultural in student populations?\nStudies have identified a greater reluctance for members of the Black, Asian, and minority ethnic communities to be vaccinated against COVID-19 despite a higher probability of greater harm from COVID-19. We conducted an anonymised questionnaire-based study of students (recruiting primarily before first reports of embolic events) at two London universities to identify whether economic or educational levels were primarily responsible for this reluctance: a postgraduate core group (PGCC) n=860 and a pilot study of undergraduate medical and nursing students (n=103). Asian and Black students were 2.0 and 3.2 times (PGCC) less likely to accept the COVID vaccine than White British students. Similar findings were noted in the pilot study students. As students were studying for Masters or PhD degrees and voluntarily paying high fees, educational and economic reasons were unlikely to be the underlying cause, and wider cultural reservations were more likely. Politicians exerted a strong negative influence, suggesting that campaigns should omit politicians.","Association between work attendance when experiencing fever or cold symptoms and company characteristics and socioeconomic status in the COVID-19 pandemic in Japanese workers: a cross-sectional study\nObjectiveThis study investigated the association between attending work while experiencing fever or cold symptoms and workers socioeconomic background and company characteristics during the COVID-19 pandemic.\n\nMethodsA cross-sectional online survey was performed. Of a total of 33,302 participants, 3,676 workers who experienced fever or cold symptoms after April 2020 were included. The odds ratios (ORs) of attending work while sick associated with workers socioeconomic background and company characteristics were evaluated using a multilevel logistic model.\n\nResultsThe OR of attending work while sick associated with a lack of policy prohibiting workers from working when ill was 2.75 (95%CI: 2.28-3.20, P<0.001).\n\nConclusionThis study suggests that clear company policies on work and illness can be effective for preventing employees from attending work while sick.","Trends of COVID-19 pediatric admissions number during the first 24 weeks of COVID-19 vaccination in Rio de Janeiro, Brazil\nObjectiveTo describe trends of COVID-19 pediatric admissions number during the first 24 weeks of COVID-19 vaccination.\n\nDesignA retrospective study was conducted in children (0-18 years), admitted in two pediatric hospitals of Rio de Janeiro city, between January 17 and July 3, 2021 with confirmed COVID-19 by reverse transcription polymerase chain reaction or serological tests. Trends of COVID-19 pediatric admissions number during the first 24 weeks of COVID-19 vaccination in Rio de Janeiro, Brazil and the pre-vaccine period were measured by linear regression.\n\nParticipantsChildren admitted in pediatric hospitals in Rio de Janeiro, city, Brazil\n\nResultsThe number of total admitted patients (with all diseases) were 5340 during the pre-vaccine period, being 94 (1.8%) of them with confirmed COVID-19, and 4182 children admitted during the vaccine period, with 86 confirmed COVID-19 patients (2.1 %) (p=0.29). Media of cases admitted per/week were 2.02 in pre-vaccine period and 3.6 during the first 24 weeks of COVID vaccination (p=0.009). One death was reported in the pre-vaccine period and four in the vaccine period (p=0.14). Trends of increase in the number of admitted cases were verified both in the pre-vaccine period as in the vaccine period, being more expressive in the last one.\n\nConclusionThere was trend of increase in number of children admitted with confirmed COVID-19 during the first 24 weeks of COVID-vaccination in Rio de Janeiro, city. Considering that few people were fully vaccinated, reducing of number of admitted children with confirmed COVID-19 was not verified.","Human phospho-signaling networks of SARS-CoV-2 infection are rewired by population genetic variants\nSARS-CoV-2 infection hijacks signaling pathways and induces protein-protein interactions between human and viral proteins. Human genetic variation may impact SARS-CoV-2 infection and COVID-19 pathology; however, the role of genetic variation in these signaling networks remains uncharacterized. We studied human single nucleotide variants (SNVs) affecting phosphorylation sites modulated by SARS-CoV-2 infection, using machine learning to identify amino acid changes altering kinase-bound sequence motifs. We found 2033 infrequent phosphorylation-associated SNVs (pSNVs) that are enriched in sequence motif alterations, potentially reflecting the evolution of signaling networks regulating host defenses. Proteins with pSNVs are involved in viral life cycle processes and host responses, including regulators of RNA splicing and interferon response, as well as glucose homeostasis pathways with potential associations with COVID-19 co-morbidities. Certain pSNVs disrupt CDK and MAPK substrate motifs and replace these with motifs recognized by Tank Binding Kinase 1 (TBK1) involved in innate immune responses, indicating consistent rewiring of infection signaling networks. Our analysis highlights potential genetic factors contributing to the variation of SARS-CoV-2 infection and COVID-19 and suggests leads for mechanistic and translational studies.","Effectiveness of a Fourth Dose of COVID-19 Vaccine among Long-Term Care Residents in Ontario, Canada\nBackgroundAs of December 30, 2021, Ontario long-term care (LTC) residents who received a third dose of COVID-19 vaccine [≥]84 days previously were offered a fourth dose to prevent a surge in COVID-19-related morbidity and mortality due to the Omicron variant.\n\nMethodsWe used a test-negative design and linked databases to estimate the marginal effectiveness (4 versus 3 doses) and vaccine effectiveness (VE; 2, 3, or 4 doses versus no doses) of mRNA vaccines among Ontario LTC residents aged [≥]60 years who were tested for SARS-CoV-2 between December 30, 2021 and March 2, 2022. Outcome measures included any Omicron infection, symptomatic infection, and severe outcomes (hospitalization or death).\n\nResultsWe included 9,957 Omicron cases and 46,849 test-negative controls. The marginal effectiveness of a fourth dose [≥]7 days after vaccination versus a third dose received [≥]84 days prior was 40% (95% Confidence Interval[CI], 34-45%) against infection, 63% (95%CI, 51-71%) against symptomatic infection, and 54% (95%CI, 31-70%) against severe outcomes. VE (compared to an unvaccinated group) increased with each additional dose, and for a fourth dose was 65% (95%CI, 60-70%), 87% (95%CI, 81-91%), and 92% (95%CI, 87-95%), against infection, symptomatic infection, and severe outcomes, respectively.\n\nConclusionsOur findings suggest that compared to a third dose received [≥]84 days ago, a fourth dose recommendation for LTC residents improved protection against infection, symptomatic infection, and severe outcomes caused by Omicron. Compared to unvaccinated individuals, fourth doses provide strong protection against symptomatic infection and severe outcomes but the duration of protection remains unknown.","The differential impact of the COVID-19 epidemic on Medicaid expansion and non-expansion states\nMedicaid expansion is a federally-funded program to expand health care access and coverage to economically challenged populations by increasing eligibility to Medicaid enrollment and investing in public health preventive services in the individual states. Yet, when the COVID-19 epidemic plagued the country, fourteen states were practicing their chosen decision not to enact the Medicaid expansion policy. We examined the consequences of this nationwide split in Medicaid design on the spread of the COVID-19 epidemic between the expansion and non-expansion states. Our study shows that, on average, the expansion states had 217.56 fewer confirmed COVID-19 cases per 100,000 residents than the non-expansion states [-210.41; 95%CI (-411.131) - (-2.05); P<0.05]. Also, the doubling time of COVID-19 cases in Medicaid expansion states was longer than that of non-expansion states by an average of 1.68 days [1.6826; 95%CI 0.4035-2.9617; P<0.05]. These findings suggest that proactive investment in public health preparedness was an effective protective policy measure in this crisis, unsurpassed by the benefits of COVID-19 emergency plans and funds. The study findings could be relevant to policymakers and healthcare strategists in non-expansion states considering their states preparations for such public health crises.","Adaptive vaccination may be needed to eliminate COVID-19: Results from a runtime-alterable strain-drift and waning-immunity model\nIn this paper, we present methods for building a Java Runtime-Alterable-Model Platform (RAMP) of complex dynamical systems. We illustrate our methods by building a multivariant SEIR (epidemic) RAMP. Underlying our RAMP is an individual-based model that includes adaptive contact rates, pathogen genetic drift, waning and cross immunity. Besides allowing parameter values, process descriptions, and scriptable runtime drivers to be easily modified during simulations, our RAMP is easily integrated into other computational platforms, such as our illustrated example with R-Studio. Processes descriptions that can be runtime altered within our SEIR RAMP include pathogen variant-dependent host shedding, environmental persistence, host transmission, and within-host pathogen mutation and replication. They also include adaptive social distancing and adaptive application of vaccination rates and variant-valency of vaccines. We present simulation results using parameter values and process descriptions relevant to the current COVID-19 pandemic. Our results suggest that if waning immunity outpaces vaccination rates, then vaccination rollouts may fail to contain the most transmissible variants, particularly if vaccine valencies do not adapt to escape mutations. Our SEIR RAMP is designed for easy-use by individuals and groups involved in formulating social-distancing and adaptive vaccination rollout policies. More generally, our RAMP concept facilitates construction of highly flexible complex systems models of all types, which can then be easily shared among researchers and policymakers as stand alone applications programs.","Neutralisation of SARS-CoV-2 Delta sub-lineage AY.4.2 and B.1.617.2+E484K by BNT162b2 mRNA vaccine-elicited sera\nSeveral factors may account for the recent increased spread of the SARS-CoV-2 Delta sublineage AY.4.2 in the United Kingdom, Romania, Poland, and Denmark. Here, we evaluate the sensitivity of AY.4.2 to neutralisation by sera from Pfizer/BioNTech (BNT162b2) vaccine recipients. AY.4.2 neutralisation was comparable to other circulating Delta lineages or sublineages. In contrast, the more rare B.1.617.2+E484K variant showed a significant >4-fold reduction in neutralisation that warrants surveillance of strains with the acquired E484K mutation.","Impact of the additional/booster dose of COVID-19 vaccine against severe disease during the epidemic phase characterized by the predominance of the Omicron variant in Italy, November 2021 - March 2022\nDespite the stunning speed with which highly effective and safe vaccines have been developed, increasingly transmissible variants are emerging. Using surveillance data from Italy (November 2021-March 2022), during the epidemic phase characterized by the predominance of the Omicron variant, vaccination with additional/booster dose significantly reduces the risk at all ages for hospitalization (relative risk (RR): 0.16; 95% confidence interval (CI): 0.13-0.19), admission to ICU (RR: 0.08; 95% CI: 0.06-0.09) and death (RR: 0.13; 95% CI: 0.10-0.16). Results support the importance of receiving a third dose of mRNA COVID-19 vaccine.","Evaluation of commercial anti-SARS-CoV-2 antibody assays and comparison of standardized titers in vaccinated healthcare workers.\nWith the availability of vaccines, commercial assays detecting anti-SARS-CoV-2 antibodies (Ab) evolved towards quantitative assays directed to the spike glycoprotein or its receptor binding domain (RBD). The main objective of the present study was to compare the Ab titers obtained with quantitative commercial binding Ab assays, after 1 dose (convalescent individuals) or 2 doses (naive individuals) of vaccine, in healthcare workers (HCW).\n\nAntibody titers were measured in 255 sera (from 150 HCW) with 5 quantitative immunoassays (Abbott RBD IgG II quant, bioMerieux RBD IgG, DiaSorin Trimeric spike IgG, Siemens Healthineers RBD IgG, Wantai RBD IgG). One qualitative total antibody anti RBD detection assay (Wantai) was used to detect previous infection before vaccination. The results are presented in binding Ab units (BAU)/mL after application, when possible, of a conversion factor provided by the manufacturers and established from a World Health Organization (WHO) internal standard.\n\nThere was a 100% seroconversion with all assays evaluated after two doses of vaccine. With assays allowing BAU/ml correction, Ab titers were correlated (Pearson correlation coefficient, {rho}, range: 0.85-0.94). The titer differences varied by a mean of 10.6% between Siemens and bioMerieux assays to 60.9% between Abbott and DiaSorin assays. These results underline the importance of BAU conversion for the comparison of Ab titer obtained with the different quantitative assays. However, significant differences persist, notably, between kits detecting Ab against the different antigens.\n\nA true standardization of the assays would be to include the International Standard in the calibration of each assays to express the results in IU/mL.","Antibody Responses In Non-Severe SARS-CoV-2 Infections Are Driven By CD4+ T cells and Age.\nSARS-CoV-2 infection causes a spectrum of clinical outcomes and diverse memory responses. Population studies indicate that viral neutralizing antibody responses are protective, but do not always develop post-infection. Other antiviral antibody effector functions, T-cell responses, or immunity to seasonal coronaviruses (OC43, 229E) have been implicated but not defined in all ages. Here, we identify that children and adult subjects generate polyfunctional antibodies to the spike protein after asymptomatic infection or mild disease, with some subjects developing cellular responses without seroconversion. Diversity in immunity was explained by two clusters distinguished by CD4+ T-cell cytokines, age, and antibodies to seasonal coronaviruses. Post-vaccination neutralizing responses were predicted by specific post-infection immune measures, including IL-2, spike-IgA, OC43-IgG1, 229E-IgM. We confirm a key role for CD4+ T cell cytokines in functionality of anti-spike antibodies, and show that antibody diversity is impacted by age, Th/Th2 cytokine biases, and antibody isotypes to SARS-CoV-2 and seasonal coronaviruses."],"string":"[\n \"Using DeepLabCut for tracking body landmarks in videos of children with dyskinetic cerebral palsy: a working methodology\\nMarkerless motion tracking is a promising technique to capture human movements and postures. It could be a clinically feasible tool to objectively assess movement disorders within severe dyskinetic cerebral palsy (CP). Here, we aim to evaluate tracking accuracy on clinically recorded video data.\\n\\nMethod94 video recordings of 33 participants (dyskinetic CP, 8-23 years; GMFCS IV-V, i.e. non-ambulatory) from a previous clinical trial were used. Twenty-second clips were cut during lying down as this is a postion for this group of children and young adults allows to freely move. Video image resolution was 0.4 cm per pixel. Tracking was performed in DeepLabCut. We evaluated a model that was pre-trained on a human healthy adult data set with an increasing number of manually labeled frames (0, 1, 2, 6, 10, 15 and 20 frames per video). To assess generalizability, we used 80% of videos for the model development and evaluated the generalizability of the model using the remaining 20%. For evaluation the mean absolute error (MAE) between DeepLabCuts prediction of the position of body points and manual labels was calculated.\\n\\nResultsUsing just the pre-trained adult human model yielded a MAE of 121 pixels. An MAE of 4.5 pixels (about 1.5 cm) could be achieved by adding 15-20 manual labels. When applied to unseen video clips (i.e. generalization set), the MAE was 33 pixels with a dedicated model trained on 20 frames per videos.\\n\\nConclusionAccuracy of tracking with a standard pre-trained model is insufficiently to automatically assess movement disorders in dyskinetic CP. However, manually adding labels improves the model performance substantially. In addition, the methodology proposed within our study is applicable to check the accuracy of DeepLabCut application within other clinical data set.\",\n \"A Solution to the Kermack and McKendrick Integro-Differential Equations\\nIn this manuscript, we derive a closed form solution to the full Kermack and McKendrick integro-differential equations (Kermack and McKendrick 1927) which we call the KMES. The KMES can be cast in the form of a step function response to the input of new infections; and that response is the time series of the total infections. We demonstrate the veracity of the KMES using independent data from the Covid 19 pandemic and derive many previously unknown and useful analytical expressions for diagnosing and managing an epidemic. These include new expressions for the viral load, the final size, the effective reproduction number, and the time to the peak in infections.\\n\\nSince the publication of Kermack and McKendricks seminal paper (1927), thousands of authors have utilized the Susceptible, Infected, and Recovered (SIR) approximations; expressions which are putatively derived from the integro-differential equations, to model epidemic dynamics. Implicit in the use of the SIR approximation are the beliefs that there is no closed form solution to the more complex integro-differential equations, that the approximation adequately reproduces the dynamics of the integro-differential equations, and that herd immunity always exists. However, as we explicate in this manuscript, the KMES demonstrates that the SIR models are not adequate representations of the integro-differential equations, and herd immunity is not guaranteed. Our conclusion is that the KMES obsoletes the need for the SIR approximations; and provides a new level of understanding of epidemic dynamics.\",\n \"Deep learning to estimate gestational age from blind ultrasound sweeps of the gravid abdomen\\nBackgroundUltrasound is indispensable to gestational age estimation, and thus to quality obstetric care, yet high equipment cost and need for trained sonographers limit its use in low-resource settings.\\n\\nMethodsFrom September 2018 through June 2021, we recruited 4,695 pregnant volunteers in North Carolina and Zambia and obtained blind ultrasound sweeps (cineloops) of the gravid abdomen alongside standard fetal biometry. We trained a neural network to estimate gestational age from the sweeps and, in three test sets, assessed performance of the model and biometry against previously established gestational age.\\n\\nResultsIn our main test set, model mean absolute error (MAE) was 3.9 days (standard error [SE] 0.12) vs. 4.7 days (SE 0.15) for biometry (difference -0.8 days; 95% CI -1.1, -0.5; p<0.001). Results were similar in North Carolina (difference -0.6 days, 95% CI -0.9, -0.2) and Zambia (-1.0 days, 95% CI -1.5, -0.5). Findings were supported in the test set of women who conceived by in vitro fertilization (model MAE 2.8 days [SE 0.28] vs. 3.6 days [SE 0.53] for biometry; difference -0.8 days, 95% CI -1.7, 0.2), and in the set of women from whom sweeps were collected by untrained users with low-cost, battery-powered devices (model MAE 4.9 days [SE 0.29] vs. 5.4 days [SE 0.28] for biometry; difference -0.6, 95% CI -1.3, 0.1).\\n\\nConclusionsOur model estimated gestational age more accurately from blindly obtained ultrasound sweeps than did trained sonographers performing fetal biometry. These results presage a future where all pregnant people - not just those in rich countries - can access the diagnostic benefits of sonography.\",\n \"Increasing trends in mental health problems among Chinese young adolescents: results from repeated cross-sectional data in Changsha 2016-2020\\nThis study performed a repeated cross-sectional analysis to explore possible trends in mental health problems among Chinese adolescents during 2016 to 2020. A total of 2837 seventh-grade students from Changsha city were surveyed in three waves in 2016, 2019 and 2020. The results showed that obsessive-compulsive tendencies, interpersonal sensitivity, depression, anxiety, academic stress and emotional disturbance problems were significantly increased in surveyed adolescents during 2016 to 2020. Moreover, positive rates of most of these problems were higher in females than males, and were significantly increased in only females. These results highlight the importance of focusing on mental health among Chinese adolescents, especially girls.\",\n \"A Machine Learning Approach to Identifying Delirium from Electronic Health Records\\nBackgroundDespite the well-known impact of delirium on long-term clinical outcomes, identification of delirium in electronic health records (EHR) remains difficult due to inadequate assessment or documentation of delirium. The purpose of this research is to present a classification model that identifies delirium using retrospective EHR data. The classification model would support the additional identification of delirium cases otherwise undocumented during routine practice.\\n\\nMethodsDelirium was confirmed with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Age, sex, Elixhauser comorbidity index, drug exposures, and diagnoses were used as features to train the logistic regression and multi-layer perceptron models. The clinical notes from the EHR were parsed to supplement the features that were not recorded in the structured data. The model performance was evaluated with a 5-fold cross-validation area under the receiver operating characteristic curve (AUC).\\n\\nResultsSeventy-six patients (17 cases and 59 controls) with at least one CAM-ICU evaluation result during ICU stay from January 30, 2018 to February 20, 2018 were included in the model. The multi-layer perceptron model achieved the best performance in identifying delirium; mean AUC of 0.967 {+/-} 0.019. The mean positive predictive value (PPV), mean negative predicted value (NPV), mean sensitivity, and mean specificity of the MLP model were 0.9, 0.88, 0.56, and 0.95, respectively.\\n\\nConclusionA simple classification model showed a mean AUC over 0.95. This model promises to identify delirium cases with EHR data, thereby enable a sustainable infrastructure to build a retrospective cohort of delirium in the ICU. The cohort would be useful for the evaluation of long-term sequelae of delirium in ICU.\",\n \"Brain Injury in COVID-19 is Associated with Autoinflammation and Autoimmunity\\nCOVID-19 has been associated with many neurological complications including stroke, delirium and encephalitis. Furthermore, many individuals experience a protracted post-viral syndrome which is dominated by neuropsychiatric symptoms, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of severe COVID-19 more broadly.\\n\\nWe sought to investigate the dynamics of, and relationship between, serum markers of brain injury (neurofilament light [NfL], Glial Fibrillary Acidic Protein [GFAP] and total Tau) and markers of dysregulated host response including measures of autoinflammation (proinflammatory cytokines) and autoimmunity. Brain injury biomarkers were measured using the Quanterix Simoa HDx platform, cytokine profiling by Luminex (R&D) and autoantibodies by a custom protein microarray.\\n\\nDuring hospitalisation, patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependant manner, and there was evidence of ongoing active brain injury at follow-up 4 months later. Raised NfL and GFAP were associated with both elevations of pro-inflammatory cytokines and the presence of autoantibodies; autoantibodies were commonly seen against lung surfactant proteins as well as brain proteins such as myelin associated glycoprotein, but reactivity was seen to a large number of different antigens.\\n\\nFurthermore, a distinct process characterised by elevation of serum total Tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses in the same manner as NfL and GFAP.\",\n \"Transferability of Psychological Interventions from Disaster-Exposed Employees to Healthcare Workers Working during the COVID-19 Pandemic\\nBackgroundThe COVID-19 Pandemic had a significant negative impact on the mental health of healthcare workers. Evidence-based interventions that could be used to mitigate this impact are lacking in the literature. This review aims to evaluate psychological interventions used for employees following previous disasters and assess the transferability of these interventions to a healthcare setting during the COVID-19 pandemic.\\n\\nMethodsIntervention information from a previously published systematic review of the literature published up to 2015 was extracted, and an additional search of studies published from 2015-2020 was conducted. Studies were assessed for transferability using a checklist derived from the PIET-T process model.\\n\\nResultsInterventions from eighteen studies were assessed for transferability (including three studies identified in an updated literature search). Interventions established as most transferable included resilience training, meditation/mindfulness interventions, and cognitive behavioural therapy. Psychological debriefing was transferable but as it is contrary to current recommendations is not deemed appropriate for adoption.\\n\\nImplicationsSeveral existing interventions have the potential to be utilised within the COVID-19 context/pandemic. More research needs to be undertaken in this area to assess these interventions upon transfer.\",\n \"A territory-wide study of arrhythmogenic right ventricular cardiomyopathy patients from Hong Kong\\nBackgroundArrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a hereditary disease characterized by fibrofatty infiltration of the right ventricular myocardium that predisposes affected patients to malignant ventricular arrhythmias, dual-chamber cardiac failure and sudden cardiac death (SCD). The present study aims to investigate the risk of detrimental cardiovascular events in an Asian population of ARVC/D patients, including the incidence of malignant ventricular arrhythmias, new-onset heart failure with reduced ejection fraction (HFrEF), as well as long-term mortality.\\n\\nMethods and ResultsThis was a territory-wide retrospective cohort study of patients diagnosed with ARVC/D between 1997 and 2019 in Hong Kong. This study consisted of 109 ARVC/D patients (median age: 61 [46-71] years; 58% male). Of these, 51 and 24 patients developed incident VT/VF and new-onset HFrEF, respectively. Five patients underwent cardiac transplantation, and 14 died during follow-up. Multivariable Cox regression identified prolonged QRS duration as a predictor of VT/VF (p < 0.05). Female gender, prolonged QTc duration, the presence of epsilon waves and T-wave inversion (TWI) in any lead except aVR/V1 predicted new-onset HFrEF (P < 0.05. The presence of epsilon waves, in addition to the parameters of prolonged QRS duration and worsening ejection fraction predicted all-cause mortality (p<0.05). Clinical scores were developed to predict incident VT/VF, new-onset HFrEF and all-cause mortality, and all were significantly improved by machine learning techniques.\\n\\nConclusionClinical and electrocardiographic parameters are important for assessing prognosis in ARVC/D patients and should in turn be used in tandem to aid risk stratification in the hospital setting.\",\n \"A very simple model to account for the rapid rise of the British variant of SARS-CoV-2 in several countries and the world\\nSince its first detection in the UK in September 2020, a highly contagious version of the coronavirus, called the British variant or B.1.1.7 SARS-CoV-2 virus lineage, is rapidly spreading across several countries and becoming the dominant strain in the outbreak.\\n\\nHere it is shown that a very simple evolutionary model, when including the latest available data from March 2021, can fit the observed change in frequency of B.1.1.7 for several countries, regions of countries and the whole world with a single parameter which is almost universal.\",\n \"Loss of recognition of SARS-CoV-2 B.1.351 variant spike epitopes but overall preservation of T cell immunity\\nSARS-CoV-2 variants have emerged that escape neutralization and potentially impact vaccine efficacy. T cell responses play a role in protection from reinfection and severe disease, but the potential for spike mutations to affect T cell immunity is poorly studied. We assessed both neutralizing antibody and T cell responses in 44 South African COVID-19 patients infected either with B.1.351, now dominant in South Africa, or infected prior to its emergence ( first wave), to provide an overall measure of immune evasion. We show for the first time that robust spike-specific CD4 and CD8 T cell responses were detectable in B.1.351-infected patients, similar to first wave patients. Using peptides spanning only the B.1.351 mutated regions, we identified CD4 T cell responses targeting the wild type peptides in 12/22 (54.5%) first wave patients, all of whom failed to recognize corresponding B.1.351-mutated peptides (p=0.0005). However, responses to the mutated regions formed only a small proportion (15.7%) of the overall CD4 response, and few patients (3/44) mounted CD8 responses that targeted the mutated regions. First wave patients showed a 12.7 fold reduction in plasma neutralization of B.1.351. This study shows that despite loss of recognition of immunodominant CD4 epitope(s), overall CD4 and CD8 T cell responses to B.1.351 are preserved. These observations may explain why, despite substantial loss of neutralizing antibody activity against B.1.351, several vaccines have retained the ability to protect against severe COVID-19 disease.\\n\\nOne Sentence SummaryT cell immunity to SARS-CoV-2 B.1.351 is preserved despite some loss of variant epitope recognition by CD4 T cells.\",\n \"COVID-19 and Herpes Simplex Virus Infection: A Cross-Sectional Study\\nBackgroundDespite being variable and poorly characterized, the reported cutaneous manifestations of COVID-19 are of increasing concern.\\n\\nAim of the StudyThis study aimed to assess the prevalence and possible association between COVID-19 and herpes simplex virus (HSV) infection.\\n\\nPatients and methodsA 9-item questionnaire was sent to 120 PCR-confirmed COVID-19 patients with a response rate of 66.67%. This cross-sectional observational study included 80 patients with mild to moderate COVID-19 infection who did not require hospitalization or steroid therapy.\\n\\nResultsOne or more HSV infections were observed in 28 patients (35%) with COVID-19 infection, including 10 males (35.7%) and 18 females (64.29%). Of the 28 patients, fever was reported in 17 patients (75%) during COVID-19. Most of the respondents (78%) described a single HSV reactivation, 14.29% had 2 attacks, and 7.14% experienced 3 attacks. Compared to previous non-COVID-19 related HSV reactivation, the COVID-19 related attacks were more severe in 12 patients (42.85%), equally severe in 5 patients (17.85%) and less severe in 1 patient (3.57%). Interestingly, 10 patients (35.71%) developed an initial symptomatic HSV attack during COVID-19 infection.\\n\\nConclusionsThis study demonstrated a possible association between COVID-19 infection and primary HSV infection and/or reactivation. The COVID-19 direct neuronal effect in addition to COVID-19 related psychological stress, fever and immunological dysregulation could play a potential role.\",\n \"Individual cardiorespiratory fitness exercise prescription in elderly based on BP neural network.\\nCardiorespiratory fitness (CRF) declines as age increases in elderly. An individualized CRF exercise prescription can maintain the CRF level and delay aging process. Traditional exercise prescriptions are general and lack of individualization. In this paper, a new study based on back-propagation (BP) neural network, is investigated to predict the individualized CRF exercise prescriptions for elderly by correlate variables (age, sex, BMI, VO2max initial value, improvement etc.). The raw data are split to two parts, 90% for training the machine and the remaining 10% for testing the performance. Based on a database with 2078 people, the exercise prescription prediction models MAE, RMSE and R2 are1.5206,1.4383 and 0.9944. 26 female subjects aged 60-79 years are recruited to test the models validity. The VO2maxs expected improvement was set at 10%. Based on the basic information of these elder women, we get personalized exercise prescription (frequency, intensity, time and volume) of each subject. All of them finished their own exercise intervention. The results show that the post VO2max was significantly different from the pre VO2max and improved by 10.1%, and a total of 20 subjects(74.1%) improved within one standard deviation and 25 subjects(92.6%)improved within 1.96 times standard deviations. Our study shows that a high degree of accuracy in exercise suggestions for elderly was achieved by applying the BP neural network model.\",\n \"Intermittent calorie restriction alters T cell subsets and metabolic markers in people with multiple sclerosis\\nBackgroundIntermittent fasting or calorie restriction (CR) diets provide anti-inflammatory and neuroprotective advantages in models of multiple sclerosis (MS); data in humans are sparse.\\n\\nMethodsWe conducted a randomized-controlled feeding study of different CR diets in 36 people with MS over 8 weeks. Patients were randomized to receive either: a daily CR diet (22% reduction in calories, 7 days/week), an intermittent CR diet (75% reduction, 2 days/week; 100%, 5 days/week), or a weight-stable diet (100%, 7 days/week). Untargeted metabolomics was performed on plasma samples at weeks 0, 4 and 8 at Metabolon Inc (Durham, NC). Flow cytometry of cryopreserved peripheral blood mononuclear cells at weeks 0 and 8 were used to identify CD4+ and CD8+ T cell subsets including effector memory, central memory, and naive cells.\\n\\nResults31 (86%) completed the trial. Over time, individuals randomized to intermittent CR had significant reductions in CD4+CM -4.87%; 95%CI: -8.59%, -1.15%; p=0.01), CD4+EM (-3.82%; 95%CI: -7.44, - 0.21; p=0.04), and CD8+EM (-6.96%; 95%CI: -11.96, -1.97; p=0.006) with proportional increases in naive subsets (CD4+Naive: 5.81%; 95%CI: -0.01, 11.63%; p=0.05; CD8+Naive: 10.11%; 95%CI: 3.30, 16.92%; p=0.006). No changes were observed for daily CR or weight-stable diets. Larger within-person changes in lysophospholipid and lysoplasmalogen metabolites in intermittent CR were associated with larger reductions in memory T cell subsets and larger increases in naive T cell subsets.\\n\\nConclusionsIn people with MS, an intermittent CR diet was associated with reduction in memory T cell subsets. The observed changes may be mediated by changes in specific classes of lipid metabolites.\\n\\nTrial RegistrationThis study is registered on Clinicaltrials.gov with identifier NCT02647502.\\n\\nFundingNational MS Society, NIH, Johns Hopkins Catalyst Award\",\n \"Effectiveness of quarantine and testing to prevent COVID-19 transmission from arriving travelers\\nObjectiveTo assess the efficacy of policies designed to reduce the risk of international travelers importing SARS-CoV-2 into a country.\\n\\nMethodWe developed a simulation model and compared mandatory quarantine, testing, and combined quarantine and testing. We assessed the sensitivity of policy effectiveness to the timing of testing, compliance with quarantine and isolation, and other factors.\\n\\nResultsIn the base scenario, a 2-day quarantine reduced more risk than testing alone. The effectiveness of a 5-day quarantine requirement with perfect compliance was similar to a 14-day quarantine with moderate compliance. Testing 72h before arrival reduced less than 10% of in-country transmission risk across all scenarios. The addition of testing to quarantine added value for shorter quarantine lengths, when testing compliance was enforced, and when testing was performed near the end of quarantine.\\n\\nConclusionsQuarantine is more effective at preventing SARS-CoV-2 transmission from arriving travelers than testing alone, but testing combined with quarantine can add value if longer quarantine requirements are infeasible. Enforcing compliance with quarantine and isolation is critical. Requiring a negative test up to 72h before arrival may have limited effectiveness.\",\n \"Brain cortical changes are related to inflammatory biomarkers in hospitalized SARS-CoV-2 patients with neurological symptoms\\nIncreasing evidence shows that the brain is a target of SARS-CoV-2. However, the consequences of the virus on the cortical regions of hospitalized patients are currently unknown. The purpose of this study was to assess brain cortical gray matter volume (GMV), thickness (Th), and surface area (SA) characteristics in SARS-CoV-2 hospitalized patients with a wide range of neurological symptoms and their association with clinical indicators of inflammatory processes. A total of 33 patients were selected from a prospective, multicenter, cross-sectional study during the ongoing pandemic (August 2020-April 2021) at Basel University Hospital. Retrospectively biobank healthy controls with the same image protocol served as controls group. For each anatomical T1w MPRAGE image, the Th and GMV segmentation were performed with the FreeSurfer-5.0. Cortical measures were compared between groups using a linear regression model. The covariates were age, gender, age*gender, MRI magnetic field strength, and total intracranial volume/mean Th/Total SA. The association between cortical features and laboratory variables was assessed using partial correlation adjusting for the same covariates. P-values were adjusted using false discovery rate (FDR). Our findings revealed a lower cortical gray matter volume in orbitofrontal and cingulate regions in patients compared to controls. The orbitofrontal grey matter volume was negatively associated with protein levels, CSF-blood/albumin ratio and CSF EN-RAGE level. CSF EN-RAGE and CSF/Blood-albumin ratio, which are neuroinflammatory biomarkers, were associated with cortical alterations in gray matter volume and thickness in frontal, orbitofrontal, and temporal regions. Our data suggest that viral-triggered inflammation leads to increased neurotoxic damage in some cortical areas.\",\n \"The relation between COVID-19 vaccinations and public governance to improve preparedness of next pandemic impacts and crisis management: a global study\\nThe goal of this study is to analyze the relationship between COVID-19 vaccinations and public governance performing a global analysis of more than 110 countries worldwide. Methodology applies the Independent Samples T-Test that compares the means of two independent groups (countries with high/low level of vaccinations) to determine whether there is statistical evidence that the associated population means of indicators of public governance are significantly different. Findings suggest that high levels of governance can support a better function of health systems in the rollout of vaccinations to cope with COVID-19 pandemic crisis. This study may assist long-run policy of governments to improve good governance and health systems of countries in order to reinforce the preparedness to face next pandemic threats and in general future crisis management in society.\",\n \"The genetic risk for COVID-19 severity is associated with defective innate immune responses\\nRecent genome-wide association studies (GWASs) of COVID-19 patients of European ancestry have identified genetic loci significantly associated with disease severity (1). Here, we employed the detailed clinical, immunological and multi-omics dataset of the Human Functional Genomics Projects (HFGP) to explore the physiological significance of the host genetic variants that influence susceptibility to severe COVID-19. A genomics investigation intersected with functional characterization of individuals with high genetic risk for severe COVID-19 susceptibility identified several major patterns: i. a large impact of genetically determined innate immune responses in COVID-19, with increased susceptibility for severe disease in individuals with defective monocyte-derived cytokine production; ii. genetic susceptibility related to ABO blood groups is probably mediated through the von Willebrand factor (VWF) and endothelial dysfunction. We further validated these identified associations at transcript and protein levels by using independent disease cohorts. These insights allow a physiological understanding of genetic susceptibility to severe COVID-19, and indicate pathways that could be targeted for prevention and therapy.\\n\\nOne Sentence summaryIn this study, we explore the physiological significance of the genetic variants associated with COVID-19 severity using detailed clinical, immunological and multi-omics data from large cohorts. Our findings allow a physiological understanding of genetic susceptibility to severe COVID-19, and indicate pathways that could be targeted for prevention and therapy.\",\n \"Seasonality in living kidney donation in the United States from 1995-2019\\nFor nearly two decades, the annual number of US living kidney donors has been characterized by worrying patterns of decline and no factors have been identified to explain and reverse these patterns. Evidence suggests that there is seasonality in living kidney donation; herein we investigate whether potentially modifiable social, economic, and structural issues might explain this seasonality. Using donor-registry data from the Scientific Registry of Transplant Recipients, we described this seasonality in living kidney donation and used Poisson regression stratified by both donor-recipient biological relationship and estimated household income tertile to quantify these trends. In every decade from 1980-2020, there was a summer-only surge in living kidney donations (13%-25% for biologically related donors and 10%-17% for unrelated donors). This summer-only surge was evident for the months of June, July, and August when compared with January for each given year and statistically significant in some groups (range of incidence rate ratio [IRR] for related donors: 1.05-1.34; IRR for unrelated donors: 1.08-1.19). We observed this summer-only surge across all three income tertiles ($73,544+, $52,635- $73,544, and <$52,635) and regardless of donor-recipient relationship. Seasonal variation in donation is associated with structural factors, which may serve as potential targets for interventions to increase donation.\",\n \"Prognosis of Acute Ischaemic Stroke in Cancer Patients: A National Inpatient Sample Study\\nBackground and PurposeWhilst cancer is a risk factor for acute ischaemic stroke (AIS), its impact on AIS prognosis between metastatic and non-metastatic (MC and NMC) disease is poorly understood. Furthermore, the receipt of intravenous thrombolysis (IVT) and endovascular thrombectomy (ET) and their outcomes is poorly researched.\\n\\nMethodsAIS admissions from the National Inpatient Sample (NIS) were included (October 2015-December 2017). Multivariable logistic regressions adjusting for a wide range of confounders analysed the relationship between NMC and MC and AIS in-hospital outcomes (mortality, prolonged hospitalisation >4 days and routine home discharge). Interaction terms with IVT and ET were also computed to explore their impact amongst cancer patients.\\n\\nResults221,249 records representative of 1,106,045 admissions were included. There were 38,855 (3.51%) patients with co-morbid cancers: NMC=53.78% and MC=46.22%. NMC was associated with 23% increased odds of in-hospital mortality (odds ratio (95% confidence interval) = 1.23 (1.07-1.42)), which was mainly driven by pancreatic and respiratory cancers. This association was entirely offset by both IVT and ET. MC was associated with 2-fold increased odds of in-hospital mortality (2.16 (1.90-2.45)), which was mainly driven by respiratory, pancreatic and colorectal cancers. This association was only offset by ET. Both NMC and MC were significantly associated with prolonged hospitalisation and decreased odds of routine discharge.\\n\\nConclusionsCancer patients are at higher odds of acute adverse outcomes after AIS and warrant robust primary prevention. IVT and ET improve these outcomes and should thus be offered routinely unless otherwise contraindicated in this group of stroke patients.\",\n \"40Hz sensory stimulation induces gamma entrainment and affects brain structure, sleep and cognition in patients with Alzheimer's dementia\\nNon-invasive Gamma ENtrainment Using Sensory stimuli (GENUS) at 40Hz reduced Alzheimers disease (AD) pathology, prevented cerebral atrophy and improved performance during behavioral testing in mouse models of AD. We report data from a safety study (NCT04042922) and a randomized, placebo-controlled trial in participants with probable mild AD dementia after 3 months of one-hour daily 40Hz light and sound GENUS (NCT04055376) to assess safety, compliance, entrainment and possible effects on brain structure, function, sleep and cognitive function. GENUS was well-tolerated and compliance was high in both groups. Electroencephalography recordings show that our GENUS device safely and effectively induced 40Hz entrainment in cognitively normal subjects and participants with mild AD. After 3 months of daily stimulation, participants with mild AD in the 40Hz GENUS group showed less ventricular enlargement and stabilization of the hippocampal size compared to the control group. Functional connectivity increased in both the default mode network and the medial visual network after 3 months of stimulation. Circadian rhythmicity also improved with GENUS. Compared to controls, the active group performed better on the face-name association delayed recall test. These results suggest that 40Hz GENUS can be used safely at home daily and shows favorable outcomes on cognitive function, daily rhythms, and structural and functional MRI biomarkers of AD-related degeneration. These results support further evaluation of GENUS in larger and longer clinical trials to evaluate its potential as a disease modifying therapeutic for Alzheimers disease.\",\n \"Validation of the RT-LAMP assay in a large cohort of nasopharyngeal swab samples shows that it is a useful screening method for detecting SARS-CoV-2 and its VOC variants\\nThe COVID-19 pandemic is challenging the global supply chain and equipment needed for mass testing with RT-qPCR, the gold standard for SARS-CoV-2 diagnosis. Here, we propose the RT-LAMP assay as an additional strategy for rapid virus diagnosis. However, its validation as a diagnostic method remains uncertain. In this work, we validated the RT-LAMP assay in 1,266 nasopharyngeal swab samples with confirmed diagnosis by CDC 2019-nCoV RT-qPCR. Our cohort was divided, the first (n=984) was used to evaluate two sets of oligonucleotides (S1 and S3) and the second (n=281) to determine whether RT-LAMP could detect samples with several types of variants. This assay can identify positive samples by color change or fluorescence within 40 minutes and shows high concordance with RT-qPCR in samples with CT [≤]35. Also, S1 and S3 are able to detect SARS-CoV-2 with a sensitivity of 68.4% and 65.8%, and a specificity of 98.9% and 97.1%, respectively. Furthermore, RT-LAMP assay identified 279 sequenced samples as positive (99.3% sensitivity) corresponding to the Alpha, Beta, Gamma, Delta, Epsilon, Iota, Kappa, Lambda, Mu and Omicron variants. In conclusion, RT-LAMP is able to identify SARS-CoV-2 with good sensitivity and excellent specificity, including all VOC, VOI, VUM and FMV variants.\",\n \"Preservation of neutralizing antibody function in COVID-19 convalescent plasma treated using a riboflavin and ultraviolet light-based pathogen reduction technology\\nBackground and ObjectiveConvalescent plasma (CP) has been embraced as a safe therapeutic option for coronavirus disease 2019 (COVID-19) while other treatments are developed. However, transfusion-transmitted disease is a risk, particularly in regions with high endemic prevalence of transfusion-transmissible diseases. Pathogen reduction can mitigate this risk; thus, the objective of this study was to evaluate the effect of riboflavin and ultraviolet light (R+UV) pathogen reduction technology on the functional properties of CCP.\\n\\nMaterials and MethodsCCP units (n = 6) from recovered COVID-19 research donors were treated with R+UV. Pre- and post-treatment samples were tested for coagulation factor and immunoglobulin retention. Antibody binding to spike protein receptor binding domain (RBD), S1, and S2 epitopes of SARS-CoV-2 was assessed by ELISA.\\n\\nNeutralizing antibody (nAb) function was assessed by pseudovirus reporter viral particle neutralization (RVPN) assay and plaque reduction neutralization test (PRNT).\\n\\nResultsMean retention of coagulation factors was [≥] 70% while retention of immunoglobulins was 100%. Starting nAb titers were low, but PRNT50 titers did not differ between pre- and post-treatment samples. No statistically significant differences were detected in levels of IgG (P [≥] 0.3665) and IgM (P [≥] 0.1208) antibodies to RBD, S1, and S2 proteins before and after treatment.\\n\\nConclusionR+UV PRT effects on coagulation factors were similar to previous reports, but no significant effects were observed on immunoglobulin concentration and antibody function. SARS-CoV-2 nAb function in COVID-19 convalescent plasma is conserved following R+UV PRT treatment.\",\n \"Vaccine Rollout Strategies: The Case for Vaccinating Essential Workers Early\\nIn planning for upcoming mass vaccinations against COVID-19, many jurisdictions have proposed using primarily age-based rollout strategies, where the oldest are vaccinated first and the youngest last. In the wake of growing evidence that approved vaccines are effective at preventing not only adverse outcomes, but also infection (and hence transmission of SARS-CoV-2), we propose that such age-based rollouts are both less equitable and less effective than strategies that prioritize essential workers. We demonstrate that strategies that target essential workers earlier consistently outperform those that do not, and that prioritizing essential work-ers provides a significant level of indirect protection for older adults. This conclusion holds across numerous outcomes, including cases, hospitalizations, Long COVID, deaths and net monetary benefit, and over a range of possible values for the efficacy of vaccination against infection. Our analysis focuses on regimes where the pandemic continues to be controlled with distancing and other measures as vaccination proceeds, and where the vaccination strategy is expected to last for over the coming 6-8 months -- for example British Columbia, Canada. In such a setting with a total population of 5M, vaccinating essential workers sooner is expected to prevent over 200,000 infections, over 600 deaths, and to produce a net monetary benefit of over $500M.\",\n \"Passively Sensing SARS-CoV-2 RNA in Public Transit Buses\\nAffordably tracking the transmission of respiratory infectious diseases in urban transport infrastructures can inform individuals about potential exposure to diseases and guide public policymakers to prepare timely responses based on geographical transmission in different areas in the city. Towards that end, we designed and tested a method to detect SARS-CoV-2 RNA in the air filters of public buses, revealing that air filters could be used as passive fabric sensors for the detection of viral presence. We placed and retrieved filters in the existing HVAC systems of public buses to test for the presence of trapped SARS-CoV-2 RNA using phenol-chloroform extraction and RT-qPCR. SARS-CoV-2 RNA was detected in 14% (5/37) of public bus filters tested in Seattle, Washington, from August 2020 to March 2021. These results indicate that this sensing system is feasible and that, if scaled, this method could provide a unique lens into the geographically relevant transmission of SARS-CoV-2 through public transit rider vectors, pooling samples of riders over time in a passive manner without installing any additional systems on transit vehicles.\\n\\nSynopsisPassive sensing of viral presence on urban transit infrastructure is proven, with forward-looking benefits for tracking pandemic spread.\",\n \"A general model for the demographic signatures of the transition from pandemic emergence to endemicity\\nAnticipating the medium- and long-term trajectory of pathogen emergence has acquired new urgency given the ongoing COVID-19 pandemic. For many human pathogens the burden of disease depends on age and prior exposure. Understanding the intersection between human population demography and transmission dynamics is therefore critical. Here, we develop a realistic age-structured (RAS) mathematical model that integrates demography, social mixing and immunity to establish the suite of possible scenarios of future age-incidence and burden of mortality. With respect to COVID-19, we identify a plausible transition in the age-structure of risks once the disease reaches seasonal endemism, whether assuming long-lasting or brief protective immunity, and across a range of assumptions of relative severity of primary versus subsequent reinfections. We train the model using diverse real-world demographies and age-structured social mixing patterns to bound expectations for changing age-incidence and disease burden. The mathematical framework is flexible and can help tailoring mitigation strategies countries worldwide with varying demographies and social mixing patterns.\\n\\nOne Sentence SummaryA shift of COVID-19 risks to younger age-classes in future endemic circulation.\",\n \"Negative impact of COVID-19 associated health system shutdown on patients diagnosed with colorectal cancer: a retrospective study from a large tertiary center in Ontario, Canada.\\nBackgroundIn March 2020, a directive to halt all elective and non-urgent procedures was issued in Ontario, Canada because of COVID-19. The directive caused a temporary slowdown of screening programs including surveillance colonoscopies for colorectal cancer (CRC). Our goal was to determine if there was a difference in patient and tumour characteristics between CRC patients treated surgically prior to the COVID-19 directive compared to CRC patients treated after the slowdown.\\n\\nMethodsCRC resections collected within the Champlain catchment area of eastern Ontario in the six months prior to COVID-19 (August 1, 2019-January 31, 2020) were compared to CRC resections collected in the six months post-COVID-19 slowdown (August 1, 2020-January 31, 2021). Clinical (e.g. gender, patient age, tumour site, clinical presentation) and pathological (tumour size, tumour stage, nodal stage, lymphovascular invasion) features were evaluated using chi square tests, T-tests and Mann-Whitney tests where appropriate.\\n\\nResults343 CRC specimens were identified (175 pre-COVID-19, 168 post-COVID-19 slowdown). CRC patients treated surgically post-COVID-19 slowdown had larger tumours (44 mm vs. 35 mm; p = 0.0048) and were more likely to have presented emergently (24% vs .10%; p < 0.001). While there was a trend towards higher tumour stage, nodal stage, and clinical stage, these differences did not reach statistical significance. Other demographic and pathologic variables including patient gender, age, and tumour site were similar between the two cohorts.\\n\\nInterpretationThe COVID-19 slowdown resulted in a shift in the severity of disease experienced by CRC patients in Ontario. Pandemic planning in the future should consider the long-term consequences to cancer diagnosis and management.\",\n \"How to coordinate vaccination and social distancing to mitigate SARS-CoV-2 outbreaks\\nMost countries have started vaccinating people against COVID-19. However, due to limited production capacities and logistical challenges it will take months/years until herd immunity is achieved. Therefore, vaccination and social distancing have to be coordinated. In this paper, we provide some insight on this topic using optimization-based control on an age-differentiated compartmental model. For real-life decision making, we investigate the impact of the planning horizon on the optimal vaccination/social distancing strategy. We find that in order to reduce social distancing in the long run, without overburdening the healthcare system, it is essential to vaccinate the people with the highest contact rates first. That is also the case if the objective is to minimize fatalities provided that the social distancing measures are sufficiently strict. However, for short-term planning it is optimal to focus on the high-risk group.\",\n \"High performances of a novel antigen detection test on nasopharyngeal specimens for SARS-CoV-2 infection diagnosis: a prospective study\\nIntroductionThe SARS-CoV-2 pandemic has become a major public health issue worldwide. Developing and evaluating rapid and easy-to-perform diagnostic tests is an absolute priority. The current study was designed to assess diagnostic performances of an antigen-based rapid detection test (COVID-VIRO(R)) in a real-life setting.\\n\\nMethodsTwo nasopharyngeal specimens of symptomatic or asymptomatic adult patients hospitalized in the Infectious Diseases Department or voluntarily accessing the COVID-19 Screening Department of the Regional Hospital of Orleans, France, were concurrently collected. COVID VIRO(R) diagnostic specificity and sensitivity were assessed in comparison to real-time reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) results. A subset of patients underwent an additional oropharyngeal and/or a saliva swab for rapid testing.\\n\\nResults121 patients already having a confirmed infection and 127 patients having no evidence of recent or ongoing infection were enrolled, for a total of 248 couple of nasopharyngeal swab specimens. Overall COVID-VIRO(R) sensitivity was 96.7% (IC: 93.5%-99.9%). In asymptomatic patients, symptomatic patients having symptoms for more than 4 days and those having a RT-qPCR Cycle threshold value [≥]32, sensitivity was of 100%, 95.8% and 91.9% respectively. The concordance between RT-qPCR and COVID VIRO(R) rapid test was 100% for the 127 patients with no SARS-CoV-2 infection.\\n\\nConclusionCOVID-VIRO(R) test had 100% specificity and above 95% sensitivity, better than WHO recommendations (specificity [≥]97-100%, sensitivity [≥]80%). These rapid tests are particularly interesting for large-scale screening in Emergency Department, low resource settings and airports.\",\n \"COVID19, Consumption and Inequality: A Systematic Analysis of Rural Population of India\\nBackgroundCOVID19 pandemic has had major impact on consumption levels and inequality within India. Government policy interventions have targeted poor households for cash and food transfers. It is important, however, to study the impact of the pandemic on consumption levels of non-poor in India, and in particular the middle class. In this paper, we aim to quantify the changes in consumption levels and inequality over time, across all groups of rural households in India.\\n\\nMethodsWe analyze three rounds of COVID 19-related shock surveys between May and September 2020. These surveys cover rural households of six large states in India and are representative of more than 442 million (52% of Indias rural population).\\n\\nFindingsIn the early phase of the pandemic, it was the bottom 40% of households that experienced the most severe decline in consumption. But as the pandemic deepened, consumption declined across all classes of households. Besides the poorest, it was particularly severe for the middle class (defined as 40%-80%). We also measure consumption inequality over time and find that the Gini coefficient of consumption distribution increased significantly.\\n\\nInterpretationIn addition to focusing on poor households, policy responses to alleviate peoples sufferings would have to consider a more comprehensive boost to consumption and compensate for the reduced consumption among middle class families as well.\\n\\nFundingNone.\",\n \"Diminishing immune responses against variants of concern in dialysis patients four months after SARS-CoV-2 mRNA vaccination\\nPatients undergoing chronic hemodialysis were among the first to receive SARS-CoV-2 vaccinations due to their increased risk for severe COVID-19 disease and high case fatality rates. To date, there have been minimal longitudinal studies in hemodialysis patients to ascertain whether protection offered by vaccination is long-lasting. To assess how surrogates for protection changed over time, we examined both the humoral and cellular response in a previously reported cohort of at-risk hemodialysis patients and healthy donors, four months after their second dose of Pfizer BNT162b2. Compared to three weeks post-second vaccination, both cellular and humoral responses against the original SARS-CoV-2 isolate as well as variants of concern were significantly reduced, with some dialyzed individuals having no B- or T-cell response. Our data strongly support the need for a third booster in hemodialysis patients and potentially other at-risk individuals.\",\n \"Trends in medical and surgical admission length of stay by race/ethnicity and socioeconomic status: a time series analysis\\nLength of stay, a metric of hospital efficiency, differs by race/ethnicity and socioeconomic status (SES). Longer LOS is associated with adverse health outcomes. We assessed differences in average adjusted length of stay (aALOS) over time by race/ethnicity, and SES stratified by discharge destination (home or non-home). Using the 2009-2014 State Inpatient Datasets from three states, we examined trends in aALOS differences by race/ethnicity, and SES (defined first vs fourth quartile of median income by zip code) controlling for patient, disease and hospital characteristics. For those discharged home, racial/ethnic and SES aALOS differences remained stable. Notably, for those discharged to non-home destinations, Black vs White, and low vs high SES aALOS differences increased significantly from 2009 to 2013, more sharply after Q3 2011, the Affordable Care Acts (ACA) introduction. Further research to understand the ACAs policy impact on hospital efficiencies, and relationship to racial/ethnic and SES differences in LOS is warranted.\",\n \"Pre-immunity: the Schrodinger's cat of immunology\\nEarly 2020, catastrophic consequences of COVID-19 was predicted in the do-nothing scenario, based on mathematical models for epidemiology. As data began to emerge, several scientists noted that growth did not seem exponential, as the models predicted, leading to speculations of pre-existing immunity or immunological dark matter to explain this pattern. On the other hand, reports of choir-rehearsals infecting most members seemed to refute this, and the topic remained inconclusive. We provide a mathematical theory in which both observations are true; on a population level, pre-immunity exists, on an individual level, it doesnt. This theory demonstrates that established formulas relating e.g. R0 and the herd-immunity threshold are wrong. We derive new mathematical formulas, which applies to any virus whose transmission dynamics is associated with large individual variability in susceptibility to the infection. Contrary to great variability in infectivity, which we show has no bearing on the mathematical modeling, variability in susceptibility actually manifests itself as pre-immunity on a macroscopic scale, thus making pre-immunity a necessity for accurate mathematical modeling.\",\n \"Saliva-based detection of COVID-19 infection in a real-world setting using reagent-free Raman spectroscopy and machine learning\\nSignificanceThe primary method of COVID-19 detection is reverse transcription polymerase chain reaction (RT-PCR) testing. PCR test sensitivity may decrease as more variants of concern arise.\\n\\nAimWe aimed to develop a reagent-free way to detect COVID-19 in a real-world setting with minimal constraints on sample acquisition.\\n\\nApproachWe present a workflow for collecting, preparing and imaging dried saliva supernatant droplets using a non-invasive, label-free technique - Raman spectroscopy - to detect changes in the molecular profile of saliva associated with COVID-19 infection.\\n\\nResultsUsing machine learning and droplet segmentation, amongst all confounding factors, we discriminated between COVID-positive and negative individuals yielding receiver operating coefficient (ROC) curves with an area under curve (AUC) of 0.8 in both males (79% sensitivity, 75% specificity) and females (84% sensitivity, 64% specificity). Taking the sex of the saliva donor into account increased the AUC by 5%.\\n\\nConclusionThese findings may pave the way for new rapid Raman spectroscopic screening tools for COVID-19 and other infectious diseases.\",\n \"COVID-19 vaccine uptake, predictors of vaccination, and self-reported barriers to vaccination among primary school teachers in Poland\\nIt has been proposed that teachers, like healthcare workers, constitute a strategic target for COVID-19 vaccine programs as immunization is a key element in protecting both them and their pupils. The present study examined vaccine uptake among primary-school teachers and sought to identify factors associated with it. A sample was recruited from 553 Polish primary schools, and data were collected at two time points: December 2020 and March 2021. Associations between vaccine uptake among teachers and their attitudes toward COVID-19 vaccination were assessed through multivariate logistic regression. 6152 participants completed both baseline and follow-up surveys. Of these, 4502 (73.2%) reported their intention at baseline to receive a COVID-19 vaccination, if available; at follow-up, 3894 (86.5%) of the same 4502 reported having received the vaccination. A significant association was revealed between vaccine uptake and perceived severity, self-efficacy, and social norms. The principal driver for vaccine acceptance was the wish to avoid contracting the disease. Conversely, the principal driver for vaccine refusal was concern about side effects and safety. A strong association exists between intention to receive the COVID-19 vaccine and actual uptake. Future COVID-19 immunization programs may benefit from a stronger understanding of the factors associated with vaccine uptake among this cohort.\",\n \"Cytokine release syndrome-like serum responses after COVID-19 vaccination are frequent but clinically inapparent in cancer patients under immune checkpoint therapy\\nCancer patients frequently receive immune checkpoint therapies (ICT) which may modulate immune responses to COVID-19 vaccines. Recently, cytokine release syndrome (CRS) was observed in a cancer patient who received the BTN162b2 vaccine under ICT. Here, we analyzed adverse events (AEs) in patients of various solid tumor types undergoing (n=64) or not undergoing (n=26) COVID-19 vaccination under ICT as an exploratory endpoint of a prospectively planned cohort study. We did not observe clinically relevant CRS after vaccination (95% CI [0,0.056]). Short term (<4 weeks) serious AEs were rare (12.5%) and overall AEs under ICT were comparable to unvaccinated patients. Despite the absence of CRS symptoms, we observed a pairwise-correlated set of CRS-associated cytokines upregulated in 42% of patients after vaccination and ICT (>1.5fold). Hence, clinically meaningful CRS appears to be rare in cancer patients under ICT and elevated serum cytokine levels are common but not sufficient to establish CRS diagnosis.\",\n \"Incorporating Vaccination into Compartment Models for Infectious Diseases\\nThe standard way of incorporating vaccination into a compartment model for an infectious disease is as a spontaneous transition process that applies to the entire susceptible class. The large degree of COVID-19 vaccine refusal and initial limitations of supply and distribution require reconsideration of this standard treatment. In this paper, we address these issues for models on endemic and epidemic time scales. On an endemic time scale, we partition the susceptible class into prevaccinated and unprotected subclasses and show that vaccine refusal has a significant impact on endemic behavior, particularly for diseases where immunity is short-lived. On an epidemic time scale, we develop a supply-limited Holling type 3 vaccination model and show that it is an excellent fit to vaccination data. We also extend the Holling model to a COVID-19 scenario in which the population is divided into two risk classes, with the high-risk class being prioritized for vaccination. For both cases with and without stratification by risk, we see significant differences in epidemiological outcomes between the Holling vaccination model and naive models. Finally, we use the new model to explore implications for public health policies in future pandemics.\",\n \"Actionable absolute risk prediction of atherosclerotic cardiovascular disease: a behavior-management approach based on data from 464,547 UK Biobank participants\\nCardiovascular diseases (CVDs) are the primary cause of all global death. Timely and accurate identification of people at risk of developing an atherosclerotic CVD and its sequelae, via risk prediction model, is a central pillar of preventive cardiology. However, currently available models only consider a limited set of risk factors and outcomes, do not focus on providing actionable advice to individuals based on their holistic medical state and lifestyle, are often not interpretable, were built with small cohort sizes or are based on lifestyle data from the 1960s, e.g. the Framingham model. The risk of developing atherosclerotic CVDs is heavily lifestyle dependent, potentially making a high percentage of occurrences preventable. Providing actionable and accurate risk prediction tools to the public could assist in atherosclerotic CVD prevention. We developed a benchmarking pipeline to find the best set of data preprocessing and algorithms to predict absolute 10-year atherosclerotic CVD risk. Based on the data of 464,547 UK Biobank participants without atherosclerotic CVD at baseline, we used a comprehensive set of 203 consolidated risk factors associated with atherosclerosis and its sequelae (e.g. heart failure).\\n\\nOur two best performing absolute atherosclerotic risk prediction models provided higher performance than Framingham and QRisk3. Using a subset of 25 risk factors identified with feature selection, our reduced model achieves similar performance while being less complex. Further, it is interpretable, actionable and highly generalizable. The model could be incorporated into clinical practice and could allow continuous personalized predictions with automated intervention suggestions.\",\n \"Early detection of patients with narcotic use disorder using a modified MEDD score based on the analysis of real-world prescription patterns\\nBackgroundAddiction to prescription narcotics is a global issue, and detection of individuals with a narcotic use disorder (NUD) at an early stage can help prevent narcotics misuse and abuse. We developed a novel index to detect early NUD based on a real-world prescription pattern analysis in a large hospital.\\n\\nMethodsWe analyzed narcotic prescriptions of 221 887 patients prescribed by 8737 doctors from July 2000 to June 2018. For the early detection of patients who could potentially progress to developing NUD after a long history of narcotic prescription, a weighted morphine equivalent daily dose (wt-MEDD) score was developed based on the number of prescription dates on which the actual MEDD was higher than the intended MEDD. Performance of the wt-MEDD scoring system in detecting patients diagnosed with NUD by doctors was compared with that of other NUD high risk indexes such as the MEDD scoring system, number of days on prescribed narcotics, the frequency/duration of prescription, narcotics prescription across multiple doctors, and the number of early refills of narcotics.\\n\\nResultsA wt-MEDD score cut-off value of 10.5 could detect all outliers, as well as patients diagnosed with NUD with 100% sensitivity and 99.6% specificity. The wt-MEDD score showed the highest sensitivity and specificity in identifying NUD among all indexes. Further, combining the wt-MEDD score with other NUD high risk indexes improved the prediction performance.\\n\\nConclusionWe developed a novel index to distinguish patients with vulnerable use patterns of narcotics. The wt-MEDD score showed excellent performance in detecting early NUD.\",\n \"Evaluating Digital Device Technology in Alzheimer's Disease via Artificial Intelligence\\nThe use of digital technologies may help to diagnose Alzheimers Disease (AD) at the pre-symptomatic stage. However, before implementation into clinical practice, digital measures (DMs) need to be evaluated for their diagnostic benefit compared to established questionnaire-based assessments, such as the Mini-Mental State Examination (MMSE) for cognition and Functional Activity Questionnaire (FAQ) for daily functioning. Moreover, the quantitative and qualitative relationship of DMs to these well understood scores needs to be clarified to aid interpretation. In this work we analyzed data from 148 subjects, 58 cognitively normal and 90 at different stages of the disease, which had performed a smartphone based virtual reality game to assess cognitive function. In addition, we used clinical data from Alzheimers Disease Neuroimaging Initiative (ADNI). We employed an Artificial Intelligence (AI) based approach to elucidate the relationship of DMs to questionnaire-based cognition and functional activity scores. In addition, we used Machine Learning (ML) and statistical methods to assess the diagnostic benefit of DMs compared to questionnaire-based scores. We found non-trivial relationships between DMs, MMSE, and FAQ which can be visualized as a complex network. DMs, in particular those reflecting scores of individual tasks in the virtual reality game, showed a better ability to discriminate between different stages of the disease than questionnaire-based methods. Our results indicate that DMs have the potential to act as a crucial measure in the early diagnosis and staging of AD.\",\n \"UK Health Care Workers' Experiences of Major System Change in Elective Surgery during the COVID-19 Pandemic: Reflections on Rapid Service Adaptation\\nBackgroundThe COVID-19 pandemic disrupted the delivery of elective surgery in the UK. The majority of planned surgery was cancelled or postponed in March 2020 for the duration of the first wave of the pandemic. We investigated the experiences of staff responsible for delivering rapid changes to surgical services during the first wave of the pandemic in the UK, with the aim of developing lessons for future major systems change.\\n\\nMethodsUsing a rapid qualitative study design, we conducted 25 interviews with frontline surgical staff during the first wave of the pandemic. We also carried out a policy review of the guidance developed for those delivering surgical services in pandemic conditions. We used framework analysis to organise and interpret findings.\\n\\nResultsStaff discussed positive and negative experiences of rapid service organisation. Clinician-led decision making, the flexibility of individual staff and teams, and the opportunity to innovate service design were all seen as positive contributors to success in service adaptation. The negative aspects of rapid change were inconsistent guidance from national government and medical bodies, top-down decisions about when to cancel and restart surgery, the challenges of delivering emergency surgical care safely and the complexity of prioritising surgical cases when services re-started.\\n\\nConclusionSuccess in the rapid reorganisation of elective surgical services can be attributed to the flexibility and adaptability of staff. However, there was an absence of involvement of staff in wider system-level pandemic decision-making and competing guidance from national bodies. Involving staff in decisions about the organisation and delivery of major systems change is essential for the sustainability of change processes.\",\n \"Healthcare workers' mental health and wellbeing during the COVID-19 pandemic: Longitudinal analysis of interview and social media data\\nThe COVID-19 pandemic has shed light on the fractures of healthcare systems around the world, particularly in relation to the healthcare workforce. Frontline staff, in particular, have been exposed to unprecedented strain and delivering care during the pandemic has impacted their safety, mental health and wellbeing. The aim of this paper was to explore the experiences of HCWs delivering care in the UK during the COVID-19 pandemic to understand their wellbeing needs, experiences and strategies used to maintain wellbeing (at individual and organizational levels). We analysed 94 telephone interviews with HCWs and 2000 tweets about HCWs mental health taking place during the first year of the COVID-19 pandemic. Results were grouped under six themes: redeployment; wellbeing support and coping strategies; mental health effects; organisational support; social network and public support. These findings demonstrate a need for open conversations, where staffs wellbeing needs and strategies can be shared and encouraged, rather than implementing solely top-down psychological interventions. At the macro level, findings also highlighted the impact on HCWs wellbeing of public and government support, as well as the need for ensuring protection through PPE, testing, and/or vaccines for frontline workers.\",\n \"Large-scale social media language analysis reveals emotions and behaviours associated with nonmedical prescription drug use\\nNonmedical use of prescription drugs (NMPDU) is a global health concern. The extent of, behaviors and emotions associated with, and reasons for NMPDU are not well-captured through traditional instruments such as surveys, prescribing databases and insurance claims. Therefore, this study analyses [~]130 million public posts from 87,718 Twitter users in terms of expressed emotions, sentiments, concerns, and potential reasons for NMPDU via natural language processing. Our results show that users in the NMPDU group express more negative emotions and less positive emotions, more concerns about family, the past and body, and less concerns related to work, leisure, home, money, religion, health and achievement, compared to a control group (i.e., users who never reported NMPDU). NMPDU posts tend to be highly polarized, indicating potential emotional triggers. Gender-specific analysis shows that female users in the NMPDU group express more content related to positive emotions, anticipation, sadness, joy, concerns about family, friends, home, health and the past, and less about anger, compared to males. The findings of the study can enrich our understanding of NMPDU.\",\n \"Urinary sodium excretion is not associated with the incidence of end-stage kidney disease and kidney-related death: results from the UK Biobank\\nBackgroundSodium reduction lowers blood pressure and albuminuria, indicating a hypothesized but yet-to-be proven association between sodium intake and kidney-related endpoints.\\n\\nObjectivesWe aimed to investigate the associations of 24-h urinary sodium excretion, reflecting daily sodium intake, with kidney-related outcomes.\\n\\nMethodsProspective cohort of 444,086 middle- to early late-aged participants from the UK Biobank. The primary outcome was a composite of incident end-stage kidney disease (ESKD) and death due to a kidney-related cause, each of which was separately examined as a secondary outcome. Death due to a non-kidney related cause prior to ESKD was considered a competing event.\\n\\nResultsThe mean 24-h urinary sodium excretion estimated from spot urinary biomarkers was 3.3 g. During a median follow-up of 11.8 years, 1,256 composite events occurred. Multivariable-adjusted cause-specific hazards models showed that, with every 1-g increment in 24-h urinary sodium excretion, hazard ratios (95% confidence intervals) were 1.03 (0.91-1.16), 1.08 (0.88-1.32), and 1.01 (0.88-1.16) for the composite outcome, incident ESKD, and kidney-related death, respectively. Similar null results were observed when the exposure was treated as binary (<2 g/d vs. [≥]2 g/d) or multicategorical (quartiles). Nonlinear associations were not detected with restricted cubic splines. The findings also held constant in prespecified sensitivity and subgroup analyses.\\n\\nConclusionsEstimated 24-h urinary sodium excretion was not linearly or nonlinearly associated with the incidence of ESKD or death due to kidney-related causes. Our findings did not support the hypothesized notion that sodium intake should be reduced to prevent kidney-related endpoints at the population level.\",\n \"Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a fourplex real-time quantitative reverse transcription-PCR assays.\\nThe early diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is required to identify and isolate contagious patients to prevent further transmission of the coronavirus disease 2019 (COVID-19). In this study, we present a multitarget real-time TaqMan reverse transcription PCR (rRT-PCR) assay for the quantitative detection of SARS-CoV-2 and some of its circulating variants harboring mutations that give SARS-CoV-2 a selective advantage. Seven different primer-probe sets that included probes containing locked nucleic acid (LNA) nucleotides were designed to amplify specific wild-type and mutant sequences in Orf1ab, Envelope (E), Spike (S), and Nucleocapsid (N) genes. Furthermore, a newly developed primer-probe set targeted human {beta}2-microglobulin (B2M) as a highly sensitive internal control for RT efficacy. All singleplex and fourplex assays detected [≤] 14 copies/reaction of quantified synthetic RNA transcripts, with a linear amplification range of 9 logarithmic orders. Primer-probe sets for detection of SARS-CoV-2 exhibited no false-positive amplifications with other common respiratory pathogens, including human coronaviruses NL63, 229E, OC43, and HKU-1. Given the emergence of SARS-CoV-2 variants and their rapid spread in some populations, fourplex rRT-PCR assay containing four primer-probe sets represents a reliable approach to detect multiple viral target sequences containing typical mutations of SARS-CoV-2 variants in a single reaction, allowing quicker detection of circulating relevant variants.\",\n \"Patients with CLL have similar high risk of death upon the omicron variant of COVID-19 as previously during the pandemic.\\nPrevious studies have shown that patients with chronic lymphocytic leukemia (CLL) and coronavirus disease 2019 (COVID-19) have high mortality rates. The omicron variant has been reported to give milder disease in the general population, but outcomes of infections with the omicron variant among immunocompromised patients have not previously been reported. In a population-based cohort we assessed rates of hospitalizations, ICU-admissions, and 30-day all-cause mortality among all patients with CLL from Eastern Denmark testing positive for severe adult respiratory syndrome coronavirus 2 (SARS-CoV-2) in time periods before and after dominance of the omicron variant. Rates of hospitalizations and ICU-admissions declined significantly, whereas 30-day mortality remained as high as 23% in the period with dominance of the omicron sublineage BA.2 variant. Thus, patients with CLL in general and in particular those above 70 years of age with one or more comorbidities should be considered for closer monitoring and pre-emptive antiviral therapy upon a positive SARS-CoV-2 test.\\n\\nKey pointsO_LIThe omicron variant of COVID-19 leads to high fatality rates in CLL, despite milder disease in the background population\\nC_LIO_LIPatients with CLL who test positive for SARS-CoV-2 in the era of the omicron variant should be considered for pre-emptive antiviral therapy\\nC_LI\\n\\nExplanation of noveltyThe omicron variant has been reported to give milder disease in the general population, but outcomes of infections with the omicron variant among immunocompromised patients have not previously been reported. These population-based data on outcome for patients with CLL upon infection with the omicron variant of SARS-CoV-2 warrants closer monitoring and pre-emptive antiviral therapy upon a positive SARS-CoV-2 test for patients with CLL.\",\n \"sMAdCAM:IL-6 (sMIL Index): A novel signature associated with COVID-19 disease progression and development of anti-SARS-CoV-2 antibodies\\nRecent studies positing the gut as a sanctuary site for viral persistence in SARS-CoV-2 infection highlight the importance of assimilating profiles of systemic as well as gut inflammatory mediators to understand the pathology of COVID-19. Also, the role of these markers in governing virus specific immunity following infection remains largely unexplored. A cohort (n=84) of SARS-C0V-2 infected individuals included a group of in-patients (n=60) at various stages of disease progression together with convalescent individuals (n=24) recruited between April and June 2020 from Mumbai, India. Follow-up of 35 in-patients at day 7 post diagnosis was carried out. Th1/Th2/Th17 cytokines along with soluble MAdCAM (sMAdCAM) levels in plasma were measured. Also, anti-viral humoral response as measured by rapid antibody test (IgG, IgM), Chemiluminescent Immunoassay (IgG) and antibodies binding to SARS-CoV-2 proteins were measured by Surface Plasmon Resonance (SPR) from plasma.IL-6 and sMAdCAM levels among in-patients inversely correlated with one another. When expressed as a novel integrated marker -sMIL index (sMAdCAM/IL-6 ratio), these levels were incrementally and significantly higher in various disease states with convalescents exhibiting the highest values. Importantly, sMAdCAM levels as well as sMIL index (fold change) correlated with peak association rates of receptor binding domain and fold change in binding to spike respectively as measured by SPR. Our results highlight key systemic and gutassociated parameters that need to be monitored and investigated further to optimally guide therapeutic and prophylactic interventions for COVID-19.\",\n \"Monocyte, Neutrophil and Whole Blood Transcriptome Dynamics Following Ischemic Stroke\\nBackgroundAfter ischemic stroke (IS), peripheral leukocytes infiltrate the damaged region and modulate the response to injury. Peripheral blood cells display distinctive gene expression signatures post IS and these transcriptional programs reflect changes in immune responses to IS. Dissecting the temporal dynamics of gene expression after IS improves our understanding of immune and clotting responses at the molecular and cellular level that are involved in acute brain injury and may assist with time-targeted, cell-specific therapy.\\n\\nMethodsThe transcriptomic profiles from peripheral monocytes, neutrophils, and whole blood from 38 ischemic stroke patients and 18 controls were analyzed with RNAseq as a function of time and etiology after stroke. Differential expression analyses were performed at 0-24 h, 24-48 h, and >48 h following stroke.\\n\\nResultsUnique patterns of temporal gene expression and pathways were distinguished for monocytes, neutrophils and whole blood with enrichment of interleukin signaling pathways for different timepoints and stroke etiologies. Compared to control subjects, gene expression was generally up-regulated in neutrophils and generally down- regulated in monocytes over all times for cardioembolic, large vessel and small vessel strokes. Self-Organizing Maps identified gene clusters with similar trajectories of gene expression over time for different stroke causes and sample types. Weighted Gene Co- expression Network Analyses identified modules of co-expressed genes that significantly varied with time after stroke and included hub genes of immunoglobulin genes in whole blood.\\n\\nConclusionsAltogether, the identified genes and pathways are critical for understanding how the immune and clotting systems change over time after stroke. This study identifies potential time- and cell-specific biomarkers and treatment targets.\",\n \"Whole genome sequencing identifies multiple loci for critical illness caused by COVID-19\\nCritical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care1 or hospitalisation2;3;4 following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study recruits critically-ill cases and compares their genomes with population controls in order to find underlying disease mechanisms.\\n\\nHere, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identify 15 new independent associations with critical COVID-19, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease.\\n\\nWe show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.\",\n \"Design and evaluation of mobile monitoring campaigns for air pollution exposure assessment in epidemiologic cohorts\\nMobile monitoring campaigns to estimate long-term air pollution levels are becoming increasingly common. Still, many campaigns have not conducted temporally-balanced sampling, and few have looked at the implications of such study designs for epidemiologic exposure assessment. We carried out a simulation study of fixed-site air quality monitors to better understand how different mobile monitoring designs involving short-term stationary measurements at fixed locations impact the resulting exposure surfaces. We used Monte Carlo resampling to simulate three archetypal monitoring designs using oxides of nitrogen (NOx) monitoring data from 69 regulatory sites in California: a year-around Balanced Design that sampled during all seasons of the year, days of the week, and all or various hours of the day; a temporally reduced Rush Hours Design; and a temporally reduced Business Hours Design. We evaluated the performance of each designs land use regression prediction model. The Balanced Design consistently yielded the most accurate annual averages; while the reduced Rush Hours and Business Hours Designs generally produced more biased results. A temporally-balanced sampling design is crucial for mobile monitoring campaigns aiming to assess accurate long-term exposure in epidemiologic cohorts.\\n\\nSynopsisAir pollution mobile monitoring campaigns rarely conduct temporally balanced sampling. We show that this results in biased annual average exposure estimates.\\n\\n\\n\\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC=\\\"FIGDIR/small/21255641v2_ufig1.gif\\\" ALT=\\\"Figure 1\\\">\\nView larger version (26K):\\norg.highwire.dtl.DTLVardef@126c8ddorg.highwire.dtl.DTLVardef@14d52e5org.highwire.dtl.DTLVardef@17d390dorg.highwire.dtl.DTLVardef@2cc3d1_HPS_FORMAT_FIGEXP M_FIG C_FIG\",\n \"COVID-19 vaccine uptake among older people in relation to sociodemographic factors: cohort results from southern Sweden\\nThe aim of this cohort study was to investigate sociodemographic determinants of COVID-19 vaccine uptake in the 70+ age group in Sk[a]ne county, Sweden (n = 216 243 at baseline). Uptake of the first dose was high (91.9%) overall, but markedly lower (75.3%) among persons born outside the Nordic countries. Vaccine uptake was generally satisfactory among native Swedes also in areas with lower socioeconomic status, but dropped substantially among non-Nordic born in those areas. The identified clusters of unvaccinated older people, mainly representing ethnic minorities in disadvantaged areas, warrants intensified efforts regarding tailored communication, easier vaccine access and local engagement.\\n\\nKey pointsO_LICOVID-19 vaccine uptake in the 70+ age group in Sk[a]ne county, Sweden, was high (91.9%) overall, but markedly lower (75.3%) within the group born outside the Nordic countries\\nC_LIO_LIInverse associations between indicators of neighbourhood deprivation and vaccine uptake were observed, which lowered the uptake among persons born outside the Nordic countries further\\nC_LIO_LIThe identified clusters of unvaccinated older people, mainly representing ethnic minorities in disadvantaged areas, warrants intensified efforts regarding tailored communication, easier vaccine access and local engagement\\nC_LI\",\n \"EVALUATION OF THE PANBIO SARS-COV-2 RAPID ANTIGEN DETECTION TEST IN THE BAHAMAS\\nIdentification and isolation of persons infected with SARS-COV-2 are key mitigation strategies in the current pandemic, and rapid antigen detection tests (RADTs) offer the promise of decreased turnaround time to diagnosis when compared with gold standard RT-PCR testing. We evaluated the analytical performance of the Abbott(R) Panbio RADT on nasopharyngeal samples stored at the Ministry of Health National Reference Lab in Nassau, Bahamas. The Panbio demonstrated a test sensitivity of 94% and a specificity of 100% on 50 PCR negative samples and 50 samples presumed to be infectious based on having PCR cycle threshold values below 30. Additionally, in our examination of operator results there was low interpersonal variation (1%) among three blind operators and significant correlation between sample Ct value and perceived signal strength on the RADT device. However, three PCR positive samples below Ct 30 were misdiagnosed by RADT, including one sample with Ct value less than 20. These results support the use of the Panbio in symptomatic persons to detect active SARS-COV-2 infections, with the caveat that RADT-negative samples should be confirmed by RT-PCR.\",\n \"Controlling the pandemic during the SARS-CoV-2 vaccination rollout: a modeling study\\nThere is a consensus that mass vaccination against SARS-CoV-2 will ultimately end the COVID-19 pandemic. However, it is not clear when and which control measures can be relaxed during the rollout of vaccination programmes. We investigate relaxation scenarios using an age-structured transmission model that has been fitted to age-specific seroprevalence data, hospital admissions, and projected vaccination coverage for Portugal. Our analyses suggest that the pressing need to restart socioeconomic activities could lead to new pandemic waves, and that substantial control efforts prove necessary throughout 2021. Using knowledge on control measures introduced in 2020, we anticipate that relaxing measures completely or to the extent as in autumn 2020 could launch a wave starting in April 2021. Additional waves could be prevented altogether if measures are relaxed as in summer 2020 or in a step-wise manner throughout 2021. We discuss at which point control of COVID-19 would be achieved for each scenario.\",\n \"All Models Are Useful: Bayesian Ensembling for Robust High Resolution COVID-19 Forecasting\\nTimely, high-resolution forecasts of infectious disease incidence are useful for policy makers in deciding intervention measures and estimating healthcare resource burden. In this paper, we consider the task of forecasting COVID-19 confirmed cases at the county level for the United States. Although multiple methods have been explored for this task, their performance has varied across space and time due to noisy data and the inherent dynamic nature of the pandemic. We present a forecasting pipeline which incorporates probabilistic forecasts from multiple statistical, machine learning and mechanistic methods through a Bayesian ensembling scheme, and has been operational for nearly 6 months serving local, state and federal policymakers in the United States. While showing that the Bayesian ensemble is at least as good as the individual methods, we also show that each individual method contributes significantly for different spatial regions and time points. We compare our models performance with other similar models being integrated into CDC-initiated COVID-19 Forecast Hub, and show better performance at longer forecast horizons. Finally, we also describe how such forecasts are used to increase lead time for training mechanistic scenario projections. Our work demonstrates that such a real-time high resolution forecasting pipeline can be developed by integrating multiple methods within a performance-based ensemble to support pandemic response.\\n\\nACM Reference FormatAniruddha Adiga, Lijing Wang, Benjamin Hurt, Akhil Peddireddy, Przemys-law Porebski,, Srinivasan Venkatramanan, Bryan Lewis, Madhav Marathe. 2021. All Models Are Useful: Bayesian Ensembling for Robust High Resolution COVID-19 Forecasting. In Proceedings of ACM Conference (Conference17). ACM, New York, NY, USA, 9 pages. https://doi.org/10.1145/nnnnnnn.nnnnnnn\",\n \"Impacts of COVID-19 public measures on country-level trade flows: Global panel regression analysis\\nAs of 10 July 2021, there have been over 186 million cases of COVID-19 and more than four million died as a result of this disease. The COVID-19 outbreak has also contributed to tremendous global decline in trade flows. The rapid spread of COVID-19 and the measures implemented by governments to contain the pandemic have had serious consequences for the worlds economies. While the pandemic has affected the international movement of people, goods and services, there is still limited systematic research regarding the possible associations between the COVID-19 measures on countries international trade flows. To fill this gap, we conducted regression analysis based on country level time series data from the United Nations and World Bank datasets. The results of the random effects panel regression models show that, the country import and export values are positively affected by health-related policies, while there is a negative association between stringency measures and import and export values. More specifically, school closing, stay-at-home requirements, and testing policy measures were found to have significant negative effects on countries trade values. In contrast, facial covering policies were found to have significant positive effects on countries import, export and total trade values.\",\n \"Measuring the digital divide among people with Severe Mental Ill Health using the Essential Digital Skills framework.\\nAimsAmidst the vast digitalisation of health and other services during the pandemic, people with no digital skills are at risk for digital exclusion. This risk might not abide by the end of the pandemic. This paper seeks to understand whether people with severe mental ill health (SMI) have the necessary digital skills to adapt to these changes and avoid digital exclusion.\\n\\nMethods249 adults with SMI across England completed a survey online or offline. They provided information on their digital skills based on the Essential Digital Skills (EDS) framework, sociodemographic information, and digital access. This is the first time the EDS is benchmarked in people with SMI.\\n\\nResults42.2% had no Foundation Skills and 46.2% lacked skills for daily life (lacking Foundation or Life Skills). 23.0% of those working lacked skills for professional life (lacking Foundation or Work Skills). The most commonly missing skills were handling passwords and using the device settings (Foundation Skills) and online problem solving (Skills for Life). People were interested in learning more about approximately half of the skills they did not have. People were more likely to lack Foundation Skills if they were older, not in employment, had a psychosis-spectrum disorder, or had no Internet access at home.\\n\\nConclusionA significant portion of people with SMI lacked Foundation Skills in this objective and benchmarked survey. This points to a high risk for digital exclusion and the need for focused policy and tailored health sector support, to ensure people retain access to key services and develop digital skills and confidence. To our knowledge this is the first time this has been described using the Essential Digital Skills (EDS) framework. Services, including the NHS, need to be aware and mitigate the risks.\",\n \"Environment-wide association study (EWAS) on cardiometabolic traits: A systematic assessment of the association of lifestyle variables on a longitudinal setting\\nThe present study aims to assess the over-time association of [~]300 lifestyle exposures with nine cardiometabolic traits with the ultimate aim of identifying exposures/exposure groups that could inform lifestyle interventions aiming at controlling cardiometabolic diseases. The analyses were undertaken in a longitudinal sample comprising >31000 adults living in northern Sweden. Linear mixed models were used to assess the average associations of lifestyle exposures and linear regression models were used to test association with 10-year change of the cardiometabolic traits. Physical activity and General Health were the exposure categories containing the highest number of tentative signals in analyses assessing the average association of lifestyle variables, while Tobacco use was the top-category for the 10-year change association analyses. Thirteen modifiable variables showed a consistent average association among the majority of cardiometabolic traits. These variables belonged to four main groups: i) Smoking, ii) Diet (secoisolariciresinol intake and brewed coffee), iii) Leisure time physical activity and iv) a group of variables more specific to the Swedish lifestyle (snuff status, hunting/fishing during leisure time and boiled coffee). Interestingly, sweet drinks, fish intake and salt content, all lifestyle exposures frequently mentioned in public health recommendations were not broadly associated with the analysed cardiometabolic traits.\",\n \"A mathematical model to estimate percentage secondary infections from margin of error of diagnostic sensitivity: Useful tool for regulatory agencies to assess the risk of propagation due to false negative outcome of diagnostics\\nFalse negative outcome of a diagnosis is one the major reasons for the dissemination of the diseases with high risk of propagation. Diagnostic sensitivity and the margin of error determine the false negative outcome of the diagnosis. A mathematical model had been developed to estimate the mean % secondary infections based on the margin of error of diagnostic sensitivity, % prevalence and R0 value. This model recommends a diagnostic test with diagnostic sensitivity [≥] 96% and at least 92% lower bound limit of the 95% CI or [≤] 4% margin of error for a highly infectious diseases like COVID-19 to curb the secondary transmission of the infection due to false negative cases. Positive relationship was found between mean % secondary infection and margin of error of sensitivity suggesting greater the margin of error of a diagnostic test sensitivity, higher the number of secondary infections in a population due to false negative cases. Negative correlation was found between number of COVID-19 test kits (>90% sensitivity) with regulatory approval and margin of error (R= -0.92, p=0.023) suggesting lesser the margin of error of a diagnostic test, higher the chances of getting approved by the regulatory agencies. However, there are no specific regulatory standards available for margin of error of the diagnostic sensitivity of COVID-19 diagnostic tests. Highly infectious disease such as COVID-19, certainly need specific regulatory standards on margin of error or 95% CI of the diagnostic sensitivity to curb the dissemination of the disease due to false negative cases and our model can be used to set the standards such as sensitivity, margin of error or lower bound limit of 95% CI.\",\n \"Association between COVID-19 Outcomes and Mask Mandates, Adherence, and Attitudes\\nWe extend previous studies on the impact of masks on COVID-19 outcomes by investigating an unprecedented breadth and depth of health outcomes, geographical resolutions, types of mask mandates, early versus later waves and controlling for other government interventions, mobility testing rate and weather. We show that mask mandates are associated with a statistically significant decrease in new cases (-3.55 per 100K), deaths (-0.13 per 100K), and the proportion of hospital admissions (-2.38 percentage points) up to 40 days after the introduction of mask mandates both at the state and county level. These effects are large, corresponding to 14% of the highest recorded number of cases, 13% of deaths, and 7% of admission proportion. We also find that mask mandates are linked to a 23.4 percentage point increase in mask adherence in four diverse states. Lastly, using a large novel survey dataset of almost half a million people in 68 countries, we introduce the novel results that community mask adherence and community attitudes towards masks are associated with a reduction in COVID-19 cases and deaths. Our results have policy implications for reinforcing the need to maintain and encourage mask-wearing by the public, especially in light of some states starting to remove their mask mandates.\",\n \"Prevalence and clinical profile of SARS-CoV-2 infection among farmworkers in Monterey County, California: June-November, 2020\\nAs essential personnel, United States farmworkers have continued working in-person throughout the COVID-19 pandemic. We undertook prospective surveillance of SARS-CoV-2 infection and antibody prevalence among farmworkers in Californias Salinas Valley from 15 June to 30 November, 2020. Over this period, we observed 22.1% (1514/6864) positivity for current SARS-CoV-2 by nucleic acid detection among farmworkers tested at federally-qualified migrant and community health clinics, as compared to 17.2% (1255/7305) among other adults from the same communities (risk ratio, 1.29; 95% confidence interval, 1.20-1.37). In a nested study enrolling 1,115 farmworkers, prevalence of current infection was 27.7% among farmworkers reporting [≥]1 potential COVID-19 symptom, and 7.2% among farmworkers without symptoms (adjusted odds ratio 4.17; 2.86-6.09). Prevalence of anti-SARS-CoV-2 IgG antibodies increased from 10.5% (6.0-18.4%) between 16 July-31 August to 21.2% (16.6-27.4%) between 1-30 November. The high observed prevalence of infection among farmworkers underscores the need for vaccination and other preventive interventions.\",\n \"Using mobile health technology to assess childhood autism in low-resource community settings in India : an innovation to address the detection gap\\nAutism Spectrum Disorders, hereafter referred to as autism, emerge early and persist throughout life, contributing significantly to global years lived with disability. Typically, an autism diagnosis depends on clinical assessments by highly trained professionals. This high resource demand poses a challenge in resource-limited areas where skilled personnel are scarce and awareness of neurodevelopmental disorder symptoms is low. We have developed and tested a novel app, START, that can be administered by non-specialists to assess several domains of the autistic phenotype (social, sensory, motor functioning) through direct observation and parent report. N=131 children (2-7 years old; 48 autistic, 43 intellectually disabled, and 40 typically developing) from low-resource settings in the Delhi-NCR region, India were assessed using START in home settings by non-specialist health workers. We observed a consistent pattern of differences between typically and atypically developing children in all three domains assessed. The two groups of children with neurodevelopmental disorders manifested lower social preference, higher sensory sensitivity, and lower fine-motor accuracy compared to their typically developing counterparts. Parent-report further distinguished autistic from non-autistic children. Machine-learning analysis combining all START-derived measures demonstrated 78% classification accuracy for the three groups (ASD, ID, TD). Qualitative analysis of the interviews with health workers and families (N= 15) of the participants suggest high acceptability and feasibility of the app. These results provide proof of principle for START, and demonstrate the potential of a scalable, mobile tool for assessing neurodevelopmental disorders in low-resource settings.\",\n \"Pilot study on the use of low molecular weight heparins in the prevention of thromboembolic disease during pregnancy and puerperium.\\nA pregnant woman is 4 to 5 times more likely to suffer a thromboembolic event than a non-pregnant woman. Furthermore, an increase in these episodes has been observed in women infected with SARS-CoV-2. Consequently, the prophylactic prescription of low-molecular-weight heparins (LMWH) in pregnant women is undergoing an increase that has not been evaluated yet. The aim of this study was to determine the prevalence of LMWH prescription in pregnant women at the Hospital Universitario Puerta de Hierro Majadahonda (HUPHM), according to their level of risk and its variation due to SARS-CoV-2 infection. To answer this question, a retrospective cohort of 113 women who gave birth during the month of February at the HUPHM was designed. The level of individual risk of thromboembolism, according to the Royal College guidelines (37a), was calculated with an interview to complete a questionnaire and the analysis of their clinical records. 53.6% of the women were prescribed LMWH as indicated in the guidelines. This high prevalence is explained by the high age of the pregnant women (over 35 years), the wave of the omicron variant (December 2021) and a high rate of cesarean sections (25%). On the other hand, the percentage of patients with COVID-19 was 17.6% but only 53% of them had received LMWH. In conclusion, LMWH is a very common prescription in obstetrics, mostly during puerperium, and has become even more relevant due to the COVID-19 pandemic\",\n \"Genetic risk prediction of COVID-19 susceptibility and severity in the Indian population\\nHost genetic variants can determine the susceptibility to COVID-19 infection and severity as noted in a recent Genome-wide Association Study (GWAS) by Pairo-Castineira et al.1. Given the prominent genetic differences in Indian sub-populations as well as differential prevalence of COVID-19, here, we deploy the previous study and compute genetic risk scores in different Indian sub-populations that may predict the severity of COVID-19 outcomes in them. We computed polygenic risk scores (PRSs) in different Indian sub-populations with the top 100 single-nucleotide polymorphisms (SNPs) with a p-value cutoff of 10-6 derived from the previous GWAS summary statistics1. We selected SNPs overlapping with the Indian Genome Variation Consortium (IGVC) and with similar frequencies in the Indian population. For each population, median PRS was calculated, and a correlation analysis was performed to test the association of these genetic risk scores with COVID-19 mortality. We found a varying distribution of PRS in Indian sub-populations. Correlation analysis indicates a positive linear association between PRS and COVID-19 deaths. This was not observed with non-risk alleles in Indian sub-populations. Our analyses suggest that Indian sub-populations differ with respect to the genetic risk for developing COVID-19 mediated critical illness. Combining PRSs with other observed risk-factors in a Bayesian framework can provide a better prediction model for ascertaining high COVID-19 risk groups. This has a potential utility in the design of more effective vaccine disbursal schemes.\",\n \"Dynamic Prediction of SARS-CoV-2 RT-PCR status on Chest Radiographs using Deep Learning Enabled Radiogenomics\\nReverse Transcription-Polymerase Chain Reaction (RT-PCR) is the gold standard for diagnosis of SARS-CoV-2 infection, but requires specialized equipment and reagents and suffers from long turnaround times. While valuable, chest imaging currently only detects COVID-19 pneumonia, but if it can predict actual RT-PCR SARS-CoV-2 status is unknown. Radiogenomics may provide an effective and accurate RT-PCR-based surrogate. We describe a deep learning radiogenomics (DLR) model (RadGen) that predicts a patient's RT-PCR SARS-CoV-2 status solely from their frontal chest radiograph (CXR).\",\n \"Impact of SARS-CoV-2 vaccination on systemic immune responses in people living with HIV\\nThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and an ongoing global pandemic. Despite the development of vaccines, which protect healthy people from severe and life-threatening COVID-19, the immunological responses of people with secondary immunodeficiencies to SARS-CoV-2 mRNA vaccines are currently not well understood. Human Immunodeficiency Virus (HIV), causing acquired immunodeficiency syndrome (AIDS), targets CD4+ T helper (Th) cells that orchestrate the immune response. Anti-retroviral therapy suppresses HIV burden and restores Th cell numbers. Here, we investigated the humoral and cellular immune responses elicited by the BTN162b2 vaccine in a cohort of people living with HIV (PLWH), who receive anti-retroviral therapy. While antibody responses in PLWH increased progressively after the first and second vaccination compared to baseline, they were reduced compared to HIV negative study participants (controls). CD8+ T cells exhibited a general activated phenotype and increased effector and effector memory compartments. In contrast, CD4+ Th cell responses exhibited a vaccination-dependent increase and were comparable between PLWH and controls. In line with their reduced humoral response, the correlation between neutralizing antibodies and the CD4+ T cell response was decreased in PLWH compared to healthy controls. Interestingly, CD4+ T cell activation negatively correlated with the CD4 to CD8 ratio, indicating that low CD4 T cell numbers do not necessarily interfere with cellular immune responses. Taken together, our data demonstrate that COVID-19 mRNA vaccination in PLWH results in potent cellular immune responses, but the reduced antibody responses suggest that booster vaccination might be required for preventing disease.\",\n \"Genetics of symptom remission in outpatients with COVID-19\\nWe conducted a genome-wide association study of time to remission of COVID-19 symptoms in 1723 outpatients with at least one risk factor for disease severity from the COLCORONA clinical trial. We found a significant association at 5p13.3 (rs1173773; P = 4.94 x 10-8) near the natriuretic peptide receptor 3 gene (NPR3). By day 15 of the study, 44%, 54% and 59% of participants with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. In 851 participants not treated with colchicine (placebo), there was a significant association at 9q33.1 (rs62575331; P = 2.95 x 10-8) in interaction with colchicine (P = 1.19 x 10-5) without impact on risk of hospitalisations, highlighting a possibly shared mechanistic pathway. By day 15 of the study, 46%, 62% and 64% of those with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. The findings need to be replicated and could contribute to the biological understanding of COVID-19 symptom remission.\",\n \"Clinical implementation of a machine learning system to detect deteriorating patients reduces time to response and intervention\\nIntroductionAcute physiological deterioration is a major contributor to in-hospital morbidity and mortality. Early detection and intervention of deteriorating patients is key to improving patient outcomes. Prior research has demonstrated the effectiveness of Early Warning Systems and other algorithmic approaches in automatically identifying these patients from passively monitoring vital signs.\\n\\nMethodsIn this work, we conduct a prospective pilot study of clinical deployment of the Mayo Clinic Bedside Patient Rescue (BPR) system using an escalating alerting logic enabled by machine learning. Among four units where the BPR system was deployed, time to response and time to intervention for deteriorating patients were significantly reduced relative to matched control units.\\n\\nResultsIn pilot units, time to response decreased by 35.4% (from 63.2 minutes to 40.8 minutes) and time to intervention decreased by 48.5% (from 106.3 minutes to 55.9 minutes). No significant differences were observed in counterbalance metrics of mortality, ICU transfer rate, and Rapid Response Team activation rate. Furthermore, the automated alerting system was well-received by clinicians participating in the pilot study, as assessed by survey.\\n\\nDiscussionThese results demonstrate a successful clinical deployment of a practice-changing machine learning alert system with demonstrable impact on improving patient care.\",\n \"Resolutive results with oral corticosteroids for patients with COVID-19 in pulmonary inflammatory phase. Successful outpatient experience during the collapse of Belem do Para Health System - Brazil.\\nIn the face of new diseases, medicine needs to reinvent itself in order to contain and control epidemics, such as the one we have recently faced, COVID-19, a disease with a wide spectrum of clinical severity. A new moment has been established, since the application of well known, effective and safe medications for other diseases, has shown high success rates in the treatment of COVID-19. Thereunto, studies with early intervention are needed, which can change the unfavorable outcome of patients. In this article, we report the successful experience using an oral strategy during the collapse of Belem do Para Health System, Brazil. Two hundred and ten patients were diagnosed with respiratory failure due to COVID-19, with no option of hospital treatment due to lack of beds and resources. These patients were then started on therapeutic regimen consisting of prednisolone, enoxaparin and macrolides associated and followed in outpatient facilities. Two hundred and eight patients had excellent therapeutic response and there were only two fatalities. These results push research boundaries, valuing outpatient treatment with early use of prednisolone in the initial pulmonary phase, preventing severe COVID-19 pneumonitis. Adoption of the proposed treatment intends to reduce the need for hospitalization, as well as lethality, with social robust benefits and incalculable economic savings since involves the use of accessible, safe and not expensive medications.\",\n \"Immune response to third SARS-CoV-2 vaccination in seronegative kidney transplant recipients: possible improvement by mycophenolate mofetil reduction\\nBackgroundModification of vaccination strategies is needed to improve the immune response to SARS-CoV-2 vaccination in kidney transplant recipients (KTRs).\\n\\nMethodsThis multicenter observational study aimed to determine antibody kinetics among 60 seropositive KTRs and analyzed the effects of the third vaccination against SARS-CoV-2 in 174 previously seronegative KTRs. We investigated whether mycophenolate mofetil (MMF) dose reduction by 25-50% prior the third vaccination influences vaccination success.\\n\\nResults18 of 60 (30%) seropositive KTRs became seronegative in the serological assay within six months. Loss of antibodies was predicted by low initial antibody levels ([≤]206.8 BAU/ml), older age, and impaired graft function. A third vaccination in previously seronegative KTRs induced seroconversion in 56 of 174 (32.1%) KTRs with median antibody levels 119 (76-353) BAU/ml and median neutralizing capacity titer of 1:10 (0- 1:40). Multivariate logistic regression revealed that initial antibody levels (OR 1.39, 95% CI 1.09-1.76), graft function (OR 0.05, 95% CI 0.01-0.39), time after transplantation (OR 1.04, 95% CI 1.02-1.07) and MMF trough levels (OR 0.43, 95% CI 0.21-0.88) correlated with seroconversion, p<0.05. After controlling for these confounders, the effect of MMF dose reduction was calculated using propensity score matching. KTRs in the MMF reduction group had significantly lower MMF serum concentrations prior to the third vaccination and were more likely to develop antibody levels [≥]35.2 BAU/ml than their matched KTRs (p=0.02).\\n\\nConclusionsTemporary reduction in MMF dose might be a promising approach to improve the immune response in KTRs.\",\n \"Electronic health record enabled track and trace inan urban hospital network: implications for infectionprevention and control\\nHealthcare-associated infections represent one of the most significant challenges for modern medicine as they can significantly impact patientslives. Carbapenemase-producing Enterobacteriaceae (CPE) pose the greatest clinical threat, given the high levels of resistance to carbapenems, which are considered as agents of last resort against life-threatening infections. Understanding patterns of CPE infection spreading in hospitals is paramount to design effective infection control protocols to mitigate the presence of CPE in hospitals. We used patient electronic health records from three urban hospitals to: i) track microbiologically confirmed carbapenemase producing Escherichia coli (CP-Ec) carriers and ii) trace the patients they shared place and time with until their identification. We show that yearly contact networks in each hospital consistently exhibit a core-periphery structure, highlighting the presence of a core set of wards where most carrier-contact interactions occured before being distributed to peripheral wards. We also identified functional communities of wards from the general patient movement network. The contact networks projected onto the general patient movement community structure showed a comprehensive coverage of the hospital. Our findings highlight that infections such as CP-Ec infections can reach virtually all parts of hospitals through first-level contacts.\",\n \"High throughput sequencing based detection of SARS-CoV-2 prevailing in wastewater of Pune, West India\\nGiven a large number of SARS-CoV-2 infected individuals, clinical detection has proved challenging. The wastewater-based epidemiological paradigm would cover the clinically escaped asymptomatic individuals owing to the faecal shedding of the virus. We hypothesised using wastewater as a valuable resource for analysing SARS-CoV-2 mutations circulating in the wastewater of Pune region (Maharashtra; India), one of the most affected during the covid-19 pandemic. We conducted a case study in open wastewater drains from December 2020-March 2021 to assess the presence of SARS-CoV-2 nucleic acid and further detect mutations using ARTIC protocol of MinION sequencing. The analysis revealed 108 mutations across six samples categorised into 40 types of mutations. We report the occurrence of mutations associated with B.1.617 lineage in March-2021 samples, simultaneously also reported as a Variant of Concern (VoC) responsible for the rapid increase in infections. The study also revealed four mutations; S:N801, S:C480R, NSP14:C279F and NSP3:L550del not currently reported from wastewater or clinical data in India but reported in the world. Further, a novel mutation NSP13:G206F mapping to NSP13 region was observed from wastewater. Notably, S:P1140del mutation was observed in December 2020 samples while it was reported in February 2021 from clinical data, indicating the instrumentality of wastewater data in early detection. This is the first study in India to conclude that wastewater-based epidemiology to identify mutations associated with SARS-CoV-2 virus from wastewater as an early warning indicator system.\",\n \"Using rapid (point-of-care) tests for COVID-19: A decision analysis comparing the expected benefit of two screening strategies\\nBackgroundRapid tests for COVID-19 could be used to augment the otherwise limited laboratory-based testing capacity, but there are concerns that their utility may be compromised by their limited accuracy. The objective of this article is to compare the expected benefit (EB) of two screening strategies, one with rapid tests (SwRT) and another one without rapid tests [Formula].\\n\\nMethodsWe performed a decision analysis, with the overall EB defined as the proportion of correctly identified individuals minus the proportion of incorrectly identified individuals. Accordingly, the SwRT strategy will be deemed a better screening strategy if its lesser EB for COVID-19 free individuals is more than compensated by its greater EB for COVID-19 individuals. Otherwise, it will not.\\n\\nResultsAs expected, the EB for COVID-19 individuals was greater for the SwRT strategy, with a far superior ability to rule out the presence of COVID-19. In fact, under the scenario of interest (i.e., 8000 ID Now rapid tests in addition to 28185 lab-based RT-PCR tests), it identified almost 16% more COVID-19 individuals than the [Formula] strategy. In addition, the EB for COVID-19 free individuals was the same for both strategies, with a perfect ability at ruling in the presence of COVID-19.\\n\\nConclusionThe SwRT strategy identified more COVID-19 individuals and this gain was not obtained at the detriment of COVID-19 free individuals who were equally well identified by both strategies. Hence, the SwRT strategy is a better screening strategy for COVID-19. It represents an opportunity to curtail the spread of SARS-CoV-2 that we may not afford to miss with new more contagious variants becoming more and more common in Canada.\",\n \"Correlates of COVID-19 vaccine acceptance, hesitancy and refusal among employees of a safety net California county health system with an early and aggressive vaccination program: Results from a cross-sectional survey\\nInformation on vaccine acceptance among healthcare workers is needed as health professionals provide front line care to COVID-19 patients. We developed and implemented an anonymous internet-based cross-sectional survey with direct solicitation among employees of a safety net health system. Items queried demographic and health-related characteristics, experience with and knowledge of COVID-19, and determinants of decisions to vaccinate. COVID-19 vaccine acceptance groups (acceptors, hesitant, refusers) were defined; an adapted version of the WHO vaccine hesitancy scale was included. The survey demonstrated good reliability (Cronbachs alpha = 0.92 for vaccine hesitancy scale; 0.93 for determinants). General linear and logistic regression methods examined factors which were univariately associated with vaccine hesitancy and vaccine acceptance, respectively. Multivariable models were constructed with stepwise model-building procedures. Race/ethnicity, marital status, job classification, immunocompromised status, flu vaccination and childhood vaccination opinions independently predicted hesitancy scale scores. Gender, education, job classification and BMI independently predicted acceptance, hesitancy and refusal groups. Among hesitant employees, uncertainty was reflected in reports of motivating factors influencing their indecision. Despite a strong employee-support environment and job protection, respondents reported physical and mental health effects. Appreciation of varied reasons for refusing vaccination should lead to culturally sensitive interventions to increase vaccination rates in healthcare workers.\",\n \"Revisiting the diagnostic criteria for emergence from the minimally conscious state: An empirical investigation\\nObjectiveTo determine whether consistent command-following (CCF) should be added to the diagnostic criteria for emergence from the minimally conscious state (MCS)\\n\\nDesignRetrospective cohort study\\n\\nSettingInpatient rehabilitation hospital\\n\\nParticipantsPatients with severe acquired brain injury and disorders of consciousness (DoC) admitted to a specialized rehabilitation program\\n\\nMain Outcome MeasureDifference between time to recovery of CCF and time to recovery of functional object use [FOU] or functional communication [FC] (the two existing criteria for emergence from MCS) as measured by the Coma Recovery Scale - Revised [CRS-R]).\\n\\nResultsOf 214 patients (median [interquartile range] age: 53 [34, 66] years, male: 134 (62.6%), traumatic etiology: 115 (53.7%), admission CRS-R total score: 10 [7, 13]) admitted to rehabilitation without CCF, FO, or FC, 162 (75.7%) recovered CCF and FOU or FC during the eight-week observation period. On average, recovery of CCF, FOU, and FC was observed within one day of one another, approximately 46 [38.25, 58] days post-injury. One hundred and sixteen patients (71.6%) recovered FOU or FC prior to or at the same time as CCF.\\n\\nConclusionsIn patients recovering from DoC, CCF reemerges around the same time as FOU and FC. This finding likely reflects the shared dependency of these behaviors on cognitive procecess (e.g., language comprehension, attention, motor control) that are essential for effective interpersonal interaction and social participation. Our results support the addition of CCF to the existing diagnostic criteria for emergence from MCS.\",\n \"Identifying patients at high risk of inappropriate drug dosing in periods with renal dysfunction\\nIntroductionDosing of renally cleared drugs in patients with kidney failure often deviates from clinical guidelines but little is known about what is predictive of receiving inappropriate doses.\\n\\nMethods and materialsWe combined data from the Danish National Patient Register and in-hospital data on drug administrations and estimated glomerular filtration rates for admissions between 1 October 2009 and 1 June 2016, from a pool of about 2.9 million persons. We trained artificial neural network and linear logistic ridge regression models to predict the risk of five outcomes (>0, [≥]1, [≥]2, [≥]3 and [≥]5 inappropriate doses daily) with index set 24 hours after admission. We used time-series validation for evaluating discrimination, calibration, clinical utility and explanations.\\n\\nResultsOf 52,451 admissions included, 42,250 (81%) were used for model development. The median age was 77 years; 50% of admissions were of women. [≥]5 drugs were used between admission start and index in 23,124 admissions (44%); the most common drug classes were analgesics, systemic antibacterials, diuretics, antithrombotics, and antacids. The neural network models had better discriminative power (all AUROCs between 0.77 and 0.81) and were better calibrated than their linear counterparts. The main prediction drivers were use of anti-inflammatory, antidiabetic and anti-Parkisons drugs as well as having a diagnosis of chronic kidney failure. Sex and age affected predictions but slightly.\\n\\nConclusionOur models can flag patients at high risk of receiving at least one inappropriate dose daily in a controlled in-silico setting. A prospective clinical study may confirm this holds in real-life settings and translates into benefits in hard endpoints.\",\n \"A comprehensive evaluation methodology for the publicly accessible AI services for medical diagnostics\\nOnline AI in telemedicine for radiology became widely available and valuable in the pandemic, particularly for chest CT analysis. On the other hand, the potentially harmful consequences of such services inappropriate usage cannot be neglected. Thus, a suitable methodology for quality assurance and quality control has to be established.\\n\\nA studys purpose was to develop and test an original methodology for a complex evaluation of open-access AI services in teleradiology. The approach included assessing the user experience, accessibility, safety, and diagnostic accuracy on the independent reference dataset. The methodology was applied to assess seven AI services for the detection of COVID-19 on a CT scan. A comparative analysis of this assessment is presented in this work. The analysis allowed us to draw conclusions about AI services quality and their value for different users - patients, physicians, and healthcare data scientists. The originality of the findings, timeliness, and interdisciplinary approach make this quality assurance methodology of particular interest for further application and spreading.\\n\\nHighlightsO_LIThe availability of diagnostic procedures increases each year with a corresponding increase of low-impact workload.\\nC_LIO_LIDuring pandemics, medical AI services have become valuable in reducing the workload on healthcare professionals.\\nC_LIO_LIQuality assurance for AI in healthcare requires an interdisciplinary approach - medicine, IT, and data science collaboration.\\nC_LIO_LISuggested methodology of AI quality assurance suits different target users groups, such as the general public, physicians, and data scientists.\\nC_LI\",\n \"Projecting the transition of COVID-19 burden towards the young population while vaccines are rolled out: a modelling study\\nObjectivesSARS-CoV-2 infection causes most cases of severe illness and fatality in older age groups. In China, over 99% of individuals aged [>=]12 years have been fully vaccinated against COVID-19 (albeit with vaccines developed against historical lineages), while 65.0% children aged 3-11 years have been vaccinated their first doses (as of November 12, 2021). Here, we aimed to assess whether, in this vaccination landscape, the importation of Delta variant infections could shift the COVID-19 burden from adults to children.\\n\\nMethodsWe developed an age-structured susceptible-infectious-removed model of SARS-CoV-2 transmission dynamics to simulate epidemics triggered by the importation of Delta variant infections and project the age-specific incidence of SARS-CoV-2 infections, cases, hospitalisations, intensive care unit (ICU) admissions, and deaths.\\n\\nResultsIn the context of the vaccination programme targeting individuals aged [≥]12 years (as it was the case until mid-October 2021), and in the absence of non-pharmaceutical interventions, the importation of Delta variant infections could have led to widespread transmission and substantial disease burden in mainland China, even with vaccination coverage as high as 97% across the eligible age groups. Extending the vaccination roll-out to include children aged 3-11 years (as it was the case since the end of October 2021) is estimated to dramatically decrease the burden of symptomatic infections and hospitalisations within this age group (54% and 81%, respectively, when considering a vaccination coverage of 99%), but would have a low impact on protecting infants (aged 0-2 years).\\n\\nConclusionsOur findings highlight the importance of including children among the target population and the need to strengthen vaccination efforts by increasing vaccine effectiveness.\",\n \"Face Masks, Public Policies and Slowing the Spread of COVID-19: Evidence from Canada\\nWe estimate the impact of indoor face mask mandates and other non-pharmaceutical interventions (NPI) on COVID-19 case growth in Canada. Mask mandate introduction was staggered from mid-June to mid-August 2020 in the 34 public health regions in Ontario, Canadas largest province by population. Using this variation, we find that mask mandates are associated with a 22 percent weekly reduction in new COVID-19 cases, relative to the trend in absence of mandate. Province-level data provide corroborating evidence. We control for mobility behaviour using Google geo-location data and for lagged case totals and case growth as information variables. Our analysis of additional survey data shows that mask mandates led to an increase of about 27 percentage points in self-reported mask wearing in public. Counterfactual policy simulations suggest that adopting a nationwide mask mandate in June could have reduced the total number of diagnosed COVID-19 cases in Canada by over 50,000 over the period July-November 2020. Jointly, our results indicate that mandating mask wearing in indoor public places can be a powerful policy tool to slow the spread of COVID-19.\\n\\nJEL codesI18, I12, C23\",\n \"Forecasting COVID-19 cases: A comparative analysis between Recurrent and Convolutional Neural Networks\\nWhen the entire world is waiting restlessly for a safe and effective COVID-19 vaccine that could soon become a reality, numerous countries around the globe are grappling with unprecedented surges of new COVID-19 cases. As the number of new cases is skyrocketing, pandemic fatigue and public apathy towards different intervention strategies are posing new challenges to the government officials to combat the pandemic. Henceforth, it is indispensable for the government officials to understand the future dynamics of COVID-19 flawlessly in order to develop strategic preparedness and resilient response planning. In light of the above circumstances, probable future outbreak scenarios in Brazil, Russia and the United kingdom have been sketched in this study with the help of four deep learning models: long short term memory (LSTM), gated recurrent unit (GRU), convolutional neural network (CNN) and multivariate convolutional neural network (MCNN). In our analysis, CNN algorithm has outperformed other deep learning models in terms of validation accuracy and forecasting consistency. It has been unearthed in our study that CNN can provide robust long term forecasting results in time series analysis due to its capability of essential features learning, distortion invariance and temporal dependence learning. However, the prediction accuracy of LSTM algorithm has been found to be poor as it tries to discover seasonality and periodic intervals from any time series dataset, which were absent in our studied countries. Our study has highlighted the promising validation of using convolutional neural networks instead of recurrent neural networks when it comes to forecasting with very few features and less amount of historical data.\",\n \"Professionals' views on the mental health problems and vulnerability of children and young people during the early phase of the COVID-19 pandemic\\nThe COVID-19 pandemic caused major disruptions to everyday life for children and young people. The aim of this study was to examine professionals views on the mental health problems and vulnerabilities of children and young people during the early phase of the COVID-19 pandemic. We conducted a secondary analysis of an online survey completed by mental health professionals in the UK between 22 April 2020 and 12 May 2020. The final sample was N = 601 professionals who at least partly worked with children and young people. Quantitative and qualitative survey data showed that professionals were concerned about young people experiencing economic disadvantage and young people from minority ethnic groups, as pre-existing social inequalities resulted in increased risk of infection and reduced access to physical and mental health care. Professionals were concerned about young people with little family support and young people at risk of relapse or deterioration in mental health, reporting the exacerbation of pre-existing mental health difficulties and challenging behaviours. Further research, involving young people as researchers, is needed to explore the continued impact for children and young people, and their families, including in comparison to their experiences before the pandemic.\",\n \"metaCOVID: An R-Shiny application for living meta-analyses of COVID-19 trials\\n\\\"Living\\\" evidence synthesis is of primary interest for decision-makers to overcome the COVID-19 pandemic. The COVID-NMA provides open-access living meta-analyses assessing different therapeutic and preventive interventions. Data are posted on a platform (https://covid-nma.com/) and analyses are updated every week. However, guideline developers and other stakeholders also need to investigate the data and perform their own analyses. This requires resources, time, statistical expertise, and software knowledge. To assist them, we created the \\\"metaCOVID\\\" application which, based on automation processes, facilitates the fast exploration of the data and the conduct of analyses tailored to end-users needs. metaCOVID has been created in R and is freely available as an R-Shiny application. The application conducts living meta-analyses for every outcome. Several options are available for subgroup and sensitivity analyses. The results are presented in downloadable forest plots. metaCOVID is freely available from https://covid-nma.com/metacovid/ and the source code from https://github.com/TEvrenoglou/metaCovid.\",\n \"Predicting vaccine hesitancy from area-level indicators: A machine learning approach\\nVaccine hesitancy (VH) might represent a serious threat to the next COVID-19 mass immunization campaign. We use machine-learning algorithms to predict communities at a high risk of VH relying on area-level indicators easily available to policymakers. We illustrate our approach on data from child immunization campaigns for seven non-mandatory vaccines carried out in 6408 Italian municipalities in 2016. A battery of machine learning models is compared in terms of area under the Receiver Operating Characteristics (ROC) curve. We find that the Random Forest algorithm best predicts areas with a high risk of VH improving the unpredictable baseline level by 24% in terms of accuracy. Among the area-level indicators, the proportion of waste recycling and the employment rate are found to be the most powerful predictors of high VH. This can support policy makers to target area-level provaccine awareness campaigns.\",\n \"Occupational exposures and mitigation strategies among homeless shelter workers at risk of COVID-19\\nObjectiveTo describe the work environment and COVID-19 mitigation measures for homeless shelter workers and assess occupational risk factors for COVID-19 infection\\n\\nMethodsBetween June 9-August 10, 2020, we conducted a self-administered survey among homeless shelter workers in Washington, Massachusetts, Utah, Maryland, and Georgia. We calculated frequencies for work environment, personal protective equipment use, and SARS-CoV-2 testing history. We used generalized linear models to produce unadjusted prevalence ratios (PR) to assess risk factors for SARS-CoV-2 infection.\\n\\nResultsOf the 106 respondents, 43.4% reported frequent close contact with clients; 75% were worried about work-related SARS-CoV-2 infections; 15% reported testing positive. Close contact with clients was associated with testing positive for SARS-CoV-2 (PR 3.97, 95%CI 1.06, 14.93).\\n\\nConclusionsHomeless shelter workers may be at higher risk of being infected with SARS-CoV-2 during the course of their work. Protecting these critical essential workers by implementing mitigation measures and prioritizing for COVID-19 vaccination, is imperative during the pandemic.\",\n \"Coronavirus GenBrowser for monitoring the transmission and evolution of SARS-CoV-2\\nGenomic epidemiology is important to study the COVID-19 pandemic and more than two million SARS-CoV-2 genomic sequences were deposited into public databases. However, the exponential increase of sequences invokes unprecedented bioinformatic challenges. Here, we present the Coronavirus GenBrowser (CGB) based on a highly efficient analysis framework and a movie maker strategy. In total, 1,002,739 high quality genomic sequences with the transmission-related metadata were analyzed and visualized. The size of the core data file is only 12.20 MB, efficient for clean data sharing. Quick visualization modules and rich interactive operations are provided to explore the annotated SARS-CoV-2 evolutionary tree. CGB binary nomenclature is proposed to name each internal lineage. The pre-analyzed data can be filtered out according to the user-defined criteria to explore the transmission of SARS-CoV-2. Different evolutionary analyses can also be easily performed, such as the detection of accelerated evolution and on-going positive selection. Moreover, the 75 genomic spots conserved in SARS-CoV-2 but non-conserved in other coronaviruses were identified, which may indicate the functional elements specifically important for SARS-CoV-2. The CGB not only enables users who have no programming skills to analyze millions of genomic sequences, but also offers a panoramic vision of the transmission and evolution of SARS-CoV-2.\",\n \"Effectiveness of the EPA-based 'Toolbox Family Medicine' on students' learning satisfaction: study protocol for a controlled trial\\nBackgroundFamily practices constitute an important learning environment for medical students. However, teaching situations markedly vary between practices, and students frequently find rotations underwhelming. Especially, students active participation in patient care varies profoundly, although it has a significant impact on students interest in primary care careers. To standardize and improve learning situations in practices, we developed the so-called Toolbox Family Medicine (TFM) using the concept of entrustable professional activities. It provides standardized learning content appropriate for students levels and allows teaching adaptable to actual practice conditions.\\n\\nMethodsUsing a controlled trial with a waiting list control arm, we will evaluate the effectiveness of the toolbox on students learning satisfaction. A total of 94 students will be allocated 1:1 to intervention and control practices. The teaching concept Toolbox Family Medicine (TFM) comprises a didactic workshop for supervising physicians and a toolbox with practice-specific tasks for medical students. The primary outcome is students overall satisfaction with their learning progress after the rotation. Secondary outcomes include the kind and number of tasks performed, the entrusted level per task, the feasibility of implementing the toolbox in actual practice settings, and students motivation to pursue a career in primary care.\\n\\nDiscussionWe assume an improvement in learning satisfaction with the intervention. The study will begin with the next practice rotations.\\n\\nAdministrative information\\n\\nO_TBL View this table:\\norg.highwire.dtl.DTLVardef@1854ffborg.highwire.dtl.DTLVardef@1460a5eorg.highwire.dtl.DTLVardef@152d543org.highwire.dtl.DTLVardef@12f4f85org.highwire.dtl.DTLVardef@10dcc59_HPS_FORMAT_FIGEXP M_TBL C_TBL\",\n \"Syncope and COVID-19 disease - a systematic review.\\nBackgroundSyncope is not a common manifestation of COVID-19, but it may occur in this context and it can be the presenting symptom in some cases. Although several mechanisms may explain the pathophysiology behind COVID-19 related syncope, a valid relationship has not been established yet. In this systematic review, we aimed to examine the current incidence of syncope in COVID-19 patients and to explore different patterns observed in this setting.\\n\\nMethodsA systematic review across PubMed, ISI Web of Knowledge and SCOPUS was performed, according to PRISMA guidelines, in order to identify all relevant articles regarding both COVID-19 and syncope.\\n\\nResultsWe identified 81 publications, of which 62 were excluded. The cumulative incidence of syncope and pre-syncope across the selected studies was 7.1% (256/3584 patients). Unspecified syncope was the most common type (76.2% of the reported episodes), followed by reflex syncope (18.1% of the cases). Orthostatic hypotension was responsible for 3.6% of the cases and syncope of presumable cardiac cause accounted for 2.0%. Arterial hypertension was present in 64.7% of the patients and either angiotensin receptor blockers or angiotensin converting enzyme inhibitors were used by 39.5% of hypertensive patients with syncope.\\n\\nConclusionSyncope, although not considered a typical symptom of the COVID-19 disease, can be associated with it, particularly in early stages. Different types of syncope were seen in this context, each with different implications requiring distinct approaches. A careful reevaluation of blood pressure whenever a patient develops COVID-19 is suggested, including reassessment of antihypertensive therapy.\",\n \"Development and validation of a length- and habitus-based method of total body weight estimation for critically ill adults requiring urgent weight-based medical intervention\\nBackgroundErroneous weight estimation during the management of emergency presentations in adults may contribute to patient harm and poor outcomes. Patients can often not be weighed during emergencies and a weight estimation is required to facilitate weight-based therapies. Many existing methods of weight estimation are either unacceptably inaccurate or very difficult to use during the provision of emergency care.\\n\\nMethodsThe weight estimation system developed in this study was based on and modified from the PAWPER XL-MAC method, a paediatric weight estimation system that uses recumbent length and mid-arm circumference (MAC) to predict total body weight. This model was validated in the 2015 - 2018 National Health and Nutrition Examination Survey (NHANES) datasets. The primary outcome measure was to achieve >95% of estimations within 20% of measured weight (P20>95%).\\n\\nResultsThe modified PAWPER XL-MAC model achieved a P20 of 96.0% and a P10 of 71.3% in the validation dataset (N=11520). This accuracy (P20>95%) was maintained in both sexes, all ages, all ethnic groups, all lengths and in all habitus-types, except for the subgroup of severely obese individuals.\\n\\nConclusionsThe modified PAWPER XL-MAC model proved to be a very accurate method of weight estimation. It is more accurate than most other published reports of existing methods of weight estimation, except for patients own estimations. It therefore could have a role in facilitating emergency drug dose calculations, if prospective studies bear out the accuracy found in this study.\",\n \"PBPK-led guidance for cystic fibrosis patients taking elexacaftor-tezacaftor-ivacaftor with nirmatrelvir-ritonavir for the treatment of COVID-19\\nBackgroundCystic fibrosis transmembrane conductance regulator (CFTR) modulating therapies including elexacaftor, tezacaftor, and ivacaftor (ETI) are primarily eliminated through cytochrome P450 (CYP) 3A-mediated metabolism. This creates a therapeutic challenge to the treatment of COVID-19 with nirmatrelvir-ritonavir in people with cystic fibrosis (pwCF) due to the potential for significant drug-drug interactions (DDI). However, pwCF are more at risk of serious illness following COVID-19 infection and hence it is important to manage the DDI risk and provide treatment options.\\n\\nMethodsCYP3A-mediated DDI of ETI was evaluated using a physiologically based pharmacokinetic (PBPK) modeling approach. Modeling was performed incorporating physiological information and drug dependent parameters of ETI to predict the effect of ritonavir (the CYP3A4 inhibiting component of the combination) on pharmacokinetics of ETI. The ETI models were verified using independent clinical pharmacokinetic and DDI data of ETI with a range of CYP3A modulators.\\n\\nResultsWhen ritonavir was administered on day 1 through 5, the predicted AUC ratio of ivacaftor (the most sensitive CYP3A substrate) on day 6 was 9.31, indicating that its metabolism was strongly inhibited. Based on the predicted DDI, the dose of ETI should be reduced when co-administered with nirmatrelvir-ritonavir to elexacaftor 200mg-tezacaftor 100mg-ivacaftor 150mg on days 1 and 5, with resumption of full dose ETI on day 9, considering the residual inhibitory effect of ritonavir as a mechanism-based inhibitor.\\n\\nConclusionsCoadministration of nirmatrelvir-ritonavir requires a significant reduction in the ETI dosing frequency with delayed resumption of full dose due to the mechanism-based inhibition with ritonavir.\",\n \"Leaders gender and the fight against COVID-19: investigation, replication, and a possible explanation\\nObjectivesTo investigate the alleged relationship between leaders gender and COVID-19 related cases and deaths in different countries across the globe.\\n\\nStudy designThe relationship between leaders gender and percent of women in parliament to COVID-19 cases and death per million was investigated in three time points (10 months) across 180 countries, controlling for possible covariates.\\n\\nMethodsThree different types of analyses were run: (1) Six basic t-tests; (2) Two repeated-measure ANOVA tests analyzing change over time; (3) Six stepwise regression analyses for both leaders gender and the percentage of women in parliament.\\n\\nResultsOur findings suggest that, contrary to some research and popular media headlines, and in-line with recent academic research, leadership gender is not a significant factor in explaining the variation between countries in the fight against the COVID-19 pandemic.\\n\\nConclusionsWe suggest that this alleged relationship may stem from an illusory correlation. We argue that the uncertainty, stress, and anxiety that prevail in these times of global pandemic may be the breeding ground for judgmental biases of this sort.\",\n \"Change in Symptoms and Immune Response in People with Post-Acute Sequelae of SARS-Cov-2 Infection (PASC) After SARS-Cov-2 Vaccination\\nAs more people are vaccinated against SARS-CoV-2, many of those already infected are still suffering from Post-Acute Sequelae (PASC). Although there is no current treatment for PASC, reports from patients that the vaccine itself improves, and in some reports, worsens, PASC symptoms may lead to a deeper understanding of the causes of PASC symptoms and viable treatments. As such, we are conducting a study that measures the changes in PASC symptoms after vaccination. We are collecting baseline self-report and biospecimens for immune assays and then are following up with participants to collect the same data at 2-weeks, 6-weeks, and 12-weeks post-vaccination (first dose). Immune assays using blood specimens will include B-cell, T-cell, and myeloid cell panels; evaluation of T-cell responsiveness to SARS-CoV-2 peptides and antigen specific response; autoantibody screening (of IgG, IgM, and IgA antibodies that attack human proteins); and TCR sequencing and antigen mapping of CD8+ T-cells. Mucosal immunity will be measured using saliva specimens. The study aims to provide answers for people with PASC, especially regarding the causes of their symptoms and how the vaccine may affect them, and clues for PASC treatment.\",\n \"Impact of the World Inflammatory Bowel Disease Day and Crohn's & Colitis Awareness Week on Population Interest between 2016 and 2020: Google Trends Analysis\\nBackgroundMore than 6 million people are affected by inflammatory bowel disease (IBD) globally. World IBD Day (WID; May 19) and Crohns and Colitis Awareness Week (CCAW; December 1-7) occur yearly as national health observances to raise public awareness of IBD, but their effects are unclear.\\n\\nMethodsThis study evaluates the impact of WID and CCAW on the public awareness of IBD in the United States (US) and worldwide from 2016 to 2020 using the relative search volume (RSV) of \\\"IBD,\\\" \\\"Ulcerative colitis,\\\" and \\\"Crohns disease\\\" in Google Trends (GT). To identify significant timepoints of trend changes (joinpoints), we performed Joinpoint regression analysis.\\n\\nResultsNo joinpoints were noted around the time of WID or CCAW during the study period in the search results of the US. Worldwide, joinpoints were noted around WID in 2020 with the search for \\\"IBD\\\" and around CAAW in 2017 and 2019 to search for \\\"ulcerative colitis.\\\" However, the extents of trend changes were modest without statistically significant increases.\\n\\nConclusionsWID and CCAD may not have worked as expected to raise public awareness of IBD. Additional measures are necessary to help raise awareness of IBD related to the health observances.\\n\\nSummaryWorld IBD Day and Crohns and Colitis Awareness Week are key health observances related to IBD. These observances, however, might not have been effective in raising public awareness of IBD in the US and worldwide, according to Google Trends analysis.\",\n \"Diminished neutralization responses towards SARS-CoV-2 Omicron VoC after mRNA or vector-based COVID-19 vaccinations\\nSARS-CoV-2 variants accumulating immune escape mutations provide a significant risk to vaccine-induced protection. The novel variant of concern (VoC) Omicron (B.1.1.529) has the largest number of amino acid alterations in its Spike protein to date. Thus, it may efficiently escape recognition by neutralizing antibodies, allowing breakthrough infections in convalescent and vaccinated individuals. We analyzed neutralization activity of sera from individuals after vaccination with all mRNA-, vector- or heterologous immunization schemes currently available in Europe by in vitro neutralization assay at peak response towards SARS-CoV-2 B.1, Omicron, Beta and Delta pseudotypes and also provide longitudinal follow-up data from BNT162b2 vaccinees. All vaccines apart from Ad26.CoV2.S showed high levels of responder rates (93-100%) towards SARS-CoV-2 wild-type, but some reductions in neutralizing Beta and Delta VoC pseudotypes. The novel Omicron variant had the biggest impact, both in terms of response rates and neutralization titers. Only mRNA-1273 showed a 100% response rate to Omicron and induced the highest level of neutralizing antibody titers, followed by heterologous prime-boost approaches. Homologous BNT162b2 vaccination or vector-based AZD1222 or Ad26.CoV2.S performed less well with peak responder rates of 33%, 50% and 9%, respectively. However, Omicron responder rates in BNT162b2 recipients were maintained in our six month longitudinal follow-up indicating that individuals with cross-protection against Omicron maintain it over time. Overall, our data strongly argues for urgent booster doses in individuals who were previously vaccinated with BNT162b2, or a vector-based immunization scheme.\",\n \"Impulse dispersion of aerosols during playing wind instruments\\nMusical activities especially singing and playing wind instruments have been singled out as potentially high-risk activities for transmission of SARS CoV-2, because of a higher rate of aerosol production and emission. Playing wind instruments can produce condensation water, droplets of saliva, and aerosol particles, which hover and convectional spread in the environmental air and can be potentially infectious.\\n\\nThe aim of this study is to investigate the primary impulse dispersion of aerosols during playing different wind instruments in comparison to breathing and speaking. Nine professional musicians (3 trumpeters, 3 cross flutists and 3 clarinetists) of the Bavarian Symphony Orchestra performed the main theme of Ludwig van Beethoven s 9th symphony, 4th movement in different pitches and loudness. Thereby, the inhaled air volume was marked with small aerosol particles produced with a commercial e-cigarette. The expelled aerosol cloud was recorded by cameras from different perspectives. Afterwards, the dimensions and dynamics of the aerosol cloud was measured by segmenting the video footage at every time point.\\n\\nOverall, the cross flutes produced the largest dispersion at the end of task of up to maximum distances of 1.88 m in front direction. Thereby it was observed an expulsion of aerosol in different directions: upwards and downwards at the mouthpiece, at the end of the instrument and along the cross flute at the key plane. In comparison, the maximum impulse dispersion generated by the trumpets and clarinets were lower in frontal and lateral direction (1.2 m and 1.0 m in front-direction). The expulsion to the sides was also lower. Consequently, a distance of 3 m to the front and to the sides of 2 m for the cross flutes in an orchestral formation is proposed, for trumpets and clarinets a safety distance of 2 m to the front and 1.5 m between instrumentalists are recommendable.\",\n \"Brain connectivity and motor improvements after ballet intervention in multiple sclerosis: pilot\\nBackground and PurposeA pilot study to determine feasibility of detecting changes in structural connectivity (SC) and resting-state functional connectivity (RSFC) occur alongside motor improvements after participation in the Targeted Ballet Program (TBP) in adults with relapsing-remitting multiple sclerosis (RRMS).\\n\\nMethodsFive participants (four female) with RRMS between the ages of 38-64 with the following characteristics at baseline: Expanded Disability Status Scale 2.0-6.0, International Cooperative Ataxia Rating Scale (ICARS) > 7, Symbol-Digit Modality Test > 22, and no relapses or initiation of medications indicated to affect mobility within the past 30 days. Participants were asked to complete 12 weeks (one hour, twice per week) of the TBP. Magnetic resonance imaging data was collected pre- and post-intervention for SC and RSFC network analysis.\\n\\nResultsIncreases in two RRMS-related graph theoretical measures (mean strength and mean clustering coefficient) for RSFC (p < 0.05) are detectable alongside significant reduction in ataxia (ICARS: p = 0.01012, Smoothness Index: p = 0.04995), and increase in balance (Mini-BESTest: p = 0.01474) following participation in the well-tolerated TBP.\\n\\nDiscussion and ConclusionsSignificant increases in mean strength and mean clustering coefficient of RSFC suggest functional neurological improvements after participation in the TBP. The relationship between these network changes and clinical improvements in balance and amelioration of ataxia after participation in the TBP requires a larger randomized-controlled clinical trial of the TBP in persons with RRMS.\",\n \"Preserved T cell responses to SARS-CoV-2 in anti-CD20 treated multiple sclerosis.\\nObjectiveTo analyze humoral and cellular immune responses to SARS-CoV-2 vaccinations and infections in anti-CD20 treated patients with multiple sclerosis (pwMS).\\n\\nMethods181 pwMS on anti-CD20 therapy and 41 pwMS who began anti-CD20 therapy were included in a prospective, observational, single-center cohort study between March 2020 and August 2021. 51 pwMS under anti-CD20 treatment, 14 anti-CD20 therapy-naive pwMS and 19 healthy controls (HC) were vaccinated twice against SARS-CoV-2. We measured SARS-CoV-2 spike protein (full-length, S1 domain and receptor binding domain) immunoglobulin (Ig)G and S1 IgA and virus neutralizing capacity and avidity of SARS-CoV-2 antibodies. SARS-CoV-2 specific T cells were determined by interferon-{gamma} release assays.\\n\\nResultsFollowing two SARS-CoV-2 vaccinations, levels of IgG and IgA antibodies to SARS-CoV-2 spike protein as well as neutralizing capacity and avidity of SARS-CoV-2 IgG were lower in anti-CD20 treated pwMS than in anti-CD20 therapy-naive pwMS and in HC (p<0.003 for all pairwise comparisons). However, in all anti-CD20 treated pwMS vaccinated twice (n=26) or infected with SARS-CoV-2 (n=2), in whom SARS-CoV-2 specific T cells could be measured, SARS-CoV-2 specific T cells were detectable, at levels similar to those of twice-vaccinated anti-CD20 therapy-naive pwMS (n=7) and HC (n=19). SARS-CoV-2 S1 IgG levels (r=0.42, p=0.002), antibody avidity (r=0.7, p<0.001) and neutralizing capacity (r=0.44, p=0.03) increased with time between anti-CD20 infusion and second vaccination. Based on detection of SARS-CoV-2 antibodies, SARS-CoV-2 infections occurred in 4/175 (2.3%) anti-CD20 treated pwMS, all of whom recovered fully.\\n\\nInterpretationThese findings should inform treatment decisions and SARS-CoV-2 vaccination management in pwMS.\",\n \"Clustering ICU patients with sepsis based on the patterns of their circulating biomarkers: a secondary analysis of the CAPTAIN prospective multicenter cohort study.\\nBackgroundAlthough sepsis is a life-threatening condition, its heterogeneous presentation likely explains the negative results of most trials on adjunctive therapy. This study in patients with sepsis aimed to identify subgroups with similar immune profiles and their clinical and outcome correlates.\\n\\nMethodsA secondary analysis used data of a prospective multicenter cohort that included patients with early assessment of sepsis. They were described using Predisposition, Insult, Response, Organ failure sepsis (PIRO) staging system. Thirty-eight circulating biomarkers (27 proteins, 11 mRNAs) were assessed at sepsis diagnosis, and their patterns were determined through principal component analysis (PCA). Hierarchical clustering was used to group the patients and k-means algorithm was applied to assess the internal validity of the clusters.\\n\\nResultsTwo hundred and three patients were assessed, of median age 64.5 [52.0-77.0] years and SAPS2 score 55 [49-61] points. Five main patterns of biomarkers and six clusters of patients (including 42%, 21%, 17%, 9%, 5% and 5% of the patients) were evidenced. Clusters were distinguished according to the certainty of the causal infection, inflammation, use of organ support, pro- and anti-inflammatory activity, and adaptive profile markers.\\n\\nConclusionsIn this cohort of patients with suspected sepsis, we individualized clusters which may be described with criteria used to stage sepsis. As these clusters are based on the patterns of circulating biomarkers, whether they might help to predict treatment responsiveness should be addressed in further studies.\\n\\nTrial registrationThe CAPTAIN study was registered on clinicaltrials.gov on June 22, 2011, # NCT01378169.\",\n \"Validation of a Novel IoT and AI based Point-of-Care Testing Laboratory: Analytical Accuracy and Clinical Agreement\\nPoint-of-care testing (POCT) offers several advantages over traditional laboratory testing. Offering less invasive testing with a faster turnaround time is not enough if not associated with an acceptable level of accuracy. Here, we show the analytical validation behind the multi-analyte POCT immunochromatography analyser, Hilab Flow (HiF). Analyses from 4,518 clinical samples were compared to College of American Pathologists accredited laboratories for ten quantitative and thirteen qualitative exams. Compatibility between methods was evaluated in terms of association/correlation and clinical agreement. Strong correlation/ concordance was observed between quantitative (CHOL, HDL-c, TG, HbA1c, Glycemia, 25-Hydroxy Vitamin D, TSH, Uric Acid, Creatinine, Urea) and qualitative methods (COVID-19 IgG/ IgM, Beta-hCG, Syphilis, Anti-HBsAg, Zika IgG/ IgM, Influenza A/B, HIV, HCV, HBsAg, Dengue NS1, COVID-19 Ag, Dengue IgG/ IgM, PSA). Approval criteria was obtaining a kappa agreement > 0.8 or a Pearson correlation > 0.9 depending on the exam. Overall percentage agreement was greater than 95% for all exams, indicating a good clinical agreement to gold-standard laboratory-based tests. Results indicate all exams are suitable for POCT and present a reliable performance. Data support the analyser is a useful tool to aid decision-making at the clinical setting, with potential to contribute with healthcare solutions in diagnostic medicine worldwide.\",\n \"Using conditional inference to quantify interaction effects of socio-demographic covariates of US COVID-19 vaccine hesitancy\\nCOVID-19 vaccine hesitancy has become a major issue in the U.S. as vaccine supply has outstripped demand and vaccination rates slow down. At least one recent global survey has sought to study the covariates of vaccine acceptance, but an inferential model that makes simultaneous use of several socio-demographic variables has been lacking. In this article, we present such a model using US-based survey data collected by Gallup. Our study agrees with the global survey results in some respects, but is also found to exhibit significant differences. For example, women and people aged between 25-54 were found to be more vaccine hesitant. Our conditional inference tree model suggests that trust in government, age and ethnicity are the most important covariates for predicting vaccine hesitancy, and can interact in ways that make them useful for communication-based outreach, especially if conjoined with census data. In particular, we found that the most vaccine hesitant individuals were those who identified as Black Republicans with a high school (or lower) education and lower income levels, who were involuntarily unemployed and trusted in the Trump administration.\",\n \"Decreased Immune Response to COVID-19 mRNA Vaccine in Patients with Inflammatory Bowel Diseases Treated with Anti TNFα\\nBackgroundPatients with inflammatory bowel diseases (IBD), specifically those treated with anti-tumor necrosis factor (TNF) biologics are at high risk for vaccine preventable infections. Their ability to mount adequate vaccine responses is unclear.\\n\\nAimto assess immune responses to mRNA-COVID-19 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared to healthy controls (HC).\\n\\nMethodsProspective, controlled, multi-center Israeli study. Subjects enrolled received two BNT162b2 (Pfizer/BioNTech) doses. Anti-spike (S) antibodies levels and functional activity, anti-TNF levels and adverse events (AEs) were detected longitudinaly.\\n\\nResultsOverall 258 subjects: 185 IBD (67 treated with anti-TNF), and 73 HC. After the first vaccine dose all HC were seropositive, while some patients with IBD, regardless of treatment, remained seronegative. After the second dose all subjects were seropositive, however anti-S levels were significantly lower in anti-TNF treated compared to untreated patients, and HC (p<0.001; p<0.001, respectively). Neutralizing and inhibitory functions were both lower in anti-TNF treated compared to untreated patients, and HC (p<0.03; p<0.0001, respectively). Anti-TNF drug levels and vaccine responses did not affect anti-S levels. Infection rate ([~]2%) and AEs were comparable in all groups. IBD activity did not change in response to BNT162b2.\\n\\nConclusionsIn this prospective study in patients with IBD stratified according to treatment all patients mounted an immune response to two doses of BNT162b2. However, its magnitude was significantly lower in patients treated with anti-TNF, regardless of administration timing and drug levels. Vaccine was safe. As vaccine immune response longevity in this group may be limited, vaccine booster dose should be considered.\",\n \"Quarantine, relaxation and mutation explaining the CoViD-19 epidemic in Sao Paulo State (Brazil)\\nBackgroundThe continuous SARS-CoV-2 transmission in several countries could contribute to the mutations appearance. The circulation of more virulent variants may increase the number of severe CoViD-19 needing hospital care and fatalities hugely.\\n\\nMethodsThe partial quarantine in Sao Paulo State and further relaxation associated with the mutations are explained by a mathematical model based on the CoViD-19 natural history encompassing the age-dependent fatality. The model parameters were fitted considering the observed data from Sao Paulo State.\\n\\nResultsThe partial quarantine was explained by the less virulent SARS-CoV-2 transmission, but the relaxation alone could not explain the epidemic observed in Sao Paulo State. However, more virulent variants plus the transmission among isolated individuals explained the increased CoViD-19 fatalities.\\n\\nConclusionsThe model described the CoViD-19 epidemic in Sao Paulo State by considering the partial quarantine, relaxation and mutations. The model provided a potential epidemiological scenario in the absence of mass vaccination.\",\n \"Gender differences in housework and childcare among Japanese workers during the COVID-19 pandemic.\\nObjectivesAlthough gender stereotypes regarding paid work and unpaid work are changing, most wives are responsible for taking care of the family and home in Japan. It is unclear how time spent on housework and childcare has changed between working men and women during the COVID-19 pandemic in Japan. The purpose of this study is to investigate how working men and womens responsibilities for housework and childcare changed during the COVID-19 pandemic in Japan depending on occupation, job type, and the number of employees in the workplace.\\n\\nMethodsA cross-sectional analysis (N=14,454) was conducted using data from an internet monitoring study (CORoNa Work Project), which was conducted in December 2020. A multilevel logistic model with nested prefectures of residence was conducted to estimate the odds ratio (OR) for change in time devoted to housework and childcare among men and women adjusting for age, household income, frequency of telecommuting, presence of spouse who work, occupation, job type, the number of employees in the workplace, and the incidence rate of COVID-19 by prefecture.\\n\\nResultsRegardless of occupation related factors, more women than men reported increased time spent on housework and childcare. Furthermore, women were significantly more likely to experience an increase in time spent on those activities than men (housework: OR 1.97, 95% CI [1.75, 2.21], p < 0.001; childcare: OR 1.66, 95% CI [1.37, 2.02], p < 0.001).\\n\\nConclusionsThe time spent by women on housework and childcare increased significantly compared to men during the COVID-19 pandemic in Japan.\",\n \"Development and validation of a modified Cambridge Multimorbidity Score for use with internationally recognized electronic health record clinical terms (SNOMED CT)\\nBackgroundPeople with multiple health conditions are more likely to have poorer health outcomes and greater care and service needs; a reliable measure of multimorbidity would inform management strategies and resource allocation. This study aims to develop and validate a modified version of the Cambridge Multimorbidity Score in an extended age range, using clinical terms which are routinely used in electronic health records across the world (SNOMED CT).\\n\\nMethods and FindingsWe curated new variables describing 37 health conditions and modelled the associations between these and 1-year mortality risk using the Cox proportional hazard model in a development dataset (n=300,000). We then developed two simplified models - a 20-condition model as per the original Cambridge Multimorbidity Score, and a variable reduction model using backward elimination with Akaike information criterion as the stopping criterion. The results were compared and validated for 1-year mortality in a synchronous validation dataset (n=150,000), and for 1-year and 5-year mortality in an asynchronous validation dataset (n=150,000).\\n\\nOur final variable reduction model retained 21 conditions, and the conditions mostly overlapped with those in the 20-condition model. The model performed similarly to the 37- and 20-condition models, showing high discrimination and good calibration following recalibration.\\n\\nConclusionsThis modified version of the Cambridge Multimorbidity Score allows reliable estimation using clinical terms which can be applied internationally across multiple healthcare settings.\",\n \"The rapid reemergence of seasonal respiratory viruses in Houston, Texas, after relaxing COVID-19 restrictions\\nBrief abstractImplementation of measures to limit the spread of the SARS-CoV-2 virus at the start of the COVID-19 pandemic resulted in a rapid decrease in all other respiratory pathogens. As COVID-19 containment measures were relaxed, the first non-COVID respiratory viruses to return to prepandemic levels were members of the rhinovirus/enterovirus, followed by the rapid return of seasonal coronaviruses, parainfluenza, and respiratory syncytial virus after the complete removal of COVID-19 precautions at the state level, including an end to mask mandates. Inasmuch as COVID-19 has dominated the landscape of respiratory infections since early 2020, it is important for clinicians to recognize the return of non-COVID respiratory pathogens may be rapid and significant when COVID-19 containment measures are removed.\",\n \"Deep-sequence phylogenetics to quantify patterns of HIV transmission in the context of a universal testing and treatment trial -- BCPP/ Ya Tsie trial\\nMathematical models predict that community-wide access to HIV testing-and-treatment can rapidly and substantially reduce new HIV infections. Yet several large universal test-and-treat HIV prevention trials in high-prevalence epidemics demonstrated variable reduction in population-level incidence. To elucidate patterns of HIV spread in universal test-and-treat trials we quantified the contribution of geographic-location, gender, age and randomized-HIV- intervention to HIV transmissions in the 30-community Ya Tsie trial in Botswana (estimated trial population: 175,664). Deep-sequence phylogenetic analysis revealed that most inferred HIV transmissions within the trial occurred within the same or between neighboring communities, and between similarly-aged partners. Transmissions into intervention communities from control communities were more common than the reverse post-baseline (30% [12.2 - 56.7] versus 3% [0.1 - 27.3]) than at baseline (7% [1.5 - 25.3] versus 5% [0.9 - 22.9]) compatible with a benefit from treatment-as-prevention. Our findings suggest that population mobility patterns are fundamental to HIV transmission dynamics and to the impact of HIV control strategies.\",\n \"Preexisting diabetes and COVID-associated hyperglycaemia in patients with COVID-19 pneumonia\\nAO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSAimC_ST_ABSThe aim of the current study was to compare clinical characteristics, laboratory findings and major outcomes of patients hospitalized for COVID-19 pneumonia with COVID-associated hyperglycaemia or preexisting diabetes.\\n\\nMethodsA cohort of 176 adult patients with a diagnosis of pre-existing diabetes (n=112) or COVID-associated hyperglycaemia (n=55) was studied. Clinical outcomes and laboratory findings were analysed according to the presence of the two conditions. The time to viral clearance was assessed during the follow-up after hospital discharge.\\n\\nResultPatients with COVID-associated hyperglycaemia had lower BMI, significantly less comorbidities and higher levels of inflammatory markers and indicators of multi-organ injury than those with preexisting diabetes. No differences between preexisting diabetes and COVID-associated hyperglycaemia were evident for symptoms at admission, humoral response against SARS-CoV-2 or autoantibodies to glutamic acid decarboxylase or interferon alpha-4. COVID-associated hyperglycaemia was independently associated with the risk of adverse clinical outcome defined as ICU admission or death (HR 2.11, 95% CI 1.34-3.31; p=0.001), even after adjustment for age, sex and other selected variables associated with COVID-19 severity. Furthermore, we documented a negative association (HR 0.661, 95% CI 0.43-1.02; p=0.063) between COVID-associated hyperglycaemia and the time to swab negativization.\\n\\nConclusionsThe recognition of hyperglycaemia as a specific clinical entity associated with COVID-19 pneumonia is relevant for early and appropriate patient management and close monitoring for the progression of disease severity.\",\n \"Up-regulated tumor intrinsic growth potential and decreased immune function orchestrate the evolution of lung adenocarcinoma\\nIntroductionLung adenocarcinoma is the most common pathological subtype of lung cancer. Precursors of lung adenocarcinoma, namely adenocarcinoma in situ and minimally invasive adenocarcinoma, have a superb 5-year survival rate after surgical resection. A deeper understanding of the key genetic changes driving the progression of lung adenocarcinoma is needed.\\n\\nMethodsIn this study, we performed whole-exome sequencing and RNA-sequencing on surgically resected 24 AIS, 74 MIA, 99 LUAD specimens and their adjacent paired normal tissues. Radiological, clinical, and pathological characteristics were recorded. Gene expression patterns were identified to find key pathways driving the progression of lung adenocarcinoma. Furthermore, genomic alterations and differential expression analyses were performed to compare tumors with different radiological manifestations. Finally, a progressive index was developed to quantitatively measure the level of imbalance between tumor intrinsic growth potential and immune microenvironment.\\n\\nResults12 patterns of gene expression were identified. Pathways associated with tumor growth and metastasis were found to be up-regulated as tumors progressed, while pathways associated with immune function were found to be down-regulated. Deconvolution of RNA-seq data also showed a decrease of CD8+ T cells and an increase of Tregs as the tumors progressed. Furthermore, tumors with more solid components on CT scan had a higher mutation frequency of tumor suppressor genes, higher tumor mutation burden and higher frequency of somatic copy number alterations. Finally, tumor progressive index demonstrated an increasing trend with the progression of lung adenocarcinoma.\\n\\nDiscussionOur results reveal the imbalance of tumor intrinsic factors and immune function orchestrate the progression of lung adenocarcinoma.\",\n \"Geographically-targeted COVID-19 vaccination is more equitable and averts more deaths than age-based thresholds alone\\nCOVID-19 mortality increases dramatically with age and is also substantially higher among Black, Indigenous, and People of Color (BIPOC) populations in the United States. These two facts introduce tradeoffs because BIPOC populations are younger than white populations. In analyses of California and Minnesota--demographically divergent states--we show that COVID vaccination schedules based solely on age benefit the older white populations at the expense of younger BIPOC populations with higher risk of death from COVID-19. We find that strategies that prioritize high-risk geographic areas for vaccination at all ages better target mortality risk than age-based strategies alone, although they do not always perform as well as direct prioritization of high-risk racial/ethnic groups.\\n\\nOne-sentence summaryAge-based COVID-19 vaccination prioritizes white people above higher-risk others; geographic prioritization improves equity.\",\n \"Machine Learning Based Prediction of COVID-19 Mortality Suggests Repositioning of Anticancer Drug for Treating Severe Cases\\nDespite available vaccinations COVID-19 case numbers around the world are still growing, and effective medications against severe cases are lacking. In this work, we developed a machine learning model which predicts mortality for COVID-19 patients using data from the multi-center Lean European Open Survey on SARS-CoV-2-infected patients (LEOSS) observational study (>100 active sites in Europe, primarily in Germany), resulting into an AUC of almost 80%. We showed that molecular mechanisms related to dementia, one of the relevant predictors in our model, intersect with those associated to COVID-19. Most notably, among these molecules was tyrosine kinase 2 (TYK2), a protein that has been patented as drug target in Alzheimers Disease but also genetically associated with severe COVID-19 outcomes. We experimentally verified that anti-cancer drugs Sorafenib and Regorafenib showed a clear anti-cytopathic effect in Caco2 and VERO-E6 cells and can thus be regarded as potential treatments against COVID-19. Altogether, our work demonstrates that interpretation of machine learning based risk models can point towards drug targets and new treatment options, which are strongly needed for COVID-19.\",\n \"Genomic Surveillance of SARS-CoV-2 in Erie County, New York\\nEarly in the SAR-CoV-2 pandemic, we established a whole genome sequencing pipeline to assess lineages circulating in Western New York. Initial sequences revealed entry into the region via Europe, similar to observations in New York City. However, as the pandemic progressed and variants of concern emerged, we observed distinct patterns in lineages relative to NYC. Notably, B.1.427 became dominant in Western New York, before it was displaced by B.1.1.7. Our hierarchical cluster analysis of B.1.1.7 lineages, which by May 2021 made up [~] 80% of all cases, indicated both multiple introductions and community spread. Our work highlights the importance of widespread, regional surveillance of SARS-CoV-2 across the United States.\",\n \"Multi-Analyte Liquid Biopsies for Molecular Pathway Guided Personalized Treatment Selection in Advanced Refractory Cancers: A Clinical Utility Pilot Study\\nPurposeThe selection of safe and efficacious anticancer regimens for treatment of broadly refractory patients with metastatic cancers remains a clinical challenge. Such patients are often fatigued by toxicities of prior failed treatments and may have no further viable standard of care treatment options. Liquid Biopsy-based multi-analyte profiling in peripheral blood can identify a majority of drug targets that can guide the selection of efficacious combination regimens.\\n\\nPatients and MethodsLIQUID IMPACT was a pilot clinical study where patients with advanced refractory cancers received combination anticancer treatment regimens based on multi-analyte liquid biopsy (MLB) profiling of circulating tumor biomarkers; this study design was based on the findings of prior feasibility analysis to determine the abundance of targetable variants in blood specimens from 1299 real-world cases of advanced refractory cancers.\\n\\nResultsAmong the 29 patients in the intent to treat (ITT) cohort of the trial, 26 were finally evaluable as per study criteria out of whom 12 patients showed Partial Response (PR) indicating an Objective Response Rate (ORR) of 46.2% and 11 patients showed Stable Disease (SD) indicating the Disease Control Rate (DCR) to be 88.5%. The median Progression-Free Survival (mPFS) and median Overall Survival (mOS) were 4.3 months (95% CI: 3.0 - 5.6 months) and 8.8 months (95% CI: 7.0 - 10.7 months), respectively. Toxicities were manageable and there were no treatment-related deaths.\\n\\nConclusionThe study findings suggest that MLB could be used to assist treatment selection in heavily pretreated patients with advanced refractory cancers.\",\n \"COVID-19 vaccine hesitancy in diverse groups in the UK - is the driver economic or cultural in student populations?\\nStudies have identified a greater reluctance for members of the Black, Asian, and minority ethnic communities to be vaccinated against COVID-19 despite a higher probability of greater harm from COVID-19. We conducted an anonymised questionnaire-based study of students (recruiting primarily before first reports of embolic events) at two London universities to identify whether economic or educational levels were primarily responsible for this reluctance: a postgraduate core group (PGCC) n=860 and a pilot study of undergraduate medical and nursing students (n=103). Asian and Black students were 2.0 and 3.2 times (PGCC) less likely to accept the COVID vaccine than White British students. Similar findings were noted in the pilot study students. As students were studying for Masters or PhD degrees and voluntarily paying high fees, educational and economic reasons were unlikely to be the underlying cause, and wider cultural reservations were more likely. Politicians exerted a strong negative influence, suggesting that campaigns should omit politicians.\",\n \"Association between work attendance when experiencing fever or cold symptoms and company characteristics and socioeconomic status in the COVID-19 pandemic in Japanese workers: a cross-sectional study\\nObjectiveThis study investigated the association between attending work while experiencing fever or cold symptoms and workers socioeconomic background and company characteristics during the COVID-19 pandemic.\\n\\nMethodsA cross-sectional online survey was performed. Of a total of 33,302 participants, 3,676 workers who experienced fever or cold symptoms after April 2020 were included. The odds ratios (ORs) of attending work while sick associated with workers socioeconomic background and company characteristics were evaluated using a multilevel logistic model.\\n\\nResultsThe OR of attending work while sick associated with a lack of policy prohibiting workers from working when ill was 2.75 (95%CI: 2.28-3.20, P<0.001).\\n\\nConclusionThis study suggests that clear company policies on work and illness can be effective for preventing employees from attending work while sick.\",\n \"Trends of COVID-19 pediatric admissions number during the first 24 weeks of COVID-19 vaccination in Rio de Janeiro, Brazil\\nObjectiveTo describe trends of COVID-19 pediatric admissions number during the first 24 weeks of COVID-19 vaccination.\\n\\nDesignA retrospective study was conducted in children (0-18 years), admitted in two pediatric hospitals of Rio de Janeiro city, between January 17 and July 3, 2021 with confirmed COVID-19 by reverse transcription polymerase chain reaction or serological tests. Trends of COVID-19 pediatric admissions number during the first 24 weeks of COVID-19 vaccination in Rio de Janeiro, Brazil and the pre-vaccine period were measured by linear regression.\\n\\nParticipantsChildren admitted in pediatric hospitals in Rio de Janeiro, city, Brazil\\n\\nResultsThe number of total admitted patients (with all diseases) were 5340 during the pre-vaccine period, being 94 (1.8%) of them with confirmed COVID-19, and 4182 children admitted during the vaccine period, with 86 confirmed COVID-19 patients (2.1 %) (p=0.29). Media of cases admitted per/week were 2.02 in pre-vaccine period and 3.6 during the first 24 weeks of COVID vaccination (p=0.009). One death was reported in the pre-vaccine period and four in the vaccine period (p=0.14). Trends of increase in the number of admitted cases were verified both in the pre-vaccine period as in the vaccine period, being more expressive in the last one.\\n\\nConclusionThere was trend of increase in number of children admitted with confirmed COVID-19 during the first 24 weeks of COVID-vaccination in Rio de Janeiro, city. Considering that few people were fully vaccinated, reducing of number of admitted children with confirmed COVID-19 was not verified.\",\n \"Human phospho-signaling networks of SARS-CoV-2 infection are rewired by population genetic variants\\nSARS-CoV-2 infection hijacks signaling pathways and induces protein-protein interactions between human and viral proteins. Human genetic variation may impact SARS-CoV-2 infection and COVID-19 pathology; however, the role of genetic variation in these signaling networks remains uncharacterized. We studied human single nucleotide variants (SNVs) affecting phosphorylation sites modulated by SARS-CoV-2 infection, using machine learning to identify amino acid changes altering kinase-bound sequence motifs. We found 2033 infrequent phosphorylation-associated SNVs (pSNVs) that are enriched in sequence motif alterations, potentially reflecting the evolution of signaling networks regulating host defenses. Proteins with pSNVs are involved in viral life cycle processes and host responses, including regulators of RNA splicing and interferon response, as well as glucose homeostasis pathways with potential associations with COVID-19 co-morbidities. Certain pSNVs disrupt CDK and MAPK substrate motifs and replace these with motifs recognized by Tank Binding Kinase 1 (TBK1) involved in innate immune responses, indicating consistent rewiring of infection signaling networks. Our analysis highlights potential genetic factors contributing to the variation of SARS-CoV-2 infection and COVID-19 and suggests leads for mechanistic and translational studies.\",\n \"Effectiveness of a Fourth Dose of COVID-19 Vaccine among Long-Term Care Residents in Ontario, Canada\\nBackgroundAs of December 30, 2021, Ontario long-term care (LTC) residents who received a third dose of COVID-19 vaccine [≥]84 days previously were offered a fourth dose to prevent a surge in COVID-19-related morbidity and mortality due to the Omicron variant.\\n\\nMethodsWe used a test-negative design and linked databases to estimate the marginal effectiveness (4 versus 3 doses) and vaccine effectiveness (VE; 2, 3, or 4 doses versus no doses) of mRNA vaccines among Ontario LTC residents aged [≥]60 years who were tested for SARS-CoV-2 between December 30, 2021 and March 2, 2022. Outcome measures included any Omicron infection, symptomatic infection, and severe outcomes (hospitalization or death).\\n\\nResultsWe included 9,957 Omicron cases and 46,849 test-negative controls. The marginal effectiveness of a fourth dose [≥]7 days after vaccination versus a third dose received [≥]84 days prior was 40% (95% Confidence Interval[CI], 34-45%) against infection, 63% (95%CI, 51-71%) against symptomatic infection, and 54% (95%CI, 31-70%) against severe outcomes. VE (compared to an unvaccinated group) increased with each additional dose, and for a fourth dose was 65% (95%CI, 60-70%), 87% (95%CI, 81-91%), and 92% (95%CI, 87-95%), against infection, symptomatic infection, and severe outcomes, respectively.\\n\\nConclusionsOur findings suggest that compared to a third dose received [≥]84 days ago, a fourth dose recommendation for LTC residents improved protection against infection, symptomatic infection, and severe outcomes caused by Omicron. Compared to unvaccinated individuals, fourth doses provide strong protection against symptomatic infection and severe outcomes but the duration of protection remains unknown.\",\n \"The differential impact of the COVID-19 epidemic on Medicaid expansion and non-expansion states\\nMedicaid expansion is a federally-funded program to expand health care access and coverage to economically challenged populations by increasing eligibility to Medicaid enrollment and investing in public health preventive services in the individual states. Yet, when the COVID-19 epidemic plagued the country, fourteen states were practicing their chosen decision not to enact the Medicaid expansion policy. We examined the consequences of this nationwide split in Medicaid design on the spread of the COVID-19 epidemic between the expansion and non-expansion states. Our study shows that, on average, the expansion states had 217.56 fewer confirmed COVID-19 cases per 100,000 residents than the non-expansion states [-210.41; 95%CI (-411.131) - (-2.05); P<0.05]. Also, the doubling time of COVID-19 cases in Medicaid expansion states was longer than that of non-expansion states by an average of 1.68 days [1.6826; 95%CI 0.4035-2.9617; P<0.05]. These findings suggest that proactive investment in public health preparedness was an effective protective policy measure in this crisis, unsurpassed by the benefits of COVID-19 emergency plans and funds. The study findings could be relevant to policymakers and healthcare strategists in non-expansion states considering their states preparations for such public health crises.\",\n \"Adaptive vaccination may be needed to eliminate COVID-19: Results from a runtime-alterable strain-drift and waning-immunity model\\nIn this paper, we present methods for building a Java Runtime-Alterable-Model Platform (RAMP) of complex dynamical systems. We illustrate our methods by building a multivariant SEIR (epidemic) RAMP. Underlying our RAMP is an individual-based model that includes adaptive contact rates, pathogen genetic drift, waning and cross immunity. Besides allowing parameter values, process descriptions, and scriptable runtime drivers to be easily modified during simulations, our RAMP is easily integrated into other computational platforms, such as our illustrated example with R-Studio. Processes descriptions that can be runtime altered within our SEIR RAMP include pathogen variant-dependent host shedding, environmental persistence, host transmission, and within-host pathogen mutation and replication. They also include adaptive social distancing and adaptive application of vaccination rates and variant-valency of vaccines. We present simulation results using parameter values and process descriptions relevant to the current COVID-19 pandemic. Our results suggest that if waning immunity outpaces vaccination rates, then vaccination rollouts may fail to contain the most transmissible variants, particularly if vaccine valencies do not adapt to escape mutations. Our SEIR RAMP is designed for easy-use by individuals and groups involved in formulating social-distancing and adaptive vaccination rollout policies. More generally, our RAMP concept facilitates construction of highly flexible complex systems models of all types, which can then be easily shared among researchers and policymakers as stand alone applications programs.\",\n \"Neutralisation of SARS-CoV-2 Delta sub-lineage AY.4.2 and B.1.617.2+E484K by BNT162b2 mRNA vaccine-elicited sera\\nSeveral factors may account for the recent increased spread of the SARS-CoV-2 Delta sublineage AY.4.2 in the United Kingdom, Romania, Poland, and Denmark. Here, we evaluate the sensitivity of AY.4.2 to neutralisation by sera from Pfizer/BioNTech (BNT162b2) vaccine recipients. AY.4.2 neutralisation was comparable to other circulating Delta lineages or sublineages. In contrast, the more rare B.1.617.2+E484K variant showed a significant >4-fold reduction in neutralisation that warrants surveillance of strains with the acquired E484K mutation.\",\n \"Impact of the additional/booster dose of COVID-19 vaccine against severe disease during the epidemic phase characterized by the predominance of the Omicron variant in Italy, November 2021 - March 2022\\nDespite the stunning speed with which highly effective and safe vaccines have been developed, increasingly transmissible variants are emerging. Using surveillance data from Italy (November 2021-March 2022), during the epidemic phase characterized by the predominance of the Omicron variant, vaccination with additional/booster dose significantly reduces the risk at all ages for hospitalization (relative risk (RR): 0.16; 95% confidence interval (CI): 0.13-0.19), admission to ICU (RR: 0.08; 95% CI: 0.06-0.09) and death (RR: 0.13; 95% CI: 0.10-0.16). Results support the importance of receiving a third dose of mRNA COVID-19 vaccine.\",\n \"Evaluation of commercial anti-SARS-CoV-2 antibody assays and comparison of standardized titers in vaccinated healthcare workers.\\nWith the availability of vaccines, commercial assays detecting anti-SARS-CoV-2 antibodies (Ab) evolved towards quantitative assays directed to the spike glycoprotein or its receptor binding domain (RBD). The main objective of the present study was to compare the Ab titers obtained with quantitative commercial binding Ab assays, after 1 dose (convalescent individuals) or 2 doses (naive individuals) of vaccine, in healthcare workers (HCW).\\n\\nAntibody titers were measured in 255 sera (from 150 HCW) with 5 quantitative immunoassays (Abbott RBD IgG II quant, bioMerieux RBD IgG, DiaSorin Trimeric spike IgG, Siemens Healthineers RBD IgG, Wantai RBD IgG). One qualitative total antibody anti RBD detection assay (Wantai) was used to detect previous infection before vaccination. The results are presented in binding Ab units (BAU)/mL after application, when possible, of a conversion factor provided by the manufacturers and established from a World Health Organization (WHO) internal standard.\\n\\nThere was a 100% seroconversion with all assays evaluated after two doses of vaccine. With assays allowing BAU/ml correction, Ab titers were correlated (Pearson correlation coefficient, {rho}, range: 0.85-0.94). The titer differences varied by a mean of 10.6% between Siemens and bioMerieux assays to 60.9% between Abbott and DiaSorin assays. These results underline the importance of BAU conversion for the comparison of Ab titer obtained with the different quantitative assays. However, significant differences persist, notably, between kits detecting Ab against the different antigens.\\n\\nA true standardization of the assays would be to include the International Standard in the calibration of each assays to express the results in IU/mL.\",\n \"Antibody Responses In Non-Severe SARS-CoV-2 Infections Are Driven By CD4+ T cells and Age.\\nSARS-CoV-2 infection causes a spectrum of clinical outcomes and diverse memory responses. Population studies indicate that viral neutralizing antibody responses are protective, but do not always develop post-infection. Other antiviral antibody effector functions, T-cell responses, or immunity to seasonal coronaviruses (OC43, 229E) have been implicated but not defined in all ages. Here, we identify that children and adult subjects generate polyfunctional antibodies to the spike protein after asymptomatic infection or mild disease, with some subjects developing cellular responses without seroconversion. Diversity in immunity was explained by two clusters distinguished by CD4+ T-cell cytokines, age, and antibodies to seasonal coronaviruses. Post-vaccination neutralizing responses were predicted by specific post-infection immune measures, including IL-2, spike-IgA, OC43-IgG1, 229E-IgM. We confirm a key role for CD4+ T cell cytokines in functionality of anti-spike antibodies, and show that antibody diversity is impacted by age, Th/Th2 cytokine biases, and antibody isotypes to SARS-CoV-2 and seasonal coronaviruses.\"\n]","isConversational":false},"cluster":{"kind":"number","value":9,"string":"9"}}},{"rowIdx":223,"cells":{"query":{"kind":"string","value":"The effect of including the Nordic Hamstring exercise on sprint and jump performance in athletes: protocol of a systematic review and meta-analyses\nThe Nordic Hamstring exercise reduces hamstring strain injuries in football and other sports, but the exercise is not well adopted in practice. Barriers from practitioners include fear of performance decrements, due to lack of specificity of the exercise with high speed running. However, in theory, increased eccentric hamstring strength could transfer to faster sprinting due to higher horizontal force production. Studies on the effect of the Nordic Hamstring exercise on performance have been conflicting and no synthesis of the evidence exists. We therefore pose the following question: does including the Nordic Hamstring exercise hamper sprint or jump performance in athletes? We will answer this question by performing a systematic review of the literature, critically appraise relevant studies, and GRADE the evidence across key outcomes and perform meta-analyses, meta-regression and subgroup analyses. In this protocol we outline the planned methods and procedures.\n\nProgress reportBesides this protocol, our data extraction form and the process of data extraction has been piloted on 3 relevant studies, along with familiarization with the Risk of Bias 2.0 tool. We have also comprised a preliminary search strategy for PubMed.\n\nSupplementary filesO_LIData Extraction Form (.pdf)\nC_LIO_LIPopulated PRISMA-P checklist (.pdf)\nC_LI"},"positive":{"kind":"list like","value":["The heart of an endurance athlete: impact of and recovery after an ultra-endurance event.\nAimsAcute bouts of ultra-endurance exercise may cause an acute reduction in cardiac function, causing a physiological cascade which releases cardiac biomarkers. This study set out to determine the cardiac stress and recovery of participation in a three-day ultra-endurance mountain biking event of athletes using heart rate variability (HRV) as an outcome measure.\n\nMethodsSixteen healthy participants (male and female) participating in a three-day ultra-endurance mountain biking event underwent a five-minute resting ECG recording in a supine position. Heart rate variability measurements were recorded two days before the race (baseline testing), after each race day, and at 24-hour post-event (recovery).\n\nResultsTime-domain and frequency domain measures showed significant (p[≤]0.05) changes from baseline in HRV parameters after each race day. The significant changes in HRV parameters reflected an increase in sympathetic activity after each day of the event. Our data revealed that the mean HR and RR variability variables did not return to baseline value after 24-hours of recovery, reflecting autonomic nervous system dysfunction, and that changes persisted for at least 24-hours post-event.\n\nConclusionOur study shows that competing in an ultra-endurance mountain bike event led to diminished vagal activity and a decrease in HRV throughout the event and persisted for at least 24-hours post-event. The body was under continuous sympathetic dominance during rest as well as during each day of racing, implying each race day can be considered a physiological stress. This may, in turn, cause a disturbance in homeostasis and an increase in autonomic nervous system dysfunction. This has implications for further research, including dysrhythmia risk, and monitoring of athletes in advising a return to strenuous activity.","Bone health risk assessment in a clinical setting: an evaluation of a new screening tool for active populations\nIntroductionRisk factors for poor bone health are not restricted to older, sedentary populations for whom current screening is focused. Furthermore, access to dual X-ray absorptiometry scanning can be limited in clinical practice. The purpose of the current study was to develop a bone health-screening tool suitable for inclusion of both younger and active populations, combined with radiofrequency echographic multi spectrometry technology (REMS).\n\nMethodology88 participants attending a physiotherapy clinic in the UK were recruited to the study: 71 women (mean age 41.5 SD 14.0 years); 17 men (mean age 40.2 SD 14.9 years). Participants completed an online bone health-screening questionnaire developed specifically for this study covering a range of lifestyle, physiological factors, combined with medical interview and received bone mineral density (BMD) measurement at the lumbar spine and femoral neck using REMS.\n\nResultsScoring of the bone health-screening questionnaire produced a distribution of bone health scores, with lower scores suggesting a higher risk for poor bone health. In women, scores ranged from -10 to +12, mean score 2.2 (SD 4.8). In men, scores ranged from 0 to 12, mean score 6.9 (SD 3.2). A positive correlation was observed between the bone health score derived from the questionnaire and lumbar spine and femoral neck BMD Z-scores (p<0.01).\n\nConclusionsThis new and comprehensive bone health-screening questionnaire with interview was effective in identifying active individuals at risk of bone fragility, who might be missed by current screening methods. The use of REMS technology to measure bone health, was feasible in the clinical setting.","Technological advances in elite marathon performance\nThere is scientific and legal controversy about recent technological advances in performance running shoes that reduce the energetic cost of running and may provide a distinct competitive advantage. To better understand the potential performance-enhancing effects of Nikes pioneering marathon racing shoes, we examined the finishing times and racing shoes of the top 50 male and 50 female runners from the World Marathon Major series in the 2010s -- before and after the introduction of new Nike shoe models (4%, NEXT%, Alphafly, and other prototypes; herein referred to as neoteric Nikes). Data for racing shoes were available for 3,886 of the 3,900 performances recorded at the four annual marathons in Boston, London, Chicago, and New York. In full cohort analyses, marathon finishing times were 2.0% or 2.8 min (138.5 {+/-} 8.1 min vs. 141.3 {+/-} 7.4 min, P<0.001) faster for male runners wearing neoteric Nikes compared to other shoes. For females, marathon finishing times were 2.6% or 4.3 min (159.1 {+/-} 10.0 min vs. 163.4 {+/-} 10.7 min, P<0.001) faster for runners wearing neoteric Nikes. In a subset of within-runner changes in marathon performances (males, n = 138; females, n = 101), marathon finishing times improved by 0.8% or 1.2 min for males wearing neoteric Nikes relative to the most recent marathon in which other shoes were worn, and this performance-enhancing effect was greater among females who demonstrated 1.6% or 3.7 min improvement (P=0.002). Our results demonstrate that marathon performances for world-class athletes are substantially faster wearing neoteric Nikes than other market-leading shoes, particularly among females.","Assessment of fractional anisotropy outcomes in combat sport athletes with mild traumatic brain injury\nAO_SCPLOWBSTRACTC_SCPLOWThe practice of combat sports increases the risk of suffering white matter injuries. That is why, it is required the early damage detection to determine to what extent the athlete may be active preserving their performance and health status. The integrity of the white matter can be quantitatively characterized in diffusion tensor images, using fractional anisotropy. This study aims at characterizing the fractional anisotropy of white matter injuries in combat athletes that are exposed to repetitive trauma and also, to detect changes in fractional anisotropy between cerebral hemispheres with and without lesions. It is proposed a global and structural analysis of the hemispheres, as well as the selection of ROI in the lesions. 14 athletes, from Boxing, Karate and Taekwondo sports, participated. The sample was divided into two groups of seven subjects each: Injured (23.428{+/-}4.157 years old) and Healthy (24.285{+/-}5.023 years old) paired by sport denomination. Diffusion tensor images were used to obtain FA values in the analysis of the hemispheres and lesions. Global and structural analysis of the hemispheres did not detect the presence of white matter lesions; however, the use of ROI selection permitted maximum approximation of the injuries location. It also improved the breakdown of FA values as it allows a local analysis of the lesion. As an additional result, there were found ROIs values, FAmed = 0.454{+/-}0.062, which exceed the average fractional anisotropy of the white matter. The cohesion of acute and chronic phase lesions were found in the same subject. The apparently contradictory results in FA values are related to the stage of the lesions.","Findings from Cardiovascular Evaluation of NCAA Division I Collegiate Student-Athletes after Asymptomatic or Mildly Symptomatic SARS-CoV-2 Infection\nObjectivesThe risk of myocardial damage after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been controversial. There is an urgent need for data to support the appropriate level of cardiovascular screening for safe return-to-play. The purpose of this study is to report the incidence of abnormal cardiovascular findings in National Collegiate Athletic Association (NCAA) Division I student-athletes with a history of SARS-CoV-2 infection.\n\nMethodsThis is a case series of student-athletes at a single NCAA Division I institution who tested positive for SARS-CoV-2 by polymerase chain reaction (PCR) or antibody testing (IgG) from 4/15/2020 to 10/31/2020. From 452 athletes who were screened, 5,124 PCR and 452 antibody tests were completed. Student-athletes were followed through 12/31/2020 (median 104 days, range 64-182 days). Cardiac work-up included clinical evaluation, troponin level, electrocardiogram (ECG), and echocardiogram. Additional work-up was ordered as clinically indicated.\n\nResults55 student-athletes tested positive for SARS-CoV-2. Of these, 38 (69%) had symptoms of Coronavirus Disease (COVID-19), 14 (26%) had a positive IgG test, and 41 (74%) had a positive PCR test. Eight abnormal cardiovascular screening evaluations necessitated further testing including cardiac magnetic resonance imaging (cMRI). Two athletes received new cardiac diagnoses, one probable early cardiomyopathy and one pericarditis, while the remaining six had normal cardiac MRIs.\n\nConclusionThese data support recent publications which recommend the de-escalation of cardiovascular testing for athletes who have recovered from asymptomatic or mildly symptomatic SARS-CoV-2 infection. Continued follow-up of these athletes for sequelae of SARS-CoV-2 is critical.","Can prognostic factors for indirect muscle injuries in elite football (soccer) players be identified using data from preseason screening? An exploratory analysis using routinely-collected periodic health examination records.\nThis study used periodic health examination (PHE) data from 134 outfield elite male football players, over 5 seasons (1st July 2013 to 19th May 2018). Univariable and multivariable logistic regression models were used to determine prognostic associations between 36 variables and time-loss, lower extremity index indirect muscle injuries (I-IMIs). Non-linear associations were explored using fractional polynomials. During 317 participant-seasons, 138 I-IMIs were recorded. Univariable associations were determined for previous calf indirect muscle injury (IMI) frequency (OR=1.80, 95% confidence interval (CI) = 1.09 to 2.97), hamstring IMI frequency (OR=1.56, 95% CI=1.17 to 2.09), if the most recent hamstring IMI occurred > 12 months but < 3 years prior to PHE (OR= 2.95, 95% CI = 1.51 to 5.73) and age (OR =1.12 per 1-year increase, 95% CI = 1.06 to 1.18). Multivariable analyses demonstrated that if a players most recent previous hamstring IMI was >12 months but <3 years prior to PHE (OR= 2.24, 95% CI = 1.11 to 4.53), then this was the only variable with added prognostic value over and above age (OR=1.12 per 1-year increase, 95%CI = 1.05 to 1.18). Allowing non-linear associations conferred no advantage over linear ones. Therefore, PHE has limited use for injury risk prediction.","The Association of COVID-19 Incidence with Sport and Face Mask Use in United States High School Athletes\nPurposeTo evaluate the influence of sport characteristics and face mask use on COVID-19 incidence among high school athletes.\n\nMethodsSurveys were distributed to high school athletic directors throughout the United States regarding sport re-initiation, COVID-19 cases, and risk reduction procedures in fall 2020.\n\nSeparate mixed effects Poisson regression models were developed to evaluate the associations between reported COVID-19 incidence and 1) sport characteristics (contact/non-contact, individual/team, indoor/outdoor) and 2) face mask use while playing (yes/no).\n\nResults991 schools had restarted fall sports, representing 152,484 athletes on 5,854 teams. 2,565 cases of COVID-19 were reported, representing a case rate of 1,682 cases per 100,000 athletes and an incidence rate of 24.6 cases per 100,000 player-days. COVID-19 incidence was lower among outdoor versus indoor sports (incidence rate ratio [IRR]=0.54, 95% CI=0.49-0.60, p<0.001) and non-contact versus contact sports (IRR=0.78 [0.70-0.87], p<0.001), but not team versus individual sports (IRR=0.96 [0.84-1.1], p=0.49). Face mask use was associated with a decreased incidence in girls volleyball (IRR=0.53 [0.37-0.73], p<0.001), boys basketball (IRR=0.53 [0.33-0.83], p=0.008) and girls basketball (IRR=0.36 [0.19-0.63], p<0.001), and approached statistical significance in football (IRR=0.79 [0.59-1.04], p=0.10) and cheer/dance (IRR=0.75 [0.53-1.03], p=0.081).\n\nConclusionsIn this nationwide survey of US high school athletic directors representing 152,484 athletes, lower COVID-19 incidence was independently associated with participation in outdoor versus indoor and non-contact versus contact sports, but not team versus individual sports. Face mask use was associated with decreased COVID-19 incidence among indoor sports, and may be protective among outdoor sports with prolonged close contact between participants.","Effects of stricter management guidelines on return-to-play timeframes following concussion in professional Australian Rules football\nBackgroundManagement of concussion remains a serious issue for professional sports, particularly with the growing knowledge on the consequences of repetitive concussion. One primary concern is the subjective assessment of recovery that dictates the time until a concussed athlete is returned to competition. In response to this concern, the Australian Football League (AFL) changed its policy in 2020 such that clearance for return-to-play was extended from one day, to a minimum of five days, prior to the next scheduled match.\n\nObjectiveWe sought to examine the impact of the AFL policy change by asking whether the time to return-to-play after concussion was increased in the 2020 season relative to previous years.\n\nMethodsRetrospective data on injury and return-to-play were sourced from publicly available tables published on the AFL website. We compared the number of matches missed and the number of days missed in concussed players across 2017 to 2020 inclusive.\n\nResultsAnalysis of data from 166 concussed players revealed no increase in the number of matches missed in 2020 relative to previous years as would have been expected from an extend recovery protocol. Considering the number of days missed in 2020 relative to 2017-19 we found, paradoxically, that there was an overall reduction in the average time to return-to-play in 2020 (11.2 vs 16.2 days).\n\nConclusionThis study demonstrates that any policy change around concussion management requires ongoing auditing to ensure clearance meets policy objectives and highlights the need for objective measures for return-to-play after concussion.","How lifestyle changes within the COVID-19 global pandemic have affected the pattern and symptoms of the menstrual cycle.\nBackgroundThe coronavirus 2019 (COVID-19) pandemic has caused significant changes to homes, working life and stress. The purpose of this research was to investigate the implications that the COVID-19 pandemic has had on the menstrual cycle and any contributing factors to these changes.\n\nMethodsA questionnaire was completed by 749 participants, whom ranged from physically active to elite, in their training status. The questionnaire captured detail on menstrual cycle symptoms and characteristics prior to and during the COVID-19 pandemic lockdown period, as well as lifestyle, stress, exercise and nutrition. Descriptive statistics and frequency distribution were reported and decision tree analysis performed. Statistical significance was assumed at p<0.05.\n\nResultsFifty-two point six percent of females experienced a change in their menstrual cycle during the lockdown period. Psychosocial symptoms had changed in over half of all participants. Participants who reported increased stress/worry in family and personal health were significantly associated with changes in menstrual symptoms. Similarly, job security stress was associated with increases in bleeding time (p<0.05).\n\nConclusionsIt is important that females and practitioners become aware of the implications of stressful environments and the possible long-term implications on fertility, particularly given the uncertainty around a second wave of the global pandemic.","A novel biomechanical injury risk score demonstrates correlation with lower limb posterior chain injury in fifty elite level rugby union athletes\nObjectivesLower limb posterior chain injury (PCI) is common amongst athletic populations, with multi-factorial risk factors including age, previous injury, strength measurements, range of motion and training load. Biomechanics are commonly considered in the prevention and rehabilitation of PCI by performance staff. However, there is no documented testing method to assess for associations between biomechanics and PCI. The aim of this study was to investigate whether there is an association between an easily applicable, novel biomechanical assessment tool and PCI.\n\nMethodsFifty male elite-level rugby union athletes (age 22.83{+/-}5.08) participating in the highest tier of England were tested at the start of the 2019 pre-season period and PCIs (N=48) were recorded over the 2019/20 playing season. Participants biomechanics were analysed using two-dimensional video analysis against an Injury Risk Score (IRS) system in the performance of the combined movement - prone hip extension and knee flexion. Participants biomechanics in carrying out this movement were scored against the 10-point IRS, where the more compensatory movement recorded sees an increase in an individuals IRS. Participants IRS were then compared against the number of PCI sustained and Spearmans correlation coefficient was utilised for analysis.\n\nResultsThere is a good significant association between IRS and PCI (R=0.573, p<0.001). Linear Regression demonstrated that an increase of 1 in IRS was associated with a 35% increase in PCI incidence (R2=0.346).\n\nConclusionA good significance between the IRS and PCI provides preliminary support for its use as an injury risk assessment tool.","Muscle Strength Explains the Protective Effect of Physical Activity against COVID-19 Hospitalization among Adults aged 50 Years and Older\nObjectivesPhysical activity has been proposed as a protective factor for COVID-19 hospitalization. However, the mechanisms underlying this association are unclear. Here, we examined the association between physical activity and COVID-19 hospitalization and whether this relationship was explained by other risk factors for severe COVID-19.\n\nMethodWe used data from adults aged 50 years and older from the Survey of Health, Ageing and Retirement in Europe. The outcome was self-reported hospitalization due to COVID-19 measured before August 2020. The main exposure was usual physical activity, self-reported between 2004 and 2017. Data were analyzed using logistic regression models.\n\nResultsAmong the 3139 participants included in the study (69.3 {+/-} 8.5 years, 1763 women), 266 were tested positive for COVID-19 and 66 were hospitalized. Results showed that individuals who engaged in physical activity more than once a week had lower odds of COVID-19 hospitalization than individuals who hardly ever or never engaged in physical activity (odds ratios = 0.41, 95% confidence interval = 0.22-0.74, p = .004). This association between physical activity and COVID-19 hospitalization was explained by muscle strength, but not by other risk factors.\n\nConclusionThese findings suggest that, after 50 years of age, engaging in physical activity more than once a week is associated with lower odds of COVID-19 hospitalization. The protective effect of physical activity on COVID-19 hospitalization is explained by muscle strength.","Beneath the surface: mental health, and harassment and abuse of athletes participating in the FINA (Aquatics) World Championships, 2019\nObjectiveTo assess the mental health and experience of sport-related harassment and abuse of athletes participating in the FINA World Championships 2019, and to analyse it in relation to gender and the aquatic disciplines.\n\nDesignCross-sectional study using an anonymous questionnaire.\n\nMethodsDuring the Championships, registered athletes (swimmers, divers, high divers, water polo players, artistic swimmers, open-water swimmers) completed a survey including the main outcome measures of depression (CES-D-10), eating disorders (BEDA-Q), the subjective need for psychotherapeutic support, and the experience of harassment and/or abuse in their sports environment.\n\nResultsA quarter of the athletes (n=62, 24.6%) were classified as depressed and more than a third (n=111, 35.0%) as having an eating disorder. More than 40% of the athletes stated that they wanted or needed psychotherapeutic support for mental health problems. Fifty-one athletes (14.9%) had experienced harassment/abuse in sport themselves, and 31 (9%) had witnessed it in another athlete. The experiences of harassment and abuse ranged from unwanted comments about body or appearance (40.2%) to rewards in sport for sexual favours (2.5%) and rape (0.3%). Athletes who had experienced harassment/abuse in sport themselves had higher average scores for depression and eating disorders, and more of them needed psychotherapeutic support. Up to a third would not talk to anybody if they saw or experienced harassment/abuse, and less than 20% would talk to an official for help.\n\nConclusionTargeted initiatives are required to address the burden of mental health issues and harassment and abuse in sport in the FINA aquatic disciplines.","Atypical resting state functional connectivity in mild traumatic brain injury\nObjectivesThis study aimed to investigate changes in three intrinsic functional connectivity networks (IFCNs; default mode (DMN), salience (SN), and task-positive networks (TPN)) in individuals who had sustained a mild traumatic brain injury (mTBI).\n\nMethodsResting-state functional magnetic resonance imaging (rs-fMRI) data was acquired from 27 mTBI patients with persistent post-concussive symptoms (PCS), along with 26 age- and sex-matched controls. These individuals were recruited from a Level-1 trauma centre, at least three months after a traumatic episode. IFCNs were established based on seed-to-voxel, region-of-interest (ROI) to ROI, and independent component analyses (ICA). Subsequently, we analyzed the relationship between functional connectivity and PCS.\n\nResultsSeed-to-voxel analysis of rs-fMRI demonstrated decreased functional connectivity in the right lateral parietal lobe, part of the DMN, and increased functional connectivity in the supramarginal gyrus, part of the SN. Our TPN showed both hypo- and hyperconnectivity, dependent on seed location. Within network hypoconnectivity was observed in the visual network, also using group comparison. Using an ICA, we identified altered network functional connectivity in regions within four IFCNs (sensorimotor, visual, DMN, and dorsal attentional). A significant negative correlation between dorsal attentional network connectivity and behavioural symptoms score was also found.\n\nConclusionsOur findings indicate that rs-fMRI may be of use clinically, in order to assess disrupted functional connectivity among IFCNs in mTBI patients. Improved mTBI diagnostic and prognostic information could be especially relevant for athletes looking to safely return to play, as well for individuals from the general population with persistent post-concussive symptoms months after injury, who hope to resume activity.","Is a fair comparison between doping tested and doping untested powerlifters possible?\nPurposePowerlifting is clearly divided into doping tested amateur competitions and doping untested pro competitions with pro competition money prizes ranging from a few thousand USD to over $120 000 USD in a single competition. However, the results of both pro and amateur powerlifting competitions are then collected and put into the same result database (although there is the possibility to filter the results using doping control status). The powerlifting results are compared by scores to have a fair comparison between different weight class athletes. This study plays with the thought of comparing doping tested and doping untested athletes, and creates a coefficient for the comparison.\n\nMethodsThe powerlifting results (noted in kg) of the 10 top ranked athletes per weight class and separately for men and women, and for doping tested and doping untested categories were collected from the openpowerlifting.org database. A weight adjusted model was fit to these results separately for men and women with the doping control status used a binary factor.\n\nResultsDoping control status was a significant factor when modelling the powerlifting results, p<0.001 for both men and women. Mens doping untested results were 1.0725 times as large as the doping tested results. Womens doping untested results were 1.1208 times as large as the doping tested results. These separate and precise factors could be used as coefficients for scoring doping tested and doping untested athletes powerlifting results. Moreover, the coefficients approximate the effect of doping on an elite level athletes results.","Sex Differences in the Incidence and Risk of Ankle-Foot Complex Stress Fractures Among U.S. Military Personnel\nBackgroundThe objective of this study was to evaluate sex differences in the incidence and risk of ankle-foot complex (AFC) stress fractures among U.S. military personnel, which could assist in developing management strategies as females assume a greater role in U.S. military operations.\n\nMethodsThe Defense Medical Epidemiological Database was used to identify all diagnosed AFC stress fractures in military personnel from 2006 to 2015. Cumulative incidence of AFC stress fractures was calculated and compared by year, service branch, and military rank. Sex differences in the risk of AFC stress fractures by occupation were examined, and integrated (i.e., male and female) occupations were compared with non-integrated (i.e., male-only) occupations.\n\nResultsA total of 43,990 AFC stress fractures were identified. The overall incidence rate was 2.76 per 1,000 person-years for males and 5.78 per 1,000 person-years for females. Females consistently had higher incidence of AFC stress fractures across all subgroups, particularly among enlisted personnel. Female enlisted service members had the highest risk of AFC stress fractures in aviation [relative risk (RR) = 5.74; 95% confidence interval [CI] 4.80-6.87] and artillery/gunnery (RR = 5.15; 95% CI 4.62-5.75) occupations. Females in integrated occupations had significantly higher rates of AFC stress fractures than males in both integrated and non-integrated occupations (i.e., special forces, infantry, and mechanized/armor).\n\nConclusionsFemales in the U.S. military have a higher risk of AFC stress fractures than males. As integration of females into previously sex-restricted occupations continues, focused prevention efforts may be needed to reduce injury burden and maximize medical readiness.","Prescribed footwear and orthoses are not prophylactic in preventing lower extremity injuries in military tactical athletes. A systematic review with meta-analysis.\nIntroductionMilitary members are exposed to high cumulative physical loads that frequently lead to injury. Prescribed footwear and orthoses have been used to prevent injury. The purpose of this systematic review with meta-analysis was to assess if prescribed prophylactic footwear or foot orthoses reduced lower extremity injury risk in military tactical athletes.\n\nMethodsMEDLINE, Embase, Web of Science, CINAHL, SportDiscus, and DTIC databases were searched for randomized controlled trials published at any time that compared foot orthoses or prescribed footwear (to include shock-absorbing insoles and socks) to a placebo intervention or a no-treatment control. Methodological quality was assessed and numbers of injuries, population at risk, and the duration of the study epoch were extracted and relative risk (RR) calculated. An omnibus meta-analysis was performed assessing all prescribed footwear and orthoses intervention studies, with subgroup analyses conducted on studies with similar interventions [i.e., basketball athletic shoes; athletic shoes (prescribed by foot type); foot orthoses; shock-absorbing insoles; socks; tropical combat boots].\n\nResultsOf 1,673 studies identified, 22 studies were included. Three of eight studies that employed orthoses demonstrated significantly reduced overuse injuries compared to no treatment controls (RR range: 0.34-0.68); one study showed neoprene insoles significantly decreased overuse injuries (RR: 0.75). There were no other significant effects in the individual studies, and no protective effects observed in the omnibus meta-analysis or in the component sub analyses.\n\nConclusionsPrescribed footwear and orthoses do not appear to have a prophylactic effect on lower quarter MSKI in military members and cannot be recommended at this time.","Runners with chronic mid-portion Achilles tendinopathy have greater Triceps surae intracortical inhibition than healthy controls\nObjectivesThis study aimed to investigate short-interval intracortical inhibition (SICI) and muscle function in the Triceps surae of runners with mid-portion Achilles tendinopathy (AT).\n\nMethodsRunners with (n=11) and without (n=13) AT were recruited. Plantar flexor isometric peak torque and rate of torque development (RTD) were measured using an isokinetic dynamometer. Triceps surae endurance was measured as single leg heel raise (SLHR) to failure test. SICI was assessed using paired-pulse transcranial magnetic stimulation during a sustained contraction at 10% of plantar flexor isometric peak torque.\n\nResultsTriceps surae SICI was 14.3% (95%CI: -2.1 to 26.4) higher in AT than control group (57.9%, 95%CI: 36.2, to 79.6; and 43.6% 95%CI:16.2 to 71.1; p=0.032) irrespective of the tested muscle. AT performed 16 (95%CI: 7.9 to 23.3, p<0.001) fewer SLHR repetitions on the symptomatic side compared to controls, and 14 (95%CI: 5.8 to 22.0, p=0.004), fewer SLHR repetitions on the non-symptomatic compared to controls. We found no between-groups differences in isometric peak torque (p=0.971) or RTD (p=0.815).\n\nPerspectiveOur data suggest greater intracortical inhibition for the Triceps surae muscles for the AT group accompanied by reduced SLHR endurance, without deficits in isometric peak torque or RTD. The increased SICI observed in the AT group could be negatively influencing Triceps surae endurance; thus, rehabilitation aiming to reduce intracortical inhibition should be considered to improve patient outcomes. Furthermore, SLHR is a useful clinical tool to assess plantar flexor function in AT patients.","The devil is in the details: Reporting and transparent research practices in sports medicine and orthopedic clinical trials\nIntroductionWhile transparent reporting of clinical trials is essential to assess the risk of bias and translate research findings into clinical practice, earlier studies have shown that deficiencies are common. This study examined current clinical trial reporting and transparent research practices in sports medicine and orthopedics.\n\nMethodsThe sample included clinical trials published in the top 25% of sports medicine and orthopedics journals over nine months. Two independent reviewers assessed pre-registration, open data and criteria related to scientific rigor, the study sample, and data analysis.\n\nResultsThe sample included 163 clinical trials from 27 journals. While the majority of trials mentioned rigor criteria, essential details were often missing. Sixty percent (confidence interval [CI] 53-68%) of trials reported sample size calculations, but only 32% (CI 25-39%) justified the expected effect size. Few trials indicated the blinding status of all main stakeholders (4%; CI 1-7%). Only 18% (CI 12-24%) included information on randomization type, method, and concealed allocation. Most trials reported participants sex/gender (95%; CI 92-98%) and information on inclusion and exclusion criteria (78%; CI 72-84%). Only 20% (CI 14-26%) of trials were pre-registered. No trials deposited data in open repositories.\n\nConclusionsThese results will aid the sports medicine and orthopedics community in developing tailored interventions to improve reporting. While authors typically mention blinding, randomization and other factors, essential details are often missing. Greater acceptance of open science practices, like pre-registration and open data, is needed. These practices have been widely encouraged, we discuss systemic interventions that may improve clinical trial reporting.\n\nRegistrationhttps://doi.org/10.17605/OSF.IO/9648H","Recent COVID-19 vaccination is associated with modest increases in the physiological demands to graded exercise\nAthletes are advised to receive the COVID-19 vaccination to protect them from SARS CoV-2 infection during major competitions. Despite this, many athletes are reluctant to get the COVID-19 vaccine due to concerns that symptoms of vaccinosis may impair athletic performance.\n\nOBJECTIVETo determine the effects of COVID-19 vaccination on the physiological responses to graded exercise.\n\nMETHODSHealthy participants completed a 20-minute bout of graded cycling exercise before and ~21 days after COVID-19 vaccination (2 dose Pfizer mRNA or 1 dose Johnson & Johnson).\n\nRESULTSOxygen uptake, CO2 production, respiratory exchange ratio, ventilation, heart rate, serum noradrenaline, and rating of perceived exertion were significantly elevated in the post vaccine trial. However, vaccination did not affect serum lactate, adrenaline, cortisol, predicted [Formula], and ventilatory threshold. Post-vaccine effects on heart rate and noradrenaline remained significant in non-infected participants that received the Pfizer vaccine. No significant effects in respiratory gas exchange parameters were found after vaccination in those previously exposed to SARS-CoV-2, but exercise adrenaline levels were significantly lower and serum lactate levels trending (p= 0.10) lower after vaccination. No changes in any physiological responses to exercise were found in control participants who completed two bouts of exercise separated by ~5 weeks without vaccination.\n\nCONCLUSIONRecent COVID-19 vaccination is associated with modest increases in the physiological demands to graded exercise in non-infected healthy people but may actually improve metabolic responses to exercise in those previously infected with SARS-CoV-2. Whether or not these small effects could impact athletic performance at the elite level warrants investigation.","Neuromuscular risk factors for non-contact knee injury: a systematic review and meta-analysis\nObjectivesIdentify neuromuscular risk factors for non-contact knee injury, using a systematic review and meta-analysis, to inform the development of preventive strategies.\n\nMethodsMedline, Web of Science and SCOPUS were searched from inception until November 2020. Prospective and nested case-control studies that analysed baseline neuromuscular characteristics as potential risk factors for subsequent non-contact knee injuries were included. Two reviewers independently appraised methodological quality using a modified Newcastle-Ottawa Scale. Meta-analysis was performed where appropriate, with standardised mean differences calculated for continuous scaled data.\n\nResultsSeventeen studies were included, comprising baseline data from 5,584 participants and 415 non-contact knee injuries (heterogeneous incidence = 7.4%). Protocols and outcome measures differed across studies, limiting data pooling. Twenty-one neuromuscular variables were included in the meta-analysis. Three were identified as risk factors. For patellofemoral pain, among military recruits: reduced non-normalised quadriceps strength at 60{o}/s (SMD -0.66; 95% CI -0.99, -0.32); reduced quadriceps strength at 240{o}/s (normalised by body mass) (SMD -0.53; CI -0.87, -0.20). For PFP/ACL injury among female military recruits: reduced quadriceps strength at 60{o}/s (normalised by body mass) (SMD -0.50; CI -0.92, -0.08).\n\nConclusionsQuadriceps weakness is a risk factor for PFP among military recruits, and for PFP/ACL injury among female military recruits. However, the effect sizes are small, and the generalisability of these findings is limited. The effectiveness of quadriceps strengthening interventions for preventing PFP and ACL injury merits evaluation in prospective randomised trials.","Anticarcinogenic effects from plasma elderly trained: the role of mitochondrial function\nThis study aimed to evaluate the effects of a multimodal exercise training on systemic cytokine levels of the elderly, and the impact of post-exercise training plasma on prostate cancer cell viability and proliferation in vitro. Fasting blood samples were collected from eight institutionalized elderly before and after eight weeks of multimodal exercise training (twice a week). The levels of interleukin(IL)-1ra, IL-1{beta}, IL-2, IL-6, IL-10, IL-17, interferon (IFN)-, tumor necrosis factor (TNF)-, fibroblast growth factor (FGF)-1, platelet-derived growth factor (PDGF) and transforming growth factor (TGF)- were evaluated in the peripheral blood. PC3 prostate cancer cell lines were incubated with 10% plasma acquired before and after exercise training from each participant. Multimodal exercise training increased the plasma levels of IL-2, IL-10, IFN-, and FGF-1, and decreased TNF- concentrations. PC3 cells presented decreased cell viability evaluated by MTT and lactate dehydrogenase activity as well as lower rates of cell proliferation after the incubation with post-training plasma samples. Furthermore, the incubation of PC-3 cells with post-training plasma decreased the mitochondrial membrane polarization and increased mitochondrial reactive oxygen species (ROS) production without changes in cytosolic ROS. Post-training plasma did not change apoptosis or necrosis rates in the PC-3 cell line. In conclusion, we showed that systemic adaptations in plasma mediators of institutionalized elderly might alter cell viability and proliferation by targeting mitochondrial ROS in a prostate cancer cell line.","Causal Associations of Self-Reported Walking Pace with Telomere Length in 405,981 middle-aged adults: a UK Biobank study\nObjectivesWalking pace is a strong marker of functional and health status. We investigated whether walking pace is also associated with leucocyte telomere length (LTL), which is causally associated with several diseases and has been proposed as a marker of biological age.\n\nMethodsWe used baseline data from UK Biobank participants recruited from March-2006 to July-2010. Walking pace was self-reported as slow, steady/average, or brisk. Accelerometer-assessed measures of total physical activity and intensity were included to support interpretation of walking pace data. LTL was measured by qPCR assay. Bi-directional Mendelian randomization (MR) analyses were undertaken to inform likely causal directions.\n\nResultsThe analysed cohort comprised 405,981 adults (54% women) with mean age of 56.5 years (SD, 8.1) and body mass index 27.2 kg/m2 (SD, 4.7). Steady/average and brisk walkers had significantly longer LTL compared with slow walkers, with a Z-standardised LTL difference of 0.066 (0.053-0.078) and 0.101 (0.088-0.113), respectively. Associations remained but were attenuated following full covariate adjustment: 0.038 (0.025-0.051) and 0.058 (0.045-0.072), respectively. Accelerometer data (n=86,002) demonstrated a non-linear association between LTL and habitual movement intensity, but not total activity. MR analysis supported a causal association of walking pace on LTL, with an increase in Z-standardised LTL of 0.192 (0.077, 0.306) for each difference in walking pace category. No evidence of a causal association was observed for LTL on walking pace.\n\nConclusionFaster walking pace may be causally associated with longer LTL, which could explain some of the beneficial effects of brisk walking on health status.","University of Texas at Arlington (UTA) in-house COVID-19 testing program\nThe pandemic caused by the spread of the virus SARS-CoV-2 threatened to severely disrupt the activities of student-athletes. (REF) In order to provide a safe environment for athletic competition, the National Collegiate Athletic Association (NCAA) mandated testing of student-athletes. The goal was to rapidly identify student-athletes and the athletic staff member who either tested positive for SARS-CoV-2 or were in contact with individuals who tested positive. Rapid identification of infected individuals and their contacts allowed the University to implement quarantine standards and quarantine facilities quickly as needed. The University of Texas at Arlington (UTA) developed an in-house testing program and was quickly able to meet the NCAA requirements, allowing UTA to continue its athletic participation with minimal forfeiture of scheduled games. The purpose of this paper is to report the implementation UTAs COVID prevention program for the universitys athletic program. This program will provide valuable information to other universities planning for the management of COVID prevention in their athletic programs. Challenges and solutions are identified.","Effect of Pre-Exercise Caffeine Intake on Endurance Performance and Core Temperature Regulation During Exercise in the Heat: A Systematic Review with Meta-Analysis\nBackgroundHeat is associated with physiological strain and endurance performance (EP) impairments. Studies have investigated the impact of caffeine intake upon EP and core temperature (CT) in the heat, but results are conflicting. There is a need to systematically determine the impact of pre-exercise caffeine intake in the heat.\n\nObjectiveUse a meta-analytical approach to determine the effect of pre-exercise caffeine intake on EP and CT in the heat.\n\nDesignSystematic review with meta-analysis.\n\nData sourcesFour databases and cross-referencing.\n\nData analysisWeighted mean effect summaries using random-effects models for EP and CT, as well as meta regressions with robust standard errors to explore confounders.\n\nStudy selectionPlacebo-controlled, randomized studies in adults ([≥] 18 yrs old) with caffeine intake at least 30 min before endurance exercise [≥] 30 min, performed in ambient conditions [≥] 27{degrees}C.\n\nResultsRespectively 6 and 12 studies examined caffeines impact on EP and CT, representing 52 and 205 endurance-trained individuals. On average, 6 mg/kg body mass of caffeine were taken 1 h before exercises of [~] 70 min conducted at 34{degrees}C and 47% relative humidity. Caffeine supplementation improved EP by 2.0 {+/-} 0.7% (95% CI: 0.6 to 3.5%) and increased the rate of change in CT by 0.10 {+/-} 0.04{degrees}C/h (95% CI: 0.03 to 0.16{degrees}C/h), compared with the ingestion of a placebo.\n\nConclusionCaffeine ingestion of 6 mg/kg body mass [~] 1 h before an exercise in the heat provides a worthwhile improvement in EP of 2%, while trivially increasing the rate of change in CT by 0.10{degrees}C/h.","Decrease of heart rate variability during exercise: an index of cardiorespiratory fitness\nThe present study proposes to measure and quantify the heart rate variability (HRV) changes during effort and to test the capacity of the produced indices to predict cardiorespiratory fitness measures. Therefore, the beat-to-beat cardiac time interval series of 18 adolescent athletes (15.2 {+/-} 2.0 years) measured during maximal graded effort test were detrended using a dynamical first-order differential equation model. Heart rate variability was then calculated as the standard deviation of the detrended RR intervals within successive windows of one minute. The variation of this measure of HRV during exercise is properly adjusted by an exponential decrease of the heart rate. The amplitude and the decay rate of this exponential trend are strongly associated with maximum oxygen consumption, maximal aerobic power, and ventilatory thresholds. It indicates that among athletes with better fitness, HRV has higher values at low heart rate and decreases faster when the heart rate increases during exercise. This analysis, based only on cardiac measurements, provides a promising tool for the study of cardiac measurements generated by portable devices.","Is the impact of adiposity on taste perceptions moderated by chronic physical activity? An overview of the data from NHANES 2013-2014.\nIntroductionTaste is a key sensory modulator of eating behaviour and thus energy intake. The effects of acute exercise has recently been confirmed especially regarding sweet and salty tastes. Physical activity is a safe and effective countermeasure to certain types of chemosensory losses, especially in older populations. Knowing that taste can be impaired with increased adiposity, it is unknown if the adoption of an active lifestyle on a regular basis can mitigate such impairments.\n\nMethodsData were extracted from NHANES 2013-2014 database. Perception of salt and bitter tastes for Tongue Tip Test and Whole Mouth Test, physical activity levels over an 8-9-day period and adiposity were analyzed. Moderation analyses were used to study the impact of adiposity on taste perceptions, with physical activity level as the moderator.\n\nResultsThe 197 participants (130 males) included in this project had a mean{+/-}standard deviation age of 49.1{+/-}5.2 years, a mean body fat percentage of 31.7{+/-}7.6% and mean daily physical activity levels of 11 084{+/-}3531 Monitor-Independent Movement Summary unit (MIMS). The positive association between adiposity and both bitter Tongue Tip Test and overall result (salt+bitter) of Tongue Tip Test were moderated by the adoption of an active lifestyle, with better taste scores observed in individuals achieving higher physical activity levels. When moderation analysis were stratified by gender, the effect of physical activity was no longer significant.\n\nPerspectivesThis study is the first to evaluate the influence of an active lifestyle on the preservation of some taste perceptions across a wide range of adiposity levels. While differences in taste can be observed regarding body fat percentage, physical activity moderates that relation only when men and women are analysed together.","EPIDEMIOLOGY EVALUATION OF ATHLETIC INJURY IN UNIVERSITY CENTER\nIntroductionAthletics is a sport with varied modalities, which are based on patterns and activities that are natural to human beings. As a sport, it has several benefits, such as improved physical condition and interpersonal interactions, but it is not free from risks, especially injuries related to competitions or training.\n\nObjectivesCharacterize injuries presented by the university athletics group of the medical course and identify possible risk factors.\n\nMethodsParticipants, enrolled in the athletics group of the medicine course, of both sexes, had anthropometric measurements evaluated and answered an injury screening questionnaire modified from the \"Injury Surveillance System\".\n\nResults31 participants responded to the questionnaire where 65% of them had at least one injury. A total of 23 injuries were reported, 20 of which were serious, with no significant difference between both sexes. The total practice time was almost 2 times longer in injured practitioners than in non-injured ones.\n\nConclusionThe practice of university athletics is associated with a high occurrence of serious injuries.\n\nSUMMARY BOXO_LICollege athletics appears to have a high incidence of injury.\nC_LIO_LIThere is an unusually high number of serious injuries in college athletic athletes participating in the study.\nC_LIO_LIMost college athletic sports injuries do not appear to be diagnosed or properly treated.\nC_LIO_LIMost injuries are concentrated in the lower body.\nC_LI","Physical activity and health: Findings from Finnish monozygotic twin pairs discordant for physical activity\nGenetic and early environmental differences including early health habits associate with future health. To provide insight on the causal nature of these associations, monozygotic (MZ) twin pairs discordant for health habits provide an interesting natural experiment. Twin pairs discordant for leisure-time physical activity (LTPA) in early adult life are thus a powerful study design to investigate the associations between long-term LTPA and indicators of health and wellbeing. We have used this study design by identifying 17 LTPA discordant twin pairs from two Finnish twin cohorts and summarize key findings of these studies in this paper. The carefully characterized rare long-term LTPA discordant MZ twin pairs have participated in multi-dimensional clinical examinations. The occurrence of type 2 diabetes and death has been evaluated on the basis of prospective questionnaire data and register follow-up among a larger number of twin pairs. Key findings highlight that, compared to less active twins in such MZ twin pairs, the twins with higher long-term LTPA have higher physical fitness, reduced body fat, reduced visceral fat, reduced liver fat, increased lumen diameters of conduit arteries to the lower limbs, increased bone mineral density in loaded bone areas, increased high-density lipoprotein cholesterol levels and reduced occurrence of type 2 diabetes. However, we have not been able to document differences in the life expectancy between the less and more active twin siblings of the LTPA discordant MZ twin pairs. The findings are in agreement with intervention studies but not with all observational studies in which genetic factors are not controlled for.","Impact of Exercise-induced Dehydration on Perceived Exertion During Endurance Exercise: A Systematic Review with Meta-analysis\nUnderstanding the impact of stressors on the rating of perceived exertion (RPE) is relevant from a performance and exercise adherence/participation standpoint. Athletes and recreationally active individuals dehydrate during exercise. No attempt has been made to systematically determine the impact of exercise-induced dehydration (EID) on RPE. The present meta-analysis aimed to determine the effect of EID on RPE during endurance exercise and examine the moderating effect of potential confounders using a meta-analytical approach. Data analyses were performed on raw RPE values using random-effects models weighted mean effect summaries and meta-regressions with robust standard errors, and with a practical meaningful effect set at 1 point difference between euhydration (EUH) and EID. Only controlled crossover studies measuring RPE with a Borg scale in healthy adults performing [≥] 30 min of continuous endurance exercise while dehydrating or drinking to maintain EUH were included. Sixteen studies were included, representing 147 individuals. Mean body mass loss with EUH was 0.5 {+/-} 0.4%, compared to 2.3 {+/-} 0.5% with EID (range 1.7 to 3.1%). Within an EID of 0.5 to 3% body mass, a maximum difference in RPE of 0.81 points (95% CI: 0.36-1.27) was observed between conditions. A meta-regression revealed that RPE increases by 0.21 points for each 1% increase in EID (95% CI: 0.12-0.31). Humidity, ambient temperature and aerobic capacity did not alter the relationship between EID and RPE. Therefore, the effect of EID on RPE is unlikely to be practically meaningful until a body mass loss of at least 3%.","Mitochondrial DNA copy number, metabolic syndrome, and insulin sensitivity: Insights from the Sugar, Hypertension, and Physical Exercise Studies\nMitochondrial DNA copy number (mtDNA-CN) measured in blood has been associated with many aging-related diseases, with higher mtDNA-CN typically associated with lower disease risk. Exercise training is an excellent preventative tool against aging-related disorders and has been shown to increase mitochondrial function in muscle. Using the Sugar, Hypertension, and Physical Exercise cohorts (N = 105), we evaluated the effect of 6-months of exercise intervention on mtDNA-CN measured in blood. Although there was no significant relationship between exercise intervention and mtDNA-CN change (P = 0.29), there was a nominally significant association between mtDNA-CN and metabolic syndrome (P = 0.04), which has been seen in previous literature. We also identified a nominally significant association between higher mtDNA-CN and higher insulin sensitivity (P = 0.02).","Assessing Open Science practices in physical activity behaviour change intervention evaluations\nObjectivesConcerns on the lack of reproducibility and transparency in science have led to a range of research practice reforms, broadly referred to as Open Science. The extent that physical activity interventions are embedding Open Science practices is currently unknown. In this study, we randomly sampled 100 reports of recent physical activity behaviour change interventions to estimate the prevalence of Open Science practices.\n\nMethodsOne hundred reports of randomised controlled trial physical activity behaviour change interventions published between 2018-2021 were identified. Open Science practices were coded in identified reports, including: study pre-registration, protocol sharing, data-, materials- and analysis scripts-sharing, replication of a previous study, open access publication, funding sources and conflict of interest statements. Coding was performed by two independent researchers, with inter-rater reliability calculated using Krippendorffs alpha.\n\nResults78% of the 100 reports provided details of study pre-registration and 41% provided evidence of a published protocol. 4% provided accessible open data, 8% provided open materials and 1% provided open analysis scripts. 73% of reports were published as open access and no studies were described as replication attempts. 93% of reports declared their sources of funding and 88% provided conflicts of interest statements. A Krippendorffs alpha of 0.73 was obtained across all coding.\n\nConclusionOpen data, materials, analysis and replication attempts are currently rare in physical activity behaviour change intervention reports, whereas funding source and conflict of interest declarations are common. Future physical activity research should increase the reproducibility of their methods and results by incorporating more Open Science practices."],"string":"[\n \"The heart of an endurance athlete: impact of and recovery after an ultra-endurance event.\\nAimsAcute bouts of ultra-endurance exercise may cause an acute reduction in cardiac function, causing a physiological cascade which releases cardiac biomarkers. This study set out to determine the cardiac stress and recovery of participation in a three-day ultra-endurance mountain biking event of athletes using heart rate variability (HRV) as an outcome measure.\\n\\nMethodsSixteen healthy participants (male and female) participating in a three-day ultra-endurance mountain biking event underwent a five-minute resting ECG recording in a supine position. Heart rate variability measurements were recorded two days before the race (baseline testing), after each race day, and at 24-hour post-event (recovery).\\n\\nResultsTime-domain and frequency domain measures showed significant (p[≤]0.05) changes from baseline in HRV parameters after each race day. The significant changes in HRV parameters reflected an increase in sympathetic activity after each day of the event. Our data revealed that the mean HR and RR variability variables did not return to baseline value after 24-hours of recovery, reflecting autonomic nervous system dysfunction, and that changes persisted for at least 24-hours post-event.\\n\\nConclusionOur study shows that competing in an ultra-endurance mountain bike event led to diminished vagal activity and a decrease in HRV throughout the event and persisted for at least 24-hours post-event. The body was under continuous sympathetic dominance during rest as well as during each day of racing, implying each race day can be considered a physiological stress. This may, in turn, cause a disturbance in homeostasis and an increase in autonomic nervous system dysfunction. This has implications for further research, including dysrhythmia risk, and monitoring of athletes in advising a return to strenuous activity.\",\n \"Bone health risk assessment in a clinical setting: an evaluation of a new screening tool for active populations\\nIntroductionRisk factors for poor bone health are not restricted to older, sedentary populations for whom current screening is focused. Furthermore, access to dual X-ray absorptiometry scanning can be limited in clinical practice. The purpose of the current study was to develop a bone health-screening tool suitable for inclusion of both younger and active populations, combined with radiofrequency echographic multi spectrometry technology (REMS).\\n\\nMethodology88 participants attending a physiotherapy clinic in the UK were recruited to the study: 71 women (mean age 41.5 SD 14.0 years); 17 men (mean age 40.2 SD 14.9 years). Participants completed an online bone health-screening questionnaire developed specifically for this study covering a range of lifestyle, physiological factors, combined with medical interview and received bone mineral density (BMD) measurement at the lumbar spine and femoral neck using REMS.\\n\\nResultsScoring of the bone health-screening questionnaire produced a distribution of bone health scores, with lower scores suggesting a higher risk for poor bone health. In women, scores ranged from -10 to +12, mean score 2.2 (SD 4.8). In men, scores ranged from 0 to 12, mean score 6.9 (SD 3.2). A positive correlation was observed between the bone health score derived from the questionnaire and lumbar spine and femoral neck BMD Z-scores (p<0.01).\\n\\nConclusionsThis new and comprehensive bone health-screening questionnaire with interview was effective in identifying active individuals at risk of bone fragility, who might be missed by current screening methods. The use of REMS technology to measure bone health, was feasible in the clinical setting.\",\n \"Technological advances in elite marathon performance\\nThere is scientific and legal controversy about recent technological advances in performance running shoes that reduce the energetic cost of running and may provide a distinct competitive advantage. To better understand the potential performance-enhancing effects of Nikes pioneering marathon racing shoes, we examined the finishing times and racing shoes of the top 50 male and 50 female runners from the World Marathon Major series in the 2010s -- before and after the introduction of new Nike shoe models (4%, NEXT%, Alphafly, and other prototypes; herein referred to as neoteric Nikes). Data for racing shoes were available for 3,886 of the 3,900 performances recorded at the four annual marathons in Boston, London, Chicago, and New York. In full cohort analyses, marathon finishing times were 2.0% or 2.8 min (138.5 {+/-} 8.1 min vs. 141.3 {+/-} 7.4 min, P<0.001) faster for male runners wearing neoteric Nikes compared to other shoes. For females, marathon finishing times were 2.6% or 4.3 min (159.1 {+/-} 10.0 min vs. 163.4 {+/-} 10.7 min, P<0.001) faster for runners wearing neoteric Nikes. In a subset of within-runner changes in marathon performances (males, n = 138; females, n = 101), marathon finishing times improved by 0.8% or 1.2 min for males wearing neoteric Nikes relative to the most recent marathon in which other shoes were worn, and this performance-enhancing effect was greater among females who demonstrated 1.6% or 3.7 min improvement (P=0.002). Our results demonstrate that marathon performances for world-class athletes are substantially faster wearing neoteric Nikes than other market-leading shoes, particularly among females.\",\n \"Assessment of fractional anisotropy outcomes in combat sport athletes with mild traumatic brain injury\\nAO_SCPLOWBSTRACTC_SCPLOWThe practice of combat sports increases the risk of suffering white matter injuries. That is why, it is required the early damage detection to determine to what extent the athlete may be active preserving their performance and health status. The integrity of the white matter can be quantitatively characterized in diffusion tensor images, using fractional anisotropy. This study aims at characterizing the fractional anisotropy of white matter injuries in combat athletes that are exposed to repetitive trauma and also, to detect changes in fractional anisotropy between cerebral hemispheres with and without lesions. It is proposed a global and structural analysis of the hemispheres, as well as the selection of ROI in the lesions. 14 athletes, from Boxing, Karate and Taekwondo sports, participated. The sample was divided into two groups of seven subjects each: Injured (23.428{+/-}4.157 years old) and Healthy (24.285{+/-}5.023 years old) paired by sport denomination. Diffusion tensor images were used to obtain FA values in the analysis of the hemispheres and lesions. Global and structural analysis of the hemispheres did not detect the presence of white matter lesions; however, the use of ROI selection permitted maximum approximation of the injuries location. It also improved the breakdown of FA values as it allows a local analysis of the lesion. As an additional result, there were found ROIs values, FAmed = 0.454{+/-}0.062, which exceed the average fractional anisotropy of the white matter. The cohesion of acute and chronic phase lesions were found in the same subject. The apparently contradictory results in FA values are related to the stage of the lesions.\",\n \"Findings from Cardiovascular Evaluation of NCAA Division I Collegiate Student-Athletes after Asymptomatic or Mildly Symptomatic SARS-CoV-2 Infection\\nObjectivesThe risk of myocardial damage after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been controversial. There is an urgent need for data to support the appropriate level of cardiovascular screening for safe return-to-play. The purpose of this study is to report the incidence of abnormal cardiovascular findings in National Collegiate Athletic Association (NCAA) Division I student-athletes with a history of SARS-CoV-2 infection.\\n\\nMethodsThis is a case series of student-athletes at a single NCAA Division I institution who tested positive for SARS-CoV-2 by polymerase chain reaction (PCR) or antibody testing (IgG) from 4/15/2020 to 10/31/2020. From 452 athletes who were screened, 5,124 PCR and 452 antibody tests were completed. Student-athletes were followed through 12/31/2020 (median 104 days, range 64-182 days). Cardiac work-up included clinical evaluation, troponin level, electrocardiogram (ECG), and echocardiogram. Additional work-up was ordered as clinically indicated.\\n\\nResults55 student-athletes tested positive for SARS-CoV-2. Of these, 38 (69%) had symptoms of Coronavirus Disease (COVID-19), 14 (26%) had a positive IgG test, and 41 (74%) had a positive PCR test. Eight abnormal cardiovascular screening evaluations necessitated further testing including cardiac magnetic resonance imaging (cMRI). Two athletes received new cardiac diagnoses, one probable early cardiomyopathy and one pericarditis, while the remaining six had normal cardiac MRIs.\\n\\nConclusionThese data support recent publications which recommend the de-escalation of cardiovascular testing for athletes who have recovered from asymptomatic or mildly symptomatic SARS-CoV-2 infection. Continued follow-up of these athletes for sequelae of SARS-CoV-2 is critical.\",\n \"Can prognostic factors for indirect muscle injuries in elite football (soccer) players be identified using data from preseason screening? An exploratory analysis using routinely-collected periodic health examination records.\\nThis study used periodic health examination (PHE) data from 134 outfield elite male football players, over 5 seasons (1st July 2013 to 19th May 2018). Univariable and multivariable logistic regression models were used to determine prognostic associations between 36 variables and time-loss, lower extremity index indirect muscle injuries (I-IMIs). Non-linear associations were explored using fractional polynomials. During 317 participant-seasons, 138 I-IMIs were recorded. Univariable associations were determined for previous calf indirect muscle injury (IMI) frequency (OR=1.80, 95% confidence interval (CI) = 1.09 to 2.97), hamstring IMI frequency (OR=1.56, 95% CI=1.17 to 2.09), if the most recent hamstring IMI occurred > 12 months but < 3 years prior to PHE (OR= 2.95, 95% CI = 1.51 to 5.73) and age (OR =1.12 per 1-year increase, 95% CI = 1.06 to 1.18). Multivariable analyses demonstrated that if a players most recent previous hamstring IMI was >12 months but <3 years prior to PHE (OR= 2.24, 95% CI = 1.11 to 4.53), then this was the only variable with added prognostic value over and above age (OR=1.12 per 1-year increase, 95%CI = 1.05 to 1.18). Allowing non-linear associations conferred no advantage over linear ones. Therefore, PHE has limited use for injury risk prediction.\",\n \"The Association of COVID-19 Incidence with Sport and Face Mask Use in United States High School Athletes\\nPurposeTo evaluate the influence of sport characteristics and face mask use on COVID-19 incidence among high school athletes.\\n\\nMethodsSurveys were distributed to high school athletic directors throughout the United States regarding sport re-initiation, COVID-19 cases, and risk reduction procedures in fall 2020.\\n\\nSeparate mixed effects Poisson regression models were developed to evaluate the associations between reported COVID-19 incidence and 1) sport characteristics (contact/non-contact, individual/team, indoor/outdoor) and 2) face mask use while playing (yes/no).\\n\\nResults991 schools had restarted fall sports, representing 152,484 athletes on 5,854 teams. 2,565 cases of COVID-19 were reported, representing a case rate of 1,682 cases per 100,000 athletes and an incidence rate of 24.6 cases per 100,000 player-days. COVID-19 incidence was lower among outdoor versus indoor sports (incidence rate ratio [IRR]=0.54, 95% CI=0.49-0.60, p<0.001) and non-contact versus contact sports (IRR=0.78 [0.70-0.87], p<0.001), but not team versus individual sports (IRR=0.96 [0.84-1.1], p=0.49). Face mask use was associated with a decreased incidence in girls volleyball (IRR=0.53 [0.37-0.73], p<0.001), boys basketball (IRR=0.53 [0.33-0.83], p=0.008) and girls basketball (IRR=0.36 [0.19-0.63], p<0.001), and approached statistical significance in football (IRR=0.79 [0.59-1.04], p=0.10) and cheer/dance (IRR=0.75 [0.53-1.03], p=0.081).\\n\\nConclusionsIn this nationwide survey of US high school athletic directors representing 152,484 athletes, lower COVID-19 incidence was independently associated with participation in outdoor versus indoor and non-contact versus contact sports, but not team versus individual sports. Face mask use was associated with decreased COVID-19 incidence among indoor sports, and may be protective among outdoor sports with prolonged close contact between participants.\",\n \"Effects of stricter management guidelines on return-to-play timeframes following concussion in professional Australian Rules football\\nBackgroundManagement of concussion remains a serious issue for professional sports, particularly with the growing knowledge on the consequences of repetitive concussion. One primary concern is the subjective assessment of recovery that dictates the time until a concussed athlete is returned to competition. In response to this concern, the Australian Football League (AFL) changed its policy in 2020 such that clearance for return-to-play was extended from one day, to a minimum of five days, prior to the next scheduled match.\\n\\nObjectiveWe sought to examine the impact of the AFL policy change by asking whether the time to return-to-play after concussion was increased in the 2020 season relative to previous years.\\n\\nMethodsRetrospective data on injury and return-to-play were sourced from publicly available tables published on the AFL website. We compared the number of matches missed and the number of days missed in concussed players across 2017 to 2020 inclusive.\\n\\nResultsAnalysis of data from 166 concussed players revealed no increase in the number of matches missed in 2020 relative to previous years as would have been expected from an extend recovery protocol. Considering the number of days missed in 2020 relative to 2017-19 we found, paradoxically, that there was an overall reduction in the average time to return-to-play in 2020 (11.2 vs 16.2 days).\\n\\nConclusionThis study demonstrates that any policy change around concussion management requires ongoing auditing to ensure clearance meets policy objectives and highlights the need for objective measures for return-to-play after concussion.\",\n \"How lifestyle changes within the COVID-19 global pandemic have affected the pattern and symptoms of the menstrual cycle.\\nBackgroundThe coronavirus 2019 (COVID-19) pandemic has caused significant changes to homes, working life and stress. The purpose of this research was to investigate the implications that the COVID-19 pandemic has had on the menstrual cycle and any contributing factors to these changes.\\n\\nMethodsA questionnaire was completed by 749 participants, whom ranged from physically active to elite, in their training status. The questionnaire captured detail on menstrual cycle symptoms and characteristics prior to and during the COVID-19 pandemic lockdown period, as well as lifestyle, stress, exercise and nutrition. Descriptive statistics and frequency distribution were reported and decision tree analysis performed. Statistical significance was assumed at p<0.05.\\n\\nResultsFifty-two point six percent of females experienced a change in their menstrual cycle during the lockdown period. Psychosocial symptoms had changed in over half of all participants. Participants who reported increased stress/worry in family and personal health were significantly associated with changes in menstrual symptoms. Similarly, job security stress was associated with increases in bleeding time (p<0.05).\\n\\nConclusionsIt is important that females and practitioners become aware of the implications of stressful environments and the possible long-term implications on fertility, particularly given the uncertainty around a second wave of the global pandemic.\",\n \"A novel biomechanical injury risk score demonstrates correlation with lower limb posterior chain injury in fifty elite level rugby union athletes\\nObjectivesLower limb posterior chain injury (PCI) is common amongst athletic populations, with multi-factorial risk factors including age, previous injury, strength measurements, range of motion and training load. Biomechanics are commonly considered in the prevention and rehabilitation of PCI by performance staff. However, there is no documented testing method to assess for associations between biomechanics and PCI. The aim of this study was to investigate whether there is an association between an easily applicable, novel biomechanical assessment tool and PCI.\\n\\nMethodsFifty male elite-level rugby union athletes (age 22.83{+/-}5.08) participating in the highest tier of England were tested at the start of the 2019 pre-season period and PCIs (N=48) were recorded over the 2019/20 playing season. Participants biomechanics were analysed using two-dimensional video analysis against an Injury Risk Score (IRS) system in the performance of the combined movement - prone hip extension and knee flexion. Participants biomechanics in carrying out this movement were scored against the 10-point IRS, where the more compensatory movement recorded sees an increase in an individuals IRS. Participants IRS were then compared against the number of PCI sustained and Spearmans correlation coefficient was utilised for analysis.\\n\\nResultsThere is a good significant association between IRS and PCI (R=0.573, p<0.001). Linear Regression demonstrated that an increase of 1 in IRS was associated with a 35% increase in PCI incidence (R2=0.346).\\n\\nConclusionA good significance between the IRS and PCI provides preliminary support for its use as an injury risk assessment tool.\",\n \"Muscle Strength Explains the Protective Effect of Physical Activity against COVID-19 Hospitalization among Adults aged 50 Years and Older\\nObjectivesPhysical activity has been proposed as a protective factor for COVID-19 hospitalization. However, the mechanisms underlying this association are unclear. Here, we examined the association between physical activity and COVID-19 hospitalization and whether this relationship was explained by other risk factors for severe COVID-19.\\n\\nMethodWe used data from adults aged 50 years and older from the Survey of Health, Ageing and Retirement in Europe. The outcome was self-reported hospitalization due to COVID-19 measured before August 2020. The main exposure was usual physical activity, self-reported between 2004 and 2017. Data were analyzed using logistic regression models.\\n\\nResultsAmong the 3139 participants included in the study (69.3 {+/-} 8.5 years, 1763 women), 266 were tested positive for COVID-19 and 66 were hospitalized. Results showed that individuals who engaged in physical activity more than once a week had lower odds of COVID-19 hospitalization than individuals who hardly ever or never engaged in physical activity (odds ratios = 0.41, 95% confidence interval = 0.22-0.74, p = .004). This association between physical activity and COVID-19 hospitalization was explained by muscle strength, but not by other risk factors.\\n\\nConclusionThese findings suggest that, after 50 years of age, engaging in physical activity more than once a week is associated with lower odds of COVID-19 hospitalization. The protective effect of physical activity on COVID-19 hospitalization is explained by muscle strength.\",\n \"Beneath the surface: mental health, and harassment and abuse of athletes participating in the FINA (Aquatics) World Championships, 2019\\nObjectiveTo assess the mental health and experience of sport-related harassment and abuse of athletes participating in the FINA World Championships 2019, and to analyse it in relation to gender and the aquatic disciplines.\\n\\nDesignCross-sectional study using an anonymous questionnaire.\\n\\nMethodsDuring the Championships, registered athletes (swimmers, divers, high divers, water polo players, artistic swimmers, open-water swimmers) completed a survey including the main outcome measures of depression (CES-D-10), eating disorders (BEDA-Q), the subjective need for psychotherapeutic support, and the experience of harassment and/or abuse in their sports environment.\\n\\nResultsA quarter of the athletes (n=62, 24.6%) were classified as depressed and more than a third (n=111, 35.0%) as having an eating disorder. More than 40% of the athletes stated that they wanted or needed psychotherapeutic support for mental health problems. Fifty-one athletes (14.9%) had experienced harassment/abuse in sport themselves, and 31 (9%) had witnessed it in another athlete. The experiences of harassment and abuse ranged from unwanted comments about body or appearance (40.2%) to rewards in sport for sexual favours (2.5%) and rape (0.3%). Athletes who had experienced harassment/abuse in sport themselves had higher average scores for depression and eating disorders, and more of them needed psychotherapeutic support. Up to a third would not talk to anybody if they saw or experienced harassment/abuse, and less than 20% would talk to an official for help.\\n\\nConclusionTargeted initiatives are required to address the burden of mental health issues and harassment and abuse in sport in the FINA aquatic disciplines.\",\n \"Atypical resting state functional connectivity in mild traumatic brain injury\\nObjectivesThis study aimed to investigate changes in three intrinsic functional connectivity networks (IFCNs; default mode (DMN), salience (SN), and task-positive networks (TPN)) in individuals who had sustained a mild traumatic brain injury (mTBI).\\n\\nMethodsResting-state functional magnetic resonance imaging (rs-fMRI) data was acquired from 27 mTBI patients with persistent post-concussive symptoms (PCS), along with 26 age- and sex-matched controls. These individuals were recruited from a Level-1 trauma centre, at least three months after a traumatic episode. IFCNs were established based on seed-to-voxel, region-of-interest (ROI) to ROI, and independent component analyses (ICA). Subsequently, we analyzed the relationship between functional connectivity and PCS.\\n\\nResultsSeed-to-voxel analysis of rs-fMRI demonstrated decreased functional connectivity in the right lateral parietal lobe, part of the DMN, and increased functional connectivity in the supramarginal gyrus, part of the SN. Our TPN showed both hypo- and hyperconnectivity, dependent on seed location. Within network hypoconnectivity was observed in the visual network, also using group comparison. Using an ICA, we identified altered network functional connectivity in regions within four IFCNs (sensorimotor, visual, DMN, and dorsal attentional). A significant negative correlation between dorsal attentional network connectivity and behavioural symptoms score was also found.\\n\\nConclusionsOur findings indicate that rs-fMRI may be of use clinically, in order to assess disrupted functional connectivity among IFCNs in mTBI patients. Improved mTBI diagnostic and prognostic information could be especially relevant for athletes looking to safely return to play, as well for individuals from the general population with persistent post-concussive symptoms months after injury, who hope to resume activity.\",\n \"Is a fair comparison between doping tested and doping untested powerlifters possible?\\nPurposePowerlifting is clearly divided into doping tested amateur competitions and doping untested pro competitions with pro competition money prizes ranging from a few thousand USD to over $120 000 USD in a single competition. However, the results of both pro and amateur powerlifting competitions are then collected and put into the same result database (although there is the possibility to filter the results using doping control status). The powerlifting results are compared by scores to have a fair comparison between different weight class athletes. This study plays with the thought of comparing doping tested and doping untested athletes, and creates a coefficient for the comparison.\\n\\nMethodsThe powerlifting results (noted in kg) of the 10 top ranked athletes per weight class and separately for men and women, and for doping tested and doping untested categories were collected from the openpowerlifting.org database. A weight adjusted model was fit to these results separately for men and women with the doping control status used a binary factor.\\n\\nResultsDoping control status was a significant factor when modelling the powerlifting results, p<0.001 for both men and women. Mens doping untested results were 1.0725 times as large as the doping tested results. Womens doping untested results were 1.1208 times as large as the doping tested results. These separate and precise factors could be used as coefficients for scoring doping tested and doping untested athletes powerlifting results. Moreover, the coefficients approximate the effect of doping on an elite level athletes results.\",\n \"Sex Differences in the Incidence and Risk of Ankle-Foot Complex Stress Fractures Among U.S. Military Personnel\\nBackgroundThe objective of this study was to evaluate sex differences in the incidence and risk of ankle-foot complex (AFC) stress fractures among U.S. military personnel, which could assist in developing management strategies as females assume a greater role in U.S. military operations.\\n\\nMethodsThe Defense Medical Epidemiological Database was used to identify all diagnosed AFC stress fractures in military personnel from 2006 to 2015. Cumulative incidence of AFC stress fractures was calculated and compared by year, service branch, and military rank. Sex differences in the risk of AFC stress fractures by occupation were examined, and integrated (i.e., male and female) occupations were compared with non-integrated (i.e., male-only) occupations.\\n\\nResultsA total of 43,990 AFC stress fractures were identified. The overall incidence rate was 2.76 per 1,000 person-years for males and 5.78 per 1,000 person-years for females. Females consistently had higher incidence of AFC stress fractures across all subgroups, particularly among enlisted personnel. Female enlisted service members had the highest risk of AFC stress fractures in aviation [relative risk (RR) = 5.74; 95% confidence interval [CI] 4.80-6.87] and artillery/gunnery (RR = 5.15; 95% CI 4.62-5.75) occupations. Females in integrated occupations had significantly higher rates of AFC stress fractures than males in both integrated and non-integrated occupations (i.e., special forces, infantry, and mechanized/armor).\\n\\nConclusionsFemales in the U.S. military have a higher risk of AFC stress fractures than males. As integration of females into previously sex-restricted occupations continues, focused prevention efforts may be needed to reduce injury burden and maximize medical readiness.\",\n \"Prescribed footwear and orthoses are not prophylactic in preventing lower extremity injuries in military tactical athletes. A systematic review with meta-analysis.\\nIntroductionMilitary members are exposed to high cumulative physical loads that frequently lead to injury. Prescribed footwear and orthoses have been used to prevent injury. The purpose of this systematic review with meta-analysis was to assess if prescribed prophylactic footwear or foot orthoses reduced lower extremity injury risk in military tactical athletes.\\n\\nMethodsMEDLINE, Embase, Web of Science, CINAHL, SportDiscus, and DTIC databases were searched for randomized controlled trials published at any time that compared foot orthoses or prescribed footwear (to include shock-absorbing insoles and socks) to a placebo intervention or a no-treatment control. Methodological quality was assessed and numbers of injuries, population at risk, and the duration of the study epoch were extracted and relative risk (RR) calculated. An omnibus meta-analysis was performed assessing all prescribed footwear and orthoses intervention studies, with subgroup analyses conducted on studies with similar interventions [i.e., basketball athletic shoes; athletic shoes (prescribed by foot type); foot orthoses; shock-absorbing insoles; socks; tropical combat boots].\\n\\nResultsOf 1,673 studies identified, 22 studies were included. Three of eight studies that employed orthoses demonstrated significantly reduced overuse injuries compared to no treatment controls (RR range: 0.34-0.68); one study showed neoprene insoles significantly decreased overuse injuries (RR: 0.75). There were no other significant effects in the individual studies, and no protective effects observed in the omnibus meta-analysis or in the component sub analyses.\\n\\nConclusionsPrescribed footwear and orthoses do not appear to have a prophylactic effect on lower quarter MSKI in military members and cannot be recommended at this time.\",\n \"Runners with chronic mid-portion Achilles tendinopathy have greater Triceps surae intracortical inhibition than healthy controls\\nObjectivesThis study aimed to investigate short-interval intracortical inhibition (SICI) and muscle function in the Triceps surae of runners with mid-portion Achilles tendinopathy (AT).\\n\\nMethodsRunners with (n=11) and without (n=13) AT were recruited. Plantar flexor isometric peak torque and rate of torque development (RTD) were measured using an isokinetic dynamometer. Triceps surae endurance was measured as single leg heel raise (SLHR) to failure test. SICI was assessed using paired-pulse transcranial magnetic stimulation during a sustained contraction at 10% of plantar flexor isometric peak torque.\\n\\nResultsTriceps surae SICI was 14.3% (95%CI: -2.1 to 26.4) higher in AT than control group (57.9%, 95%CI: 36.2, to 79.6; and 43.6% 95%CI:16.2 to 71.1; p=0.032) irrespective of the tested muscle. AT performed 16 (95%CI: 7.9 to 23.3, p<0.001) fewer SLHR repetitions on the symptomatic side compared to controls, and 14 (95%CI: 5.8 to 22.0, p=0.004), fewer SLHR repetitions on the non-symptomatic compared to controls. We found no between-groups differences in isometric peak torque (p=0.971) or RTD (p=0.815).\\n\\nPerspectiveOur data suggest greater intracortical inhibition for the Triceps surae muscles for the AT group accompanied by reduced SLHR endurance, without deficits in isometric peak torque or RTD. The increased SICI observed in the AT group could be negatively influencing Triceps surae endurance; thus, rehabilitation aiming to reduce intracortical inhibition should be considered to improve patient outcomes. Furthermore, SLHR is a useful clinical tool to assess plantar flexor function in AT patients.\",\n \"The devil is in the details: Reporting and transparent research practices in sports medicine and orthopedic clinical trials\\nIntroductionWhile transparent reporting of clinical trials is essential to assess the risk of bias and translate research findings into clinical practice, earlier studies have shown that deficiencies are common. This study examined current clinical trial reporting and transparent research practices in sports medicine and orthopedics.\\n\\nMethodsThe sample included clinical trials published in the top 25% of sports medicine and orthopedics journals over nine months. Two independent reviewers assessed pre-registration, open data and criteria related to scientific rigor, the study sample, and data analysis.\\n\\nResultsThe sample included 163 clinical trials from 27 journals. While the majority of trials mentioned rigor criteria, essential details were often missing. Sixty percent (confidence interval [CI] 53-68%) of trials reported sample size calculations, but only 32% (CI 25-39%) justified the expected effect size. Few trials indicated the blinding status of all main stakeholders (4%; CI 1-7%). Only 18% (CI 12-24%) included information on randomization type, method, and concealed allocation. Most trials reported participants sex/gender (95%; CI 92-98%) and information on inclusion and exclusion criteria (78%; CI 72-84%). Only 20% (CI 14-26%) of trials were pre-registered. No trials deposited data in open repositories.\\n\\nConclusionsThese results will aid the sports medicine and orthopedics community in developing tailored interventions to improve reporting. While authors typically mention blinding, randomization and other factors, essential details are often missing. Greater acceptance of open science practices, like pre-registration and open data, is needed. These practices have been widely encouraged, we discuss systemic interventions that may improve clinical trial reporting.\\n\\nRegistrationhttps://doi.org/10.17605/OSF.IO/9648H\",\n \"Recent COVID-19 vaccination is associated with modest increases in the physiological demands to graded exercise\\nAthletes are advised to receive the COVID-19 vaccination to protect them from SARS CoV-2 infection during major competitions. Despite this, many athletes are reluctant to get the COVID-19 vaccine due to concerns that symptoms of vaccinosis may impair athletic performance.\\n\\nOBJECTIVETo determine the effects of COVID-19 vaccination on the physiological responses to graded exercise.\\n\\nMETHODSHealthy participants completed a 20-minute bout of graded cycling exercise before and ~21 days after COVID-19 vaccination (2 dose Pfizer mRNA or 1 dose Johnson & Johnson).\\n\\nRESULTSOxygen uptake, CO2 production, respiratory exchange ratio, ventilation, heart rate, serum noradrenaline, and rating of perceived exertion were significantly elevated in the post vaccine trial. However, vaccination did not affect serum lactate, adrenaline, cortisol, predicted [Formula], and ventilatory threshold. Post-vaccine effects on heart rate and noradrenaline remained significant in non-infected participants that received the Pfizer vaccine. No significant effects in respiratory gas exchange parameters were found after vaccination in those previously exposed to SARS-CoV-2, but exercise adrenaline levels were significantly lower and serum lactate levels trending (p= 0.10) lower after vaccination. No changes in any physiological responses to exercise were found in control participants who completed two bouts of exercise separated by ~5 weeks without vaccination.\\n\\nCONCLUSIONRecent COVID-19 vaccination is associated with modest increases in the physiological demands to graded exercise in non-infected healthy people but may actually improve metabolic responses to exercise in those previously infected with SARS-CoV-2. Whether or not these small effects could impact athletic performance at the elite level warrants investigation.\",\n \"Neuromuscular risk factors for non-contact knee injury: a systematic review and meta-analysis\\nObjectivesIdentify neuromuscular risk factors for non-contact knee injury, using a systematic review and meta-analysis, to inform the development of preventive strategies.\\n\\nMethodsMedline, Web of Science and SCOPUS were searched from inception until November 2020. Prospective and nested case-control studies that analysed baseline neuromuscular characteristics as potential risk factors for subsequent non-contact knee injuries were included. Two reviewers independently appraised methodological quality using a modified Newcastle-Ottawa Scale. Meta-analysis was performed where appropriate, with standardised mean differences calculated for continuous scaled data.\\n\\nResultsSeventeen studies were included, comprising baseline data from 5,584 participants and 415 non-contact knee injuries (heterogeneous incidence = 7.4%). Protocols and outcome measures differed across studies, limiting data pooling. Twenty-one neuromuscular variables were included in the meta-analysis. Three were identified as risk factors. For patellofemoral pain, among military recruits: reduced non-normalised quadriceps strength at 60{o}/s (SMD -0.66; 95% CI -0.99, -0.32); reduced quadriceps strength at 240{o}/s (normalised by body mass) (SMD -0.53; CI -0.87, -0.20). For PFP/ACL injury among female military recruits: reduced quadriceps strength at 60{o}/s (normalised by body mass) (SMD -0.50; CI -0.92, -0.08).\\n\\nConclusionsQuadriceps weakness is a risk factor for PFP among military recruits, and for PFP/ACL injury among female military recruits. However, the effect sizes are small, and the generalisability of these findings is limited. The effectiveness of quadriceps strengthening interventions for preventing PFP and ACL injury merits evaluation in prospective randomised trials.\",\n \"Anticarcinogenic effects from plasma elderly trained: the role of mitochondrial function\\nThis study aimed to evaluate the effects of a multimodal exercise training on systemic cytokine levels of the elderly, and the impact of post-exercise training plasma on prostate cancer cell viability and proliferation in vitro. Fasting blood samples were collected from eight institutionalized elderly before and after eight weeks of multimodal exercise training (twice a week). The levels of interleukin(IL)-1ra, IL-1{beta}, IL-2, IL-6, IL-10, IL-17, interferon (IFN)-, tumor necrosis factor (TNF)-, fibroblast growth factor (FGF)-1, platelet-derived growth factor (PDGF) and transforming growth factor (TGF)- were evaluated in the peripheral blood. PC3 prostate cancer cell lines were incubated with 10% plasma acquired before and after exercise training from each participant. Multimodal exercise training increased the plasma levels of IL-2, IL-10, IFN-, and FGF-1, and decreased TNF- concentrations. PC3 cells presented decreased cell viability evaluated by MTT and lactate dehydrogenase activity as well as lower rates of cell proliferation after the incubation with post-training plasma samples. Furthermore, the incubation of PC-3 cells with post-training plasma decreased the mitochondrial membrane polarization and increased mitochondrial reactive oxygen species (ROS) production without changes in cytosolic ROS. Post-training plasma did not change apoptosis or necrosis rates in the PC-3 cell line. In conclusion, we showed that systemic adaptations in plasma mediators of institutionalized elderly might alter cell viability and proliferation by targeting mitochondrial ROS in a prostate cancer cell line.\",\n \"Causal Associations of Self-Reported Walking Pace with Telomere Length in 405,981 middle-aged adults: a UK Biobank study\\nObjectivesWalking pace is a strong marker of functional and health status. We investigated whether walking pace is also associated with leucocyte telomere length (LTL), which is causally associated with several diseases and has been proposed as a marker of biological age.\\n\\nMethodsWe used baseline data from UK Biobank participants recruited from March-2006 to July-2010. Walking pace was self-reported as slow, steady/average, or brisk. Accelerometer-assessed measures of total physical activity and intensity were included to support interpretation of walking pace data. LTL was measured by qPCR assay. Bi-directional Mendelian randomization (MR) analyses were undertaken to inform likely causal directions.\\n\\nResultsThe analysed cohort comprised 405,981 adults (54% women) with mean age of 56.5 years (SD, 8.1) and body mass index 27.2 kg/m2 (SD, 4.7). Steady/average and brisk walkers had significantly longer LTL compared with slow walkers, with a Z-standardised LTL difference of 0.066 (0.053-0.078) and 0.101 (0.088-0.113), respectively. Associations remained but were attenuated following full covariate adjustment: 0.038 (0.025-0.051) and 0.058 (0.045-0.072), respectively. Accelerometer data (n=86,002) demonstrated a non-linear association between LTL and habitual movement intensity, but not total activity. MR analysis supported a causal association of walking pace on LTL, with an increase in Z-standardised LTL of 0.192 (0.077, 0.306) for each difference in walking pace category. No evidence of a causal association was observed for LTL on walking pace.\\n\\nConclusionFaster walking pace may be causally associated with longer LTL, which could explain some of the beneficial effects of brisk walking on health status.\",\n \"University of Texas at Arlington (UTA) in-house COVID-19 testing program\\nThe pandemic caused by the spread of the virus SARS-CoV-2 threatened to severely disrupt the activities of student-athletes. (REF) In order to provide a safe environment for athletic competition, the National Collegiate Athletic Association (NCAA) mandated testing of student-athletes. The goal was to rapidly identify student-athletes and the athletic staff member who either tested positive for SARS-CoV-2 or were in contact with individuals who tested positive. Rapid identification of infected individuals and their contacts allowed the University to implement quarantine standards and quarantine facilities quickly as needed. The University of Texas at Arlington (UTA) developed an in-house testing program and was quickly able to meet the NCAA requirements, allowing UTA to continue its athletic participation with minimal forfeiture of scheduled games. The purpose of this paper is to report the implementation UTAs COVID prevention program for the universitys athletic program. This program will provide valuable information to other universities planning for the management of COVID prevention in their athletic programs. Challenges and solutions are identified.\",\n \"Effect of Pre-Exercise Caffeine Intake on Endurance Performance and Core Temperature Regulation During Exercise in the Heat: A Systematic Review with Meta-Analysis\\nBackgroundHeat is associated with physiological strain and endurance performance (EP) impairments. Studies have investigated the impact of caffeine intake upon EP and core temperature (CT) in the heat, but results are conflicting. There is a need to systematically determine the impact of pre-exercise caffeine intake in the heat.\\n\\nObjectiveUse a meta-analytical approach to determine the effect of pre-exercise caffeine intake on EP and CT in the heat.\\n\\nDesignSystematic review with meta-analysis.\\n\\nData sourcesFour databases and cross-referencing.\\n\\nData analysisWeighted mean effect summaries using random-effects models for EP and CT, as well as meta regressions with robust standard errors to explore confounders.\\n\\nStudy selectionPlacebo-controlled, randomized studies in adults ([≥] 18 yrs old) with caffeine intake at least 30 min before endurance exercise [≥] 30 min, performed in ambient conditions [≥] 27{degrees}C.\\n\\nResultsRespectively 6 and 12 studies examined caffeines impact on EP and CT, representing 52 and 205 endurance-trained individuals. On average, 6 mg/kg body mass of caffeine were taken 1 h before exercises of [~] 70 min conducted at 34{degrees}C and 47% relative humidity. Caffeine supplementation improved EP by 2.0 {+/-} 0.7% (95% CI: 0.6 to 3.5%) and increased the rate of change in CT by 0.10 {+/-} 0.04{degrees}C/h (95% CI: 0.03 to 0.16{degrees}C/h), compared with the ingestion of a placebo.\\n\\nConclusionCaffeine ingestion of 6 mg/kg body mass [~] 1 h before an exercise in the heat provides a worthwhile improvement in EP of 2%, while trivially increasing the rate of change in CT by 0.10{degrees}C/h.\",\n \"Decrease of heart rate variability during exercise: an index of cardiorespiratory fitness\\nThe present study proposes to measure and quantify the heart rate variability (HRV) changes during effort and to test the capacity of the produced indices to predict cardiorespiratory fitness measures. Therefore, the beat-to-beat cardiac time interval series of 18 adolescent athletes (15.2 {+/-} 2.0 years) measured during maximal graded effort test were detrended using a dynamical first-order differential equation model. Heart rate variability was then calculated as the standard deviation of the detrended RR intervals within successive windows of one minute. The variation of this measure of HRV during exercise is properly adjusted by an exponential decrease of the heart rate. The amplitude and the decay rate of this exponential trend are strongly associated with maximum oxygen consumption, maximal aerobic power, and ventilatory thresholds. It indicates that among athletes with better fitness, HRV has higher values at low heart rate and decreases faster when the heart rate increases during exercise. This analysis, based only on cardiac measurements, provides a promising tool for the study of cardiac measurements generated by portable devices.\",\n \"Is the impact of adiposity on taste perceptions moderated by chronic physical activity? An overview of the data from NHANES 2013-2014.\\nIntroductionTaste is a key sensory modulator of eating behaviour and thus energy intake. The effects of acute exercise has recently been confirmed especially regarding sweet and salty tastes. Physical activity is a safe and effective countermeasure to certain types of chemosensory losses, especially in older populations. Knowing that taste can be impaired with increased adiposity, it is unknown if the adoption of an active lifestyle on a regular basis can mitigate such impairments.\\n\\nMethodsData were extracted from NHANES 2013-2014 database. Perception of salt and bitter tastes for Tongue Tip Test and Whole Mouth Test, physical activity levels over an 8-9-day period and adiposity were analyzed. Moderation analyses were used to study the impact of adiposity on taste perceptions, with physical activity level as the moderator.\\n\\nResultsThe 197 participants (130 males) included in this project had a mean{+/-}standard deviation age of 49.1{+/-}5.2 years, a mean body fat percentage of 31.7{+/-}7.6% and mean daily physical activity levels of 11 084{+/-}3531 Monitor-Independent Movement Summary unit (MIMS). The positive association between adiposity and both bitter Tongue Tip Test and overall result (salt+bitter) of Tongue Tip Test were moderated by the adoption of an active lifestyle, with better taste scores observed in individuals achieving higher physical activity levels. When moderation analysis were stratified by gender, the effect of physical activity was no longer significant.\\n\\nPerspectivesThis study is the first to evaluate the influence of an active lifestyle on the preservation of some taste perceptions across a wide range of adiposity levels. While differences in taste can be observed regarding body fat percentage, physical activity moderates that relation only when men and women are analysed together.\",\n \"EPIDEMIOLOGY EVALUATION OF ATHLETIC INJURY IN UNIVERSITY CENTER\\nIntroductionAthletics is a sport with varied modalities, which are based on patterns and activities that are natural to human beings. As a sport, it has several benefits, such as improved physical condition and interpersonal interactions, but it is not free from risks, especially injuries related to competitions or training.\\n\\nObjectivesCharacterize injuries presented by the university athletics group of the medical course and identify possible risk factors.\\n\\nMethodsParticipants, enrolled in the athletics group of the medicine course, of both sexes, had anthropometric measurements evaluated and answered an injury screening questionnaire modified from the \\\"Injury Surveillance System\\\".\\n\\nResults31 participants responded to the questionnaire where 65% of them had at least one injury. A total of 23 injuries were reported, 20 of which were serious, with no significant difference between both sexes. The total practice time was almost 2 times longer in injured practitioners than in non-injured ones.\\n\\nConclusionThe practice of university athletics is associated with a high occurrence of serious injuries.\\n\\nSUMMARY BOXO_LICollege athletics appears to have a high incidence of injury.\\nC_LIO_LIThere is an unusually high number of serious injuries in college athletic athletes participating in the study.\\nC_LIO_LIMost college athletic sports injuries do not appear to be diagnosed or properly treated.\\nC_LIO_LIMost injuries are concentrated in the lower body.\\nC_LI\",\n \"Physical activity and health: Findings from Finnish monozygotic twin pairs discordant for physical activity\\nGenetic and early environmental differences including early health habits associate with future health. To provide insight on the causal nature of these associations, monozygotic (MZ) twin pairs discordant for health habits provide an interesting natural experiment. Twin pairs discordant for leisure-time physical activity (LTPA) in early adult life are thus a powerful study design to investigate the associations between long-term LTPA and indicators of health and wellbeing. We have used this study design by identifying 17 LTPA discordant twin pairs from two Finnish twin cohorts and summarize key findings of these studies in this paper. The carefully characterized rare long-term LTPA discordant MZ twin pairs have participated in multi-dimensional clinical examinations. The occurrence of type 2 diabetes and death has been evaluated on the basis of prospective questionnaire data and register follow-up among a larger number of twin pairs. Key findings highlight that, compared to less active twins in such MZ twin pairs, the twins with higher long-term LTPA have higher physical fitness, reduced body fat, reduced visceral fat, reduced liver fat, increased lumen diameters of conduit arteries to the lower limbs, increased bone mineral density in loaded bone areas, increased high-density lipoprotein cholesterol levels and reduced occurrence of type 2 diabetes. However, we have not been able to document differences in the life expectancy between the less and more active twin siblings of the LTPA discordant MZ twin pairs. The findings are in agreement with intervention studies but not with all observational studies in which genetic factors are not controlled for.\",\n \"Impact of Exercise-induced Dehydration on Perceived Exertion During Endurance Exercise: A Systematic Review with Meta-analysis\\nUnderstanding the impact of stressors on the rating of perceived exertion (RPE) is relevant from a performance and exercise adherence/participation standpoint. Athletes and recreationally active individuals dehydrate during exercise. No attempt has been made to systematically determine the impact of exercise-induced dehydration (EID) on RPE. The present meta-analysis aimed to determine the effect of EID on RPE during endurance exercise and examine the moderating effect of potential confounders using a meta-analytical approach. Data analyses were performed on raw RPE values using random-effects models weighted mean effect summaries and meta-regressions with robust standard errors, and with a practical meaningful effect set at 1 point difference between euhydration (EUH) and EID. Only controlled crossover studies measuring RPE with a Borg scale in healthy adults performing [≥] 30 min of continuous endurance exercise while dehydrating or drinking to maintain EUH were included. Sixteen studies were included, representing 147 individuals. Mean body mass loss with EUH was 0.5 {+/-} 0.4%, compared to 2.3 {+/-} 0.5% with EID (range 1.7 to 3.1%). Within an EID of 0.5 to 3% body mass, a maximum difference in RPE of 0.81 points (95% CI: 0.36-1.27) was observed between conditions. A meta-regression revealed that RPE increases by 0.21 points for each 1% increase in EID (95% CI: 0.12-0.31). Humidity, ambient temperature and aerobic capacity did not alter the relationship between EID and RPE. Therefore, the effect of EID on RPE is unlikely to be practically meaningful until a body mass loss of at least 3%.\",\n \"Mitochondrial DNA copy number, metabolic syndrome, and insulin sensitivity: Insights from the Sugar, Hypertension, and Physical Exercise Studies\\nMitochondrial DNA copy number (mtDNA-CN) measured in blood has been associated with many aging-related diseases, with higher mtDNA-CN typically associated with lower disease risk. Exercise training is an excellent preventative tool against aging-related disorders and has been shown to increase mitochondrial function in muscle. Using the Sugar, Hypertension, and Physical Exercise cohorts (N = 105), we evaluated the effect of 6-months of exercise intervention on mtDNA-CN measured in blood. Although there was no significant relationship between exercise intervention and mtDNA-CN change (P = 0.29), there was a nominally significant association between mtDNA-CN and metabolic syndrome (P = 0.04), which has been seen in previous literature. We also identified a nominally significant association between higher mtDNA-CN and higher insulin sensitivity (P = 0.02).\",\n \"Assessing Open Science practices in physical activity behaviour change intervention evaluations\\nObjectivesConcerns on the lack of reproducibility and transparency in science have led to a range of research practice reforms, broadly referred to as Open Science. The extent that physical activity interventions are embedding Open Science practices is currently unknown. In this study, we randomly sampled 100 reports of recent physical activity behaviour change interventions to estimate the prevalence of Open Science practices.\\n\\nMethodsOne hundred reports of randomised controlled trial physical activity behaviour change interventions published between 2018-2021 were identified. Open Science practices were coded in identified reports, including: study pre-registration, protocol sharing, data-, materials- and analysis scripts-sharing, replication of a previous study, open access publication, funding sources and conflict of interest statements. Coding was performed by two independent researchers, with inter-rater reliability calculated using Krippendorffs alpha.\\n\\nResults78% of the 100 reports provided details of study pre-registration and 41% provided evidence of a published protocol. 4% provided accessible open data, 8% provided open materials and 1% provided open analysis scripts. 73% of reports were published as open access and no studies were described as replication attempts. 93% of reports declared their sources of funding and 88% provided conflicts of interest statements. A Krippendorffs alpha of 0.73 was obtained across all coding.\\n\\nConclusionOpen data, materials, analysis and replication attempts are currently rare in physical activity behaviour change intervention reports, whereas funding source and conflict of interest declarations are common. Future physical activity research should increase the reproducibility of their methods and results by incorporating more Open Science practices.\"\n]","isConversational":false},"negative":{"kind":"list like","value":["KIM-1/TIM-1 is a Receptor for SARS-CoV-2 in Lung and Kidney\nSARS-CoV-2 precipitates respiratory distress by infection of airway epithelial cells and is often accompanied by acute kidney injury. We report that Kidney Injury Molecule-1/T cell immunoglobulin mucin domain 1 (KIM-1/TIM-1) is expressed in lung and kidney epithelial cells in COVID-19 patients and is a receptor for SARS-CoV-2. Human and mouse lung and kidney epithelial cells express KIM-1 and endocytose nanoparticles displaying the SARS-CoV-2 spike protein (virosomes). Uptake was inhibited by anti-KIM-1 antibodies and TW-37, a newly discovered inhibitor of KIM-1-mediated endocytosis. Enhanced KIM-1 expression by human kidney tubuloids increased uptake of virosomes. KIM-1 binds to the SARS-CoV-2 Spike protein in vitro. KIM-1 expressing cells, not expressing angiotensin-converting enzyme 2 (ACE2), are permissive to SARS-CoV-2 infection. Thus, KIM-1 is an alternative receptor to ACE2 for SARS-CoV-2. KIM-1 targeted therapeutics may prevent and/or treat COVID-19.","Clinical interpretation of machine learning models for prediction of diabetic complications using electronic health records\nType 2 diabetes is a massive public health issue that continues to grow. The rate of diabetic complication progression varies across individuals. Understanding factors that alter the rate of complication onset may uncover new clinical interventions and help prioritize individuals for more aggressive management. Here, we explore how various machine learning models and types of electronic health records can predict fast versus slow diabetic complication onset using only patient data prior to diabetes diagnosis. We find that optimized random forests generally perform best among the tested models and combining all data sources yields the best predictive performance. A key differentiator of our study is our model interpretation, which identifies specific patient metrics from each dataset that play a unique role in the progression of each complication. Overall, our clinical interpretation of machine learning models can identify patients at risk for poorer outcomes years in advance of their diabetic complication.","BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations\nPurposeHeterozygous variants in BCL11A underlie an intellectual developmental disorder with persistence of fetal hemoglobin (BCL11A-IDD, a.k.a. Dias-Logan syndrome). We sought to delineate the genotypic and phenotypic spectrum of BCL11A-IDD.\n\nMethodsWe performed an in-depth analysis of 42 patients with BCL11A-IDD ascertained through a collaborative network of clinical and research colleagues. We also reviewed 33 additional affected individuals previously reported in the literature or available through public repositories with clinical information.\n\nResultsMolecular and clinical data analysis of 75 patients with BCL11A-IDD identified 60 unique variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique CNVs (microdeletions involving BCL11A only). We redefined the most frequent manifestations of the condition: intellectual disability, hypotonia, behavioral abnormalities, postnatal microcephaly and autism spectrum disorder. Two thirds of patients have brain MRI abnormalities, and we identified a recurrent posterior fossa phenotype of vermian hypoplasia and/or small brainstem. Truncating BCL11A variants, particularly those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S) isoform, were associated with increased severity.\n\nConclusionsWe expand the clinical delineation of BCL11A-IDD and identify a potential isoform-specific genotype-phenotype correlation. We show that BCL11A-IDD is associated with posterior fossa anomalies and highlight the differences between BCL11A-IDD and 2p16.1p15 microdeletion syndrome.","Causality of Abdominal Obesity on Cognition: a Trans-ethnic Mendelian Randomization study\nObesity has been associated with cognition in observational studies; however, whether its effect is confounding, reverse causality, or causal remains inconclusive. Using two-sample Mendelian randomization (MR) analyses, we investigated the causality of overall obesity, measured by BMI, and abdominal adiposity, measured by waist-hip ratio adjusted for BMI (WHRadjBMI), on cognition. Using summary data from the GIANT consortium, COGENT consortium, and UK Biobank of European ancestry, there was no causal effect of BMI on cognition performance (beta[95% CI]=-0.04[-0.12,0.04], p-value=0.35); however, a 1-SD increase in WHRadjBMI was associated with 0.07 standardized decrease in cognition performance (beta[95% CI]=-0.07[-0.12,-0.02], p=0.006). Using raw data from the Taiwan Biobank of Asian ancestry, there was no causal effect of BMI on cognitive aging (beta[95% CI]=0.00[-0.09,0.09], p-value=0.95); however, a 1-SD increase in WHRadjBMI was associated with a 0.17 standardized decrease in cognitive aging (beta[95% CI]=-0.17[-0.30,-0.03], p=0.02). This trans-ethnic MR study reveals that abdominal adiposity impairs cognition.","Extended Invariant Information Clustering is Effective for Leave-One- Site-Out Cross-Validation in Resting State Functional Connectivity Modelling\nHerein, we propose a new deep neural network model based on invariant information clustering (IIC), proposed by Ji et al., to improve the modeling performance of the leave-one-site-out cross-validation (LOSO-CV) for a multi-source dataset. Our Extended IIC (EIIC) is a type of contrastive learning; however, unlike the original IIC, it is characterized by transfer learning with labeled data pairs, but without the need for a data augmentation technique. Each site in LOSO-CV is left out in turn from the remaining sites used for training and receives a value for modeling evaluation. We applied the EIIC to the resting state functional connectivity magnetic resonance imaging dataset of the Autism Brain Imaging Data Exchange. The challenging nature of brain analysis for autism spectrum disorder (ASD) can be attributed to the variability of subjects, particularly the rapid change in the neural system of children as the target ASD age group. However, EIIC demonstrated higher LOSO-CV classification accuracy for the majority of scanning locations than previously used methods. Particularly, with the adjustment of a mini-batch size, EIIC outperformed other classifiers with an accuracy >0.8 for the sites with highest mean age of the subjects. Considering its effectiveness, our proposed method might be promising for harmonization in other domains, owing to its simplicity and intrinsic flexibility. We are currently submitting this manuscript to Frontiers in Neuroinformatics.","IT ambidexterity driven patient agility and hospital patient service performance: a variance approach\nHospitals are currently exploring digital options to transform their clinical procedures and their overall engagement with patients. This paper investigates how hospital departments can leverage the ability of firms to simultaneously explore new IT resources and practices (IT exploration) as well as exploit their current IT resources and practices (IT exploitation), i.e., IT ambidexterity, to adequately sense and respond to patients needs and demands, i.e., patient agility. This study embraces the dynamic capability view and develops a research model, and tests it accordingly using cross-sectional data from 90 clinical hospital departments from the Netherlands through an online survey. The models hypothesized relationships are tested using Partial Least Squares (PLS) structural equation modeling (SEM). The outcomes demonstrate the significance of IT ambidexterity in developing patient agility, positively influencing patient service performance. The study outcomes support the theorized model can the outcomes shed light on how to transform clinical practice and drive patient agility.","Teaching an Old Dog New Tricks: Serum Troponin T as a Biomarker in Amyotrophic Lateral Sclerosis\nAmyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. Diagnosis, management and therapeutic trials are hampered by a lack of informative biomarkers. Troponins (Tn) are components of skeletal and cardiac muscles. Acute elevation of cardiac isoforms of troponin I (cTnI) and T (cTnT) in serum indicates myocardial injury. Case reports suggested that serum levels of cTnT, but not cTnI are chronically elevated in ALS and other neuromuscular disorders.\n\nUsing standard clinical laboratory methodologies we studied serum troponin levels in a multicentric cross-sectional cohort of 75 ALS patients and sixty controls (DESCRIBE-ALS cohort) and in a real-world cohort of 179 consecutive patients from our ALS clinic at the University Hospital Bonn.\n\nWe found that serum cTnT, is elevated in >60% of ALS patients while cTnI is always normal. Serum cTnT levels increase over time and correlate with disease severity as measured with the revised ALS FRS score. There was no correlation with the phosphorylated neurofilament heavy chain (pNfH) levels in the cerebrospinal fluid. We propose that cTnT elevations in ALS are of non-cardiac origin and may serve as a proxy of lower motor neuron or skeletal muscle involvement. They potentially help to stratify patients according to lower motoneuron involvement. Further research will determine the biological origin of the cTnT elevation and its validity as a diagnostic and/or prognostic marker. Our finding also serves as a reminder to interpret cTnT with caution elevations in patients with neuromuscular diseases.","Clinical Validation of a Proteomic Biomarker Threshold for Increased Risk of Spontaneous Preterm Birth\nPreterm births are prevalent and a leading cause of neonatal death in the United States. Despite the availability of effective interventions, to date there is not a robust and widely applicable test to identify pregnancies at high risk for spontaneous preterm birth (sPTB). Previously, a sPTB predictor based on the ratio of two proteins, IBP4/SHBG, was validated as an accurate predictor of sPTB in the observational study Proteomic Assessment of Preterm Risk (PAPR). Here it is demonstrated that the same predictor threshold associated with 2-fold increased risk of sPTB, namely -1.4, is also statistically significant for predicting elevated risk of sPTB in the observational study Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor (TreeToP).","TreatmentPatterns: An R package to analyze treatment patterns of a study population of interest\nBackground and objectivesThere is an increasing interest to use real-world data to illustrate how patients with specific medical conditions are treated in real life. Insight in the current treatment practices helps to improve and tailor patient care. We aim to provide an easy tool to support the development and analysis of treatment pathways for a wide variety of medical conditions.\n\nMethodsWe formally defined the process of constructing treatment pathways and developed an open-source R package TreatmentPatterns (https://github.com/mi-erasmusmc/TreatmentPatterns) to enable a reproducible and timely analysis of treatment patterns.\n\nResultsThe developed package supports the analysis of treatment patterns of specific populations of interest. We demonstrate the functionality of the package by analyzing the treatment patterns of three common chronic diseases (type II diabetes mellitus, hypertension, and depression) in the Dutch Integrated Primary Care Information (IPCI) database.\n\nConclusionTreatmentPatterns is a tool to make the analysis of treatment patterns more accessible, more standardized, and more interpretation friendly. This tool can facilitate and contribute to the accumulation of knowledge on real-world treatment patterns across disease domains. We encourage researchers to further adjust and add custom analysis to the package based on their research needs.","Medication use and physical assaults in the psychiatric emergency room\nObjectiveTo evaluate the relationship between medications used to treat acute agitation (antipsychotics, mood stabilizers and benzodiazepines) and subsequent assault incidence in the psychiatric emergency room.\n\nMethodsMedication orders and assault incident reports were obtained from electronic health records for 17,052 visits to an urban psychiatric emergency room from 2014-2019. Assault risk was modeled longitudinally using Poisson mixed-effect regression.\n\nResultsAssaults were reported during 0.5% of visits. Intramuscular medications (IMs) were administered in 23.3% of visits overall, and predominately administered within the first 4-hours of a visit. IM administration was correlated with assault (IRR=24.2 [5.33, 110.0]), often because IM medication was administered immediately subsequent to reported assaults. Interacted with time, IMs were not significantly associated with reduction in future assaults (IRR=0.700 [0.467, 1.04]). Neither benzodiazepines nor mood stabilizers were associated with subsequent changes to the risk of reported assault. By contrast, antipsychotic medications were associated with decreased assault risk across time (IRR=0.583 [0.360, 0.942]).\n\nConclusionsIM order rates are high relative to overall assault incident risk. Of the three major categories of medications administered commonly in the psychiatric emergency setting, only antipsychotic medications were associated with measurable decreases in subsequent assault risk. Careful weighing of the risks and benefits of medications is encouraged; antipsychotic medication can have a significant side effect burden, and other medications (IMs, benzodiazepines, mood stabilizers) were not associated with subsequent reduction in assault risk in this analysis.","Distinctive modularity and resilience of structural covariance network in first-episode antipsychotic-naive psychoses\nObjectiveDivergent findings in structural brain alterations in psychoses suggest that often-observed regions may exist within a network of susceptible regions. We built structural covariance networks (SCN) of volumes, cortical thickness, and surface area using the Human Connectome Project atlas-based parcellation of 358 regions on structural MRI data from 79 first-episode antipsychotic-naive psychosis patients (FEAP) and 68 controls.\n\nMethodsUsing graph theoretic methods, we obtained representative graph metrics of integration, segregation, resilience, centrality, importance, community structure, and hub distribution for all 3-morphometric features. We compared networks for resilience by simulated removal (\"attacks\") of nodes and hubs, and simulated replacement of correlations among nodes in FEAP with that of controls using DeltaCon metric.\n\nResultsVolume and thickness SCNs of FEAP showed differences in many graph metrics in opposite directions compared to controls but not surface area SCN. Network resilience did not show differences in the replacement simulation and hub \"attacks, but betweenness centrality-based node \"attacks\" showed FEAP network disintegrating with relatively fewer node removals with preserved global efficiency compared to controls. In FEAP, communities consisted of regions from different lobes and hubs were more distributed than in controls.\n\nConclusionsOur findings suggest decreased heterogeneity and less differentiated community structure of FEAP network that may not be attributed to illness chronicity and medications. Contribution of cortical thickness but not surface area suggests that disease/developmental processes may preferentially affect cortical thickness. Near-similar resilience of FEAP and control networks may shield controls from developing illness but may prevent fuller long-term recovery in FEAP.","Multi-omic landscaping of human midbrains identifies neuroinflammation as major disease mechanism in advanced-stage Parkinson's disease\nParkinsons disease (PD) is the second most common neurodegenerative disorder whose prevalence is rapidly increasing worldwide. The disease mechanisms of sporadic PD are not yet completely understood. Therefore, causative therapies are still lacking. To obtain a more integrative view of disease-mediated alterations, we investigated the molecular landscape of PD in human post-mortem midbrains. Tissue from 13 PD patients and 10 controls was subjected to small RNA sequencing, transcriptomics, and proteomics analysis. Differential expression analyses were performed reveal multiple deregulated molecular targets linked to known pathomechanisms of PD as well as novel processes. We found significant differential expression of miR-539-3p, miR-376a-5p, miR-218-5p, and miR-369-3p, the valid miRNA-mRNA interacting pairs of miR-218-5p/RAB6C, and miR-369-3p/GTF2H3, as well as multiple proteins relevant in the pathology of PD, including CHI3L1, SELENBP1, PRDX1, HSPA1B, and TH. Vertical integration of multiple omics analyses allowed to validate disease-mediated molecular alterations across different molecular layers and functional annotation of differentially expressed targets identified a strong enrichment of pathways related to inflammation and activation of the immune response. This suggests that neuroinflammation may significantly contribute to disease progression in PD and may be a promising therapeutic target in advanced stages of PD.","Automated Detection of Candidate Subjects with Cerebral Microbleeds using Machine Learning\nCerebral microbleeds (CMBs) appear as small, circular, well defined hypointense lesions of a few mm in size on T2*-weighted gradient recalled echo (T2*-GRE) images and appear enhanced on susceptibility weighted images (SWI). Due to their small size, contrast variations and other mimics (e.g. blood vessels), CMBs are highly challenging to detect automatically. In large datasets (e.g. the UK Biobank dataset), exhaustively labelling CMBs manually is difficult and time consuming. Hence it would be useful to preselect candidate CMB subjects in order to focus on those for manual labelling, which is essential for training and testing automated CMB detection tools on these datasets. In this work, we aim to detect CMB candidate subjects from a larger dataset, UK Biobank, using a machine learning-based, computationally light pipeline. For our evaluation, we used 3 different datasets, with different intensity characteristics, acquired with different scanners. They include the UK Biobank dataset and two clinical datasets with different pathological conditions. We developed and evaluated our pipelines on different types of images, consisting of SWI or GRE images. We also used the UK Biobank dataset to compare our approach with alternative CMB preselection methods using non-imaging factors and/or imaging data. Finally, we evaluated the pipelines generalisability across datasets. Our method provided subject-level detection accuracy > 80% on all the datasets (withindataset results), and showed good generalisability across datasets, providing a consistent accuracy of over 80%, even when evaluated across different modalities.","Analysis of Mutational Profile of Hypopharyngeal and Laryngeal Head and Neck Cancers Identifies KMT2C as a Potential Tumor Suppressor\nHypopharyngeal cancer represents one of worst types of head and neck tumors with only few studies focusing on the genomic profile of this type of cancer. Using targeted next-generation sequencing we analyzed 48 HPV-negative tumor samples including 23 originating from hypopharynx, and 25 from larynx. Among genes previously described as significantly mutated, TP53, FAT1, NOTCH1, KMT2C and CDKN2A were found to be most frequently mutated. We also found that more than three-fourths of our patients harbored candidate actionable or prognostic alterations in genes belonging to RTK/ERK/PI3K, cell-cycle and DNA-damage repair pathways. Using previously published data we compared 67 hypopharyngeal cancers to 595 head and neck cancers from other sites and found no prominent differences in mutational frequency except for CASP8 and HRAS genes. Since we observed relatively frequent mutations of KTM2C (MLL3) in our dataset, we analyzed their role in vitro by generating KMT2C-mutant hypopharyngeal cancer cell line FaDu with CRISPR-Cas9. We demonstrate that KMT2C loss-of-function results in increased colony formation and proliferation, in concordance with its previously published results. In summary, our results show that mutational profile of hypopharyngeal cancers might be similar to the one observed for other head and neck cancers with respect to minor differences and includes multiple candidate actionable and prognostic genetic alterations. We also demonstrate for the first time that KMT2C gene may play a role of tumor suppressor in head and neck cancer, which opens new possibilities in the search for new targeted treatment approaches.","Outward and inward protections of different mask designs for different respiratory activities\nWe evaluate the outward and inward protections of different mask types (N95, surgical and two cloth mask designs) taking into account the imperfect fit on the wearer. To this end, we built a manikin to simulate exhaling, coughing and inhaling of aerosol droplets 0.3-5.0 {micro}m in diameters. The outward and inward protections depend on many factors, including the droplet size, the mask fit and the presence of a filter layer. Here, we show that cloth and surgical masks with a non-woven filter layer can achieve a combined outward and inward protections between 50% and 90%. Removing the filter layer greatly reduces the protection efficiency to below 20% for the smallest droplet size. While a well-fitted N95 masks offer protection efficiency close to 100%, a poorly fitted N95 mask with gaps offers less protection than a well-fitted surgical/cloth mask. We also found that double masking--the wearing of cloth mask on top of a surgical mask--is only effective at reducing outward droplet emissions when coughing, while offering no additional protection when exhaling/inhaling as compared to a single cloth/surgical mask. The results of our work can inform the implementation of mask mandates to minimize airborne transmissions of coronavirus disease of 2019 (COVID-19).\n\nPractical implicationsO_LIA single cloth/surgical mask with non-woven filter layer offers significant protection against airborne transmissions.\nC_LIO_LIFiltering facepiece masks such as N95 respirators are unlikely to achieve the advertised high protection for the general public due to poor mask fit.\nC_LIO_LIDouble-masking offers little to no additional protection over a single cloth/surgical mask.\nC_LI","Developing A Deep Learning Natural Language Processing Algorithm For Automated Reporting Of Adverse Drug Reactions\nThe detection of adverse drug reactions (ADRs) is critical to our understanding of the safety and risk-benefit profile of medications. With an incidence that has not changed over the last 30 years, ADRs are a significant source of patient morbidity, responsible for 5-10% of acute care hospital admissions worldwide. Spontaneous reporting of ADRs has long been the standard method of reporting, however this approach is known to have high rates of under-reporting, a problem that limits pharmacovigilance efforts. Automated ADR reporting presents an alternative pathway to increase reporting rates, although this may be limited by over-reporting of other drug-related adverse events.\n\nWe developed a deep learning natural language processing algorithm to identify ADRs in discharge summaries at a single academic hospital centre. Our model was developed in two stages: first, a pre-trained model (DeBERTa) was further pre-trained on 150,000 unlabelled discharge summaries; secondly, this model was fine-tuned to detect ADR mentions in a corpus of 861 annotated discharge summaries. To ensure that our algorithm could differentiate ADRs from other drug-related adverse events, the annotated corpus was enriched for both validated ADR reports and confounding drug-related adverse events using. The final model demonstrated good performance with a ROC-AUC of 0.934 (95% CI 0.931 - 0.955) for the task of identifying discharge summaries containing ADR mentions.","The development and usability testing of digital knowledge translation tools for parents of children with acute otitis media\nAcute otitis media (AOM) is the most common bacterial ear infection affecting up to 80% of children before the age of three. Despite the common occurrence of the illness and the wide range of material available at clinics and online, parents are not always aware of these resources and they are often difficult to understand. We worked with parents to develop and assess the usability of a whiteboard animation video and interactive infographic for AOM in children. Parents rated the tools highly across all usability items, suggesting that creative tools developed using multi-method development processes can be useful, relevant, understandable, and will be used by the intended audience.\n\nFollowing the completion of the English-language products, our team culturally adapted the tools for the Pakistan context and evaluated the usability of these adapted tools. During usability testing, parents indicated that they felt the tools were useful, demonstrating that culturally adapted version of knowledge translations tools are effective in ensuring that parents could understand complex health information.","Development of Novel Measures for Alzheimer's Disease Prevention Trials (NoMAD)\nIntroductionAssessment of cognition and everyday function is essential in clinical trials for Alzheimers disease (AD). Two novel measures of cognition (No Practice Effects (NPE) cognitive battery and Miami Computerized Functional Assessment Scale (CFAS)) were designed to have robust psychometric properties and reduced practice and ceiling effects. This study aims to evaluate if the NPE and CFAS demonstrate stronger psychometric properties and reduced practice effects compared with established measures, including the Preclinical Alzheimer Cognitive Composite (PACC), Alzheimers Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Functional Activities Questionnaire (FAQ).\n\nMethodsThis parallel group, four-site study will randomize 320 cognitively intact adults aged 60 to 85 years to novel or well-established measures of cognition and function. All participants will receive assessments at baseline (week 0), week 12, and week 52, as well as a brain MRI scan and Apolipoprotein E genetic test at study entry. Analyses will determine psychometric properties of the NPE and CFAS, compare the sensitivity of measures to AD risk markers, and identify cognitive domains within the NPE.\n\nDiscussionPractice effects have been a major limitation of Alzheimers disease clinical trials that typically assess cognitive changes over serial assessments. Detection of functional impairment in cognitively normal individuals with biomarkers for Alzheimers disease requires instruments sensitive to very subtle functional changes. This study is intended to support the validation of two new composite measures, the NPE battery and the CFAS, which may advance clinical testing of interventions for individuals across the spectrum of early stage Alzheimers disease.\n\nTrial RegistrationNCT03900273","L18F substrain of SARS-CoV-2 VOC-202012/01 is rapidly spreading in England\nThe Variant of Concern (VOC)-202012/01 (also known as B.1.1.7) is a rapidly growing lineage of SARS-CoV-2. In January 2021, VOC-202012/01 constituted about 80% of SARS-CoV-2 genomes sequenced in England and was present in 27 out of 29 countries that reported at least 50 viral genomes. As this strain will likely spread globally towards fixation, it is important to monitor its molecular evolution. Based on GISAID data we systematically estimated growth rates of mutations acquired by the VOC lineage to find that L18F substitution in viral spike protein has initiated a substrain characterized by replicative advantage of 1.70 [95% CI: 1.56-1.96] in relation to the remaining VOC-202012/01 substrains. The L18F mutation is of significance because when recently analyzed in the context of the South African strain 501Y.V2 it has been found to compromise binding of neutralizing antibodies. We additionally indicate three mutations that were acquired by VOC-202012/01 in the receptor binding motif of spike, specifically E484K, F490S, and S494P, that may also give rise to escape mutants. Such mutants may hinder efficiency of existing vaccines and expand in response to the increasing after-infection or vaccine-induced seroprevalence.","Combining Navigator and Optical Prospective Motion Correction for High-Quality 500 μm Resolution Quantitative Multi-Parameter Mapping at 7T\nPURPOSEHigh-resolution quantitative multi-parameter mapping shows promise for non-invasively characterizing human brain microstructure but is limited by physiological artifacts. We implemented corrections for rigid head movement and respiration-related B0-fluctuations and evaluated them in healthy volunteers and dementia patients.\n\nMETHODSCamera-based optical prospective motion correction (PMC) and free-induction decay (FID) navigator correction were implemented in a gradient and RF-spoiled multi-echo 3D gradient echo sequence for mapping proton density (PD), longitudinal relaxation rate (R1) and effective transverse relaxation rate (R2*). We studied their effectiveness separately and in concert in young volunteers and then evaluated the navigator correction (NAVcor) with PMC in a group of elderly volunteers and dementia patients. We used spatial homogeneity within white matter (WM) and gray matter (GM) and scan-rescan measures as quality metrics.\n\nRESULTSNAVcor and PMC reduced artifacts and improved the homogeneity and reproducibility of parameter maps. In elderly participants, NAVcor improved scan-rescan reproducibility of parameter maps (coefficient of variation decreased by 14.7% and 11.9% within WM and GM respectively). Spurious inhomogeneities within WM were reduced more in the elderly than in the young cohort (by 9% vs 2%). PMC increased regional GM/WM contrast and was especially important in the elderly cohort, which moved twice as much as the young cohort. We did not find a significant interaction between the two corrections.\n\nCONCLUSIONNavigator correction and PMC significantly improved the quality of PD, R1 and R2* maps, particularly in less compliant elderly volunteers and dementia patients.","LABELLING HUMAN KINEMATICS DATA USING CLASSIFICATION MODELS\nThe goal of this study is to develop a classification model that can accurately and efficiently label human kinematics data. Kinematics data provides information about the movement of individuals by placing sensors on the human body and tracking their velocity, acceleration and position in three dimensions. These data points are available in C3D format that contains numerical data transformed from 3D data captured from the sensors. The data points can be used to analyse movements of injured patients or patients with physical disorders. To get an accurate view of the movements, the datasets generated by the sensors need to be properly labelled. Due to inconsistencies in the data capture process, there are instances where the markers have missing data or missing labels. The missing labels are a hindrance in motion analysis as it introduces noise and produces incomplete datapoints of sensors positioning in 3 dimensional space. Labelling the data manually introduces substantial effort in the analysis process. In this paper, we will describe approaches to pre-process the kinematics data from its raw format and label the data points with missing markers using classification models.","The long-term effects of free care on birth outcomes: Evidence from a national policy reform in Zambia\nAs women in many countries still fail to give birth in facilities due to financial barriers, many see the abolition of user fees as a key step on the path towards universal coverage. We exploited the staggered removal of user charges in Zambia from 2006 to estimate the effect of user fee removal over up to five years after the policy change. We used data from the birth histories of two nationally representative Demographic and Health Surveys to implement a difference-in-differences analysis and identify the causal impact of removing user charges on institutional and assisted deliveries, caesarean sections and neonatal deaths. We also used the rich survey data to explore heterogeneous effects of the policy. Removing fees had little effect in the short term but large positive effects appeared about two years after the policy change. Institutional deliveries in treated areas increased by 25 to 35%, driven entirely by a reduction in home births. However, there was no evidence that the reform changed the behaviours of women with lower education, the proportion of caesarean sections or reduced neonatal mortality. Institutional deliveries increased where care quality was high, but not where it was low. While abolishing user charges may reduce financial hardship from healthcare payments, it does not necessarily improve equitable access to care or health outcomes. Shifting away from user fees is a necessary but insufficient step towards universal health coverage, and concurrent reforms are needed to target vulnerable populations and improve quality of care.","Fecal microbiota transplantation increases colonic IL-25 and dampens tissue inflammation in patients with recurrent Clostridioides difficile\nBackgroundClostridioides difficile infection (CDI) is the most common hospital-acquired infection in the United States. Antibiotic-induced dysbiosis is the primary cause of susceptibility and fecal microbiota transplantation (FMT) has emerged as an effective therapy for recurrence. We previously demonstrated in the mouse model of CDI that antibiotic-induced dysbiosis reduced colonic expression of IL-25, and that FMT protected in part by restoring gut commensal bacteria-mediated IL-25 signaling. Here we conducted a prospective clinical trial to test the impact of FMT on immunity, specifically testing in humans if FMT induced IL-25 expression in the colon.\n\nMethodsSubjects received colonic biopsies and blood sampling at the time of FMT and 60-days later. Colon biopsies were assayed for IL-25 by immunoassay, for mRNA by RNAseq, and for bacterial content by 16 S rDNA sequencing. High dimensional flow cytometry was also conducted on peripheral blood mononuclear cells pre- and post-FMT.\n\nResultsAll 10 subjects who received FMT had no CDI recurrences over a 2 year follow-up post FMT. FMT increased alpha diversity of the colonic microbiota and was associated with several immunologic changes. The cytokine IL-25 was increased in colonic tissue. In addition, increased expression of homeostatic genes and repression of inflammatory genes was observed in colonic mRNA transcripts. Finally, circulating Th17 cells were decreased post-FMT.\n\nConclusionThe increase in the cytokine IL-25 accompanied by decreased inflammation is consistent with FMT acting in part to protect from recurrent CDI via restoration of commensal activation of type 2 immunity.","Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly\nThe Kennedy pathways catalyze the de novo synthesis of phosphatidylcholine and phosphatidylethanolamine, the most abundant components of eukaryotic cell membranes. In recent years, these pathways have moved into clinical focus since four out of ten genes involved have been associated with a range of autosomal recessive rare diseases such as a neurodevelopmental disorder with muscular dystrophy (CHKB), bone abnormalities and cone-rod dystrophy (PCYT1A), and spastic paraplegia (PCYT2, SELENOI).\n\nWe identified six individuals from five families with bi-allelic variants in CHKA presenting with severe global developmental delay, epilepsy, movement disorders, and microcephaly. Using structural molecular modeling and functional testing of the variants in a in a cell-based S. cerevisiae model, we determined that these variants reduce the enzymatic activity of CHKA and confer a significant impairment of the first enzymatic step of the Kennedy pathway.\n\nIn summary, we present CHKA as a novel autosomal recessive gene for a neurodevelopmental disorder with epilepsy and microcephaly.","RBDAct: Home screening of REM sleep behaviour disorder based on wrist actigraphy in Parkinson's patients\nBackgroundREM sleep behaviour disorder (RBD) is a disabling, often overlooked sleep disorder affecting up to 70% of patients with Parkinsons disease. Identifying and treating RBD is critical to prevent severe sleep-related injuries, both to patients and bedpartners. Current diagnosis relies on nocturnal video-polysomnography, which is an expensive and cumbersome exam requiring specific clinical expertise.\n\nObjectivesTo design, optimise, and validate a novel home-screening tool, termed RBDAct, that automatically identifies RBD in Parkinsons patients based on wrist actigraphy only.\n\nMethodsTwenty-six Parkinsons patients underwent two-week home wrist actigraphy worn on their more affected arm, followed by two non-consecutive in-lab evaluations. Patients were classified as RBD versus non-RBD based on dream enactment history and video-polysomnography. We characterised patients movement patterns during sleep using raw tri-axial accelerometer signals from wrist actigraphy. Machine learning classification algorithms were then trained to discriminate between patients with or without RBD using actigraphic features that described patients movements. Classification performance was quantified with respect to clinical diagnosis, separately for in-lab and at-home recordings.\n\nResultsClassification performance from in-lab actigraphic data reached an accuracy of 92.9{+/-}8.16% (sensitivity 94.9{+/-}7.4%, specificity 92.7{+/-}13.8%). When tested on home recordings, accuracy rose to 100% over the two-week window. Features showed robustness across tests and conditions.\n\nConclusionsRBDAct provides reliable predictions of RBD in Parkinsons patients based on home wrist actigraphy only. These results open new perspectives for faster, cheaper and more regular screening of sleep disorders, both for routine clinical practice and for clinical trials.","Long-term Complications of Unintentional Dural Puncture During Labor Epidural Analgesia: A Case-Control Study.\nIntroductionEpidural analgesia is the preferred method to manage pain during labor and delivery. The insertion of the epidural catheter can be complicated by unintentional dural puncture that may result in postdural puncture headache. There is limited evidence on the long term implications of this complication. We sought to investigate if women who sustained a dural puncture have a higher risk of developing chronic headache, low back pain and visual or auditory impairment.\n\nMethodsWe conducted a 1:1 case-control study with women who delivered at our institution from January 2015 to December 2019. Cases were women who received epidural analgesia and sustained an unintentional dural puncture and controls were women who received epidural analgesia but did not sustain such complication. We matched cases and controls for date of delivery, age, and BMI. All women completed an online survey with validated questionnaires for diagnosis of chronic headache and chronic back pain. We used dichotomic (yes/no) questions to look for the presence of chronic visual and auditory impairment.\n\nResultsSixty-three case-control pairs were studied. Women who sustained a dural puncture during their epidural catheter insertion had a higher risk of developing chronic headache [14.3%, versus 4.8%, p=0.049, AOR: 3.36 (1.05, 12.82)] and chronic back pain [39.7% versus 19.1%, p=0.009, AOR: 2.67 (1.25, 5.72)] than women who did not sustain a dural puncture. The incidence of chronic auditory impairment was also higher in the dural puncture group [14.3% versus 1.6%, p=0.007, AOR: 9.98 (1.21, 82.62)].\n\nConclusionsAn unintentional dural puncture during epidural catheter insertion in parturients is associated with increased risk of chronic headache, back pain and auditory impairment.","Primary care and point-of-care testing during a pandemic: Clinician's perspectives on integrating rapid testing for COVID-19 into the primary care pathway\nBackgroundReal-world evidence to support the adoption of SARS-CoV-2 point-of-care (POC) tests in primary care is limited. As the first point of contact of the health system for most patients, POC testing can potentially support general practitioners (GPs) quickly identify infectious and non-infectious individuals to rapidly inform patient triaging, clinical management, and safely restore more in-person services.\n\nObjectivesTo explore the potential role of SARS-CoV-2 point-of-care testing in primary care services.\n\nDesignA qualitative study using an inductive thematic analysis.\n\nSetting21 general practices located across three regions in England.\n\nResultsThree major themes were identified related to POC test implementation in primary care: (1) Insights into SARS-CoV-2 POC tests; (2) System and organisational factors; and (3) Practice-level service delivery strategies. Thematic subcategories included involvement in rapid testing, knowledge and perception of the current POC testing landscape, capacity for testing, economic concerns, resource necessities, perception of personal risk and safety, responsibility for administering the test, and targeted testing strategies.\n\nConclusionGPs knowledge of POC tests influences their degree of trust, uncertainty, and their perception of risk of POC test use. Concerns around funding, occupational exposure, and workload play a crucial role in GPs hesitation to provide POC testing services. These concerns could potentially be addressed with government funding, the use of targeted testing, and improved triaging strategies to limit testing to essential patient cohorts.","Multi-type branching and graph product theory of infectious disease outbreaks\nThe heterogeneity of human populations is a challenge to mathematical descriptions of epidemic outbreaks. Numerical simulations are deployed to account for the many factors influencing the spreading dynamics. Yet, the results from numerical simulations are often as complicated as the reality, leaving us with a sense of confusion about how the different factors account for the simulation results. Here, using a multi-type branching together with a graph tensor product approach, I derive a single equation for the effective reproductive number of an infectious disease outbreak. Using this equation I deconvolute the impact of crowd management, targeted testing, contact heterogeneity, stratified vaccination, mask use and smartphone tracing app use. This equation can be used to gain a basic understanding of infectious disease outbreaks and their simulations.","Google Trends as a method to predict new COVID-19 cases\nIn this paper, we develop a method that can detect and predict the emergence of new cases of COVID-19 at an early stage. With this method, we try to lay the empirical basis for the development of the model of digital monitoring and prediction of the occurrence of new cases of COVID-19 in Croatia, relying on the analytical tool Google Trends (GT).\n\nResultsIn Croatia search activities using GT for terms such as PCR +Covid\", \"PCR + test\", and symptoms \"cough + corona\", \"pneumonia + corona\"; \"muscle pain + corona\" correlate strongly with officially reported cases of the disease. Google Trends tools are suitable for predicting the emergence of new COVID-19 cases in Croatia, and that the data collected by this method correlate with official data.\n\nThe benefit of this method is reliable estimates that can enable public health officials to prepare and better respond to the possible return of a pandemic in certain parts of the country. If a region experiences an early, sharp increase in Covid-19-like-illness Google searches, it may be possible to focus additional resources on that region to identify the etiology of the outbreak, providing extra medical capacity or raising local media awareness as necessary.\n\nBecause the relative frequency of certain queries is highly correlated with the percentage of physician visits in which a patient presents with Covid-19 symptoms, this method can serve as an early alarm to predict the emergence of new cases of COVID-19 in the specific area in Croatia.","The Anorexia Nervosa Care Pathway: Closing the Treatment Gap to Improve Care for Patients Admitted to Medical Hospitals\nIntroductionMedical complications of malnutrition and refeeding account for approximately half of deaths in anorexia nervosa (AN). The AN Care Pathway (ANCP) was introduced at our institution in 2016 to improve quality of care of patients admitted for medical observation and management. We report results from our review of medical complications and report the impact and adoption of the ANCP.\n\nMethodsThe ANCP was developed in response to a need to improve quality of medical monitoring of patients with severe AN using Squire Guidelines and the Plan-Do-Study-Act cycle. All patients admitted to a medical hospital with AN between 2010-2020 were included after hospital inpatient enquiry and medical records were reviewed. Descriptive statistics were calculated using Stata (Statcorp).\n\nResultsFifty-one patients (63 admissions) were included. Median BMI was 13.8 kg/m (11.9-22.5). After ANCP implementation in 2016, compliance with recommended daily ECG, thiamine and blood tests improved from 30% (n=8/27) to 86% (n=21/36). We report a high rate of medical complications of severe AN including anaemia (n=24, 47%), neutropoenia (n=18, 35%), abnormal liver bloods (n=15, 29%) and half developed refeeding syndrome. One-third patients had cardiovascular compromise including reduced cardiac contractility (n=13, 25%), pericardial effusion (n=7, 14%) and one death. Low BMI was associated with cardiovascular complications (mean BMI 13.5 kg/m vs 15.5 kg/m, p=0.01) and neutropoenia (mean BMI 13.4 kg/m vs 15.4 kg/m, p=0.02).\n\nConclusionIntroduction of the ANCP improved quality of care during medical stabilisation. We report a high rate of medical complications of severe AN in patients admitted to a medical hospital. Use of multidisciplinary care protocols may contribute to quality improvement and improved consistency of care for this vulnerable population.","Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis\nIdiopathic pulmonary fibrosis (IPF) is a chronic lung condition with poor survival times. We previously published a genome-wide meta-analysis of IPF risk across three studies with independent replication of associated variants in two additional studies. To maximise power and to generate more accurate effect size estimates, we performed a genome-wide meta-analysis across all five studies included in the previous IPF risk GWAS. We utilised the distribution of effect sizes across the five studies to assess the replicability of the results and identified five robust novel genetic association signals implicating mTOR signalling, telomere maintenance and spindle assembly genes in IPF risk.","Breast cancer risks associated with missense variants in breast cancer susceptibility genes\nBACKGROUNDProtein truncating variants in ATM, BRCA1, BRCA2, CHEK2 and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain.\n\nMETHODSCombining 59,639 breast cancer cases and 53,165 controls, we sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1,146 training variants), BRCA1 (644), BRCA2 (1,425), CHEK2 (325) and PALB2 (472). We evaluated breast cancer risks according to five in-silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated.\n\nRESULTSThe most predictive in-silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1 and BRCA2, data were compatible with small subsets (approximately 7%, 2% and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set.\n\nCONCLUSIONSThese results will inform risk prediction models and the selection of candidate variants for functional assays, and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.","Automated Detection of Cerebral Microbleeds on MR images using Knowledge Distillation Framework\nCerebral microbleeds (CMBs) are associated with white matter damage, various neu-rodegenerative and cerebrovascular diseases. CMBs occur as small, circular hypointense lesions on T2*-weighted gradient recalled echo (GRE) and susceptibility weighted imaging (SWI) images, and hyperintense on quantitative susceptibility mapping (QSM) images due to their paramagnetic nature. Accurate detection of CMBs would help to determine the CMB lesion count and distribution, which would be further useful to understand the clinical impact of CMBs and to obtain quantitative imaging biomarkers. In this work, we propose a fully automated, deep learning-based, 2-step algorithm, using structural and anatomical properties of CMBs from any single input image modality (e.g. GRE / SWI / QSM) for their accurate detection. Our method consists of an initial candidate detection step, that detects CMBs with high sensitivity and a candidate discrimination step using a knowledge distillation framework to classify CMB and non-CMB instances, followed by a morphological clean-up step. We used 4 datasets consisting of different modalities specified above, acquired using various protocols and with a variety of pathological and demographic characteristics. On cross-validation within datasets, our method achieved a cluster-wise true positive rate (TPR) over 90% with an average of less than 2 false positives per subject. Our method is flexible in terms of the input modality and provides comparable cluster-wise TPR and a better cluster-wise precision compared to existing state-of-the-art methods. When evaluated across different datasets, our method showed good generalisability with a cluster-wise TPR greater than 80% with different modalities.","North Carolina macular dystrophy: phenotypic variability and computational analysis of disease-implicated non-coding variants\nPurposeNorth Carolina macular dystrophy (NCMD) is an autosomal dominant, congenital disorder affecting the central retina. Here, we report clinical and genetic findings in three families segregating NCMD and use epigenomic datasets from human tissues to gain insights into the effect of NCMD-implicated variants.\n\nMethodsClinical assessment and genetic testing were performed. Publicly-available transcriptomic and epigenomic datasets were analyzed and the Activity-by-Contact (ABC) method for scoring enhancer elements and linking them to target genes was used.\n\nResultsA previously-described, heterozygous, non-coding variant upstream of the PRDM13 gene was detected in all six affected study participants (chr6:100,040,987G>C [GRCh37/hg19]). Inter- and intra-familial variability were observed; the visual acuity ranged from 0.0 to 1.6 LogMAR and fundoscopic findings ranged from visually insignificant, confluent, drusen-like macular deposits to coloboma-like macular lesions. Variable degrees of peripheral retinal spots (which were easily detected on widefield retinal imaging) were observed in all study subjects. Notably, a 6-year-old patient developed choroidal neovascularization and required treatment with intravitreal bevacizumab injections. Computational analysis of the five single nucleotide variants that have been implicated in NCMD revealed that these non-coding changes lie within two putative enhancer elements; these elements are predicted to interact with PRDM13 in the developing human retina. PRDM13 was found to be expressed in the fetal retina, with highest expression in the amacrine precursor cell population.\n\nConclusionsWe provide further evidence supporting the role of PRDM13 dysregulation in the pathogenesis of NCMD and highlight the utility of widefield retinal imaging in individuals suspected to have this condition.","Decision curve analysis to identify optimal candidates of liver resection for intermediate-stage hepatocellular carcinoma with hepatitis B cirrhosis：A cohort study\nBackgroundThe selection criterion for liver resection (LR) in intermediate-stage (IM) hepatocellular carcinoma (HCC) is still controversial. This study aims to compare LR and transarterial chemoembolization in the range of predicted death risk\n\nMethodsThe multivariable Cox regression model (MVR) was estimated to predict mortality at 5yr. The cut-off values were determined by a two-piece-wise linear regression model, decision curve analysis with MVR model, and hazard ratio curve for treatment plotted against the predicted mortality.\n\nResults825 IM-HCC with hepatitis B cirrhosis were included for analysis (TACE, n=622; LR, n=203). The 5-yr overall survival rate of LR patients was higher than the TACE group (52.8% vs. 20.8%; P<0.0001). The line of LR and TACE were crossing with predicted death risk at 100% (P for interaction =0.008). The benefit of LR versus TACE decreased progressively as predicted death risk>0.55 (95%CI: 0.45,0.62). When predicted death risk over 0.7, decision curve analysis suggested that LR and TACE did not increase net benefit. Patients were then divided into four subgroups by the cut-off values (<0.45, 0.45[≥] /<0.62, 0.62[≥] /<0.7, [≥] 0.7). The stratified analysis of treatment in different subgroups, hazard ratios were 0.39 (95%CI: 0.27, 0.56), 0.36 (95%CI: 0.23, 0.56), 0.51 (95%CI: 0.27, 0.98), and 0.46 (95%CI: 0.27, 0.80), respectively.\n\nConclusionsLR reached the maximal relative utility in the interval of 0.45 to 0.62, and both LR and TACE did not increase net benefit at the 5-yr death risk over 0.7.","Feasibility of Continuous Distal Body Temperature for Passive, Early Pregnancy Detection\nThe majority of American women become aware of pregnancy ~3-7 weeks after conception, and all must seek testing to confirm their pregnant status. The delay between conception and awareness is often a time in which contraindicated behaviors take place. However, there is long standing evidence that passive, early pregnancy detection may be possible using body temperature. To address this possibility, we analyzed 30 individuals continuous distal body temperature (DBT) in the 180 days surrounding self-reported conception in comparison to self-reported pregnancy confirmation. Features of DBT nightly maxima changed rapidly following self-reported conception, reaching uniquely elevated values after a median of 5.5 {+/-} 3.5 days, whereas individuals reported a positive pregnancy test result at a median of 14.5 {+/-} 4.2 days. Together, we were able to generate a retrospective, hypothetical alert a median of 9 {+/-} 3.9 days prior to the date at which individuals received a positive pregnancy test. Continuous temperature-derived features can provide early, passive indication of pregnancy onset. We propose these features for testing and refinement in clinical settings, and for exploration in large, diverse cohorts. The development of pregnancy detection using DBT may reduce the delay from conception to awareness and increase the agency of pregnant individuals.","A Progeroid Syndrome Caused by RAF1 deficiency Underscores the importance of RTK signaling for Human Development\nSomatic and germline gain-of-function point mutations in RAF, the first oncogene to be discovered in humans, delineate a group of tumor-prone syndromes known as RASopathies. In this study, we document the first human phenotype resulting from the germline loss of function of the proto-oncogene RAF1 (a.k.a. CRAF). In a consanguineous family, we uncovered a homozygous p.Thr543Met mutation segregating with a neonatal lethal progeroid syndrome with cutaneous, craniofacial, cardiac and limb anomalies. Structure-based prediction and functional tests using human knock-in cells showed that threonine 543 is essential to: 1) ensure RAF1s stability and phosphorylation, 2) maintain its kinase activity towards substrates of the MAPK pathway and 3) protect from stress-induced apoptosis. When injected in Xenopus embryos mutant RAF1T543M failed to phenocopy the effects of overactive FGF/MAPK signaling confirming its hypomorphic activity. Collectively, our data disclose the genetic and molecular etiology of a novel segmental progeroid syndrome which highlights the importance of RTK signaling for human development and homeostasis.\n\nShort summaryA germline homozygous recessive loss-of-function mutation p.T453M in RAF1 causes a neonatal lethal progeroid syndrome. In vitro and in vivo tests demonstrate that Thr543 is necessary for RAF1s protein stability, to transduce signaling to the MAPK pathway and to respond to stress-induced apoptosis.","COVID-19 vaccine-associated cerebral venous thrombosis in Germany\nObjectiveReports of cerebral sinus and venous thrombosis (CVT) after ChAdOx1 vaccination against SARS-CoV-2 have raised safety concerns. We aimed to estimate the incidence of CVT within one month from first dose administration and the frequency of vaccine-induced immune thrombotic thrombocytopenia (VITT) as the underlying mechanism after vaccination with BNT162b2, ChAdOx1, and mRNA-1273, in Germany.\n\nMethodsA web-based questionnaire was e-mailed to all Departments of Neurology. We asked to report cases of CVT within one month of a COVID-19 vaccination. Other cerebral events could also be reported. Incidence rates of CVT were calculated by using official statistics of nine German States.\n\nResultsA total of 45 CVT cases were reported. In addition, 9 primary ischemic strokes, 4 primary intracerebral hemorrhages, and 4 other neurological events were recorded. Of the CVT patients, 35 (77.8%) were female, and 36 (80.0%) were below the age of 60 years. Fifty-three events were observed after vaccination with ChAdOx1 (85.5%), 9 after BNT162b2 (14.5%), and none after mRNA-1273 vaccination. After 7,126,434 first vaccine doses, the incidence rate of CVT within one month from first dose administration was 6.5 (95% CI, 4.4-9.2) per 100,000 person-years for all vaccines and 17.9 (11.8-26.1) for ChAdOx1 (after 2,320,535 ChAdOx1 first doses). The adjusted incidence rate ratio was 9.68 (3.46-34.98) for ChAdOx1 compared to mRNA-based vaccines and 3.14 (1.22-10.65) for women compared to non-women. In 26/45 patients with CVT (57.8%), VITT was graded highly probable.\n\nConclusionsGiven an incidence of 0.22-1.75 per 100,000 person-years for CVT in the general population, these findings point towards a higher risk for CVT after ChAdOx1 vaccination, especially for women.","Is Footedness Driving Right Lower Extremity Arthroplasty Becoming Commoner Than Left Lower Extremity Arthroplasty?\nThe question arises whether footedness transforms into asymmetrical incidence of wear and tear within lower extremity joints. After obtaining institutional review board approval for exempt research, the author manually counted the number of patients who underwent right or left or bilateral, hip or knee, primary or revision arthroplasty over a five-year period (2016-2020) at a university-affiliated hospital in the United States. Overall, right lower extremity arthroplasty was significantly commoner than left lower extremity arthroplasty (P=0.002). Individually, only right primary hip arthroplasty (P=0.033) and right revision knee arthroplasty (P=0.041) were significantly commoner procedures than their left counterparts. These results should set up the stage for future investigations into footedness retrospectively and prospectively to rule out if commoner right footedness in itself is driving this asymmetrical incidence of lower extremity arthroplasty or whether automatic transmission vehicular driving is independently contributing to this asymmetrical incidence.","Human gain-of-function variants in HNF1A confer protection from diabetes but independently increase hepatic secretion of multiple cardiovascular disease risk factors\nLoss-of-function mutations in Hepatocyte Nuclear Factor 1A (HNF1A) are known to cause rare forms of diabetes and alter hepatic physiology through unclear mechanisms. In the general population, 1:100 individuals carry a rare protein-coding variant in HNF1A, most of unknown functional consequence. To characterize the full allelic series, we performed deep mutational scanning of 11,970 protein-coding HNF1A variants in human hepatocytes and clinical correlation with 553,246 exome-sequenced individuals. Surprisingly, we found [~]1:5 rare protein-coding HNF1A variants found in the general population cause molecular gain-of-function (GOF), increasing the transcriptional activity of HNF1A by up to 50%. GOF in HNF1A conferred protection from type 2 diabetes (T2D) (OR=0.60, p=8.4 x 10-7), but not against coronary artery disease. Independently of T2D, increased hepatic expression of HNF1A promoted a pro-inflammatory and pro-atherogenic serum profile mediated in part by enhanced transcription of risk genes including PCSK9. In summary, [~]1:300 individuals carry a GOF variant in HNF1A that protects carriers from diabetes but enhances hepatic secretion of metabolic disease risk factors.","Prospective validation of host transcriptomic biomarkers for pulmonary tuberculosis by real-time PCR\nWe tested performance of host-blood transcriptomic tuberculosis (TB) signatures for active case-finding. Among 20,207 HIV-uninfected and 963 HIV-infected adults screened; 2,923 and 861 were enrolled from five South African communities. Eight signatures were measured by microfluidic RT-qPCR and participants were microbiologically-investigated for pulmonary TB at baseline, and actively surveilled for incident disease through 15 months. Diagnostic AUCs for 61 HIV-uninfected (weighted-prevalence 1.1%) and 10 HIV-infected (prevalence 1.2%) prevalent TB cases for the 8 signatures were 0.63-0.79 and 0.65-0.88, respectively. Thereafter, 24 HIV-uninfected and 9 HIV-infected participants progressed to incident TB (1.1 and 1.0 per 100 person-years, respectively). Prognostic AUCs through 15-months follow-up were 0.49-0.66 and 0.54-0.81, respectively. Prognostic performance for incident TB occurring within 6-12 months in HIV-negative participants was higher for all signatures. None of the signatures met WHO Target Product Profile criteria for a triage test to diagnose asymptomatic TB; most signatures met the criteria for symptomatic TB. Prognostic accuracy of most signatures for incident TB within six months of testing met the criteria for an incipient TB test.","Context Matters! Depression following childbirth or a chronic disease diagnosis shows specific risk factor profiles.\nProgress towards understanding the etiology of major depression (MD) is compromised by its clinical heterogeneity. The variety of contexts underlying the development of a major depressive episode may contribute to such heterogeneity. Here, we aimed to compare risk factor profiles of three subgroups of MD according to episode context.\n\nUsing self-report questionnaires and administrative records from the UK Biobank, we characterised three contextual subgroups of MD: postpartum depression (3,581 cases), depression following diagnosis of a chronic disease (409 cases) and a more typical (named heterogeneous) MD phenotype excluding the two prior contexts (34,699 cases). Controls with the same exposure were also defined. We tested each subgroup for association with MD polygenic risk scores (PRS) and other risk factors previously associated with MD (bipolar disorder PRS, neuroticism, reported trauma in childhood and adulthood, socioeconomic status, family history of depression, education).\n\nMD polygenic risk scores were associated with all subgroups, however, postpartum depression cases had higher PRS than heterogeneous MD cases (OR = 1.06, 95% CI: 1.02 - 1.10). Relative to heterogeneous depression, postpartum depression was more weakly associated with adulthood trauma and neuroticism. Relative to heterogeneous depression, depression following diagnosis of a chronic disease did not have higher MD polygenic risk scores but had weaker associations with neuroticism and reported trauma in adulthood and childhood.\n\nThe observed differences in risk factor profiles according to the context of a major depressive episode help provide insight into the heterogeneity of depression. Future studies dissecting such heterogeneity could help reveal more refined etiological insights.","Beyond poverty as a proxy: reducing inequality in infant mortality by identifying and targeting higher risk births\nInfant mortality remains high and uneven in much of sub-Saharan Africa. Given finite resources, reducing premature mortality requires effective tools to identifying left-behind populations at greatest risk. While countries routinely use income- or poverty-based thresholds to target policies, we examine whether models that consider other factors can substantially improve our ability to target policies to higher-risk births. Using machine learning methods, and 25 commonly available variables that can be observed prior to birth, we construct child-level risk scores for births in 22 sub-Saharan African countries. We find that targeting based on poverty, proxied by income, is only slightly better than random targeting, with the poorest 10 percent of the population experiencing approximately 10 percent of total infant mortality burden. By contrast the 10 percent of the population at highest risk according to our model accounts for 15-30% of infants deaths, depending on country. A hypothetical intervention that can be administered to 10% of the population and prevents just 5% of the deaths that would otherwise occur, for example, would save roughly 841,000 lives if targeted to the poorest decile, but over 1.6 million if targeted using our approach.","Detection of malignant peripheral nerve sheath tumors in patients with neurofibromatosis using aneuploidy and mutation identification in plasma\nMalignant peripheral nerve sheath tumors (MPNST) are the deadliest cancer that arises in individuals diagnosed with neurofibromatosis and account for nearly 5% of the 15,000 soft tissue sarcomas diagnosed in the United States each year. Comprised of neoplastic Schwann cells, primary risk factors for developing MPNST include existing plexiform neurofibromas (PN), prior radiotherapy treatment, and expansive germline mutations involving the entire NF1 gene and surrounding genes. PN develop in nearly 30-50% of patients with NF1 and most often grow rapidly in the first decade of life. One of the most important aspects of clinical care for NF1 patients is monitoring PN for signs of malignant transformation to MPNST that occurs in 10-15% of patients.\n\nWe perform aneuploidy analysis on ctDNA from 883 ostensibly healthy individuals and 28 patients with neurofibromas, including 7 patients with benign neurofibroma, 9 patients with PN and 12 patients with MPNST. Overall sensitivity for detecting MPNST using genome wide aneuploidy scoring was 33%, and analysis of sub-chromosomal copy number alterations (CNAs) improved sensitivity to 50% while retaining a high specificity of 97%. In addition, we performed mutation analysis on plasma cfDNA for a subset of patients and identified mutations in NF1, NF2, RB1, TP53BP2, and GOLGA2. Given the high throughput and relatively low sequencing coverage required by our assay, liquid biopsy represents a promising technology to identify incipient MPNST.","Impact of real-time assessment on the training of trainers for the introduction of rotavirus vaccine in India\nObjectivesTo assess the effectiveness of training workshops for knowledge enhancement of program managers prior to rotavirus vaccine (RVV) introduction in the routine immunization program.\n\nMethodThe study was conducted among the participants attending two training workshops for the introduction of RVV; a state workshop in Pune and a regional workshop in Guwahati. The participants who attended the workshops and participated in both the pre and post-test - 53 for Guwahati and 59 for Pune. Data was collected in real-time via pre-post-test.\n\nResultsIn both workshops, a comparison of pre-test and post-test scores of all questions taken together showed a significant increase in the knowledge level of the participants (p<0.05). In Guwahati, the knowledge of the participants regarding doses of RVV, inadequate dosing, Vaccine Vial Monitor (VVM), open vial policy, operationalization of RVV, and monetary incentive increased significantly. In Pune, the knowledge of the participants regarding doses of RVV, bundling approach, schedule and dose, storage temperature for Rotavirus vaccine, VVM, open vial policy, vaccine delivery, and operationalization of RVV increased significantly after the training.\n\nConclusionsA pre-planned and well-designed knowledge assessment tool can be used to understand the impact of training workshops in enhancing the knowledge and practical skills of the participants prior to the introduction of a new vaccine.","Signatures of immune senescence predict outcomes and define checkpoint blockade-unresponsive microenvironments in acute myeloid leukemia\nThe function of senescent-like T cells, transcriptomic features of immune effector senescence (IES) and their influence on therapeutic response were investigated in independent AML clinical cohorts comprising 1,864 patients treated with chemotherapy and/or immune checkpoint blockade (ICB). We show that senescent-like bone marrow CD8+ T cells are impaired in killing autologous AML blasts, and that their proportion negatively correlates with overall survival (OS). We define new IES signatures using two gene expression platforms and report that IES scores correlate with adverse-risk molecular lesions, stemness, and poor outcomes as a potentially more powerful predictor of OS than 2017-ELN risk or LSC17 stemness score. IES expression signatures also identify an ICB- unresponsive tumor microenvironment and predict significantly worse OS in AML as well as in solid tumors. The newly described IES scores provide improved AML risk stratification and could facilitate the delivery of personalized immunotherapies to patients who are most likely to benefit.","Masks in a Post COVID-19 World: A Better Alternative to Curtailing Influenza?\nOver the course of the coronavirus pandemic, it has become apparent that non-pharmaceutical interventions such as masks and social distancing are of great help in mitigating the transmission of airborne infectious diseases. Additionally, data from respiratory specimen analysis from the past year show that current mask mandates established for COVID-19 have inadvertently reduced the rates of other respiratory diseases, including influenza. Thus, the question arises as to whether comparatively mild measures should be kept in place after the pandemic to reduce the impact of influenza. In this study, we employed a series of differential equations to simulate past influenza seasons, assuming people wore face masks. This was achieved by introducing a variable to account for the efficacy and prevalence of masks and then analyzing its impact on influenza transmission rate in an SEIR model fit to the actual past seasons. We then compared influenza rates in this hypothetical scenario with the actual rates over the seasons. Our results show that several combinations of mask efficacy and prevalence can significantly reduce the burden of seasonal influenza. Particularly, our simulations suggest that a minority of individuals wearing masks greatly reduce the number of influenza infections. Considering the efficacy rates of masks and the relatively insignificant monetary cost, we highlight that it may be a viable alternative or complement to influenza vaccinations. We conclude with a brief discussion of our results and other practical aspects","Loss of nucleoporin Nup50 is a risk factor for amyotrophic lateral sclerosis\nThe genetic basis of amyotrophic lateral sclerosis (ALS) is still incompletely understood. Using two independent genetic strategies, we show here that a large part of ALS heritability lies in genes expressed in inhibitory and excitatory neurons, especially at splicing sites regulated by a defined set of RNA binding proteins including TDP-43 and FUS. We conducted a transcriptome wide association study (TWAS) and identified 59 loci associated with ALS, including 14 previously identified genes, some of them not previously reaching significance in genome wide association studies. Among the 45 novel genes, several genes are involved in pathways known to be affected in ALS such as mitochondrial metabolism (including ATP5H, ATP5D, BCS1L), proteostasis (including COPS7A, G2E3, TMEM175, USP35) or gene expression and RNA metabolism (including ARID1B, ATXN3, PTBP2, TAF10). Interestingly, decreased expression of NUP50, a constrained gene encoding a nuclear pore basket protein, was associated with ALS in TWAS (Zscore = -4, FDR = 0.034). 11 potentially pathogenic variants (CADD score > 20) in 23 patients were identified in the NUP50 gene, most of them in the region of the protein mediating interaction with Importin alpha, and including 2 frameshift mutations. In cells from two patients carrying NUP50 variants, we showed decreased levels of NUP50 protein. Importantly, knocking down Nup50 led to increased neuronal death associated with p62 and nucleoporin inclusions in cultured neurons, and motor defects in Drosophila and zebrafish models. In all, our study identifies alterations in splicing in neurons as a critical pathogenic process in ALS, uncovers several new loci potentially contributing to ALS missing heritability, and provides genetic evidence linking nuclear pore defects to ALS.","Contamination of personal protective equipment during COVID-19 autopsies\nConfronted with an emerging infectious disease, the medical community faced relevant concerns regarding the performance of autopsies of COVID-19 deceased at the beginning of the pandemic. This attitude has changed, and autopsies are now recognized as indispensable tools for elucidating COVID-19; despite this, the true risk of infection for autopsy staff is still debated. To elucidate the rate of SARS-CoV-2 contamination in personal protective equipment (PPE), swabs were taken at nine locations of the PPE of one physician and an assistant each from 11 full autopsies performed at four different centers. Further samples were obtained for three minimally invasive autopsies (MIA) conducted at a fifth center. Lung/bronchus swabs of the deceased served as positive controls. SARS-CoV-2 RNA was detected by RT-qPCR. In 9/11 full autopsies PPE samples were tested RNA positive with PCR, in total 21% of all PPE samples taken. The main contaminated parts of the PPE were the gloves (64% positive), the aprons (50% positive), and the upper sides of shoes (36% positive) while for example the fronts of safety goggles were only positive in 4.5% of the samples and all face masks were negative. In MIA, viral RNA was observed in one sample from a glove, but not in other swabs. Infectious virus isolation in cell culture was performed in RNA positive swabs from full autopsies. Of all RNA positive PPE samples, 21% of the glove samples were positive for infectious virus taken in 3/11 full autopsies. In conclusion, in >80% of autopsies, PPE was contaminated with viral RNA. In >25% of autopsies, PPE was found to be even contaminated with infectious virus, signifying a potential risk of infection among autopsy staff. Adequate PPE and hygiene measures, including appropriate waste deposition, are therefore mandatory to enable safe work environment.","A combined polygenic score of 21,293 rare and 22 common variants significantly improves diabetes diagnosis based on hemoglobin A1C levels\nPolygenic scores (PS), constructed from the combined effects of many genetic variants1, have been shown to predict risk or treatment strategies for certain common diseases2-6. As most PS to date are based on common variants7, the benefit of adding rare variation to PS remains largely unknown and methodically challenging. We developed and validated a method for constructing a rare variant PS and applied it to a previously identified clinical scenario, in which genetic variants modify the hemoglobin A1C (HbA1C) threshold recommended for type 2 diabetes (T2D) diagnosis6, 8-10. The resultant rare variant PS is highly polygenic (21,293 variants across 144 genes), depends on ultra-rare variants (72.7% of variants observed in <3 people), and identifies significantly more undiagnosed T2D cases than expected by chance (OR=2.71, p=1.51x10-6). A model combining the rare variant PS with a previously published common variant PS6 is expected to identify 4.9M misdiagnosed T2D cases in the USA, nearly 1.5-fold more than the common variant PS alone. These results provide a method for constructing complex trait PS from rare variants and suggest that rare variants will augment common variants in precision medicine approaches for common disease.","Human studies of mitochondrial biology demonstrate an overall lack of binary sex differences: A multivariate meta-analysis\nMitochondria are maternally inherited organelles that play critical tissue-specific roles, including hormone synthesis and energy production, that influence development, health, and aging. However, whether mitochondria from women and men exhibit consistent biological differences remains unclear, representing a major gap in biomedical knowledge. This meta-analysis systematically examined 4 domains and 6 subdomains of mitochondrial biology (total 39 measures), including mitochondrial content, respiratory capacity, reactive oxygen species (ROS) production, morphometry, and mitochondrial DNA copy number. Standardized effect sizes (Hedges g) of sex differences were computed for each measure using data in 2,258 participants (51.5% women) from 50 studies. Only two measures demonstrated aggregate binary sex differences: higher mitochondrial content in women (g = 0.20, {chi}2 p = 0.01), and higher ROS production in skeletal muscle in men (g = 0.49, {chi}2 p < 0.0001). differences showed weak to Sex no correlation with age or BMI. Studies with small sample sizes tended to overestimate effect sizes (r = -0.17, p < 0.001), and sex differences varied by tissue examined. Our findings point to a wide variability of findings in the literature concerning possible binary sex differences in mitochondrial biology. Studies specifically designed to capture sex- and gender-related differences in mitochondrial biology are needed, including detailed considerations of physical activity and sex hormones.","Automated Enhancement and Curation of Healthcare Data\nSocial and behavioral aspects of our lives significantly impact our health, yet minimal social determinants of health (SDOH) data elements are collected in the healthcare system. In this study we developed a repeatable SDOH enrichment and integration process to incorporate dynamically evolving SDOH domain concepts from consumers into clinical data. This process included SDOH mapping, linking compiled consumer data, data quality analysis and preprocessing, storage, and visualization. Our preliminary analysis shows commercial consumer data can be a viable source of SDOH factor at an individual-level for clinical data thus providing a path for clinicians to improve patient treatment and care.","DNA methylation and general psychopathology in childhood: An epigenome-wide meta-analysis from the PACE consortium\nThe general psychopathology factor (GPF) has been proposed as a way to capture variance shared between psychiatric symptoms. Despite a growing body of evidence showing both genetic and environmental influences on GPF, the biological mechanisms underlying these influences remain unclear. In the current study, we conducted epigenome-wide meta-analyses to identify both probe- and region-level associations of DNA methylation (DNAm) with school-age general psychopathology in six cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. DNAm was examined both at birth (cord blood; prospective analysis) and during school-age (peripheral whole blood; cross-sectional analysis) in total samples of N=2,178 and N=2,190, respectively. At school-age, we identified one probe (cg11945228) located in the Bromodomain-containing protein 2 gene (BRD2) that negatively associated with GPF (p=8.58x10-8). We also identified a significant DMR at school-age (p=1.63x10-8), implicating the SHC Adaptor Protein 4 (SHC4) gene that has been previously implicated in multiple types of psychiatric disorders in adulthood, including obsessive compulsive disorder and major depressive disorder. In contrast, no prospective associations were identified with DNAm at birth. Taken together, results of this study revealed some evidence of an association between DNAm at school-age and GPF. Future research with larger samples is needed to further assess DNAm variation associated with GPF.","Redeployment and training of healthcare professionals to Intensive Care during COVID-19: a systematic review\nBackgroundA rapid influx of patients to intensive care and infection control measures during the COVID-19 pandemic required the rapid development of innovative redeployment and training strategies.\n\nMethodsWe conducted a systematic search of 9 databases including key terms related to intensive care AND training AND redeployment AND healthcare workers. Analysis consisted of a narrative synthesis of quantitative study outputs, and a framework-based thematic analysis of qualitative study outputs and grey literature. These results were then combined applying an interpretative synthesis.\n\nResultsTwenty papers were analysed. These took place primarily in the UK (N=8, 40%) and USA (N=5, 25%). Themes included in the results are Redeployment: Implementation strategies and learnings; Redeployed staff experience and strategies to address their needs; Redeployed staff learning needs; Training formats offered and training evaluations; and Future redeployment and training concerns. Some of the redeployment implementation and training strategies documented in this review are: Skills-based redeployment, buddy support systems, and agreeing on locally-specific principles, rather than strict procedures.\n\nConclusionThe COVID-19 pandemic presented unique challenges to deliver training promptly while following infection control recommendations and develop flexible redeployment strategies. This study synthesises original approaches to tackle these challenges which are relevant to inform the development of targeted and adaptative training and redeployment plans.","Chronic kidney disease is associated with attenuated plasma metabolome response to oral glucose tolerance testing\nChronic kidney disease (CKD), a major public health problem, is associated with decreased anabolic response to insulin contributing to protein-energy wasting. Targeted metabolic profiling of the response to oral glucose tolerance testing (OGTT) may help identify metabolic pathways contributing to disruptions to insulin response in CKD. Using targeted metabolic profiling, we examined plasma metabolome in 41 moderate-to-severe non-diabetic CKD patients with estimated glomerular filtration rate (eGFR)<60ml/min per 1.73m2 (38.9{+/-}12.7) and 20 healthy controls with normal eGFR (87.2{+/-}17.7) before and after 2h of 75g oral glucose load. Compared to controls, CKD participants had higher lactate: pyruvate (L:P) ratio both at fasting and after oral glucose challenge. Total energy production estimated through GTP:GDP ratio was impaired during OGTT despite similar fasting GTP:GDP ratio. CKD group had sustained elevation of vitamin B family members, TCA cycle metabolites, and purine nucleotides in response to glucose challenge. Metabolic profiling in response to OGTT suggests a broad disruption of mitochondrial energy metabolism in CKD patients. These findings motivate further investigation into insulin sensitizers in patients with non-diabetic CKD and their impact on energy metabolism.","Large-scale social media language analysis reveals emotions and behaviours associated with nonmedical prescription drug use\nNonmedical use of prescription drugs (NMPDU) is a global health concern. The extent of, behaviors and emotions associated with, and reasons for NMPDU are not well-captured through traditional instruments such as surveys, prescribing databases and insurance claims. Therefore, this study analyses [~]130 million public posts from 87,718 Twitter users in terms of expressed emotions, sentiments, concerns, and potential reasons for NMPDU via natural language processing. Our results show that users in the NMPDU group express more negative emotions and less positive emotions, more concerns about family, the past and body, and less concerns related to work, leisure, home, money, religion, health and achievement, compared to a control group (i.e., users who never reported NMPDU). NMPDU posts tend to be highly polarized, indicating potential emotional triggers. Gender-specific analysis shows that female users in the NMPDU group express more content related to positive emotions, anticipation, sadness, joy, concerns about family, friends, home, health and the past, and less about anger, compared to males. The findings of the study can enrich our understanding of NMPDU.","Health service research definition builder: An R Shiny application for exploring diagnosis codes associated with services reported in routinely collected health data\nMany administrative health data-based studies define patient cohorts using procedure and diagnosis codes. The impact these criteria have on a studys final cohort is not always transparent to co-investigators or other audiences if access to the research data is restricted. We developed a SAS and R Shiny interactive research support tool which generates and displays the diagnosis code summaries associated with a selected medical service or procedure. This allows non-analyst users to interrogate claims data and groupings of reported diagnosis codes. The SAS program uses a tree classifier to find associated diagnosis codes with the service claims compared against a matched, random sample of claims without the service. Claims are grouped based on the overlap of these associated diagnosis codes. The Health Services Research (HSR) Definition Builder Shiny application uses this input to create interactive table and graphics, which updates estimated claim counts of the selected service as users select inclusion and exclusion criteria. This tool can help researchers develop preliminary and shareable definitions for cohorts for administrative health data research. It allows an additional validation step of examining frequency of all diagnosis codes associated with a service, reducing the risk of incorrect included or omitted codes from the final definition. In our results, we explore use of the application on three example services in 2016 US Medicare claims for patients aged over 65: knee arthroscopy, spinal fusion procedures and urinalysis. Readers can access the application at https://kelsey209.shinyapps.io/hsrdefbuilder/ and the code at https://github.com/kelsey209/hsrdefbuilder.","Unsupervised Learning for Large Scale Data: The ATHLOS Project\n1Recent technological advancements in various domains, such as the biomedical and health, offer a plethora of big data for analysis. Part of this data pool is the experimental studies that record various and several features for each instance. It creates datasets having very high dimensionality with mixed data types, with both numerical and categorical variables. On the other hand, unsupervised learning has shown to be able to assist in high-dimensional data, allowing the discovery of unknown patterns through clustering, visualization, dimensionality reduction, and in some cases, their combination. This work highlights unsupervised learning methodologies for large-scale, high-dimensional data, providing the potential of a unified framework that combines the knowledge retrieved from clustering and visualization. The main purpose is to uncover hidden patterns in a high-dimensional mixed dataset, which we achieve through our application in a complex, real-world dataset. The experimental analysis indicates the existence of notable information exposing the usefulness of the utilized methodological framework for similar high-dimensional and mixed, real-world applications.","Pre-conceptional maternal vitamin B12 supplementation improves offspring neurodevelopment at 2 years of age: PRIYA trial\nBackgroundNutritional interventions during the first 1000 days of life improves lifelong health. Better pre-conceptional maternal nutrition improves the nutrition of the early embryo. Vitamins B12 and folate are important for fetal neural development. Vitamin B12 deficiency is common in India.\n\nMethodsIn the Pune Rural Intervention in Young Adolescents (PRIYA) adolescents (N=557, 226 females) were provided with vitamin B12 (2{micro}g/day) with or without multiple micronutrients, or a placebo, from preconception until delivery. All groups received mandatory iron and folic acid. We used the Bayleys Scale of Infant Development (BSID-III) at 24-42 months of age to investigate effects on offspring neurodevelopment. We examined cord blood concentrations of brain-derived neurotropic factor (BDNF).\n\nResultsParticipants in the three groups had similar baseline B12 levels. These improved in the B12 supplemented groups at pre-conceptional and pregnancy (28 weeks gestation) measurements, reflected in higher cord holo-TC levels compared to the placebo. Neurodevelopmental outcomes are available for 74 children. Offspring in the B12 alone group (n=21) performed better than the placebo (n=27) on cognition (p=0.044) and language (p=0.020) domains (adjusted for maternal baseline B12 levels). There were no differences between the B12+MMN (n=26) and placebo group. Cord blood BDNF levels were highest in the B12 alone group (not statistically significant).\n\nConclusionPre-conceptional vitamin B12 supplementation improved maternal B12 status and offspring neurodevelopment at 2 years of age. The usefulness of cord BDNF as a marker of brain development needs further investigation. Our results highlight the importance of intervening in the pre-conceptional period.","Anthropometric measures and their relationship to corneal refractive power in the United States population\nPurposeTo determine the relationship between anthropometric measures and corneal refractive power (CRP).\n\nMethodsParticipants from the 1999-2008 United States National Health and Nutrition Examination Survey (NHANES) visual exam with demographic, ocular, and anthropometric data (20,165 subjects) were included. Cases with steep cornea were defined by corneal power [≥] 48.0 diopters (n = 171) while controls had dioptric power < 48.0 D (n = 19,994). Multivariable analyses were performed for pooled and sex-stratified populations. Separate models assessed body mass index, height, and weight in relation to steep cornea.\n\nResultsA relationship between BMI and steep cornea in the pooled population was not detected (P for trend = 0.78). There was a strong inverse relationship between height and steep cornea in the pooled population (P for trend <0.0001) and women (P for trend <0.0001). For every 1-inch increase in height, there was a 16% reduced odds of steep cornea in the pooled population (OR, 0.84; 95% CI: 0.78-0.91). There was also a significant inverse relationship between weight and steep cornea in the pooled population (P for trend = 0.01) and in men (P for trend = 0.02). For each 10-pound increase in weight there was a 7% reduced odds of steep cornea (OR, 0.927; 95% CI: 0.882-0.975) in the pooled analysis.\n\nConclusionsGreater height and greater weight were associated with a lower risk of steep cornea. These findings can contribute to an improved understanding of the pathogenesis of corneal ectasias.","Association between telecommuting environment and low back pain among Japanese telecommuting workers: A cross-sectional study\nObjectivesWe evaluated the relationship between telecommuting environment and low back pain (LBP) among desk-based workers in Japan.\n\nMethodsThis cross-sectional study included 3,663 desk-based, telecommuting workers. LBP was assessed using a 0-10 numerical rating scale. The telecommuting environment was evaluated using subjective questions. Mixed-effects logistic regression analysis was used to evaluate this association.\n\nResultsThe results of mixed-effects logistic model revealed that not having a place or room to concentrate on work, desk not well-lit enough for work, lack of space on the desk to work, not having enough legroom, and uncomfortable temperature and humidity conditions in the workspace were significantly associated with higher odds of LBP.\n\nConclusionsOur findings suggest that telecommuting environment is associated with the prevalence of LBP.","CLINICAL OPPORTUNITIES FOR GERMLINE PHARMACOGENETICS AND MANAGEMENT OF DRUG-DRUG INTERACTIONS IN PATIENTS WITH ADVANCED SOLID CANCERS\nPURPOSEPrecision medicine approaches, including germline pharmacogenetics (PGx) and management of drug-drug interactions (DDIs), are likely to benefit advanced cancer patients who are frequently prescribed multiple concomitant medications to treat cancer and associated conditions. Our objective was to assess the potential opportunities for PGx and DDI management within a cohort of adults with advanced cancer.\n\nPATIENTS AND METHODSMedication data were collected from the electronic health records (EHRs) for 481 subjects since their first cancer diagnosis. All subjects were genotyped for variants with clinically actionable recommendations in Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for 13 pharmacogenes. DDIs were defined as concomitant prescription of strong inhibitors or inducers with sensitive substrates of the same drug-metabolizing enzyme and were assessed for six major cytochrome P450 (CYP) enzymes.\n\nRESULTSApproximately 60% of subjects were prescribed at least one medication with CPIC recommendations, and [~]14% of subjects had an instance for actionable PGx, defined as prescription of a drug in a subject with an actionable genotype. The overall subject-level prevalence of DDIs and serious DDIs were 50.3% and 34.8%, respectively. Serious DDIs were most common for CYP3A, CYP2D6, and CYP2C19, occurring in 24.9%, 16.8%, and 11.7% of subjects, respectively. When assessing PGx and DDIs together, [~]40% of subjects had at least one opportunity for a precision medicine-based intervention and [~]98% of subjects had an actionable phenotype for at least one CYP enzyme.\n\nCONCLUSIONOur findings demonstrate numerous clinical opportunities for germline PGx and DDI management in adults with advanced cancer.","Clinical performance of two EUA-approved anti-COVID-19 IgG/IgM rapid lateral flow immunoassays using whole blood finger-sticks\nSerological, or antibody, tests detect immunoglobulins produced by the hosts plasma B cells following exposure to foreign antigens. Venipuncture blood draws to collect human venous whole blood, plasma from anticoagulated blood (Li+ heparin, K2EDTA and sodium citrate), or serum are commonly utilized and require refrigerated temperatures during transport to the testing facility. Subsequent laboratory testing by enzyme-linked immunosorbent assays (ELISA) or chemiluminescence immunoassays (CLIA) can take an additional 2-5 hours. In the context of the COVID-19 pandemic, rapid diagnostic tests (RDT) to be used in point-of-care (POC) and remote settings have become essential during mandatory quarantine and isolation periods. RDTs allowed for more cost-effective testing using less collection materials with an immediate (5-10 minutes) test result. However, the majority of emerging RDTs receiving Emergency Use Authorization (EUA) approval by the Food and Drug Administration (FDA) for qualitative detection and differentiation of IgM and IgG antibodies to SARS-CoV-2 were only approved for use in human venous whole blood, plasma or serum. In this study we summarize performance characteristics of one RDT (COVID-19 IgG/IgM lateral flow immunoassay rapid cassette) to another by simultaneous application of whole blood finger-stick specimens (n = 32). The study was performed over 5 different days, with daily quality controls consisting of serum previously verified to be positive or negative by COVID-19 IgG/IgM ELISA testing.","The role of HIV infection in the clinical spectrum of COVID-19: a population-based cohort analysis based on US National COVID Cohort Collaborative (N3C) Enclave data\nThe authors have withdrawn this manuscript because of the accidental low cell size in the supplementary materials. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.","Seroconversion rate and socioeconomic and ethnic risk factors for SARS-CoV-2 infection in children in a population-based cohort\nIntroductionSocioeconomic and ethnic background have been discussed as possible risk factors for SARS-CoV-2 infections in children. Improved knowledge could lead way to tailored prevention strategies and help to improve infection control.\n\nMethodsObservational population-based cohort study in children (6mo. - 18 ys.) scheduled for legally required preventive examination and their parents in a metropolitan region in Germany. Primary endpoint was the SARS-CoV-2 seroconversion rate during study period. Risk factors assessed included age, pre-existing medical conditions, socioeconomic factors, and ethnicity.\n\nResults2124 children and their parents were included. Seroconversion rates among children in all age groups increased by 3-4-fold from 06/2020 to 02/2021. Only 41% of seropositive children were symptomatic. In 51% of infected children at least one parent was also SARS-CoV-2 positive.\n\nLow level of parental education (OR 3.13 (0.72-13.69)) significantly increased the risk of infection. Of the total cohort, 38.5% had a migration background. Specifically, 9% were of Turkish and 5% of Middle Eastern origin. These children had the highest risk for SARS-CoV-2 infections (OR 6.24 (1.38-28.12) and 6.44 (1.14-36.45) after adjustment for other risk factors.\n\nDiscussionSeroprevalence of SARS-CoV-2 infections in children increased by 3-4-fold within the study period. Frequently, more than one family member was infected. Children from families with lower socioeconomic status were at higher risk. The highest risk for SARS-CoV-2 infection was identified in families with Turkish or Middle Eastern background. Culture sensitive approaches are essential to improve infection control and serve as a blueprint for vaccination strategies in this population.\n\nTrial RegistrationBMBF funding registration 01KI20173 (Corkid)","Antigen-specific tolerization in human autoimmunity: Inhibition of interferon-beta1a anti-drug antibodies in multiple sclerosis\nBackgroundAntigen-specific tolerance in auto-immune diseases is the goal for effective treatment with minimal side-effects. Whilst this is achievable in animal models, notably via intravenous delivery of the model-specific autoantigen following transient CD4 T cell depletion, specific multiple sclerosis autoantigens remain unproven. However, anti-drug antibodies to human therapeutic proteins represent a model human autoimmune condition, which may be used to examine immune-tolerance induction. Some people with MS (PwMS) on interferon-beta1a (IFN{beta}1a) develop neutralizing antibodies to IFN{beta}1a that do not disappear in repeated tests over years.\n\nMethodsOne PwMS was recruited, as part of a planned phase IIa trial (n=15), who had developed neutralizing antibodies to subcutaneous IFN{beta}1a. Mitoxantrone (12mg/m2) was administered as a lymphocyte depleting agent followed by four days of (88g/day + three 132g/day) intravenous IFN{beta}1a. Subcutaneous IFN{beta}1a three times a week was maintained during follow-up. IFN{beta}1a neutralizing antibody responses in serum were measured during treatment and three-monthly for 12 months.\n\nFindingsOne participant was recruited and, within 6 months of tolerization, the neutralizing antibodies were undetectable. The tolerization treatment was well tolerated. However, the study was terminated after the first enrolment, on ethical grounds, as treatment alternatives became available and the potential risks of mitoxantrone use increased.\n\nInterpretationThe data suggest that it may be possible to induce antigen-specific tolerance by providing tolerogenic antigen following transient immune depletion. Further studies are warranted.\n\nFundingThe study was supported by an unrestricted research grant from Merck-Serono.","Central oxidative stress and early vocational outcomes in first episode psychosis: A 7-Tesla Magnetic Resonance Spectroscopy study of glutathione\nFollowing the first episode of psychosis, some patients develop poor social and occupational outcomes, while others display a pattern of preserved functioning. Several lines of evidence from preclinical, genetic and biochemical studies suggest a role for high oxidative stress in poor functional outcomes. The measurement of intracortical glutathione (GSH) using magnetic resonance spectroscopy (MRS) provides an opportunity to investigate the relationship between central antioxidant tone and functional outcomes at the time of first episode psychosis (FEP). A body of epidemiological studies indicates better functional outcomes in patients at early stages of schizophrenia compared to patients at a chronic, established phase of illness. We scanned 57 patients with FEP and 30 matched healthy controls and estimated GSH resonance using 7-Tesla MRS. We minimised the confounding effects of illness chronicity, long-term treatment exposure and metabolic complications by recruiting patients with <2 weeks of lifetime antipsychotic exposure on average and followed up this cohort for the next 1 year to determine functional outcomes. Patients with FEP who achieved employment/education or training status (EET) in the first year, had higher GSH at the baseline than healthy controls. Social and occupational functioning assessment scale (SOFAS) scores were also significantly higher in patients with higher GSH levels at the outset, after adjusting for various confounds including baseline SOFAS. Patients who were not in employment, education or training (NEET) did not differ from healthy subjects in their GSH levels. Our observations support a key role for the central antioxidant tone in the functional outcomes of early psychosis.","Integrated Single Cell and Spatial Transcriptomics Reveal Autoreactive Differentiated B Cells in Joints of Early Rheumatoid Arthritis\nRheumatoid Arthritis (RA) is a prevalent autoimmune disease characterized by inflammation of peripheral joints. Patients can be subdivided by the presence or absence of Rheumatoid Factor and anti-citrullinated protein antibodies (ACPA) in their circulation. Inflammation of the joint tissue is associated with infiltration of leukocytes from the blood, which can result in generation of lymphoid structures composed of B and T cells. Previous studies have shown that both memory B cells and antibody-secreting plasma cells populate the rheumatic joint tissue when captured from established and often long-standing disease. However, it has remained unclear, whether these cells are autoreactive and whether the associated lymphoid structures are present at the site of inflammation already at the time of diagnosis. Here, we used an integrated single cell and spatial transcriptomic approach to study B and plasma cells in synovial tissue of ACPA- and ACPA+ RA patients at this early time point. We found evidence for T cell help to B cells and presence of memory B and plasma cell pools in ACPA- as well as in ACPA+ RA. Our results demonstrated common supportive microenvironments in both patient subgroups, clonal relationships between the memory B and plasma cell pools and autoreactivity within the plasma cell compartment. These findings challenge our understanding of the dynamics of local adaptive immune responses in the RA joint of ACPA- and ACPA+ patients at the time of diagnosis, with direct implications for B and T cell targeting therapies for both patient subgroups.\n\nOne Sentence SummaryA B cell maturation and plasma cell maintenance niche is evident at onset of Rheumatoid arthritis in both ACPA- and ACPA+ patients.","Characterization and mitigation of aerosols and splatters from ultrasonic scalers\nBackgroundDental procedures often produce aerosols and splatter which have the potential to transmit pathogens such as SARS-CoV-2. The existing literature is limited.\n\nMethodsAerosols and splatter were generated from an ultrasonic scaling procedure on a dental mannequin and characterized by two optical imaging methods - digital inline holography (DIH) and laser sheet imaging (LSI). Capture efficiencies of various aerosol mitigation devices were evaluated and compared.\n\nResultsThe ultrasonic scaling procedure generates a wide size range of aerosols up to a few hundred micrometers and occasional large splatter which emit at low velocity (mostly below 3 m/s). Use of a saliva ejector (SE) and high-volume evacuator (HVE) resulted in 63% and 88% of overall reduction respectively while an extraoral local extractor (ELE) resulted in a reduction of 96% at the nominal design flow setting.\n\nConclusionsThe study results showed that the use of ELE or HVE significantly reduced aerosol and splatter emission. The use of HVE generally requires an additional person to assist a hygienist, while an ELE can be operated \"hands-free\" when a dental hygienist is performing ultrasonic scaling and other operations.\n\nPractical ImplicationsAn extraoral local extractor aids in the reduction of aerosols and splatters during ultrasonic scaling procedures, potentially reducing transmission of oral or respiratory pathogens, like SARS-CoV-2. Position and airflow of the device are important to effective aerosol mitigation.","Development of health and safety training for Vietnamese American nail salon owners and workers\nBackgroundNail salon workers are an underserved worker population that faces multiple barriers to accessing occupational health training and services. We developed a series of occupational health training modules, which were culturally tailored to Vietnamese-speaking workers, covering topics on infection control, musculoskeletal disorder prevention, chemical safety, and labor practices. We delivered the training online (due to COVID-19) to a small group of Vietnamese owners and workers in the Philadelphia metro area to obtain feedback on the training content and potential implementation challenges.\n\nMethodsSeven participants (three owners and four workers) were recruited to attend the training. Qualitative feedback was obtained after each training session, followed by a more in-depth interviewer-assisted open-ended questionnaire to gain better understanding of the potential challenges of implementing the recommended changes. The Health Belief Model was used to guide the analysis of the participants responses to identify the perceived benefits and barriers of the training.\n\nResultsThemes of perceived benefits of the training were bridging the gap of cosmetology school training, offering practical tips to protect their health at work, and inspiring conversations about work dignity and labor practices. Themes of perceived barriers were availability of affordable safer products and lack of resources, desire to please customers, lack of commitment from owners, and ubiquitous low wage that impacts employees job satisfaction and motivation to change, and difficulty in obtaining a work license.\n\nConclusionsOur study revealed the multitude of social and economic barriers facing immigrant nail salon owners and workers. Potential policies and strategies to overcome some of these structural barriers are discussed for the long-term health protection of nail salon workers.","Impulse dispersion of aerosols during playing wind instruments\nMusical activities especially singing and playing wind instruments have been singled out as potentially high-risk activities for transmission of SARS CoV-2, because of a higher rate of aerosol production and emission. Playing wind instruments can produce condensation water, droplets of saliva, and aerosol particles, which hover and convectional spread in the environmental air and can be potentially infectious.\n\nThe aim of this study is to investigate the primary impulse dispersion of aerosols during playing different wind instruments in comparison to breathing and speaking. Nine professional musicians (3 trumpeters, 3 cross flutists and 3 clarinetists) of the Bavarian Symphony Orchestra performed the main theme of Ludwig van Beethoven s 9th symphony, 4th movement in different pitches and loudness. Thereby, the inhaled air volume was marked with small aerosol particles produced with a commercial e-cigarette. The expelled aerosol cloud was recorded by cameras from different perspectives. Afterwards, the dimensions and dynamics of the aerosol cloud was measured by segmenting the video footage at every time point.\n\nOverall, the cross flutes produced the largest dispersion at the end of task of up to maximum distances of 1.88 m in front direction. Thereby it was observed an expulsion of aerosol in different directions: upwards and downwards at the mouthpiece, at the end of the instrument and along the cross flute at the key plane. In comparison, the maximum impulse dispersion generated by the trumpets and clarinets were lower in frontal and lateral direction (1.2 m and 1.0 m in front-direction). The expulsion to the sides was also lower. Consequently, a distance of 3 m to the front and to the sides of 2 m for the cross flutes in an orchestral formation is proposed, for trumpets and clarinets a safety distance of 2 m to the front and 1.5 m between instrumentalists are recommendable.","Antibody responses to SARS-CoV-2 vaccination in patients with acute leukaemia and high risk MDS on active anti-cancer therapies\nPatients with haematological malignancies, such as acute leukaemia and high-risk MDS (HR-MDS), have significantly increased mortality and morbidity from COVID-19. However vaccine efficacy in these patients and the impact of systemic anti-cancer therapy (SACT) on vaccine response remains to be fully established. SARS-CoV-2 antibody responses in 53 patients with ALL, AML or HR-MDS receiving SACT were characterised following two doses of either BNT162b2 or ChAdOx1nCoV-19. All patients were tested for anti-S antibodies after 2 doses, 60% after the first dose and anti-N antibody testing was performed on 46 patients (87%). Seropositivity rates after 2 vaccine doses were 95% in AML/HR-MDS patients and 79% in ALL. After stratification by prior SARS-CoV-2 infection, naive patients with AML/HR-MDS had higher seroconversion rates and median anti-S antibody titres compared to ALL (median 291U/mL versus 5.06U/mL), and significant increases in anti-S titres with consecutive vaccine doses, not seen in ALL. No difference was seen in serological response between patients receiving intensive chemotherapy or non-intensive therapies (HMA) but significantly reduced titres were present in AML/HR-MDS patients who received venetoclax-based regimens compared to other therapies. All ALL patients received intensive chemotherapy, with no further impact of anti-CD20 immunotherapy on serological response. Understanding the impact of disease subtypes and therapy on vaccine response is essential to enable decisions on modifying or delaying treatment in the context of either SARS-CoV-2 infection or vaccination.","The Immunogenetic Basis of Idiopathic Bone Marrow Failure Syndromes: A Paradox of Similarity and Self-Presentation\nIdiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure disorder initiated by a human leukocyte antigen (HLA)-restricted T-cell response to unknown antigens. Immunogenetic patterns associated with self-antigenic presentation remain unclear. Herein we analyzed the molecular landscape of HLA complexes and T-cell receptor (TCR) repertoires of a large cohort of IAA patients and controls. We show that antigen binding sites of class II HLA molecules in IAA are characterized by a high level of structural homology, only partially explained by specific risk allele profiles, implying reduced binding capabilities compared to controls. Few amino acids within the synapsis HLA-DRB1-antigen-TCR, are identified as strongly associated with IAA phenotype. Those structural patterns may affect TCR repertoires, promoting immunological cross-reactivity and autoimmunity. These findings inform on the immunogenetic risk associated with IAA and on general pathophysiological mechanisms potentially involved in autoimmunity.\n\nKey pointsO_LIClass II human leukocyte antigen (HLA) loci in idiopathic bone marrow failure (BMF) syndromes are characterized by low functional divergence and decreased peptide binding capabilities, only partially explained by enrichment in risk alleles.\nC_LIO_LIA superstructure at the interface with the peptide binding site of DRB1 locus, potentially involved in the presentation of self-antigenic specificities, can be identified in BMF patients.\nC_LIO_LIThis immunogenetic pattern may contribute to decrease T-cell receptor repertoire diversity, expand autoreactive T-cell clones and increase autoimmune propensity in BMF.\nC_LI","Statistical challenges of investigating a disease with a complex diagnosis\nGiven the absence of a disease-specific biomarker, there are more than 20 symptoms-based case definitions of myalgic encephalomyelitis/chronic fatigue syndrome. As a consequence, the diagnosis for a given patient could vary from one case definition to another. In this context, we analyse data from a biobank dedicated to this disease in order to study the agreement between different case definitions, the similarity between symptoms profile among all participants including healthy controls and patients with multiple sclerosis. We also investigate the impact of patients misclassification on a hypothetical association analysis using data simulation.","Transmission of SARS-CoV-2 associated with cruise ship travel: protocol for a systematic review (Version 1)\nBackgroundMaritime and river travel, including cruise ships, have been implicated with spreading viruses through infected passengers and crew. Given the novelty of the SARS-CoV-2 infection, early cruise ship travel transmission models of spread are based on what is known of the dynamics of other respiratory viral infections. Our objective is to provide a rapid summary and evaluation of relevant data on SARS-CoV-2 transmission aboard cruise ships, report policy implications, and highlight research gaps requiring attention.\n\nMethodsWe will search LitCovid, medRxiv, Google Scholar, and the WHO Covid-19 database using COVID-19, SARS-CoV-2, transmission, and cruise ship appropriate synonyms. We will also search the reference lists of included studies for additional relevant studies. We will include studies reporting onboard SARS-CoV-2 transmission from passengers and/or crew to passengers and/or crew. We will consider any potential transmission mode. We will assess study quality based on five criteria and report important findings. The outcome will consist of the onboard cruise ships transmission of SARS-CoV-2. We will provide a narrative summary of the data and report the outcomes, including quantitative estimates where feasible and relevant. Where possible, compatible datasets may be pooled for meta-analysis.\n\nExpected resultsWe will present the evidence in three distinct packages: study description, methodological quality assessment and data extracted. We will summarize the evidence and will draw conclusions as to the quality of the evidence.","Social connectedness as a determinant of mental health: A scoping review\nPublic health and epidemiologic research have established that social connectedness promotes overall health. Yet there have been no recent reviews of findings from research examining social connectedness as a determinant of mental health. The goal of this review was to evaluate recent longitudinal research probing the effects of social connectedness on depression and anxiety symptoms and diagnoses in the general population. A scoping review was performed of PubMed and PsychInfo databases from January 2015 to December 2020 following PRISMA-ScR guidelines using a defined search strategy. The search yielded 56 articles representing 52 unique studies. In research with other than pregnant women, 84% (16 of 19) studies reported that social support benefited symptoms of depression with the remaining 16% (3 of 19) reporting minimal or no evidence that lower levels of social support predict depression at follow-up. In research with pregnant women, 80% (21 of 26 studies) found that low social support increased postpartum depressive symptoms. Among 3 of 4 studies that focused on loneliness, feeling lonely at baseline was related to adverse outcomes at follow-up including higher risks of major depressive disorder, depressive symptom severity, generalized anxiety disorder, and lower levels of physical activity. In 5 of 7 reports, smaller social network size predicted depressive symptoms or disorder at follow-up. In summary, most recent relevant longitudinal studies have demonstrated that social support protects adults in the general population from depressive symptoms and disorders. The results, which were largely consistent across settings, exposure measures, and populations, support efforts to improve clinical detection of high-risk patients, including adults with low social support and elevated loneliness.","Medical Evaluation of Unanticipated Monogenic Disease Risks Identified through Newborn Genomic Screening: Findings from the BabySeq Project\nGenomic sequencing of healthy newborns to screen for medically important genetic information has long been anticipated but data around downstream medical consequences are lacking. Among 159 infants randomized to the sequencing arm in the BabySeq Project, an unanticipated monogenic disease risk (uMDR) was discovered in 18 (11.3%). We assessed uMDR actionability by visualizing scores from a modified ClinGen Actionability SemiQuantitative Metric and tracked medical outcomes in these infants for 3-5 years. All uMDRs scored as highly actionable (mean 9, range: 7-11 on a 0-12 scale) and had readily available clinical interventions. In 4 cases, uMDRs revealed unsuspected genetic etiologies for existing phenotypes, and in the remaining 14 cases provided risk stratification for future surveillance. In 8 cases, uMDRs prompted screening for multiple at-risk family members. These results suggest that actionable uMDRs are more common than previously thought and support ongoing efforts to evaluate population-based newborn genomic screening.","Machine learning-based single cell and integrative analysis reveals that baseline mDC predisposition predicts protective Hepatitis B vaccine response\nVaccination to prevent infectious disease is one of the most successful public health interventions ever developed. And yet, variability in individual vaccine effectiveness suggests a better mechanistic understanding of vaccine-induced immune responses could improve vaccine design and efficacy. We have previously shown that protective antibody levels could be elicited in a subset of recipients with only a single dose of the hepatitis B virus (HBV) vaccine. Why some, but not all, recipients responded in this way was not clear. Using single cell RNA sequencing of sorted innate immune cell subsets, we identified two distinct myeloid dendritic cell subsets (NDRG1-expressing mDC2 and CDKN1C-expressing mDC4), the ratio of which at baseline (pre-vaccination) predicted immune response to a single dose of HBV vaccine. Our results suggest that the participants in our vaccine study were in one of two different dendritic cell dispositional states at baseline - an NDRG2-mDC2 state in which the vaccine elicited an antibody response after a single immunization or a CDKN1C-mDC4 state in which the vaccine required two or three doses for induction of antibody responses. Genes expressed in these mDC subsets were used as an approach for feature selection prior to the construction of a predictive model using supervised canonical correlation machine learning. The resulting model showed an improved ability to predict serum antibody titers in response to vaccination. Taken together, these results suggest that the propensity of circulating dendritic cells toward either activation or suppression, their \"dispositional endotype\", could dictate response to vaccination. The fact that these mDCs could be modulated via TLR stimulation could guide progress towards design of effective single dose vaccination strategies.","Integrated Bile Acid Profile Analysis for The Non-invasive Staging Diagnosis of Ulcerative Colitis\nClinical staging diagnosis and progression tracking for ulcerative colitis (UC) is challenging as poor patient compliance of endoscopic biopsy, we aimed to explore a non-invasive integrative biochemical index to quantitative track and monitor pathological activity. Here we perform a study that integrates bile acid metabolomic profiling, metagenomic sequencing and clinical monitoring on serum and feacal samples from 24 active-state UC patients, 25 remission-state UC patients and 20 healthy volunteers from China. Besides known associations of Fusobacterium nucleatum and Peptostreptococcus stomatis with UC, we found several bile acid-transforming species, including 7-dehydroxygenase and 7/{beta}-dehydrogenase expressing microbiota, were significant correlated with UC pathological activity. We identified 7 microbial gene markers that differentiated active and remission-stage UC and healthy control microbiomes. Relevantly, decreased serum deoxycholic acid /cholic acid ratio and increased fecal ursodeoxycholic acid/chenodeoxycholic acid ratio were associated with pathological activity of UC. Moreover, receiver operating characteristic analysis based on serum/fecal bile acids ratios was much accurate in prediction of active and remission stage outcome. This species-specific temporal change and bile acid dysregulation pattern linked to disease severity indicating that integrated microbiome-bile acid profile maybe implied for disease activity prediction, and that targeting microbiome-mediated restoring gut flora and bile acids homeostasis may be implicative of therapy efficacy. Collectively, these insights will help improve clinical diagnosis and optimize existing medical treatments.","Gender Balance and Readability of COVID-19 Scientific Publishing: A Quantitative Analysis of 90,000 Preprint Manuscripts\nReleasing preprints is a popular way to hasten the speed of research but may carry hidden risks for public discourse. The COVID-19 pandemic caused by the novel SARS-CoV-2 infection highlighted the risk of rushing the publication of unvalidated findings, leading to damaging scientific miscommunication in the most extreme scenarios. Several high-profile preprints, later found to be deeply flawed, have indeed exacerbated widespread skepticism about the risks of the COVID-19 disease - at great cost to public health. Here, preprint article quality during the pandemic is examined by distinguishing papers related to COVID-19 from other research studies. Importantly, our analysis also investigated possible factors contributing to manuscript quality by assessing the relationship between preprint quality and gender balance in authorship within each research discipline. Using a comprehensive data set of preprint articles from medRxiv and bioRxiv from January to May 2020, we construct both a new index of manuscript quality including length, readability, and spelling correctness and a measure of gender mix among a manuscripts authors. We find that papers related to COVID-19 are less well-written than unrelated papers, but that this gap is significantly mitigated by teams with better gender balance, even when controlling for variation by research discipline. Beyond contributing to a systematic evaluation of scientific publishing and dissemination, our results have broader implications for gender and representation as the pandemic has led female researchers to bear more responsibility for childcare under lockdown, inducing additional stress and causing disproportionate harm to women in science.","Identification of a novel FUS/ETV4 fusion and comparative analysis with other Ewing sarcoma fusion proteins\nEwing sarcoma is an aggressive pediatric bone cancer defined by a chromosomal translocation fusing one of the FET family members to a member of the ETS transcription factor family. To date, there have been seven reported translocations, with the most recent translocation reported over a decade ago. We now report the first identification of a novel translocation occurring between the FUS gene and ETS family member ETV4 detected in a neonatal patient with Ewing sarcoma. Given its apparent rarity, we conducted an initial characterization of FUS/ETV4 function by performing genomic localization and transcriptional regulatory studies. We knocked down endogenous EWS/FLI in the A673 cell line, and expressed FUS/ETV4 in its stead, and performed CUT&Tag and RNA-sequencing analyses. We compared these data to similar \"knock-down/rescue\" analyses of other rare (non-EWS/FLI) Ewing sarcoma-associated translocation products. Through this comparative analysis in the same genetic background, we demonstrate significant similarities across these fusions, and in doing so, validate this novel FUS/ETV4 translocation as a bona fide Ewing sarcoma translocation. This study presents the first genomic comparisons of the rare Ewing sarcoma-associated translocation products, and reveals that the FET/ETS fusions share highly similar, but not identical, genomic localization and transcriptional regulation patterns. These data provide insights into the roles of both the FET and ETS sides of these fusions, and provide a generic strategy to provide further strength to the notion that FET/ETS fusions are key drivers of, and thus pathognomonic for, Ewing sarcoma.\n\nSignificanceIdentification and initial characterization of the novel Ewing sarcoma fusion, FUS/ETV4, expands the family of Ewing-fusions and extends the diagnostic possibilities for this aggressive tumor of adolescents and young adults.","Two-step strategy for the identification of SARS-CoV-2 variant of concern 202012/01 and other variants with spike deletion H69-V70, France, August to December 2020\nWe report the implementation of a two-step strategy for the identification of SARS-CoV-2 variants carrying the spike deletion H69-V70 ({Delta}H69/{Delta}V70). This spike deletion resulted in a S-gene target failure (SGTF) of a three-target RT-PCR assay (TaqPath kit). Whole genome sequencing performed on 37 samples with SGTF revealed several receptor-binding domain mutations co-occurring with {Delta}H69/{Delta}V70. More importantly, this strategy enabled the first detection of the variant of concern 202012/01 in France on December 21th 2020.\n\nSince September a SARS-CoV-2 spike (S) deletion H69-V70 ({Delta}H69/{Delta}V70) has attracted increasing attention. This deletion was detected in the cluster-5 variant identified both in minks and humans in Denmark. This cluster-5 variant carries a receptor binding domain (RBD) mutation Y453F and was associated with reduced susceptibility to neutralizing antibodies to sera from recovered COVID-19 patients [1-3]. The {Delta}H69/{Delta}V70 has also co-occurred with two other RBD mutations of increasing interest [4]: N439K that is currently spreading in Europe and might also have reduced susceptibility to SARS-CoV-2 antibodies [5]; and N501Y that is part of the SARS-CoV-2 variant of concern (VOC) 202012/01 recently detected in England [6]. Although the impact of {Delta}H69/{Delta}V70 on SARS-CoV-2 pathogenesis is not clear, enhanced surveillance is urgently needed. Herein we report the implementation of a two-step strategy enabling a rapid detection of VOC 202012/01 or other variants carrying {Delta}H69/{Delta}V70.","Cost effective sequencing enables longitudinal profiling of clonal hematopoiesis\nClonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of mutant hematopoietic stem cells, confers risk for multiple diseases of aging including hematologic cancer and cardiovascular disease. Whole-exome or genome sequencing can detect CHIP, but due to its high cost, most population studies have been cross-sectional, sequencing only a single timepoint. Here we describe a cost-effective sequencing assay for detecting CHIP. We validate this technology on a set of 548 longitudinal and multi-timepoint samples from 182 participants in the Womens Health Initiative cohort over median 16 years, including 85 participants with [≥]3 timepoints assayed. The majority (52.1%) of clonal mutations expanded over time (with a median doubling period of 7.43 years), with the others remaining static or decreasing in size in the absence of any cytotoxic therapy. This assay provides a cost-effective and sensitive platform for investigating the associations between CHIP dynamics and health outcomes at a biobank scale.","DIETARY MANIPULATION OF THE GUT MICROBIOME IN INFLAMMATORY BOWEL DISEASE PATIENTS: PROOF OF CONCEPT\nDiet is a modifiable, non-invasive, inexpensive behavior that is crucial in shaping the intestinal microbiome. A microbiome \"imbalance\" or dysbiosis in inflammatory bowel disease (IBD) is linked to inflammation. Here, we aim to define the impact of specific foods on bacterial species commonly depleted in patients with IBD to better inform dietary treatment. We performed a single-arm, pre-post intervention trial. After a baseline period, a dietary intervention with the IBD-Anti-Inflammatory Diet (IBD-AID) was initiated. We collected stool and blood samples and assessed dietary intake throughout the study. We applied advanced computational approaches to define and model complex interactions between the foods reported and the microbiome. A dense dataset comprising 553 dietary records and 340 stool samples was obtained from 22 participants. Consumption of prebiotics, probiotics, and beneficial foods correlated with increased abundance of Clostridia and Bacteroides, commonly depleted in IBD cohorts. We further show that the IBD-AID intervention affects the immune tone by lowering IL-8 and increasing GM-CSF with certain foods correlating with levels of those cytokines. By using robust predictive analytics, this study represents the first steps to detangle diet-microbiome interactions to inform personalized nutrition for patients suffering from dysbiosis-related IBD.","Corneal cisterns as drainage aqueducts\nImportanceAnterior chamber paracentesis (ACP) is a known method of rapid reduction of IOP. The mechanism of how corneal fluid clears after ACP is not well described.\n\nObjectiveTo determine the mechanism of instantaneous corneal clearing of edema after ACP.\n\nDesign, setting, and participantsThis case series includes consecutive patients with high IOP and associated corneal edema, who presented to the Glaucoma Services of our tertiary care center. Pre- and post-intervention (ACP) ASOCTs were analyzed.\n\nMain outcome measuresResolution of corneal edema (clinical picture) and imaging of peripheral cornea and iridocorneal angle area.\n\nResultsTen consecutive patients who underwent an ACP were included in this study. The mean IOP pre-intervention was 48.4 {+/-} 8.2 mmHg. ASOCT showed ill-defined conventional pathways of aqueous outflow, which were blocked by peripheral anterior synechiae in 4 eyes. Immediately post ACP, the IOP was 16.3 {+/-} 5.6 mmHg (p < 0.001) and corneal edema resolved immediately. We found on ASOCT, that the intrastromal hypolucency of the peripheral cornea, (corneal cistern) which was limited in extent and U shaped, showed a posterior extension into the corneo-limbal junction to form well-defined anastomoses with the conventional aqueous drainage channels demonstrating a direct conduit for intracorneal fluid to egress. In 2/10 eyes, Schlemms canal opened intracamerally as well, suggesting direct reflux of intra-corneal fluid into the anterior chamber.\n\nConclusion and RelevanceAfter an ACP, in eyes with corneal edema to relieve IOP, we observed that the intracorneal cisterns undergo peripheral extension to drain corneal fluid through the conventional distal outflow channels.","Griffin: Framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA\nCell-free DNA (cfDNA) has the potential to inform tumor subtype classification and help guide clinical precision oncology. Here we developed Griffin, a new method for profiling nucleosome protection and accessibility from cfDNA to study the phenotype of tumors using as low as 0.1x coverage whole genome sequencing (WGS) data. Griffin employs a novel GC correction procedure tailored to variable cfDNA fragment sizes, which improves the prediction of chromatin accessibility. Griffin achieved excellent performance for detecting tumor cfDNA in early-stage cancer patients (AUC=0.96). Next, we applied Griffin for the first demonstration of estrogen receptor (ER) subtyping in metastatic breast cancer from cfDNA. We analyzed 254 samples from 139 patients and predicted ER subtype with high performance (AUC=0.89), leading to insights about tumor heterogeneity. In summary, Griffin is a framework for accurate clinical subtyping and can be generalizable to other cancer types for precision oncology applications.","A Patient-Reported Measure of Locomotor Function Derived from the Functional Assessment Questionnaire\nBackgroundLocomotor function is often impaired in children diagnosed with cerebral palsy (CP). Improving locomotor function is a common goal of treatment. The current gold standard for assessing locomotor function in CP is the gross motor function measure (GMFM-66). The GMFM-66 requires an in-person assessment by a trained clinician. It would be useful to have a measure of function that is like the GMFM-66 but can be assessed through patient report.\n\nMethodsWe queried the clinical databases of two motion analysis centers (Gillette Childrens Specialty Healthcare and Shriners Hospital - Salt Lake City) for individuals with a diagnosis of cerebral palsy (CP) who were 18 years old or younger and had undergone instrumented clinical gait analysis that included the functional assessment questionnaire (FAQ). We computed the transformed FAQ (FAQt) as the weighted sum of the skills an individual was able to perform, where the weighting was the difficulty of the skills. We assessed concurrent and external validity of the FAQt by comparing it to the GMFM-66.\n\nResultsThe FAQt exhibited strong concurrent and external validity. Linear regression showed that the GMFM-66 explained 54% of the variance in FAQt, and the linear fit was independent of center. The FAQt evolved with age in a manner similar to the GMFM-66, with higher functioning individuals, as measured by gross motor function classification system level, achieving higher levels of function at a higher rate and an earlier age compared to their lower functioning peers. The findings with respect to GMFM-66 did not depend on the center at which the data was acquired.\n\nConclusionsThe FAQt demonstrates strong concurrent and external validity, making it a useful measure of locomotor function.","Direct comparison of venipuncture serum draws versus whole blood finger-stick specimens by anti-COVID-19 IgG/IgM rapid lateral flow immunoassay and ELISA.\nDuring the COVID-19 pandemic, manufacturers have developed several diagnostic test kits that include lateral flow immunoassays (LFIA) also known as rapid cassette testing. Rapid cassette testing provides qualitative test results indicating the presence or absence of IgG and IgM antibodies to determine COVID-19 (SARS-CoV-2) infection among individuals. Venipuncture blood draws have been the traditional and widely proposed sample collection method but is costly and not applicable to point-of-care testing (POC) and in remote settings. Whole blood finger-stick blood collections traditionally used by diabetics for glucose level testing is an ideal scenario, but raises concerns regarding the outcome of test results in regards to specificity and sensitivity. In this study we directly compare simultaneous collections of venipuncture serum (SST) blood draws and whole blood finger-sticks (n = 75) to detect human Anti-COVID-19 IgG and IgM antibodies using an EUA-approved lateral flow immunoassay, showing equal to enhanced performance characteristics for this specimen type.","Computer adaptive testing to assess impairing behavioral health problems in emergency department patients\nStudy ObjectiveTo assess the prevalence of several impairing behavioral health domains in stable patients presenting to the emergency department (ED) through the use of computer adaptive testing and the association among the domains, standard assessments, and ED utilization.\n\nMethodsThis was a single-center observational study of 828 randomly selected adult patients presenting to the ED from May 2019 to March 2020. The main outcomes of interest were the self-administered, validated computer adaptive assessments of suicidality, depression, anxiety, PTSD, and substance abuse using computer adaptive testing, the CAT-MH. We estimated the association among the CAT-MH subscales, standard assessments, and the number of ED visits in the year prior and 30 days after enrollment.\n\nResultsThe proportion of those who scored above the threshold of low/mild risk were: 24.1% (suicidality), 8.3% (depression), 16.5% (anxiety), 12.3% (PTSD), and 20.4% (substance use). While the CAT-MH subscales were highly correlated with other self-report assessments, they were not highly associated with standard ED assessments of suicidality. When examining associations with ED use, for example, individuals who had two or more ED visits in the prior year had 51% increased odds of being in the intermediate-high suicide risk category (95% Confidence Interval [CI], 1.03-2.23) compared to those with zero prior ED visits.\n\nConclusionThe CAT-MH can document the high prevalence of mental health conditions in the ED, which were missed by standard ED practices. Mental health problems are associated with ED utilization in a population of patients presenting largely for somatic complaints.","Comparing the predictive value of suicide risk screening to the detection of suicide risk using electronic health records in an urban pediatric emergency department\nObjectiveTo compare the accuracy, sensitivity and utility of brief screening to predictive modeling for identifying suicide-related outcomes in a pediatric emergency department. Our hypothesis was that predictive modeling would be more accurate and useful compared to brief screening.\n\nMethodsThis was a retrospective cohort study at an urban pediatric Emergency Department (PED) in the United States. Patients were aged 8 to 18 years old who presented from January 1, 2017 to June 30, 2019. Predictors included positive suicide risk screen and/or demographic, medical and mental health diagnostic Electronic Health Record (EHR) data at the time of visit. The main outcome was subsequent PED visit with suicide-related presenting problem (i.e. ideation or attempt) within a 3-month follow-up period.\n\nResultsOf the N=13420 individuals, n=141 had a subsequent suicide-related ED visit. Approximately 63% identified as Black Non-Hispanic. Results showed that a model based only on EHR data performed only slightly worse than the ASQ alone. Combining ASQ screening and EHR data resulted in a 17.4% improvement in sensitivity and 13.4% increase in AUC compared to the ASQ alone. The LASSO models indicated a diagnosis of major depressive disorder in addition to the ASQ improved the AUC by 9%.\n\nConclusions, Implications, Future DirectionsOur findings show that EHR data is helpful either in the absence or as an addition to brief suicide screening. To our knowledge, this is the first study to compare brief screening to EHR based predictive modeling and adds to our understanding of how best to identify youth at risk of suicidal behaviors in clinical care settings.","CHA2DS2-VASc score on admission to predict mortality in COVID-19 patients: A meta-analysis\nBackgroundCHA2DS2-VASc score is used in non-valvular AF patients to predict thromboembolic risk. Recent studies have tried to evaluate CHA2DS2-VASc score on admission in COVID-19 patients to predict mortality.\n\nMethodsWe conducted a literature search on 14 April 2021 to retrieve all published studies, pre-prints and grey literature related to the predictive power of CHA2DS2-VASc score in COVID-19 patients of admission and mortality. Screening of studies and data extraction was done by two authors independently. We used the Quality in Prognosis Studies (QUIPS) tool for the methodological quality assessment of the included studies.\n\nResultsFive studies involving 5,941 patients reported the predictive value of CHA2DS2-VASc score for mortality in COVID-19 patients. The pooled sensitivity (SEN), specificity (SPE) and area under curve were 0.72 (95% CI 0.63-0.79), 0.74 (95% CI 0.67-0.81) and 0.80 (95% CI 0.76-0.83).\n\nConclusionsCHA2DS2-VASc score at admission has good predictive value for mortality in patients with COVID-19 infection and can help clinicians identify potentially severe cases early. Early initiation of effective management in these cases may help in reducing overall mortality due to COVID-19.\n\nTrial registryWe prospectively registered this meta-analysis on PROSPERO database (Reg number: CRD42021248398).","Intrinsic Capacity of Rural Elderly in Thar Desert using WHO ICOPE (Integrated Care for Older Persons) Screening Tool: A Pilot Study\nIntroductionICOPE (Integrated Care for Older Persons) screening tool helps to address declines in physical and mental capacities in older people. In India majority of the older population resides in rural areas and there is a paucity of studies that demonstrates the utility of the ICOPE screening tool in India. Thus, this study was conducted to demonstrate the feasibility of using WHO ICOPE screening tool in a rural population.\n\nMethodsA cross-sectional study was conducted in the two villages of Jodhpur. WHO ICOPE screening was done for a comprehensive geriatric assessment of intrinsic capacity by determining cognitive decline, the decline in mobility, malnutrition, sensory loss, depressive symptoms, health risks, social care, and support. Additionally, demographic details and information about health conditions were gathered.\n\nResultA total 451 participants (Male=54.5% and Female= 45.5%) surveyed. The mean age was 68.36 (SD=7.73) years and the majority of participants (68.3%) were illiterate. Most of the elderly have good families and lived with their children. Cognitive decline was found to be prevalent in 31.5% (n=142) of the participants, while mobility was diminished in 52.1% (n=235) participants. Eye problems were observed in 49.4% (n=223) participants, while 68.3% (n=308) were observed to be suffering from hearing loss. Limitation in mobility observed with the chair rise test and feeling of pain was found to be significantly associated with gender difference, with more limitation in females than males (p = 0.005; {chi}2 = 7.95) and more pain felt by females than males (p = 0.001; {chi}2 = 15.64).\n\nConclusionThis tool seems suitable in identifying the intrinsic capacity of the rural elderly.","Estimating the increased transmissibility of the B.1.1.7 strain over previously circulating strains in England using fractions of GISAID sequences and the distribution of serial intervals\nThe B.1.1.7 strain, also referred to as Alpha variant, is a variant strain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The Alpha variant is considered to possess higher transmissibility compared to the strains previously circulating in England. This paper proposes a new method to estimate the selective advantage of a mutant strain over another strain using the time course of strain frequencies and the distribution of the serial interval of infections. This method allows the instantaneous reproduction numbers of infections to vary over calendar time. The proposed method also assumes that the selective advantage of a mutant strain over previously circulating strains is constant. Applying the method to SARS-CoV-2 sequence data from England, the instantaneous reproduction number of the B.1.1.7 strain was estimated to be 26.6-45.9% higher than previously circulating strains in England. This result indicates that control measures should be strengthened by 26.6-45.9% when the B.1.1.7 strain is newly introduced to a country where viruses with similar transmissibility to the preexisting strain in England are predominant.","Interactions between seasonal human coronaviruses and implications for the SARS-CoV-2 pandemic: A retrospective study in Stockholm, Sweden, 2009-2020\nObjectivesThe four seasonal coronaviruses 229E, NL63, OC43, and HKU1 are frequent causes of respiratory infections and show annual and seasonal variation. Increased understanding about these patterns could be informative about the epidemiology of SARS-CoV-2.\n\nMethodsResults from PCR diagnostics for the seasonal coronaviruses, and other respiratory viruses, were obtained for 55,190 clinical samples analysed at the Karolinska University Hospital, Stockholm, Sweden, between 14 September 2009 and 2 April 2020.\n\nResultsSeasonal coronaviruses were detected in 2,130 samples (3.9%) and constituted 8.1% of all virus detections. OC43 was most commonly detected (28.4% of detections), followed by NL63 (24.0%), HKU1 (17.6%), and 229E (15.3%). The overall fraction of positive samples was similar between seasons, but at species level there were distinct biennial alternating peak seasons for the Alphacoronaviruses, 229E and NL63, and the Betacoronaviruses, OC43 and HKU1, respectively. The Betacoronaviruses peaked earlier in the winter season (Dec-Jan) than the Alphacoronaviruses (Feb-Mar). Coronaviruses were detected across all ages, but diagnostics were more frequently requested for paediatric patients than adults and the elderly. OC43 and 229E incidence was relatively constant across age strata, while that of NL63 and HKU1 decreased with age.\n\nConclusionsBoth the Alphacoronaviruses and Betacoronaviruses showed alternating biennial winter incidence peaks, which suggests some type of immune mediated interaction. Symptomatic reinfections in adults and the elderly appear relatively common. Both findings may be of relevance for the epidemiology of SARS-CoV-2.","Early prediction of preeclampsia in pregnancy with circulating cell-free RNA\nLiquid biopsies that measure circulating cell-free RNA (cfRNA) offer an unprecedented opportunity to noninvasively study the development of pregnancy-related complications and to bridge gaps in clinical care. Here, we used 404 blood samples from 199 pregnant mothers to identify and validate cfRNA transcriptomic changes that are associated with preeclampsia (PE), a multi-organ syndrome which is the second largest cause of maternal death globally. We find that changes in cfRNA gene expression between normotensive (NT) and preeclamptic mothers are striking and stable early in gestation, well before the onset of symptoms. These changes are enriched for genes specific to neuromuscular, endothelial, and immune cell types and tissues that reflect important aspects of PE physiology and suggest new hypotheses for disease progression. This enabled identification and independent validation of a panel of 18 genes whose measurement between 5-16 weeks of gestation can form the basis of a liquid biopsy test that would identify mothers at risk of PE well before the clinical symptoms manifest themselves. Finally, we demonstrate that cfRNA changes reflect the multifactorial nature of PE and provide a means to non-invasively monitor maternal organ health. Tests based on these observations could help predict and manage who is at risk for PE, an important and until now unachieved objective for obstetric care.","Oscillations of pause-burst neurons in the STN correlate with the severity of motor signs in Parkinson's disease\nBackgroundOscillatory activity in the subthalamic nucleus (STN) in Parkinsons disease (PD) is under extensive study. While rhythmic features of local field potentials are implicated in the manifestation of PD motor signs, less is known about single unit activity (SUA). SUA parameters inside the STN show significant heterogeneity, and various firing patterns may contribute unequally to PD pathophysiology.\n\nObjectivesWe searched for correlations between SUA parameters and PD motor signs, taking neuronal activity patterns into account.\n\nMethods829 spike trains for STN SUA were recorded during 25 DBS surgeries. We have isolated three firing patterns (tonic, irregular burst and pause-burst) and, using mixed linear models, examined several ISI parameters and burst descriptors (for the last two patterns) for their correlation with the UPDRS 3 score and bradykinesia and rigidity scores on the contralateral body side.\n\nResultsThe predominance of pause-burst as opposed to tonic activity was associated with an increase in UPDRS 3 score. Oscillation scores in the alpha range correlated with bradykinesia and rigidity scores, and oscillation scores in the beta range correlated with bradykinesia score only for pause-burst neurons, while other patterns showed no correlation with PD motor signs. There was also significant negative correlation between bradykinesia score and theta oscillations for pause-burst pattern.\n\nConclusionsPause-burst pattern and rhythmic neurons oscillating in the alpha range may affect motor processing in the basal ganglia more prominently than other activity patterns, probably reflecting progressive switching from tonic to burst to rhythmic activity in the parkinsonian state.","Effect of fasting therapy on vitamin D, vitality and quality of life. A randomized control trial\nBackgroundThe aim of the present study was to determine the effects of prolonged fasting (10 days) in the vitamin D, B12 levels, body mass index (BMI), weight, hemoglobin, vitality and quality of life (QoL) compared to normal diet.\n\nMethodsThis randomized control trial included 52 participants (aged 19-74 years) randomized in to a fasting group (FG) or a normal diet group (NDG) with 26 participants in each group. The study was conducted at an in-patient setting where the FG were on a fasting diet (500 kCal/day) which included holy basil herbal tea, lemon honey juice and water (3 L). The NDG (1500 kCal/day) consumed routine diet that included Indian breads, pulses, steamed rice, vegetable salads and beverages.\n\nResultsThe FG has shown significant increase in the Vitamin D levels (p=0.003, d=0.475), vitality (p=0.006, d=0.425), physical QoL (p<0.001, d=0.549), psychological QoL (p=0.002, d=0.488), environmental QoL (p=0.004, d=0.457) compared to NDG. No significant changes were observed in Vitamin B12, weight, BMI, hemoglobin and social QoL. A weak to moderate ({rho}= 0.330-0.483) positive correlation was observed between vitality scores and QoL domains, whereas BMI scores showed an inverse correlation ({rho}=-0.280) with vitamin D levels.\n\nDiscussionThe results suggest that prolonged fasting can improve the vitamin D levels, vitality and promote quality life compared to normal diet. Unlike previous studies FG does not differ from NDG with respect to weight and BMI. Nevertheless, fasting may be utilized as an effective tool to tackle vitamin d deficiency and associated health insufficiencies.\n\nTrial RegistryClinical Trial Registry of India CTRI/2022/02/040446.","Neural Dysregulation in Post-Covid Fatigue\nFollowing infection from SARS-CoV-2, a substantial minority of people develop lingering after-effects known as long COVID. Fatigue is a common complaint with substantial impact on daily life, but the neural mechanisms behind post-COVID fatigue remain unclear.\n\nWe recruited 37 volunteers with self-reported fatigue after a mild COVID infection and carried out a battery of behavioural and neurophysiological tests assessing the central, peripheral and autonomic nervous systems.\n\nIn comparison to age and sex matched volunteers without fatigue (n=52), we show underactivity in specific cortical circuits, dysregulation of autonomic function, and myopathic change in skeletal muscle. Cluster analysis revealed no sub-groupings, suggesting post-COVID fatigue is a single entity with individual variation, rather than a small number of distinct syndromes. Based on our analysis we were also able to exclude dysregulation in sensory feedback circuits and descending neuromodulatory control.\n\nThese abnormalities on objective tests may indicate novel avenues for principled therapeutic intervention, and could act as fast and reliable biomarkers for diagnosing and monitoring the progression of fatigue over time.","Impact and cost-effectiveness of frequent HIV re-testing among key populations in Viet Nam: a modeling study\nBackgroundHIV testing and counseling is a key component of HIV prevention and the entry point into the treatment cascade, which improves for individual clinical outcomes and reduces onward HIV transmission. Current guidelines recommend at least annual testing for key populations. More frequent testing could provide health benefits, but these additional services increase the program the cost-effectiveness is not well-evaluated.\n\nMethodsWe used a compartmental mathematical model to simulate the health and economic impact of HIV testing one to four times per year for men who have sex with men, people who inject drugs, and female sex workers in Viet Nam. Model outcomes included costs, HIV infections, HIV-related deaths, and disability-adjusted life years (DALYs) associated with each scenario. We used an opportunity cost-based cost-effectiveness threshold of US $2,255 per DALY averted, discounted costs and health benefits at 3% annually, and used a time horizon from 2021 to 2030 to calculate incremental cost-effectiveness ratios (ICERs).\n\nResultsCompared to the baseline scenario, more frequent HIV testing was estimated to incrementally avert 10.2%, 5.2%, 3.0%, and 1.6% discounted infections for one-, two-, three-, and four-tests per year, respectively. ICERs associated with each scenario ranged from $464, $1,190, $1,762, and $2,727 per DALY averted for one-, two-, three-, and four-tests per year, respectively.\n\nConclusionsIncreased HIV testing frequency for key populations was projected to avert HIV incidence, mortality, and disability in Viet Nam and was cost-effective. Settings with a similar context should consider strategies on how to optimize retesting among key populations.","Sepsis Subphenotyping Based on Organ Dysfunction Trajectory\nPurposeAlthough organ dysfunction is a defining element of sepsis, its trajectory is not well studied. We sought to identify whether there are distinct Sequential Organ Failure Assessment (SOFA) score trajectory-based subphenotypes in sepsis.\n\nMethodsWe created 72-hour SOFA score trajectories in patients with sepsis from two diverse intensive care unit (ICU) cohorts. We then used Dynamic Time Warping (DTW) to compute patient similarities to capture evolving heterogeneous sequences and establish similarities between groups with distinct trajectories. Hierarchical agglomerative clustering (HAC) was utilized to identify subphenotypes based on SOFA trajectory similarities. Patient characteristics were compared between subphenotypes and a random forest model was developed to predict subphenotype membership, within 6 hours of ICU arrival. The model was then tested on the validation cohort.\n\nResultsA total of 4,678 and 3,665 unique sepsis patients were included in development and validation cohorts. In the development cohort, four subphenotypes of organ dysfunction were identified: Rapidly Worsening (n=612, 13.08%), Delayed Worsening (n=960, 20.52%), Rapidly Improving (n=1,932, 41.3%) and Delayed Improving (n=1174, 25.1%). In-hospital mortality for patients within different subphenotypes demonstrated distinct patterns over time. Similar subphenotypes and their associated outcome patterns were replicated in the multicenter validation cohort.\n\nConclusionFour novel, clinically-defined, trajectory-based sepsis subphenotypes were identified and validated. Trajectory based subphenotyping is useful for describing the natural history of sepsis in the ICU. Understanding the pathophysiology of these differential trajectories may reveal unanticipated therapeutic targets for patients with sepsis and identify more precise populations and endpoints for the predictive enrichment of clinical trials.","Differences in medication reconciliation interventions between six hospitals: a mixed method study\nBackgroundAlthough medication reconciliation (MedRec) is mandated and effective in decreasing preventable medication errors during transition of care, hospitals implement MedRec differently.\n\nObjectiveQuantitatively compare the number and type of MedRec interventions between hospitals upon admission and discharge, followed by a qualitative analysis on potential reasons for these differences.\n\nMethodsThis explanatory retrospective mixed method study included patients from six hospitals and various wards in case MedRec was performed both on hospital admission and discharge. Information on pharmacy interventions to resolve unintended discrepancies and medication optimizations were collected. Based on these quantitative results, interviews and a focus group was performed to give insight in MedRec processes. Descriptive analysis was used for the quantitative-, content analysis for the qualitative part.\n\nResultsOn admission, patients with at least one discrepancy varied from 36-95% (mean per patient 2.2 (SD{+/-} 2.4) Upon discharge, these numbers ranged from 5-28% while optimizations reached 2% (admission) to 95% (discharge).The main themes explaining differences in numbers of interventions were patient-mix, healthcare professionals involved, location and moment of the interview plus embedding and extent of medication optimization.\n\nConclusionsHospitals differed greatly in the number of interventions performed during MedRec. A combination of patient-mix, healthcare professionals involved, location and timing of the interview plus embedding and extent of medication optimization resulted in the highest yield of MedRec interventions on unintended medication discrepancies and optimizations. This study supports to give direction to optimize MedRec processes in hospitals.","Evaluating the effects of second-dose vaccine-delay policies in European countries: A simulation study based on data from Greece\nThe results of a simulation-based evaluation of several policies for vaccine rollout are reported, particularly focusing on the effects of delaying the second dose of two-dose vaccines. In the presence of limited vaccine supply, the specific policy choice is a pressing issue for several countries worldwide, and the adopted course of action will affect the extension or easing of non-pharmaceutical interventions in the next months. We employ a suitably generalised, age-structure, stochastic SEIR (Susceptible [->] Exposed [->] Infectious [->] Removed) epidemic model that can accommodate quantitative descriptions of the major effects resulting from distinct vaccination strategies. The different rates of social contacts among distinct age-groups (as well as some other model parameters) are informed by a recent survey conducted in Greece, but the conclusions are much more widely applicable. The results are summarised and evaluated in terms of the total number of deaths and infections as well as life years lost. The optimal strategy is found to be one based on fully vaccinating the elderly/at risk as quickly as possible, while extending the time-interval between the two vaccine doses to 12 weeks for all individuals below 75 years old, in agreement with epidemic theory which suggests targeting a combination of susceptibility and infectivity. This policy, which is similar to the approaches adopted in the UK and in Canada, is found to be effective in reducing deaths and life years lost in the period while vaccination is still being carried out.","Comparative Effectiveness of Standard and Contingency-based Cleaning in Acute and Long-Term Care Facilities amidst Staff Shortages and a COVID-19 Surge\nBackgroundCleanliness of hospital surfaces helps prevent healthcare-associated infections, but larger evaluations of the effectiveness of various cleaning strategies during SARS-CoV-2 surges and worker shortages are scarce.\n\nMethodsIn an acute care hospital (ACH) and a long-term care facility (LTCF), 417 surfaces were tested for SARS-CoV-2 and adenosine triphosphate before and after various cleaning strategies, including ultraviolet light (UV-C), electrostatic spraying, and room fogging.\n\nResultsACH surface contamination differed among outbreak and non-outbreak wards (p = 0.001). RNA was detected on 66% of surfaces before cleaning and on 23% of those surfaces immediately after terminal cleaning, for a 65% post-cleaning reduction (p = 0.001). UV-C resulted in an 87% reduction (p = 0.023), while spraying with electrostatic bleach resulted in a 47% reduction (p = 0.010). LTCF contamination rates differed between the dementia, rehabilitation, and the residential units (p = 0.005). 67% of surfaces had RNA after room fogging without terminal-style wiping. Fogging with wiping led to an 11% reduction in the proportion of positive surfaces.\n\nDiscussionBaseline contamination varied by type of unit and outbreak conditions, but not facility type. Removal of viral RNA varied according to strategy. Unlike previous reports, time spent cleaning was associated with cleaning thoroughness.","Extension of Community Healthcare Outcomes in Parkinson Disease (Parkinson ECHO): A Feasibility Study\nParkinsons disease is the second most common neurodegenerative disorder and presents with a heterogeneous group of symptoms. Managing these symptoms requires coordinated care from a neurology specialist and a primary care provider. Access to neurology care is limited for those patients with Parkinsons disease who reside in rural areas given financial and mobility constraints along with the rarity of specialty providers. To close this gap, we developed and implemented a telehealth-based Project ECHO(R) (Extension for Community Healthcare Outcomes) program, \"Parkinson ECHO,\" to provide education and support for rural clinicians and allied health members. We assessed the feasibility of this tele-mentoring educational offering and the effect it had on clinician confidence in diagnosing and treating Parkinsons disease. Participants from across Oregon (n=33), of whom 70% served rural and/or medically underserved communities, attended the biweekly sessions. The sessions focused on a topic within Parkinsons disease diagnosis or management followed by case discussions. We assessed clinician confidence and acceptability using surveys before and after their participation in the program. The COVID-19 pandemic was an unexpected obstacle in executing this project, delaying the program by several months and likely accounting for a lower number of attendees for the last two sessions. Nevertheless, we found Parkinson ECHO did significantly increase participant confidence levels in diagnosing and managing Parkinsons disease.","Machine-learning based preoperative analytics for the prediction of anastomotic insufficiency in colorectal surgery: a single-centre pilot study\nBackgroundAnastomotic insufficiency (AI) is a relatively common but grave complication after colorectal surgery. This study aims to determine whether AI can be predicted from simple preoperative data using machine learning (ML) algorithms.\n\nMethodsIn this retrospective analysis, patients undergoing colorectal surgery with creation of a bowel anastomosis from the University Hospital of Basel were included. Data was split into a training set (80%) and a test set (20%). The group of patients with AI was oversampled to a ratio of 50:50 in the training set and missing values were imputed. Known predictors of AI were included as inputs: age, gender, BMI, smoking status, alcohol abuse, prior abdominal surgery, leukocytosis, haemoglobin and albumin levels, steroid use, the Charlson Comorbidity Index, the American Society of Anesthesiologists score, and renal function.\n\nResultsOf the 593 included patients, 88 experienced AI. At internal validation on unseen patients from the test set, area under the curve (AUC) was 0.64 (95% confidence interval [CI]: 0.44-0.82), calibration slope was 0.21 (95% CI: -0.02-0.46) and calibration intercept was 0.06 (95% CI: 0.01-0.1). We observed a specificity of 0.76 (95% CI: 0.68-0.84), sensitivity of 0.36 (95% CI: 0.08-0.7), and accuracy of 0.72 (95% CI: 0.65-0.8).\n\nConclusionBy using 13 patient-related risk factors associated with AI, we demonstrate the feasibility of ML-based prediction of AI after colorectal surgery. Nevertheless, it is crucial to include multicenter data and higher sample sizes to develop a robust and generalisable model, which will subsequently allow for deployment of the algorithm in a web-based application.","Integrated genomics identify novel immunotherapy targets for malignant mesothelioma\nBackgroundMalignant pleural mesothelioma (MPM) is an aggressive malignancy with limited effective therapies.\n\nMethodsIn order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells.\n\nResultsPreviously unrecognised losses of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary MPM cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin.\n\nConclusionsOur results suggest new therapeutic avenues in MPM and provide targets and biomarkers for immunotherapy.","Fusion of Imaging and Non-Imaging Data for Disease Trajectory Prediction for COVID-19 Patients\nABSTRCATO_ST_ABSPurposeC_ST_ABSThis study investigates whether graph-based fusion of imaging data with non-imaging EHR data can improve the prediction of disease trajectory for COVID-19 patients, beyond the prediction performance of only imaging or non-imaging EHR data.\n\nMaterials and MethodsWe present a novel graph-based framework for fine-grained clinical outcome prediction (discharge, ICU admission, or death) that fuses imaging and non-imaging information using a similarity-based graph structure. Node features are represented by image embedding and edges are encoded with clinical or demographic similarity.\n\nResultsOur experiments on data collected from Emory Healthcare network indicate that our fusion modeling scheme performs consistently better than predictive models using only imaging or non-imaging features, with f1-scores of 0.73, 0.77, and 0.66 for discharge from hospital, mortality, and ICU admission, respectively. External validation was performed on data collected from Mayo Clinic. Our scheme highlights known biases in the model prediction such as bias against patients with alcohol abuse history and bias based on insurance status.\n\nConclusionThe study signifies the importance of fusion of multiple data modalities for accurate prediction of clinical trajectory. Proposed graph structure can model relationships between patients based on non-imaging EHR data and graph convolutional networks can fuse this relationship information with imaging data to effectively predict future disease trajectory more effectively than models employing only imaging or non-imaging data. Forecasting clinical events can enable intelligent resource allocation in hospitals. Our graph-based fusion modeling frameworks can be easily extended to other prediction tasks to efficiently combine imaging data with non-imaging clinical data.","Validation of a transcriptome-based assay for classifying cancers of unknown primary origin\nCancers assume a variety of distinct histologies and may originate from a myriad of sites including solid organs, hematopoietic cells, and connective tissue. Clinical decision making based on consensus guidelines such as NCCN is often predicated on a specific histologic and anatomic diagnosis, supported by clinical features and pathologist interpretation of morphology and immunohistochemical (IHC) staining patterns. However, in patients with nonspecific morphologic and IHC findings - in addition to ambiguous clinical presentations such as recurrence versus new primary - a definitive diagnosis may not be possible, resulting in the patient being categorized as having a cancer of unknown primary (CUP). Therapeutic options and clinical outcomes are poor for CUP patients, with a median survival of 8-11 months. Here we describe and validate the Tempus Tumor Origin (Tempus TO) assay, an RNA-seq-based machine learning classifier capable of discriminating between 68 clinically relevant cancer subtypes. We show that the Tempus TO model is 91% accurate when assessed on retrospectively and prospectively held out cohorts of containing 9,210 samples with known diagnoses. When evaluated on a cohort of CUPs, the model recapitulated established associations between genomic alterations and cancer subtype. Combining diagnostic prediction tests (e.g., Tempus TO) with sequencing-based variant reporting (e.g., Tempus xT) may expand therapeutic options for patients with cancers of unknown primary or uncertain histology.","Natural language inference for clinical registry curation\nClinical registries - structured databases of demographic, diagnosis, and treatment information for patients with specific diseases or phenotypes - play vital roles in high-quality retrospective studies, operational planning, and assessment of patient eligibility for research, including clinical trials. However, registries are extremely time and resource intensive to curate. Natural language processing (NLP) can help, but standard NLP methods require specially annotated training sets or the construction of separate models for each of dozens or hundreds of different registry fields, rendering them insufficient for registry curation at scale. Natural language inference (NLI), a specific branch of NLP focused on logical relationships between statements, presents a possible solution, but NLI methods are largely unexplored in the clinical domain outside the realm of conference shared tasks and computer science benchmarks. Here we convert registry curation into an NLI problem, applying five state-of-the-art, pretrained, deep learning based NLI models to clinical, laboratory, and pathology notes to infer information about 43 different breast oncology registry fields. We evaluate the models inferences against a manually curated, 7439 patient breast oncology research database. The NLI models show considerable variation in performance, both within and across registry fields. One model, ALBERT, outperforms the others (BART, RoBERTa, XLNet, and ELECTRA) on 22 out of 43 fields. A detailed error analysis reveals that incorrect inferences primarily arise through models misinterpretations of temporality--they interpret historical findings as current and vice versa--as well as confusion based on subtle terminology and abbreviation variants common in clinical notes. However, modern NLI methods show promise for increasing the efficiency of registry curation, even when used \"out of the box\" with no additional training.","An expanded population of CD8dim T cells with features of mitochondrial dysfunction and senescence is associated with persistent HIV-associated Kaposis sarcoma under ART\nHIV-associated Kaposis sarcoma (KS), which is caused by Kaposis sarcoma-associated herpesvirus, usually arises in the context of uncontrolled HIV replication and immunosuppression. However, disease occasionally persists in individuals with durable HIV viral suppression and CD4 T cell recovery under anti-retroviral therapy (ART). The underlying mechanisms associated with this persistence are unclear. Suppression of viral infections can be mediated by CD8 T cells that detect infected cells via their T cell receptor and the CD8 co-receptor. However, CD8 T cells exhibit signs of functional exhaustion in untreated HIV infection that may not be fully reversed under ART. To investigate whether persistent KS under ART was associated with phenotypic and functional perturbations of CD8 T cells, we performed a cross-sectional study comparing HIV-infected individuals with persistent KS under effective ART (HIV+ KS+) to HIV-infected individuals receiving effective ART with no documented history of KS (HIV+ KSneg). A subset of T cells with low cell surface expression of CD8 (\"CD8dim T cells\") was expanded in HIV+ KS+ compared with HIV+ KSneg participants. Relative to CD8bright T cells, CD8dim T cells exhibited signs of senescence (CD57) and mitochondrial perturbations (PGC-1, MitoTracker) ex vivo. Mitochondrial activity (MitoTracker) was also reduced in proliferating CD8dim T cells. These findings indicate that an expanded CD8dim T cell population displaying features of senescence and mitochondrial dysfunction is associated with KS persistence under ART. CD8 co-receptor down-modulation may be symptomatic of ongoing disease.","Sex differences, cross-ancestry generalizability, and noise-smoking interactions in the polygenic architecture of hearing loss in adults\nWe conducted a comprehensive genome-wide investigation of hearing loss (HL) in 748,668 adult participants of the UK Biobank, the Nurses Health Studies (I and II), the Health Professionals Follow-up Study, and the Million Veteran Program. We identified 54 risk loci and characterized HL polygenic architecture, exploring sex differences, polygenic risk across ancestries, tissue-specific transcriptomic regulation, cause-effect relationships with genetically-correlated traits, and gene interactions with HL environmental risk factors. Our transcriptomic regulation analysis highlighted the potential role of the central nervous system in HL pathogenesis. This was supported by the multivariate interaction analysis that showed how genes involved in brain development interact with sex, noise pollution, and tobacco smoking in relation to their HL associations. Additionally, the genetically-informed causal inference analysis showed that HL is linked to many physical and mental health outcomes. These results provide many novel insights into the complex biology and epidemiology of HL in adults.","Asymptomatic carriers of the p.A53T SNCA mutation: data from the PPMI study\nIntroductionThere has been great interest in the prodromal phase of Parkinsons disease (PD), especially in subjects who are asymptomatic carriers of genetic mutations leading to PD because of the high risk to convert to PD. The objective of the present study was to assess non motor characteristics of asymptomatic p.A53T mutation carriers (A53T-AC) compared with healthy controls (HC).\n\nMethodsWe compared 12 A53T-AC with 36 matched HC enrolled into in the Parkinsons Progression Markers Initiative (PPMI) study. Baseline data extracted from the PPMI database, contained demographics and non-motor symptoms (e.g. the Montreal Cognitive Assessment (MOCA) for cognition, the University of Pennsylvania Smell Identification Test (UPSIT) for olfaction, MDS-UPDRS I etc.)\n\nResultsThe mean UPSIT score was lower in A53T-AC vs HC (p =0.000). MoCA test showed a trend towards lower scores in A53T AC. We found a significant positive correlation between UPSIT score and MOCA in A53T-AC (rs = 0,68, p=0,021) but not in HC. Total scores for MDS-UPDRS I did not differ between the groups but the subscore of anxiety was more prevalent in A53T-AC.\n\nConclusionThe more affected olfaction in A53T-AC may indicate that olfactory function is affected quite early in A53T carriers. The strong positive correlation between UPSIT and MOCA in the A53T-AC group may indicate that cognitive dysfunction and olfactory impairment progress alongside, prior to nigrostriatal degeneration. Anxiety was also more prevalent in A53T-AC and may represent an additional prodromal feature in this group of subjects.","Is Google Trends a useful tool for tracking mental and social distress during a public health emergency?: A time-series analysis\nBackgroundGoogle Trends data are increasingly used by researchers as an indicator of population mental health, but few studies have investigated the validity of this approach.\n\nMethodsRelative search volumes (RSV) for the topics depression, anxiety, self-harm, suicide, suicidal ideation, loneliness, and abuse were obtained from Google Trends. We used graphical and time-series approaches to compare daily trends in searches for these topics against population measures of these outcomes recorded using validated scales (PHQ-9; GAD-7; UCLA-3) in a weekly survey (n=[~]70,000) of the impact COVID-19 on psychological and social experiences in the UK population (12/03/2020 to 21/08/ 2020).\n\nResultsSelf-reported levels of depression, anxiety, suicidal ideation, self-harm, loneliness and abuse decreased during the period studied. There was no evidence of an association between self-reported anxiety, self-harm, abuse and RSV on Google Trends. Trends in reported depression symptoms and suicidal ideation declined over the study period, whereas Google topic RSV increased (p=0.03 and p=0.04 respectively). There was some evidence that suicidal ideation searches preceded reported self-harm (p=0.05), but graphical evidence suggested this was an inverse association. However, there was statistical and graphical evidence that self-report and Google searches for loneliness (p<0.001) tracked one another.\n\nLimitationsNo age/sex breakdown of Google Trends data are available. Survey respondents were not representative of the UK population and no pre-pandemic data were available.\n\nConclusionGoogle Trends data do not appear to be a useful indicator of changing levels of population mental health during a public health emergency, but may have some value as an indicator of loneliness.","LED transillumination of the chest and abdomen in the diagnosis of neonatal conditions\nAir leak syndromes, such as pneumothorax and pneumoperitoneum, are commonly diagnosed in Neonatal Intensive Care Units. However, this finding is usually detected with radiographic studies when the neonate is in poor condition. LED transillumination is an alternative method that allows a fast, inexpensive, and non-invasive diagnosis. We aimed to evaluate the clinical utility of LED transillumination in neonates by comparing the results to chest and abdomen radiograph as reference test.\n\nMethodologydiagnostic and prospective study that included 56 neonates. We used a simple and inexpensive handcrafted LED transilluminator to evaluate the chest and abdomen of patients, blind to the final diagnosis. The findings were compared to the radiographs.\n\nResultsthe study presented 3 true positive pneumothorax cases (sensibility 100%, 95%CI 29.24-100; specificity 100%, 95%CI 93.28-100), 1 true positive pneumoperitoneum case (sensibility 100%, 95%CI 2.50-100; specificity 100%, 95%CI 93.51-100), 10 true positive and 5 false negatives cases of gastric dilation (sensibility 66.67%, 95%CI 38.38-88.18; specificity 100%, 95%CI 91.19-100; negative likelihood ratio 0.33, 95%CI 0.16-0.68) and 4 true positive cases of dilation of bowel loops (sensibility 100%, 95%CI 39.76-100; specificity 100%, 95%CI 93.02-100).\n\nDiscussionLED transillumination is a safe, inexpensive, and easy-to-use clinical tool that may be employed to promote early intervention during severe cases of air leak syndrome that require immediate action, especially in low-income and rural areas. Further research with larger sample sizes is required to properly define the efficacy and usefulness of LED transillumination in routine use.","Selection of appropriate reference genes for normalization of qRT-PCR based gene expression analysis in SARS-CoV-2, and Covid-associated Mucormycosis infection\nSelection of reference genes in quantitative PCR is critical to determine accurate and reliable mRNA expression. Despite this knowledge, not a single study has investigated the expression stability of housekeeping genes to determine their suitability to act as reference gene in SARS-CoV-2 or Covid19 associated mucormycosis (CAM) infections. Herein, we address these gaps by investigating the expression stability of nine most commonly used housekeeping genes including TBP, CypA, B2M, 18S, PGC-1, GUSB, HPRT-1, {beta}-ACTIN and GAPDH in the patients of varying severity (asymptomatic, mild, moderate and severe). We observed significant differences in the expression of candidate genes across the disease spectrum. Next, using various statistical algorithms (delta Ct, Normfinder, Bestkeeper, RefFinder and GeNorm), we observed that CypA demonstrated the most consistent expression across the patients of varying severity and emerged as the most suitable gene in Covid19, and CAM infections. Incidentally, the most commonly used reference gene GAPDH showed maximum variations and found to be the least suitable. Lastly, comparative evaluation of expression of NRF2 is performed following normalization with GAPDH and CypA to highlight the relevance of an appropriate reference gene. Our results reinforce the idea of a selection of housekeeping genes only after validation especially during infections.","Evaluation on the Effectiveness on the Implementation of WHO-CST Programme in Hong Kong: A RCT Protocol\nDevelopmental delays/disorders in young children are identified as a public health priority. WHO and Autism Speaks co-designed a training programme titled \"WHO-Caregiver Skills Training\" (WHO-CST) which aims at providing training for caregivers whose children are with possible symptoms of Autism spectrum disorder (ASD) symptoms and pervasive developmental disorders (PDD), so that they can learn better strategies on managing the daily lives of their children and foster better communication between the parent-children dyad. The WHO-CST programme is currently implemented in more than 30 regions worldwide and it started in Hong Kong from 2018. As the programme is newly developed, only a few studies tried to evaluate the effectiveness of the programme in qualitative approaches, or in quantitative approach with relatively small sample (e.g. n < 10). In the present study, our team, who is responsible for the implementation and evaluation of the WHO-CST programme in Hong Kong, attempt to assess the effectiveness of the training in WHO-CST under a randomized controlled trial (RCT) design with about 120 eligible caregivers who will be randomly assigned in experimental and control groups. Our measurement will include the Joint Engagement Rating Inventory (JERI) developed by experts in WHO to gauge how parents engage their children in a 10-minute video recording their dyadic interaction and behaviors in a defined play setting. A set of other measurements on the caregivers experience of using intervention skills and their enhancement of knowledges will also be measured. We hypothesize that caregivers in treatment group will have better growth in scores of both JERI and measurements of other outcome than the wait-list control groups after the 12-week WHO-CST training, and also persistence of skill and knowledge level should also be found after a 30-day follow-up test.","Artificial Intelligence for the Diagnosis and Treatment of Diabetes Kidney Disease: a systematic review\nBackgroundDiabetic nephropathy (DN) is a serious microvascular complication that affects 40% of diabetes patients. In the last decade, artificial intelligence (AI) has been widely used in both structured and unstructured clinical data to improve the treatment of patients/potential patients with DN.\n\nMethodsThis systematic review aims to cover all applications of AI in the clinical use of DN or related topics. Studies were searched in four open-access databases (Pubmed, IEEE Xplore, DBLP Computer Science Bibliography, and ACM digital library). Finally, the author manually searched the reference list of included studies in the study for additional relevant articles.\n\nResultsFinally, a total of 24 original peers reviewed articles were included in this study. Through a manual data extraction, the summary of key information such as applied AI algorithm, main outcomes, performance evaluation etc. was taken. Then the included studies underwent a quality assessment criterion, assessing the reproducibility, generalizability etc. Most of the included studies revealed that the AI frameworks outperformed conventional statistical methods. A summary of the limitations, such as lack of data availability or external validation of the framework, in the included studies, was also included.\n\nConclusionThe rapid advancement of the AI framework and the exponential data generation in healthcare can be utilized and applied in clinical practices. The aid of AI can be instrumental in the treatment of DN.","Point-of-care semiquantitative test for adherence to tenofovir alafenamide or tenofovir disoproxil fumarate\nSynopsisO_ST_ABSObjectiveC_ST_ABSObjective measurement of antiretrovirals may aid clinical interventions for improving adherence to HIV prevention or treatment regimens. A point-of-care urine test could provide real-time information about recent adherence to regimens containing tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). We developed a lateral flow immunoassay (LFA) and enzyme-linked immunoassay (ELISA) for urinary tenofovir.\n\nMethodsIntensity of the LFA test line was quantified using an optical reader and visually scored 0 - 5 by two independent people, using a reference card. The sensitivity and specificity of both the ELISA and LFA were determined for two different tenofovir concentration cutoffs for TDF and TAF adherence--1,500 ng/mL and 150 ng/mL, respectively. To validate the assays, we measured 586 urine samples from 28 individuals collected as part of a study of tenofovir pharmacokinetics in adults, which were also measured by mass spectrometry as ground truth.\n\nResultsBoth the LFA signal and ELISA signal were each strongly correlated to drug concentrations (0.91 and 0.92 respectively). The LFA signal and ELISA were highly sensitive and specific at both thresholds (LFA se/sp TDF 89%/96%, TAF 90%/96%; ELISA se/sp TDF 94%/94%, TAF 92%/84%). Visual scoring of the LFA was also highly sensitive and specific at both the TDF and TAF thresholds (se/sp TDF 91%/94%, TAF 87%/90%).\n\nConclusionsOur rapid semi-quantitative test can measure TFV concentrations relevant to both TAF or TDF adherence, which may support adherence-promoting interventions across a range of HIV care settings.","Actionable absolute risk prediction of atherosclerotic cardiovascular disease: a behavior-management approach based on data from 464,547 UK Biobank participants\nCardiovascular diseases (CVDs) are the primary cause of all global death. Timely and accurate identification of people at risk of developing an atherosclerotic CVD and its sequelae, via risk prediction model, is a central pillar of preventive cardiology. However, currently available models only consider a limited set of risk factors and outcomes, do not focus on providing actionable advice to individuals based on their holistic medical state and lifestyle, are often not interpretable, were built with small cohort sizes or are based on lifestyle data from the 1960s, e.g. the Framingham model. The risk of developing atherosclerotic CVDs is heavily lifestyle dependent, potentially making a high percentage of occurrences preventable. Providing actionable and accurate risk prediction tools to the public could assist in atherosclerotic CVD prevention. We developed a benchmarking pipeline to find the best set of data preprocessing and algorithms to predict absolute 10-year atherosclerotic CVD risk. Based on the data of 464,547 UK Biobank participants without atherosclerotic CVD at baseline, we used a comprehensive set of 203 consolidated risk factors associated with atherosclerosis and its sequelae (e.g. heart failure).\n\nOur two best performing absolute atherosclerotic risk prediction models provided higher performance than Framingham and QRisk3. Using a subset of 25 risk factors identified with feature selection, our reduced model achieves similar performance while being less complex. Further, it is interpretable, actionable and highly generalizable. The model could be incorporated into clinical practice and could allow continuous personalized predictions with automated intervention suggestions.","Human cytomegalovirus strain diversity and dynamics reveal the donor lung as a major contributor after transplantation\nMixed human cytomegalovirus (HCMV) strain infections are frequent in lung transplant recipients (LTRs). To date, the influence of the donor (D) and recipient (R) HCMV-serostatus on intra-host HCMV strain composition and replication dynamics after transplantation is only poorly understood.\n\nHere, we investigated ten pre-transplant lungs from HCMV-seropositive donors, and 163 sequential HCMV-DNA positive plasma and bronchoalveolar lavage samples from 50 LTRs with multiviremic episodes post-transplantation. The study cohort included D+R+ (38%), D+R- (36%), and D-R+ (26%) patients. All samples were subjected to quantitative genotyping by short amplicon deep sequencing, and 24 thereof were additionally PacBio long-read sequenced for genotype linkages.\n\nWe find that D+R+ patients show a significantly elevated intra-host strain diversity compared to D+R- and D-R+ patients (P=0.0089). Both D+ patient groups display significantly higher replication dynamics than D- patients (P=0.0061). Five out of ten pre-transplant donor lungs were HCMV-DNA positive, whereof in three multiple HCMV strains were detected, indicating that multi-strain transmission via lung transplantation is likely. Using long reads, we show that intra-host haplotypes can share distinctly linked genotypes, which limits overall intra-host diversity in mixed infections. Together, our findings demonstrate donor-derived strains as a main source for increased HCMV strain diversity and dynamics post-transplantation, while a relatively limited number of intra-host strains may facilitate rapid adaptation to changing environments in the host. These results foster targeted strategies to mitigate the potential transmission of the donor strain reservoir with the allograft."],"string":"[\n \"KIM-1/TIM-1 is a Receptor for SARS-CoV-2 in Lung and Kidney\\nSARS-CoV-2 precipitates respiratory distress by infection of airway epithelial cells and is often accompanied by acute kidney injury. We report that Kidney Injury Molecule-1/T cell immunoglobulin mucin domain 1 (KIM-1/TIM-1) is expressed in lung and kidney epithelial cells in COVID-19 patients and is a receptor for SARS-CoV-2. Human and mouse lung and kidney epithelial cells express KIM-1 and endocytose nanoparticles displaying the SARS-CoV-2 spike protein (virosomes). Uptake was inhibited by anti-KIM-1 antibodies and TW-37, a newly discovered inhibitor of KIM-1-mediated endocytosis. Enhanced KIM-1 expression by human kidney tubuloids increased uptake of virosomes. KIM-1 binds to the SARS-CoV-2 Spike protein in vitro. KIM-1 expressing cells, not expressing angiotensin-converting enzyme 2 (ACE2), are permissive to SARS-CoV-2 infection. Thus, KIM-1 is an alternative receptor to ACE2 for SARS-CoV-2. KIM-1 targeted therapeutics may prevent and/or treat COVID-19.\",\n \"Clinical interpretation of machine learning models for prediction of diabetic complications using electronic health records\\nType 2 diabetes is a massive public health issue that continues to grow. The rate of diabetic complication progression varies across individuals. Understanding factors that alter the rate of complication onset may uncover new clinical interventions and help prioritize individuals for more aggressive management. Here, we explore how various machine learning models and types of electronic health records can predict fast versus slow diabetic complication onset using only patient data prior to diabetes diagnosis. We find that optimized random forests generally perform best among the tested models and combining all data sources yields the best predictive performance. A key differentiator of our study is our model interpretation, which identifies specific patient metrics from each dataset that play a unique role in the progression of each complication. Overall, our clinical interpretation of machine learning models can identify patients at risk for poorer outcomes years in advance of their diabetic complication.\",\n \"BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations\\nPurposeHeterozygous variants in BCL11A underlie an intellectual developmental disorder with persistence of fetal hemoglobin (BCL11A-IDD, a.k.a. Dias-Logan syndrome). We sought to delineate the genotypic and phenotypic spectrum of BCL11A-IDD.\\n\\nMethodsWe performed an in-depth analysis of 42 patients with BCL11A-IDD ascertained through a collaborative network of clinical and research colleagues. We also reviewed 33 additional affected individuals previously reported in the literature or available through public repositories with clinical information.\\n\\nResultsMolecular and clinical data analysis of 75 patients with BCL11A-IDD identified 60 unique variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique CNVs (microdeletions involving BCL11A only). We redefined the most frequent manifestations of the condition: intellectual disability, hypotonia, behavioral abnormalities, postnatal microcephaly and autism spectrum disorder. Two thirds of patients have brain MRI abnormalities, and we identified a recurrent posterior fossa phenotype of vermian hypoplasia and/or small brainstem. Truncating BCL11A variants, particularly those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S) isoform, were associated with increased severity.\\n\\nConclusionsWe expand the clinical delineation of BCL11A-IDD and identify a potential isoform-specific genotype-phenotype correlation. We show that BCL11A-IDD is associated with posterior fossa anomalies and highlight the differences between BCL11A-IDD and 2p16.1p15 microdeletion syndrome.\",\n \"Causality of Abdominal Obesity on Cognition: a Trans-ethnic Mendelian Randomization study\\nObesity has been associated with cognition in observational studies; however, whether its effect is confounding, reverse causality, or causal remains inconclusive. Using two-sample Mendelian randomization (MR) analyses, we investigated the causality of overall obesity, measured by BMI, and abdominal adiposity, measured by waist-hip ratio adjusted for BMI (WHRadjBMI), on cognition. Using summary data from the GIANT consortium, COGENT consortium, and UK Biobank of European ancestry, there was no causal effect of BMI on cognition performance (beta[95% CI]=-0.04[-0.12,0.04], p-value=0.35); however, a 1-SD increase in WHRadjBMI was associated with 0.07 standardized decrease in cognition performance (beta[95% CI]=-0.07[-0.12,-0.02], p=0.006). Using raw data from the Taiwan Biobank of Asian ancestry, there was no causal effect of BMI on cognitive aging (beta[95% CI]=0.00[-0.09,0.09], p-value=0.95); however, a 1-SD increase in WHRadjBMI was associated with a 0.17 standardized decrease in cognitive aging (beta[95% CI]=-0.17[-0.30,-0.03], p=0.02). This trans-ethnic MR study reveals that abdominal adiposity impairs cognition.\",\n \"Extended Invariant Information Clustering is Effective for Leave-One- Site-Out Cross-Validation in Resting State Functional Connectivity Modelling\\nHerein, we propose a new deep neural network model based on invariant information clustering (IIC), proposed by Ji et al., to improve the modeling performance of the leave-one-site-out cross-validation (LOSO-CV) for a multi-source dataset. Our Extended IIC (EIIC) is a type of contrastive learning; however, unlike the original IIC, it is characterized by transfer learning with labeled data pairs, but without the need for a data augmentation technique. Each site in LOSO-CV is left out in turn from the remaining sites used for training and receives a value for modeling evaluation. We applied the EIIC to the resting state functional connectivity magnetic resonance imaging dataset of the Autism Brain Imaging Data Exchange. The challenging nature of brain analysis for autism spectrum disorder (ASD) can be attributed to the variability of subjects, particularly the rapid change in the neural system of children as the target ASD age group. However, EIIC demonstrated higher LOSO-CV classification accuracy for the majority of scanning locations than previously used methods. Particularly, with the adjustment of a mini-batch size, EIIC outperformed other classifiers with an accuracy >0.8 for the sites with highest mean age of the subjects. Considering its effectiveness, our proposed method might be promising for harmonization in other domains, owing to its simplicity and intrinsic flexibility. We are currently submitting this manuscript to Frontiers in Neuroinformatics.\",\n \"IT ambidexterity driven patient agility and hospital patient service performance: a variance approach\\nHospitals are currently exploring digital options to transform their clinical procedures and their overall engagement with patients. This paper investigates how hospital departments can leverage the ability of firms to simultaneously explore new IT resources and practices (IT exploration) as well as exploit their current IT resources and practices (IT exploitation), i.e., IT ambidexterity, to adequately sense and respond to patients needs and demands, i.e., patient agility. This study embraces the dynamic capability view and develops a research model, and tests it accordingly using cross-sectional data from 90 clinical hospital departments from the Netherlands through an online survey. The models hypothesized relationships are tested using Partial Least Squares (PLS) structural equation modeling (SEM). The outcomes demonstrate the significance of IT ambidexterity in developing patient agility, positively influencing patient service performance. The study outcomes support the theorized model can the outcomes shed light on how to transform clinical practice and drive patient agility.\",\n \"Teaching an Old Dog New Tricks: Serum Troponin T as a Biomarker in Amyotrophic Lateral Sclerosis\\nAmyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. Diagnosis, management and therapeutic trials are hampered by a lack of informative biomarkers. Troponins (Tn) are components of skeletal and cardiac muscles. Acute elevation of cardiac isoforms of troponin I (cTnI) and T (cTnT) in serum indicates myocardial injury. Case reports suggested that serum levels of cTnT, but not cTnI are chronically elevated in ALS and other neuromuscular disorders.\\n\\nUsing standard clinical laboratory methodologies we studied serum troponin levels in a multicentric cross-sectional cohort of 75 ALS patients and sixty controls (DESCRIBE-ALS cohort) and in a real-world cohort of 179 consecutive patients from our ALS clinic at the University Hospital Bonn.\\n\\nWe found that serum cTnT, is elevated in >60% of ALS patients while cTnI is always normal. Serum cTnT levels increase over time and correlate with disease severity as measured with the revised ALS FRS score. There was no correlation with the phosphorylated neurofilament heavy chain (pNfH) levels in the cerebrospinal fluid. We propose that cTnT elevations in ALS are of non-cardiac origin and may serve as a proxy of lower motor neuron or skeletal muscle involvement. They potentially help to stratify patients according to lower motoneuron involvement. Further research will determine the biological origin of the cTnT elevation and its validity as a diagnostic and/or prognostic marker. Our finding also serves as a reminder to interpret cTnT with caution elevations in patients with neuromuscular diseases.\",\n \"Clinical Validation of a Proteomic Biomarker Threshold for Increased Risk of Spontaneous Preterm Birth\\nPreterm births are prevalent and a leading cause of neonatal death in the United States. Despite the availability of effective interventions, to date there is not a robust and widely applicable test to identify pregnancies at high risk for spontaneous preterm birth (sPTB). Previously, a sPTB predictor based on the ratio of two proteins, IBP4/SHBG, was validated as an accurate predictor of sPTB in the observational study Proteomic Assessment of Preterm Risk (PAPR). Here it is demonstrated that the same predictor threshold associated with 2-fold increased risk of sPTB, namely -1.4, is also statistically significant for predicting elevated risk of sPTB in the observational study Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor (TreeToP).\",\n \"TreatmentPatterns: An R package to analyze treatment patterns of a study population of interest\\nBackground and objectivesThere is an increasing interest to use real-world data to illustrate how patients with specific medical conditions are treated in real life. Insight in the current treatment practices helps to improve and tailor patient care. We aim to provide an easy tool to support the development and analysis of treatment pathways for a wide variety of medical conditions.\\n\\nMethodsWe formally defined the process of constructing treatment pathways and developed an open-source R package TreatmentPatterns (https://github.com/mi-erasmusmc/TreatmentPatterns) to enable a reproducible and timely analysis of treatment patterns.\\n\\nResultsThe developed package supports the analysis of treatment patterns of specific populations of interest. We demonstrate the functionality of the package by analyzing the treatment patterns of three common chronic diseases (type II diabetes mellitus, hypertension, and depression) in the Dutch Integrated Primary Care Information (IPCI) database.\\n\\nConclusionTreatmentPatterns is a tool to make the analysis of treatment patterns more accessible, more standardized, and more interpretation friendly. This tool can facilitate and contribute to the accumulation of knowledge on real-world treatment patterns across disease domains. We encourage researchers to further adjust and add custom analysis to the package based on their research needs.\",\n \"Medication use and physical assaults in the psychiatric emergency room\\nObjectiveTo evaluate the relationship between medications used to treat acute agitation (antipsychotics, mood stabilizers and benzodiazepines) and subsequent assault incidence in the psychiatric emergency room.\\n\\nMethodsMedication orders and assault incident reports were obtained from electronic health records for 17,052 visits to an urban psychiatric emergency room from 2014-2019. Assault risk was modeled longitudinally using Poisson mixed-effect regression.\\n\\nResultsAssaults were reported during 0.5% of visits. Intramuscular medications (IMs) were administered in 23.3% of visits overall, and predominately administered within the first 4-hours of a visit. IM administration was correlated with assault (IRR=24.2 [5.33, 110.0]), often because IM medication was administered immediately subsequent to reported assaults. Interacted with time, IMs were not significantly associated with reduction in future assaults (IRR=0.700 [0.467, 1.04]). Neither benzodiazepines nor mood stabilizers were associated with subsequent changes to the risk of reported assault. By contrast, antipsychotic medications were associated with decreased assault risk across time (IRR=0.583 [0.360, 0.942]).\\n\\nConclusionsIM order rates are high relative to overall assault incident risk. Of the three major categories of medications administered commonly in the psychiatric emergency setting, only antipsychotic medications were associated with measurable decreases in subsequent assault risk. Careful weighing of the risks and benefits of medications is encouraged; antipsychotic medication can have a significant side effect burden, and other medications (IMs, benzodiazepines, mood stabilizers) were not associated with subsequent reduction in assault risk in this analysis.\",\n \"Distinctive modularity and resilience of structural covariance network in first-episode antipsychotic-naive psychoses\\nObjectiveDivergent findings in structural brain alterations in psychoses suggest that often-observed regions may exist within a network of susceptible regions. We built structural covariance networks (SCN) of volumes, cortical thickness, and surface area using the Human Connectome Project atlas-based parcellation of 358 regions on structural MRI data from 79 first-episode antipsychotic-naive psychosis patients (FEAP) and 68 controls.\\n\\nMethodsUsing graph theoretic methods, we obtained representative graph metrics of integration, segregation, resilience, centrality, importance, community structure, and hub distribution for all 3-morphometric features. We compared networks for resilience by simulated removal (\\\"attacks\\\") of nodes and hubs, and simulated replacement of correlations among nodes in FEAP with that of controls using DeltaCon metric.\\n\\nResultsVolume and thickness SCNs of FEAP showed differences in many graph metrics in opposite directions compared to controls but not surface area SCN. Network resilience did not show differences in the replacement simulation and hub \\\"attacks, but betweenness centrality-based node \\\"attacks\\\" showed FEAP network disintegrating with relatively fewer node removals with preserved global efficiency compared to controls. In FEAP, communities consisted of regions from different lobes and hubs were more distributed than in controls.\\n\\nConclusionsOur findings suggest decreased heterogeneity and less differentiated community structure of FEAP network that may not be attributed to illness chronicity and medications. Contribution of cortical thickness but not surface area suggests that disease/developmental processes may preferentially affect cortical thickness. Near-similar resilience of FEAP and control networks may shield controls from developing illness but may prevent fuller long-term recovery in FEAP.\",\n \"Multi-omic landscaping of human midbrains identifies neuroinflammation as major disease mechanism in advanced-stage Parkinson's disease\\nParkinsons disease (PD) is the second most common neurodegenerative disorder whose prevalence is rapidly increasing worldwide. The disease mechanisms of sporadic PD are not yet completely understood. Therefore, causative therapies are still lacking. To obtain a more integrative view of disease-mediated alterations, we investigated the molecular landscape of PD in human post-mortem midbrains. Tissue from 13 PD patients and 10 controls was subjected to small RNA sequencing, transcriptomics, and proteomics analysis. Differential expression analyses were performed reveal multiple deregulated molecular targets linked to known pathomechanisms of PD as well as novel processes. We found significant differential expression of miR-539-3p, miR-376a-5p, miR-218-5p, and miR-369-3p, the valid miRNA-mRNA interacting pairs of miR-218-5p/RAB6C, and miR-369-3p/GTF2H3, as well as multiple proteins relevant in the pathology of PD, including CHI3L1, SELENBP1, PRDX1, HSPA1B, and TH. Vertical integration of multiple omics analyses allowed to validate disease-mediated molecular alterations across different molecular layers and functional annotation of differentially expressed targets identified a strong enrichment of pathways related to inflammation and activation of the immune response. This suggests that neuroinflammation may significantly contribute to disease progression in PD and may be a promising therapeutic target in advanced stages of PD.\",\n \"Automated Detection of Candidate Subjects with Cerebral Microbleeds using Machine Learning\\nCerebral microbleeds (CMBs) appear as small, circular, well defined hypointense lesions of a few mm in size on T2*-weighted gradient recalled echo (T2*-GRE) images and appear enhanced on susceptibility weighted images (SWI). Due to their small size, contrast variations and other mimics (e.g. blood vessels), CMBs are highly challenging to detect automatically. In large datasets (e.g. the UK Biobank dataset), exhaustively labelling CMBs manually is difficult and time consuming. Hence it would be useful to preselect candidate CMB subjects in order to focus on those for manual labelling, which is essential for training and testing automated CMB detection tools on these datasets. In this work, we aim to detect CMB candidate subjects from a larger dataset, UK Biobank, using a machine learning-based, computationally light pipeline. For our evaluation, we used 3 different datasets, with different intensity characteristics, acquired with different scanners. They include the UK Biobank dataset and two clinical datasets with different pathological conditions. We developed and evaluated our pipelines on different types of images, consisting of SWI or GRE images. We also used the UK Biobank dataset to compare our approach with alternative CMB preselection methods using non-imaging factors and/or imaging data. Finally, we evaluated the pipelines generalisability across datasets. Our method provided subject-level detection accuracy > 80% on all the datasets (withindataset results), and showed good generalisability across datasets, providing a consistent accuracy of over 80%, even when evaluated across different modalities.\",\n \"Analysis of Mutational Profile of Hypopharyngeal and Laryngeal Head and Neck Cancers Identifies KMT2C as a Potential Tumor Suppressor\\nHypopharyngeal cancer represents one of worst types of head and neck tumors with only few studies focusing on the genomic profile of this type of cancer. Using targeted next-generation sequencing we analyzed 48 HPV-negative tumor samples including 23 originating from hypopharynx, and 25 from larynx. Among genes previously described as significantly mutated, TP53, FAT1, NOTCH1, KMT2C and CDKN2A were found to be most frequently mutated. We also found that more than three-fourths of our patients harbored candidate actionable or prognostic alterations in genes belonging to RTK/ERK/PI3K, cell-cycle and DNA-damage repair pathways. Using previously published data we compared 67 hypopharyngeal cancers to 595 head and neck cancers from other sites and found no prominent differences in mutational frequency except for CASP8 and HRAS genes. Since we observed relatively frequent mutations of KTM2C (MLL3) in our dataset, we analyzed their role in vitro by generating KMT2C-mutant hypopharyngeal cancer cell line FaDu with CRISPR-Cas9. We demonstrate that KMT2C loss-of-function results in increased colony formation and proliferation, in concordance with its previously published results. In summary, our results show that mutational profile of hypopharyngeal cancers might be similar to the one observed for other head and neck cancers with respect to minor differences and includes multiple candidate actionable and prognostic genetic alterations. We also demonstrate for the first time that KMT2C gene may play a role of tumor suppressor in head and neck cancer, which opens new possibilities in the search for new targeted treatment approaches.\",\n \"Outward and inward protections of different mask designs for different respiratory activities\\nWe evaluate the outward and inward protections of different mask types (N95, surgical and two cloth mask designs) taking into account the imperfect fit on the wearer. To this end, we built a manikin to simulate exhaling, coughing and inhaling of aerosol droplets 0.3-5.0 {micro}m in diameters. The outward and inward protections depend on many factors, including the droplet size, the mask fit and the presence of a filter layer. Here, we show that cloth and surgical masks with a non-woven filter layer can achieve a combined outward and inward protections between 50% and 90%. Removing the filter layer greatly reduces the protection efficiency to below 20% for the smallest droplet size. While a well-fitted N95 masks offer protection efficiency close to 100%, a poorly fitted N95 mask with gaps offers less protection than a well-fitted surgical/cloth mask. We also found that double masking--the wearing of cloth mask on top of a surgical mask--is only effective at reducing outward droplet emissions when coughing, while offering no additional protection when exhaling/inhaling as compared to a single cloth/surgical mask. The results of our work can inform the implementation of mask mandates to minimize airborne transmissions of coronavirus disease of 2019 (COVID-19).\\n\\nPractical implicationsO_LIA single cloth/surgical mask with non-woven filter layer offers significant protection against airborne transmissions.\\nC_LIO_LIFiltering facepiece masks such as N95 respirators are unlikely to achieve the advertised high protection for the general public due to poor mask fit.\\nC_LIO_LIDouble-masking offers little to no additional protection over a single cloth/surgical mask.\\nC_LI\",\n \"Developing A Deep Learning Natural Language Processing Algorithm For Automated Reporting Of Adverse Drug Reactions\\nThe detection of adverse drug reactions (ADRs) is critical to our understanding of the safety and risk-benefit profile of medications. With an incidence that has not changed over the last 30 years, ADRs are a significant source of patient morbidity, responsible for 5-10% of acute care hospital admissions worldwide. Spontaneous reporting of ADRs has long been the standard method of reporting, however this approach is known to have high rates of under-reporting, a problem that limits pharmacovigilance efforts. Automated ADR reporting presents an alternative pathway to increase reporting rates, although this may be limited by over-reporting of other drug-related adverse events.\\n\\nWe developed a deep learning natural language processing algorithm to identify ADRs in discharge summaries at a single academic hospital centre. Our model was developed in two stages: first, a pre-trained model (DeBERTa) was further pre-trained on 150,000 unlabelled discharge summaries; secondly, this model was fine-tuned to detect ADR mentions in a corpus of 861 annotated discharge summaries. To ensure that our algorithm could differentiate ADRs from other drug-related adverse events, the annotated corpus was enriched for both validated ADR reports and confounding drug-related adverse events using. The final model demonstrated good performance with a ROC-AUC of 0.934 (95% CI 0.931 - 0.955) for the task of identifying discharge summaries containing ADR mentions.\",\n \"The development and usability testing of digital knowledge translation tools for parents of children with acute otitis media\\nAcute otitis media (AOM) is the most common bacterial ear infection affecting up to 80% of children before the age of three. Despite the common occurrence of the illness and the wide range of material available at clinics and online, parents are not always aware of these resources and they are often difficult to understand. We worked with parents to develop and assess the usability of a whiteboard animation video and interactive infographic for AOM in children. Parents rated the tools highly across all usability items, suggesting that creative tools developed using multi-method development processes can be useful, relevant, understandable, and will be used by the intended audience.\\n\\nFollowing the completion of the English-language products, our team culturally adapted the tools for the Pakistan context and evaluated the usability of these adapted tools. During usability testing, parents indicated that they felt the tools were useful, demonstrating that culturally adapted version of knowledge translations tools are effective in ensuring that parents could understand complex health information.\",\n \"Development of Novel Measures for Alzheimer's Disease Prevention Trials (NoMAD)\\nIntroductionAssessment of cognition and everyday function is essential in clinical trials for Alzheimers disease (AD). Two novel measures of cognition (No Practice Effects (NPE) cognitive battery and Miami Computerized Functional Assessment Scale (CFAS)) were designed to have robust psychometric properties and reduced practice and ceiling effects. This study aims to evaluate if the NPE and CFAS demonstrate stronger psychometric properties and reduced practice effects compared with established measures, including the Preclinical Alzheimer Cognitive Composite (PACC), Alzheimers Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Functional Activities Questionnaire (FAQ).\\n\\nMethodsThis parallel group, four-site study will randomize 320 cognitively intact adults aged 60 to 85 years to novel or well-established measures of cognition and function. All participants will receive assessments at baseline (week 0), week 12, and week 52, as well as a brain MRI scan and Apolipoprotein E genetic test at study entry. Analyses will determine psychometric properties of the NPE and CFAS, compare the sensitivity of measures to AD risk markers, and identify cognitive domains within the NPE.\\n\\nDiscussionPractice effects have been a major limitation of Alzheimers disease clinical trials that typically assess cognitive changes over serial assessments. Detection of functional impairment in cognitively normal individuals with biomarkers for Alzheimers disease requires instruments sensitive to very subtle functional changes. This study is intended to support the validation of two new composite measures, the NPE battery and the CFAS, which may advance clinical testing of interventions for individuals across the spectrum of early stage Alzheimers disease.\\n\\nTrial RegistrationNCT03900273\",\n \"L18F substrain of SARS-CoV-2 VOC-202012/01 is rapidly spreading in England\\nThe Variant of Concern (VOC)-202012/01 (also known as B.1.1.7) is a rapidly growing lineage of SARS-CoV-2. In January 2021, VOC-202012/01 constituted about 80% of SARS-CoV-2 genomes sequenced in England and was present in 27 out of 29 countries that reported at least 50 viral genomes. As this strain will likely spread globally towards fixation, it is important to monitor its molecular evolution. Based on GISAID data we systematically estimated growth rates of mutations acquired by the VOC lineage to find that L18F substitution in viral spike protein has initiated a substrain characterized by replicative advantage of 1.70 [95% CI: 1.56-1.96] in relation to the remaining VOC-202012/01 substrains. The L18F mutation is of significance because when recently analyzed in the context of the South African strain 501Y.V2 it has been found to compromise binding of neutralizing antibodies. We additionally indicate three mutations that were acquired by VOC-202012/01 in the receptor binding motif of spike, specifically E484K, F490S, and S494P, that may also give rise to escape mutants. Such mutants may hinder efficiency of existing vaccines and expand in response to the increasing after-infection or vaccine-induced seroprevalence.\",\n \"Combining Navigator and Optical Prospective Motion Correction for High-Quality 500 μm Resolution Quantitative Multi-Parameter Mapping at 7T\\nPURPOSEHigh-resolution quantitative multi-parameter mapping shows promise for non-invasively characterizing human brain microstructure but is limited by physiological artifacts. We implemented corrections for rigid head movement and respiration-related B0-fluctuations and evaluated them in healthy volunteers and dementia patients.\\n\\nMETHODSCamera-based optical prospective motion correction (PMC) and free-induction decay (FID) navigator correction were implemented in a gradient and RF-spoiled multi-echo 3D gradient echo sequence for mapping proton density (PD), longitudinal relaxation rate (R1) and effective transverse relaxation rate (R2*). We studied their effectiveness separately and in concert in young volunteers and then evaluated the navigator correction (NAVcor) with PMC in a group of elderly volunteers and dementia patients. We used spatial homogeneity within white matter (WM) and gray matter (GM) and scan-rescan measures as quality metrics.\\n\\nRESULTSNAVcor and PMC reduced artifacts and improved the homogeneity and reproducibility of parameter maps. In elderly participants, NAVcor improved scan-rescan reproducibility of parameter maps (coefficient of variation decreased by 14.7% and 11.9% within WM and GM respectively). Spurious inhomogeneities within WM were reduced more in the elderly than in the young cohort (by 9% vs 2%). PMC increased regional GM/WM contrast and was especially important in the elderly cohort, which moved twice as much as the young cohort. We did not find a significant interaction between the two corrections.\\n\\nCONCLUSIONNavigator correction and PMC significantly improved the quality of PD, R1 and R2* maps, particularly in less compliant elderly volunteers and dementia patients.\",\n \"LABELLING HUMAN KINEMATICS DATA USING CLASSIFICATION MODELS\\nThe goal of this study is to develop a classification model that can accurately and efficiently label human kinematics data. Kinematics data provides information about the movement of individuals by placing sensors on the human body and tracking their velocity, acceleration and position in three dimensions. These data points are available in C3D format that contains numerical data transformed from 3D data captured from the sensors. The data points can be used to analyse movements of injured patients or patients with physical disorders. To get an accurate view of the movements, the datasets generated by the sensors need to be properly labelled. Due to inconsistencies in the data capture process, there are instances where the markers have missing data or missing labels. The missing labels are a hindrance in motion analysis as it introduces noise and produces incomplete datapoints of sensors positioning in 3 dimensional space. Labelling the data manually introduces substantial effort in the analysis process. In this paper, we will describe approaches to pre-process the kinematics data from its raw format and label the data points with missing markers using classification models.\",\n \"The long-term effects of free care on birth outcomes: Evidence from a national policy reform in Zambia\\nAs women in many countries still fail to give birth in facilities due to financial barriers, many see the abolition of user fees as a key step on the path towards universal coverage. We exploited the staggered removal of user charges in Zambia from 2006 to estimate the effect of user fee removal over up to five years after the policy change. We used data from the birth histories of two nationally representative Demographic and Health Surveys to implement a difference-in-differences analysis and identify the causal impact of removing user charges on institutional and assisted deliveries, caesarean sections and neonatal deaths. We also used the rich survey data to explore heterogeneous effects of the policy. Removing fees had little effect in the short term but large positive effects appeared about two years after the policy change. Institutional deliveries in treated areas increased by 25 to 35%, driven entirely by a reduction in home births. However, there was no evidence that the reform changed the behaviours of women with lower education, the proportion of caesarean sections or reduced neonatal mortality. Institutional deliveries increased where care quality was high, but not where it was low. While abolishing user charges may reduce financial hardship from healthcare payments, it does not necessarily improve equitable access to care or health outcomes. Shifting away from user fees is a necessary but insufficient step towards universal health coverage, and concurrent reforms are needed to target vulnerable populations and improve quality of care.\",\n \"Fecal microbiota transplantation increases colonic IL-25 and dampens tissue inflammation in patients with recurrent Clostridioides difficile\\nBackgroundClostridioides difficile infection (CDI) is the most common hospital-acquired infection in the United States. Antibiotic-induced dysbiosis is the primary cause of susceptibility and fecal microbiota transplantation (FMT) has emerged as an effective therapy for recurrence. We previously demonstrated in the mouse model of CDI that antibiotic-induced dysbiosis reduced colonic expression of IL-25, and that FMT protected in part by restoring gut commensal bacteria-mediated IL-25 signaling. Here we conducted a prospective clinical trial to test the impact of FMT on immunity, specifically testing in humans if FMT induced IL-25 expression in the colon.\\n\\nMethodsSubjects received colonic biopsies and blood sampling at the time of FMT and 60-days later. Colon biopsies were assayed for IL-25 by immunoassay, for mRNA by RNAseq, and for bacterial content by 16 S rDNA sequencing. High dimensional flow cytometry was also conducted on peripheral blood mononuclear cells pre- and post-FMT.\\n\\nResultsAll 10 subjects who received FMT had no CDI recurrences over a 2 year follow-up post FMT. FMT increased alpha diversity of the colonic microbiota and was associated with several immunologic changes. The cytokine IL-25 was increased in colonic tissue. In addition, increased expression of homeostatic genes and repression of inflammatory genes was observed in colonic mRNA transcripts. Finally, circulating Th17 cells were decreased post-FMT.\\n\\nConclusionThe increase in the cytokine IL-25 accompanied by decreased inflammation is consistent with FMT acting in part to protect from recurrent CDI via restoration of commensal activation of type 2 immunity.\",\n \"Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly\\nThe Kennedy pathways catalyze the de novo synthesis of phosphatidylcholine and phosphatidylethanolamine, the most abundant components of eukaryotic cell membranes. In recent years, these pathways have moved into clinical focus since four out of ten genes involved have been associated with a range of autosomal recessive rare diseases such as a neurodevelopmental disorder with muscular dystrophy (CHKB), bone abnormalities and cone-rod dystrophy (PCYT1A), and spastic paraplegia (PCYT2, SELENOI).\\n\\nWe identified six individuals from five families with bi-allelic variants in CHKA presenting with severe global developmental delay, epilepsy, movement disorders, and microcephaly. Using structural molecular modeling and functional testing of the variants in a in a cell-based S. cerevisiae model, we determined that these variants reduce the enzymatic activity of CHKA and confer a significant impairment of the first enzymatic step of the Kennedy pathway.\\n\\nIn summary, we present CHKA as a novel autosomal recessive gene for a neurodevelopmental disorder with epilepsy and microcephaly.\",\n \"RBDAct: Home screening of REM sleep behaviour disorder based on wrist actigraphy in Parkinson's patients\\nBackgroundREM sleep behaviour disorder (RBD) is a disabling, often overlooked sleep disorder affecting up to 70% of patients with Parkinsons disease. Identifying and treating RBD is critical to prevent severe sleep-related injuries, both to patients and bedpartners. Current diagnosis relies on nocturnal video-polysomnography, which is an expensive and cumbersome exam requiring specific clinical expertise.\\n\\nObjectivesTo design, optimise, and validate a novel home-screening tool, termed RBDAct, that automatically identifies RBD in Parkinsons patients based on wrist actigraphy only.\\n\\nMethodsTwenty-six Parkinsons patients underwent two-week home wrist actigraphy worn on their more affected arm, followed by two non-consecutive in-lab evaluations. Patients were classified as RBD versus non-RBD based on dream enactment history and video-polysomnography. We characterised patients movement patterns during sleep using raw tri-axial accelerometer signals from wrist actigraphy. Machine learning classification algorithms were then trained to discriminate between patients with or without RBD using actigraphic features that described patients movements. Classification performance was quantified with respect to clinical diagnosis, separately for in-lab and at-home recordings.\\n\\nResultsClassification performance from in-lab actigraphic data reached an accuracy of 92.9{+/-}8.16% (sensitivity 94.9{+/-}7.4%, specificity 92.7{+/-}13.8%). When tested on home recordings, accuracy rose to 100% over the two-week window. Features showed robustness across tests and conditions.\\n\\nConclusionsRBDAct provides reliable predictions of RBD in Parkinsons patients based on home wrist actigraphy only. These results open new perspectives for faster, cheaper and more regular screening of sleep disorders, both for routine clinical practice and for clinical trials.\",\n \"Long-term Complications of Unintentional Dural Puncture During Labor Epidural Analgesia: A Case-Control Study.\\nIntroductionEpidural analgesia is the preferred method to manage pain during labor and delivery. The insertion of the epidural catheter can be complicated by unintentional dural puncture that may result in postdural puncture headache. There is limited evidence on the long term implications of this complication. We sought to investigate if women who sustained a dural puncture have a higher risk of developing chronic headache, low back pain and visual or auditory impairment.\\n\\nMethodsWe conducted a 1:1 case-control study with women who delivered at our institution from January 2015 to December 2019. Cases were women who received epidural analgesia and sustained an unintentional dural puncture and controls were women who received epidural analgesia but did not sustain such complication. We matched cases and controls for date of delivery, age, and BMI. All women completed an online survey with validated questionnaires for diagnosis of chronic headache and chronic back pain. We used dichotomic (yes/no) questions to look for the presence of chronic visual and auditory impairment.\\n\\nResultsSixty-three case-control pairs were studied. Women who sustained a dural puncture during their epidural catheter insertion had a higher risk of developing chronic headache [14.3%, versus 4.8%, p=0.049, AOR: 3.36 (1.05, 12.82)] and chronic back pain [39.7% versus 19.1%, p=0.009, AOR: 2.67 (1.25, 5.72)] than women who did not sustain a dural puncture. The incidence of chronic auditory impairment was also higher in the dural puncture group [14.3% versus 1.6%, p=0.007, AOR: 9.98 (1.21, 82.62)].\\n\\nConclusionsAn unintentional dural puncture during epidural catheter insertion in parturients is associated with increased risk of chronic headache, back pain and auditory impairment.\",\n \"Primary care and point-of-care testing during a pandemic: Clinician's perspectives on integrating rapid testing for COVID-19 into the primary care pathway\\nBackgroundReal-world evidence to support the adoption of SARS-CoV-2 point-of-care (POC) tests in primary care is limited. As the first point of contact of the health system for most patients, POC testing can potentially support general practitioners (GPs) quickly identify infectious and non-infectious individuals to rapidly inform patient triaging, clinical management, and safely restore more in-person services.\\n\\nObjectivesTo explore the potential role of SARS-CoV-2 point-of-care testing in primary care services.\\n\\nDesignA qualitative study using an inductive thematic analysis.\\n\\nSetting21 general practices located across three regions in England.\\n\\nResultsThree major themes were identified related to POC test implementation in primary care: (1) Insights into SARS-CoV-2 POC tests; (2) System and organisational factors; and (3) Practice-level service delivery strategies. Thematic subcategories included involvement in rapid testing, knowledge and perception of the current POC testing landscape, capacity for testing, economic concerns, resource necessities, perception of personal risk and safety, responsibility for administering the test, and targeted testing strategies.\\n\\nConclusionGPs knowledge of POC tests influences their degree of trust, uncertainty, and their perception of risk of POC test use. Concerns around funding, occupational exposure, and workload play a crucial role in GPs hesitation to provide POC testing services. These concerns could potentially be addressed with government funding, the use of targeted testing, and improved triaging strategies to limit testing to essential patient cohorts.\",\n \"Multi-type branching and graph product theory of infectious disease outbreaks\\nThe heterogeneity of human populations is a challenge to mathematical descriptions of epidemic outbreaks. Numerical simulations are deployed to account for the many factors influencing the spreading dynamics. Yet, the results from numerical simulations are often as complicated as the reality, leaving us with a sense of confusion about how the different factors account for the simulation results. Here, using a multi-type branching together with a graph tensor product approach, I derive a single equation for the effective reproductive number of an infectious disease outbreak. Using this equation I deconvolute the impact of crowd management, targeted testing, contact heterogeneity, stratified vaccination, mask use and smartphone tracing app use. This equation can be used to gain a basic understanding of infectious disease outbreaks and their simulations.\",\n \"Google Trends as a method to predict new COVID-19 cases\\nIn this paper, we develop a method that can detect and predict the emergence of new cases of COVID-19 at an early stage. With this method, we try to lay the empirical basis for the development of the model of digital monitoring and prediction of the occurrence of new cases of COVID-19 in Croatia, relying on the analytical tool Google Trends (GT).\\n\\nResultsIn Croatia search activities using GT for terms such as PCR +Covid\\\", \\\"PCR + test\\\", and symptoms \\\"cough + corona\\\", \\\"pneumonia + corona\\\"; \\\"muscle pain + corona\\\" correlate strongly with officially reported cases of the disease. Google Trends tools are suitable for predicting the emergence of new COVID-19 cases in Croatia, and that the data collected by this method correlate with official data.\\n\\nThe benefit of this method is reliable estimates that can enable public health officials to prepare and better respond to the possible return of a pandemic in certain parts of the country. If a region experiences an early, sharp increase in Covid-19-like-illness Google searches, it may be possible to focus additional resources on that region to identify the etiology of the outbreak, providing extra medical capacity or raising local media awareness as necessary.\\n\\nBecause the relative frequency of certain queries is highly correlated with the percentage of physician visits in which a patient presents with Covid-19 symptoms, this method can serve as an early alarm to predict the emergence of new cases of COVID-19 in the specific area in Croatia.\",\n \"The Anorexia Nervosa Care Pathway: Closing the Treatment Gap to Improve Care for Patients Admitted to Medical Hospitals\\nIntroductionMedical complications of malnutrition and refeeding account for approximately half of deaths in anorexia nervosa (AN). The AN Care Pathway (ANCP) was introduced at our institution in 2016 to improve quality of care of patients admitted for medical observation and management. We report results from our review of medical complications and report the impact and adoption of the ANCP.\\n\\nMethodsThe ANCP was developed in response to a need to improve quality of medical monitoring of patients with severe AN using Squire Guidelines and the Plan-Do-Study-Act cycle. All patients admitted to a medical hospital with AN between 2010-2020 were included after hospital inpatient enquiry and medical records were reviewed. Descriptive statistics were calculated using Stata (Statcorp).\\n\\nResultsFifty-one patients (63 admissions) were included. Median BMI was 13.8 kg/m (11.9-22.5). After ANCP implementation in 2016, compliance with recommended daily ECG, thiamine and blood tests improved from 30% (n=8/27) to 86% (n=21/36). We report a high rate of medical complications of severe AN including anaemia (n=24, 47%), neutropoenia (n=18, 35%), abnormal liver bloods (n=15, 29%) and half developed refeeding syndrome. One-third patients had cardiovascular compromise including reduced cardiac contractility (n=13, 25%), pericardial effusion (n=7, 14%) and one death. Low BMI was associated with cardiovascular complications (mean BMI 13.5 kg/m vs 15.5 kg/m, p=0.01) and neutropoenia (mean BMI 13.4 kg/m vs 15.4 kg/m, p=0.02).\\n\\nConclusionIntroduction of the ANCP improved quality of care during medical stabilisation. We report a high rate of medical complications of severe AN in patients admitted to a medical hospital. Use of multidisciplinary care protocols may contribute to quality improvement and improved consistency of care for this vulnerable population.\",\n \"Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis\\nIdiopathic pulmonary fibrosis (IPF) is a chronic lung condition with poor survival times. We previously published a genome-wide meta-analysis of IPF risk across three studies with independent replication of associated variants in two additional studies. To maximise power and to generate more accurate effect size estimates, we performed a genome-wide meta-analysis across all five studies included in the previous IPF risk GWAS. We utilised the distribution of effect sizes across the five studies to assess the replicability of the results and identified five robust novel genetic association signals implicating mTOR signalling, telomere maintenance and spindle assembly genes in IPF risk.\",\n \"Breast cancer risks associated with missense variants in breast cancer susceptibility genes\\nBACKGROUNDProtein truncating variants in ATM, BRCA1, BRCA2, CHEK2 and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain.\\n\\nMETHODSCombining 59,639 breast cancer cases and 53,165 controls, we sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1,146 training variants), BRCA1 (644), BRCA2 (1,425), CHEK2 (325) and PALB2 (472). We evaluated breast cancer risks according to five in-silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated.\\n\\nRESULTSThe most predictive in-silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1 and BRCA2, data were compatible with small subsets (approximately 7%, 2% and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set.\\n\\nCONCLUSIONSThese results will inform risk prediction models and the selection of candidate variants for functional assays, and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.\",\n \"Automated Detection of Cerebral Microbleeds on MR images using Knowledge Distillation Framework\\nCerebral microbleeds (CMBs) are associated with white matter damage, various neu-rodegenerative and cerebrovascular diseases. CMBs occur as small, circular hypointense lesions on T2*-weighted gradient recalled echo (GRE) and susceptibility weighted imaging (SWI) images, and hyperintense on quantitative susceptibility mapping (QSM) images due to their paramagnetic nature. Accurate detection of CMBs would help to determine the CMB lesion count and distribution, which would be further useful to understand the clinical impact of CMBs and to obtain quantitative imaging biomarkers. In this work, we propose a fully automated, deep learning-based, 2-step algorithm, using structural and anatomical properties of CMBs from any single input image modality (e.g. GRE / SWI / QSM) for their accurate detection. Our method consists of an initial candidate detection step, that detects CMBs with high sensitivity and a candidate discrimination step using a knowledge distillation framework to classify CMB and non-CMB instances, followed by a morphological clean-up step. We used 4 datasets consisting of different modalities specified above, acquired using various protocols and with a variety of pathological and demographic characteristics. On cross-validation within datasets, our method achieved a cluster-wise true positive rate (TPR) over 90% with an average of less than 2 false positives per subject. Our method is flexible in terms of the input modality and provides comparable cluster-wise TPR and a better cluster-wise precision compared to existing state-of-the-art methods. When evaluated across different datasets, our method showed good generalisability with a cluster-wise TPR greater than 80% with different modalities.\",\n \"North Carolina macular dystrophy: phenotypic variability and computational analysis of disease-implicated non-coding variants\\nPurposeNorth Carolina macular dystrophy (NCMD) is an autosomal dominant, congenital disorder affecting the central retina. Here, we report clinical and genetic findings in three families segregating NCMD and use epigenomic datasets from human tissues to gain insights into the effect of NCMD-implicated variants.\\n\\nMethodsClinical assessment and genetic testing were performed. Publicly-available transcriptomic and epigenomic datasets were analyzed and the Activity-by-Contact (ABC) method for scoring enhancer elements and linking them to target genes was used.\\n\\nResultsA previously-described, heterozygous, non-coding variant upstream of the PRDM13 gene was detected in all six affected study participants (chr6:100,040,987G>C [GRCh37/hg19]). Inter- and intra-familial variability were observed; the visual acuity ranged from 0.0 to 1.6 LogMAR and fundoscopic findings ranged from visually insignificant, confluent, drusen-like macular deposits to coloboma-like macular lesions. Variable degrees of peripheral retinal spots (which were easily detected on widefield retinal imaging) were observed in all study subjects. Notably, a 6-year-old patient developed choroidal neovascularization and required treatment with intravitreal bevacizumab injections. Computational analysis of the five single nucleotide variants that have been implicated in NCMD revealed that these non-coding changes lie within two putative enhancer elements; these elements are predicted to interact with PRDM13 in the developing human retina. PRDM13 was found to be expressed in the fetal retina, with highest expression in the amacrine precursor cell population.\\n\\nConclusionsWe provide further evidence supporting the role of PRDM13 dysregulation in the pathogenesis of NCMD and highlight the utility of widefield retinal imaging in individuals suspected to have this condition.\",\n \"Decision curve analysis to identify optimal candidates of liver resection for intermediate-stage hepatocellular carcinoma with hepatitis B cirrhosis：A cohort study\\nBackgroundThe selection criterion for liver resection (LR) in intermediate-stage (IM) hepatocellular carcinoma (HCC) is still controversial. This study aims to compare LR and transarterial chemoembolization in the range of predicted death risk\\n\\nMethodsThe multivariable Cox regression model (MVR) was estimated to predict mortality at 5yr. The cut-off values were determined by a two-piece-wise linear regression model, decision curve analysis with MVR model, and hazard ratio curve for treatment plotted against the predicted mortality.\\n\\nResults825 IM-HCC with hepatitis B cirrhosis were included for analysis (TACE, n=622; LR, n=203). The 5-yr overall survival rate of LR patients was higher than the TACE group (52.8% vs. 20.8%; P<0.0001). The line of LR and TACE were crossing with predicted death risk at 100% (P for interaction =0.008). The benefit of LR versus TACE decreased progressively as predicted death risk>0.55 (95%CI: 0.45,0.62). When predicted death risk over 0.7, decision curve analysis suggested that LR and TACE did not increase net benefit. Patients were then divided into four subgroups by the cut-off values (<0.45, 0.45[≥] /<0.62, 0.62[≥] /<0.7, [≥] 0.7). The stratified analysis of treatment in different subgroups, hazard ratios were 0.39 (95%CI: 0.27, 0.56), 0.36 (95%CI: 0.23, 0.56), 0.51 (95%CI: 0.27, 0.98), and 0.46 (95%CI: 0.27, 0.80), respectively.\\n\\nConclusionsLR reached the maximal relative utility in the interval of 0.45 to 0.62, and both LR and TACE did not increase net benefit at the 5-yr death risk over 0.7.\",\n \"Feasibility of Continuous Distal Body Temperature for Passive, Early Pregnancy Detection\\nThe majority of American women become aware of pregnancy ~3-7 weeks after conception, and all must seek testing to confirm their pregnant status. The delay between conception and awareness is often a time in which contraindicated behaviors take place. However, there is long standing evidence that passive, early pregnancy detection may be possible using body temperature. To address this possibility, we analyzed 30 individuals continuous distal body temperature (DBT) in the 180 days surrounding self-reported conception in comparison to self-reported pregnancy confirmation. Features of DBT nightly maxima changed rapidly following self-reported conception, reaching uniquely elevated values after a median of 5.5 {+/-} 3.5 days, whereas individuals reported a positive pregnancy test result at a median of 14.5 {+/-} 4.2 days. Together, we were able to generate a retrospective, hypothetical alert a median of 9 {+/-} 3.9 days prior to the date at which individuals received a positive pregnancy test. Continuous temperature-derived features can provide early, passive indication of pregnancy onset. We propose these features for testing and refinement in clinical settings, and for exploration in large, diverse cohorts. The development of pregnancy detection using DBT may reduce the delay from conception to awareness and increase the agency of pregnant individuals.\",\n \"A Progeroid Syndrome Caused by RAF1 deficiency Underscores the importance of RTK signaling for Human Development\\nSomatic and germline gain-of-function point mutations in RAF, the first oncogene to be discovered in humans, delineate a group of tumor-prone syndromes known as RASopathies. In this study, we document the first human phenotype resulting from the germline loss of function of the proto-oncogene RAF1 (a.k.a. CRAF). In a consanguineous family, we uncovered a homozygous p.Thr543Met mutation segregating with a neonatal lethal progeroid syndrome with cutaneous, craniofacial, cardiac and limb anomalies. Structure-based prediction and functional tests using human knock-in cells showed that threonine 543 is essential to: 1) ensure RAF1s stability and phosphorylation, 2) maintain its kinase activity towards substrates of the MAPK pathway and 3) protect from stress-induced apoptosis. When injected in Xenopus embryos mutant RAF1T543M failed to phenocopy the effects of overactive FGF/MAPK signaling confirming its hypomorphic activity. Collectively, our data disclose the genetic and molecular etiology of a novel segmental progeroid syndrome which highlights the importance of RTK signaling for human development and homeostasis.\\n\\nShort summaryA germline homozygous recessive loss-of-function mutation p.T453M in RAF1 causes a neonatal lethal progeroid syndrome. In vitro and in vivo tests demonstrate that Thr543 is necessary for RAF1s protein stability, to transduce signaling to the MAPK pathway and to respond to stress-induced apoptosis.\",\n \"COVID-19 vaccine-associated cerebral venous thrombosis in Germany\\nObjectiveReports of cerebral sinus and venous thrombosis (CVT) after ChAdOx1 vaccination against SARS-CoV-2 have raised safety concerns. We aimed to estimate the incidence of CVT within one month from first dose administration and the frequency of vaccine-induced immune thrombotic thrombocytopenia (VITT) as the underlying mechanism after vaccination with BNT162b2, ChAdOx1, and mRNA-1273, in Germany.\\n\\nMethodsA web-based questionnaire was e-mailed to all Departments of Neurology. We asked to report cases of CVT within one month of a COVID-19 vaccination. Other cerebral events could also be reported. Incidence rates of CVT were calculated by using official statistics of nine German States.\\n\\nResultsA total of 45 CVT cases were reported. In addition, 9 primary ischemic strokes, 4 primary intracerebral hemorrhages, and 4 other neurological events were recorded. Of the CVT patients, 35 (77.8%) were female, and 36 (80.0%) were below the age of 60 years. Fifty-three events were observed after vaccination with ChAdOx1 (85.5%), 9 after BNT162b2 (14.5%), and none after mRNA-1273 vaccination. After 7,126,434 first vaccine doses, the incidence rate of CVT within one month from first dose administration was 6.5 (95% CI, 4.4-9.2) per 100,000 person-years for all vaccines and 17.9 (11.8-26.1) for ChAdOx1 (after 2,320,535 ChAdOx1 first doses). The adjusted incidence rate ratio was 9.68 (3.46-34.98) for ChAdOx1 compared to mRNA-based vaccines and 3.14 (1.22-10.65) for women compared to non-women. In 26/45 patients with CVT (57.8%), VITT was graded highly probable.\\n\\nConclusionsGiven an incidence of 0.22-1.75 per 100,000 person-years for CVT in the general population, these findings point towards a higher risk for CVT after ChAdOx1 vaccination, especially for women.\",\n \"Is Footedness Driving Right Lower Extremity Arthroplasty Becoming Commoner Than Left Lower Extremity Arthroplasty?\\nThe question arises whether footedness transforms into asymmetrical incidence of wear and tear within lower extremity joints. After obtaining institutional review board approval for exempt research, the author manually counted the number of patients who underwent right or left or bilateral, hip or knee, primary or revision arthroplasty over a five-year period (2016-2020) at a university-affiliated hospital in the United States. Overall, right lower extremity arthroplasty was significantly commoner than left lower extremity arthroplasty (P=0.002). Individually, only right primary hip arthroplasty (P=0.033) and right revision knee arthroplasty (P=0.041) were significantly commoner procedures than their left counterparts. These results should set up the stage for future investigations into footedness retrospectively and prospectively to rule out if commoner right footedness in itself is driving this asymmetrical incidence of lower extremity arthroplasty or whether automatic transmission vehicular driving is independently contributing to this asymmetrical incidence.\",\n \"Human gain-of-function variants in HNF1A confer protection from diabetes but independently increase hepatic secretion of multiple cardiovascular disease risk factors\\nLoss-of-function mutations in Hepatocyte Nuclear Factor 1A (HNF1A) are known to cause rare forms of diabetes and alter hepatic physiology through unclear mechanisms. In the general population, 1:100 individuals carry a rare protein-coding variant in HNF1A, most of unknown functional consequence. To characterize the full allelic series, we performed deep mutational scanning of 11,970 protein-coding HNF1A variants in human hepatocytes and clinical correlation with 553,246 exome-sequenced individuals. Surprisingly, we found [~]1:5 rare protein-coding HNF1A variants found in the general population cause molecular gain-of-function (GOF), increasing the transcriptional activity of HNF1A by up to 50%. GOF in HNF1A conferred protection from type 2 diabetes (T2D) (OR=0.60, p=8.4 x 10-7), but not against coronary artery disease. Independently of T2D, increased hepatic expression of HNF1A promoted a pro-inflammatory and pro-atherogenic serum profile mediated in part by enhanced transcription of risk genes including PCSK9. In summary, [~]1:300 individuals carry a GOF variant in HNF1A that protects carriers from diabetes but enhances hepatic secretion of metabolic disease risk factors.\",\n \"Prospective validation of host transcriptomic biomarkers for pulmonary tuberculosis by real-time PCR\\nWe tested performance of host-blood transcriptomic tuberculosis (TB) signatures for active case-finding. Among 20,207 HIV-uninfected and 963 HIV-infected adults screened; 2,923 and 861 were enrolled from five South African communities. Eight signatures were measured by microfluidic RT-qPCR and participants were microbiologically-investigated for pulmonary TB at baseline, and actively surveilled for incident disease through 15 months. Diagnostic AUCs for 61 HIV-uninfected (weighted-prevalence 1.1%) and 10 HIV-infected (prevalence 1.2%) prevalent TB cases for the 8 signatures were 0.63-0.79 and 0.65-0.88, respectively. Thereafter, 24 HIV-uninfected and 9 HIV-infected participants progressed to incident TB (1.1 and 1.0 per 100 person-years, respectively). Prognostic AUCs through 15-months follow-up were 0.49-0.66 and 0.54-0.81, respectively. Prognostic performance for incident TB occurring within 6-12 months in HIV-negative participants was higher for all signatures. None of the signatures met WHO Target Product Profile criteria for a triage test to diagnose asymptomatic TB; most signatures met the criteria for symptomatic TB. Prognostic accuracy of most signatures for incident TB within six months of testing met the criteria for an incipient TB test.\",\n \"Context Matters! Depression following childbirth or a chronic disease diagnosis shows specific risk factor profiles.\\nProgress towards understanding the etiology of major depression (MD) is compromised by its clinical heterogeneity. The variety of contexts underlying the development of a major depressive episode may contribute to such heterogeneity. Here, we aimed to compare risk factor profiles of three subgroups of MD according to episode context.\\n\\nUsing self-report questionnaires and administrative records from the UK Biobank, we characterised three contextual subgroups of MD: postpartum depression (3,581 cases), depression following diagnosis of a chronic disease (409 cases) and a more typical (named heterogeneous) MD phenotype excluding the two prior contexts (34,699 cases). Controls with the same exposure were also defined. We tested each subgroup for association with MD polygenic risk scores (PRS) and other risk factors previously associated with MD (bipolar disorder PRS, neuroticism, reported trauma in childhood and adulthood, socioeconomic status, family history of depression, education).\\n\\nMD polygenic risk scores were associated with all subgroups, however, postpartum depression cases had higher PRS than heterogeneous MD cases (OR = 1.06, 95% CI: 1.02 - 1.10). Relative to heterogeneous depression, postpartum depression was more weakly associated with adulthood trauma and neuroticism. Relative to heterogeneous depression, depression following diagnosis of a chronic disease did not have higher MD polygenic risk scores but had weaker associations with neuroticism and reported trauma in adulthood and childhood.\\n\\nThe observed differences in risk factor profiles according to the context of a major depressive episode help provide insight into the heterogeneity of depression. Future studies dissecting such heterogeneity could help reveal more refined etiological insights.\",\n \"Beyond poverty as a proxy: reducing inequality in infant mortality by identifying and targeting higher risk births\\nInfant mortality remains high and uneven in much of sub-Saharan Africa. Given finite resources, reducing premature mortality requires effective tools to identifying left-behind populations at greatest risk. While countries routinely use income- or poverty-based thresholds to target policies, we examine whether models that consider other factors can substantially improve our ability to target policies to higher-risk births. Using machine learning methods, and 25 commonly available variables that can be observed prior to birth, we construct child-level risk scores for births in 22 sub-Saharan African countries. We find that targeting based on poverty, proxied by income, is only slightly better than random targeting, with the poorest 10 percent of the population experiencing approximately 10 percent of total infant mortality burden. By contrast the 10 percent of the population at highest risk according to our model accounts for 15-30% of infants deaths, depending on country. A hypothetical intervention that can be administered to 10% of the population and prevents just 5% of the deaths that would otherwise occur, for example, would save roughly 841,000 lives if targeted to the poorest decile, but over 1.6 million if targeted using our approach.\",\n \"Detection of malignant peripheral nerve sheath tumors in patients with neurofibromatosis using aneuploidy and mutation identification in plasma\\nMalignant peripheral nerve sheath tumors (MPNST) are the deadliest cancer that arises in individuals diagnosed with neurofibromatosis and account for nearly 5% of the 15,000 soft tissue sarcomas diagnosed in the United States each year. Comprised of neoplastic Schwann cells, primary risk factors for developing MPNST include existing plexiform neurofibromas (PN), prior radiotherapy treatment, and expansive germline mutations involving the entire NF1 gene and surrounding genes. PN develop in nearly 30-50% of patients with NF1 and most often grow rapidly in the first decade of life. One of the most important aspects of clinical care for NF1 patients is monitoring PN for signs of malignant transformation to MPNST that occurs in 10-15% of patients.\\n\\nWe perform aneuploidy analysis on ctDNA from 883 ostensibly healthy individuals and 28 patients with neurofibromas, including 7 patients with benign neurofibroma, 9 patients with PN and 12 patients with MPNST. Overall sensitivity for detecting MPNST using genome wide aneuploidy scoring was 33%, and analysis of sub-chromosomal copy number alterations (CNAs) improved sensitivity to 50% while retaining a high specificity of 97%. In addition, we performed mutation analysis on plasma cfDNA for a subset of patients and identified mutations in NF1, NF2, RB1, TP53BP2, and GOLGA2. Given the high throughput and relatively low sequencing coverage required by our assay, liquid biopsy represents a promising technology to identify incipient MPNST.\",\n \"Impact of real-time assessment on the training of trainers for the introduction of rotavirus vaccine in India\\nObjectivesTo assess the effectiveness of training workshops for knowledge enhancement of program managers prior to rotavirus vaccine (RVV) introduction in the routine immunization program.\\n\\nMethodThe study was conducted among the participants attending two training workshops for the introduction of RVV; a state workshop in Pune and a regional workshop in Guwahati. The participants who attended the workshops and participated in both the pre and post-test - 53 for Guwahati and 59 for Pune. Data was collected in real-time via pre-post-test.\\n\\nResultsIn both workshops, a comparison of pre-test and post-test scores of all questions taken together showed a significant increase in the knowledge level of the participants (p<0.05). In Guwahati, the knowledge of the participants regarding doses of RVV, inadequate dosing, Vaccine Vial Monitor (VVM), open vial policy, operationalization of RVV, and monetary incentive increased significantly. In Pune, the knowledge of the participants regarding doses of RVV, bundling approach, schedule and dose, storage temperature for Rotavirus vaccine, VVM, open vial policy, vaccine delivery, and operationalization of RVV increased significantly after the training.\\n\\nConclusionsA pre-planned and well-designed knowledge assessment tool can be used to understand the impact of training workshops in enhancing the knowledge and practical skills of the participants prior to the introduction of a new vaccine.\",\n \"Signatures of immune senescence predict outcomes and define checkpoint blockade-unresponsive microenvironments in acute myeloid leukemia\\nThe function of senescent-like T cells, transcriptomic features of immune effector senescence (IES) and their influence on therapeutic response were investigated in independent AML clinical cohorts comprising 1,864 patients treated with chemotherapy and/or immune checkpoint blockade (ICB). We show that senescent-like bone marrow CD8+ T cells are impaired in killing autologous AML blasts, and that their proportion negatively correlates with overall survival (OS). We define new IES signatures using two gene expression platforms and report that IES scores correlate with adverse-risk molecular lesions, stemness, and poor outcomes as a potentially more powerful predictor of OS than 2017-ELN risk or LSC17 stemness score. IES expression signatures also identify an ICB- unresponsive tumor microenvironment and predict significantly worse OS in AML as well as in solid tumors. The newly described IES scores provide improved AML risk stratification and could facilitate the delivery of personalized immunotherapies to patients who are most likely to benefit.\",\n \"Masks in a Post COVID-19 World: A Better Alternative to Curtailing Influenza?\\nOver the course of the coronavirus pandemic, it has become apparent that non-pharmaceutical interventions such as masks and social distancing are of great help in mitigating the transmission of airborne infectious diseases. Additionally, data from respiratory specimen analysis from the past year show that current mask mandates established for COVID-19 have inadvertently reduced the rates of other respiratory diseases, including influenza. Thus, the question arises as to whether comparatively mild measures should be kept in place after the pandemic to reduce the impact of influenza. In this study, we employed a series of differential equations to simulate past influenza seasons, assuming people wore face masks. This was achieved by introducing a variable to account for the efficacy and prevalence of masks and then analyzing its impact on influenza transmission rate in an SEIR model fit to the actual past seasons. We then compared influenza rates in this hypothetical scenario with the actual rates over the seasons. Our results show that several combinations of mask efficacy and prevalence can significantly reduce the burden of seasonal influenza. Particularly, our simulations suggest that a minority of individuals wearing masks greatly reduce the number of influenza infections. Considering the efficacy rates of masks and the relatively insignificant monetary cost, we highlight that it may be a viable alternative or complement to influenza vaccinations. We conclude with a brief discussion of our results and other practical aspects\",\n \"Loss of nucleoporin Nup50 is a risk factor for amyotrophic lateral sclerosis\\nThe genetic basis of amyotrophic lateral sclerosis (ALS) is still incompletely understood. Using two independent genetic strategies, we show here that a large part of ALS heritability lies in genes expressed in inhibitory and excitatory neurons, especially at splicing sites regulated by a defined set of RNA binding proteins including TDP-43 and FUS. We conducted a transcriptome wide association study (TWAS) and identified 59 loci associated with ALS, including 14 previously identified genes, some of them not previously reaching significance in genome wide association studies. Among the 45 novel genes, several genes are involved in pathways known to be affected in ALS such as mitochondrial metabolism (including ATP5H, ATP5D, BCS1L), proteostasis (including COPS7A, G2E3, TMEM175, USP35) or gene expression and RNA metabolism (including ARID1B, ATXN3, PTBP2, TAF10). Interestingly, decreased expression of NUP50, a constrained gene encoding a nuclear pore basket protein, was associated with ALS in TWAS (Zscore = -4, FDR = 0.034). 11 potentially pathogenic variants (CADD score > 20) in 23 patients were identified in the NUP50 gene, most of them in the region of the protein mediating interaction with Importin alpha, and including 2 frameshift mutations. In cells from two patients carrying NUP50 variants, we showed decreased levels of NUP50 protein. Importantly, knocking down Nup50 led to increased neuronal death associated with p62 and nucleoporin inclusions in cultured neurons, and motor defects in Drosophila and zebrafish models. In all, our study identifies alterations in splicing in neurons as a critical pathogenic process in ALS, uncovers several new loci potentially contributing to ALS missing heritability, and provides genetic evidence linking nuclear pore defects to ALS.\",\n \"Contamination of personal protective equipment during COVID-19 autopsies\\nConfronted with an emerging infectious disease, the medical community faced relevant concerns regarding the performance of autopsies of COVID-19 deceased at the beginning of the pandemic. This attitude has changed, and autopsies are now recognized as indispensable tools for elucidating COVID-19; despite this, the true risk of infection for autopsy staff is still debated. To elucidate the rate of SARS-CoV-2 contamination in personal protective equipment (PPE), swabs were taken at nine locations of the PPE of one physician and an assistant each from 11 full autopsies performed at four different centers. Further samples were obtained for three minimally invasive autopsies (MIA) conducted at a fifth center. Lung/bronchus swabs of the deceased served as positive controls. SARS-CoV-2 RNA was detected by RT-qPCR. In 9/11 full autopsies PPE samples were tested RNA positive with PCR, in total 21% of all PPE samples taken. The main contaminated parts of the PPE were the gloves (64% positive), the aprons (50% positive), and the upper sides of shoes (36% positive) while for example the fronts of safety goggles were only positive in 4.5% of the samples and all face masks were negative. In MIA, viral RNA was observed in one sample from a glove, but not in other swabs. Infectious virus isolation in cell culture was performed in RNA positive swabs from full autopsies. Of all RNA positive PPE samples, 21% of the glove samples were positive for infectious virus taken in 3/11 full autopsies. In conclusion, in >80% of autopsies, PPE was contaminated with viral RNA. In >25% of autopsies, PPE was found to be even contaminated with infectious virus, signifying a potential risk of infection among autopsy staff. Adequate PPE and hygiene measures, including appropriate waste deposition, are therefore mandatory to enable safe work environment.\",\n \"A combined polygenic score of 21,293 rare and 22 common variants significantly improves diabetes diagnosis based on hemoglobin A1C levels\\nPolygenic scores (PS), constructed from the combined effects of many genetic variants1, have been shown to predict risk or treatment strategies for certain common diseases2-6. As most PS to date are based on common variants7, the benefit of adding rare variation to PS remains largely unknown and methodically challenging. We developed and validated a method for constructing a rare variant PS and applied it to a previously identified clinical scenario, in which genetic variants modify the hemoglobin A1C (HbA1C) threshold recommended for type 2 diabetes (T2D) diagnosis6, 8-10. The resultant rare variant PS is highly polygenic (21,293 variants across 144 genes), depends on ultra-rare variants (72.7% of variants observed in <3 people), and identifies significantly more undiagnosed T2D cases than expected by chance (OR=2.71, p=1.51x10-6). A model combining the rare variant PS with a previously published common variant PS6 is expected to identify 4.9M misdiagnosed T2D cases in the USA, nearly 1.5-fold more than the common variant PS alone. These results provide a method for constructing complex trait PS from rare variants and suggest that rare variants will augment common variants in precision medicine approaches for common disease.\",\n \"Human studies of mitochondrial biology demonstrate an overall lack of binary sex differences: A multivariate meta-analysis\\nMitochondria are maternally inherited organelles that play critical tissue-specific roles, including hormone synthesis and energy production, that influence development, health, and aging. However, whether mitochondria from women and men exhibit consistent biological differences remains unclear, representing a major gap in biomedical knowledge. This meta-analysis systematically examined 4 domains and 6 subdomains of mitochondrial biology (total 39 measures), including mitochondrial content, respiratory capacity, reactive oxygen species (ROS) production, morphometry, and mitochondrial DNA copy number. Standardized effect sizes (Hedges g) of sex differences were computed for each measure using data in 2,258 participants (51.5% women) from 50 studies. Only two measures demonstrated aggregate binary sex differences: higher mitochondrial content in women (g = 0.20, {chi}2 p = 0.01), and higher ROS production in skeletal muscle in men (g = 0.49, {chi}2 p < 0.0001). differences showed weak to Sex no correlation with age or BMI. Studies with small sample sizes tended to overestimate effect sizes (r = -0.17, p < 0.001), and sex differences varied by tissue examined. Our findings point to a wide variability of findings in the literature concerning possible binary sex differences in mitochondrial biology. Studies specifically designed to capture sex- and gender-related differences in mitochondrial biology are needed, including detailed considerations of physical activity and sex hormones.\",\n \"Automated Enhancement and Curation of Healthcare Data\\nSocial and behavioral aspects of our lives significantly impact our health, yet minimal social determinants of health (SDOH) data elements are collected in the healthcare system. In this study we developed a repeatable SDOH enrichment and integration process to incorporate dynamically evolving SDOH domain concepts from consumers into clinical data. This process included SDOH mapping, linking compiled consumer data, data quality analysis and preprocessing, storage, and visualization. Our preliminary analysis shows commercial consumer data can be a viable source of SDOH factor at an individual-level for clinical data thus providing a path for clinicians to improve patient treatment and care.\",\n \"DNA methylation and general psychopathology in childhood: An epigenome-wide meta-analysis from the PACE consortium\\nThe general psychopathology factor (GPF) has been proposed as a way to capture variance shared between psychiatric symptoms. Despite a growing body of evidence showing both genetic and environmental influences on GPF, the biological mechanisms underlying these influences remain unclear. In the current study, we conducted epigenome-wide meta-analyses to identify both probe- and region-level associations of DNA methylation (DNAm) with school-age general psychopathology in six cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. DNAm was examined both at birth (cord blood; prospective analysis) and during school-age (peripheral whole blood; cross-sectional analysis) in total samples of N=2,178 and N=2,190, respectively. At school-age, we identified one probe (cg11945228) located in the Bromodomain-containing protein 2 gene (BRD2) that negatively associated with GPF (p=8.58x10-8). We also identified a significant DMR at school-age (p=1.63x10-8), implicating the SHC Adaptor Protein 4 (SHC4) gene that has been previously implicated in multiple types of psychiatric disorders in adulthood, including obsessive compulsive disorder and major depressive disorder. In contrast, no prospective associations were identified with DNAm at birth. Taken together, results of this study revealed some evidence of an association between DNAm at school-age and GPF. Future research with larger samples is needed to further assess DNAm variation associated with GPF.\",\n \"Redeployment and training of healthcare professionals to Intensive Care during COVID-19: a systematic review\\nBackgroundA rapid influx of patients to intensive care and infection control measures during the COVID-19 pandemic required the rapid development of innovative redeployment and training strategies.\\n\\nMethodsWe conducted a systematic search of 9 databases including key terms related to intensive care AND training AND redeployment AND healthcare workers. Analysis consisted of a narrative synthesis of quantitative study outputs, and a framework-based thematic analysis of qualitative study outputs and grey literature. These results were then combined applying an interpretative synthesis.\\n\\nResultsTwenty papers were analysed. These took place primarily in the UK (N=8, 40%) and USA (N=5, 25%). Themes included in the results are Redeployment: Implementation strategies and learnings; Redeployed staff experience and strategies to address their needs; Redeployed staff learning needs; Training formats offered and training evaluations; and Future redeployment and training concerns. Some of the redeployment implementation and training strategies documented in this review are: Skills-based redeployment, buddy support systems, and agreeing on locally-specific principles, rather than strict procedures.\\n\\nConclusionThe COVID-19 pandemic presented unique challenges to deliver training promptly while following infection control recommendations and develop flexible redeployment strategies. This study synthesises original approaches to tackle these challenges which are relevant to inform the development of targeted and adaptative training and redeployment plans.\",\n \"Chronic kidney disease is associated with attenuated plasma metabolome response to oral glucose tolerance testing\\nChronic kidney disease (CKD), a major public health problem, is associated with decreased anabolic response to insulin contributing to protein-energy wasting. Targeted metabolic profiling of the response to oral glucose tolerance testing (OGTT) may help identify metabolic pathways contributing to disruptions to insulin response in CKD. Using targeted metabolic profiling, we examined plasma metabolome in 41 moderate-to-severe non-diabetic CKD patients with estimated glomerular filtration rate (eGFR)<60ml/min per 1.73m2 (38.9{+/-}12.7) and 20 healthy controls with normal eGFR (87.2{+/-}17.7) before and after 2h of 75g oral glucose load. Compared to controls, CKD participants had higher lactate: pyruvate (L:P) ratio both at fasting and after oral glucose challenge. Total energy production estimated through GTP:GDP ratio was impaired during OGTT despite similar fasting GTP:GDP ratio. CKD group had sustained elevation of vitamin B family members, TCA cycle metabolites, and purine nucleotides in response to glucose challenge. Metabolic profiling in response to OGTT suggests a broad disruption of mitochondrial energy metabolism in CKD patients. These findings motivate further investigation into insulin sensitizers in patients with non-diabetic CKD and their impact on energy metabolism.\",\n \"Large-scale social media language analysis reveals emotions and behaviours associated with nonmedical prescription drug use\\nNonmedical use of prescription drugs (NMPDU) is a global health concern. The extent of, behaviors and emotions associated with, and reasons for NMPDU are not well-captured through traditional instruments such as surveys, prescribing databases and insurance claims. Therefore, this study analyses [~]130 million public posts from 87,718 Twitter users in terms of expressed emotions, sentiments, concerns, and potential reasons for NMPDU via natural language processing. Our results show that users in the NMPDU group express more negative emotions and less positive emotions, more concerns about family, the past and body, and less concerns related to work, leisure, home, money, religion, health and achievement, compared to a control group (i.e., users who never reported NMPDU). NMPDU posts tend to be highly polarized, indicating potential emotional triggers. Gender-specific analysis shows that female users in the NMPDU group express more content related to positive emotions, anticipation, sadness, joy, concerns about family, friends, home, health and the past, and less about anger, compared to males. The findings of the study can enrich our understanding of NMPDU.\",\n \"Health service research definition builder: An R Shiny application for exploring diagnosis codes associated with services reported in routinely collected health data\\nMany administrative health data-based studies define patient cohorts using procedure and diagnosis codes. The impact these criteria have on a studys final cohort is not always transparent to co-investigators or other audiences if access to the research data is restricted. We developed a SAS and R Shiny interactive research support tool which generates and displays the diagnosis code summaries associated with a selected medical service or procedure. This allows non-analyst users to interrogate claims data and groupings of reported diagnosis codes. The SAS program uses a tree classifier to find associated diagnosis codes with the service claims compared against a matched, random sample of claims without the service. Claims are grouped based on the overlap of these associated diagnosis codes. The Health Services Research (HSR) Definition Builder Shiny application uses this input to create interactive table and graphics, which updates estimated claim counts of the selected service as users select inclusion and exclusion criteria. This tool can help researchers develop preliminary and shareable definitions for cohorts for administrative health data research. It allows an additional validation step of examining frequency of all diagnosis codes associated with a service, reducing the risk of incorrect included or omitted codes from the final definition. In our results, we explore use of the application on three example services in 2016 US Medicare claims for patients aged over 65: knee arthroscopy, spinal fusion procedures and urinalysis. Readers can access the application at https://kelsey209.shinyapps.io/hsrdefbuilder/ and the code at https://github.com/kelsey209/hsrdefbuilder.\",\n \"Unsupervised Learning for Large Scale Data: The ATHLOS Project\\n1Recent technological advancements in various domains, such as the biomedical and health, offer a plethora of big data for analysis. Part of this data pool is the experimental studies that record various and several features for each instance. It creates datasets having very high dimensionality with mixed data types, with both numerical and categorical variables. On the other hand, unsupervised learning has shown to be able to assist in high-dimensional data, allowing the discovery of unknown patterns through clustering, visualization, dimensionality reduction, and in some cases, their combination. This work highlights unsupervised learning methodologies for large-scale, high-dimensional data, providing the potential of a unified framework that combines the knowledge retrieved from clustering and visualization. The main purpose is to uncover hidden patterns in a high-dimensional mixed dataset, which we achieve through our application in a complex, real-world dataset. The experimental analysis indicates the existence of notable information exposing the usefulness of the utilized methodological framework for similar high-dimensional and mixed, real-world applications.\",\n \"Pre-conceptional maternal vitamin B12 supplementation improves offspring neurodevelopment at 2 years of age: PRIYA trial\\nBackgroundNutritional interventions during the first 1000 days of life improves lifelong health. Better pre-conceptional maternal nutrition improves the nutrition of the early embryo. Vitamins B12 and folate are important for fetal neural development. Vitamin B12 deficiency is common in India.\\n\\nMethodsIn the Pune Rural Intervention in Young Adolescents (PRIYA) adolescents (N=557, 226 females) were provided with vitamin B12 (2{micro}g/day) with or without multiple micronutrients, or a placebo, from preconception until delivery. All groups received mandatory iron and folic acid. We used the Bayleys Scale of Infant Development (BSID-III) at 24-42 months of age to investigate effects on offspring neurodevelopment. We examined cord blood concentrations of brain-derived neurotropic factor (BDNF).\\n\\nResultsParticipants in the three groups had similar baseline B12 levels. These improved in the B12 supplemented groups at pre-conceptional and pregnancy (28 weeks gestation) measurements, reflected in higher cord holo-TC levels compared to the placebo. Neurodevelopmental outcomes are available for 74 children. Offspring in the B12 alone group (n=21) performed better than the placebo (n=27) on cognition (p=0.044) and language (p=0.020) domains (adjusted for maternal baseline B12 levels). There were no differences between the B12+MMN (n=26) and placebo group. Cord blood BDNF levels were highest in the B12 alone group (not statistically significant).\\n\\nConclusionPre-conceptional vitamin B12 supplementation improved maternal B12 status and offspring neurodevelopment at 2 years of age. The usefulness of cord BDNF as a marker of brain development needs further investigation. Our results highlight the importance of intervening in the pre-conceptional period.\",\n \"Anthropometric measures and their relationship to corneal refractive power in the United States population\\nPurposeTo determine the relationship between anthropometric measures and corneal refractive power (CRP).\\n\\nMethodsParticipants from the 1999-2008 United States National Health and Nutrition Examination Survey (NHANES) visual exam with demographic, ocular, and anthropometric data (20,165 subjects) were included. Cases with steep cornea were defined by corneal power [≥] 48.0 diopters (n = 171) while controls had dioptric power < 48.0 D (n = 19,994). Multivariable analyses were performed for pooled and sex-stratified populations. Separate models assessed body mass index, height, and weight in relation to steep cornea.\\n\\nResultsA relationship between BMI and steep cornea in the pooled population was not detected (P for trend = 0.78). There was a strong inverse relationship between height and steep cornea in the pooled population (P for trend <0.0001) and women (P for trend <0.0001). For every 1-inch increase in height, there was a 16% reduced odds of steep cornea in the pooled population (OR, 0.84; 95% CI: 0.78-0.91). There was also a significant inverse relationship between weight and steep cornea in the pooled population (P for trend = 0.01) and in men (P for trend = 0.02). For each 10-pound increase in weight there was a 7% reduced odds of steep cornea (OR, 0.927; 95% CI: 0.882-0.975) in the pooled analysis.\\n\\nConclusionsGreater height and greater weight were associated with a lower risk of steep cornea. These findings can contribute to an improved understanding of the pathogenesis of corneal ectasias.\",\n \"Association between telecommuting environment and low back pain among Japanese telecommuting workers: A cross-sectional study\\nObjectivesWe evaluated the relationship between telecommuting environment and low back pain (LBP) among desk-based workers in Japan.\\n\\nMethodsThis cross-sectional study included 3,663 desk-based, telecommuting workers. LBP was assessed using a 0-10 numerical rating scale. The telecommuting environment was evaluated using subjective questions. Mixed-effects logistic regression analysis was used to evaluate this association.\\n\\nResultsThe results of mixed-effects logistic model revealed that not having a place or room to concentrate on work, desk not well-lit enough for work, lack of space on the desk to work, not having enough legroom, and uncomfortable temperature and humidity conditions in the workspace were significantly associated with higher odds of LBP.\\n\\nConclusionsOur findings suggest that telecommuting environment is associated with the prevalence of LBP.\",\n \"CLINICAL OPPORTUNITIES FOR GERMLINE PHARMACOGENETICS AND MANAGEMENT OF DRUG-DRUG INTERACTIONS IN PATIENTS WITH ADVANCED SOLID CANCERS\\nPURPOSEPrecision medicine approaches, including germline pharmacogenetics (PGx) and management of drug-drug interactions (DDIs), are likely to benefit advanced cancer patients who are frequently prescribed multiple concomitant medications to treat cancer and associated conditions. Our objective was to assess the potential opportunities for PGx and DDI management within a cohort of adults with advanced cancer.\\n\\nPATIENTS AND METHODSMedication data were collected from the electronic health records (EHRs) for 481 subjects since their first cancer diagnosis. All subjects were genotyped for variants with clinically actionable recommendations in Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for 13 pharmacogenes. DDIs were defined as concomitant prescription of strong inhibitors or inducers with sensitive substrates of the same drug-metabolizing enzyme and were assessed for six major cytochrome P450 (CYP) enzymes.\\n\\nRESULTSApproximately 60% of subjects were prescribed at least one medication with CPIC recommendations, and [~]14% of subjects had an instance for actionable PGx, defined as prescription of a drug in a subject with an actionable genotype. The overall subject-level prevalence of DDIs and serious DDIs were 50.3% and 34.8%, respectively. Serious DDIs were most common for CYP3A, CYP2D6, and CYP2C19, occurring in 24.9%, 16.8%, and 11.7% of subjects, respectively. When assessing PGx and DDIs together, [~]40% of subjects had at least one opportunity for a precision medicine-based intervention and [~]98% of subjects had an actionable phenotype for at least one CYP enzyme.\\n\\nCONCLUSIONOur findings demonstrate numerous clinical opportunities for germline PGx and DDI management in adults with advanced cancer.\",\n \"Clinical performance of two EUA-approved anti-COVID-19 IgG/IgM rapid lateral flow immunoassays using whole blood finger-sticks\\nSerological, or antibody, tests detect immunoglobulins produced by the hosts plasma B cells following exposure to foreign antigens. Venipuncture blood draws to collect human venous whole blood, plasma from anticoagulated blood (Li+ heparin, K2EDTA and sodium citrate), or serum are commonly utilized and require refrigerated temperatures during transport to the testing facility. Subsequent laboratory testing by enzyme-linked immunosorbent assays (ELISA) or chemiluminescence immunoassays (CLIA) can take an additional 2-5 hours. In the context of the COVID-19 pandemic, rapid diagnostic tests (RDT) to be used in point-of-care (POC) and remote settings have become essential during mandatory quarantine and isolation periods. RDTs allowed for more cost-effective testing using less collection materials with an immediate (5-10 minutes) test result. However, the majority of emerging RDTs receiving Emergency Use Authorization (EUA) approval by the Food and Drug Administration (FDA) for qualitative detection and differentiation of IgM and IgG antibodies to SARS-CoV-2 were only approved for use in human venous whole blood, plasma or serum. In this study we summarize performance characteristics of one RDT (COVID-19 IgG/IgM lateral flow immunoassay rapid cassette) to another by simultaneous application of whole blood finger-stick specimens (n = 32). The study was performed over 5 different days, with daily quality controls consisting of serum previously verified to be positive or negative by COVID-19 IgG/IgM ELISA testing.\",\n \"The role of HIV infection in the clinical spectrum of COVID-19: a population-based cohort analysis based on US National COVID Cohort Collaborative (N3C) Enclave data\\nThe authors have withdrawn this manuscript because of the accidental low cell size in the supplementary materials. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.\",\n \"Seroconversion rate and socioeconomic and ethnic risk factors for SARS-CoV-2 infection in children in a population-based cohort\\nIntroductionSocioeconomic and ethnic background have been discussed as possible risk factors for SARS-CoV-2 infections in children. Improved knowledge could lead way to tailored prevention strategies and help to improve infection control.\\n\\nMethodsObservational population-based cohort study in children (6mo. - 18 ys.) scheduled for legally required preventive examination and their parents in a metropolitan region in Germany. Primary endpoint was the SARS-CoV-2 seroconversion rate during study period. Risk factors assessed included age, pre-existing medical conditions, socioeconomic factors, and ethnicity.\\n\\nResults2124 children and their parents were included. Seroconversion rates among children in all age groups increased by 3-4-fold from 06/2020 to 02/2021. Only 41% of seropositive children were symptomatic. In 51% of infected children at least one parent was also SARS-CoV-2 positive.\\n\\nLow level of parental education (OR 3.13 (0.72-13.69)) significantly increased the risk of infection. Of the total cohort, 38.5% had a migration background. Specifically, 9% were of Turkish and 5% of Middle Eastern origin. These children had the highest risk for SARS-CoV-2 infections (OR 6.24 (1.38-28.12) and 6.44 (1.14-36.45) after adjustment for other risk factors.\\n\\nDiscussionSeroprevalence of SARS-CoV-2 infections in children increased by 3-4-fold within the study period. Frequently, more than one family member was infected. Children from families with lower socioeconomic status were at higher risk. The highest risk for SARS-CoV-2 infection was identified in families with Turkish or Middle Eastern background. Culture sensitive approaches are essential to improve infection control and serve as a blueprint for vaccination strategies in this population.\\n\\nTrial RegistrationBMBF funding registration 01KI20173 (Corkid)\",\n \"Antigen-specific tolerization in human autoimmunity: Inhibition of interferon-beta1a anti-drug antibodies in multiple sclerosis\\nBackgroundAntigen-specific tolerance in auto-immune diseases is the goal for effective treatment with minimal side-effects. Whilst this is achievable in animal models, notably via intravenous delivery of the model-specific autoantigen following transient CD4 T cell depletion, specific multiple sclerosis autoantigens remain unproven. However, anti-drug antibodies to human therapeutic proteins represent a model human autoimmune condition, which may be used to examine immune-tolerance induction. Some people with MS (PwMS) on interferon-beta1a (IFN{beta}1a) develop neutralizing antibodies to IFN{beta}1a that do not disappear in repeated tests over years.\\n\\nMethodsOne PwMS was recruited, as part of a planned phase IIa trial (n=15), who had developed neutralizing antibodies to subcutaneous IFN{beta}1a. Mitoxantrone (12mg/m2) was administered as a lymphocyte depleting agent followed by four days of (88g/day + three 132g/day) intravenous IFN{beta}1a. Subcutaneous IFN{beta}1a three times a week was maintained during follow-up. IFN{beta}1a neutralizing antibody responses in serum were measured during treatment and three-monthly for 12 months.\\n\\nFindingsOne participant was recruited and, within 6 months of tolerization, the neutralizing antibodies were undetectable. The tolerization treatment was well tolerated. However, the study was terminated after the first enrolment, on ethical grounds, as treatment alternatives became available and the potential risks of mitoxantrone use increased.\\n\\nInterpretationThe data suggest that it may be possible to induce antigen-specific tolerance by providing tolerogenic antigen following transient immune depletion. Further studies are warranted.\\n\\nFundingThe study was supported by an unrestricted research grant from Merck-Serono.\",\n \"Central oxidative stress and early vocational outcomes in first episode psychosis: A 7-Tesla Magnetic Resonance Spectroscopy study of glutathione\\nFollowing the first episode of psychosis, some patients develop poor social and occupational outcomes, while others display a pattern of preserved functioning. Several lines of evidence from preclinical, genetic and biochemical studies suggest a role for high oxidative stress in poor functional outcomes. The measurement of intracortical glutathione (GSH) using magnetic resonance spectroscopy (MRS) provides an opportunity to investigate the relationship between central antioxidant tone and functional outcomes at the time of first episode psychosis (FEP). A body of epidemiological studies indicates better functional outcomes in patients at early stages of schizophrenia compared to patients at a chronic, established phase of illness. We scanned 57 patients with FEP and 30 matched healthy controls and estimated GSH resonance using 7-Tesla MRS. We minimised the confounding effects of illness chronicity, long-term treatment exposure and metabolic complications by recruiting patients with <2 weeks of lifetime antipsychotic exposure on average and followed up this cohort for the next 1 year to determine functional outcomes. Patients with FEP who achieved employment/education or training status (EET) in the first year, had higher GSH at the baseline than healthy controls. Social and occupational functioning assessment scale (SOFAS) scores were also significantly higher in patients with higher GSH levels at the outset, after adjusting for various confounds including baseline SOFAS. Patients who were not in employment, education or training (NEET) did not differ from healthy subjects in their GSH levels. Our observations support a key role for the central antioxidant tone in the functional outcomes of early psychosis.\",\n \"Integrated Single Cell and Spatial Transcriptomics Reveal Autoreactive Differentiated B Cells in Joints of Early Rheumatoid Arthritis\\nRheumatoid Arthritis (RA) is a prevalent autoimmune disease characterized by inflammation of peripheral joints. Patients can be subdivided by the presence or absence of Rheumatoid Factor and anti-citrullinated protein antibodies (ACPA) in their circulation. Inflammation of the joint tissue is associated with infiltration of leukocytes from the blood, which can result in generation of lymphoid structures composed of B and T cells. Previous studies have shown that both memory B cells and antibody-secreting plasma cells populate the rheumatic joint tissue when captured from established and often long-standing disease. However, it has remained unclear, whether these cells are autoreactive and whether the associated lymphoid structures are present at the site of inflammation already at the time of diagnosis. Here, we used an integrated single cell and spatial transcriptomic approach to study B and plasma cells in synovial tissue of ACPA- and ACPA+ RA patients at this early time point. We found evidence for T cell help to B cells and presence of memory B and plasma cell pools in ACPA- as well as in ACPA+ RA. Our results demonstrated common supportive microenvironments in both patient subgroups, clonal relationships between the memory B and plasma cell pools and autoreactivity within the plasma cell compartment. These findings challenge our understanding of the dynamics of local adaptive immune responses in the RA joint of ACPA- and ACPA+ patients at the time of diagnosis, with direct implications for B and T cell targeting therapies for both patient subgroups.\\n\\nOne Sentence SummaryA B cell maturation and plasma cell maintenance niche is evident at onset of Rheumatoid arthritis in both ACPA- and ACPA+ patients.\",\n \"Characterization and mitigation of aerosols and splatters from ultrasonic scalers\\nBackgroundDental procedures often produce aerosols and splatter which have the potential to transmit pathogens such as SARS-CoV-2. The existing literature is limited.\\n\\nMethodsAerosols and splatter were generated from an ultrasonic scaling procedure on a dental mannequin and characterized by two optical imaging methods - digital inline holography (DIH) and laser sheet imaging (LSI). Capture efficiencies of various aerosol mitigation devices were evaluated and compared.\\n\\nResultsThe ultrasonic scaling procedure generates a wide size range of aerosols up to a few hundred micrometers and occasional large splatter which emit at low velocity (mostly below 3 m/s). Use of a saliva ejector (SE) and high-volume evacuator (HVE) resulted in 63% and 88% of overall reduction respectively while an extraoral local extractor (ELE) resulted in a reduction of 96% at the nominal design flow setting.\\n\\nConclusionsThe study results showed that the use of ELE or HVE significantly reduced aerosol and splatter emission. The use of HVE generally requires an additional person to assist a hygienist, while an ELE can be operated \\\"hands-free\\\" when a dental hygienist is performing ultrasonic scaling and other operations.\\n\\nPractical ImplicationsAn extraoral local extractor aids in the reduction of aerosols and splatters during ultrasonic scaling procedures, potentially reducing transmission of oral or respiratory pathogens, like SARS-CoV-2. Position and airflow of the device are important to effective aerosol mitigation.\",\n \"Development of health and safety training for Vietnamese American nail salon owners and workers\\nBackgroundNail salon workers are an underserved worker population that faces multiple barriers to accessing occupational health training and services. We developed a series of occupational health training modules, which were culturally tailored to Vietnamese-speaking workers, covering topics on infection control, musculoskeletal disorder prevention, chemical safety, and labor practices. We delivered the training online (due to COVID-19) to a small group of Vietnamese owners and workers in the Philadelphia metro area to obtain feedback on the training content and potential implementation challenges.\\n\\nMethodsSeven participants (three owners and four workers) were recruited to attend the training. Qualitative feedback was obtained after each training session, followed by a more in-depth interviewer-assisted open-ended questionnaire to gain better understanding of the potential challenges of implementing the recommended changes. The Health Belief Model was used to guide the analysis of the participants responses to identify the perceived benefits and barriers of the training.\\n\\nResultsThemes of perceived benefits of the training were bridging the gap of cosmetology school training, offering practical tips to protect their health at work, and inspiring conversations about work dignity and labor practices. Themes of perceived barriers were availability of affordable safer products and lack of resources, desire to please customers, lack of commitment from owners, and ubiquitous low wage that impacts employees job satisfaction and motivation to change, and difficulty in obtaining a work license.\\n\\nConclusionsOur study revealed the multitude of social and economic barriers facing immigrant nail salon owners and workers. Potential policies and strategies to overcome some of these structural barriers are discussed for the long-term health protection of nail salon workers.\",\n \"Impulse dispersion of aerosols during playing wind instruments\\nMusical activities especially singing and playing wind instruments have been singled out as potentially high-risk activities for transmission of SARS CoV-2, because of a higher rate of aerosol production and emission. Playing wind instruments can produce condensation water, droplets of saliva, and aerosol particles, which hover and convectional spread in the environmental air and can be potentially infectious.\\n\\nThe aim of this study is to investigate the primary impulse dispersion of aerosols during playing different wind instruments in comparison to breathing and speaking. Nine professional musicians (3 trumpeters, 3 cross flutists and 3 clarinetists) of the Bavarian Symphony Orchestra performed the main theme of Ludwig van Beethoven s 9th symphony, 4th movement in different pitches and loudness. Thereby, the inhaled air volume was marked with small aerosol particles produced with a commercial e-cigarette. The expelled aerosol cloud was recorded by cameras from different perspectives. Afterwards, the dimensions and dynamics of the aerosol cloud was measured by segmenting the video footage at every time point.\\n\\nOverall, the cross flutes produced the largest dispersion at the end of task of up to maximum distances of 1.88 m in front direction. Thereby it was observed an expulsion of aerosol in different directions: upwards and downwards at the mouthpiece, at the end of the instrument and along the cross flute at the key plane. In comparison, the maximum impulse dispersion generated by the trumpets and clarinets were lower in frontal and lateral direction (1.2 m and 1.0 m in front-direction). The expulsion to the sides was also lower. Consequently, a distance of 3 m to the front and to the sides of 2 m for the cross flutes in an orchestral formation is proposed, for trumpets and clarinets a safety distance of 2 m to the front and 1.5 m between instrumentalists are recommendable.\",\n \"Antibody responses to SARS-CoV-2 vaccination in patients with acute leukaemia and high risk MDS on active anti-cancer therapies\\nPatients with haematological malignancies, such as acute leukaemia and high-risk MDS (HR-MDS), have significantly increased mortality and morbidity from COVID-19. However vaccine efficacy in these patients and the impact of systemic anti-cancer therapy (SACT) on vaccine response remains to be fully established. SARS-CoV-2 antibody responses in 53 patients with ALL, AML or HR-MDS receiving SACT were characterised following two doses of either BNT162b2 or ChAdOx1nCoV-19. All patients were tested for anti-S antibodies after 2 doses, 60% after the first dose and anti-N antibody testing was performed on 46 patients (87%). Seropositivity rates after 2 vaccine doses were 95% in AML/HR-MDS patients and 79% in ALL. After stratification by prior SARS-CoV-2 infection, naive patients with AML/HR-MDS had higher seroconversion rates and median anti-S antibody titres compared to ALL (median 291U/mL versus 5.06U/mL), and significant increases in anti-S titres with consecutive vaccine doses, not seen in ALL. No difference was seen in serological response between patients receiving intensive chemotherapy or non-intensive therapies (HMA) but significantly reduced titres were present in AML/HR-MDS patients who received venetoclax-based regimens compared to other therapies. All ALL patients received intensive chemotherapy, with no further impact of anti-CD20 immunotherapy on serological response. Understanding the impact of disease subtypes and therapy on vaccine response is essential to enable decisions on modifying or delaying treatment in the context of either SARS-CoV-2 infection or vaccination.\",\n \"The Immunogenetic Basis of Idiopathic Bone Marrow Failure Syndromes: A Paradox of Similarity and Self-Presentation\\nIdiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure disorder initiated by a human leukocyte antigen (HLA)-restricted T-cell response to unknown antigens. Immunogenetic patterns associated with self-antigenic presentation remain unclear. Herein we analyzed the molecular landscape of HLA complexes and T-cell receptor (TCR) repertoires of a large cohort of IAA patients and controls. We show that antigen binding sites of class II HLA molecules in IAA are characterized by a high level of structural homology, only partially explained by specific risk allele profiles, implying reduced binding capabilities compared to controls. Few amino acids within the synapsis HLA-DRB1-antigen-TCR, are identified as strongly associated with IAA phenotype. Those structural patterns may affect TCR repertoires, promoting immunological cross-reactivity and autoimmunity. These findings inform on the immunogenetic risk associated with IAA and on general pathophysiological mechanisms potentially involved in autoimmunity.\\n\\nKey pointsO_LIClass II human leukocyte antigen (HLA) loci in idiopathic bone marrow failure (BMF) syndromes are characterized by low functional divergence and decreased peptide binding capabilities, only partially explained by enrichment in risk alleles.\\nC_LIO_LIA superstructure at the interface with the peptide binding site of DRB1 locus, potentially involved in the presentation of self-antigenic specificities, can be identified in BMF patients.\\nC_LIO_LIThis immunogenetic pattern may contribute to decrease T-cell receptor repertoire diversity, expand autoreactive T-cell clones and increase autoimmune propensity in BMF.\\nC_LI\",\n \"Statistical challenges of investigating a disease with a complex diagnosis\\nGiven the absence of a disease-specific biomarker, there are more than 20 symptoms-based case definitions of myalgic encephalomyelitis/chronic fatigue syndrome. As a consequence, the diagnosis for a given patient could vary from one case definition to another. In this context, we analyse data from a biobank dedicated to this disease in order to study the agreement between different case definitions, the similarity between symptoms profile among all participants including healthy controls and patients with multiple sclerosis. We also investigate the impact of patients misclassification on a hypothetical association analysis using data simulation.\",\n \"Transmission of SARS-CoV-2 associated with cruise ship travel: protocol for a systematic review (Version 1)\\nBackgroundMaritime and river travel, including cruise ships, have been implicated with spreading viruses through infected passengers and crew. Given the novelty of the SARS-CoV-2 infection, early cruise ship travel transmission models of spread are based on what is known of the dynamics of other respiratory viral infections. Our objective is to provide a rapid summary and evaluation of relevant data on SARS-CoV-2 transmission aboard cruise ships, report policy implications, and highlight research gaps requiring attention.\\n\\nMethodsWe will search LitCovid, medRxiv, Google Scholar, and the WHO Covid-19 database using COVID-19, SARS-CoV-2, transmission, and cruise ship appropriate synonyms. We will also search the reference lists of included studies for additional relevant studies. We will include studies reporting onboard SARS-CoV-2 transmission from passengers and/or crew to passengers and/or crew. We will consider any potential transmission mode. We will assess study quality based on five criteria and report important findings. The outcome will consist of the onboard cruise ships transmission of SARS-CoV-2. We will provide a narrative summary of the data and report the outcomes, including quantitative estimates where feasible and relevant. Where possible, compatible datasets may be pooled for meta-analysis.\\n\\nExpected resultsWe will present the evidence in three distinct packages: study description, methodological quality assessment and data extracted. We will summarize the evidence and will draw conclusions as to the quality of the evidence.\",\n \"Social connectedness as a determinant of mental health: A scoping review\\nPublic health and epidemiologic research have established that social connectedness promotes overall health. Yet there have been no recent reviews of findings from research examining social connectedness as a determinant of mental health. The goal of this review was to evaluate recent longitudinal research probing the effects of social connectedness on depression and anxiety symptoms and diagnoses in the general population. A scoping review was performed of PubMed and PsychInfo databases from January 2015 to December 2020 following PRISMA-ScR guidelines using a defined search strategy. The search yielded 56 articles representing 52 unique studies. In research with other than pregnant women, 84% (16 of 19) studies reported that social support benefited symptoms of depression with the remaining 16% (3 of 19) reporting minimal or no evidence that lower levels of social support predict depression at follow-up. In research with pregnant women, 80% (21 of 26 studies) found that low social support increased postpartum depressive symptoms. Among 3 of 4 studies that focused on loneliness, feeling lonely at baseline was related to adverse outcomes at follow-up including higher risks of major depressive disorder, depressive symptom severity, generalized anxiety disorder, and lower levels of physical activity. In 5 of 7 reports, smaller social network size predicted depressive symptoms or disorder at follow-up. In summary, most recent relevant longitudinal studies have demonstrated that social support protects adults in the general population from depressive symptoms and disorders. The results, which were largely consistent across settings, exposure measures, and populations, support efforts to improve clinical detection of high-risk patients, including adults with low social support and elevated loneliness.\",\n \"Medical Evaluation of Unanticipated Monogenic Disease Risks Identified through Newborn Genomic Screening: Findings from the BabySeq Project\\nGenomic sequencing of healthy newborns to screen for medically important genetic information has long been anticipated but data around downstream medical consequences are lacking. Among 159 infants randomized to the sequencing arm in the BabySeq Project, an unanticipated monogenic disease risk (uMDR) was discovered in 18 (11.3%). We assessed uMDR actionability by visualizing scores from a modified ClinGen Actionability SemiQuantitative Metric and tracked medical outcomes in these infants for 3-5 years. All uMDRs scored as highly actionable (mean 9, range: 7-11 on a 0-12 scale) and had readily available clinical interventions. In 4 cases, uMDRs revealed unsuspected genetic etiologies for existing phenotypes, and in the remaining 14 cases provided risk stratification for future surveillance. In 8 cases, uMDRs prompted screening for multiple at-risk family members. These results suggest that actionable uMDRs are more common than previously thought and support ongoing efforts to evaluate population-based newborn genomic screening.\",\n \"Machine learning-based single cell and integrative analysis reveals that baseline mDC predisposition predicts protective Hepatitis B vaccine response\\nVaccination to prevent infectious disease is one of the most successful public health interventions ever developed. And yet, variability in individual vaccine effectiveness suggests a better mechanistic understanding of vaccine-induced immune responses could improve vaccine design and efficacy. We have previously shown that protective antibody levels could be elicited in a subset of recipients with only a single dose of the hepatitis B virus (HBV) vaccine. Why some, but not all, recipients responded in this way was not clear. Using single cell RNA sequencing of sorted innate immune cell subsets, we identified two distinct myeloid dendritic cell subsets (NDRG1-expressing mDC2 and CDKN1C-expressing mDC4), the ratio of which at baseline (pre-vaccination) predicted immune response to a single dose of HBV vaccine. Our results suggest that the participants in our vaccine study were in one of two different dendritic cell dispositional states at baseline - an NDRG2-mDC2 state in which the vaccine elicited an antibody response after a single immunization or a CDKN1C-mDC4 state in which the vaccine required two or three doses for induction of antibody responses. Genes expressed in these mDC subsets were used as an approach for feature selection prior to the construction of a predictive model using supervised canonical correlation machine learning. The resulting model showed an improved ability to predict serum antibody titers in response to vaccination. Taken together, these results suggest that the propensity of circulating dendritic cells toward either activation or suppression, their \\\"dispositional endotype\\\", could dictate response to vaccination. The fact that these mDCs could be modulated via TLR stimulation could guide progress towards design of effective single dose vaccination strategies.\",\n \"Integrated Bile Acid Profile Analysis for The Non-invasive Staging Diagnosis of Ulcerative Colitis\\nClinical staging diagnosis and progression tracking for ulcerative colitis (UC) is challenging as poor patient compliance of endoscopic biopsy, we aimed to explore a non-invasive integrative biochemical index to quantitative track and monitor pathological activity. Here we perform a study that integrates bile acid metabolomic profiling, metagenomic sequencing and clinical monitoring on serum and feacal samples from 24 active-state UC patients, 25 remission-state UC patients and 20 healthy volunteers from China. Besides known associations of Fusobacterium nucleatum and Peptostreptococcus stomatis with UC, we found several bile acid-transforming species, including 7-dehydroxygenase and 7/{beta}-dehydrogenase expressing microbiota, were significant correlated with UC pathological activity. We identified 7 microbial gene markers that differentiated active and remission-stage UC and healthy control microbiomes. Relevantly, decreased serum deoxycholic acid /cholic acid ratio and increased fecal ursodeoxycholic acid/chenodeoxycholic acid ratio were associated with pathological activity of UC. Moreover, receiver operating characteristic analysis based on serum/fecal bile acids ratios was much accurate in prediction of active and remission stage outcome. This species-specific temporal change and bile acid dysregulation pattern linked to disease severity indicating that integrated microbiome-bile acid profile maybe implied for disease activity prediction, and that targeting microbiome-mediated restoring gut flora and bile acids homeostasis may be implicative of therapy efficacy. Collectively, these insights will help improve clinical diagnosis and optimize existing medical treatments.\",\n \"Gender Balance and Readability of COVID-19 Scientific Publishing: A Quantitative Analysis of 90,000 Preprint Manuscripts\\nReleasing preprints is a popular way to hasten the speed of research but may carry hidden risks for public discourse. The COVID-19 pandemic caused by the novel SARS-CoV-2 infection highlighted the risk of rushing the publication of unvalidated findings, leading to damaging scientific miscommunication in the most extreme scenarios. Several high-profile preprints, later found to be deeply flawed, have indeed exacerbated widespread skepticism about the risks of the COVID-19 disease - at great cost to public health. Here, preprint article quality during the pandemic is examined by distinguishing papers related to COVID-19 from other research studies. Importantly, our analysis also investigated possible factors contributing to manuscript quality by assessing the relationship between preprint quality and gender balance in authorship within each research discipline. Using a comprehensive data set of preprint articles from medRxiv and bioRxiv from January to May 2020, we construct both a new index of manuscript quality including length, readability, and spelling correctness and a measure of gender mix among a manuscripts authors. We find that papers related to COVID-19 are less well-written than unrelated papers, but that this gap is significantly mitigated by teams with better gender balance, even when controlling for variation by research discipline. Beyond contributing to a systematic evaluation of scientific publishing and dissemination, our results have broader implications for gender and representation as the pandemic has led female researchers to bear more responsibility for childcare under lockdown, inducing additional stress and causing disproportionate harm to women in science.\",\n \"Identification of a novel FUS/ETV4 fusion and comparative analysis with other Ewing sarcoma fusion proteins\\nEwing sarcoma is an aggressive pediatric bone cancer defined by a chromosomal translocation fusing one of the FET family members to a member of the ETS transcription factor family. To date, there have been seven reported translocations, with the most recent translocation reported over a decade ago. We now report the first identification of a novel translocation occurring between the FUS gene and ETS family member ETV4 detected in a neonatal patient with Ewing sarcoma. Given its apparent rarity, we conducted an initial characterization of FUS/ETV4 function by performing genomic localization and transcriptional regulatory studies. We knocked down endogenous EWS/FLI in the A673 cell line, and expressed FUS/ETV4 in its stead, and performed CUT&Tag and RNA-sequencing analyses. We compared these data to similar \\\"knock-down/rescue\\\" analyses of other rare (non-EWS/FLI) Ewing sarcoma-associated translocation products. Through this comparative analysis in the same genetic background, we demonstrate significant similarities across these fusions, and in doing so, validate this novel FUS/ETV4 translocation as a bona fide Ewing sarcoma translocation. This study presents the first genomic comparisons of the rare Ewing sarcoma-associated translocation products, and reveals that the FET/ETS fusions share highly similar, but not identical, genomic localization and transcriptional regulation patterns. These data provide insights into the roles of both the FET and ETS sides of these fusions, and provide a generic strategy to provide further strength to the notion that FET/ETS fusions are key drivers of, and thus pathognomonic for, Ewing sarcoma.\\n\\nSignificanceIdentification and initial characterization of the novel Ewing sarcoma fusion, FUS/ETV4, expands the family of Ewing-fusions and extends the diagnostic possibilities for this aggressive tumor of adolescents and young adults.\",\n \"Two-step strategy for the identification of SARS-CoV-2 variant of concern 202012/01 and other variants with spike deletion H69-V70, France, August to December 2020\\nWe report the implementation of a two-step strategy for the identification of SARS-CoV-2 variants carrying the spike deletion H69-V70 ({Delta}H69/{Delta}V70). This spike deletion resulted in a S-gene target failure (SGTF) of a three-target RT-PCR assay (TaqPath kit). Whole genome sequencing performed on 37 samples with SGTF revealed several receptor-binding domain mutations co-occurring with {Delta}H69/{Delta}V70. More importantly, this strategy enabled the first detection of the variant of concern 202012/01 in France on December 21th 2020.\\n\\nSince September a SARS-CoV-2 spike (S) deletion H69-V70 ({Delta}H69/{Delta}V70) has attracted increasing attention. This deletion was detected in the cluster-5 variant identified both in minks and humans in Denmark. This cluster-5 variant carries a receptor binding domain (RBD) mutation Y453F and was associated with reduced susceptibility to neutralizing antibodies to sera from recovered COVID-19 patients [1-3]. The {Delta}H69/{Delta}V70 has also co-occurred with two other RBD mutations of increasing interest [4]: N439K that is currently spreading in Europe and might also have reduced susceptibility to SARS-CoV-2 antibodies [5]; and N501Y that is part of the SARS-CoV-2 variant of concern (VOC) 202012/01 recently detected in England [6]. Although the impact of {Delta}H69/{Delta}V70 on SARS-CoV-2 pathogenesis is not clear, enhanced surveillance is urgently needed. Herein we report the implementation of a two-step strategy enabling a rapid detection of VOC 202012/01 or other variants carrying {Delta}H69/{Delta}V70.\",\n \"Cost effective sequencing enables longitudinal profiling of clonal hematopoiesis\\nClonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of mutant hematopoietic stem cells, confers risk for multiple diseases of aging including hematologic cancer and cardiovascular disease. Whole-exome or genome sequencing can detect CHIP, but due to its high cost, most population studies have been cross-sectional, sequencing only a single timepoint. Here we describe a cost-effective sequencing assay for detecting CHIP. We validate this technology on a set of 548 longitudinal and multi-timepoint samples from 182 participants in the Womens Health Initiative cohort over median 16 years, including 85 participants with [≥]3 timepoints assayed. The majority (52.1%) of clonal mutations expanded over time (with a median doubling period of 7.43 years), with the others remaining static or decreasing in size in the absence of any cytotoxic therapy. This assay provides a cost-effective and sensitive platform for investigating the associations between CHIP dynamics and health outcomes at a biobank scale.\",\n \"DIETARY MANIPULATION OF THE GUT MICROBIOME IN INFLAMMATORY BOWEL DISEASE PATIENTS: PROOF OF CONCEPT\\nDiet is a modifiable, non-invasive, inexpensive behavior that is crucial in shaping the intestinal microbiome. A microbiome \\\"imbalance\\\" or dysbiosis in inflammatory bowel disease (IBD) is linked to inflammation. Here, we aim to define the impact of specific foods on bacterial species commonly depleted in patients with IBD to better inform dietary treatment. We performed a single-arm, pre-post intervention trial. After a baseline period, a dietary intervention with the IBD-Anti-Inflammatory Diet (IBD-AID) was initiated. We collected stool and blood samples and assessed dietary intake throughout the study. We applied advanced computational approaches to define and model complex interactions between the foods reported and the microbiome. A dense dataset comprising 553 dietary records and 340 stool samples was obtained from 22 participants. Consumption of prebiotics, probiotics, and beneficial foods correlated with increased abundance of Clostridia and Bacteroides, commonly depleted in IBD cohorts. We further show that the IBD-AID intervention affects the immune tone by lowering IL-8 and increasing GM-CSF with certain foods correlating with levels of those cytokines. By using robust predictive analytics, this study represents the first steps to detangle diet-microbiome interactions to inform personalized nutrition for patients suffering from dysbiosis-related IBD.\",\n \"Corneal cisterns as drainage aqueducts\\nImportanceAnterior chamber paracentesis (ACP) is a known method of rapid reduction of IOP. The mechanism of how corneal fluid clears after ACP is not well described.\\n\\nObjectiveTo determine the mechanism of instantaneous corneal clearing of edema after ACP.\\n\\nDesign, setting, and participantsThis case series includes consecutive patients with high IOP and associated corneal edema, who presented to the Glaucoma Services of our tertiary care center. Pre- and post-intervention (ACP) ASOCTs were analyzed.\\n\\nMain outcome measuresResolution of corneal edema (clinical picture) and imaging of peripheral cornea and iridocorneal angle area.\\n\\nResultsTen consecutive patients who underwent an ACP were included in this study. The mean IOP pre-intervention was 48.4 {+/-} 8.2 mmHg. ASOCT showed ill-defined conventional pathways of aqueous outflow, which were blocked by peripheral anterior synechiae in 4 eyes. Immediately post ACP, the IOP was 16.3 {+/-} 5.6 mmHg (p < 0.001) and corneal edema resolved immediately. We found on ASOCT, that the intrastromal hypolucency of the peripheral cornea, (corneal cistern) which was limited in extent and U shaped, showed a posterior extension into the corneo-limbal junction to form well-defined anastomoses with the conventional aqueous drainage channels demonstrating a direct conduit for intracorneal fluid to egress. In 2/10 eyes, Schlemms canal opened intracamerally as well, suggesting direct reflux of intra-corneal fluid into the anterior chamber.\\n\\nConclusion and RelevanceAfter an ACP, in eyes with corneal edema to relieve IOP, we observed that the intracorneal cisterns undergo peripheral extension to drain corneal fluid through the conventional distal outflow channels.\",\n \"Griffin: Framework for clinical cancer subtyping from nucleosome profiling of cell-free DNA\\nCell-free DNA (cfDNA) has the potential to inform tumor subtype classification and help guide clinical precision oncology. Here we developed Griffin, a new method for profiling nucleosome protection and accessibility from cfDNA to study the phenotype of tumors using as low as 0.1x coverage whole genome sequencing (WGS) data. Griffin employs a novel GC correction procedure tailored to variable cfDNA fragment sizes, which improves the prediction of chromatin accessibility. Griffin achieved excellent performance for detecting tumor cfDNA in early-stage cancer patients (AUC=0.96). Next, we applied Griffin for the first demonstration of estrogen receptor (ER) subtyping in metastatic breast cancer from cfDNA. We analyzed 254 samples from 139 patients and predicted ER subtype with high performance (AUC=0.89), leading to insights about tumor heterogeneity. In summary, Griffin is a framework for accurate clinical subtyping and can be generalizable to other cancer types for precision oncology applications.\",\n \"A Patient-Reported Measure of Locomotor Function Derived from the Functional Assessment Questionnaire\\nBackgroundLocomotor function is often impaired in children diagnosed with cerebral palsy (CP). Improving locomotor function is a common goal of treatment. The current gold standard for assessing locomotor function in CP is the gross motor function measure (GMFM-66). The GMFM-66 requires an in-person assessment by a trained clinician. It would be useful to have a measure of function that is like the GMFM-66 but can be assessed through patient report.\\n\\nMethodsWe queried the clinical databases of two motion analysis centers (Gillette Childrens Specialty Healthcare and Shriners Hospital - Salt Lake City) for individuals with a diagnosis of cerebral palsy (CP) who were 18 years old or younger and had undergone instrumented clinical gait analysis that included the functional assessment questionnaire (FAQ). We computed the transformed FAQ (FAQt) as the weighted sum of the skills an individual was able to perform, where the weighting was the difficulty of the skills. We assessed concurrent and external validity of the FAQt by comparing it to the GMFM-66.\\n\\nResultsThe FAQt exhibited strong concurrent and external validity. Linear regression showed that the GMFM-66 explained 54% of the variance in FAQt, and the linear fit was independent of center. The FAQt evolved with age in a manner similar to the GMFM-66, with higher functioning individuals, as measured by gross motor function classification system level, achieving higher levels of function at a higher rate and an earlier age compared to their lower functioning peers. The findings with respect to GMFM-66 did not depend on the center at which the data was acquired.\\n\\nConclusionsThe FAQt demonstrates strong concurrent and external validity, making it a useful measure of locomotor function.\",\n \"Direct comparison of venipuncture serum draws versus whole blood finger-stick specimens by anti-COVID-19 IgG/IgM rapid lateral flow immunoassay and ELISA.\\nDuring the COVID-19 pandemic, manufacturers have developed several diagnostic test kits that include lateral flow immunoassays (LFIA) also known as rapid cassette testing. Rapid cassette testing provides qualitative test results indicating the presence or absence of IgG and IgM antibodies to determine COVID-19 (SARS-CoV-2) infection among individuals. Venipuncture blood draws have been the traditional and widely proposed sample collection method but is costly and not applicable to point-of-care testing (POC) and in remote settings. Whole blood finger-stick blood collections traditionally used by diabetics for glucose level testing is an ideal scenario, but raises concerns regarding the outcome of test results in regards to specificity and sensitivity. In this study we directly compare simultaneous collections of venipuncture serum (SST) blood draws and whole blood finger-sticks (n = 75) to detect human Anti-COVID-19 IgG and IgM antibodies using an EUA-approved lateral flow immunoassay, showing equal to enhanced performance characteristics for this specimen type.\",\n \"Computer adaptive testing to assess impairing behavioral health problems in emergency department patients\\nStudy ObjectiveTo assess the prevalence of several impairing behavioral health domains in stable patients presenting to the emergency department (ED) through the use of computer adaptive testing and the association among the domains, standard assessments, and ED utilization.\\n\\nMethodsThis was a single-center observational study of 828 randomly selected adult patients presenting to the ED from May 2019 to March 2020. The main outcomes of interest were the self-administered, validated computer adaptive assessments of suicidality, depression, anxiety, PTSD, and substance abuse using computer adaptive testing, the CAT-MH. We estimated the association among the CAT-MH subscales, standard assessments, and the number of ED visits in the year prior and 30 days after enrollment.\\n\\nResultsThe proportion of those who scored above the threshold of low/mild risk were: 24.1% (suicidality), 8.3% (depression), 16.5% (anxiety), 12.3% (PTSD), and 20.4% (substance use). While the CAT-MH subscales were highly correlated with other self-report assessments, they were not highly associated with standard ED assessments of suicidality. When examining associations with ED use, for example, individuals who had two or more ED visits in the prior year had 51% increased odds of being in the intermediate-high suicide risk category (95% Confidence Interval [CI], 1.03-2.23) compared to those with zero prior ED visits.\\n\\nConclusionThe CAT-MH can document the high prevalence of mental health conditions in the ED, which were missed by standard ED practices. Mental health problems are associated with ED utilization in a population of patients presenting largely for somatic complaints.\",\n \"Comparing the predictive value of suicide risk screening to the detection of suicide risk using electronic health records in an urban pediatric emergency department\\nObjectiveTo compare the accuracy, sensitivity and utility of brief screening to predictive modeling for identifying suicide-related outcomes in a pediatric emergency department. Our hypothesis was that predictive modeling would be more accurate and useful compared to brief screening.\\n\\nMethodsThis was a retrospective cohort study at an urban pediatric Emergency Department (PED) in the United States. Patients were aged 8 to 18 years old who presented from January 1, 2017 to June 30, 2019. Predictors included positive suicide risk screen and/or demographic, medical and mental health diagnostic Electronic Health Record (EHR) data at the time of visit. The main outcome was subsequent PED visit with suicide-related presenting problem (i.e. ideation or attempt) within a 3-month follow-up period.\\n\\nResultsOf the N=13420 individuals, n=141 had a subsequent suicide-related ED visit. Approximately 63% identified as Black Non-Hispanic. Results showed that a model based only on EHR data performed only slightly worse than the ASQ alone. Combining ASQ screening and EHR data resulted in a 17.4% improvement in sensitivity and 13.4% increase in AUC compared to the ASQ alone. The LASSO models indicated a diagnosis of major depressive disorder in addition to the ASQ improved the AUC by 9%.\\n\\nConclusions, Implications, Future DirectionsOur findings show that EHR data is helpful either in the absence or as an addition to brief suicide screening. To our knowledge, this is the first study to compare brief screening to EHR based predictive modeling and adds to our understanding of how best to identify youth at risk of suicidal behaviors in clinical care settings.\",\n \"CHA2DS2-VASc score on admission to predict mortality in COVID-19 patients: A meta-analysis\\nBackgroundCHA2DS2-VASc score is used in non-valvular AF patients to predict thromboembolic risk. Recent studies have tried to evaluate CHA2DS2-VASc score on admission in COVID-19 patients to predict mortality.\\n\\nMethodsWe conducted a literature search on 14 April 2021 to retrieve all published studies, pre-prints and grey literature related to the predictive power of CHA2DS2-VASc score in COVID-19 patients of admission and mortality. Screening of studies and data extraction was done by two authors independently. We used the Quality in Prognosis Studies (QUIPS) tool for the methodological quality assessment of the included studies.\\n\\nResultsFive studies involving 5,941 patients reported the predictive value of CHA2DS2-VASc score for mortality in COVID-19 patients. The pooled sensitivity (SEN), specificity (SPE) and area under curve were 0.72 (95% CI 0.63-0.79), 0.74 (95% CI 0.67-0.81) and 0.80 (95% CI 0.76-0.83).\\n\\nConclusionsCHA2DS2-VASc score at admission has good predictive value for mortality in patients with COVID-19 infection and can help clinicians identify potentially severe cases early. Early initiation of effective management in these cases may help in reducing overall mortality due to COVID-19.\\n\\nTrial registryWe prospectively registered this meta-analysis on PROSPERO database (Reg number: CRD42021248398).\",\n \"Intrinsic Capacity of Rural Elderly in Thar Desert using WHO ICOPE (Integrated Care for Older Persons) Screening Tool: A Pilot Study\\nIntroductionICOPE (Integrated Care for Older Persons) screening tool helps to address declines in physical and mental capacities in older people. In India majority of the older population resides in rural areas and there is a paucity of studies that demonstrates the utility of the ICOPE screening tool in India. Thus, this study was conducted to demonstrate the feasibility of using WHO ICOPE screening tool in a rural population.\\n\\nMethodsA cross-sectional study was conducted in the two villages of Jodhpur. WHO ICOPE screening was done for a comprehensive geriatric assessment of intrinsic capacity by determining cognitive decline, the decline in mobility, malnutrition, sensory loss, depressive symptoms, health risks, social care, and support. Additionally, demographic details and information about health conditions were gathered.\\n\\nResultA total 451 participants (Male=54.5% and Female= 45.5%) surveyed. The mean age was 68.36 (SD=7.73) years and the majority of participants (68.3%) were illiterate. Most of the elderly have good families and lived with their children. Cognitive decline was found to be prevalent in 31.5% (n=142) of the participants, while mobility was diminished in 52.1% (n=235) participants. Eye problems were observed in 49.4% (n=223) participants, while 68.3% (n=308) were observed to be suffering from hearing loss. Limitation in mobility observed with the chair rise test and feeling of pain was found to be significantly associated with gender difference, with more limitation in females than males (p = 0.005; {chi}2 = 7.95) and more pain felt by females than males (p = 0.001; {chi}2 = 15.64).\\n\\nConclusionThis tool seems suitable in identifying the intrinsic capacity of the rural elderly.\",\n \"Estimating the increased transmissibility of the B.1.1.7 strain over previously circulating strains in England using fractions of GISAID sequences and the distribution of serial intervals\\nThe B.1.1.7 strain, also referred to as Alpha variant, is a variant strain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The Alpha variant is considered to possess higher transmissibility compared to the strains previously circulating in England. This paper proposes a new method to estimate the selective advantage of a mutant strain over another strain using the time course of strain frequencies and the distribution of the serial interval of infections. This method allows the instantaneous reproduction numbers of infections to vary over calendar time. The proposed method also assumes that the selective advantage of a mutant strain over previously circulating strains is constant. Applying the method to SARS-CoV-2 sequence data from England, the instantaneous reproduction number of the B.1.1.7 strain was estimated to be 26.6-45.9% higher than previously circulating strains in England. This result indicates that control measures should be strengthened by 26.6-45.9% when the B.1.1.7 strain is newly introduced to a country where viruses with similar transmissibility to the preexisting strain in England are predominant.\",\n \"Interactions between seasonal human coronaviruses and implications for the SARS-CoV-2 pandemic: A retrospective study in Stockholm, Sweden, 2009-2020\\nObjectivesThe four seasonal coronaviruses 229E, NL63, OC43, and HKU1 are frequent causes of respiratory infections and show annual and seasonal variation. Increased understanding about these patterns could be informative about the epidemiology of SARS-CoV-2.\\n\\nMethodsResults from PCR diagnostics for the seasonal coronaviruses, and other respiratory viruses, were obtained for 55,190 clinical samples analysed at the Karolinska University Hospital, Stockholm, Sweden, between 14 September 2009 and 2 April 2020.\\n\\nResultsSeasonal coronaviruses were detected in 2,130 samples (3.9%) and constituted 8.1% of all virus detections. OC43 was most commonly detected (28.4% of detections), followed by NL63 (24.0%), HKU1 (17.6%), and 229E (15.3%). The overall fraction of positive samples was similar between seasons, but at species level there were distinct biennial alternating peak seasons for the Alphacoronaviruses, 229E and NL63, and the Betacoronaviruses, OC43 and HKU1, respectively. The Betacoronaviruses peaked earlier in the winter season (Dec-Jan) than the Alphacoronaviruses (Feb-Mar). Coronaviruses were detected across all ages, but diagnostics were more frequently requested for paediatric patients than adults and the elderly. OC43 and 229E incidence was relatively constant across age strata, while that of NL63 and HKU1 decreased with age.\\n\\nConclusionsBoth the Alphacoronaviruses and Betacoronaviruses showed alternating biennial winter incidence peaks, which suggests some type of immune mediated interaction. Symptomatic reinfections in adults and the elderly appear relatively common. Both findings may be of relevance for the epidemiology of SARS-CoV-2.\",\n \"Early prediction of preeclampsia in pregnancy with circulating cell-free RNA\\nLiquid biopsies that measure circulating cell-free RNA (cfRNA) offer an unprecedented opportunity to noninvasively study the development of pregnancy-related complications and to bridge gaps in clinical care. Here, we used 404 blood samples from 199 pregnant mothers to identify and validate cfRNA transcriptomic changes that are associated with preeclampsia (PE), a multi-organ syndrome which is the second largest cause of maternal death globally. We find that changes in cfRNA gene expression between normotensive (NT) and preeclamptic mothers are striking and stable early in gestation, well before the onset of symptoms. These changes are enriched for genes specific to neuromuscular, endothelial, and immune cell types and tissues that reflect important aspects of PE physiology and suggest new hypotheses for disease progression. This enabled identification and independent validation of a panel of 18 genes whose measurement between 5-16 weeks of gestation can form the basis of a liquid biopsy test that would identify mothers at risk of PE well before the clinical symptoms manifest themselves. Finally, we demonstrate that cfRNA changes reflect the multifactorial nature of PE and provide a means to non-invasively monitor maternal organ health. Tests based on these observations could help predict and manage who is at risk for PE, an important and until now unachieved objective for obstetric care.\",\n \"Oscillations of pause-burst neurons in the STN correlate with the severity of motor signs in Parkinson's disease\\nBackgroundOscillatory activity in the subthalamic nucleus (STN) in Parkinsons disease (PD) is under extensive study. While rhythmic features of local field potentials are implicated in the manifestation of PD motor signs, less is known about single unit activity (SUA). SUA parameters inside the STN show significant heterogeneity, and various firing patterns may contribute unequally to PD pathophysiology.\\n\\nObjectivesWe searched for correlations between SUA parameters and PD motor signs, taking neuronal activity patterns into account.\\n\\nMethods829 spike trains for STN SUA were recorded during 25 DBS surgeries. We have isolated three firing patterns (tonic, irregular burst and pause-burst) and, using mixed linear models, examined several ISI parameters and burst descriptors (for the last two patterns) for their correlation with the UPDRS 3 score and bradykinesia and rigidity scores on the contralateral body side.\\n\\nResultsThe predominance of pause-burst as opposed to tonic activity was associated with an increase in UPDRS 3 score. Oscillation scores in the alpha range correlated with bradykinesia and rigidity scores, and oscillation scores in the beta range correlated with bradykinesia score only for pause-burst neurons, while other patterns showed no correlation with PD motor signs. There was also significant negative correlation between bradykinesia score and theta oscillations for pause-burst pattern.\\n\\nConclusionsPause-burst pattern and rhythmic neurons oscillating in the alpha range may affect motor processing in the basal ganglia more prominently than other activity patterns, probably reflecting progressive switching from tonic to burst to rhythmic activity in the parkinsonian state.\",\n \"Effect of fasting therapy on vitamin D, vitality and quality of life. A randomized control trial\\nBackgroundThe aim of the present study was to determine the effects of prolonged fasting (10 days) in the vitamin D, B12 levels, body mass index (BMI), weight, hemoglobin, vitality and quality of life (QoL) compared to normal diet.\\n\\nMethodsThis randomized control trial included 52 participants (aged 19-74 years) randomized in to a fasting group (FG) or a normal diet group (NDG) with 26 participants in each group. The study was conducted at an in-patient setting where the FG were on a fasting diet (500 kCal/day) which included holy basil herbal tea, lemon honey juice and water (3 L). The NDG (1500 kCal/day) consumed routine diet that included Indian breads, pulses, steamed rice, vegetable salads and beverages.\\n\\nResultsThe FG has shown significant increase in the Vitamin D levels (p=0.003, d=0.475), vitality (p=0.006, d=0.425), physical QoL (p<0.001, d=0.549), psychological QoL (p=0.002, d=0.488), environmental QoL (p=0.004, d=0.457) compared to NDG. No significant changes were observed in Vitamin B12, weight, BMI, hemoglobin and social QoL. A weak to moderate ({rho}= 0.330-0.483) positive correlation was observed between vitality scores and QoL domains, whereas BMI scores showed an inverse correlation ({rho}=-0.280) with vitamin D levels.\\n\\nDiscussionThe results suggest that prolonged fasting can improve the vitamin D levels, vitality and promote quality life compared to normal diet. Unlike previous studies FG does not differ from NDG with respect to weight and BMI. Nevertheless, fasting may be utilized as an effective tool to tackle vitamin d deficiency and associated health insufficiencies.\\n\\nTrial RegistryClinical Trial Registry of India CTRI/2022/02/040446.\",\n \"Neural Dysregulation in Post-Covid Fatigue\\nFollowing infection from SARS-CoV-2, a substantial minority of people develop lingering after-effects known as long COVID. Fatigue is a common complaint with substantial impact on daily life, but the neural mechanisms behind post-COVID fatigue remain unclear.\\n\\nWe recruited 37 volunteers with self-reported fatigue after a mild COVID infection and carried out a battery of behavioural and neurophysiological tests assessing the central, peripheral and autonomic nervous systems.\\n\\nIn comparison to age and sex matched volunteers without fatigue (n=52), we show underactivity in specific cortical circuits, dysregulation of autonomic function, and myopathic change in skeletal muscle. Cluster analysis revealed no sub-groupings, suggesting post-COVID fatigue is a single entity with individual variation, rather than a small number of distinct syndromes. Based on our analysis we were also able to exclude dysregulation in sensory feedback circuits and descending neuromodulatory control.\\n\\nThese abnormalities on objective tests may indicate novel avenues for principled therapeutic intervention, and could act as fast and reliable biomarkers for diagnosing and monitoring the progression of fatigue over time.\",\n \"Impact and cost-effectiveness of frequent HIV re-testing among key populations in Viet Nam: a modeling study\\nBackgroundHIV testing and counseling is a key component of HIV prevention and the entry point into the treatment cascade, which improves for individual clinical outcomes and reduces onward HIV transmission. Current guidelines recommend at least annual testing for key populations. More frequent testing could provide health benefits, but these additional services increase the program the cost-effectiveness is not well-evaluated.\\n\\nMethodsWe used a compartmental mathematical model to simulate the health and economic impact of HIV testing one to four times per year for men who have sex with men, people who inject drugs, and female sex workers in Viet Nam. Model outcomes included costs, HIV infections, HIV-related deaths, and disability-adjusted life years (DALYs) associated with each scenario. We used an opportunity cost-based cost-effectiveness threshold of US $2,255 per DALY averted, discounted costs and health benefits at 3% annually, and used a time horizon from 2021 to 2030 to calculate incremental cost-effectiveness ratios (ICERs).\\n\\nResultsCompared to the baseline scenario, more frequent HIV testing was estimated to incrementally avert 10.2%, 5.2%, 3.0%, and 1.6% discounted infections for one-, two-, three-, and four-tests per year, respectively. ICERs associated with each scenario ranged from $464, $1,190, $1,762, and $2,727 per DALY averted for one-, two-, three-, and four-tests per year, respectively.\\n\\nConclusionsIncreased HIV testing frequency for key populations was projected to avert HIV incidence, mortality, and disability in Viet Nam and was cost-effective. Settings with a similar context should consider strategies on how to optimize retesting among key populations.\",\n \"Sepsis Subphenotyping Based on Organ Dysfunction Trajectory\\nPurposeAlthough organ dysfunction is a defining element of sepsis, its trajectory is not well studied. We sought to identify whether there are distinct Sequential Organ Failure Assessment (SOFA) score trajectory-based subphenotypes in sepsis.\\n\\nMethodsWe created 72-hour SOFA score trajectories in patients with sepsis from two diverse intensive care unit (ICU) cohorts. We then used Dynamic Time Warping (DTW) to compute patient similarities to capture evolving heterogeneous sequences and establish similarities between groups with distinct trajectories. Hierarchical agglomerative clustering (HAC) was utilized to identify subphenotypes based on SOFA trajectory similarities. Patient characteristics were compared between subphenotypes and a random forest model was developed to predict subphenotype membership, within 6 hours of ICU arrival. The model was then tested on the validation cohort.\\n\\nResultsA total of 4,678 and 3,665 unique sepsis patients were included in development and validation cohorts. In the development cohort, four subphenotypes of organ dysfunction were identified: Rapidly Worsening (n=612, 13.08%), Delayed Worsening (n=960, 20.52%), Rapidly Improving (n=1,932, 41.3%) and Delayed Improving (n=1174, 25.1%). In-hospital mortality for patients within different subphenotypes demonstrated distinct patterns over time. Similar subphenotypes and their associated outcome patterns were replicated in the multicenter validation cohort.\\n\\nConclusionFour novel, clinically-defined, trajectory-based sepsis subphenotypes were identified and validated. Trajectory based subphenotyping is useful for describing the natural history of sepsis in the ICU. Understanding the pathophysiology of these differential trajectories may reveal unanticipated therapeutic targets for patients with sepsis and identify more precise populations and endpoints for the predictive enrichment of clinical trials.\",\n \"Differences in medication reconciliation interventions between six hospitals: a mixed method study\\nBackgroundAlthough medication reconciliation (MedRec) is mandated and effective in decreasing preventable medication errors during transition of care, hospitals implement MedRec differently.\\n\\nObjectiveQuantitatively compare the number and type of MedRec interventions between hospitals upon admission and discharge, followed by a qualitative analysis on potential reasons for these differences.\\n\\nMethodsThis explanatory retrospective mixed method study included patients from six hospitals and various wards in case MedRec was performed both on hospital admission and discharge. Information on pharmacy interventions to resolve unintended discrepancies and medication optimizations were collected. Based on these quantitative results, interviews and a focus group was performed to give insight in MedRec processes. Descriptive analysis was used for the quantitative-, content analysis for the qualitative part.\\n\\nResultsOn admission, patients with at least one discrepancy varied from 36-95% (mean per patient 2.2 (SD{+/-} 2.4) Upon discharge, these numbers ranged from 5-28% while optimizations reached 2% (admission) to 95% (discharge).The main themes explaining differences in numbers of interventions were patient-mix, healthcare professionals involved, location and moment of the interview plus embedding and extent of medication optimization.\\n\\nConclusionsHospitals differed greatly in the number of interventions performed during MedRec. A combination of patient-mix, healthcare professionals involved, location and timing of the interview plus embedding and extent of medication optimization resulted in the highest yield of MedRec interventions on unintended medication discrepancies and optimizations. This study supports to give direction to optimize MedRec processes in hospitals.\",\n \"Evaluating the effects of second-dose vaccine-delay policies in European countries: A simulation study based on data from Greece\\nThe results of a simulation-based evaluation of several policies for vaccine rollout are reported, particularly focusing on the effects of delaying the second dose of two-dose vaccines. In the presence of limited vaccine supply, the specific policy choice is a pressing issue for several countries worldwide, and the adopted course of action will affect the extension or easing of non-pharmaceutical interventions in the next months. We employ a suitably generalised, age-structure, stochastic SEIR (Susceptible [->] Exposed [->] Infectious [->] Removed) epidemic model that can accommodate quantitative descriptions of the major effects resulting from distinct vaccination strategies. The different rates of social contacts among distinct age-groups (as well as some other model parameters) are informed by a recent survey conducted in Greece, but the conclusions are much more widely applicable. The results are summarised and evaluated in terms of the total number of deaths and infections as well as life years lost. The optimal strategy is found to be one based on fully vaccinating the elderly/at risk as quickly as possible, while extending the time-interval between the two vaccine doses to 12 weeks for all individuals below 75 years old, in agreement with epidemic theory which suggests targeting a combination of susceptibility and infectivity. This policy, which is similar to the approaches adopted in the UK and in Canada, is found to be effective in reducing deaths and life years lost in the period while vaccination is still being carried out.\",\n \"Comparative Effectiveness of Standard and Contingency-based Cleaning in Acute and Long-Term Care Facilities amidst Staff Shortages and a COVID-19 Surge\\nBackgroundCleanliness of hospital surfaces helps prevent healthcare-associated infections, but larger evaluations of the effectiveness of various cleaning strategies during SARS-CoV-2 surges and worker shortages are scarce.\\n\\nMethodsIn an acute care hospital (ACH) and a long-term care facility (LTCF), 417 surfaces were tested for SARS-CoV-2 and adenosine triphosphate before and after various cleaning strategies, including ultraviolet light (UV-C), electrostatic spraying, and room fogging.\\n\\nResultsACH surface contamination differed among outbreak and non-outbreak wards (p = 0.001). RNA was detected on 66% of surfaces before cleaning and on 23% of those surfaces immediately after terminal cleaning, for a 65% post-cleaning reduction (p = 0.001). UV-C resulted in an 87% reduction (p = 0.023), while spraying with electrostatic bleach resulted in a 47% reduction (p = 0.010). LTCF contamination rates differed between the dementia, rehabilitation, and the residential units (p = 0.005). 67% of surfaces had RNA after room fogging without terminal-style wiping. Fogging with wiping led to an 11% reduction in the proportion of positive surfaces.\\n\\nDiscussionBaseline contamination varied by type of unit and outbreak conditions, but not facility type. Removal of viral RNA varied according to strategy. Unlike previous reports, time spent cleaning was associated with cleaning thoroughness.\",\n \"Extension of Community Healthcare Outcomes in Parkinson Disease (Parkinson ECHO): A Feasibility Study\\nParkinsons disease is the second most common neurodegenerative disorder and presents with a heterogeneous group of symptoms. Managing these symptoms requires coordinated care from a neurology specialist and a primary care provider. Access to neurology care is limited for those patients with Parkinsons disease who reside in rural areas given financial and mobility constraints along with the rarity of specialty providers. To close this gap, we developed and implemented a telehealth-based Project ECHO(R) (Extension for Community Healthcare Outcomes) program, \\\"Parkinson ECHO,\\\" to provide education and support for rural clinicians and allied health members. We assessed the feasibility of this tele-mentoring educational offering and the effect it had on clinician confidence in diagnosing and treating Parkinsons disease. Participants from across Oregon (n=33), of whom 70% served rural and/or medically underserved communities, attended the biweekly sessions. The sessions focused on a topic within Parkinsons disease diagnosis or management followed by case discussions. We assessed clinician confidence and acceptability using surveys before and after their participation in the program. The COVID-19 pandemic was an unexpected obstacle in executing this project, delaying the program by several months and likely accounting for a lower number of attendees for the last two sessions. Nevertheless, we found Parkinson ECHO did significantly increase participant confidence levels in diagnosing and managing Parkinsons disease.\",\n \"Machine-learning based preoperative analytics for the prediction of anastomotic insufficiency in colorectal surgery: a single-centre pilot study\\nBackgroundAnastomotic insufficiency (AI) is a relatively common but grave complication after colorectal surgery. This study aims to determine whether AI can be predicted from simple preoperative data using machine learning (ML) algorithms.\\n\\nMethodsIn this retrospective analysis, patients undergoing colorectal surgery with creation of a bowel anastomosis from the University Hospital of Basel were included. Data was split into a training set (80%) and a test set (20%). The group of patients with AI was oversampled to a ratio of 50:50 in the training set and missing values were imputed. Known predictors of AI were included as inputs: age, gender, BMI, smoking status, alcohol abuse, prior abdominal surgery, leukocytosis, haemoglobin and albumin levels, steroid use, the Charlson Comorbidity Index, the American Society of Anesthesiologists score, and renal function.\\n\\nResultsOf the 593 included patients, 88 experienced AI. At internal validation on unseen patients from the test set, area under the curve (AUC) was 0.64 (95% confidence interval [CI]: 0.44-0.82), calibration slope was 0.21 (95% CI: -0.02-0.46) and calibration intercept was 0.06 (95% CI: 0.01-0.1). We observed a specificity of 0.76 (95% CI: 0.68-0.84), sensitivity of 0.36 (95% CI: 0.08-0.7), and accuracy of 0.72 (95% CI: 0.65-0.8).\\n\\nConclusionBy using 13 patient-related risk factors associated with AI, we demonstrate the feasibility of ML-based prediction of AI after colorectal surgery. Nevertheless, it is crucial to include multicenter data and higher sample sizes to develop a robust and generalisable model, which will subsequently allow for deployment of the algorithm in a web-based application.\",\n \"Integrated genomics identify novel immunotherapy targets for malignant mesothelioma\\nBackgroundMalignant pleural mesothelioma (MPM) is an aggressive malignancy with limited effective therapies.\\n\\nMethodsIn order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells.\\n\\nResultsPreviously unrecognised losses of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary MPM cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin.\\n\\nConclusionsOur results suggest new therapeutic avenues in MPM and provide targets and biomarkers for immunotherapy.\",\n \"Fusion of Imaging and Non-Imaging Data for Disease Trajectory Prediction for COVID-19 Patients\\nABSTRCATO_ST_ABSPurposeC_ST_ABSThis study investigates whether graph-based fusion of imaging data with non-imaging EHR data can improve the prediction of disease trajectory for COVID-19 patients, beyond the prediction performance of only imaging or non-imaging EHR data.\\n\\nMaterials and MethodsWe present a novel graph-based framework for fine-grained clinical outcome prediction (discharge, ICU admission, or death) that fuses imaging and non-imaging information using a similarity-based graph structure. Node features are represented by image embedding and edges are encoded with clinical or demographic similarity.\\n\\nResultsOur experiments on data collected from Emory Healthcare network indicate that our fusion modeling scheme performs consistently better than predictive models using only imaging or non-imaging features, with f1-scores of 0.73, 0.77, and 0.66 for discharge from hospital, mortality, and ICU admission, respectively. External validation was performed on data collected from Mayo Clinic. Our scheme highlights known biases in the model prediction such as bias against patients with alcohol abuse history and bias based on insurance status.\\n\\nConclusionThe study signifies the importance of fusion of multiple data modalities for accurate prediction of clinical trajectory. Proposed graph structure can model relationships between patients based on non-imaging EHR data and graph convolutional networks can fuse this relationship information with imaging data to effectively predict future disease trajectory more effectively than models employing only imaging or non-imaging data. Forecasting clinical events can enable intelligent resource allocation in hospitals. Our graph-based fusion modeling frameworks can be easily extended to other prediction tasks to efficiently combine imaging data with non-imaging clinical data.\",\n \"Validation of a transcriptome-based assay for classifying cancers of unknown primary origin\\nCancers assume a variety of distinct histologies and may originate from a myriad of sites including solid organs, hematopoietic cells, and connective tissue. Clinical decision making based on consensus guidelines such as NCCN is often predicated on a specific histologic and anatomic diagnosis, supported by clinical features and pathologist interpretation of morphology and immunohistochemical (IHC) staining patterns. However, in patients with nonspecific morphologic and IHC findings - in addition to ambiguous clinical presentations such as recurrence versus new primary - a definitive diagnosis may not be possible, resulting in the patient being categorized as having a cancer of unknown primary (CUP). Therapeutic options and clinical outcomes are poor for CUP patients, with a median survival of 8-11 months. Here we describe and validate the Tempus Tumor Origin (Tempus TO) assay, an RNA-seq-based machine learning classifier capable of discriminating between 68 clinically relevant cancer subtypes. We show that the Tempus TO model is 91% accurate when assessed on retrospectively and prospectively held out cohorts of containing 9,210 samples with known diagnoses. When evaluated on a cohort of CUPs, the model recapitulated established associations between genomic alterations and cancer subtype. Combining diagnostic prediction tests (e.g., Tempus TO) with sequencing-based variant reporting (e.g., Tempus xT) may expand therapeutic options for patients with cancers of unknown primary or uncertain histology.\",\n \"Natural language inference for clinical registry curation\\nClinical registries - structured databases of demographic, diagnosis, and treatment information for patients with specific diseases or phenotypes - play vital roles in high-quality retrospective studies, operational planning, and assessment of patient eligibility for research, including clinical trials. However, registries are extremely time and resource intensive to curate. Natural language processing (NLP) can help, but standard NLP methods require specially annotated training sets or the construction of separate models for each of dozens or hundreds of different registry fields, rendering them insufficient for registry curation at scale. Natural language inference (NLI), a specific branch of NLP focused on logical relationships between statements, presents a possible solution, but NLI methods are largely unexplored in the clinical domain outside the realm of conference shared tasks and computer science benchmarks. Here we convert registry curation into an NLI problem, applying five state-of-the-art, pretrained, deep learning based NLI models to clinical, laboratory, and pathology notes to infer information about 43 different breast oncology registry fields. We evaluate the models inferences against a manually curated, 7439 patient breast oncology research database. The NLI models show considerable variation in performance, both within and across registry fields. One model, ALBERT, outperforms the others (BART, RoBERTa, XLNet, and ELECTRA) on 22 out of 43 fields. A detailed error analysis reveals that incorrect inferences primarily arise through models misinterpretations of temporality--they interpret historical findings as current and vice versa--as well as confusion based on subtle terminology and abbreviation variants common in clinical notes. However, modern NLI methods show promise for increasing the efficiency of registry curation, even when used \\\"out of the box\\\" with no additional training.\",\n \"An expanded population of CD8dim T cells with features of mitochondrial dysfunction and senescence is associated with persistent HIV-associated Kaposis sarcoma under ART\\nHIV-associated Kaposis sarcoma (KS), which is caused by Kaposis sarcoma-associated herpesvirus, usually arises in the context of uncontrolled HIV replication and immunosuppression. However, disease occasionally persists in individuals with durable HIV viral suppression and CD4 T cell recovery under anti-retroviral therapy (ART). The underlying mechanisms associated with this persistence are unclear. Suppression of viral infections can be mediated by CD8 T cells that detect infected cells via their T cell receptor and the CD8 co-receptor. However, CD8 T cells exhibit signs of functional exhaustion in untreated HIV infection that may not be fully reversed under ART. To investigate whether persistent KS under ART was associated with phenotypic and functional perturbations of CD8 T cells, we performed a cross-sectional study comparing HIV-infected individuals with persistent KS under effective ART (HIV+ KS+) to HIV-infected individuals receiving effective ART with no documented history of KS (HIV+ KSneg). A subset of T cells with low cell surface expression of CD8 (\\\"CD8dim T cells\\\") was expanded in HIV+ KS+ compared with HIV+ KSneg participants. Relative to CD8bright T cells, CD8dim T cells exhibited signs of senescence (CD57) and mitochondrial perturbations (PGC-1, MitoTracker) ex vivo. Mitochondrial activity (MitoTracker) was also reduced in proliferating CD8dim T cells. These findings indicate that an expanded CD8dim T cell population displaying features of senescence and mitochondrial dysfunction is associated with KS persistence under ART. CD8 co-receptor down-modulation may be symptomatic of ongoing disease.\",\n \"Sex differences, cross-ancestry generalizability, and noise-smoking interactions in the polygenic architecture of hearing loss in adults\\nWe conducted a comprehensive genome-wide investigation of hearing loss (HL) in 748,668 adult participants of the UK Biobank, the Nurses Health Studies (I and II), the Health Professionals Follow-up Study, and the Million Veteran Program. We identified 54 risk loci and characterized HL polygenic architecture, exploring sex differences, polygenic risk across ancestries, tissue-specific transcriptomic regulation, cause-effect relationships with genetically-correlated traits, and gene interactions with HL environmental risk factors. Our transcriptomic regulation analysis highlighted the potential role of the central nervous system in HL pathogenesis. This was supported by the multivariate interaction analysis that showed how genes involved in brain development interact with sex, noise pollution, and tobacco smoking in relation to their HL associations. Additionally, the genetically-informed causal inference analysis showed that HL is linked to many physical and mental health outcomes. These results provide many novel insights into the complex biology and epidemiology of HL in adults.\",\n \"Asymptomatic carriers of the p.A53T SNCA mutation: data from the PPMI study\\nIntroductionThere has been great interest in the prodromal phase of Parkinsons disease (PD), especially in subjects who are asymptomatic carriers of genetic mutations leading to PD because of the high risk to convert to PD. The objective of the present study was to assess non motor characteristics of asymptomatic p.A53T mutation carriers (A53T-AC) compared with healthy controls (HC).\\n\\nMethodsWe compared 12 A53T-AC with 36 matched HC enrolled into in the Parkinsons Progression Markers Initiative (PPMI) study. Baseline data extracted from the PPMI database, contained demographics and non-motor symptoms (e.g. the Montreal Cognitive Assessment (MOCA) for cognition, the University of Pennsylvania Smell Identification Test (UPSIT) for olfaction, MDS-UPDRS I etc.)\\n\\nResultsThe mean UPSIT score was lower in A53T-AC vs HC (p =0.000). MoCA test showed a trend towards lower scores in A53T AC. We found a significant positive correlation between UPSIT score and MOCA in A53T-AC (rs = 0,68, p=0,021) but not in HC. Total scores for MDS-UPDRS I did not differ between the groups but the subscore of anxiety was more prevalent in A53T-AC.\\n\\nConclusionThe more affected olfaction in A53T-AC may indicate that olfactory function is affected quite early in A53T carriers. The strong positive correlation between UPSIT and MOCA in the A53T-AC group may indicate that cognitive dysfunction and olfactory impairment progress alongside, prior to nigrostriatal degeneration. Anxiety was also more prevalent in A53T-AC and may represent an additional prodromal feature in this group of subjects.\",\n \"Is Google Trends a useful tool for tracking mental and social distress during a public health emergency?: A time-series analysis\\nBackgroundGoogle Trends data are increasingly used by researchers as an indicator of population mental health, but few studies have investigated the validity of this approach.\\n\\nMethodsRelative search volumes (RSV) for the topics depression, anxiety, self-harm, suicide, suicidal ideation, loneliness, and abuse were obtained from Google Trends. We used graphical and time-series approaches to compare daily trends in searches for these topics against population measures of these outcomes recorded using validated scales (PHQ-9; GAD-7; UCLA-3) in a weekly survey (n=[~]70,000) of the impact COVID-19 on psychological and social experiences in the UK population (12/03/2020 to 21/08/ 2020).\\n\\nResultsSelf-reported levels of depression, anxiety, suicidal ideation, self-harm, loneliness and abuse decreased during the period studied. There was no evidence of an association between self-reported anxiety, self-harm, abuse and RSV on Google Trends. Trends in reported depression symptoms and suicidal ideation declined over the study period, whereas Google topic RSV increased (p=0.03 and p=0.04 respectively). There was some evidence that suicidal ideation searches preceded reported self-harm (p=0.05), but graphical evidence suggested this was an inverse association. However, there was statistical and graphical evidence that self-report and Google searches for loneliness (p<0.001) tracked one another.\\n\\nLimitationsNo age/sex breakdown of Google Trends data are available. Survey respondents were not representative of the UK population and no pre-pandemic data were available.\\n\\nConclusionGoogle Trends data do not appear to be a useful indicator of changing levels of population mental health during a public health emergency, but may have some value as an indicator of loneliness.\",\n \"LED transillumination of the chest and abdomen in the diagnosis of neonatal conditions\\nAir leak syndromes, such as pneumothorax and pneumoperitoneum, are commonly diagnosed in Neonatal Intensive Care Units. However, this finding is usually detected with radiographic studies when the neonate is in poor condition. LED transillumination is an alternative method that allows a fast, inexpensive, and non-invasive diagnosis. We aimed to evaluate the clinical utility of LED transillumination in neonates by comparing the results to chest and abdomen radiograph as reference test.\\n\\nMethodologydiagnostic and prospective study that included 56 neonates. We used a simple and inexpensive handcrafted LED transilluminator to evaluate the chest and abdomen of patients, blind to the final diagnosis. The findings were compared to the radiographs.\\n\\nResultsthe study presented 3 true positive pneumothorax cases (sensibility 100%, 95%CI 29.24-100; specificity 100%, 95%CI 93.28-100), 1 true positive pneumoperitoneum case (sensibility 100%, 95%CI 2.50-100; specificity 100%, 95%CI 93.51-100), 10 true positive and 5 false negatives cases of gastric dilation (sensibility 66.67%, 95%CI 38.38-88.18; specificity 100%, 95%CI 91.19-100; negative likelihood ratio 0.33, 95%CI 0.16-0.68) and 4 true positive cases of dilation of bowel loops (sensibility 100%, 95%CI 39.76-100; specificity 100%, 95%CI 93.02-100).\\n\\nDiscussionLED transillumination is a safe, inexpensive, and easy-to-use clinical tool that may be employed to promote early intervention during severe cases of air leak syndrome that require immediate action, especially in low-income and rural areas. Further research with larger sample sizes is required to properly define the efficacy and usefulness of LED transillumination in routine use.\",\n \"Selection of appropriate reference genes for normalization of qRT-PCR based gene expression analysis in SARS-CoV-2, and Covid-associated Mucormycosis infection\\nSelection of reference genes in quantitative PCR is critical to determine accurate and reliable mRNA expression. Despite this knowledge, not a single study has investigated the expression stability of housekeeping genes to determine their suitability to act as reference gene in SARS-CoV-2 or Covid19 associated mucormycosis (CAM) infections. Herein, we address these gaps by investigating the expression stability of nine most commonly used housekeeping genes including TBP, CypA, B2M, 18S, PGC-1, GUSB, HPRT-1, {beta}-ACTIN and GAPDH in the patients of varying severity (asymptomatic, mild, moderate and severe). We observed significant differences in the expression of candidate genes across the disease spectrum. Next, using various statistical algorithms (delta Ct, Normfinder, Bestkeeper, RefFinder and GeNorm), we observed that CypA demonstrated the most consistent expression across the patients of varying severity and emerged as the most suitable gene in Covid19, and CAM infections. Incidentally, the most commonly used reference gene GAPDH showed maximum variations and found to be the least suitable. Lastly, comparative evaluation of expression of NRF2 is performed following normalization with GAPDH and CypA to highlight the relevance of an appropriate reference gene. Our results reinforce the idea of a selection of housekeeping genes only after validation especially during infections.\",\n \"Evaluation on the Effectiveness on the Implementation of WHO-CST Programme in Hong Kong: A RCT Protocol\\nDevelopmental delays/disorders in young children are identified as a public health priority. WHO and Autism Speaks co-designed a training programme titled \\\"WHO-Caregiver Skills Training\\\" (WHO-CST) which aims at providing training for caregivers whose children are with possible symptoms of Autism spectrum disorder (ASD) symptoms and pervasive developmental disorders (PDD), so that they can learn better strategies on managing the daily lives of their children and foster better communication between the parent-children dyad. The WHO-CST programme is currently implemented in more than 30 regions worldwide and it started in Hong Kong from 2018. As the programme is newly developed, only a few studies tried to evaluate the effectiveness of the programme in qualitative approaches, or in quantitative approach with relatively small sample (e.g. n < 10). In the present study, our team, who is responsible for the implementation and evaluation of the WHO-CST programme in Hong Kong, attempt to assess the effectiveness of the training in WHO-CST under a randomized controlled trial (RCT) design with about 120 eligible caregivers who will be randomly assigned in experimental and control groups. Our measurement will include the Joint Engagement Rating Inventory (JERI) developed by experts in WHO to gauge how parents engage their children in a 10-minute video recording their dyadic interaction and behaviors in a defined play setting. A set of other measurements on the caregivers experience of using intervention skills and their enhancement of knowledges will also be measured. We hypothesize that caregivers in treatment group will have better growth in scores of both JERI and measurements of other outcome than the wait-list control groups after the 12-week WHO-CST training, and also persistence of skill and knowledge level should also be found after a 30-day follow-up test.\",\n \"Artificial Intelligence for the Diagnosis and Treatment of Diabetes Kidney Disease: a systematic review\\nBackgroundDiabetic nephropathy (DN) is a serious microvascular complication that affects 40% of diabetes patients. In the last decade, artificial intelligence (AI) has been widely used in both structured and unstructured clinical data to improve the treatment of patients/potential patients with DN.\\n\\nMethodsThis systematic review aims to cover all applications of AI in the clinical use of DN or related topics. Studies were searched in four open-access databases (Pubmed, IEEE Xplore, DBLP Computer Science Bibliography, and ACM digital library). Finally, the author manually searched the reference list of included studies in the study for additional relevant articles.\\n\\nResultsFinally, a total of 24 original peers reviewed articles were included in this study. Through a manual data extraction, the summary of key information such as applied AI algorithm, main outcomes, performance evaluation etc. was taken. Then the included studies underwent a quality assessment criterion, assessing the reproducibility, generalizability etc. Most of the included studies revealed that the AI frameworks outperformed conventional statistical methods. A summary of the limitations, such as lack of data availability or external validation of the framework, in the included studies, was also included.\\n\\nConclusionThe rapid advancement of the AI framework and the exponential data generation in healthcare can be utilized and applied in clinical practices. The aid of AI can be instrumental in the treatment of DN.\",\n \"Point-of-care semiquantitative test for adherence to tenofovir alafenamide or tenofovir disoproxil fumarate\\nSynopsisO_ST_ABSObjectiveC_ST_ABSObjective measurement of antiretrovirals may aid clinical interventions for improving adherence to HIV prevention or treatment regimens. A point-of-care urine test could provide real-time information about recent adherence to regimens containing tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). We developed a lateral flow immunoassay (LFA) and enzyme-linked immunoassay (ELISA) for urinary tenofovir.\\n\\nMethodsIntensity of the LFA test line was quantified using an optical reader and visually scored 0 - 5 by two independent people, using a reference card. The sensitivity and specificity of both the ELISA and LFA were determined for two different tenofovir concentration cutoffs for TDF and TAF adherence--1,500 ng/mL and 150 ng/mL, respectively. To validate the assays, we measured 586 urine samples from 28 individuals collected as part of a study of tenofovir pharmacokinetics in adults, which were also measured by mass spectrometry as ground truth.\\n\\nResultsBoth the LFA signal and ELISA signal were each strongly correlated to drug concentrations (0.91 and 0.92 respectively). The LFA signal and ELISA were highly sensitive and specific at both thresholds (LFA se/sp TDF 89%/96%, TAF 90%/96%; ELISA se/sp TDF 94%/94%, TAF 92%/84%). Visual scoring of the LFA was also highly sensitive and specific at both the TDF and TAF thresholds (se/sp TDF 91%/94%, TAF 87%/90%).\\n\\nConclusionsOur rapid semi-quantitative test can measure TFV concentrations relevant to both TAF or TDF adherence, which may support adherence-promoting interventions across a range of HIV care settings.\",\n \"Actionable absolute risk prediction of atherosclerotic cardiovascular disease: a behavior-management approach based on data from 464,547 UK Biobank participants\\nCardiovascular diseases (CVDs) are the primary cause of all global death. Timely and accurate identification of people at risk of developing an atherosclerotic CVD and its sequelae, via risk prediction model, is a central pillar of preventive cardiology. However, currently available models only consider a limited set of risk factors and outcomes, do not focus on providing actionable advice to individuals based on their holistic medical state and lifestyle, are often not interpretable, were built with small cohort sizes or are based on lifestyle data from the 1960s, e.g. the Framingham model. The risk of developing atherosclerotic CVDs is heavily lifestyle dependent, potentially making a high percentage of occurrences preventable. Providing actionable and accurate risk prediction tools to the public could assist in atherosclerotic CVD prevention. We developed a benchmarking pipeline to find the best set of data preprocessing and algorithms to predict absolute 10-year atherosclerotic CVD risk. Based on the data of 464,547 UK Biobank participants without atherosclerotic CVD at baseline, we used a comprehensive set of 203 consolidated risk factors associated with atherosclerosis and its sequelae (e.g. heart failure).\\n\\nOur two best performing absolute atherosclerotic risk prediction models provided higher performance than Framingham and QRisk3. Using a subset of 25 risk factors identified with feature selection, our reduced model achieves similar performance while being less complex. Further, it is interpretable, actionable and highly generalizable. The model could be incorporated into clinical practice and could allow continuous personalized predictions with automated intervention suggestions.\",\n \"Human cytomegalovirus strain diversity and dynamics reveal the donor lung as a major contributor after transplantation\\nMixed human cytomegalovirus (HCMV) strain infections are frequent in lung transplant recipients (LTRs). To date, the influence of the donor (D) and recipient (R) HCMV-serostatus on intra-host HCMV strain composition and replication dynamics after transplantation is only poorly understood.\\n\\nHere, we investigated ten pre-transplant lungs from HCMV-seropositive donors, and 163 sequential HCMV-DNA positive plasma and bronchoalveolar lavage samples from 50 LTRs with multiviremic episodes post-transplantation. The study cohort included D+R+ (38%), D+R- (36%), and D-R+ (26%) patients. All samples were subjected to quantitative genotyping by short amplicon deep sequencing, and 24 thereof were additionally PacBio long-read sequenced for genotype linkages.\\n\\nWe find that D+R+ patients show a significantly elevated intra-host strain diversity compared to D+R- and D-R+ patients (P=0.0089). Both D+ patient groups display significantly higher replication dynamics than D- patients (P=0.0061). Five out of ten pre-transplant donor lungs were HCMV-DNA positive, whereof in three multiple HCMV strains were detected, indicating that multi-strain transmission via lung transplantation is likely. Using long reads, we show that intra-host haplotypes can share distinctly linked genotypes, which limits overall intra-host diversity in mixed infections. Together, our findings demonstrate donor-derived strains as a main source for increased HCMV strain diversity and dynamics post-transplantation, while a relatively limited number of intra-host strains may facilitate rapid adaptation to changing environments in the host. These results foster targeted strategies to mitigate the potential transmission of the donor strain reservoir with the allograft.\"\n]","isConversational":false},"cluster":{"kind":"number","value":10,"string":"10"}}},{"rowIdx":224,"cells":{"query":{"kind":"string","value":"Hepatic resection versus transarterial chemoembolization for the intermediate stage hepatocellular carcinoma：A cohort study\nBackgroundThe selection criterion for hepatic resection(HR) in intermediate-stage(IM) hepatocellular carcinoma(HCC) is still controversial. We used real-world data to evaluate the overall survival (OS) treated with HR or TACE.\n\nMethodsIn all, 942 patients with IM-HCC were categorized in HR and TACE groups. OS was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score- matched (PSM) analyses. The smooth curve was performed through the generalized additive model. The interaction test was performed to evaluate the HR impact on OS concerning risk factors. Also, we used multiple imputation to deal with the missing data.\n\nResultsTotally, 23.0% (n=225) of patients received HR. At a median overall survival of 23.7 months, HR was associated with the improved OS on multivariate analysis (hazard ratio, 0.45; 95%CI: 0.35, 0.58; after PSM: 0.56; 95%CI: 0.41, 0.77). Landmark analyses limited to long-term survivors of [≥] 6 months, [≥] 1, and [≥] 2 years demonstrated better OS with HR in all subsets (all P<0.05). After PSM analysis, however, HR increased 20% risk of death (HR, 1.20; 95%CI: 0.67, 2.15) in the subgroup of LDH [≤]192 U/L (P for interaction = 0.037). Furthermore, the significant interaction was robust between the LDH and the HR with respect to 1-, 3-, and 5-year observed survival rate (all P<0.05).\n\nConclusionHepatic resection was superior to TACE for intermediate-stage HCC in the range of LDH level > 192 U/L. Moreover, TACE might be suitable for patients with LDH level [≤] 192 U/L.\n\nSynopsisO_LIHepatectomy was superior to TACE for BCLC-B HCC.\nC_LIO_LIHepatectomy increased 20% risk of death for LDH < 192 U/L after matching.\nC_LIO_LIA significant interaction was robust between LDH and with respect to hepatectomy the 1-, 3-, and 5-year observed survival rate.\nC_LI"},"positive":{"kind":"list like","value":["Post operative acute kidney injury in abdominal Surgeries. A retrospective analysis of single center in western India.\nAIMThe aim of our study was to evaluate the incidence and causative factors for acute kidney injury in abdominal surgeries.\n\nMaterial and MethodsAll the abdominal surgeries performed between April 2018 to December 2020, in our institution have been analyzed for acute kidney injury. Acute kidney injury defined according to acute kidney injury network classification. Categorical variables were evaluated by chi-square t-test or fishers t-test wherever appropriate and continuous variables by Mann Whitney U test for nonparametric data and student t-test for parametric test after skewness and kurtosis analysis. Statistical analysis was done using SPSS version 23. P< 0.05 was considered statistically significant.\n\nResultsWe performed 402 gastrointestinal and hepatobiliary surgery from April 2018 to December 2020. After exclusion 372 patients were included in the study population. 20 patients (5.37%) were defined as having acute kidney injury according to acute kidney injury network classifications. On univariate analysis acute kidney injury was associated with open surgery (p= 0.003), Intraoperative hypotension (p<0.001), Colorectal surgeries (p<0.0001), Emergency surgery (p=0.028), CDC grade of surgery (p<0.001), increased used to blood products (p=0.001), higher ASA grade (p<0.0001), increased operative time(p<0.0001). On multivariate logistic regression analysis higher ASA grade (p<0.0001) and increased operative time (0.049) independently predicted acute kidney injury. Acute kidney injury was also significantly associated with 90 days mortality. (p= <0.0001).\n\nConclusionPost-operative acute kidney injury was associated with significant mortality in abdominal surgery. Higher ASA grades and increased operative time predicted acute kidney injury.","Impact of gastric resection and enteric anastomotic configuration on delayed gastric emptying after pancreaticoduodenectomy: a network meta-analysis of randomized trials\nIntroductionDelayed gastric emptying (DGE) is frequent after pancreaticoduodenectomy (PD). Several randomised controlled trials (RCTs) have explored operative strategies to minimise DGE, however, the optimal combination of gastric resection approach, anastomotic route, and configuration, role of Braun enteroenterostomy remains unclear.\n\nMethodsMEDLINE, Embase, and CENTRAL databases were systematically searched for RCTs comparing gastric resection (Classic Whipple, pylorus-resecting, and pylorus-preserving), anastomotic route (antecolic vs retrocolic) and configuration (Billroth II vs Roux-en-Y), and enteroenterostomy (Braun vs no Braun). A random-effects, Bayesian network meta-analysis with non-informative priors was conducted to determine the optimal combination of approaches to PD for minimising DGE.\n\nResultsTwenty-four RCTs, including 2526 patients and 14 approaches were included. There was some heterogeneity, although inconsistency was low. The overall incidence of DGE was 25.6% (n = 647). Pylorus-resecting, antecolic, Billroth II with Braun enteroenterostomy was associated with the lowest rates of DGE and ranked the best in 35% of comparisons. Classic Whipple, retrocolic, Billroth II with Braun ranked the worst for DGE in 32% of comparisons. Pairwise meta-analysis of retrocolic vs antecolic route of gastro-jejunostomy found increased risk of DGE with the retrocolic route (OR 2.1, 95% CrI; 0.92 - 4.7). Pairwise meta-analysis of Braun enteroenterostomy found a trend towards lower DGE rates with Braun compared to no Braun (OR 1.9, 95% CrI; 0.92 - 3.9). Having a Braun enteroenterostomy ranked the best in 96% of comparisons.\n\nConclusionBased on existing RCT evidence, a pylorus-resecting, antecolic, Billroth II with Braun enteroenterostomy may be associated with the lowest rates of DGE.","Outcomes following out-of-hours cholecystectomy: A systematic review and meta-analysis\nBackgroundCholecystectomy is one of the most commonly performed abdominal operations. Demands on acute operating theatre availability have led to out-of-hours (evenings, nights, or weekend) cholecystectomy being performed, although it is not known whether outcomes differ between out-of-hours and in-hours (daytime on weekdays) cholecystectomy.\n\nObjectiveThis systematic review and meta-analysis aimed to compare outcomes following out-of-hours versus in-hours urgent cholecystectomy.\n\nMethodsMEDLINE, EMBASE and Scopus databases were systematically searched from inception to December 2020 for studies comparing outcomes from out-of-hours and in-hours urgent cholecystectomy in adults. The outcomes of interest were rates of bile leakage, bile duct injury (BDI), overall post-operative complications, conversion to open cholecystectomy, specific intra- and post-operative complications, length of stay (LOS), readmission and mortality. Sensitivity analysis of adjusted multivariate results was also performed.\n\nResultsIn total, 194,135 urgent cholecystectomies (30,001 out-of-hours; 164,134 in-hours) from 11 studies were included. Most studies were of high (64%) or medium (18%) quality. There were no differences between out-of-hours and in-hours cholecystectomy for rates of bile leakage, BDI, overall post-operative complications, conversion to open cholecystectomy, operative duration, readmission, mortality, and post-operative LOS. Higher rates of post-operative sepsis (odds ratio (OR) 1.58, 95% CI: 1.04-2.41; p=0.03) and pneumonia (OR 1.55, 95% CI: 1.06-2.26; p=0.02) were observed following out-of-hours cholecystectomy on univariate meta-analysis but not on adjusted multivariate meta-analysis.\n\nConclusionsThere was no increased risk or difference in specific complications associated with out-of-hours compared with in-hours urgent cholecystectomy.","Tissue Stress from Laparoscopic Grasper Use and Bowel Injury in Humans: Establishing Intraoperative Force Boundaries\nBackgroundInappropriate force in laparoscopic surgery can lead to inadvertent tissue injury. It is currently unknown however at what magnitude of compressive stress trauma occurs in gastrointestinal tissues.\n\nMethodsThis study included 10 small bowel and 10 colon samples. Each was compressed with pressures ranging from 100 kPa to 600 kPa by a novel device to induce compressive \"grasps\" to simulate those of a laparoscopic grasper. Experimentation was performed ex-vivo, in-vitro. Grasp conditions of 0 to 600 kPa for a duration of 10 seconds were utilized. Two pathologists who were blinded to all study conditions, performed a histological analysis of the tissues. Patients were eligible if their surgery procured healthy tissue margins for experimentation (a convenience sample). 26 patient samples were procured; six samples were unusable. 10 colon and 10 small bowel samples were tested for a total of 120 experimental cases. No patients withdrew their consent. Two metrics of damage were quantified: an intestinal layer thickness calculation where the serosa layer was measured in the area of compression and compared to a local control and a histological scoring scale for tissue trauma.\n\nResultsSmall bowel (10), M:F was 7:3, average age was 54.3 years. Colon (10), M:F was 1:1, average age was 65.2 years. All 20 patients experienced a significant difference (p<0.05) in serosal thickness post-compression at both 500 and 600 kPa for both tissue types. A logistic regression analysis with a sensitivity of 100% and a specificity of 84.6% on a test set of data predicts a safety threshold of 329-330 kPa.\n\nConclusionA threshold was discovered that corresponded to both significant serosal thickness change and a positive histological trauma score rating. This \"force limit\" could be used in novel sensorized laparoscopic tools to avoid intraoperative tissue injury.","Management Algorithm of External Fixation in Lower Leg Arterial Injury for Limb Salvages\nPurposeThe purpose of this study was to review the roles of using external fixation to rescue the patients who sustained arterial injuries in the lower legs.\n\nMethodsDemographics, surgical treatment and outcomes in 88 patients with lower leg arterial injuries treated by external fixation at two trauma centers from 2009 to 2018 were reviewed. The primary outcome was the rate of successful lower leg salvage, while secondary outcomes were complications and functional recovery.\n\nResults80 patients (90 legs) maintained a successful lower leg salvage. The patients were followed up for an average of 15.5{+/-}5.5 months. 6 patients (8 pins) experienced pin-tract infection, pins loosening happened in 2 patients (4 pins), 7 patients (7 legs) developed wound superficial infection, 3 patients (3 legs) with a deep infection developed osteomyelitis, 16 patients (17 legs) suffered the bone nonunion or bone defect. The average healing time of fracture was 5.6{+/-}4.3months. The maintain of external fixation average time was 5.8{+/-}3.6 months.\n\nConclusionWith correctly judging the condition of limb ischemia, mastering reasonably the operation indications, and preventing complications, good clinical effects can be achieved when external fixation is used.\n\nLevel of evidenceRetrospective cohort, level IV.","Impact of the COVID-19 pandemic on surgical procedures in Brazil: a descriptive study\nBackgroundThe COVID-19 pandemic has deeply affected medical practice, and changes in healthcare activities were needed to minimize the overload and avoid healthcare systems collapse. The aim of this study was to evaluate the impact of the pandemic on surgical procedures in Brazil.\n\nMaterials and MethodsWe conducted a descriptive study of the number of hospitalizations for surgical procedures in Brazil from 2016 to 2020. Data were collected from the Brazilian Department of Informatics of the Unified Health System (DATASUS). Analyzes were performed according to the type of procedure, geographical region, subgroups of surgical procedures, and the number of surgeries from 2020 were compared with the average from 2016 to 2019.\n\nResultsThere were 4,009,116 hospitalizations for surgical procedures in the Brazilian Public Health System in 2020. When comparing it to the average of hospitalizations from 2016-2019, there was a decrease of 14.88% [95%IC (14.82-14.93)]. Decrease rates were 34.82% [95%IC (34.73-34.90)] for elective procedures and 1.11% [95%IC (1.07-1.13)] for urgent procedures. Decrease rates were similar in all the five regions of the country (average 14.17%). Surgical procedure subgroups with the highest decrease rates were endocrine gland surgery (48.03%), breast surgery (40.68%), oral and maxillofacial surgery (37.03%), surgery of the upper airways, face, head and neck (36.06%), and minor surgeries and surgeries of skin, subcutaneous tissue and mucosa (33.16%). Conclusion: The overload of healthcare facilities has demanded a reduction of non-urgent activities to prevent a collapse of healthcare systems, resulting in a decrease in elective surgeries. Recommendations about the performance of surgical procedures were made, and continuous refinements of these recommendations are encouraged.","A comparative analysis of the health, financial, equity, and cost-effectiveness impacts of maxillofacial surgery in Guinea\nBackgroundNon-governmental organizations (NGOs) play a substantive role in the delivery of surgical services in in low- and middle-income countries (LMICs).\n\nAssessment of their outcomes, especially as they relate to outcomes of surgery done in country, remains limited.\n\nMethodsA prospective analysis of maxillofacial surgery in Guinea. Outcomes of interest were changes in patient health, subjective well-being, and financial status; hardship financing and catastrophic expenditure; equitable distribution of surgical access; and cost-effectiveness.\n\nResultsWe followed 569 patients requiring maxillofacial surgery in Conakry, Guinea, 114 of whom got care at local university hospitals, and 455 of whom got their care with Mercy Ships, a surgical NGO. Patients were followed for between three months (local) and one year (NGO). All patients reported significant improvement in objective and subjective measures of health and in financial status. Approximately half had to borrow and sell to get care, with NGO patients borrowing less, on average. However, NGO patients faced more risk of catastrophic expenditure (41.2% vs. 28.1%, p < 0.001). NGO patients were significantly poorer, whether financial status was measured by asset wealth or monthly income (p < 0.001). Finally, surgical care by the NGO was cost effective.\n\nConclusionsIn a prospective analysis of surgical patients in an LMIC, we find that surgery improves health and financial well-being. NGOs may be able to reach patients who would not be able to get care through their local system; however, this comes at a cost of increased initial financial risk. Finally, NGO-based surgical care is cost-effective.","Racial and Ethnic Inequities in Mortality During Hospitalization for Traumatic Brain Injury: A Call to Action\nThe health disparities which drive inequities in health outcomes have long plagued our already worn healthcare system and are often dismissed as being a result of social determinants of health. Herein, we explore the nature of these inequities by comparing outcomes for racial and ethnic minorities patients suffering from traumatic brain injury (TBI). We retrospectively reviewed all patients enrolled in the Trauma One Database at the Oregon Health & Science University Hospital from 2006 to October 2017 with an abbreviated injury scale (AIS) for the head or neck greater than 2. Racial and ethnic minority patients were defined as non-White or Hispanic. A total of 6,352 patients were included in our analysis with 1,504 in the racial and ethnic minority cohort vs. 4,848 in the non-minority cohort. A propensity score (PS) model was generated to account for differences in baseline characteristics between these cohorts to generate 1,500 matched pairs. The adjusted hazard ratio for in-hospital mortality for minority patients was 2.21 (95% Confidence Interval (CI) 1.43-3.41, p<0.001) using injury type, probability of survival, and operative status as covariates. Overall, this study is the first to specifically look at racial and ethnic disparities in the field of neurosurgical trauma. This research has demonstrated significant inequities in the mortality of TBI patients based on race and ethnicity and indicates a substantive need to reshape the current healthcare system and advocate for safer and more supportive pre-hospital social systems to prevent these life-threatening sequelae.","Postoperative morbidity after liver resection- A Systemic review, meta-analysis, and metaregression of factors affecting them.\nAim of the studyThis systemic review and meta-analysis aimed to analyze post-operative morbidity after liver resection, and also study various factors associated with mortality via metaregression analysis.\n\nMaterial and MethodsPubMed, Cochrane Library, Embase, google scholar, web of science with keywords like liver resection\"; \"mortality\";\" hepatectomy\". Weighted percentage post-operative morbidities were analyzed. Meta-analysis and meta-regression were done by the DerSimonian-Liard random effect model. Heterogeneity was assessed using the Higgins I2 test. Publication bias was assessed using a funnel plot. Funnel plot asymmetry was evaluated by Eggers test. Morbidity was defined as any postoperative morbidity mentioned.\n\nResultsA total of 46 studies was included in the final analysis. Total 45771 patients underwent liver resections. 16111 patients experienced complications during the postoperative period. Weighted post-operative morbidity was 30.2% (95 % C.I. 24.8-35.7%). Heterogeneity was high with I2 99.46% and p-value <0.01. On univariate analysis, major liver resections were significantly associated with heterogeneity. (p=0.024). However, residual heterogeneity was still high with I2 98.62%, p<0.001. So, multifactor metaregression analysis major hepatectomy (p<0.001), Open hepatectomy (p=0.001), cirrhotic liver (p=0.002), age (p<0.001), blood loss (p<0.001), and colorectal metastasis (p<0.001) independently associated with postoperative morbidity. Residual heterogeneity was moderate I2= 39.9% and nonsignificant p=0.189.\n\nConclusionLiver resection is associated with high postoperative morbidity and various factors like major hepatectomy, Open hepatectomy, cirrhotic liver, blood loss, and colorectal metastasis were associated with morbidity and responsible for heterogeneity across the studies.","Laser speckle contrast imaging for visualizing blood flow during cerebral aneurysm surgery: A comparison with indocyanine green angiography\nLaser speckle contrast imaging (LSCI) has emerged as a promising tool for intraoperative cerebral blood flow (CBF) monitoring because it produces real-time full-field blood flow maps non-invasively and label-free. In this study, we compare LSCI with indocyanine green angiography (ICGA) to assess CBF during aneurysm clipping surgery in humans. LSCI hardware was attached to the surgical microscope prior to the start of each surgery and did not interfere with the sterile draping of the microscope or normal operation of the microscope. LSCI and ICGA were performed simultaneously to visualize CBF in n=4 aneurysm clipping cases, and LSCI was performed throughout each surgery when the microscope was positioned over the patient. To more easily visualize CBF in real-time, LSCI images were overlaid on the built-in microscope white light camera images and displayed to the neurosurgeon in real-time. Blood flow changes before, during, and after an aneurysm clipping were visualized with LSCI and later verified with ICGA. LSCI was performed continuously throughout the aneurysm clipping process, providing the surgeon with immediate actionable information on the success of the clipping. The results demonstrate that LSCI and ICGA provide different, yet complementary information about vessel perfusion.","Effects of Acute Normovolemic Hemodilution on Post-Cardiopulmonary Bypass Coagulation Tests and Allogeneic Blood Transfusion in Thoracic Aortic Repair Surgery: An Observational Cohort Study\nBackground and AimPerioperative blood transfusion is associated with increased morbidity and mortality. Acute normovolemic hemodilution (ANH) is a blood conservation strategy associated with variable success, and rarely studied in more complex cardiac procedures. The study aim was to evaluate whether acute ANH improves coagulopathy and reduces blood transfusions in thoracic aortic surgeries.\n\nMethodsSingle-center observational cohort study comparing ANH and standard institutional practice in patients who underwent thoracic aortic repair from 2019 to 2021.\n\nResults89 patients underwent ANH and 116 standard practice. There were no significant differences between the groups in terms of demographic or major perioperative characteristics. In the ANH group coagulation tests before and after transfusion of autologous blood showed decreased INR and increased platelets, fibrinogen, all with p<0.0005. Coagulation results in the ANH and control groups were not statistically different. The average number of transfused allogeneic products per patient was lower in the ANH vs control group: FFP 1.1 {+/-}1.6 vs 1.9 {+/-}2.3 (p=0.003), platelets 0.6 {+/-}0.8 vs 1.2 {+/-}1.3 (p=0.0008), and cryoprecipitate 0.3 {+/-}0.7 vs 0.7 {+/-}1.1 (p=0.008). Reduction in RBC transfusion was not statistically significant. The percentage of patients who received any transfusion was 53.9% in ANH and 59.5% in the control group (p=0.42). There was no significant difference in major adverse outcomes.\n\nConclusionsANH is a safe blood conservation strategy for surgical repairs of the thoracic aorta. Laboratory data suggests that ANH can improve coagulopathy after separation from CPB, and significantly reduce the number of transfused FFP, platelets and cryoprecipitate.","REPAIR OF ABDOMINAL WALL DEFECTS WITH ACELLULAR BOVINE PERICARDIUM MATRIX - A MULTICENTER PROSPECTIVE STUDY\nBackgroundThe association of prosthetic meshes in the abdominal wall repair, reducing the recurrence rates in an impactful way, has become an almost mandatory routine for the success of these surgeries. After decades using non-biological synthetic implants, from the 90s onwards biological membranes of animal or human origin were introduced - the so called acellular biological matrices - beginning a new era in abdominal wall defects correction.\n\nMethodsThirty patients underwent repair for different abdominal wall deformities, with acellular matrices of bovine pericardium, in a total of 40 anatomically individualized implants. The median follow-up was 22 months, with patients evaluated clinically and radiologically. In three cases, biopsies of the implanted areas were performed, allowing histological analysis of the material.\n\nResultsThere was no recurrence of hernias in any of the cases, both clinically and radiologically. There was also no record of hematomas, infections or any phenomenon of a local or systemic reaction nature. Radiologically, it was not possible to visualize the matrices at the implantation site in any of the analysed postoperative periods. Biopsies showed important tissue neoformation replacing the implanted membranes, with important deposition of collagen, normal-looking cellularized tissue, and absence of foreign body reactions.\n\nConclusionsThe analysed matrices showed similarity to other biological membranes described in the international literature. Representing an important update and conceptual evolution, biological matrices must be incorporated into the therapeutic arsenal in abdominal wall repairs.","Soft robotic steerable micro-catheter for the endovascular treatment of cerebral disorders\nCatheters used for endovascular navigation in interventional procedures lack dexterity at the distal tip. Neurointerventionists, in particular, encounter challenges in up to 25% of aneurysm cases largely due to the inability to steer and navigate the tip of the micro-catheters through tortuous vasculature to access aneurysms. We overcome this problem with sub-millimeter diameter, hydraulically-actuated hyperelastic polymer devices at the distal tip of micro- catheters to enable active steerability. Controlled by hand, the devices offer complete 3D orientation of the tip. Using pressures up to 400 kPa (4 atm) we demonstrate guidewire-free navigation, access, and coil deployment in vivo, offering safety, ease of use, and design flexibility absent in other approaches to endovascular intervention. We demonstrate the ability of our device to navigate through vessels and to deliver embolization coils to the cerebral vessels in a live porcine model. This indicates the potential for microhydraulic soft robotics to solve difficult access and treatment problems in endovascular intervention.","Use of autologous platelet derivatives for secondary alveoloplasty in patients with cleft lip and palate: a protocol for a systematic review and meta-analysis\nObjectiveTo assess the effectiveness and safety of autologous platelet derivatives, specifically platelet-rich plasma (PRP) or platelet-rich fibrin (PRF), for secondary alveoloplasty in patients with cleft lip and palate.\n\nEligibility criteriaWe will include randomized trials evaluating the effect of autologous platelet derivatives on newly bone formed after secondary alveoloplasty in cleft lip and palate patients. Two reviewers will independently screen each study for eligibility, data extraction, and bias assessment using the Cochrane \"risk of bias \"tool. We will pool the results using meta-analysis and apply the GRADE system to assess the certainty of the evidence for each outcome.\n\nData sourcesA comprehensive search will include all relevant randomized controlled trials (RCTs), the ongoing investigation reported in specialty congresses and trials regardless of language or publication status (published, unpublished, in press, and progress). We will conduct searches in the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), PUBMED, Embase, and LILACS. We will screen trial registries and other sources in order to identify articles that might have been missed in the electronic searches.\n\nEthics and disseminationAs researchers will not access information that could identify an individual participant, obtaining ethical approval was waived.","The retrospective observational study of clinical outcomes of single dose infusion of warm blood cardioplegia in patients undergoing cardiac surgery\nObjectiveThe aim of the study was to assess the safety and efficacy of a normothermic cardioplegia solution N use and obtain additional information about dosing regimens during normothermic or mild hypothermic cardiac surgery.\n\nMethodsA retrospective observational study included 150 cardio surgery patients. The primary endpoint was the intraoperative acute heart failure development. The secondary endpoints were the postoperative Troponin T concentrations, the need for catecholamine support, and the repeated infusion of a cardioplegia solution.\n\nResultsThe duration of aortic cross-clamping varied from 17 to 154 minutes, median 59 [interquartile range, 46 - 73] minutes. Spontaneous sinus rhythm recovery was observed in 136 (90.7%) patients. Intraoperative acute heart failure was observed in 1 case. The Troponin T concentrations were 0.331{+/-}0.143 ng/mL after surgery. Mortality was 2% (3 patients). Eight patients received an additional volume of N solution to maintain asystole. Among 16 patients with a cross-clamp duration greater than 90 minutes epinephrine was used in 3 (18.8%) patients in dose of more than 0.05 mcg/kg/min. Among 134 patients cross-clamp duration less than 90 minutes the catecholamine support was used in 4 (3%) patients, p=0.027.\n\nConclusionsA primary single-dose infusion of cardioplegia solution N provides myocardial protection for 59 [interquartile range, 46 - 73] minutes and up to 154 minutes. The catecholamine support in the group of aortic cross-clamp duration less than 90 minutes was used lesser than in the group of aortic cross-clamp duration greater than 90 minutes (3% and 18.8%, respectively). The cardioprotection during cardiopulmonary bypass surgery especially in elderly patients with concomitant disease needs to be confirmed in a future investigations.","Hemodilution in High Risk Cardiac Surgery: Laboratory Values, Physiological Parameters and Outcomes\nBackgroundAcute normovolemic hemodilution (ANH) is a blood conservation strategy in cardiac surgery, predominantly used in coronary artery bypass graft (CABG) and/or valve procedures. Although higher complexity cardiac procedures may benefit from ANH, concerns for hemodynamic instability and organ injury during hemodilution hinder its wider acceptance. Laboratory and physiological parameters during hemodilution in complex cardiac surgeries have not been described.\n\nStudy Design and MethodsThis observational cohort (2019-2021) study included 169 patients who underwent thoracic aortic repair, multiple valve procedure, concomitant CABG with the aforementioned procedure, and/or redo sternotomies. Patients who received allogeneic blood were excluded. Statistical comparisons were performed between ANH (N=66) and non ANH controls (N=103). ANH consisted of removal of blood at the beginning of surgery and its return after cardiopulmonary bypass (CPB).\n\nResultsIntraoperatively, the ANH group received more albumin (p=0.04) and vasopressor medications (p=0.01); while urine output was no different between ANH and controls. Bilateral cerebral oximetry (rSO2) values were similar before and after hemodilution. During bypass rSO2 were discretely lower in the ANH vs. control group (right rSO2 p=0.03, left rSO2 (p=0.05). No differences in lactic acid values were detected across the procedural continuum. Postoperatively, no differences in extubation times, ICU length of stay, kidney injury, stroke or infection were demonstrated.\n\nDiscussionThis study suggests hemodilution to be a safe and comparable blood conservation technique, even without accounting for potential benefits of reduced allogenic blood administration. The study may contribute to better understanding and wider acceptance of ANH protocols in high risk cardiac surgeries.","Premature Atrial Stimulation Accentuates Conduction Abnormalities in Cardiac Surgery Patients that Develop Postoperative Atrial Fibrillation\nBACKGROUNDpostoperative atrial fibrillation (POAF) is a common cardiac surgery complication that is associated with increased complications and negative outcomes, but the association between presurgical atrial conduction abnormalities and POAF has not been investigated clinically during premature atrial S1S2 stimulation. This clinical study sought to examine whether intraoperative premature atrial stimulation reveals increased areas of slowed and/or blocked conduction in patients that develop POAF.\n\nMETHODSHigh-density intraoperative epicardial left atrial mapping was conducted in 20 cardiac surgery patients with no prior history of atrial fibrillation (AF). In 20 patients, 6 (30%) developed POAF. A flexible-array of 240-electrodes was placed on the posterior left atrial wall in between the pulmonary veins. Activation maps were generated for sinus and premature atrial S1S2 stimulated beats. The area of conduction block (CB), conduction delay (CD) and the combination of both (CDCB) for conduction velocity <0.1, 0.1[≤]x<0.2 and <0.2 m/s, respectively were quantified.\n\nRESULTSFor a premature atrial S2 beat with shortest cycle length captured, conduction velocity maps revealed a significantly higher area for CD (13.19{+/-}6.59 versus 6.06{+/-}4.22 mm2, p=0.028) and CDCB (17.36{+/-}8.75 versus 7.41{+/-}6.39 mm2, p=0.034), and a trend toward a larger area for CB (4.17{+/-}3.66 versus 1.34{+/-}2.86 mm2, p=0.063) in patients who developed POAF in comparison to those that remained in the sinus. Sinus and S1 paced beats did not show substantial differences in abnormal conduction areas between patients with and without POAF.\n\nCONCLUSIONIn comparison to sinus and S1 beats, premature atrial S2 beats accentuate conduction abnormalities in cardiac surgery patients that developed POAF.","Acute kidney injury after liver resection: A systematic review, meta-analysis, and metaregression of factors affecting it.\nAimThis systematic review and meta-analysis aimed to study the incidence of acute kidney injury after liver resection and to analyze various factors affecting it by metaregression analysis.\n\nMethodsThe study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (2020) and MOOSE guidelines. The meta-analysis was done using Review Manager 5.4 and the JASP Team (2020). JASP (Version 0.14.1)(University of Amsterdam). Weighted percentage incidence with 95% confidence intervals were used. Univariate metaregression was done by DerSimonian-Laird methods. Factors with a p-value less than 0.05 in the univariate metaregression model were entered in the multivariate metaregression model. Heterogeneity was assessed using the Higgins I2 test. The random-effects model was used in meta-analysis.\n\nResultsTotal 14 studies including 15510 patients were included in the final analysis. 1247 patients developed Acute Kidney Injury. Weighted Acute kidney injury percentage after liver resection was 15% with a 95% confidence interval of 11%-19%. On univariate metaregression analysis major hepatectomy (p=0.001), Underlying cirrhosis of liver (p=0.031), AKIN definition used (0.017), male sex (p<0.001), open surgery (p=0.032), underlying diabetes (0.026). On multivariate metaregression analysis major hepatectomy (p=0.003), underlying cirrhosis (p<0.001), male sex (p<0.001), AKIN classification used for defining acute kidney injury (p < 0.001, independently predicted heterogeneity and hence acute kidney injury.\n\nConclusionLiver resection is associated with a high incidence of acute kidney injury. Major hepatectomy, male sex, underlying cirrhosis were independently predicting acute kidney injury.","Wound Complications Following Surgery to the Lymph Nodes: A protocol for a systematic review and meta-analysis\nBackgroundMalignancies that spread to the lymph nodes may be identified through surgical biopsy, and treatment of metastatic disease may be through lymph node dissection. These surgeries, however, may be associated with significant adverse outcomes, particularly wound complications, the true incidence of which remains unknown. Multiple studies have reported their individual rates of complications in isolation. The aim of this study will be to systematically evaluate data that presents the incidence of wound complications in patients undergoing these surgeries.\n\nMethodsWe have designed and registered a protocol for a systematic review and meta-analysis of studies presenting incidence data. We will search MEDLINE, EMBASE and CENTRAL for relevant articles published before March 30th, 2021. Meta-analysis will be undertaken to synthesise an overall incidence of surgical site infection, wound dehiscence, haematoma and seroma. Subgroup analyses will investigate the effects of anatomical location, primary malignancy and study design on pooled incidence. Risk of bias will be evaluated for each included study using bespoke tools matched to the study design.\n\nDiscussionThe results of this study will provide the incidence of wound complications and secondary complications following lymph node surgery. This will directly impact upon the consent process, and may influence the nature of future research studies aimed at reducing post-operative complications.","Population-based Cross-sectional Analysis of the Epidemiology of the Surgical Correction of Hyperhidrosis in 1216 Patients over 11 years.\nAO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSEndoscopic thoracic sympathectomy is the definitive surgical treatment for hyperhidrosis, and a nationwide study suggested that it has been performed in a higher rate than which could have been expected due to climate characteristics, comparing to the national statistics.\n\nObjectivesTo study the epidemiology of sympathectomy to treat hyperhidrosis in Sao Paulo, the largest city in the Southeast.\n\nDesign and settingpopulation-based cross-sectional study.\n\nMethodsdata on sympathectomies to treat hyperhidrosis between 2008 and 2018 were assessed from the database of the Municipal Health Secretary of Sao Paulo, Brazil.\n\nResults65.29% of the patients were female, 66.2% aged between 20 and 39 years and 37.59% had addresses registered outside Sao Paulo. 1216 procedures were performed in the city of Sao Paulo from 2008 to 2018, 78.45% of which in only two public hospitals. The number of procedures significantly declined over the years (p = 0.001). 71.63% of the procedures were associated with 2 to 3 days of hospital stay, only 78 intensive care unit days were billed and we did not observe any intra-hospital death.\n\nConclusionssympathectomies for the treatment of HH were widely performed in the city of Sao Paulo (1216 procedures), mainly in young (20 -39 years) and female patients, with more than one third of the patients having addresses registered outside the city. This is a very safe surgery, with low need for intensive care units and no mortality in our series. There was a decreasing trend in the number of surgeries over the years.","PERIPHERAL ARTERIOVENOUS MALFORMATIONS AND THEIR RESPONSE TO TREATMENT MODALITIES: A SINGLE SURGEON'S EXPERIENCE AT TERTIARY CARE HOSPITALS\nBackgroundPeripheral arteriovenous malformations (AVMs) are congenital defects resulting in abnormal connections between veins and arteries. We investigated a group of patients with peripheral AVMs to determine whether there were any gender differences in disease presentation and the response of AVMs to various modalities of treatment.\n\nMethodologyThe patients in this cross-sectional study were divided into two groups based on gender and their demographic data, clinical presentation at the time of diagnosis and response to treatment was assessed. Both surgical and nonsurgical treatment options were used. Nonsurgical options employed in the study included immunotherapy, embolotherapy and ultrasound-guided foam sclerotherapy (UGFS)\n\nResultsOut of 43 patients, 74.4% were females with a male to female ratio of 1:3. The mean age at presentation in males was 27 years and 17 years in females. 60% of the male patients presented with high-flow AVMs while 81% of the female patients presented with low-flow lesions instead. Half of the AVMs in males were on the trunk whereas, in females, 93.9% were on the extremities. UGFS alone was used in 95.3% of patients while 32.5% of patients underwent UGFS followed by surgical excision. One patient was treated with sirolimus. In 4.6% of cases, embolization followed by surgical excision was performed. Recurrence was recorded in 20.9% of cases.\n\nConclusionsThe clinical presentation of AVMs is notably different among the two genders. Sclerotherapy and embolotherapy proved to be effective treatment options. Larger studies, however, are needed to substantiate these claims.","Shared decision making and specific informed consent in patients with aortic aneurysms\nIntroductionStudies show that vascular surgery patients have the desire to participate more actively in their treatment, but that they find it difficult to express themselves. Patients prefer to know all the therapeutic options available, not just those that the surgeon considers appropriate. With this knowledge, patients can begin to choose the most appropriate therapeutic modality for themselves, also becoming responsible for the therapeutic decision. Therefore, the objective of this paper was to analyze the refusal rate of elective aortic aneurysm surgery in asymptomatic patients after the presentation of a detailed IC form followed by a meeting where the patient and his or her family could analyze each item;\n\nMethodsData from 49 patients who had aneurysms and were offered surgical treatment were retrospectively collected and analyzed.\n\nResultsAfter reading the IC and the described meeting, among the 49 patients, 13 (26.5%) refused surgery. We observed that patients who refused surgery had statistically smaller aneurysms than patients who accepted surgery (9% versus 26%).\n\nConclusionOne-quarter of patients who were indicated for elective surgical correction of aortic aneurysms rejected surgery after SDM, which consisted of the presentation of an IC form followed by a clarification meeting for the patient and his or her family to analyze each item. The only factor that significantly influenced a rejection of the procedure was the size of the aneurysm, so patients who rejected surgery had smaller aneurysms than those who accepted surgery.","Plaque Contact Surface Area and Flow Lumen Volume Predict Stroke Risk in Extracranial Carotid Artery Stenosis\nThe standard indication for intervention in asymptomatic disease is currently percent stenosis in the internal carotid artery as measured by the NASCET method, which remains limited in discriminating power. CT angiography (CTA) is widely used to calculate NASCET stenosis but also offers the opportunity to analyze carotid artery plaques from a morphological perspective that has not been widely utilized. We aim to improve stroke risk stratification of patients with carotid artery stenosis using plaque 3D modeling and image analysis. Patients with CTAs appropriate for 3D reconstruction were identified from an NIH designated stroke center database, and carotid arteries were segmented and analyzed using software algorithms to calculate contact surface area between the plaque and blood flow (CSA), and volume of the flow lumen within the region of the plaque (FLV). These novel parameters factor in the 3D morphometry inherent to each carotid plaque. A total of 134 carotid arteries were analyzed, 33 of which were associated with an ipsilateral stroke. Plaques associated with stroke demonstrated statistically significant increases in average CSA and FLV when compared to those not associated with stroke. When compared to NASCET percent stenosis, CSA and FLV both demonstrated a larger area under the receiver operating characteristics curve (AUC) in predicting stroke risk in patients with carotid stenosis. The data presented here demonstrate morphological features of carotid plaques that are independent of NASCET criteria stratification and may present an improved method in assessing stroke risk in patients with carotid artery stenosis.","Hemodynamics After Fontan Procedure are Determined by Patient Characteristics and Anastomosis Placement Not Graft Selection: a Patient-Specific Multiscale Computational Study\nObjectivesPatient-specific multiscale modeling simulates virtual surgeries of the Fontan procedure using three different graft options. Predictive modeling details post-operative outcomes that can help inform clinical decision support.\n\nMethodsSix patients underwent preoperative cardiac magnetic resonance imaging and catheterization. Virtual surgery is carried out for each patient to test the resulting hemodynamics of three Fontan graft options: ECC, 9mm Y-graft, and 12mm Y-graft.\n\nResults1) one-way ANOVA p>0.998 in all systemic pressures and flows between graft options, 2) p=0.706 for hepatic flow distribution between graft options, 3) local power loss differences do not affect the systemic circulation, 4) anastomosis positioning modification of the same Y-graft in the same patient changed left PA hepatic distribution from 0.66 to 0.49\n\nConclusionsSystemic pressures and blood flow after the Fontan procedure are not affected by graft selection but are well influenced by patient pulmonary vascular impedance. The hepatic distribution can be affected by anastomosis placement.\n\nUltra-mini abstractWe present the first case series of patient-specific multiscale modeling of the Fontan procedure. Despite noticeable local power loss differences, graft selection does not affect systemic pressure and flow rates or other clinically relevant quantities. Anastomosis placement can affect hepatic distribution.","Current surgical practice for children born with a cleft lip and/or palate in the United Kingdom\nBackgroundThis study describes primary surgical reconstructions performed for children born with a cleft lip and/or palate in the United Kingdom.\n\nMethodsData were obtained from the Cleft Collective, a national longitudinal cohort study. Data forms completed at the time of surgery included details on timing, technique and adjuncts used during the operative period. Demographic data on participants were validated via parental questionnaires.\n\nResultsBetween 2015 and 2021, 1782 Cleft Collective surgical forms were included, relating to the primary reconstructions of 1514 individual children. The median age at primary cheiloplasty was 4.3 months. Unilateral cleft lips were reconstructed with an anatomical subunit approximation technique in 53%, whereas bilateral cleft lips were reconstructed with a broader range of eponymous techniques. Clefts of the soft palate were reconstructed at a median age of 10.3 months with an intravelar veloplasty in 94% cases. Clefts of the hard palate were reconstructed with a vomer flap in 84% cases in a bi-modal age distribution, relating to reconstruction carried out simultaneously with either lip or soft palate reconstruction. Antibiotics were used in 96% of cases, with an at-induction-only regimen used more commonly for cheiloplasties (p<0.001) and a 5-7day post-operative regime used more commonly for soft palatoplasties (p<0.001). Peri-operative steroids were used more commonly in palatoplasties than cheiloplasties (p<0.001) but tranexamic acid use was equivalent (p=0.73).\n\nConclusionThis study contributes to our understanding of current cleft surgical pathways in the United Kingdom and will provide a baseline for analysis of the effectiveness of utilised protocols.","The preoperative abundance of Prevotella associates with anastomotic healing after colorectal surgery.\nAnastomotic leakage (AL) is a frequent and potentially life-threatening postoperative complication in patients undergoing colorectal surgery with a multifactorial yet unknown pathophysiology. In the present study, we aimed to unravel AL etiology and intestinal anastomotic healing (AH) physiology focusing on both host epithelial and gut microbial components. We make use of patients-related samples and two high throughput next generation sequencing analysis approaches, including anastomotic tissue-associated bulk RNA sequencing and preoperative fecal 16S rRNA gene sequencing. We find that in the absence of host epithelial gene expression differences, the preoperative fecal microbiota of patients who undergo colorectal resection with successful AH differs in the group of patients who develop AL in the abundance of Prevotella and suggests a potential beneficial role of Prevotella that may prove useful as predictive biomarker for AH.","Analyzing Surgical Volumes, Rates, and Need in Rural India\nBackgroundGlobally, 5 billion people lack timely access to safe and affordable surgical care, with over a fifth of them living in India. Solving Indias surgical access issues can have high returns on investment. While healthcare access and unaffordability problems are well-known in India particularly among its rural people, research on surgical volumes and need is scant. This study attempts to fill the research gap through high-resolution nationwide estimates that have direct implications for Indias national surgical plan.\n\nMethodsSecondary data analysis with a diverse geospatial and statistical toolbox was used to create the national, state, and district-level estimates for surgical rates and c- section proportions and their corresponding met need w.r.t. to the globally prescribed thresholds - 5000 major surgeries (those requiring anesthesia) per 100,000 (Lancet Commission on Global Surgery) and 10-15% of all institutional deliveries (World Health Organization).\n\nResultsNationally, only 6.81% of need for major surgical operations was met for rural India. 13.6% of the institutional deliveries were c-sections falling within the WHO- prescribed range of 10-15%. There were marked variations at state and district-levels and significant rural-urban differences for surgical rates and c-section proportions. We validate our estimates based on data from Health Management and Information System against existing sources that are commonly used in academic and policy research.\n\nConclusionsOur methodological workflow has high translational value for global surgery research in low-and-middle-income countries. For India, these are the first such nationwide findings that can direct the development of a National Surgical, Obstetric, and Anesthesia Plan (NSOAP).","A cross-sectional study exploring the justification of opportunistic breast cancer screening in Thailand\nObjectiveBreast cancer is currently the most common malignant disease in Thailand. The present study aims to evaluate the most beneficial method of breast cancer screening in different breast densities by analyzing the benefits of screening mammography with additional breast ultrasonography classified by breast density.\n\nMethod49 middle-aged and elderly Bangkokian women who had undergone both mammography and ultrasonography were picked at random for analysis. BI-RADS scores were assigned based on mammography results alone and based on combined mammography and ultrasonography results. Concordance/discordance rates between the 2 radiographic techniques were compared in women stratified based on their breast densities.\n\nResultsAll of our participants were given a score between BIRADS 1 and 3, while over 40% of participants are in the BIRADS 2 category. 60% of subjects with extremely dense breasts benefit from screening mammography with additional breast ultrasonography, while only 50% of samples with heterogeneous density and 34.21% samples with heterogeneous fibroglandular breasts benefit from the extra intervention.\n\nConclusionOur study concludes that women with higher breast density are more likely to benefit from screening using ultrasonography in addition to mammography as opposed to mammography screening alone. We recommend both mammography and ultrasonography for initial breast cancer screening. For follow-up visits, we suggest the screening method in accordance with breast density, using ultrasonography alone for women with high breast densities and mammography for women with heterogeneously dense breasts.","Machine-learning based preoperative analytics for the prediction of anastomotic insufficiency in colorectal surgery: a single-centre pilot study\nBackgroundAnastomotic insufficiency (AI) is a relatively common but grave complication after colorectal surgery. This study aims to determine whether AI can be predicted from simple preoperative data using machine learning (ML) algorithms.\n\nMethodsIn this retrospective analysis, patients undergoing colorectal surgery with creation of a bowel anastomosis from the University Hospital of Basel were included. Data was split into a training set (80%) and a test set (20%). The group of patients with AI was oversampled to a ratio of 50:50 in the training set and missing values were imputed. Known predictors of AI were included as inputs: age, gender, BMI, smoking status, alcohol abuse, prior abdominal surgery, leukocytosis, haemoglobin and albumin levels, steroid use, the Charlson Comorbidity Index, the American Society of Anesthesiologists score, and renal function.\n\nResultsOf the 593 included patients, 88 experienced AI. At internal validation on unseen patients from the test set, area under the curve (AUC) was 0.64 (95% confidence interval [CI]: 0.44-0.82), calibration slope was 0.21 (95% CI: -0.02-0.46) and calibration intercept was 0.06 (95% CI: 0.01-0.1). We observed a specificity of 0.76 (95% CI: 0.68-0.84), sensitivity of 0.36 (95% CI: 0.08-0.7), and accuracy of 0.72 (95% CI: 0.65-0.8).\n\nConclusionBy using 13 patient-related risk factors associated with AI, we demonstrate the feasibility of ML-based prediction of AI after colorectal surgery. Nevertheless, it is crucial to include multicenter data and higher sample sizes to develop a robust and generalisable model, which will subsequently allow for deployment of the algorithm in a web-based application.","Ketamine Sedation Facilitates Asleep DBS: a multicenter retrospective study\nDeep brain stimulation (DBS) is commonly and safely performed for selective Parkinsons disease patients. Many centers perform DBS lead positioning exclusively under local anesthesia, to allow for brain microelectrode recordings (MER) and testing of stimulation-related therapeutic and side effects. These measures enable physiological identification of the DBS targets based on electrophysiological properties like firing rates and patterns, optimization of lead placement accuracy, and intra-operative evaluation of therapeutic window. Nevertheless, due to the challenges of awake surgery, some centers use sedation or general anesthesia, despite the distortion of discharge properties, and potential impact on clinical outcomes. Thus, there is a need for a novel anesthesia regimen that enables sedation without compromising intra-operative monitoring. This study investigates the use of low-dose ketamine for conscious sedation during lead positioning in subthalamic nucleus (STN) DBS for Parkinsons disease patients.\n\nThree anesthetic regimens were retrospectively compared in 38 surgeries across three DBS centers: 1) Interleaved propofol-ketamine (PK), 2) Interleaved propofol-awake (PA), and 3) Fully awake (AA).\n\nAll anesthesia regimens achieved satisfactory MER. Automatic detection of STN borders and subdomains using a Hidden Markov Model was similar between the groups. Patients symptoms and cooperation during stimulation testing in the ketamine group was not altered. No major adverse effects were reported in the different anesthesia protocols.\n\nThese results support the use of low-dose ketamine as a novel alternative for the existing DBS anesthesia regimens, optimizing patients experience while preserving lead placement accuracy. A prospective study should be performed to confirm these findings.","\"It affects every aspect of your life\": A qualitative study of the impact of delaying surgery during COVID-19\nBackgroundThe COVID-19 pandemic has overwhelmed healthcare systems, leading many jurisdictions to reduce surgical services to create capacity (beds and staff) to care for the surge of patients with COVID-19. These decisions were made in haste, and little is known about the impact on patients whose surgery was delayed. This study explores the impact of delaying non-urgent surgeries on patients, from their perspective.\n\nMethodsUsing an interpretative description approach, we conducted interviews with adult patients and their caregivers who had their surgery delayed or cancelled during the COVID-19 pandemic in Alberta, Canada. Trained interviewers conducted semi-structured interviews. Interviews were iteratively analyzed by two independent reviewers using an inductive approach to thematic content analysis to understand key elements of the patient experience.\n\nResultsWe conducted 16 interviews with participants ranging from 27 to 75 years of age with a variety of surgical procedures delayed. We identified four interconnected themes: individual-level impacts (physical health, mental health, family and friends, work, quality of life), system-level factors (healthcare resources, communication, perceived accountability/responsibility), unique issues related to COVID-19, and uncertainty.\n\nInterpretationThe patient-reported impact of having a surgery delayed during the COVID-19 pandemic was diffuse and consequential. While the decision to delay non-urgent surgeries was made to manage the strain on healthcare systems, our study illustrates the consequences of these decisions. We advocate for the development and adoption of strategies to mitigate the burden of distress that waiting for surgery during and after COVID-19 has on patients and their family/caregivers."],"string":"[\n \"Post operative acute kidney injury in abdominal Surgeries. A retrospective analysis of single center in western India.\\nAIMThe aim of our study was to evaluate the incidence and causative factors for acute kidney injury in abdominal surgeries.\\n\\nMaterial and MethodsAll the abdominal surgeries performed between April 2018 to December 2020, in our institution have been analyzed for acute kidney injury. Acute kidney injury defined according to acute kidney injury network classification. Categorical variables were evaluated by chi-square t-test or fishers t-test wherever appropriate and continuous variables by Mann Whitney U test for nonparametric data and student t-test for parametric test after skewness and kurtosis analysis. Statistical analysis was done using SPSS version 23. P< 0.05 was considered statistically significant.\\n\\nResultsWe performed 402 gastrointestinal and hepatobiliary surgery from April 2018 to December 2020. After exclusion 372 patients were included in the study population. 20 patients (5.37%) were defined as having acute kidney injury according to acute kidney injury network classifications. On univariate analysis acute kidney injury was associated with open surgery (p= 0.003), Intraoperative hypotension (p<0.001), Colorectal surgeries (p<0.0001), Emergency surgery (p=0.028), CDC grade of surgery (p<0.001), increased used to blood products (p=0.001), higher ASA grade (p<0.0001), increased operative time(p<0.0001). On multivariate logistic regression analysis higher ASA grade (p<0.0001) and increased operative time (0.049) independently predicted acute kidney injury. Acute kidney injury was also significantly associated with 90 days mortality. (p= <0.0001).\\n\\nConclusionPost-operative acute kidney injury was associated with significant mortality in abdominal surgery. Higher ASA grades and increased operative time predicted acute kidney injury.\",\n \"Impact of gastric resection and enteric anastomotic configuration on delayed gastric emptying after pancreaticoduodenectomy: a network meta-analysis of randomized trials\\nIntroductionDelayed gastric emptying (DGE) is frequent after pancreaticoduodenectomy (PD). Several randomised controlled trials (RCTs) have explored operative strategies to minimise DGE, however, the optimal combination of gastric resection approach, anastomotic route, and configuration, role of Braun enteroenterostomy remains unclear.\\n\\nMethodsMEDLINE, Embase, and CENTRAL databases were systematically searched for RCTs comparing gastric resection (Classic Whipple, pylorus-resecting, and pylorus-preserving), anastomotic route (antecolic vs retrocolic) and configuration (Billroth II vs Roux-en-Y), and enteroenterostomy (Braun vs no Braun). A random-effects, Bayesian network meta-analysis with non-informative priors was conducted to determine the optimal combination of approaches to PD for minimising DGE.\\n\\nResultsTwenty-four RCTs, including 2526 patients and 14 approaches were included. There was some heterogeneity, although inconsistency was low. The overall incidence of DGE was 25.6% (n = 647). Pylorus-resecting, antecolic, Billroth II with Braun enteroenterostomy was associated with the lowest rates of DGE and ranked the best in 35% of comparisons. Classic Whipple, retrocolic, Billroth II with Braun ranked the worst for DGE in 32% of comparisons. Pairwise meta-analysis of retrocolic vs antecolic route of gastro-jejunostomy found increased risk of DGE with the retrocolic route (OR 2.1, 95% CrI; 0.92 - 4.7). Pairwise meta-analysis of Braun enteroenterostomy found a trend towards lower DGE rates with Braun compared to no Braun (OR 1.9, 95% CrI; 0.92 - 3.9). Having a Braun enteroenterostomy ranked the best in 96% of comparisons.\\n\\nConclusionBased on existing RCT evidence, a pylorus-resecting, antecolic, Billroth II with Braun enteroenterostomy may be associated with the lowest rates of DGE.\",\n \"Outcomes following out-of-hours cholecystectomy: A systematic review and meta-analysis\\nBackgroundCholecystectomy is one of the most commonly performed abdominal operations. Demands on acute operating theatre availability have led to out-of-hours (evenings, nights, or weekend) cholecystectomy being performed, although it is not known whether outcomes differ between out-of-hours and in-hours (daytime on weekdays) cholecystectomy.\\n\\nObjectiveThis systematic review and meta-analysis aimed to compare outcomes following out-of-hours versus in-hours urgent cholecystectomy.\\n\\nMethodsMEDLINE, EMBASE and Scopus databases were systematically searched from inception to December 2020 for studies comparing outcomes from out-of-hours and in-hours urgent cholecystectomy in adults. The outcomes of interest were rates of bile leakage, bile duct injury (BDI), overall post-operative complications, conversion to open cholecystectomy, specific intra- and post-operative complications, length of stay (LOS), readmission and mortality. Sensitivity analysis of adjusted multivariate results was also performed.\\n\\nResultsIn total, 194,135 urgent cholecystectomies (30,001 out-of-hours; 164,134 in-hours) from 11 studies were included. Most studies were of high (64%) or medium (18%) quality. There were no differences between out-of-hours and in-hours cholecystectomy for rates of bile leakage, BDI, overall post-operative complications, conversion to open cholecystectomy, operative duration, readmission, mortality, and post-operative LOS. Higher rates of post-operative sepsis (odds ratio (OR) 1.58, 95% CI: 1.04-2.41; p=0.03) and pneumonia (OR 1.55, 95% CI: 1.06-2.26; p=0.02) were observed following out-of-hours cholecystectomy on univariate meta-analysis but not on adjusted multivariate meta-analysis.\\n\\nConclusionsThere was no increased risk or difference in specific complications associated with out-of-hours compared with in-hours urgent cholecystectomy.\",\n \"Tissue Stress from Laparoscopic Grasper Use and Bowel Injury in Humans: Establishing Intraoperative Force Boundaries\\nBackgroundInappropriate force in laparoscopic surgery can lead to inadvertent tissue injury. It is currently unknown however at what magnitude of compressive stress trauma occurs in gastrointestinal tissues.\\n\\nMethodsThis study included 10 small bowel and 10 colon samples. Each was compressed with pressures ranging from 100 kPa to 600 kPa by a novel device to induce compressive \\\"grasps\\\" to simulate those of a laparoscopic grasper. Experimentation was performed ex-vivo, in-vitro. Grasp conditions of 0 to 600 kPa for a duration of 10 seconds were utilized. Two pathologists who were blinded to all study conditions, performed a histological analysis of the tissues. Patients were eligible if their surgery procured healthy tissue margins for experimentation (a convenience sample). 26 patient samples were procured; six samples were unusable. 10 colon and 10 small bowel samples were tested for a total of 120 experimental cases. No patients withdrew their consent. Two metrics of damage were quantified: an intestinal layer thickness calculation where the serosa layer was measured in the area of compression and compared to a local control and a histological scoring scale for tissue trauma.\\n\\nResultsSmall bowel (10), M:F was 7:3, average age was 54.3 years. Colon (10), M:F was 1:1, average age was 65.2 years. All 20 patients experienced a significant difference (p<0.05) in serosal thickness post-compression at both 500 and 600 kPa for both tissue types. A logistic regression analysis with a sensitivity of 100% and a specificity of 84.6% on a test set of data predicts a safety threshold of 329-330 kPa.\\n\\nConclusionA threshold was discovered that corresponded to both significant serosal thickness change and a positive histological trauma score rating. This \\\"force limit\\\" could be used in novel sensorized laparoscopic tools to avoid intraoperative tissue injury.\",\n \"Management Algorithm of External Fixation in Lower Leg Arterial Injury for Limb Salvages\\nPurposeThe purpose of this study was to review the roles of using external fixation to rescue the patients who sustained arterial injuries in the lower legs.\\n\\nMethodsDemographics, surgical treatment and outcomes in 88 patients with lower leg arterial injuries treated by external fixation at two trauma centers from 2009 to 2018 were reviewed. The primary outcome was the rate of successful lower leg salvage, while secondary outcomes were complications and functional recovery.\\n\\nResults80 patients (90 legs) maintained a successful lower leg salvage. The patients were followed up for an average of 15.5{+/-}5.5 months. 6 patients (8 pins) experienced pin-tract infection, pins loosening happened in 2 patients (4 pins), 7 patients (7 legs) developed wound superficial infection, 3 patients (3 legs) with a deep infection developed osteomyelitis, 16 patients (17 legs) suffered the bone nonunion or bone defect. The average healing time of fracture was 5.6{+/-}4.3months. The maintain of external fixation average time was 5.8{+/-}3.6 months.\\n\\nConclusionWith correctly judging the condition of limb ischemia, mastering reasonably the operation indications, and preventing complications, good clinical effects can be achieved when external fixation is used.\\n\\nLevel of evidenceRetrospective cohort, level IV.\",\n \"Impact of the COVID-19 pandemic on surgical procedures in Brazil: a descriptive study\\nBackgroundThe COVID-19 pandemic has deeply affected medical practice, and changes in healthcare activities were needed to minimize the overload and avoid healthcare systems collapse. The aim of this study was to evaluate the impact of the pandemic on surgical procedures in Brazil.\\n\\nMaterials and MethodsWe conducted a descriptive study of the number of hospitalizations for surgical procedures in Brazil from 2016 to 2020. Data were collected from the Brazilian Department of Informatics of the Unified Health System (DATASUS). Analyzes were performed according to the type of procedure, geographical region, subgroups of surgical procedures, and the number of surgeries from 2020 were compared with the average from 2016 to 2019.\\n\\nResultsThere were 4,009,116 hospitalizations for surgical procedures in the Brazilian Public Health System in 2020. When comparing it to the average of hospitalizations from 2016-2019, there was a decrease of 14.88% [95%IC (14.82-14.93)]. Decrease rates were 34.82% [95%IC (34.73-34.90)] for elective procedures and 1.11% [95%IC (1.07-1.13)] for urgent procedures. Decrease rates were similar in all the five regions of the country (average 14.17%). Surgical procedure subgroups with the highest decrease rates were endocrine gland surgery (48.03%), breast surgery (40.68%), oral and maxillofacial surgery (37.03%), surgery of the upper airways, face, head and neck (36.06%), and minor surgeries and surgeries of skin, subcutaneous tissue and mucosa (33.16%). Conclusion: The overload of healthcare facilities has demanded a reduction of non-urgent activities to prevent a collapse of healthcare systems, resulting in a decrease in elective surgeries. Recommendations about the performance of surgical procedures were made, and continuous refinements of these recommendations are encouraged.\",\n \"A comparative analysis of the health, financial, equity, and cost-effectiveness impacts of maxillofacial surgery in Guinea\\nBackgroundNon-governmental organizations (NGOs) play a substantive role in the delivery of surgical services in in low- and middle-income countries (LMICs).\\n\\nAssessment of their outcomes, especially as they relate to outcomes of surgery done in country, remains limited.\\n\\nMethodsA prospective analysis of maxillofacial surgery in Guinea. Outcomes of interest were changes in patient health, subjective well-being, and financial status; hardship financing and catastrophic expenditure; equitable distribution of surgical access; and cost-effectiveness.\\n\\nResultsWe followed 569 patients requiring maxillofacial surgery in Conakry, Guinea, 114 of whom got care at local university hospitals, and 455 of whom got their care with Mercy Ships, a surgical NGO. Patients were followed for between three months (local) and one year (NGO). All patients reported significant improvement in objective and subjective measures of health and in financial status. Approximately half had to borrow and sell to get care, with NGO patients borrowing less, on average. However, NGO patients faced more risk of catastrophic expenditure (41.2% vs. 28.1%, p < 0.001). NGO patients were significantly poorer, whether financial status was measured by asset wealth or monthly income (p < 0.001). Finally, surgical care by the NGO was cost effective.\\n\\nConclusionsIn a prospective analysis of surgical patients in an LMIC, we find that surgery improves health and financial well-being. NGOs may be able to reach patients who would not be able to get care through their local system; however, this comes at a cost of increased initial financial risk. Finally, NGO-based surgical care is cost-effective.\",\n \"Racial and Ethnic Inequities in Mortality During Hospitalization for Traumatic Brain Injury: A Call to Action\\nThe health disparities which drive inequities in health outcomes have long plagued our already worn healthcare system and are often dismissed as being a result of social determinants of health. Herein, we explore the nature of these inequities by comparing outcomes for racial and ethnic minorities patients suffering from traumatic brain injury (TBI). We retrospectively reviewed all patients enrolled in the Trauma One Database at the Oregon Health & Science University Hospital from 2006 to October 2017 with an abbreviated injury scale (AIS) for the head or neck greater than 2. Racial and ethnic minority patients were defined as non-White or Hispanic. A total of 6,352 patients were included in our analysis with 1,504 in the racial and ethnic minority cohort vs. 4,848 in the non-minority cohort. A propensity score (PS) model was generated to account for differences in baseline characteristics between these cohorts to generate 1,500 matched pairs. The adjusted hazard ratio for in-hospital mortality for minority patients was 2.21 (95% Confidence Interval (CI) 1.43-3.41, p<0.001) using injury type, probability of survival, and operative status as covariates. Overall, this study is the first to specifically look at racial and ethnic disparities in the field of neurosurgical trauma. This research has demonstrated significant inequities in the mortality of TBI patients based on race and ethnicity and indicates a substantive need to reshape the current healthcare system and advocate for safer and more supportive pre-hospital social systems to prevent these life-threatening sequelae.\",\n \"Postoperative morbidity after liver resection- A Systemic review, meta-analysis, and metaregression of factors affecting them.\\nAim of the studyThis systemic review and meta-analysis aimed to analyze post-operative morbidity after liver resection, and also study various factors associated with mortality via metaregression analysis.\\n\\nMaterial and MethodsPubMed, Cochrane Library, Embase, google scholar, web of science with keywords like liver resection\\\"; \\\"mortality\\\";\\\" hepatectomy\\\". Weighted percentage post-operative morbidities were analyzed. Meta-analysis and meta-regression were done by the DerSimonian-Liard random effect model. Heterogeneity was assessed using the Higgins I2 test. Publication bias was assessed using a funnel plot. Funnel plot asymmetry was evaluated by Eggers test. Morbidity was defined as any postoperative morbidity mentioned.\\n\\nResultsA total of 46 studies was included in the final analysis. Total 45771 patients underwent liver resections. 16111 patients experienced complications during the postoperative period. Weighted post-operative morbidity was 30.2% (95 % C.I. 24.8-35.7%). Heterogeneity was high with I2 99.46% and p-value <0.01. On univariate analysis, major liver resections were significantly associated with heterogeneity. (p=0.024). However, residual heterogeneity was still high with I2 98.62%, p<0.001. So, multifactor metaregression analysis major hepatectomy (p<0.001), Open hepatectomy (p=0.001), cirrhotic liver (p=0.002), age (p<0.001), blood loss (p<0.001), and colorectal metastasis (p<0.001) independently associated with postoperative morbidity. Residual heterogeneity was moderate I2= 39.9% and nonsignificant p=0.189.\\n\\nConclusionLiver resection is associated with high postoperative morbidity and various factors like major hepatectomy, Open hepatectomy, cirrhotic liver, blood loss, and colorectal metastasis were associated with morbidity and responsible for heterogeneity across the studies.\",\n \"Laser speckle contrast imaging for visualizing blood flow during cerebral aneurysm surgery: A comparison with indocyanine green angiography\\nLaser speckle contrast imaging (LSCI) has emerged as a promising tool for intraoperative cerebral blood flow (CBF) monitoring because it produces real-time full-field blood flow maps non-invasively and label-free. In this study, we compare LSCI with indocyanine green angiography (ICGA) to assess CBF during aneurysm clipping surgery in humans. LSCI hardware was attached to the surgical microscope prior to the start of each surgery and did not interfere with the sterile draping of the microscope or normal operation of the microscope. LSCI and ICGA were performed simultaneously to visualize CBF in n=4 aneurysm clipping cases, and LSCI was performed throughout each surgery when the microscope was positioned over the patient. To more easily visualize CBF in real-time, LSCI images were overlaid on the built-in microscope white light camera images and displayed to the neurosurgeon in real-time. Blood flow changes before, during, and after an aneurysm clipping were visualized with LSCI and later verified with ICGA. LSCI was performed continuously throughout the aneurysm clipping process, providing the surgeon with immediate actionable information on the success of the clipping. The results demonstrate that LSCI and ICGA provide different, yet complementary information about vessel perfusion.\",\n \"Effects of Acute Normovolemic Hemodilution on Post-Cardiopulmonary Bypass Coagulation Tests and Allogeneic Blood Transfusion in Thoracic Aortic Repair Surgery: An Observational Cohort Study\\nBackground and AimPerioperative blood transfusion is associated with increased morbidity and mortality. Acute normovolemic hemodilution (ANH) is a blood conservation strategy associated with variable success, and rarely studied in more complex cardiac procedures. The study aim was to evaluate whether acute ANH improves coagulopathy and reduces blood transfusions in thoracic aortic surgeries.\\n\\nMethodsSingle-center observational cohort study comparing ANH and standard institutional practice in patients who underwent thoracic aortic repair from 2019 to 2021.\\n\\nResults89 patients underwent ANH and 116 standard practice. There were no significant differences between the groups in terms of demographic or major perioperative characteristics. In the ANH group coagulation tests before and after transfusion of autologous blood showed decreased INR and increased platelets, fibrinogen, all with p<0.0005. Coagulation results in the ANH and control groups were not statistically different. The average number of transfused allogeneic products per patient was lower in the ANH vs control group: FFP 1.1 {+/-}1.6 vs 1.9 {+/-}2.3 (p=0.003), platelets 0.6 {+/-}0.8 vs 1.2 {+/-}1.3 (p=0.0008), and cryoprecipitate 0.3 {+/-}0.7 vs 0.7 {+/-}1.1 (p=0.008). Reduction in RBC transfusion was not statistically significant. The percentage of patients who received any transfusion was 53.9% in ANH and 59.5% in the control group (p=0.42). There was no significant difference in major adverse outcomes.\\n\\nConclusionsANH is a safe blood conservation strategy for surgical repairs of the thoracic aorta. Laboratory data suggests that ANH can improve coagulopathy after separation from CPB, and significantly reduce the number of transfused FFP, platelets and cryoprecipitate.\",\n \"REPAIR OF ABDOMINAL WALL DEFECTS WITH ACELLULAR BOVINE PERICARDIUM MATRIX - A MULTICENTER PROSPECTIVE STUDY\\nBackgroundThe association of prosthetic meshes in the abdominal wall repair, reducing the recurrence rates in an impactful way, has become an almost mandatory routine for the success of these surgeries. After decades using non-biological synthetic implants, from the 90s onwards biological membranes of animal or human origin were introduced - the so called acellular biological matrices - beginning a new era in abdominal wall defects correction.\\n\\nMethodsThirty patients underwent repair for different abdominal wall deformities, with acellular matrices of bovine pericardium, in a total of 40 anatomically individualized implants. The median follow-up was 22 months, with patients evaluated clinically and radiologically. In three cases, biopsies of the implanted areas were performed, allowing histological analysis of the material.\\n\\nResultsThere was no recurrence of hernias in any of the cases, both clinically and radiologically. There was also no record of hematomas, infections or any phenomenon of a local or systemic reaction nature. Radiologically, it was not possible to visualize the matrices at the implantation site in any of the analysed postoperative periods. Biopsies showed important tissue neoformation replacing the implanted membranes, with important deposition of collagen, normal-looking cellularized tissue, and absence of foreign body reactions.\\n\\nConclusionsThe analysed matrices showed similarity to other biological membranes described in the international literature. Representing an important update and conceptual evolution, biological matrices must be incorporated into the therapeutic arsenal in abdominal wall repairs.\",\n \"Soft robotic steerable micro-catheter for the endovascular treatment of cerebral disorders\\nCatheters used for endovascular navigation in interventional procedures lack dexterity at the distal tip. Neurointerventionists, in particular, encounter challenges in up to 25% of aneurysm cases largely due to the inability to steer and navigate the tip of the micro-catheters through tortuous vasculature to access aneurysms. We overcome this problem with sub-millimeter diameter, hydraulically-actuated hyperelastic polymer devices at the distal tip of micro- catheters to enable active steerability. Controlled by hand, the devices offer complete 3D orientation of the tip. Using pressures up to 400 kPa (4 atm) we demonstrate guidewire-free navigation, access, and coil deployment in vivo, offering safety, ease of use, and design flexibility absent in other approaches to endovascular intervention. We demonstrate the ability of our device to navigate through vessels and to deliver embolization coils to the cerebral vessels in a live porcine model. This indicates the potential for microhydraulic soft robotics to solve difficult access and treatment problems in endovascular intervention.\",\n \"Use of autologous platelet derivatives for secondary alveoloplasty in patients with cleft lip and palate: a protocol for a systematic review and meta-analysis\\nObjectiveTo assess the effectiveness and safety of autologous platelet derivatives, specifically platelet-rich plasma (PRP) or platelet-rich fibrin (PRF), for secondary alveoloplasty in patients with cleft lip and palate.\\n\\nEligibility criteriaWe will include randomized trials evaluating the effect of autologous platelet derivatives on newly bone formed after secondary alveoloplasty in cleft lip and palate patients. Two reviewers will independently screen each study for eligibility, data extraction, and bias assessment using the Cochrane \\\"risk of bias \\\"tool. We will pool the results using meta-analysis and apply the GRADE system to assess the certainty of the evidence for each outcome.\\n\\nData sourcesA comprehensive search will include all relevant randomized controlled trials (RCTs), the ongoing investigation reported in specialty congresses and trials regardless of language or publication status (published, unpublished, in press, and progress). We will conduct searches in the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), PUBMED, Embase, and LILACS. We will screen trial registries and other sources in order to identify articles that might have been missed in the electronic searches.\\n\\nEthics and disseminationAs researchers will not access information that could identify an individual participant, obtaining ethical approval was waived.\",\n \"The retrospective observational study of clinical outcomes of single dose infusion of warm blood cardioplegia in patients undergoing cardiac surgery\\nObjectiveThe aim of the study was to assess the safety and efficacy of a normothermic cardioplegia solution N use and obtain additional information about dosing regimens during normothermic or mild hypothermic cardiac surgery.\\n\\nMethodsA retrospective observational study included 150 cardio surgery patients. The primary endpoint was the intraoperative acute heart failure development. The secondary endpoints were the postoperative Troponin T concentrations, the need for catecholamine support, and the repeated infusion of a cardioplegia solution.\\n\\nResultsThe duration of aortic cross-clamping varied from 17 to 154 minutes, median 59 [interquartile range, 46 - 73] minutes. Spontaneous sinus rhythm recovery was observed in 136 (90.7%) patients. Intraoperative acute heart failure was observed in 1 case. The Troponin T concentrations were 0.331{+/-}0.143 ng/mL after surgery. Mortality was 2% (3 patients). Eight patients received an additional volume of N solution to maintain asystole. Among 16 patients with a cross-clamp duration greater than 90 minutes epinephrine was used in 3 (18.8%) patients in dose of more than 0.05 mcg/kg/min. Among 134 patients cross-clamp duration less than 90 minutes the catecholamine support was used in 4 (3%) patients, p=0.027.\\n\\nConclusionsA primary single-dose infusion of cardioplegia solution N provides myocardial protection for 59 [interquartile range, 46 - 73] minutes and up to 154 minutes. The catecholamine support in the group of aortic cross-clamp duration less than 90 minutes was used lesser than in the group of aortic cross-clamp duration greater than 90 minutes (3% and 18.8%, respectively). The cardioprotection during cardiopulmonary bypass surgery especially in elderly patients with concomitant disease needs to be confirmed in a future investigations.\",\n \"Hemodilution in High Risk Cardiac Surgery: Laboratory Values, Physiological Parameters and Outcomes\\nBackgroundAcute normovolemic hemodilution (ANH) is a blood conservation strategy in cardiac surgery, predominantly used in coronary artery bypass graft (CABG) and/or valve procedures. Although higher complexity cardiac procedures may benefit from ANH, concerns for hemodynamic instability and organ injury during hemodilution hinder its wider acceptance. Laboratory and physiological parameters during hemodilution in complex cardiac surgeries have not been described.\\n\\nStudy Design and MethodsThis observational cohort (2019-2021) study included 169 patients who underwent thoracic aortic repair, multiple valve procedure, concomitant CABG with the aforementioned procedure, and/or redo sternotomies. Patients who received allogeneic blood were excluded. Statistical comparisons were performed between ANH (N=66) and non ANH controls (N=103). ANH consisted of removal of blood at the beginning of surgery and its return after cardiopulmonary bypass (CPB).\\n\\nResultsIntraoperatively, the ANH group received more albumin (p=0.04) and vasopressor medications (p=0.01); while urine output was no different between ANH and controls. Bilateral cerebral oximetry (rSO2) values were similar before and after hemodilution. During bypass rSO2 were discretely lower in the ANH vs. control group (right rSO2 p=0.03, left rSO2 (p=0.05). No differences in lactic acid values were detected across the procedural continuum. Postoperatively, no differences in extubation times, ICU length of stay, kidney injury, stroke or infection were demonstrated.\\n\\nDiscussionThis study suggests hemodilution to be a safe and comparable blood conservation technique, even without accounting for potential benefits of reduced allogenic blood administration. The study may contribute to better understanding and wider acceptance of ANH protocols in high risk cardiac surgeries.\",\n \"Premature Atrial Stimulation Accentuates Conduction Abnormalities in Cardiac Surgery Patients that Develop Postoperative Atrial Fibrillation\\nBACKGROUNDpostoperative atrial fibrillation (POAF) is a common cardiac surgery complication that is associated with increased complications and negative outcomes, but the association between presurgical atrial conduction abnormalities and POAF has not been investigated clinically during premature atrial S1S2 stimulation. This clinical study sought to examine whether intraoperative premature atrial stimulation reveals increased areas of slowed and/or blocked conduction in patients that develop POAF.\\n\\nMETHODSHigh-density intraoperative epicardial left atrial mapping was conducted in 20 cardiac surgery patients with no prior history of atrial fibrillation (AF). In 20 patients, 6 (30%) developed POAF. A flexible-array of 240-electrodes was placed on the posterior left atrial wall in between the pulmonary veins. Activation maps were generated for sinus and premature atrial S1S2 stimulated beats. The area of conduction block (CB), conduction delay (CD) and the combination of both (CDCB) for conduction velocity <0.1, 0.1[≤]x<0.2 and <0.2 m/s, respectively were quantified.\\n\\nRESULTSFor a premature atrial S2 beat with shortest cycle length captured, conduction velocity maps revealed a significantly higher area for CD (13.19{+/-}6.59 versus 6.06{+/-}4.22 mm2, p=0.028) and CDCB (17.36{+/-}8.75 versus 7.41{+/-}6.39 mm2, p=0.034), and a trend toward a larger area for CB (4.17{+/-}3.66 versus 1.34{+/-}2.86 mm2, p=0.063) in patients who developed POAF in comparison to those that remained in the sinus. Sinus and S1 paced beats did not show substantial differences in abnormal conduction areas between patients with and without POAF.\\n\\nCONCLUSIONIn comparison to sinus and S1 beats, premature atrial S2 beats accentuate conduction abnormalities in cardiac surgery patients that developed POAF.\",\n \"Acute kidney injury after liver resection: A systematic review, meta-analysis, and metaregression of factors affecting it.\\nAimThis systematic review and meta-analysis aimed to study the incidence of acute kidney injury after liver resection and to analyze various factors affecting it by metaregression analysis.\\n\\nMethodsThe study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (2020) and MOOSE guidelines. The meta-analysis was done using Review Manager 5.4 and the JASP Team (2020). JASP (Version 0.14.1)(University of Amsterdam). Weighted percentage incidence with 95% confidence intervals were used. Univariate metaregression was done by DerSimonian-Laird methods. Factors with a p-value less than 0.05 in the univariate metaregression model were entered in the multivariate metaregression model. Heterogeneity was assessed using the Higgins I2 test. The random-effects model was used in meta-analysis.\\n\\nResultsTotal 14 studies including 15510 patients were included in the final analysis. 1247 patients developed Acute Kidney Injury. Weighted Acute kidney injury percentage after liver resection was 15% with a 95% confidence interval of 11%-19%. On univariate metaregression analysis major hepatectomy (p=0.001), Underlying cirrhosis of liver (p=0.031), AKIN definition used (0.017), male sex (p<0.001), open surgery (p=0.032), underlying diabetes (0.026). On multivariate metaregression analysis major hepatectomy (p=0.003), underlying cirrhosis (p<0.001), male sex (p<0.001), AKIN classification used for defining acute kidney injury (p < 0.001, independently predicted heterogeneity and hence acute kidney injury.\\n\\nConclusionLiver resection is associated with a high incidence of acute kidney injury. Major hepatectomy, male sex, underlying cirrhosis were independently predicting acute kidney injury.\",\n \"Wound Complications Following Surgery to the Lymph Nodes: A protocol for a systematic review and meta-analysis\\nBackgroundMalignancies that spread to the lymph nodes may be identified through surgical biopsy, and treatment of metastatic disease may be through lymph node dissection. These surgeries, however, may be associated with significant adverse outcomes, particularly wound complications, the true incidence of which remains unknown. Multiple studies have reported their individual rates of complications in isolation. The aim of this study will be to systematically evaluate data that presents the incidence of wound complications in patients undergoing these surgeries.\\n\\nMethodsWe have designed and registered a protocol for a systematic review and meta-analysis of studies presenting incidence data. We will search MEDLINE, EMBASE and CENTRAL for relevant articles published before March 30th, 2021. Meta-analysis will be undertaken to synthesise an overall incidence of surgical site infection, wound dehiscence, haematoma and seroma. Subgroup analyses will investigate the effects of anatomical location, primary malignancy and study design on pooled incidence. Risk of bias will be evaluated for each included study using bespoke tools matched to the study design.\\n\\nDiscussionThe results of this study will provide the incidence of wound complications and secondary complications following lymph node surgery. This will directly impact upon the consent process, and may influence the nature of future research studies aimed at reducing post-operative complications.\",\n \"Population-based Cross-sectional Analysis of the Epidemiology of the Surgical Correction of Hyperhidrosis in 1216 Patients over 11 years.\\nAO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSEndoscopic thoracic sympathectomy is the definitive surgical treatment for hyperhidrosis, and a nationwide study suggested that it has been performed in a higher rate than which could have been expected due to climate characteristics, comparing to the national statistics.\\n\\nObjectivesTo study the epidemiology of sympathectomy to treat hyperhidrosis in Sao Paulo, the largest city in the Southeast.\\n\\nDesign and settingpopulation-based cross-sectional study.\\n\\nMethodsdata on sympathectomies to treat hyperhidrosis between 2008 and 2018 were assessed from the database of the Municipal Health Secretary of Sao Paulo, Brazil.\\n\\nResults65.29% of the patients were female, 66.2% aged between 20 and 39 years and 37.59% had addresses registered outside Sao Paulo. 1216 procedures were performed in the city of Sao Paulo from 2008 to 2018, 78.45% of which in only two public hospitals. The number of procedures significantly declined over the years (p = 0.001). 71.63% of the procedures were associated with 2 to 3 days of hospital stay, only 78 intensive care unit days were billed and we did not observe any intra-hospital death.\\n\\nConclusionssympathectomies for the treatment of HH were widely performed in the city of Sao Paulo (1216 procedures), mainly in young (20 -39 years) and female patients, with more than one third of the patients having addresses registered outside the city. This is a very safe surgery, with low need for intensive care units and no mortality in our series. There was a decreasing trend in the number of surgeries over the years.\",\n \"PERIPHERAL ARTERIOVENOUS MALFORMATIONS AND THEIR RESPONSE TO TREATMENT MODALITIES: A SINGLE SURGEON'S EXPERIENCE AT TERTIARY CARE HOSPITALS\\nBackgroundPeripheral arteriovenous malformations (AVMs) are congenital defects resulting in abnormal connections between veins and arteries. We investigated a group of patients with peripheral AVMs to determine whether there were any gender differences in disease presentation and the response of AVMs to various modalities of treatment.\\n\\nMethodologyThe patients in this cross-sectional study were divided into two groups based on gender and their demographic data, clinical presentation at the time of diagnosis and response to treatment was assessed. Both surgical and nonsurgical treatment options were used. Nonsurgical options employed in the study included immunotherapy, embolotherapy and ultrasound-guided foam sclerotherapy (UGFS)\\n\\nResultsOut of 43 patients, 74.4% were females with a male to female ratio of 1:3. The mean age at presentation in males was 27 years and 17 years in females. 60% of the male patients presented with high-flow AVMs while 81% of the female patients presented with low-flow lesions instead. Half of the AVMs in males were on the trunk whereas, in females, 93.9% were on the extremities. UGFS alone was used in 95.3% of patients while 32.5% of patients underwent UGFS followed by surgical excision. One patient was treated with sirolimus. In 4.6% of cases, embolization followed by surgical excision was performed. Recurrence was recorded in 20.9% of cases.\\n\\nConclusionsThe clinical presentation of AVMs is notably different among the two genders. Sclerotherapy and embolotherapy proved to be effective treatment options. Larger studies, however, are needed to substantiate these claims.\",\n \"Shared decision making and specific informed consent in patients with aortic aneurysms\\nIntroductionStudies show that vascular surgery patients have the desire to participate more actively in their treatment, but that they find it difficult to express themselves. Patients prefer to know all the therapeutic options available, not just those that the surgeon considers appropriate. With this knowledge, patients can begin to choose the most appropriate therapeutic modality for themselves, also becoming responsible for the therapeutic decision. Therefore, the objective of this paper was to analyze the refusal rate of elective aortic aneurysm surgery in asymptomatic patients after the presentation of a detailed IC form followed by a meeting where the patient and his or her family could analyze each item;\\n\\nMethodsData from 49 patients who had aneurysms and were offered surgical treatment were retrospectively collected and analyzed.\\n\\nResultsAfter reading the IC and the described meeting, among the 49 patients, 13 (26.5%) refused surgery. We observed that patients who refused surgery had statistically smaller aneurysms than patients who accepted surgery (9% versus 26%).\\n\\nConclusionOne-quarter of patients who were indicated for elective surgical correction of aortic aneurysms rejected surgery after SDM, which consisted of the presentation of an IC form followed by a clarification meeting for the patient and his or her family to analyze each item. The only factor that significantly influenced a rejection of the procedure was the size of the aneurysm, so patients who rejected surgery had smaller aneurysms than those who accepted surgery.\",\n \"Plaque Contact Surface Area and Flow Lumen Volume Predict Stroke Risk in Extracranial Carotid Artery Stenosis\\nThe standard indication for intervention in asymptomatic disease is currently percent stenosis in the internal carotid artery as measured by the NASCET method, which remains limited in discriminating power. CT angiography (CTA) is widely used to calculate NASCET stenosis but also offers the opportunity to analyze carotid artery plaques from a morphological perspective that has not been widely utilized. We aim to improve stroke risk stratification of patients with carotid artery stenosis using plaque 3D modeling and image analysis. Patients with CTAs appropriate for 3D reconstruction were identified from an NIH designated stroke center database, and carotid arteries were segmented and analyzed using software algorithms to calculate contact surface area between the plaque and blood flow (CSA), and volume of the flow lumen within the region of the plaque (FLV). These novel parameters factor in the 3D morphometry inherent to each carotid plaque. A total of 134 carotid arteries were analyzed, 33 of which were associated with an ipsilateral stroke. Plaques associated with stroke demonstrated statistically significant increases in average CSA and FLV when compared to those not associated with stroke. When compared to NASCET percent stenosis, CSA and FLV both demonstrated a larger area under the receiver operating characteristics curve (AUC) in predicting stroke risk in patients with carotid stenosis. The data presented here demonstrate morphological features of carotid plaques that are independent of NASCET criteria stratification and may present an improved method in assessing stroke risk in patients with carotid artery stenosis.\",\n \"Hemodynamics After Fontan Procedure are Determined by Patient Characteristics and Anastomosis Placement Not Graft Selection: a Patient-Specific Multiscale Computational Study\\nObjectivesPatient-specific multiscale modeling simulates virtual surgeries of the Fontan procedure using three different graft options. Predictive modeling details post-operative outcomes that can help inform clinical decision support.\\n\\nMethodsSix patients underwent preoperative cardiac magnetic resonance imaging and catheterization. Virtual surgery is carried out for each patient to test the resulting hemodynamics of three Fontan graft options: ECC, 9mm Y-graft, and 12mm Y-graft.\\n\\nResults1) one-way ANOVA p>0.998 in all systemic pressures and flows between graft options, 2) p=0.706 for hepatic flow distribution between graft options, 3) local power loss differences do not affect the systemic circulation, 4) anastomosis positioning modification of the same Y-graft in the same patient changed left PA hepatic distribution from 0.66 to 0.49\\n\\nConclusionsSystemic pressures and blood flow after the Fontan procedure are not affected by graft selection but are well influenced by patient pulmonary vascular impedance. The hepatic distribution can be affected by anastomosis placement.\\n\\nUltra-mini abstractWe present the first case series of patient-specific multiscale modeling of the Fontan procedure. Despite noticeable local power loss differences, graft selection does not affect systemic pressure and flow rates or other clinically relevant quantities. Anastomosis placement can affect hepatic distribution.\",\n \"Current surgical practice for children born with a cleft lip and/or palate in the United Kingdom\\nBackgroundThis study describes primary surgical reconstructions performed for children born with a cleft lip and/or palate in the United Kingdom.\\n\\nMethodsData were obtained from the Cleft Collective, a national longitudinal cohort study. Data forms completed at the time of surgery included details on timing, technique and adjuncts used during the operative period. Demographic data on participants were validated via parental questionnaires.\\n\\nResultsBetween 2015 and 2021, 1782 Cleft Collective surgical forms were included, relating to the primary reconstructions of 1514 individual children. The median age at primary cheiloplasty was 4.3 months. Unilateral cleft lips were reconstructed with an anatomical subunit approximation technique in 53%, whereas bilateral cleft lips were reconstructed with a broader range of eponymous techniques. Clefts of the soft palate were reconstructed at a median age of 10.3 months with an intravelar veloplasty in 94% cases. Clefts of the hard palate were reconstructed with a vomer flap in 84% cases in a bi-modal age distribution, relating to reconstruction carried out simultaneously with either lip or soft palate reconstruction. Antibiotics were used in 96% of cases, with an at-induction-only regimen used more commonly for cheiloplasties (p<0.001) and a 5-7day post-operative regime used more commonly for soft palatoplasties (p<0.001). Peri-operative steroids were used more commonly in palatoplasties than cheiloplasties (p<0.001) but tranexamic acid use was equivalent (p=0.73).\\n\\nConclusionThis study contributes to our understanding of current cleft surgical pathways in the United Kingdom and will provide a baseline for analysis of the effectiveness of utilised protocols.\",\n \"The preoperative abundance of Prevotella associates with anastomotic healing after colorectal surgery.\\nAnastomotic leakage (AL) is a frequent and potentially life-threatening postoperative complication in patients undergoing colorectal surgery with a multifactorial yet unknown pathophysiology. In the present study, we aimed to unravel AL etiology and intestinal anastomotic healing (AH) physiology focusing on both host epithelial and gut microbial components. We make use of patients-related samples and two high throughput next generation sequencing analysis approaches, including anastomotic tissue-associated bulk RNA sequencing and preoperative fecal 16S rRNA gene sequencing. We find that in the absence of host epithelial gene expression differences, the preoperative fecal microbiota of patients who undergo colorectal resection with successful AH differs in the group of patients who develop AL in the abundance of Prevotella and suggests a potential beneficial role of Prevotella that may prove useful as predictive biomarker for AH.\",\n \"Analyzing Surgical Volumes, Rates, and Need in Rural India\\nBackgroundGlobally, 5 billion people lack timely access to safe and affordable surgical care, with over a fifth of them living in India. Solving Indias surgical access issues can have high returns on investment. While healthcare access and unaffordability problems are well-known in India particularly among its rural people, research on surgical volumes and need is scant. This study attempts to fill the research gap through high-resolution nationwide estimates that have direct implications for Indias national surgical plan.\\n\\nMethodsSecondary data analysis with a diverse geospatial and statistical toolbox was used to create the national, state, and district-level estimates for surgical rates and c- section proportions and their corresponding met need w.r.t. to the globally prescribed thresholds - 5000 major surgeries (those requiring anesthesia) per 100,000 (Lancet Commission on Global Surgery) and 10-15% of all institutional deliveries (World Health Organization).\\n\\nResultsNationally, only 6.81% of need for major surgical operations was met for rural India. 13.6% of the institutional deliveries were c-sections falling within the WHO- prescribed range of 10-15%. There were marked variations at state and district-levels and significant rural-urban differences for surgical rates and c-section proportions. We validate our estimates based on data from Health Management and Information System against existing sources that are commonly used in academic and policy research.\\n\\nConclusionsOur methodological workflow has high translational value for global surgery research in low-and-middle-income countries. For India, these are the first such nationwide findings that can direct the development of a National Surgical, Obstetric, and Anesthesia Plan (NSOAP).\",\n \"A cross-sectional study exploring the justification of opportunistic breast cancer screening in Thailand\\nObjectiveBreast cancer is currently the most common malignant disease in Thailand. The present study aims to evaluate the most beneficial method of breast cancer screening in different breast densities by analyzing the benefits of screening mammography with additional breast ultrasonography classified by breast density.\\n\\nMethod49 middle-aged and elderly Bangkokian women who had undergone both mammography and ultrasonography were picked at random for analysis. BI-RADS scores were assigned based on mammography results alone and based on combined mammography and ultrasonography results. Concordance/discordance rates between the 2 radiographic techniques were compared in women stratified based on their breast densities.\\n\\nResultsAll of our participants were given a score between BIRADS 1 and 3, while over 40% of participants are in the BIRADS 2 category. 60% of subjects with extremely dense breasts benefit from screening mammography with additional breast ultrasonography, while only 50% of samples with heterogeneous density and 34.21% samples with heterogeneous fibroglandular breasts benefit from the extra intervention.\\n\\nConclusionOur study concludes that women with higher breast density are more likely to benefit from screening using ultrasonography in addition to mammography as opposed to mammography screening alone. We recommend both mammography and ultrasonography for initial breast cancer screening. For follow-up visits, we suggest the screening method in accordance with breast density, using ultrasonography alone for women with high breast densities and mammography for women with heterogeneously dense breasts.\",\n \"Machine-learning based preoperative analytics for the prediction of anastomotic insufficiency in colorectal surgery: a single-centre pilot study\\nBackgroundAnastomotic insufficiency (AI) is a relatively common but grave complication after colorectal surgery. This study aims to determine whether AI can be predicted from simple preoperative data using machine learning (ML) algorithms.\\n\\nMethodsIn this retrospective analysis, patients undergoing colorectal surgery with creation of a bowel anastomosis from the University Hospital of Basel were included. Data was split into a training set (80%) and a test set (20%). The group of patients with AI was oversampled to a ratio of 50:50 in the training set and missing values were imputed. Known predictors of AI were included as inputs: age, gender, BMI, smoking status, alcohol abuse, prior abdominal surgery, leukocytosis, haemoglobin and albumin levels, steroid use, the Charlson Comorbidity Index, the American Society of Anesthesiologists score, and renal function.\\n\\nResultsOf the 593 included patients, 88 experienced AI. At internal validation on unseen patients from the test set, area under the curve (AUC) was 0.64 (95% confidence interval [CI]: 0.44-0.82), calibration slope was 0.21 (95% CI: -0.02-0.46) and calibration intercept was 0.06 (95% CI: 0.01-0.1). We observed a specificity of 0.76 (95% CI: 0.68-0.84), sensitivity of 0.36 (95% CI: 0.08-0.7), and accuracy of 0.72 (95% CI: 0.65-0.8).\\n\\nConclusionBy using 13 patient-related risk factors associated with AI, we demonstrate the feasibility of ML-based prediction of AI after colorectal surgery. Nevertheless, it is crucial to include multicenter data and higher sample sizes to develop a robust and generalisable model, which will subsequently allow for deployment of the algorithm in a web-based application.\",\n \"Ketamine Sedation Facilitates Asleep DBS: a multicenter retrospective study\\nDeep brain stimulation (DBS) is commonly and safely performed for selective Parkinsons disease patients. Many centers perform DBS lead positioning exclusively under local anesthesia, to allow for brain microelectrode recordings (MER) and testing of stimulation-related therapeutic and side effects. These measures enable physiological identification of the DBS targets based on electrophysiological properties like firing rates and patterns, optimization of lead placement accuracy, and intra-operative evaluation of therapeutic window. Nevertheless, due to the challenges of awake surgery, some centers use sedation or general anesthesia, despite the distortion of discharge properties, and potential impact on clinical outcomes. Thus, there is a need for a novel anesthesia regimen that enables sedation without compromising intra-operative monitoring. This study investigates the use of low-dose ketamine for conscious sedation during lead positioning in subthalamic nucleus (STN) DBS for Parkinsons disease patients.\\n\\nThree anesthetic regimens were retrospectively compared in 38 surgeries across three DBS centers: 1) Interleaved propofol-ketamine (PK), 2) Interleaved propofol-awake (PA), and 3) Fully awake (AA).\\n\\nAll anesthesia regimens achieved satisfactory MER. Automatic detection of STN borders and subdomains using a Hidden Markov Model was similar between the groups. Patients symptoms and cooperation during stimulation testing in the ketamine group was not altered. No major adverse effects were reported in the different anesthesia protocols.\\n\\nThese results support the use of low-dose ketamine as a novel alternative for the existing DBS anesthesia regimens, optimizing patients experience while preserving lead placement accuracy. A prospective study should be performed to confirm these findings.\",\n \"\\\"It affects every aspect of your life\\\": A qualitative study of the impact of delaying surgery during COVID-19\\nBackgroundThe COVID-19 pandemic has overwhelmed healthcare systems, leading many jurisdictions to reduce surgical services to create capacity (beds and staff) to care for the surge of patients with COVID-19. These decisions were made in haste, and little is known about the impact on patients whose surgery was delayed. This study explores the impact of delaying non-urgent surgeries on patients, from their perspective.\\n\\nMethodsUsing an interpretative description approach, we conducted interviews with adult patients and their caregivers who had their surgery delayed or cancelled during the COVID-19 pandemic in Alberta, Canada. Trained interviewers conducted semi-structured interviews. Interviews were iteratively analyzed by two independent reviewers using an inductive approach to thematic content analysis to understand key elements of the patient experience.\\n\\nResultsWe conducted 16 interviews with participants ranging from 27 to 75 years of age with a variety of surgical procedures delayed. We identified four interconnected themes: individual-level impacts (physical health, mental health, family and friends, work, quality of life), system-level factors (healthcare resources, communication, perceived accountability/responsibility), unique issues related to COVID-19, and uncertainty.\\n\\nInterpretationThe patient-reported impact of having a surgery delayed during the COVID-19 pandemic was diffuse and consequential. While the decision to delay non-urgent surgeries was made to manage the strain on healthcare systems, our study illustrates the consequences of these decisions. We advocate for the development and adoption of strategies to mitigate the burden of distress that waiting for surgery during and after COVID-19 has on patients and their family/caregivers.\"\n]","isConversational":false},"negative":{"kind":"list like","value":["Reliability and validity of the Japanese version of the Mental Health Literacy Scale (MHLS) among undergraduate and graduate students in the medical field\nObjectiveMental health literacy (MHL) is a fundamental basis of reducing stigma towards mental disorders and promoting early help-seeking. However, there is no internationally standardized scale covering all the attributes of MHL available in Japan. This study aimed to examine the reliability and validity of the Japanese version of the Mental Health Literacy Scale (MHLS) developed by OConnor et al. (2015).\n\nMethodsThe MHLS was translated in accordance with international guidelines. Japanese students in the medical field were invited to complete an online questionnaire twice at baseline and two-week follow-up. Using the data, Cronbachs alphas, intra-class correlation coefficient (ICC), and measurement errors were calculated for internal consistency and test-retest reliability. Correlations with mental health-related behavior (RIBS), accurate knowledge about mental disorders (MIDUS), intentions to seek help (GHSQ), and psychological distress (K6) were used to examine the convergent validity. Confirmatory factor analysis (CFA) and exploratory factor analysis (EFA) were performed to test structural validity.\n\nResultsA total of 183 and 150 students responded at baseline and follow-up. Cronbachs alpha coefficient was 0.76 and the ICC was 0.77 for the total score. The MHLS had a strong positive correlation with RIBS and moderate positive correlations with MIDUS and GHSQ. The CFA did not show a good fit either for one-or six-factor models, and the EFA yielded a four-factor structure.\n\nConclusionsThe Japanese version of the MHLS demonstrated adequate reliability and validity, while the factor structure did not fit previously proposed models. This scale may be useful for assessing the degree of MHL among medical field students in Japan.","Antibody kinetics to SARS-CoV-2 at 13.5 months, by disease severity\nBackgroundUnderstanding humoral responses and seroprevalence in SARS-CoV-2 infection is essential for guiding vaccination strategies in both infected and uninfected individuals.\n\nMethodsWe determine the kinetics of IgM against the nucleocapsid (N) and IgG against the spike (S) and N proteins of SARS-CoV-2 in a cohort of 860 health professionals (healthy and infected) in northern Barcelona. We model the kinetics of IgG and IgM at nine time points over 13.5 months from infection, using non-linear mixed models by sex and clinical disease severity.\n\nResultsOf the 781 participants who were followed up, 478 (61.2%) became infected with SARS-CoV-2. Significant differences were found for the three antibodies by disease severity and sex. At day 270 after diagnosis, median IgM(N) levels were already below the positivity threshold in patients with asymptomatic and mild-moderate disease, while IgG(N, S) levels remained positive to days 360 and 270, respectively. Kinetic modelling showed a general rise in both IgM(N) and IgG(N) levels up to day 30, followed by a decay whose rate depended on disease severity. IgG(S) levels increased at day 15 and remained relatively constant over time.\n\nConclusionsWe describe kinetic models of IgM(N) and IgG(N, S) SARS-CoV-2 antibodies at 13.5 months from infection and disease spectrum. Our analyses delineate differences in the kinetics of IgM and IgG over a year and differences in the levels of IgM and IgG as early as 15 days from symptoms onset in severe cases. These results can inform public health policies around vaccination criteria.\n\nFunded by the regional Ministry of Health of the Generalitat de Catalunya (Call COVID19-PoC SLT16_04; NCT04885478)","Molecular diagnosis of causality in T cell mediated severe cutaneous adverse drug reactions\nBackgroundOne of the most severe forms of T cell mediated cutaneous adverse drug reactions is drug reaction with eosinophilia and systemic symptoms (DRESS), hence subsequent avoidance of the causal drug is imperative. However, attribution of drug culpability in DRESS is challenging and standard skin allergy tests are not recommended due to for patient safety reasons. We sought to identify potential biomarkers for development of a diagnostic test.\n\nMethodsPeripheral blood mononuclear cells (PBMCs) from a discovery cohort (n=5) challenged to drug or control were analysed for transcriptomic profile. A signature panel of genes was then tested in a validation cohort (n=6), and compared to tolerant controls and other inflammatory conditions which can clinically mimic DRESS. A scoring system to identify presence of drug hypersensitivity was developed based on gene expression alterations of this panel.\n\nResultsWhole transcriptome analysis identified 4 major gene clusters including those regulating T cell activation via NFAT and cytokine receptor activity. 22 differentially expressed gene transcripts were identified as a DRESS signature including Type 1 interferon pathways and Th2 activation. The DRESS transcriptomic panel identified antibiotic-DRESS cases in a validation cohort but was not altered in other inflammatory conditions. Machine learning or differential expression selection of a biomarker panel showed high sensitivity and specificity (100% and 85.7-100% respectively) for identification of the culprit drug in DRESS.\n\nConclusionTranscriptomic analysis of DRESS revealed important insights into the key activated pathways and identified a transcriptional signature which shows potential as a test with high sensitivity for drug culpability attribution.","Evaluation of the Implementation of the 4C Mortality Score in United Kingdom hospitals during the second pandemic wave\nThe 4C Mortality Score (4C Score) was designed to risk stratify hospitalised patients with COVID-19. We assessed inclusion of 4C Score in COVID-19 management guidance and its documentation in patients case notes in January 2021 in UK hospitals. 4C Score was included within guidance by 50% of sites, though score documentation in case notes was highly variable. Higher documentation of 4C Score was associated with score integration within admissions proformas, inclusion of 4C Score variables or link to online calculator, and management decisions. Integration of 4C Score within clinical pathways may encourage more widespread use.","Vagus nerve cross-sectional area in patients with Parkinsons Disease; an ultrasound case-control study\nBackgroundVagal parasympathetic neurons are prone to degeneration in Parkinsons disease (PD). High-resolution ultrasound can precisely estimate the cross-sectional area (CSA) of peripheral nerves. Here, we tested the hypothesis that vagus CSA is reduced in PD.\n\nMethodsWe included 56 healthy controls (HCs) and 63 patients with PD. Using a high-end ultrasound system equipped with a high-frequency transducer, five images were obtained of each nerve. The hypoechoic neuronal tissue was delineated offline with dedicated software and the CSA extracted.\n\nResultsIn the initial PD vs. HC comparison, no statistically significant differences were observed in mean left vagus CSA (HC: 1.97mm2, PD: 1.89mm2, P=0.36) or in mean right vagus CSA (HC: 2.37mm2, PD: 2.23mm2, P=0.17). The right vagus CSA was significantly larger than the left vagus CSA in both groups (P<0.0001). Females were overrepresented in the HC group and presented with generally smaller vagus CSAs. Consequently, sex-adjusted CSA was significantly smaller for the right vagus nerve of the PD group (P=0.041), but not for the left.\n\nConclusionA small but significant reduction in sex-adjusted right vagus CSA was observed in patients with PD. The left vagus CSA was not significantly reduced in patients with PD. Ultrasound may not be a suitable method to detecting vagal axonal loss in individual patients.","Performance evaluation of the BD SARS-CoV-2 reagents for the BD MAX™ system\nBackgroundThe RT-qPCR assay for detecting SARS-CoV-2 virus is the favorable approach to test suspected COVID-19 cases. However, discordant results can occur when two or more assays are compared. Variability in analytical sensitivities between assays, among other factors, may account for these differences in reporting.\n\nMethodsThe limits of detection (LOD) for the BD SARS-CoV-2 Reagents for BD MAX System (\"MAX SARS-CoV-2 assay\"), the Biomerieux BioFire(R) Respiratory Panel 2.1 (\"BioFire SARS-CoV-2 assay\"), the Roche cobas SARS-CoV-2 assay (\"cobas SARS-CoV-2 assay\"), and the Hologic Aptima(R) SARS-CoV-2 assay Panther(R) (\"Aptima SARS-CoV-2 assay\") RT-qPCR systems were determined using a total of 84 contrived nasopharyngeal specimens with seven target levels for each comparator. The positive and negative percent agreement (PPA and NPA, respectively) for the MAX SARS-CoV-2 assay were compared to the Aptima SARS-CoV-2 assay in a post-market clinical study utilizing 708 paired nasopharyngeal specimens collected from suspected COVID-19 cases. Discordant results were further tested by the cobas and BioFire SARS-CoV-2 assays.\n\nResultsThe measured LOD for the MAX SARS-CoV-2 assay (251 copies/mL) was comparable to the cobas SARS-CoV-2 assay (298 copies/mL) and the BioFire SARS-CoV-2 assay (302 copies/mL); the Aptima SARS-CoV-2 assay had a LOD of 612 copies/mL. The MAX SARS-CoV-2 assay had a PPA of 100% (95%CI: [97.3%-100.0%]) and a NPA of 96.7% (95%CI: [94.9%-97.9%]) when compared to the Aptima SARS-CoV-2 assay.\n\nConclusionsThe MAX SARS-CoV-2 assay exhibited a high analytical sensitivity and specificity for SARS-CoV-2 detection. The clinical performance of the MAX SARS-CoV-2 assay agreed with another sensitive EUA cleared assay.","Deceased donor kidney degradomics indicates cytoskeletal proteolytic alterations impacting post-transplant function.\nBackgroundIn brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys that adversely impacts the quality of grafts. Here, we hypothesized that DBD kidneys may undergo proteolytic processes that renders grafts susceptible to post-transplant dysfunction.\n\nMaterial & MethodsUsing mass spectrometry and immunoblotting analyses, we profiled degradation patterns of cytoskeletal proteins in deceased (n=55) and living (n=10) donor kidneys.\n\nResultsWe found that in DBD kidneys, key podocyte cytoskeletal proteins had been proteolytically cleaved. Generated degradation profiles were not associated to donor related demographic and clinical factors but were associated to suboptimal post-transplant function. Strikingly, -actinin -4 and Talin-1 degradation profiles were not observed in circulatory-death or living-donor kidneys. As Talin-1 is a specific proteolytic target of Calpain-1, we investigated a potential trigger of Calpain activation and Talin-1 degradation using ex-vivo precision-cut human kidney slices and in-vitro immortalised human podocytes. Notably, we found that Transforming-Growth Factor-{beta} (TGF-{beta}) activated Calpain-1 and proteolytically cleaved Talin-1 to generate distinct peptide fragments. These peptide fragments were of similar size and matched the degradation patterns observed in DBD kidneys. Talin-1 degradation was prevented in vitro by Calpain-1 inhibition.\n\nConclusionsHere, we provide initial evidence that DBD kidneys are susceptible to cytoskeletal protein degradation that impacts posttransplant kidney function. Subsequent studies should aim to further investigate the link between brain death and activation of proteolytic pathways exploring new therapeutic opportunities.","Upper Limb Motor Improvement after TBI: Systematic Review of Interventions\nBackgroundTraumatic Brain Injury (TBI) is a leading cause of adult morbidity and mortality. Individuals with TBI have impairments in both cognitive and motor domains. Motor improvements post-TBI are attributable to adaptive neuroplasticity and motor learning. Majority of the studies focus on remediation of balance and mobility issues. There is limited understanding on the use of interventions for upper limb (UL) motor improvements in this population.\n\nObjectiveWe examined the evidence regarding the effectiveness of different interventions to augment UL motor improvement after a TBI.\n\nMethodsWe systematically examined the evidence published in English from 1990-2020. The modified Downs and Black checklist helped assess study quality (total score:28). Studies were classified as excellent:24-28, good:19-23, fair:14-18 and poor:[≤]13 in quality. Effect sizes helped quantify intervention effectiveness.\n\nResultsTwenty-three studies were retrieved. Study quality was excellent(n=1), good(n=5) or fair(n=17). Interventions used included strategies to decrease muscle tone (n=6), constraint induced movement therapy (n=4), virtual reality gaming (n=5), noninvasive stimulation (n=3), arm motor ability training (n=1), stem-cell transplant (n=1); task-oriented training (n=2) and feedback provision (n=1). Motor impairment outcomes included Fugl-Meyer Assessment, Modified Ashworth Scale, and kinematic outcomes (error and movement straightness). Activity limitation outcomes included Wolf Motor Function Test and Motor Activity Log. Effect sizes for majority of the interventions ranged from medium(0.5-0.79) to large([≥]0.8). Only ten studies included retention testing.\n\nConclusionThere is preliminary evidence that using some interventions may enhance UL motor improvement after a TBI. Answers to emergent questions can help select the most appropriate interventions in this population.","A Deep Learning Method to Detect Opioid Prescription and Opioid Use Disorder from Electronic Health Records\nObjectiveAs the opioid epidemic continues across the United States, methods are needed to accurately and quickly identify patients at risk for opioid use disorder (OUD). The purpose of this study is to develop two predictive algorithms: one to predict opioid prescription and one to predict OUD.\n\nMaterials and MethodsWe developed an informatics algorithm that trains two deep learning models over patient EHRs using the MIMIC-III database. We utilize both the structured and unstructured parts of the EHR and show that it is possible to predict both of these challenging outcomes.\n\nResultsOur deep learning models incorporate both structured and unstructured data elements from the EHRs to predict opioid prescription with an F1-score of 0.88 {+/-} 0.003 and an AUC-ROC of 0.93 {+/-} 0.002. We also constructed a model to predict OUD diagnosis achieving an F1-score of 0.82 {+/-} 0.05 and AUC-ROC of 0.94 {+/-} 0.008.\n\nDiscussionOur model for OUD prediction outperformed prior algorithms for specificity, F1 score and AUC-ROC while achieving equivalent sensitivity. This demonstrates the importance of a.) deep learning approaches in predicting OUD and b.) incorporating both structured and unstructured data for this prediction task. No prediction models for opioid prescription as an outcome were found in the literature and therefore this represents an important contribution of our work as opioid prescriptions are more common than OUDs.\n\nConclusionAlgorithms such as those described in this paper will become increasingly important to understand the drivers underlying this national epidemic.","Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease\nBackgroundOver 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target variants to improve lung function, but marked variability in response exists and current therapies do not address all CF-causing variants highlighting unmet needs. Alternative epithelial ion channel/transporters such as SLC26A9 could compensate for CFTR dysfunction, providing therapeutic targets that may benefit all individuals with CF.\n\nMethodWe investigate the relationship between rs7512462, a marker of SLC26A9 activity, and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD).\n\nResultsRs7512462 CC genotype is associated with greater lung function in CF individuals with minimal function variants (for which there are currently no approved therapies; p=0.008); and for gating (p=0.033) and p.Phe508del/ p.Phe508del (p=0.006) genotypes upon treatment with CFTR modulators. In parallel, human nasal epithelia with CC and p.Phe508del/p.Phe508del after Ussing chamber analysis of a combination of approved and experimental modulator treatments show greater CFTR function (p=0.0022). Beyond CF, rs7512462 is associated with lung function in a meta-analysis of the UK Biobank and Spirometa Consortium (min p=2.74x0-44) and provides p=0.0891 in an analysis of COPD case-control status in the UK Biobank defined by spirometry.\n\nConclusionThese findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases.","Trajectories: a framework for detecting temporal clinical event sequences from health data standardized to the OMOP Common Data Model\nObjectiveTo develop a framework for identifying prominent clinical event trajectories from OMOP-formatted observational healthcare data.\n\nMethodsA four-step framework based on significant temporal event pair detection is described and implemented as an open-source R package. It is used on a population-based Estonian dataset to first replicate a large Danish population-based study and second, to conduct a disease trajectory detection study for Type 2 Diabetes patients in the Estonian and Dutch databases as an example.\n\nResultsAs a proof of concept, we apply the methods in the Estonian database and provide a detailed breakdown of our findings. All Estonian population-based event pairs are shown. We compare the event pairs identified from Estonia to Danish and Dutch data and discuss the causes of the differences.\n\nConclusionsFor the first time, there is a complete software package for detecting disease trajectories in health data.","Extubation generates lung volume inhomogeneity in preterm infants\nObjectiveTo evaluate the feasibility of EIT to describe the regional tidal ventilation (VT) and change in end-expiratory lung volume (EELV) patterns in preterm infants during the process of extubation from invasive to non-invasive respiratory support.\n\nDesignProspective observational study\n\nSettingSingle-centre tertiary neonatal intensive care unit\n\nPatientsPreterm infants born <32 weeks gestation who were being extubated to nasal continuous positive airway pressure (nCPAP) as per clinician discretion.\n\nInterventionsElectrical Impedance Tomography measurements were taken in supine infants during elective extubation from synchronised positive pressure ventilation (SIPPV) before extubation, during and then at 2 and 20 minutes after commencing nCPAP. Extubation and pressure settings were determined by clinicians.\n\nMain outcome measuresGlobal and regional {Delta}EELV and {Delta}VT were measured. Heart rate, respiratory rate and oxygen saturation were measured throughout.\n\nResultsThirty infants of median (range) 2 (1, 21) days were extubated to a median (range) CPAP 7 (6, 8) cmH2O. SpO2/FiO2 ratio was mean (95% CI) 50 (35, 65) lower 20 minutes after nCPAP compared with SIPPV. EELV was lower at all points after extubation compared to SIPPV, and EELV loss was primarily in the ventral lung (p=0.04). VT was increased immediately after extubation, especially in the central and ventral regions of the lung, but the application of nCPAP returned VT to pre-extubation patterns.\n\nConclusionsLung behaviour during the transition from invasive positive pressure ventilation to CPAP at moderate distending pressures is variable and associated with lung volume loss in the ventral lung.","Effectiveness of COVID-19 vaccines against hospitalization and death in Canada: A multiprovincial test-negative design study\nBackgroundA major goal of COVID-19 vaccination is to prevent severe outcomes (hospitalizations and deaths). We estimated the effectiveness of mRNA and ChAdOx1 COVID-19 vaccines against severe outcomes in four Canadian provinces between December 2020 and September 2021.\n\nMethodsWe conducted this multiprovincial retrospective test-negative study among community-dwelling adults aged [≥]18 years in Ontario, Quebec, British Columbia, and Manitoba using linked provincial databases and a common study protocol. Multivariable logistic regression was used to estimate province-specific vaccine effectiveness against COVID-19 hospitalization and/or death. Estimates were pooled using random effects models.\n\nResultsWe included 2,508,296 tested subjects, with 31,776 COVID-19 hospitalizations and 5,842 deaths. Vaccine effectiveness was 83% after a first dose, and 98% after a second dose, against both hospitalization and death (separately). Against severe outcomes (hospitalization or death), effectiveness was 87% (95%CI: 71%-94%) [≥]84 days after a first dose of mRNA vaccine, increasing to 98% (95%CI: 96%-99%) [≥]112 days after a second dose. Vaccine effectiveness against severe outcomes for ChAdOx1 was 88% (95%CI: 75%-94%) [≥]56 days after a first dose, increasing to 97% (95%CI: 91%-99%) [≥]56 days after a second dose. Lower one-dose effectiveness was observed for adults aged [≥]80 years and those with comorbidities, but effectiveness became comparable after a second dose. Two doses of vaccines provided very high protection for both homologous and heterologous schedules, and against Alpha, Gamma, and Delta variants.\n\nConclusionsTwo doses of mRNA or ChAdOx1 vaccines provide excellent protection against severe outcomes of hospitalization and death.","CNV-ClinViewer: Enhancing the clinical interpretation of large copy-number variants online\nPurposeLarge copy number variants (CNVs) can cause a heterogeneous spectrum of rare and severe disorders. However, most CNVs are benign and are part of natural variation in human genomes. CNV pathogenicity classification, genotype-phenotype analyses, and therapeutic target identification are challenging and time-consuming tasks that require the integration and analysis of information from multiple scattered sources by experts.\n\nMethodsWe developed a web-application combining >250,000 patient and population CNVs together with a large set of biomedical annotations and provide tools for CNV classification based on ACMG/ClinGen guidelines and gene-set enrichment analyses.\n\nResultsHere, we introduce the CNV-ClinViewer (https://cnv-ClinViewer.broadinstitute.org), an open-source web-application for clinical evaluation and visual exploration of CNVs. The application enables real-time interactive exploration of large CNV datasets in a user-friendly designed interface.\n\nConclusionOverall, this resource facilitates semi-automated clinical CNV interpretation and genomic loci exploration and, in combination with clinical judgment, enables clinicians and researchers to formulate novel hypotheses and guide their decision-making process. Subsequently, the CNV-ClinViewer enhances for clinical investigators patient care and for basic scientists translational genomic research.","Longitudinal prediction of motor dysfunction after stroke: a disconnectome study.\nMotricity is the most commonly affected ability after a stroke. While many clinical studies attempt to predict motor symptoms at different chronic time points after a stroke, longitudinal acute-to-chronic studies remain scarce. Taking advantage of recent advances in mapping brain disconnections, we predict motor outcomes in 62 patients assessed longitudinally two weeks, three months, and one year after their stroke. Results indicate that brain disconnection patterns accurately predict motor impairments. However, disconnection patterns leading to impairment differ between the three time points and between left and right motor impairments. These results were cross-validated using resampling techniques. In sum, we demonstrated that while some neuroplasticity mechanisms exist changing the structure-function relationship, disconnection patterns prevail when predicting motor impairment at different time points after stroke.","A seq2seq model to forecast the COVID-19 cases, deaths and reproductive R numbers in US counties\nThe global pandemic of coronavirus disease 2019 (COVID-19) has killed almost two million people worldwide and over 400 thousand in the United States (US). As the pandemic evolves, informed policy-making and strategic resource allocation relies on accurate forecasts. To predict the spread of the virus within US counties, we curated an array of county-level demographic and COVID-19-relevant health risk factors. In combination with the county-level case and death numbers curated by John Hopkins university, we developed a forecasting model using deep learning (DL). We implemented an autoencoder-based Seq2Seq model with gated recurrent units (GRUs) in the deep recurrent layers. We trained the model to predict future incident cases, deaths and the reproductive number, R. For most counties, it makes accurate predictions of new incident cases, deaths and R values, up to 30 days in the future. Our framework can also be used to predict other targets that are useful indices for policymaking, for example hospitalization or the occupancy of intensive care units. Our DL framework is publicly available on GitHub and can be adapted for other indices of the COVID-19 spread. We hope that our forecasts and model can help local governments in the continued fight against COVID-19.","An AI-based quantitative home-use framework for assessing fertility and identifying novel hormone trends by recording urine hormones\nFertility testing using urinary hormones has been used to effectively improve the likelihood of pregnancy. To provide fertility scores, the existing home-use systems measure one or two hormones. However, the hormone profiles vary depending on cycle duration, fertility-related disorders, drugs and other treatments. Here, we introduce Inito, a mobile-phone connected reader that is scalable to multiple hormone tests. In this report, we assess the accuracy of the quantitative home-based fertility monitor, the Inito Fertility Monitor (IFM), and suggest using IFM as a device to monitor and analyse female hormone patterns. There were two aspects of the study: i. evaluation of the efficacy of IFM in quantifying urinary Estrone-3-glucuronide (E3G), pregnanediol glucuronide (PdG) and luteinizing hormone (LH), and ii. A retrospective study of patients hormone profiles using IFM. We observed that with all three hormones, IFM had an accurate recovery percentage and had a CV of less than 10 percent. Furthermore, in predicting the concentration of urinary hormones, IFM showed a high correlation with ELISA. Using Inito in clinical trials, we report a novel criterion for earlier confirmation of ovulation compared to existing criteria. We also present a novel hormone pattern consistent across most menstrual cycles included in the study. In conclusion, the Inito Fertility Monitor is an effective tool for calculating the urinary concentrations of E3G, PdG and LH and can also be used to provide accurate fertility scores and confirm ovulation. In addition, the sensitivity of IFM facilitates the monitoring of menstrual cycle-related hormone patterns, therefore also making it a great tool for physicians to track the hormones of their patients.","Insights into genetic factors contributing to variability in SARS-CoV-2 susceptibility and COVID-19 disease severity\nVariability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we applied colocalization to compare summary statistics for 16 GWASs from the COVID-19 Host Genetics Initiative to investigate similarities and differences in their genetic signals. We identified 9 loci associated with susceptibility (one with two independent GWAS signals; one with an ethnicity-specific signal), 14 associated with severity (one with two independent GWAS signals; two with ethnicity-specific signals) and one harboring two discrepant GWAS signals (one for susceptibility; one for severity). Utilizing colocalization we also identified 45 GTEx tissues that had eQTL(s) for 18 genes strongly associated with GWAS signals in eleven loci (1-4 genes per locus). Some of these genes showed tissue-specific altered expression and others showed altered expression in up to 41 different tissue types. Our study provides insights into the complex molecular mechanisms underlying inherited predispositions to COVID-19-disease phenotypes.","One vaccine to counter many diseases? Modelling the economics of oral polio vaccine against child mortality and COVID-19\nBackgroundRecent reviews summarize evidence that some vaccines have heterologous or non-specific effects (NSE), potentially offering protection against multiple pathogens. Numerous economic evaluations examine vaccines pathogen-specific effects, but we have found only two economic evaluations of NSE. This paper starts to fill this gap by reporting economic evaluations of the NSE of oral polio vaccine (OPV) against under-five mortality and COVID-19.\n\nMethodsWe studied two settings: (1) reducing child mortality in a high-mortality setting (Guinea-Bissau) and (2) preventing COVID-19 in India. In the former, the intervention involves three annual campaigns in which children receive OPV incremental to routine immunization. In the latter, a susceptible-exposed-infectious-recovered model was developed to estimate the population benefits of two scenarios, in which OPV would be co-administered alongside COVID-19 vaccines. Incremental cost-effectiveness and benefit-cost ratios were modelled for ranges of intervention effectiveness estimates to supplement the headline numbers and account for heterogeneity and uncertainty.\n\nResultsFor child mortality, headline cost-effectiveness was $650 per child death averted. For COVID-19, assuming OPV had 20% effectiveness, incremental cost per death averted was $23,000-65,000 if it were administered simultaneously with a COVID-19 vaccine less than 200 days into a wave of the epidemic. If the COVID-19 vaccine availability were delayed, the cost per averted death would decrease to $2600-6100. Estimated benefit-to-cost ratios vary but are consistently high.\n\nConclusionEconomic evaluation suggests the potential of OPV to efficiently reduce child mortality in high mortality environments. Likewise, within a broad range of assumed effect sizes OPV could play an economically attractive role against COVID-19.","Knowledge and Impact of COVID-19 on Middle-Aged and Older People living with HIV in Lima, Peru\nCOVID-19 has had an unprecedented worldwide impact, and Peru has had one of the highest COVID-19 case rates despite implementation of an early strict nationwide quarantine. Repercussions on Perus healthcare system may impact vulnerable populations, particularly people with HIV (PWH). We explored the knowledge of COVID-19 and the socioeconomic and health impact of the pandemic among middle-aged and older PWH. A cross-sectional telephone survey was administered to 156 PWH age [≥]40 years receiving care in one of two large HIV clinics in Lima, Peru. The majority of PWH (age 52{+/-}7.7 years, 41% female, 65% completed secondary school or less) were knowledgeable regarding COVID-19 symptoms and prevention methods. Nearly half of those employed prior to the pandemic reported job loss. Female sex (unadjusted prevalence ratio [PR] 1.85 [95%CI 1.27-2.69]), low educational level (PR 1.62 [1.06-2.48]) and informal work (PR 1.58 [1.06-2.36]) were risk factors for unemployment but not in adjusted models. Increased anxiety was reported in 64% and stress in 77%. COVID-19 has had a substantial socioeconomic and mental health impact on PWH living in Lima, Peru, particularly those with lower educational levels and informal workers. Efforts are needed to ensure continued medical care and socioeconomic support of PWH in Peru.","Alcohol consumption and telomere length: observational and Mendelian randomization approaches\nAlcohols impact on telomere length, a proposed marker of biological age, is unclear. We performed the largest observational study to date and compared findings with Mendelian randomization (MR) estimates. Two-sample MR used data from a recent genome-wide association study (GWAS) of telomere length. Genetic variants were selected on the basis of associations with alcohol consumption and alcohol use disorder (AUD). Non-linear MR employed UK Biobank individual data. MR analyses suggest a causal relationship between alcohol and telomere length: both genetically predicted alcohol traits were inversely associated with telomere length. 1 S.D. higher genetically-predicted log-transformed alcoholic drinks weekly had a -0.07 S.D. effect on telomere length (95% confidence interval [CI]:-0.14 to -0.01); genetically-predicted AUD - 0.06 S.D. effect (CI:-0.10 to -0.02). Results were consistent across methods and independent from smoking. Non-linear analyses indicated a potential threshold relationship between alcohol and telomere length. Our findings have implications for potential aging-related disease prevention strategies.","Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity.\nThe combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole exome sequencing data of about 4,000 SARS-CoV-2-positive individuals were used to define an interpretable machine learning model for predicting COVID-19 severity. Firstly, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthly, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management.","Preliminary Rasch analysis of the Multidimensional Assessment of Interoceptive Awareness in adults with stroke\nPurposeThe Multidimensional Assessment of Interoceptive Awareness (MAIA) measures interoceptive body awareness, which includes aspects such as attention regulation, self-regulation, and body listening. Our purpose was to validate the MAIA in adults with stroke using Rasch Measurement Theory.\n\nMethodsThe original MAIA has 32 items grouped into eight separately scored subscales that measure aspects of body awareness. Using Rasch Measurement Theory, we evaluated the unidimensionality of the entire scale and investigated person and item fit, person separation reliability, targeting, local item dependence, and principal components analysis of residuals.\n\nResultsForty-one adults with chronic stroke (average 3.8 years post-stroke, 13 women, and average age, 57{+/-}13 years) participated in the study. Overall fit (X2=62.26, p=0.26) and item fit were obtained after deleting 3 items and rescoring 26 items. One participant did not fit the model (2.44%). There were no floor (0.00%) or ceiling effects (0.00%). Local item dependence was found in 42 pairs. The person separation reliability was 0.91, and the person mean location was 0.06{+/-}1.12 logits.\n\nConclusionsThe MAIA demonstrated good targeting and reliability, as well as good item and person fit in adults with chronic stroke. A study with a larger sample size is needed to validate our findings.","Immuno-proteomic profiling reveals abundant airway CD8 T cells and ongoing epithelial injury in prolonged post-COVD19 respiratory disease\nSome patients hospitalized with acute COVID19 suffer respiratory symptoms that persist for many months. To characterize the local and systemic immune responses associated with this form of Long COVID, we delineated the immune and proteomic landscape in the airway and peripheral blood of normal volunteers and patients from 3 to 6 months after hospital discharge. The bronchoalveolar lavage (but not peripheral blood) proteome was abnormal in patients with post-COVID19 lung disease with significantly elevated concentration of proteins associated with apoptosis, tissue repair and epithelial injury. This correlated with an increase in cytotoxic lymphocytes (especially tissue resident CD8+ T cells), lactate dehydrogenase and albumin (biomarkers of cell death and barrier integrity). Follow-up of a subset of these patients greater than 1-year post-COVID19 indicated these abnormalities resolved over time. Collectively, these data indicate that COVID-19 results in a prolonged change to the airway immune landscape in those with persistent lung disease, with evidence of cell death and tissue repair linked to ongoing activation of cytotoxic T cells.\n\nHighlightsO_LIThe post-COVID19 airway is characterized by increased cytotoxic lymphocytes.\nC_LIO_LIDistinct airway proteomes are associated with the airway immune cell landscape.\nC_LIO_LIThe peripheral blood does not predict immune-proteome alterations in the airway post-COVID19.\nC_LIO_LIPersistent abnormalities in the airway immune-proteome post-COVID19 airways correlate with ongoing epithelial damage.\nC_LI","Improvement of behavioural pattern and alpha-synuclein levels in autism spectrum disorder after consumption of a beta-glucan food supplement in a randomized, parallel-group pilot clinical study\nBackgroundAutism spectrum disorders (ASDs) are a wide range of behavioural disabilities for which there are no definite interventional modalities available. Remedial therapies remain the only option but with varying outcomes. We have evaluated the childhood autism rating scale (CARS) and alpha-synuclein levels in this parallel-group, multiple-arm pilot clinical study after supplementation with a biological response modifier beta-glucan food supplement (Nichi Glucan).\n\nMethodsSix subjects with ASD (n = 6) Gr. 1 underwent conventional treatment comprising remedial behavioural therapies and L-carnosine 500 mg per day, and 12 subjects (n = 12) Gr. 2 underwent supplementation with the Nichi Glucan 0.5 g twice daily along with the conventional treatment.\n\nResultsThere was a significant decrease in the CARS score in all of the children of the Nichi Glucan Gr.2 compared to the control (p-value = 0.034517). Plasma levels of alpha-synuclein were significantly higher in Gr. 2 (Nichi Glucan) than in the control group Gr. 1 (p-value = 0.091701).\n\nConclusionImprovement of the behavioural pattern CARS score and a correlating alpha-synuclein level, followed by a safe beta-glucan food supplement, warrants further research on other parameters, such as gut-microbiota evaluation, and relevant neuronal biomarkers which is likely to cast light on novel solutions.","Mortality audit of cancer patients with SARS-CoV-2 positivity or COVID-19\nCoronavirus disease-2019 (COVID-19) has disrupted cancer care services globally. The present review of cause of deaths was conducted in a tertiary care cancer center in the North East India. In our institute, all cancer patients requiring admission for surgery, chemotherapy, and other daycare procedures require testing for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). From 09 July 2020 to 16 May 2021, 119 cancer patients with SARS-CoV-2 positive report or COVID-19 have been admitted at our institute Covid ward. A total of 19 cancer patients with COVID-19 succumbed. Of 19 deaths, 13 (68.4%) patients were men and 6 (31.6%) patients were women. The age range from 27 years to 74 years (median =55 years). Vomiting alone or with diarrhea was the most common symptom requiring admission after testing (4/19, 21.0%), followed by bleeding from primary tumour site (3/19, 15.7%). The antecedent and underlying cause of deaths in 19 (100%) patients was cancer. SARS-CoV-2 infection should not be a hindrance for cancer treatment and management.","An expanded population of CD8dim T cells with features of mitochondrial dysfunction and senescence is associated with persistent HIV-associated Kaposis sarcoma under ART\nHIV-associated Kaposis sarcoma (KS), which is caused by Kaposis sarcoma-associated herpesvirus, usually arises in the context of uncontrolled HIV replication and immunosuppression. However, disease occasionally persists in individuals with durable HIV viral suppression and CD4 T cell recovery under anti-retroviral therapy (ART). The underlying mechanisms associated with this persistence are unclear. Suppression of viral infections can be mediated by CD8 T cells that detect infected cells via their T cell receptor and the CD8 co-receptor. However, CD8 T cells exhibit signs of functional exhaustion in untreated HIV infection that may not be fully reversed under ART. To investigate whether persistent KS under ART was associated with phenotypic and functional perturbations of CD8 T cells, we performed a cross-sectional study comparing HIV-infected individuals with persistent KS under effective ART (HIV+ KS+) to HIV-infected individuals receiving effective ART with no documented history of KS (HIV+ KSneg). A subset of T cells with low cell surface expression of CD8 (\"CD8dim T cells\") was expanded in HIV+ KS+ compared with HIV+ KSneg participants. Relative to CD8bright T cells, CD8dim T cells exhibited signs of senescence (CD57) and mitochondrial perturbations (PGC-1, MitoTracker) ex vivo. Mitochondrial activity (MitoTracker) was also reduced in proliferating CD8dim T cells. These findings indicate that an expanded CD8dim T cell population displaying features of senescence and mitochondrial dysfunction is associated with KS persistence under ART. CD8 co-receptor down-modulation may be symptomatic of ongoing disease.","Association between metabolic syndrome and humoral immune response to Pfizer BioNTech vaccine in healthcare workers\nPurposeThe clustering of metabolic abnormalities may weaken vaccine-induced immunity, but epidemiological data regarding SARS-CoV-2 vaccines are scarce. The present study examined the cross-sectional association between metabolic syndrome (MetS) and humoral immune response to Pfizer-BioNTech vaccine among healthcare workers.\n\nMethodsParticipants were 946 healthcare workers, aged 21-75 years, who had completed the second dose of Pfizer-BioNTech vaccine 1-3 months before the survey. MetS was defined according to the Joint Interim Statement. SARS-CoV-2 spike immunoglobulin G (IgG) antibody was measured using quantitative assays. Multivariable linear regression was used to estimate the geometric mean titers (GMT) and geometric mean ratio (GMR) of IgG titers, relative to MetS status.\n\nResultsA total of 51 participants (5.4%) had MetS. Healthcare workers with MetS had a significantly lower IgG titer (GMT 3882; 95% confidence interval [CI], 3124-4824) than those without MetS (GMT 5033; 95% CI, 4395-5764); the GMR was 0.77 (95% CI 0.64-0.93). The GMR for IgG titers among those having 0 (reference group), 1, 2, 3, or [≥] 4 MetS components was 1.00, 1.00, 0.89, 0.86 and 0.61, respectively (Ptrend = 0.004).\n\nConclusionResults suggest that having MetS and a greater number of its components are associated with a weaker humoral immune response to the Pfizer-BioNTech vaccine.","Evolution of SARS-CoV-2 immune responses in nursing home residents following full dose of the Comirnaty COVID-19 vaccine\nObjectivesThere is scarce information as to the durability of immune responses elicited by the Comirnaty(R) COVID-19 vaccine in nursing home residents. Here, we assessed SARS-CoV-2-Spike (S)-targeted antibody and functional T cell responses at around 6 months after complete vaccination.\n\nMethodsThe sample comprised 46 residents (34 females; age, 60-100 years), of whom 10 had COVID-19 prior to vaccination. Baseline (median of 17.5 days after vaccination) and follow-up (median, 195 days) plasma specimens were available for quantitation of SARS-CoV-2-S antibodies and enumeration of SARS-CoV-2-S-reactive IFN-{gamma} CD4+ and CD8+ T cells by flow cytometry.\n\nResultsIn total, 44/45 participants had detectable SARS-CoV-2-S antibodies at follow-up. Overall, antibody levels were found to decrease (median, 4.8 fold). Antibodies waning was more frequent (P<0.001) in SARS-CoV-2 naive (29/35) than in recovered (1/10) residents. SARS-CoV-2-S IFN-{gamma} CD8+ T cells were detected in 33/46 and 24/46 at baseline and follow-up, respectively. The figures for CD4+ T cell counterparts were 12/46 and 30/46. Detectable SARS-CoV-2 IFN-{gamma} CD8+ and CD4+ T cell responses at follow-up were more common in recovered (8/10 and 7/10, respectively) than in naive residents (9/36 and 25/36, respectively). For those with detectable responses at both time points, SARS-CoV-2-S IFN-{gamma} CD8+ T cell frequencies decreased significantly (P=0.001) over time whereas the opposite (P=0.01) was observed in CD4+ T cells.\n\nConclusionAlmost all residents displayed detectable SARS-CoV-2-S-reactive antibodies and T cell responses, respectively, by around 6 months after complete vaccination with Comirnaty(R) COVID-19 vaccine, albeit generally waning in magnitude over time.","Specific gait changes in prodromal hereditary spastic paraplegia type 4 - The preSPG4 study\nBackgroundIn hereditary spastic paraplegia type 4 (SPG4), subclinical gait changes might occur years before patients realize gait disturbances. The prodromal phase of neurodegenerative disease is of particular interest to halt disease progression by future interventions before impairment has manifested.\n\nObjectivesIdentification of specific movement abnormalities before manifestation of gait impairment and quantification of disease progression in the prodromal phase.\n\nMethods70 subjects participated in gait assessment, including 30 prodromal SPAST mutation carriers, 17 patients with mild-to-moderate manifest SPG4, and 23 healthy controls. Gait was assessed by an infrared-camera-based motion capture system to analyze features like range of motion and continuous angle trajectories. Those features were correlated with disease severity as assessed by the Spastic Paraplegia Rating Scale (SPRS) and neurofilament light chain (NfL) as a fluid biomarker indicating neurodegeneration.\n\nResultsCompared to healthy controls, we found an altered gait pattern in prodromal mutation carriers during the swing phase in segmental angles of the lower leg (p<0.05) and foot (p<0.01), and in heel ground clearance (p<0.01). Furthermore, ranges of motion of segmental angles were reduced for foot (p<0.001) and lower leg (p<0.01). These changes occurred in prodromal mutation carriers without quantified leg spasticity in clinical examination. Gait features correlated with NfL levels and SPRS score.\n\nConclusionGait analysis can quantify changes in prodromal and mild-to-moderate manifest SPG4 patients. Thus, gait features constitute promising motor biomarkers characterizing the subclinical progression of spastic gait and might help to evaluate interventions in early disease stages.","Large Registry Based Analysis of Genetic Predisposition to Tuberculosis Identifies Genetic Risk Factors at HLA\nTuberculosis is a significant public health concern resulting in the death of over 1 million individuals each year worldwide. While treatment options and vaccines exist, a substantial number of infections still remain untreated or are caused by treatment resistant strains. Therefore, it is important to identify mechanisms that contribute to risk and prognosis of tuberculosis as this may provide tools to understand disease mechanisms and provide novel treatment options for those with severe infection. Our goal was to identify genetic risk factors that contribute to the risk of tuberculosis and to understand biological mechanisms and causality behind the risk of tuberculosis. A total of 1,895 individuals in the FinnGen study had ICD-based tuberculosis diagnosis. GWAS analysis identified genetic variants with statistically significant association with tuberculosis at the Human leukocyte antigen (HLA) region (p<5e-8) and at rs560595454 in gene INPP5A. Fine mapping the HLA-association provided evidence for one protective haplotype tagged by HLA DQB1*05:01 (p=1.82E-06, OR = 0.81 [CI 95 % 0.74-0.88]), and predisposing alleles tagged by HLA DRB1*13:02 (p=0.00011, OR = 1.35 [CI 95% 1.16-1.57]). Furthermore, genetic correlation analysis showed association with earlier reported risk factors including smoking (p<0.05). Mendelian randomization supported smoking as a risk factor for tuberculosis (inverse-variance weighted p<0.05, OR = 1.83 [CI 95 % 1.15-2.93]) with no significant evidence of pleiotropy. Our findings indicate that specific HLA alleles and INPP5A associate with the risk of tuberculosis. In addition, lifestyle risk factors such as smoking contribute to the risk of developing tuberculosis.","Quantitative Digitography Solves the Remote Measurement Problem in Parkinson's disease\nBackgroundAssessment of motor signs in Parkinsons disease (PD) has required an in-person examination. However, 50% of people with PD do not have access to a neurologist. Wearable sensors can provide remote measures of some motor signs but require continuous data acquisition for several days. A major unmet need is reliable metrics of all cardinal motor signs, including rigidity, from a simple short active task that can be performed remotely or in the clinic.\n\nObjectiveInvestigate whether thirty seconds of repetitive alternating finger tapping (RAFT) on a portable quantitative digitography (QDG) device, which measures amplitude and timing, produces reliable metrics of all cardinal motor signs in PD\n\nMethodsNinety-six individuals with PD and forty-two healthy controls performed a thirty-second QDG-RAFT task and clinical motor assessment. Eighteen individuals were followed longitudinally with repeated assessments for an average of three years and up to six years.\n\nResultsQDG-RAFT metrics differentiated individuals with PD from controls and provided validated metrics for total motor disability (MDS-UPDRS III) and for rigidity, bradykinesia, tremor, gait impairment and freezing of gait (FOG). Additionally, QDG-RAFT tracked disease progression over several years off therapy, and differentiated akinetic rigid from tremor dominant phenotypes, as well as people with from those without FOG.\n\nConclusionsQDG is a reliable technology, which will improve access to care, allows complex remote disease management, and accurate monitoring of disease progression over time in PD. QDG-RAFT also provides the comprehensive PD motor metrics needed for therapeutic trials.","Seroconversion rate and socioeconomic and ethnic risk factors for SARS-CoV-2 infection in children in a population-based cohort\nIntroductionSocioeconomic and ethnic background have been discussed as possible risk factors for SARS-CoV-2 infections in children. Improved knowledge could lead way to tailored prevention strategies and help to improve infection control.\n\nMethodsObservational population-based cohort study in children (6mo. - 18 ys.) scheduled for legally required preventive examination and their parents in a metropolitan region in Germany. Primary endpoint was the SARS-CoV-2 seroconversion rate during study period. Risk factors assessed included age, pre-existing medical conditions, socioeconomic factors, and ethnicity.\n\nResults2124 children and their parents were included. Seroconversion rates among children in all age groups increased by 3-4-fold from 06/2020 to 02/2021. Only 41% of seropositive children were symptomatic. In 51% of infected children at least one parent was also SARS-CoV-2 positive.\n\nLow level of parental education (OR 3.13 (0.72-13.69)) significantly increased the risk of infection. Of the total cohort, 38.5% had a migration background. Specifically, 9% were of Turkish and 5% of Middle Eastern origin. These children had the highest risk for SARS-CoV-2 infections (OR 6.24 (1.38-28.12) and 6.44 (1.14-36.45) after adjustment for other risk factors.\n\nDiscussionSeroprevalence of SARS-CoV-2 infections in children increased by 3-4-fold within the study period. Frequently, more than one family member was infected. Children from families with lower socioeconomic status were at higher risk. The highest risk for SARS-CoV-2 infection was identified in families with Turkish or Middle Eastern background. Culture sensitive approaches are essential to improve infection control and serve as a blueprint for vaccination strategies in this population.\n\nTrial RegistrationBMBF funding registration 01KI20173 (Corkid)","Using Geographically Weighted Linear Regression for County-Level Breast Cancer Modeling in the United States\nDue to the continued disparities in breast cancer, improved models are being needed to inform policy related to existing social disparities related to cancer. First ordinal least squares regression was used to determine the relationship of sociodemographic measures (i.e. poverty rate and social inequity) on breast cancer incidence in the United States. Gini coefficient was used as a measure of income inequality. Next, Geographically Weighted Regression (GWR), a local spatial model, was used to explore the impact location has on the relationship between sociodemographic measures and breast cancer. Mappings of the results are presented, which can assist policymakers to address inequities and social determinants when funding cancer interventions. The GWR model is then compared to linear regression models that do not take into consideration location, highlighting the benefits of spatial models in cancer policy research. More studies applying spatial regression techniques are needed in order to accurately inform policy.","Microsampling for monitoring gentamicin in neonates.\nGentamicin is recommended as first-line treatment of neonatal sepsis. The use of gentamicin is associated with toxicity which complicates neonatal dosing and necessitates therapeutic drug monitoring (TDM).\n\nIn a proof-of-concept investigation, we sought to compare (1) gentamicin concentrations obtained using volumetric absorptive microsampling (VAMS) to standard TDM plasma samples, and (2) the time taken to report results obtained using VAMS compared to standard TDM by the local hospital chemical pathology service.\n\nThe difference between gentamicin concentrations obtained from plasma collected for routine clinical care and calculated plasma concentrations, based on samples collected in whole blood using VAMS, was -18.0% and -0.4% for two patients. The research laboratory reported results within the time taken for the routine chemical pathology laboratory to report results. This proof-of-concept study demonstrates that the use of microsampling for TDM by pathology services can fulfil the requirements of providing an accurate gentamicin concentration in a timely manner.","Proteomic deconvolution reveals distinct immune cell fractions in different body sites in SARS-Cov-2 positive individuals\nBackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be a significant public health challenge globally. SARS-CoV-2 is a novel virus, and what constitutes immunological responses in different human body sites in infected individuals is yet to be presented. We set to determine the various immune cell fractions in gargle solution, bronchoalveolar lavage fluid, nasopharyngeal, and urine samples post-SARS-CoV-2 infection in humans.\n\nMaterials and methodsWe downloaded proteomics data from (https://www.ebi.ac.uk/pride/) with the following identifiers: PXD019423, n=3 (gargle solution), PXD018970, n=15 (urine), PXD022085, n=5 (Bronchoalveolar lavage fluid), PXD022889, n=18 (nasopharyngeal). MaxQuant was used for the peptide spectral matching using humans, and SARS-CoV-2 was downloaded from the UniProt database (Access date 9th January 2022). The protein count matrix was extracted from the proteins group file and used as an input for the cibersort for the immune cells fraction determination.\n\nResultsThe body of individuals infected with the SARS-CoV-2 virus is characterized by different fractions of immune cells in Bronchoalveolar lavage fluid (BALF), nasopharyngeal, urine, and gargle solution. BALF has more abundant memory B cells, CD8, activated mast cells, and resting macrophages than urine, nasopharyngeal, and gargle solution. Our analysis also demonstrates that each body site comprises different immune cell fractions post-SARS-CoV-2 infection in humans.\n\nConclusionDifferent body sites are characterized by different immune cells fractions in SARS-CoV-2 infected individuals. The findings in this study can inform public health policies and health professionals on treatment strategies and drive SARS-CoV-2 diagnosis procedures.","Small Patient Datasets Reveal Genetic Drivers of Non-Small Cell Lung Cancer Subtypes using a Novel Machine Learning Approach\nThere are many small datasets of significant value in the medical space that are being underutilized. Due to the heterogeneity of complex disorders found in oncology, systems capable of discovering patient subpopulations while elucidating etiologies is of great value as it can indicate leads for innovative drug discovery and development. Here, we report on a machine intelligence-based study that utilized a combination of two small non-small cell lung cancer (NSCLC) datasets consisting of 58 samples of adenocarcinoma (ADC) and squamous cell carcinoma (SCC) and 45 samples from the gene expression analysis of human lung cancer and control samples series (GSE18842). Utilizing a novel machine learning approach, we were able to uncover subpopulations of ADC and SCC while simultaneously extracting which genes, in combination, were significantly involved in defining the subpopulations. An interactive hypothesis-generating interface designed to work with machine learning methods allowed us to explore the hypotheses generated by the unsupervised components of the system. Using these methods, we were able to uncover genes implicated by other methods and accurately discover known subpopulations without being asked, such as different levels of aggressiveness within the SCC and ADC subtypes. Furthermore, PIGX was a novel gene implicated in this study that warrants further study due to its role in breast cancer proliferation. Here we demonstrate the ability to learn from small datasets and reveal well-established properties of NSCLC. These machine learning techniques can reveal the driving factors behind subpopulations of patients altering the approach to drug discovery and development by making precision medicine a reality.","Surgical interventions targeting the nucleus caudalis for craniofacial pain: a systematic and historical review.\nIntroductionChronic facial pain is a prevalent group of conditions and when refractory to common treatments poses a social and economic burden. The last decade has seen a multitude of advancements in the multimodal management of pain. Ablative or neuromodulatory interventions targeting the nucleus caudalis (NC) of the trigeminocervical complex is one such treatment that has remained underutilized.\n\nMethodsHere we present a systematic review of the literature and historical perspective regarding interventions targeting the NC. We examine the various intervention techniques, clinical indications, and procedural efficacy. A novel outcome reporting scheme was devised to allow comparison between studies using differing outcome reporting methods.\n\nResultsA review of the literature revealed 49 retrospective studies published over the last 80 years, reporting on 858 patients. The most common technique was the open NC dorsal root entry zone nucleotomy/tractotomy (n=515, 60.0%); however, there has been an emergence of novel approaches such as endoscopic (n=6, 0.7%) and spinal cord stimulation (n=20, 2.3%) in the last 10 years. Regardless of intervention technique or preoperative diagnosis, 90.4% of patients demonstrated some improvement from treatment.\n\nConclusionThis systematic review highlights recent advancements in NC intervention technique and the wide range of facial pain syndromes for which these interventions show promising efficacy. New and less invasive techniques continue to emerge, however prospective studies remain absent in the literature. Future work should address efficacy comparisons between intervention type and preoperative diagnosis.","Frequent Cocaine Use is Associated with Larger HIV Latent Reservoir Size\nBackgroundWith the success of combination antiretroviral therapy, HIV is now treated as a chronic disease, including among drug users. Cocaine--one of the most frequently abused illicit drugs among persons living with HIV (PLWH)-- slows the decline of viral production after ART, and is associated with higher HIV viral load, more rapid HIV progression, and increased mortality. We examined the impact of cocaine use on the CD4+ T-cell HIV Latent Reservoir (HLR) in virally suppressed PLWH.\n\nMethodsCD4+ T-cell genomic DNA was isolated from peripheral blood mononuclear cells collected from 434 women of diverse ancestry (i.e., 75% Black, 14% Hispanic, 12% White) who self-reported cocaine use (i.e., 160 cocaine users, 59 prior users, 215 non-users). Participants had to have an undetectable HIV RNA viral load measured by commercial assay for at least 6 months. The Intact Proviral HIV DNA Assay (IPDA) provided estimates of intact provirus per 106 CD4+ T-cells.\n\nResultsThe HLR size differed by cocaine use (i.e., median [interquartile range]: 72 [14, 193] for never users, for prior users 165 [63, 387], 184 [28, 502] for current users), which was statistically significantly larger in both prior (p=0.023) and current (p=0.001) cocaine users compared with never users.\n\nConclusionOur study is the first to provide evidence that cocaine use may contribute to a larger replication competent HLR in CD4* T-cells among virologically suppressed women living with HIV. Our findings are important, because women are under-represented in HIV reservoir studies and in studies of the impact of cocaine use on outcomes among PLWH.","Decreased Immune Response to COVID-19 mRNA Vaccine in Patients with Inflammatory Bowel Diseases Treated with Anti TNFα\nBackgroundPatients with inflammatory bowel diseases (IBD), specifically those treated with anti-tumor necrosis factor (TNF) biologics are at high risk for vaccine preventable infections. Their ability to mount adequate vaccine responses is unclear.\n\nAimto assess immune responses to mRNA-COVID-19 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared to healthy controls (HC).\n\nMethodsProspective, controlled, multi-center Israeli study. Subjects enrolled received two BNT162b2 (Pfizer/BioNTech) doses. Anti-spike (S) antibodies levels and functional activity, anti-TNF levels and adverse events (AEs) were detected longitudinaly.\n\nResultsOverall 258 subjects: 185 IBD (67 treated with anti-TNF), and 73 HC. After the first vaccine dose all HC were seropositive, while some patients with IBD, regardless of treatment, remained seronegative. After the second dose all subjects were seropositive, however anti-S levels were significantly lower in anti-TNF treated compared to untreated patients, and HC (p<0.001; p<0.001, respectively). Neutralizing and inhibitory functions were both lower in anti-TNF treated compared to untreated patients, and HC (p<0.03; p<0.0001, respectively). Anti-TNF drug levels and vaccine responses did not affect anti-S levels. Infection rate ([~]2%) and AEs were comparable in all groups. IBD activity did not change in response to BNT162b2.\n\nConclusionsIn this prospective study in patients with IBD stratified according to treatment all patients mounted an immune response to two doses of BNT162b2. However, its magnitude was significantly lower in patients treated with anti-TNF, regardless of administration timing and drug levels. Vaccine was safe. As vaccine immune response longevity in this group may be limited, vaccine booster dose should be considered.","Head-to-head performance comparison of self-collected nasal versus professional-collected nasopharyngeal swab for a WHO-listed SARS-CoV-2 antigen-detecting rapid diagnostic test\nBackgroundIn 2020, the World Health Organization (WHO) recommended two SARS-CoV-2 lateral flow antigen detecting rapid diagnostics tests (Ag-RDTs), both initially with nasopharyngeal (NP) sample collection. Independent head-to-head studies demonstrated for SARS-CoV-2 Ag-RDTs nasal sampling to be a comparable and reliable alternative for nasopharyngeal (NP) sampling.\n\nMethodsWe conducted a head-to-head comparison study of a supervised, self-collected nasal mid-turbinate (NMT) swab and a professional-collected NP swab, using the Panbio Ag-RDT (the second WHO-listed SARS-CoV-2 Ag-RDT, distributed by Abbott). We calculated positive and negative percent agreement and, compared to the reference standard reverse transcription polymerase chain reaction (RT-PCR), sensitivity and specificity for both sampling techniques.\n\nResultsA SARS-CoV-2 infection could be diagnosed by RT-PCR in 45 of 290 participants (15.5%). Comparing the NMT and NP sampling the positive percent agreement of the Ag-RDT was 88.1% (37/42 PCR positives detected; CI 75.0% - 94.8%). The negative percent agreement was 98.8% (245/248; CI 96.5% - 99.6%). The overall sensitivity of Panbio with NMT sampling was 84.4% (38/45; CI 71.2% - 92.3%) and 88.9% (40/45; CI 76.5% - 95.5%) with NP sampling. Specificity was 99.2% (243/245; CI 97.1% - 99.8%) for both, NP and NMT sampling. The sensitivity of the Panbio test in participants with high viral load (> 7 log10 SARS-CoV-2 RNA copies/mL) was 96.3% (CI 81.7% - 99.8%) for both, NMT and NP sampling.\n\nConclusionFor the Panbio Ag-RDT supervised NMT self-sampling yields to results comparable to NP sampling. This suggests that nasal self-sampling could be used for scale-up population testing.","Lower probability and shorter duration of infections after Covid-19 vaccine correlate with anti-SARS-CoV-2 circulating IgGs\nThe correlation between immune responses and protection from SARS-CoV-2 infections and its duration remains unclear. We performed a sanitary surveillance at the European Institute of Oncology (IEO) in Milan over a 17 months period. Pre-vaccination, in 1,493 participants, we scored 266 infections (17.8%) and 8 possible reinfections (3%). Post-vaccination, we identified 30 infections in 2,029 vaccinated individuals (1.5%). We report that the probability of infection post-vaccination is i) significantly lower compared to natural infection, ii) associated with a significantly shorter median duration of infection than that of first infection and reinfection, iii) anticorrelated with circulating antibody levels.","Tau-PET and in vivo Braak-staging as a prognostic marker in Alzheimer's disease\nINTRODUCTIONTau pathology in Alzheimers disease tracks clinical status more closely than beta-amyloid. Thus, tau-PET may be a promising prognostic marker for cognitive decline. Here, we systematically compared tau-PET and Braak-staging vs. amyloid-PET as predictors of cognitive decline.\n\nMETHODSWe included 396 cognitively normal to dementia subjects with 18F-Flutemetamol/18F-Florbetapir-amyloid-PET, 18F-Flortaucipir-tau-PET and ~2-year cognitive assessments. Annual cognitive change rates were calculated via linear-mixed models. We determined global amyloid-PET, global tau-PET, and tau-PET-based Braak-stage (Braak0/BraakI+/BraakI-IV+/BraakI-VI+/Braakatypical+). In bootstrapped linear regression, we assessed whether tau-PET outperformed amyloid-PET in predicting cognitive decline. Using ANCOVAs, we tested whether later Braak-stage predicted accelerated cognitive decline and determined Braak-stage-specific conversion risk to MCI or dementia.\n\nRESULTSGlobal tau-PET was a better predictor of cognitive decline than global amyloid-PET (p<0.001). Advanced Braak-stage was associated with faster cognitive decline (p<0.001) and elevated clinical conversion risk.\n\nDISCUSSIONTau-PET and Braak-staging show promise for predicting patient-specific risk of clinical AD progression.","Atypical resting state functional connectivity in mild traumatic brain injury\nObjectivesThis study aimed to investigate changes in three intrinsic functional connectivity networks (IFCNs; default mode (DMN), salience (SN), and task-positive networks (TPN)) in individuals who had sustained a mild traumatic brain injury (mTBI).\n\nMethodsResting-state functional magnetic resonance imaging (rs-fMRI) data was acquired from 27 mTBI patients with persistent post-concussive symptoms (PCS), along with 26 age- and sex-matched controls. These individuals were recruited from a Level-1 trauma centre, at least three months after a traumatic episode. IFCNs were established based on seed-to-voxel, region-of-interest (ROI) to ROI, and independent component analyses (ICA). Subsequently, we analyzed the relationship between functional connectivity and PCS.\n\nResultsSeed-to-voxel analysis of rs-fMRI demonstrated decreased functional connectivity in the right lateral parietal lobe, part of the DMN, and increased functional connectivity in the supramarginal gyrus, part of the SN. Our TPN showed both hypo- and hyperconnectivity, dependent on seed location. Within network hypoconnectivity was observed in the visual network, also using group comparison. Using an ICA, we identified altered network functional connectivity in regions within four IFCNs (sensorimotor, visual, DMN, and dorsal attentional). A significant negative correlation between dorsal attentional network connectivity and behavioural symptoms score was also found.\n\nConclusionsOur findings indicate that rs-fMRI may be of use clinically, in order to assess disrupted functional connectivity among IFCNs in mTBI patients. Improved mTBI diagnostic and prognostic information could be especially relevant for athletes looking to safely return to play, as well for individuals from the general population with persistent post-concussive symptoms months after injury, who hope to resume activity.","ARE GEOGRAPHIC FACTORS ASSOCIATED WITH POORER OUTCOMES IN PATIENTS DIAGNOSED WITH COVID-19?\nBackgroundThe prognosis of patients with COVID-19, with older age and comorbidities, is associated with a more severe course and higher fatality rates but no analysis has yet included factors related to the geographical area/municipality in which the affected patients live. So the objective of this study is to analyse the prognosis of patients with COVID-19 in terms of sex, age, comorbidities, and geographic variables.\n\nMethodsA retrospective cohort of 6286 patients diagnosed with COVID-19 was analysed, considering demographic data, previous comorbidities and geographic variables. The main study variables were hospital admission, Intensive Care Unit (ICU) admission and death due to worsening symptoms; and the secondary variables were sex, age, comorbidities and geographic variables (size of the area of residence, distance to the hospital and the driving time to the hospital). A comparison analysis and a multivariate Cox model were performed.\n\nResultsThe multivariate Cox model showed that women had a better prognosis in any type of analysed prognosis. Most of the comorbidities studied were related to a poorer prognosis except for dementia, which is related to lower admissions and higher mortality. Suburban areas were associated with greater mortality and with less hospital or ICU admission. Distance to the hospital was also associated with hospital admission.\n\nConclusionsFactors such as type of municipality and distance to hospital act as social health determinants. This fact must be taken account in order to stablish specifics prevention measures and treatment protocols.","Comparison of clinical course and outcomes of critically ill patients with SARS-CoV2 infection managed in traditional ICU and \"Flex\" ICU during the surge of the pandemic in the Bronx.\nBACKGROUNDAs part of the response to increase critical care capacity during the unprecedented surge of COVID-19 infections, NYC Health + Hospital systems identified and resourced areas in the hospital that could deliver critical care as \"Flex\" ICUs to complement the traditional ICUs to manage the rapid influx of critically ill patients.\n\nOBJECTIVEComparison of clinical features and outcomes of mechanically ventilated COVID-19 patients admitted to the traditional and \"Flex\" ICUs during the surge of the pandemic\n\nMETHODSRetrospective comparative cohort study of patients with confirmed SARS-CoV-2 infection on mechanical ventilation admitted to traditional ICU and Flex ICU. Univariate and multivariate analysis to detect factors associated with death from COVID-19 patients in mechanical ventilation were performed with the Cox proportional hazards regression model\n\nRESULTSOut of the 312 patients on mechanical ventilation, 111 were admitted to the traditional ICU and 201 to the Flex ICU. The mortality rate was higher in the Flex ICU compared with the traditional ICU, but the adjusted risk model was not significantly associated with increased mortality\n\nCONCLUSION\"Flex\" ICUs played a crucial role in the management of critically ill patients during the pandemic. Mortality risk of patients in the \"Flex\" ICUs were comparable to traditional ICUs in the adjusted analysis. While there is enough evidence for Intensivist managed ICUs to have better outcomes, our study demonstrates the feasibility of non-intensivist led Flex\" ICUs during a crisis.","The Statistical Monitoring by Adaptive RMSTD Tests: an efficient, informative, and customizable method for the complete internal quality control intended for low-frequent sampling of control measures\nTwo control mechanisms are relevant to perform an internal quality assurance: a permissible limit LSMC applied to single measures of control samples and a retrospective statistical analysis to detect increased imprecision and baseline drifts. A common statistical metric is the root mean square (total) deviation (RMSD/RMSTD). To focus on recent changes under low-frequent sampling conditions, the monitored amount of retrospective data is usually very small. Unfortunately, the calculated RMSTD of a small data set with n<50 samples has a significant statistical uncertainty that needs to be considered in adequate limit definitions. In particular, the minimum reasonable limit LRMSTD(n), applied to the RMSTD of a series of n samples, decreases from LSMC (e.g., 2.33*standard_deviation+bias) for n=1 towards Ltrue_RMSTD for n[->]{infty} (long-term statistics). Two mathematical approaches were derived to reliably estimate an optimal function to adjust LRMSTD(n) to small sample sizes.\n\nThis knowledge led to the development of a new quality-control method: the Statistical Monitoring by Adaptive RMSTD Tests (SMART). SMART requires just one mandatory limit (either LSMC or Ltrue_RMSTD) per analyte. By definition of up to 7 possible alert levels, SMART can early recognize and evaluate both the significance of a single outlier and establishing critical trends or shifts in recent SMC data. SMART is intended to efficiently monitor and evaluate small amounts of control data.","Individualized diversity in the extracellular metabolome of live human gliomas\nCancer metabolism is of increasing interest for drug development but few methods exist to evaluate live human malignancies. We utilized high molecular weight (HMW) microdialysis with elevated flow rate pumps under an investigational device exemption to sample the microenvironments of live human gliomas and adjacent brain during neurosurgical resections. Untargeted metabolic profiles spanning over 300 named metabolites were captured from 20{micro}L of microdialysate representing 10 minutes of intra-operative collection time. Five patients were each analyzed via 3 catheters with analysis of >300 named metabolites and 5 drugs. Rank-based analyses and machine learning highlighted metabolic heterogeneity across and between patients, as well as marked metabolic convergence within the most aggressive regions of molecularly diverse tumors. A novel glioma-associated metabolite, guanidinoacetatic acid (GAA), topped the list of extracellular glioma metabolites reflecting altered amino acid and energy metabolism. Intraoperative HMW microdialysis offers improved opportunities to accelerate individualized translational progress for glioma.","Anthropometric measures and their relationship to corneal refractive power in the United States population\nPurposeTo determine the relationship between anthropometric measures and corneal refractive power (CRP).\n\nMethodsParticipants from the 1999-2008 United States National Health and Nutrition Examination Survey (NHANES) visual exam with demographic, ocular, and anthropometric data (20,165 subjects) were included. Cases with steep cornea were defined by corneal power [≥] 48.0 diopters (n = 171) while controls had dioptric power < 48.0 D (n = 19,994). Multivariable analyses were performed for pooled and sex-stratified populations. Separate models assessed body mass index, height, and weight in relation to steep cornea.\n\nResultsA relationship between BMI and steep cornea in the pooled population was not detected (P for trend = 0.78). There was a strong inverse relationship between height and steep cornea in the pooled population (P for trend <0.0001) and women (P for trend <0.0001). For every 1-inch increase in height, there was a 16% reduced odds of steep cornea in the pooled population (OR, 0.84; 95% CI: 0.78-0.91). There was also a significant inverse relationship between weight and steep cornea in the pooled population (P for trend = 0.01) and in men (P for trend = 0.02). For each 10-pound increase in weight there was a 7% reduced odds of steep cornea (OR, 0.927; 95% CI: 0.882-0.975) in the pooled analysis.\n\nConclusionsGreater height and greater weight were associated with a lower risk of steep cornea. These findings can contribute to an improved understanding of the pathogenesis of corneal ectasias.","A unique dexamethasone-dependent gene expression profile in the lungs of COVID-19 patients\nLocal immunopathogenesis of COVID-19 acute respiratory distress syndrome (CARDS) and the effects of systemic dexamethasone (DXM) treatment on pulmonary immunity in COVID-19 remain insufficiently understood. To provide further insight into insight into immune regulatory mechanisms in the lungs of CARDS (with and without DXM treatment) and critically ill non-COVID-19 patients (without DXM treatment), transcriptomic RNA-seq analysis of bronchoalveolar lavage fluid (BALF) was performed in these patients. Functional analysis was performed using gene ontology and a blood transcription module, and gene expression of select pro-inflammatory cytokines, interferon-stimulated genes (ISGs) and auto-IFN antibodies were assessed. We found 550 and 2173 differentially expressed genes in patients with non-DXM-CARDS and DXM-CARDS, respectively. DXM-CARDS was characterized by upregulation of genes related to pulmonary innate and adaptive immunity, notably B-cell and complement pathway activation, antigen presentation, phagocytosis and FC-gamma receptor signalling. Pro-inflammatory genes were not differentially expressed in CARDS vs. non-COVID-19, nor did they differ according to DXM. Most ISGs were specifically upregulated in CARDS, particularly in non-DXM-CARDS. Auto-IFN autoantibodies were detectable in BALF of some CARDS patients. In conclusion, DXM treatment was not associated with regulation of pro-inflammatory pathways in CARDS but with regulation of other specific local innate and adaptive immune responses.\n\nsummaryThis study identifies differentially expressed genes in bronchoalveolar fluid of COVID-19 acute respiratory distress patients with a distinct RNA expression profile of those treated with dexamethasone. These results challenge the concept of a COVID-19 specific cytokine storm.","Predicting longitudinal brain atrophy in Parkinson's disease using a Susceptible-Infected-Removed agent-based model\nParkinsons disease (PD) is a progressive neurodegenerative disorder characterized by accumulation of abnormal isoforms of alpha-synuclein. Alpha-synuclein is proposed to act as a prion in PD: in its misfolded pathologic state it favours the misfolding of normal alpha-synuclein molecules, spreads trans-neuronally, and causes neuronal or synaptic damage as it accumulates. This theory remains controversial. We have previously developed a Susceptible-Infected-Removed (SIR) computational model that simulates the templating, propagation and toxicity of alpha-synuclein molecules in the brain. Here we test this model with longitudinal MRI collected over four years from the Parkinson Progression Markers Initiative (1068 T1 MRI scans, 790 PD, 278 matched controls). We find that brain deformation progresses in subcortical and cortical regions. The SIR model, using structural connectivity from diffusion MRI, recapitulates the spatiotemporal distribution of brain atrophy observed in PD. We show that connectome topology and geometry significantly contribute to model fit. We also show that the spatial expression of two genes implicated in alpha-synuclein synthesis and clearance, SNCA and GBA, also influences the atrophy pattern. We conclude that the progression of atrophy in PD is consistent with the prion-like hypothesis and that the SIR model is a promising tool to investigate multifactorial neurodegenerative diseases over time.","Genomic answers for children: Dynamic analyses of >1000 pediatric rare disease genomes\nPURPOSETo provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids (GA4K) program.\n\nMETHODSExtensive analyses of 960 families with suspected genetic disorders including short-read exome (ES) and genome sequencing (srGS); PacBio HiFi long-read GS (HiFi-GS); variant calling for small-nucleotide (SNV), structural (SV) and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants and pedigrees are stored in PhenoTips database, with data sharing through controlled access (dbGAP).\n\nRESULTSDiagnostic rates ranged from 11% for cases with prior negative genetic tests to 34.5% in naive patients. Incorporating SVs from GS added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with >4-fold more rare coding SVs than srGS. Variants and genes of unknown significance (VUS/GUS) remain the most common finding (58% of non-diagnostic cases).\n\nCONCLUSIONComputational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated by HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation, and by providing HiFi variant (SNV/SV) resources from >1,000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.","Thyroid function and risk of anemia: a multivariable-adjusted and Mendelian Randomization analysis in the UK Biobank\nContextThyroid dysfunction is associated with higher anemia prevalence, though causality remains unclear.\n\nObjectiveTo investigate a potential causal relationship between thyroid function and anemia.\n\nDesignCross-sectional and Mendelian Randomization study\n\nSettingEuropeans from UK Biobank\n\nParticipants445,482 participants, mean age 56.77 years (SD 8.0) and 54.2% were women. Self-reported clinical diagnosis of hypothyroidism was stated by 21,860 (4.9%); self-reported clinical diagnosis of hyperthyroidism by 3,431 (0.8%).\n\nMain Outcome MeasureAnemia, defined as hemoglobin level of <13 g/dL in men and <12 g/dL in women, was present in 18,717 (4.2%) participants.\n\nResultsIn cross-sectional logistic regression analyses, self-reported clinical diagnoses of hypo- and hyperthyroidism were associated with higher odds of anemia (OR 1.12, 95%CI 1.05-1.19 and OR 1.09, 95%CI 0.91-1.30), though with wide confidence intervals for hyperthyroidism. Although we considered a possible non-linear relationship, we did not observe an association of higher or lower genetically-influenced thyrotropin (TSH) with anemia (versus middle tertile: OR lowest tertile 0.98, 95% CI 0.95-1.02; highest tertile 1.02, 95% CI 0.98-1.06), nor of genetically-influenced free thyroxine (fT4) with anemia. Individuals with genetic variants in the DIO3OS gene implicated in intracellular regulation of thyroid hormones had a higher anemia risk (OR 1.05, 95% CI 1.02-1.10); no association was observed with variants in DIO1 or DIO2 genes.\n\nConclusionsWhile self-reported clinical diagnosis of hypothyroidism was associated with a higher prevalence of anemia, we did not found evidence supporting this association was causal. However, intracellular regulation of thyroid hormones might play a role in developing anemia.","Accurate and reproducible prediction of ICU readmissions\nReadmission in the intensive care unit (ICU) is associated with poor clinical outcomes and high costs. Traditional scoring methods to help clinicians deciding whether a patient is ready for discharge have failed to meet expectations, paving the way for machine learning based approaches. Freely available datasets such as MIMIC-III have served as benchmarking media to compare such tools. We used the OMOP-CDM version of MIMIC-III (MIMIC-OMOP) to train and evaluate a lightweight tree boosting method to predict readmission in ICU at different time points after discharge (3, 7 and 30 days), outperforming existing solutions with an AUROC of 0.805 for 3-days readmission.","Choosing questions before methods in dementia research with competing events and causal goals\nSeveral of the hypothesized or studied exposures that may affect dementia risk are known to increase the risk of death. This may explain counterintuitive results, where exposures that are known to be harmful for mortality risk sometimes seem protective for the risk of dementia. Authors have attempted to explain these counterintuitive results as biased, but the bias associated with a particular analytic method cannot be defined or assessed if the causal question is not explicitly specified. Indeed, we can consider several causal questions when competing events like death, which cannot be prevented by design, are present. Current dementia research guidelines have not explicitly considered what constitutes a meaningful causal question in this setting or, more generally, how this choice justifies and should drive particular analytic decisions. To contextualize current practices, we first perform a systematic review of the conduct and interpretation of longitudinal studies focused on dementia outcomes where death is a competing event. We then describe and demonstrate how to address different causal questions (referred here as \"the total effect\" and \"the controlled direct effect\") with traditional analytic approaches under explicit assumptions. Our application focuses on smoking cessation in late-midlife. To illustrate core concepts, we discuss this example both in terms of a hypothetical randomized trial and with an emulation of such a trial using observational data from the Rotterdam Study.","Fed-GLMM: A Privacy-Preserving and Computation-Efficient Federated Algorithm for Generalized Linear Mixed Models to Analyze Correlated Electronic Health Records Data\nLarge collaborative research networks provide opportunities to jointly analyze multicenter electronic health record (EHR) data, which can improve the sample size, diversity of the study population, and generalizability of the results. However, there are challenges to analyzing multicenter EHR data including privacy protection, large-scale computation, heterogeneity across sites, and correlated observations. In this paper, we propose a federated algorithm for generalized linear mixed models (Fed-GLMM), which can flexibly model multicenter longitudinal or correlated data while accounting for site-level heterogeneity. Fed-GLMM can be applied to both federated and centralized research networks to enable privacy-preserving data integration and improve computational efficiency. By communicating only a limited amount of summary statistics, Fed-GLMM can achieve nearly identical results as the gold-standard method where the GLMM is directly fitted on the pooled dataset. We demonstrate the performance of Fed-GLMM in both numerical experiments and an application to longitudinal EHR data from multiple healthcare facilities.","Personalized Computational Heart Models with T1-Mapped Fibrotic Remodeling Predict Risk of Sudden Death Risk in Patients with Hypertrophic Cardiomyopathy\nHypertrophic cardiomyopathy (HCM) causes sudden cardiac death (SCD) due to ventricular arrhythmias (VA) manifesting from myocardial fibrosis proliferation. Current clinical risk stratification criteria inadequately identify at-risk patients in need of primary prevention of VA. Here, we use mechanistic computational modeling of the heart to analyze how HCM-specific remodeling of the heart promotes arrhythmogenesis and to develop a personalized strategy to forecast risk of VAs in these patients. We combine contrast-enhanced cardiac magnetic-resonance (CMR) imaging and T1 mapping data to construct digital replicas of HCM patient hearts that represent the patient-specific distribution of focal and diffuse fibrosis and evaluate the substrate propensity to VA. Our analysis indicates that the presence of diffuse fibrosis, which is rarely assessed in these patients, increases arrhythmogenic propensity. In forecasting future VA events in HCM patients, the imaging-based computational heart approach achieved 84.6%, 76.9%, and 80.1% sensitivity, specificity, and accuracy, respectively, and significantly outperformed current clinical risk predictors. This novel VA risk assessment may have the potential to prevent SCD and help deploy primary prevention appropriately in HCM patients.","Epidemiological characteristics of three SARS-CoV-2 variants of concern and implications for future COVID-19 pandemic outcomes\nThree SARS-CoV-2 variants classified as variants of concern - B.1.1.7, B.1.351, and P.1 - have spread globally. To characterize their viral and epidemiological properties in support of public health planning, we develop and apply a model-inference system to estimate the changes in transmissibility and immune escape for each variant, based on case and mortality data from the country where each variant emerged. Accounting for under-detection of infection, disease seasonality, concurrent non-pharmaceutical interventions, and mass-vaccination, we estimate that B.1.1.7 has a 46.6% (95% CI: 32.3 - 54.6%) increase in transmissibility but nominal immune escape from protection induced by prior wild-type infection; B.1.351 has a 32.4% (95% CI: 14.6 - 48.0%) increase in transmissibility and 61.3% (95% CI: 42.6 - 85.8%) immune escape; and P.1 has a 43.3% (95% CI: 30.3 - 65.3%) increase in transmissibility and 52.5% (95% CI: 0 - 75.8%) immune escape. Model simulations indicate that B.1.351 and P.1 could supplant B.1.1.7 dominance and lead to increased infections. Our findings highlight the importance of preventing the spread of B.1.351 and P.1, in addition to B.1.1.7, via continued preventive measures, prompt mass-vaccination of all populations, continued monitoring of vaccine efficacy, and possible updating of vaccine formulations to ensure high efficacy.","Differences in detected viral loads guide use of SARS-CoV-2 antigen-detection assays towards symptomatic college students and children.\nLimitations in timely testing for SARS-CoV-2 drive the need for new approaches in suspected COVID-19 disease. We queried whether viral load (VL) in the upper airways at presentation could improve the management and diagnosis of patients. This study was conducted in a 9 hospital system in Allegheny County, Pennsylvania between March 1-August 31 2020. Viral load was determined by PCR assays for patients presenting to the Emergency Departments (ED), community pediatrics practices and college health service. We found that for the ED patients, VL did not vary substantially between those admitted and not. VL was relatively equivalent across ages, except for the under 25 age groups that tended to present with higher loads. To determine if rapid antigen testing (RAT) could aid diagnosis in certain populations, we compared BD Veritor and Quidel Sofia to SOC PCR-based tests. The antigen assay provided a disease-detection sensitivity of >90% in a selection of 32 positive students and was modeled to have an 80% sensitivity in all positive students. In the outpatient pediatric population, the antigen assay detected 70% of PCR-positives. Extrapolating these findings to viral loads in older hospitalized patients, a minority would be detected by RAT (40%). Higher loads did correlate with death, though the prognostic value was marginal (ROC AUC of only 0.66). VL did not distinguish between those needing mechanical ventilation and routine inpatients. We conclude that VL in upper airways, while not prognostic for disease management, may aid in selecting proper testing methodologies for certain patient populations.","Assessing the contribution of rare-to-common protein-coding variants to circulating metabolic biomarker levels via 412,394 UK Biobank exome sequences\nGenome-wide association studies have established the contribution of common and low frequency variants to metabolic biomarkers in the UK Biobank (UKB); however, the role of rare variants remains to be assessed systematically. We evaluated rare coding variants for 198 metabolic biomarkers, including metabolites assayed by Nightingale Health, using exome sequencing in participants from four genetically diverse ancestries in the UKB (N=412,394). Gene-level collapsing analysis - that evaluated a range of genetic architectures - identified a total of 1,303 significant relationships between genes and metabolic biomarkers (p<1x10-8), encompassing 207 distinct genes. These include associations between rare non-synonymous variants in GIGYF1 and glucose and lipid biomarkers, SYT7 and creatinine, and others, which may provide insights into novel disease biology. Comparing to a previous microarray-based genotyping study in the same cohort, we observed that 40% of gene-biomarker relationships identified in the collapsing analysis were novel. Finally, we applied Gene-SCOUT, a novel tool that utilises the gene-biomarker association statistics from the collapsing analysis to identify genes having similar biomarker fingerprints and thus expand our understanding of gene networks.","In situ transcriptional profile of a germinal center plasmablastic burst hints at MYD88/CD79B mutants-enriched Diffuse Large B-cell Lymphomas.\nThe germinal center (GC) reaction results in the selection of B-cells acquiring effector Ig secreting ability by progressing towards plasmablastic differentiation. This transition is associated with exclusion from the GC microenvironment. The aberrant expansion of plasmablastic elements within the GC fringes configures an atypical condition, the biological characteristics of which have not been defined yet. We investigated the in situ immunophenotypical and transcriptional characteristics of a non-clonal germinotropic expansion of plasmablastic elements (GEx) occurring in the tonsil of a young patient. Compared to neighboring GC and peri-follicular regions, the GEx showed a distinctive signature featuring key regulators of plasmacytic differentiation, cytokine signaling, and cell metabolism. The GEx signature was tested in the setting of diffuse large B-cell lymphoma (DLBCL) as a prototypical model of lymphomagenesis encompassing transformation at different stages of GC and post-GC functional differentiation. The signature outlined DLBCL clusters with different immune microenvironment composition and enrichment in genetic subtypes.\n\nSignificanceThis report represents the first insight into the transcriptional features of a germinotropic plasmablastic burst, shedding light into the molecular hallmarks of B cells undergoing plasmablastic differentiation and aberrant expansion within the non-canonical setting of the GC microenvironment.","Developing and validating a multivariable prediction model for predicting costs of Colorectal Surgery\nHospitals are faced with a burden to predict and therefore to calculate and also to manage various cost factors in regard to the patients and their treatments. Especially the increased costs which occur if a patient suffers from an anastomotic insufficiency. This can lead to an unavoidable deficit in the final revenue of these medical centers.\n\nThis study aims to determine whether machine learning (ML) algorithms can predict the cost factors based on patients with and without colon anastomosis after colorectal surgery. For the forecasting, multiple predictors will be taken into the model to provide a tool which can be helpful for hospitals to manage their costs which can end up in operating more cost effectively. This proof of principle will lay the groundwork for an efficient ML-based prediction tool based on multicenter data from a range of international centers in the subsequent phases of the study.\n\nWith a % MAPE result of 18 to 25.6 the prediction if our model showed decent results in order to forecast the costs in regard to various diagnosed factors and surgery approaches. There is an urgent need for further studies on predicting cost factors, especially for cases with and without anastomotic leakage to minimize unnecessary costs for the hospitals.","The unmutated common ancestor of Gp41 conformational epitope targeting variable heavy chain 1-02 utilizing antibodies maintains antibody dependent cell cytotoxicity\nIn studies on monoclonal Abs (mAbs) from long-term non-progressors (LTNPs), our laboratory has previously described highly mutated Abs against a complex conformational epitope with contributions from both gp41 heptad repeat regions. Despite using the VH1-02 gene segment, known to contribute to some of the broadest neutralizing Abs against HIV, members of these Abs, termed group 76C Abs, did not exhibit broad neutralization.\n\nBecause of the excessive mutations and use of VH1-02, our goal was to characterize the non-neutralizing functions of Abs of group 76C, to assess targeting of the epitope in various clinical presentations, and to assess the development of these Abs by comparison to their predicted common ancestor. Serum competition assays showed group 76C Abs were enriched in LTNPs, in comparison to VRC-01. Specific group 76C clones 6F5 and 6F11, expressed as recombinant Abs, both have robust ADCC activity, despite their sequence disparity. Sequence analysis predicted the common ancestor of this clonal group would utilize the germline non-mutated variable gene. We produced a recombinant ancestor Ab (76Canc) with a heavy chain utilizing the germline variable gene sequence paired to the 6F5 light chain. Competition with group 76C recombinant Ab 6F5 confirms 76Canc binds HIV envelope constructs near the original group C epitope. 76Canc demonstrates comparable ADCC to 6F5 and 6F11 when targeting both clade B and C HIV constructs. The functional capability of Abs utilizing germline VH1-02 has implications for disease control and vaccine development.","COVID-19 mortality risk correlates inversely with vitamin D3 status, and a mortality rate close to zero could theoretically be achieved at 50 ng/ml 25(OH)D3: Results of a systematic review and meta-analysis\nBackgroundMuch research shows that blood calcidiol (25(OH)D3) levels correlate strongly with SARS-CoV-2 infection severity. There is open discussion regarding whether low D3 is caused by the infection or if deficiency negatively affects immune defense. The aim of this study was to collect further evidence on this topic.\n\nMethodsSystematic literature search was performed to identify retrospective cohort as well as clinical studies on COVID-19 mortality rates versus D3 blood levels. Mortality rates from clinical studies were corrected for age, sex and diabetes. Data were analyzed using correlation and linear regression.\n\nResultsOne population study and seven clinical studies were identified, which reported D3 blood levels pre-infection or on the day of hospital admission. They independently showed a negative Pearson correlation of D3 levels and mortality risk (r(17)=-.4154, p=.0770/r(13)=-.4886, p=.0646). For the combined data, median (IQR) D3 levels were 23.2 ng/ml (17.4 - 26.8), and a significant Pearson correlation was observed (r(32)=-.3989, p=.0194). Regression suggested a theoretical point of zero mortality at approximately 50 ng/ml D3.\n\nConclusionsThe two datasets provide strong evidence that low D3 is a predictor rather than a side effect of the infection. Despite ongoing vaccinations, we recommend raising serum 25(OH)D levels to above 50 ng/ml to prevent or mitigate new outbreaks due to escape mutations or decreasing antibody activity.\n\nTrial registrationNot applicable.","Post discharge persistent symptoms after COVID-19 in rheumatic and musculoskeletal diseases\nOBJECTIVESTo describe persistent symptoms and consequences in Rheumatic and Musculoskeletal diseases (RMD) discharged from the hospital after Covid-19; to assess the roll of autoimmune rheumatic diseases (ARD) compared to and non-autoimmune rheumatic and musculoskeletal diseases (NARD) on persistent symptoms and consequences.\n\nMETHODSWe performed a cross-sectional observational study. RMD attended at a rheumatology outpatient clinic in Madrid with Covid-19 that required hospital admission were included. The main outcomes were persistence of symptoms and health consequences related to Covid19 after discharge. Independent variable was RMD group (ARD and NARD) and covariates were sociodemographic, clinical, and treatments. We ran a multivariable logistic regression model to assess the risk by RMD group on main outcomes.\n\nRESULTSWe included 105 patients and 51.5% had ARD. 68.57% reported at least one persistent symptom. The most frequent were dyspnea, fatigue, and chest pain. 31 patients had consequences. Lung damage was found in 11.4% of the patients, 18% had blood test abnormalities (10% lymphopenia), two died, one developed central retinal vein occlusion and one patient developed optic neuritis. 11 patients required readmission due to Covid-19 problems (16.7% ARD vs 3.9% NARD; p=0.053). No statistically significant differences by RMD groups were found in the final models.\n\nCONCLUSIONMany RMD patients have persistent symptoms, similar to other populations. This study also highlights that lung damage is the most frequent consequence. ARD compared to NARD does not seem to differ in terms of persistent symptoms or consequences, although ARD might have a greater number of readmissions due to Covid-19.","Assessing the impact of race on glomerular filtration rate (GFR) prediction\nBackgroundThe appropriate use and the implications of using variables that attempt to encode a patients race in clinical predictive algorithms remain unclear. The clinical algorithm for estimating glomerular filtration rate (GFR) adjusts for race, but the observed difference between Black and non-Black participants lacks biologically substantiated evidence. We investigated the impact of using a race variable on GFR prediction by race-stratified error analysis.\n\nMethodsWe implemented three predictive algorithms with varied amount of input information from an electronic health record database to estimate GFR. We compared the prediction error of the estimated GFR with and without the variable race between Black patients and White patients.\n\nResultsThe prediction error for patients coded as Black was higher than that for patients coded as White across all three algorithms. Removing race from the prediction algorithm did not lower the prediction error for patients coded as Black, neither did it decrease the difference in error between the two groups. The algorithm that included the most information with thousands of variables but excluding race produced the most accurate estimate for both groups and minimized the difference in performance between the two groups.\n\nConclusionThe prediction error for patients coded as Black was higher compared to those coded as White, regardless of inclusion of race as a variable. Using a large amount of information represented in electronic health record variables achieved a more accurate prediction of GFR and the least difference in prediction error across racial groups.","Low-field thoracic magnetic stimulation increases peripheral oxygen saturation levels in coronavirus disease (COVID-19) patients: a single-blind, sham-controlled, crossover study\nThe severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may cause low oxygen saturation (SpO2) and respiratory failure in coronavirus disease (COVID-19) patients. Hence the increase of SpO2 levels could be crucial for the quality of life and recovery of these patients. Here we introduce an electromagnetic device termed low-field thoracic magnetic stimulation (LF-ThMS) system. This device was designed to non-invasively deliver a pulsed magnetic field from 100 to 118 Hz and 10.5 to 13.1 mT (i.e., 105 to 131 Gauss) to the dorsal thorax. We show that these frequencies and magnetic flux densities are safe for the patients. We also present a proof-of-concept that a single session of LF-ThMS applied for 30 minutes to the dorsal thorax of 17 COVID-19 patients significantly increases their SpO2 levels. We designed a single-blind, sham-controlled, crossover study on 5 COVID-19 patients who underwent two sessions of the study (real and sham LF-ThMS) and 12 COVID-19 patients who underwent only the real LF-ThMS. We found a statistically significant correlation between magnetic flux density, frequency, or temperature associated with the real LF-ThMS and SpO2 levels in all COVID-19 patients. However, the five patients of the sham-controlled study did not exhibit a significant change in their SpO2 levels during sham stimulation. All the patients did not present adverse events after the LF-ThMS intervention.\n\nTrial registrationClinicalTrials.gov\n\nIdentifierNCT04895267","Accounting for health inequities in the design of contact tracing interventions: a rapid review\nContextContact tracing has been a central COVID-19 transmission control measure. However, without the consideration of the needs of specific populations, public health interventions can exacerbate health inequities.\n\nPurposeThe purpose of this rapid review was to determine if and how health inequities were included in the design of contact tracing interventions in epidemic settings.\n\nMethodWe conducted a search of the electronic databases MEDLINE and Web of Science. Our inclusion criteria included articles that: (i) described the design of contact tracing interventions, (ii) have been published between 2013 and 2020 in English, French, Spanish, Chinese, or Portuguese, (iii) and included at least 50% of empiricism, according to the Automated Classifier of Texts on Scientific Studies (ATCER) tool. We relied on various tools to extract data.\n\nResultFollowing the titles and abstracts screening of 230 articles, 39 articles met the inclusion criteria. Only seven references were retained after full text review. None of the selected studies considered health inequities in the design of contact tracing interventions.\n\nConclusionThe use of tools/concepts for incorporating health inequities, such as the REFLEX-ISS tool, and \"proportionate universalism\" when designing contact tracing interventions, would enable practitioners, decision makers, and researchers to better consider health inequities.","Pathogens detected using a syndromic molecular diagnostic platform in patients hospitalized with severe respiratory illness in South Africa in 2017\nBackgroundPneumonia continues to be a leading cause of death globally; however, in >50% of cases, an etiological agent is not identified. We describe the use of a multi-pathogen platform, TaqMan array card (TAC) real-time PCR, for the detection of pathogens in patients hospitalized with severe respiratory illness (SRI).\n\nMethodsWe conducted prospective hospital-based surveillance for SRI among patients at two sentinel sites in South Africa between January and December 2017. Patients were included in this study if a blood specimen and at least one respiratory specimen (naso- and oro-pharyngeal (NP/OP) swabs and/or sputum) were available for testing. We tested respiratory specimens for 21 respiratory pathogens and blood samples for nine bacteria using TAC. Pathogen detection was compared by age group and HIV status using the chi-squared test.\n\nResultsDuring 2017, 956 patients were enrolled in SRI surveillance, and of these, 637 (67%) patients were included in this study (637 blood, 487 NP/OP and 411 sputum specimens tested). At least one pathogen was detected in 83% (527/637) of patients. Common pathogens detected included H. influenzae (225/637; 35%), S. pneumoniae (224/637; 35%), rhinovirus (144/637; 23%), S. aureus (129/637; 20%), K. pneumoniae (85/637; 13%), M. tuberculosis (75/637; 12%), and respiratory syncytial virus (57/637; 9%). Multiple pathogens ([≥]2) were co-detected in 57% (364/637) of patients.\n\nConclusionWhile use of a multi-pathogen platform was useful in the detection of a pathogen in the majority of the patients, pathogen co-detections were common and would need clinical assessment for usefulness in individual-level treatment and management decisions.","Safety Assessment of BNT162b2 Vaccine in Adolescents Aged 12-15 Years\nPresent evidence of the safety of BNT162b2 Vaccine in adolescents of 12 to 15 years relies only on 2260 subjects involved in phase 3 study. Therefore, clinical and post-clinical safety assessment of BNT162b2 Vaccine in Age Group of 12 to 15 Years is urgently needed to make an accurate judgment for mass vaccination. A rapid systemic review was conducted to determine safety profile of BNT162b2 Vaccine in Age Group of 12 to 15 Years following the PRISMA guidelines. Published literature before August 15, 2021 were searched in PubMed, Scopus, Web of Science, Embase, the Cochrane library and MedRxiv, using the defined search words. 135 records found from 6 databases, of which 4 studies (2 studies from NEJM and 2 MMWR), total subject who received at least one dose of vaccine: 64969, were included in this systemic review per the inclusion criteria. The major events reported in clinical phase and post-authorisation observational studies are pain at injection site (local), fatigue (systemic), headache (systemic), chill (systemic), diarrhoea (systemic) and joint pain (systemic). Post-authorisation observational study (n = 62,709) reported about 50% lower major systemic events, specifically, fatigue, headache, chill, diarrhoea and join pain and about 25% lower major local event, specifically, pain at injection site, than phase 3 clinical study (n = 1,131). Our study suggest that higher adherence rate (>97 percent received second dose) in clinical phase 3 and significantly lower incident of major local and systemic events in post-authorisation observational study indicating that BNT162b2 vaccine has highly favourable safety profile.","Polygenic risk vectors (PRV) improve genetic risk stratification for cardio-metabolic diseases\n1.Accurate disease risk stratification can lead to more precise and personalized prevention and treatment of diseases. As an important component to disease risk, genetic risk factors can be utilized as an early and stable predictor for disease onset. Recently, the polygenic risk score (PRS) method has combined the effects from hundreds to millions of single nucleotide polymorphisms (SNPs) into a score that can be used for genetic risk stratification. However, current PRS approaches only utilize the additive associations between SNPs and disease risk in a one-dimensional score. Here, we show that leveraging multiple types of genetic effects in multi-dimensional risk vectors, or a polygenic risk vector (PRV), can improve the stratification of cardio-metabolic diseases risks. Using data from UK Biobank (UKBB) and Electronic Medical Records and Genomics (eMERGE) Network biobank linked electronic health records (EHR) as development and evaluation data, we found that the combined effects between the additive PRS and the dominant PRS outperformed either one in terms of disease risk stratification, especially for the individuals in the high-risk group. Our results demonstrate that disease risks are likely to be influenced by multiple types of genetic effects, and PRV could utilize these effects for better risk stratification while retaining the simplicity of the PRS method.","Long-lasting neutralizing antibody responses in SARS-CoV-2 seropositive individuals are robustly boosted by immunization with the CoronaVac and BNT162b2 vaccines\nThe durability of circulating neutralizing antibody (nAb) responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and their boosting by vaccination remains to be defined. We show that outpatient and hospitalized SARS-CoV-2 seropositive individuals mount a robust neutralizing antibody (nAb) response that peaks at days 23 and 27 post-symptom onset, respectively. Although nAb titers remained higher in hospitalized patients, both study groups showed long-lasting nAb responses that can persist for up to 12 months after natural infection. These nAb responses in previously seropositive individuals can be significantly boosted through immunization with two doses of the CoronaVac (Sinovac) or one dose of the BNT162b2 (BioNTech/Pfizer) vaccines, suggesting a substantial induction of B cell memory responses. Noteworthy, three obese previously seropositive individuals failed to mount a booster response upon vaccination, warranting further studies in this population. Immunization of naive individuals with two doses of the CoronaVac vaccine or one dose of the BNT162b2 vaccine elicited similar levels of nAbs compared to seropositive individuals 4.2 to 13.3 months post-infection with SARS-CoV-2. Thus, this preliminary evidence suggests that both, seropositive and naive individuals, require two doses of CoronaVac to ensure the induction of robust nAb titers.","Spread of the SARS-CoV-2 UK-variant in the South East of France: impact on COVID-19 patients age, comorbidity profiles and clinical presentation, week 50 2020 to week 8 2021\nObjectivesThe variant 20I/501Y.V1, associated to a higher risk of transmissibility, emerged in Nice city (South East of France, French Riviera) during January 2021. The pandemic has resumed late December 2020 in this aera. A high incidence rate together with a fast turn-over of the main circulating variants, provided us the opportunity to analyze modifications in clinical profile and outcome traits.\n\nMethodsObservational study in the University hospital of Nice from December 2020 to February 2021. We analyzed data of sequencing of SARS-CoV-2 from the sewage collector and PCR screening from all positive samples at the hospital. Then, we described the characteristics of all COVID-19 patients admitted in the emergency department (ED) (n=1247) and those hospitalized in the infectious diseases ward or ICU (n=232). Demographic data, clinical signs and severity were recorded by the NEWS-2, SAPS-2 and SOFA scores were recorded and analyzed.\n\nResultsthe UK-variant was absent in the area in December, then increasingly spread in January representing 59% of the PCR screening performed mid-February. The rate of patients over 65 years admitted to the ED decreased from 63% to 50% (p=0.001). The mean age of hospitalized patients in the infectious diseases ward decreased from 70.7 to 59.2 (p<0.001) while the proportion of patients without comorbidity increased from 16% to 42% (p=0.007). Neither the NEWS-2 score nor the main signs of clinical severity have changed over time.\n\nConclusionSpread of the UK-variant in the South East of France affects younger and healthier patients.","A game theory based analysis of network connectivity reveals that state transition is crucial for epilepsy surgery outcome prediction\nSeizures recur in half of patients who undergo epilepsy surgery. Presurgical workup mainly focuses on seizures, but only partially helps predicting outcomes, even after invasive electroencephalography. We conceived a generalizable model to detect epileptogenic networks through connectivity changes and identified the crucial role of the transition from pre-seizure to seizure, achieving the highest outcome prediction (93%) to date in a chronological cohort of 21 patients with 3-year follow-up or more.","Age-specific effects of childhood BMI on multiple sclerosis risk: a Mendelian Randomisation study\nObjectiveHigher Body Mass Index (BMI) during early life is thought to be a causal risk factor for Multiple Sclerosis (MS). We used longitudinal mendelian randomisation (MR) to determine whether there is a critical window during which BMI influences MS risk.\n\nMethodsSummary statistics for childhood BMI and for MS susceptibility were obtained from recent large GWAS. We generated exposure instruments for BMI during four non-overlapping epochs (< 3 months, 3 months-1.5 years, 2-5 years, and 7-8 years) and performed MR using the inverse-variance weighted method with standard sensitivity analyses. Multivariable MR was used to account for effects mediated via later-life BMI.\n\nResultsFor all time epochs other than birth, genetically determined higher BMI was associated with an increased liability to MS: Birth (OR 0.81, 95% CI 0.50-1.31, NSNPs=7, p=0.39), Infancy (OR 1.18, 95%CI 1.04-1.33, NSNPs=18, p=0.01), Early childhood (OR 1.31, 95%CI 1.03-1.66, NSNPs=4, p=0.03), Later childhood (OR 1.34, 95% CI 1.08-1.66, NSNPs=4, p=0.01). Multivariable MR suggested that these effects may be mediated by effects on adult BMI.\n\nConclusionWe provide evidence using MR that genetically-determined higher BMI during early life is associated with increased MS risk. This effect may be driven by shared genetic architecture with later-life BMI.","Optical Genome Mapping And Single Nucleotide Polymorphism Microarray: An Integrated Approach For Investigating Challenging Cases Of Products Of Conception.\nConventional cytogenetic analysis of products of conception (POC) is of limited utility because of failed cultures, microbial and maternal cell contamination (MCC). Optical genome mapping (OGM) is an emerging technology that has the potential to replace conventional cytogenetic methods. The use of OGM precludes the requirement for culturing (and related microbial contamination). However, a high percentage of MCC impedes a definitive diagnosis, which can be addressed by an additional pre-analytical quality control step that includes histological assessment of H&E stained slides from FFPE tissue with macro-dissection for Chorionic villi to enrich fetal tissue component for Single nucleotide polymorphism (SNP) microarray analysis. An internal audit of POC cases subjected to karyotype-only analysis showed a low yield on clinically actionable information that contributed to patient care. To improve the diagnostic yield, an integrated workflow was devised that included MCC characterization of POC tissue, followed by OGM for MCC negative cases or SNPM with histological assessment for MCC positive cases. A result was obtained in 93% (29/31) cases with a diagnostic yield of 45.1% (14/31) with proposed workflow compared to 9.6% (3/31) and 6.4% (2/31) with routine workflow, respectively. The integrated workflow with these technologies demonstrates the clinical utility and higher diagnostic yield in evaluating POC specimens.","Mendelian randomization analyses reveal mediating factors of the causal effect of height on coronary artery disease\nAn inverse correlation between stature and risk of coronary artery disease (CAD) has been observed in several epidemiologic studies, and recent Mendelian randomization (MR) experiments have suggested evidence that this association may be causal. However, the extent to which the effect estimated by MR can be explained by established cardiovascular risk factors is unclear, with a recent report suggesting that lung function traits could fully explain the height-CAD effect. To clarify this relationship, we utilized the largest set of genetic instruments for human stature to date, comprising >2,000 genetic variants for height and CAD. In univariable analysis, we confirmed that a one standard deviation decrease in height ([~]6.5 cm) was associated with a 12.0% increase in the risk of CAD, consistent with previous reports. In multivariable analysis accounting for effects from up to 12 established risk factors, we observed a >3-fold attenuation in the causal effect of height on CAD susceptibility (3.7%, p = 2.1x10-2). We observed minimal effects of lung function traits on CAD risk in our analyses, indicating that these traits are unlikely to explain the residual association between height and CAD risk. In sum, these results suggest that height does not add meaningful clinical impact on CAD risk prediction beyond established risk factors.","Low-dose IL-2 reduces IL-21+ T cells and induces a long-lived anti-inflammatory gene expression signature inversely modulated in COVID-19 patients\nDespite early clinical success, the mechanisms of action of low-dose interleukin-2 (LD-IL-2) immunotherapy remain only partly understood. Here, we examine the effects of interval administration of low-dose recombinant IL-2 (iLD-IL-2) using high-resolution, single-cell multiomics. We confirmed that iLD-IL-2 selectively expands thymic-derived FOXP3+HELIOS+ Tregs and CD56br NK cells, and provide new evidence for an IL-2-induced reduction of highly differentiated IL-21-producing CD4+ T cells. We also discovered that iLD-IL-2 induces an anti-inflammatory gene expression signature, which was detected in all T and NK cell subsets even one month after treatment. The same signature was present in COVID-19 patients, but in the opposite direction. These findings indicate that the sustained Treg and CD56br NK cell increases induced by our 4-week iLD-IL2 treatment create a long-lasting and global anti-inflammatory environment, warranting further investigations of the potential clinical benefits of iLD-IL-2 in immunotherapy, including the possibility of reversing the pro-inflammatory environment in COVID-19 patients.","Metformin Is Associated with Favorable Outcomes in Patients with COVID-19 and Type 2 Diabetes Mellitus\nAimCoronavirus disease 2019 (COVID-19) is a new pandemic the entire world is facing since December of 2019. In this retrospective study, we aim to address whether metformin use offers a low mortality on patients with COVID-19 and pre-existing type 2 diabetes mellitus (T2DM).\n\nMaterials and MethodsA cohort of 1356 hospitalized patients with COVID-19 and pre-existing T2DM was analyzed by multivariate regression. Covariates that potentially confound the association were further adjusted using propensity score matching or inverse probability of treatment weighting. A meta-analysis of the present study along with 5 published studies with metformin use prior to admission in patients with COVID-19 and T2DM was carried out.\n\nResultsWe found that metformin therapy prior to admission in patients with COVID-19 and T2DM was significantly associated with less primary outcome events including in-hospital mortality and hospice care enrollment with an odds ratio (OR) of 0.25 (95% CI, 0.06-0.74) and less in-hospital length of stay, compared to non-metformin group. There were no statistical differences between the metformin group and non-metformin group for all three inflammatory markers (ferritin, CRP, and IL-6) on admission or peak levels during hospitalization. Furthermore, meta-analysis demonstrated that metformin use was significantly correlated with reduced mortality with an OR of 0.73 (95% CI, 0.65-0.82) in the fixed effect model and 0.58 (95% CI, 0.42-0.80) for the random effect model.\n\nConclusionsOur results provide supporting evidence that metformin may confer increased survival in patients with COVID-19 and T2DM treated with Metformin prior to hospitalization.","A functional TGFB1 polymorphism in the donor associates with long-term graft survival after kidney transplantation.\nIntroductionImprovement of long-term outcomes in kidney transplantation remains one of the most pressing challenges, yet drug development is stagnating. Human genetics offers an opportunity for much-needed target validation in transplantation. Conflicting data exists about the effect of transforming growth factor-beta 1 (TGF-{beta}1) on kidney transplant survival, since TGF-{beta}1 has profibrotic and protective effects. We therefore the impact of a recently discovered functional TGBF1 polymorphism on long-term kidney graft survival.\n\nMethodsWe performed an observational cohort study analyzing recipient and donor DNA in 1,271 kidney transplant-pairs from the University Medical Center Groningen in The Netherlands and associated a low-producing TGBF1 polymorphism (rs1800472-C>T) with 5, 10, and 15-year death-censored kidney graft survival.\n\nResultsDonor genotype frequencies of s1800472 in TGBF1 differed significantly between patients with and without graft loss (P=0.042). Additionally, the low-producing TGBF1 polymorphism in the donor was associated with an increased risk of graft loss following kidney transplantation (HR 2.13 for the T-allele; 95%-CI 1.16-3.90; P=0.015). The incidence of graft loss within 15 years of follow-up 16.4% in the CC-genotype group and 28.9% in the CT-genotype group. After adjustment for transplant-related covariates, the association between the TGBF1 polymorphism in the donor and graft loss remained significant. In contrast, there was no association between the TGBF1 polymorphism in the recipient and graft loss.\n\nConclusionKidney allografts possessing a low-producing TGBF1 polymorphism have a higher risk of late graft loss. Our study adds to a growing body of evidence that TGF-{beta}1 is beneficial, rather than harmful, for kidney transplant survival.","SARS-CoV-2 serostatus of healthcare worker in the Austrian state Vorarlberg between June 2020 and January 2021\nBackgroundAustria, and particularly its westernmost federal state Vorarlberg, developed an extremely high COVID-19 incidence rate in November 2020. Health care workers (HCW) may be at higher risk of contracting the disease within the working environment and therefore the seroprevalence in this population is of particular interest. Here, we analyzed SARS-CoV-2-specific antibody response in Vorarlberg HCW in a prospective cohort study.\n\nMethodsA total of 395 HCW have been tested at three different time points for the prevalence of anti-SARS-CoV-2 IgG antibodies specific for NP and RBD. Enrollment started in June 2020 (t1), two months after the end of the first wave. Re-testing took place between October to November at the beginning of the second wave (t2), and again at the end of the second wave in January 2021 (t3).\n\nResultsAt t1, 3% of HCW showed a strong IgG-specific responses to either NP or RBD. At t2, the rate increased to 4%, and after the second wave in January 2021, 14% had a strong response, which was assessed to be stable for up to ten months. The amount of HCW with anti-SARS-CoV-2 IgG antibodies was 38% higher than the number of infections found by RT-PCR.\n\nConclusionWe found low numbers of SARS-CoV-2-seropositive HCW in a hotspot setting after the first wave but a very high increase during the second massive wave. Though the seroprevalence in HCW was comparable to the general population. Our findings offer support for the routine application of serological testing in management of the ongoing COVID-19 pandemic.\n\nMain summaryA relatively low percentage of 3% SARS-CoV-2 seropositive HCW with strong IgG-specific antibody responses was found in the Austrian federal state Vorarlberg after the first wave increasing to 14% after the second massive wave lasting until January 2021.","Trans-ancestry genome-wide association study identifies novel genetic mechanisms in rheumatoid arthritis\nTrans-ancestry genetic research promises to improve power to detect genetic signals, fine-mapping resolution, and performances of polygenic risk score (PRS). We here present a large-scale genome-wide association study (GWAS) of rheumatoid arthritis (RA) which includes 276,020 samples of five ancestral groups. We conducted a trans-ancestry meta-analysis and identified 124 loci (P < 5 x 10-8), of which 34 were novel. Candidate genes at the novel loci suggested essential roles of the immune system (e.g., TNIP2 and TNFRSF11A) and joint tissues (e.g., WISP1) in RA etiology. Trans-ancestry fine mapping identified putatively causal variants with biological insights (e.g., LEF1). Moreover, PRS based on trans-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between European and East Asian populations. Our study provides multiple insights into the etiology of RA and improves genetic predictability of RA.","Analyzing Healthcare Safety Climate Through A Collaborative Filtering of Safety Attitudes Questionnaire for A Hospital Case Study\nBackgroundPatient safety climate in healthcare is an important element to improve quality of current healthcare system globally. Safety Attitudes Questionnaire (SAQ), one of measurable tools for patient safety climate, is applied as an effective research survey to collect opinions and information from medical workers in a long term.\n\nMethodSAQ data in this study consists of medical employee scores to 46 questions in 8 aspects or dimensions and personal information during 2014 to 2017 from a teaching hospital. A quantitative analysis with a core user based collaborative filtering method is conducted to analyze the SAQ data for discovering the latent inter-related pattern among different SAQ aspects of sub-sectors in this hospital for four years.\n\nResultsThere are not interrelationships between these 8 independent aspects for wards at different level (A, B and C) consistently across 4 years. The correlation patterns of aspects are not strong consistent over years for wards.\n\nConclusionObservations in this study can be used to support understanding patient safety climate assessment. They are contributed to further study in this area and understand SAQ aspects dynamically in a real hospital case.","Phenome-wide association analysis of substance use disorders in a deeply phenotyped sample\nBackgroundSubstance use disorders (SUDs) are associated with a variety of co-occurring psychiatric disorders and other SUDs, which partly reflects genetic pleiotropy. Polygenic risk scores (PRS) and phenome-wide association studies (PheWAS) are useful in evaluating pleiotropic effects. The comparatively low prevalence of SUDs and lack of detailed information available in electronic health records limits their informativeness for such analyses.\n\nMethodsWe used the deeply-phenotyped Yale-Penn sample [(N=10,610; 46.3% African ancestry (AFR), 53.7% European ancestry (EUR)], recruited for genetic studies of substance dependence, to examine pleiotropy for 4 major substance-related traits: alcohol use disorder (AUD), opioid use disorder (OUD), smoking initiation (SMK), and lifetime cannabis use (CAN). The sample includes both affected and control subjects interviewed using the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA), a comprehensive psychiatric interview.\n\nResultsIn AFR individuals PRS for AUD, and in EUR individuals PRS for AUD, OUD, and SMK, were associated with their respective primary DSM diagnoses. These PRS were also associated with additional phenotypes involving the same substance. PheWAS analyses of PRS in EUR individuals identified associations across multiple phenotypic domains, including phenotypes not commonly assessed in PheWAS analyses, such as family environment and early childhood experiences.\n\nConclusionsSmaller, deeply-phenotyped samples can complement large biobank genetic studies with limited phenotyping by providing greater phenotypic granularity. These efforts allow associations to be identified between specific features of disorders and genetic liability for SUDs, which help to inform our understanding of the pleiotropic pathways underlying them.","A Systematic Review of the Methodological Quality of Economic Evaluations in Genetic Screening and Testing for Monogenic Disorders\nPurposeUnderstanding the value of genetic screening and testing for monogenic disorders requires high-quality, methodologically robust economic evaluations. This systematic review sought to assess the methodological quality among such studies and examine opportunities for improvement.\n\nMethodsWe searched Pubmed, Cochrane, Embase, and Web of Science for economic evaluations of genetic screening/testing (2013-2019). Methodological rigor and adherence to best practices were systematically assessed using the BMJ checklist.\n\nResultsAcross 47 identified studies, there was substantial variation in modeling approaches, reporting detail, and sophistication. Models ranged from simple decision trees to individual-level microsimulation, comparing between two and >20 alternative interventions. Many studies failed to report sufficient detail to enable replication or did not justify modeling assumptions, especially for costing methods and utility values. Meta-analyses, systematic reviews, or calibration were rarely used to derive parameter estimates. Nearly all studies conducted some sensitivity analysis, and more sophisticated studies implemented probabilistic sensitivity/uncertainty analysis, threshold analysis, and value of information analysis.\n\nConclusionWe describe a heterogeneous body of work and present recommendations and exemplar studies across the methodological domains of (1) perspective, scope, and parameter selection, (2) use of uncertainty/sensitivity analyses, and (3) reporting transparency for improvement in the economic evaluation of genetic screening/testing.","Cardiovascular disease biomarkers derived from circulating cell-free DNA methylation\nAcute coronary syndromes (ACS) remain a major cause of worldwide mortality. ACS diagnosis is done by a combination of factors, such as electrocardiogram and plasma biomarkers. These biomarkers, however, lack the power to accurately stratify patients into different risk groups. Instead, we used changes in the circulating cell-free DNA (ccfDNA) methylation profiles to estimate the extent of heart injury and the severity of ACS. Our approach relies on the fact that dying cells in acutely damaged tissue release DNA into the blood, causing an increase in the ccfDNA. In addition, each cell type has a distinct DNA methylation profile. We leverage cell type/state specificity of DNA methylation to deconvolute the cell types of origin for ccfDNA and also find DNA methylation-based biomarkers that stratify patient cohorts. The cohorts consisted of healthy subjects, and patients from three ACS conditions: ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina (UA). We have used two cohorts of patients - discovery, and validation, both consisting of the same conditions. We have sequenced the ccfDNA from the discovery cohort using Whole Bisulfite Genome Sequencing (WBGS), to obtain an unbiased overview of plasma DNA methylation profiles. We have found a total of 1,614 differential methylated regions (DMRs) in the three ACS groups. Many of the regions are associated with genes involved in cardiovascular conditions and inflammation. Using linear models, we were able to narrow down to 254 DMRs significantly associated with ACS severity. The reduced list of DMRs enabled a more accurate stratification of ACS patients. The predictive power of the DMRs was validated in the confirmation cohort using targeted methylation sequencing of the validation cohort.","Alpha-1 adrenoreceptor antagonism mitigates extracellular mitochondrial DNA accumulation in lung fibrosis models and in patients with IPF\nIdiopathic Pulmonary Fibrosis is increasingly associated with adrenergic innervation and endogenous innate immune ligands such as mitochondrial DNA (mtDNA). Interestingly, a connection between these entities has not been explored. Here we report that noradrenaline (NA) derived from the lungs adrenergic nerve supply drives the accumulation of SMA-expressing fibroblasts via a mechanism involving 1 adrenoreceptors and mtDNA. Using the bleomycin model of lung fibrosis we compared the effect of lung specific adrenergic denervation achieved via the inhalational administration of the sympathetic neurotoxin 6-hydroxydopamine to surgically mediated adrenal ablation and found that NA derived from local but not adrenal sources drives lung fibrosis. Bleomycin induced the appearance of a SMA+ fibroblast population co-expressing the adrenoreceptor alpha-1D (ADRA1D). Therapeutic delivery of the 1 adrenoreceptor antagonist terazosin reversed these changes and suppressed the accumulation of extracellular mtDNA. TGF{beta}1-stimulated normal human lung fibroblasts treated with TGF{beta}1 and Noradrenaline expressed ADRA1D and developed reduced SMA expression and extracellular mtDNA concentrations when treated with terazosin. IPF patients prescribed 1 adrenoreceptor antagonists for non-pulmonary indications showed improved survival and reduced concentrations of plasma mtDNA. These findings link nerve-derived NA and 1 adrenoreceptor antagonism with mtDNA accumulation and lung fibrogenesis in mouse models, cultured cells, and humans with IPF. Further study of this neuro-innate connection may yield new avenues for investigation in the clinical and basic science realms.","Spatial covariance analysis of FDG-PET and HMPAO-SPECT for the differential diagnosis of dementia with Lewy bodies and Alzheimer's disease.\nWe investigated diagnostic characteristics of spatial covariance analysis (SCA) of FDG-PET and HMPAO-SPECT scans in the differential diagnosis of dementia with Lewy bodies (DLB) and Alzheimers disease (AD), in comparison with visual ratings and region of interest (ROI) analysis. Sixty-seven patients (DLB 29, AD 38) had both HMPAO-SPECT and FDG-PET scans. Spatial covariance patterns were used to separate AD and DLB in an initial derivation group (DLB n=15, AD n=19), before being forward applied to an independent group (DLB n=14, AD n=19). Visual ratings were by consensus, with ROI analysis utilising medial occipital/medial temporal uptake ratios. SCA of HMPAO-SPECT performed poorly (AUC 0.59{+/-}0.10), whilst SCA of FDG-PET (AUC 0.83{+/-}0.07) was significantly better. For FDG-PET, SCA showed similar diagnostic performance to ROI analysis (AUC 0.84{+/-}0.08) and visual rating (AUC 0.82{+/-}0.08). In contrast to ROI analysis, there was little concordance between SCA and visual ratings of FDG-PET scans. We conclude that SCA of FDG-PET outperforms that of HMPAO-SPECT and performed similarly to other analytical approaches, with the potential to improve with larger derivation groups. Compared to visual rating, SCA of FDG-PET relies on different sources of group variance to separate DLB from AD.","Comparative analysis unveils novel changes in serum metabolites and metabolomic networks of retinopathy of prematurity infants\nBackgroundAdvances in mass spectrometry are providing new insights into the role of metabolomics in the aetiology of many diseases. Studies in retinopathy of prematurity (ROP), for instance, overlooked the role of metabolic alterations in disease development. Here, we employed comprehensive metabolic profiling and gold-standard metabolic analysis to explore major metabolites and metabolic pathways significantly affected in early stages of pathogenesis toward ROP.\n\nMethodsThis is a multicentre, retrospective case-control study. We collected serums from 57 ROP cases and 57 strictly baseline matched non-ROP controls. Non-targeted ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) from Metabolon, Inc. was used to detect the metabolites in serum samples. Machine learning was used to unravel most affected metabolites and pathways in ROP development.\n\nResultsCompared to non-ROP controls, we found a significant metabolic perturbation in the ROP serums, featured with an increase in lipid, nucleotide, carbohydrate metabolites and a lower level of peptides. Machine leaning helped to distinguish a cluster of metabolic pathways (glycometabolism, redox homeostasis, lipid metabolism and arginine pathway) that were strongly related to the development of ROP. In addition, we found that the severity of ROP was related to the level of creatinine and ribitol.\n\nConclusionIn the current study, our results suggested a strong link between metabolic profiling and retinal neovascularization during ROP pathogenesis. These findings provided an insight into identifying novel metabolic biomarkers for ROP diagnosis and prevention.","Fitting the Reproduction number from UK coronavirus case data, and why it is close to 1\nWe present a method for rapid calculation of coronavirus growth rates and R-numbers tailored to the publicly available data in the UK. The R-number is derived from time-series of case data, using bespoke data processing to remove systematic and errors and stochastic fluctuations. In principle, growth rate can be obtained by differentiating the reported case numbers, but in fact daily stochastic fluctuations disqualify this method. We therefore assume that the case data comprises a smooth, underlying trend which is differentiable and a noise term. The approach produces, up-to-date estimates of the R-number throughout the period of data availability. Our method is validated against published consensus R-numbers from the UK government, and shown to produce comparable results. A significant advantage of our method is that it is stable up to the most recent data, this enables us to make R-number estimates available over two weeks ahead of the published consensus. The short-lived peaks observed in the R-number and case data cannot be explained by a well-mixed model and are suggestive of spread on a localised network. Such a localised spread model tends to give an Rt number close to 1, regardless of how large R0 is. The case-driven approach is combined with Weight-Shift-Scale (WSS) methods to monitor trends in the epidemic and for medium term predictions. Using case-fatality ratios, we create a narrative for trends in the UK epidemic increased infectiousness of the alpha and delta variants, and the effectiveness of vaccination in reducing severity of infection.","Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium\nSchizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.64 years (95% CI: 3.01, 4.26; I2 = 55.28%) compared to controls, after adjusting for age and sex (Cohens d = 0.50). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.","High incidence of pulmonary thromboembolism in hospitalized SARS-CoV-2 infected patients\nIntroductionSARS-CoV-2 infected patients present thrombotic complications caused by direct endothelial cells injury of the microvessels. Pulmonary thromboembolism (PE) has been reported by Computed Tomography pulmonary angiogram (CTPA) in patients with COVID-19 pneumonia with high D-dimer levels.\n\nObjectivesWe present the characteristics of SARS-CoV-2 infected patients diagnosed of PE by CTPA in our hospital. We also present the comparison of these findings with non-infected patients with PE data.\n\nMethodsPatients 18 years of age or older with SARS-CoV2 virus infection, and patients with suspected infection at beginning of admission but with negative PCR, were studied with CTPA for suspicion of VTE, during their hospitalization.\n\nResultsDuring the study period, 52 CTPA were performed in our hospital, sixteen in SARS-CoV-2 infected patients. No significant differences in age (p=0.43) and sex (p=0.31) were found between the two groups, infected and non-infected patients. In the infected group, the patients who had PE had a much lower median age (47.8 years) than those without PE (73.3 years). No differences between infected and non-infected patients were detected in the diagnosis of PE with CTPA, 28.6% versus 27.8% (p=1.00). Overall patient mortality was 1.9%; one patient died (6.3%) in the infected group, and none in the non-infected group (p=0.31).\n\nConclusionA considerable incidence of PE diagnosed by CTPA in SARS-CoV-2 infected patients has been observed, despite thrombo-prophylaxis.","Transmission blocking activity of low dose tafenoquine in healthy volunteers experimentally infected with Plasmodium falciparum\nBackgroundBlocking the transmission of parasites from humans to mosquitoes is a key component of malaria control. Tafenoquine exhibits activity against all stages of the malaria parasite and may have utility as a transmission blocking agent. We aimed to characterize the transmission blocking activity of low dose tafenoquine.\n\nMethodsHealthy adults were inoculated with P. falciparum 3D7-infected erythrocytes on day 0. Piperaquine was administered on days 9 and 11 to clear asexual parasitemia while allowing gametocyte development. A single 50 mg oral dose of tafenoquine was administered on day 25. Transmission was determined by enriched membrane feeding assays pre-dose and at 1, 4 and 7 days post-dose. Artemether-lumefantrine was administered following the final assay. Outcomes were the reduction in mosquito infection and gametocytemia post-tafenoquine, and safety parameters.\n\nResultsSix participants were enrolled, and all were infective to mosquitoes pre-tafenoquine, with a median 86% (range: 22-98) of mosquitoes positive for oocysts and 57% (range: 4-92) positive for sporozoites. By day 4 post-tafenoquine, the oocyst and sporozoite positivity rate had reduced by a median 35% (IQR: 16-46) and 52% (IQR: 40-62), respectively, and by day 7, 81% (IQR 36-92) and 77% (IQR 52-98), respectively. The decline in gametocyte density post-tafenoquine was not significant. No significant participant safety concerns were identified.\n\nConclusionLow dose tafenoquine reduces P. falciparum transmission to mosquitoes, with a delay in effect.\n\nTrial registrationAustralian New Zealand Clinical Trials Registry (ACTRN12620000995976).\n\nFundingQIMR Berghofer Medical Research Institute.","Dysbiosis in pre-cancerous mucosa may drive immune dysfunction: a study of immune system: microbiota interaction in familial adenomatous polyposis\nObjectivesFamilial adenomatous polyposis (FAP) is a condition caused by a constitutional pathogenic variant of the adenomatous polyposis coli (APC) gene that results in intestinal adenoma formation and colorectal cancer (CRC), necessitating pre-emptive colectomy. We sought to examine interaction between the mucosal immune system and commensal bacteria in FAP to test for immune dysfunction that might accelerate tumorigenesis.\n\nMethodsColonic biopsies were obtained from macroscopically normal mucosal tissue from 14 healthy donors and 13 patients with FAP during endoscopy or from surgical specimens. Intraepithelial and lamina propria lymphocytes were phenotyped. Intraepithelial microbes were labelled with anti-IgA/IgG and analyzed by flow cytometry.\n\nResultsProportions of resident memory CD103-expressing CD8+ and {gamma}{delta} T cell receptor+ intraepithelial lymphocytes were dramatically reduced in both left and right colon of patients with FAP compared to healthy controls. In lamina propria, T-cells expressed less CD103 and CD4+ CD103+ cells expressed less CD73 ectonucleotidase. IgA coating of epithelia-associated bacteria, IgA+ peripheral B cells and CD4 T-cell memory responses to commensal bacteria were increased in FAP.\n\nConclusionsLoss of resident memory T-cells and {gamma}{delta} T-cells in mucosal tissue of patients with FAP accompanies intestinal microbial dysbiosis previously reported in this pre-cancerous state and suggests impaired cellular immunity and tumor surveillance. This may lead to barrier dysfunction, possible loss of regulatory T-cell function and excess IgA antibody secretion. Our data are the first to implicate mucosal immune dysfunction as a contributing factor in this genetically driven disease and identify potentially critical pathways in the etiology of CRC.","Dynamic balance recovery in chronic Acquired Brain Injury participants following a perturbation training.\nBackgroundAcquired Brain Injury (ABI) is defined as a damage to the brain that occurs after birth. Subjects post-ABI suffer from dynamic balance impairments that persist years after the injury.\n\nObjectiveTo explore the effect of a perturbation method which is consisted of unexpected balance perturbations using Re-Step technology on the recovery of dynamic balance and gait velocity in chronic ABI participants.\n\nMethodsIn a clinical trial, 35 chronic ABI participants (stroke and traumatic brain injury) participated in 22 sessions of perturbation-training, twice a week for 3 months. Dynamic balance was assessed pre and post-training using Community Balance and Mobility Scale (CB&M). Gait velocity was also assessed in the stroke participants using the 10-meter walk test (10MWT).\n\nResultsDynamic balance improved significantly post-training (p=0.001). This improvement was greater than the improvement that was observed in a sub-group that was tested twice before training (p=0.04). 16 participants (45.7%) out of 35 met or exceeded minimal detectable change (MDC) of the CB&M Scale. Self-paced velocity also improved significantly (p=0.02) but only 2 participants (9.5%) out of 21 exceeded the MDC of 10MWT post-stroke.\n\nConclusionsUnexpected balance perturbation-training using Re-Step technology led to an improvement in dynamic balance and gait velocity in chronic ABI participants. The advantage of Re-Step technology training compared to conventional balance training should be further examined.","Torque teno virus load predicts allograft rejection but not viral infection after kidney transplantation\nThe main challenge of immunosuppressive therapy after solid organ transplantation is to create a new immunological balance that prevents organ rejection and does not promote opportunistic infection. Torque teno virus (TTV) a ubiquitous and non-pathogenic single-stranded DNA virus has been proposed as a marker of functional immunity in immunocompromised patients. Here investigate whether TTV loads predict the risk of common viral infection and allograft rejection in kidney transplantation recipients.\n\nIn a retrospective cohort of 389 kidney transplantation recipients, individual TTV loads in were measured by qPCR in consecutive plasma samples during one year follow-up. The endpoints were allograft rejection, BK polyomavirus (BKPyV) viremia and cytomegalovirus (CMV) viremia. Repeated TTV measurements and rejection and infection survival data were analysed in a joint model.\n\nDuring follow-up, TTV DNA detection in the transplant recipients increased from 85 to 100%. The median viral load increased to 107 genome copies/ml within three months after transplantation. Rejection, BKPyV viremia and CMV viremia occurred in 23%, 27% and 17% of the patients, respectively. With every 10-fold TTV load-increase, the risk of rejection decreased considerably (HR: 0.74, CI 95%: 0.71-0.76), while the risk of BKPyV and CMV viremia remained the same (HR: 1.03, CI 95%: 1.03-1.04 and HR: 1.01, CI 95%: 1.01-1.01).\n\nIn conclusion, TTV load kinetics predict allograft rejection in kidney transplantation recipients, but not the BKPyV and CMV infection. The potential use of TTV load levels as a guide for optimal immunosuppressive drug dosage to prevent allograft rejection deserves further validation.","Machine learning enabled subgroup analysis with real-world data to inform better clinical trial design\nRestrictive eligibility criteria for clinical trials may limit the generalizability of treatment effectiveness and safety to real-world patients. In this paper, we propose a machine learning approach to derive patient subgroups from real-world data (RWD), such that the patients within the same subgroup share similar clinical characteristics and safety outcomes. The effectiveness of our approach was validated on two existing clinical trials with the electronic health records (EHRs) from a large clinical research network. One is the donepezil trial for Alzheimers disease (AD), and the other is the Bevacizumab trial on colon cancer (CRC). The results show that our proposed algorithm can identify patient subgroups with coherent clinical manifestations and similar risk levels of encountering severe adverse events (SAEs). We further exemplify that potential rules for describing the patient subgroups with less SAEs can be derived to inform the design of clinical trial eligibility criteria.","Laboratory-Developed Test for SARS-CoV-2 Using Saliva Samples at the University of California, Riverside\nHere we describe a relatively quick, simple, economical and accurate laboratory developed test (LDT) for detection of SARS-CoV-2 in heated and diluted saliva samples without RNA extraction. Our protocol is a variation of the University of Illinois Urbana-Champaign SHIELD LDT. Differences include chilling of the samples during dilution and using a reduced volume for the qRT-PCR reactions. The level of detection for our LDT is 3125 copies/ml, which compares favorably with other saliva-based tests. Initial validation studies with a limited number of patient samples have demonstrated excellent agreement between results using our LDT and those obtained from external laboratories. The cost of consumables for our test is under $8 and a throughput of 1000 tests/day can be achieved with 3-4 personnel.","Longitudinal analysis shows durable and broad immune memory after SARS-CoV-2 infection with persisting antibody responses and memory B and T cells\nEnding the COVID-19 pandemic will require long-lived immunity to SARS-CoV-2. Here, we evaluate 254 COVID-19 patients longitudinally up to eight months and find durable broad-based immune responses. SARS-CoV-2 spike binding and neutralizing antibodies exhibit a bi-phasic decay with an extended half-life of >200 days suggesting the generation of longer-lived plasma cells. SARS-CoV-2 infection also boosts antibody titers to SARS-CoV-1 and common betacoronaviruses. In addition, spike-specific IgG+ memory B cells persist, which bodes well for a rapid antibody response upon virus re-exposure or vaccination. Virus-specific CD4+ and CD8+ T cells are polyfunctional and maintained with an estimated half-life of 200 days. Interestingly, CD4+ T cell responses equally target several SARS-CoV-2 proteins, whereas the CD8+ T cell responses preferentially target the nucleoprotein, highlighting the potential importance of including the nucleoprotein in future vaccines. Taken together, these results suggest that broad and effective immunity may persist long-term in recovered COVID-19 patients.","Predicting bloodstream infection outcome using machine learning\nBloodstream infections (BSI) are a main cause of infectious disease morbidity and mortality world-wide. Early prediction of patients at high risk of poor outcomes of BSI is important for earlier decision making and effective patient stratification. We developed electronic medical record-based machine learning models that predict patient outcomes of BSI. The area under the receiver-operating characteristics curve was 0.82 for a full featured inclusive model, and 0.81 for a compact model using only 25 features. Our models were trained, using electronic medical records that include demographics, blood tests, and the medical and diagnosis history of 7,889 hospitalized patients diagnosed with BSI. Among the implications of this work is implementation of the models as a basis for selective rapid microbiological identification, toward earlier administration of appropriate antibiotic therapy. Additionally, our models may help reduce the development of BSI and its associated adverse health outcomes and complications.","Distinct cellular dynamics associated with response to CAR-T therapy for refractory B-cell lymphoma\nChimeric Antigen Receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies. Approximately half of patients with refractory large B-cell lymphomas achieve durable responses from CD19-targeting CAR-T treatment; however, failure mechanisms are identified in only a fraction of cases. To gain novel insights into the basis of clinical response, we performed single-cell transcriptome sequencing of 105 pre- and post-treatment peripheral blood mononuclear cell samples, and infusion products collected from 32 individuals with high-grade B cell lymphoma treated with either of two CD19 CAR-T products: axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). Expansion of proliferative memory-like CD8 clones was a hallmark of tisa-cel response, whereas axi-cel responders displayed more heterogeneous populations. Elevations in CAR-T regulatory cells (CAR-Tregs) among non-responders to axi-cel were detected, and these populations were capable of suppressing conventional CAR-T cell expansion and driving late relapses in an in vivo model. Our analyses reveal the temporal dynamics of effective responses to CAR-T therapy, the distinct molecular phenotypes of CAR-T cells with differing designs, and the capacity for even small increases in CAR-Tregs to drive relapse.","Peripheral optical coherence tomography assisted by scleral depression in retinopathy of prematurity\nObjectiveTo determine whether handheld widefield optical coherence tomography (OCT) can be used to document retinopathy of prematurity (ROP) stage while using scleral depression to improve peripheral views.\n\nDesignProspective observational study\n\nParticipantsConsecutive neonates admitted to the neonatal intensive care unit (NICU) in a single academic medical center who also met criteria for ROP screening and consented for research imaging.\n\nMethodsScleral depression was combined with widefield OCT using an investigational 400-kHz, 55-degree field of view handheld OCT during ROP screening from October 28, 2020 to March 03, 2021.\n\nMain Outcome MeasuresAcquisition of en face and B-scan imaging of the peripheral retina to objectively assess early vitreoretinal pathology, including the demarcation between vascularized and anterior avascular retina, the presence of early ridge formation, and small neovascular tufts.\n\nResultsVarious stages of ROP were detected using a rapid acquisition OCT system. In one neonate, serial OCT imaging over a five-week period demonstrated accumulation of neovascular tufts with progression to stage 3 ROP with extraretinal fibrovascular proliferation along the ridge. Videography of this technique is included in this report for instructional purposes.\n\nConclusionsSerial examinations using widefield OCT and scleral depression may improve detection and documentation of ROP disease progression. Earlier detection of ROP-related proliferation may prevent vitreoretinal traction, retinal detachment, and blindness.","The impact of population mobility on COVID-19 incidence and socioeconomic disparities at the sub-city level in 314 Latin American cities\nBackgroundLittle is known about the impact of changes in mobility at the sub-city level on subsequent COVID-19 incidence or the contribution of mobility to socioeconomic disparities in COVID-19 incidence.\n\nMethodsWe compiled aggregated mobile phone location data, COVID-19 confirmed cases, and features of the urban and social environments to analyze linkages between population mobility, COVID-19 incidence, and educational attainment at the sub-city level among cities with >100,000 inhabitants in Argentina, Brazil, Colombia, Guatemala, and Mexico from March to August 2020. We used mixed effects negative binomial regression to examine longitudinal associations between changes in weekly mobility (lags 1-6 weeks) and subsequent COVID-19 incidence at the sub-city level, adjusting for urban environmental factors.\n\nFindingsAmong 1,031 sub-cities representing 314 cities in five Latin American countries, 10% higher weekly mobility was associated with 8.5% (95% CI 7.4% to 9.5%) higher weekly COVID-19 incidence the following week. This association gradually declined as the lag between mobility and COVID-19 incidence increased and was not different from the null at a six-week lag. We found evidence that suggests differences in mobility reductions are a driver of socioeconomic disparities in COVID-19 incidence.\n\nInterpretationLower population movement within a sub-city is associated with lower risk of subsequent COVID-19 incidence among residents of that sub-city. Implementing policies that reduce population mobility at the sub-city level may be an impactful COVID-19 mitigation strategy that takes equity into consideration and reduces economic and social disruption at the city or regional level.\n\nFundingWellcome Trust","Breakthrough SARS-CoV-2 infections in MS patients on disease modifying therapies\nBackgroundPatients with Multiple Sclerosis (pwMS) treated with anti-CD20 or fingolimod showed a reduced humoral response to SARS-CoV-2 vaccines. In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in pwMS on different Disease Modifying Therapy (DMT).\n\nMethodsData on number of vaccinated patients and of patients with a breakthrough infection were retrospectively collected in 27 Italian MS centers. We estimated the rate of breakthrough infections and of infection requiring hospitalization per DMT.\n\nFindings19641 vaccinated pwMS were included in the database. After a median follow-up of 8 months, we observed 137 breakthrough infections. As compared to the other DMTs, the rate of breakthrough infections was significantly higher on ocrelizumab (0.57% vs 2.00%, RR=3.55,95%CI=2.74-4.58, p<0.001) and fingolimod (0.58% vs 1.62%, RR=2.65,95%CI=1.75-4.00, p<0.001), while there were no significant differences in any other DMT group. In the ocrelizumab group the hospitalization rate was 16.7% vs 19.4% in the pre-vaccination era (RR=0.86,p=0.74) and it was 3.9% in all the other DMT groups vs 11.9% in the pre-vaccination period (RR=0.33,p=0.02).\n\nInterpretationThe risk of breakthrough SARS-CoV-2 infections is higher in patients treated with ocrelizumab and fingolimod, and the rate of severe infections was significantly reduced in all the DMTs excluding ocrelizumab.","Assessment of Genetic Susceptibility to Multiple Primary Cancers through Whole-Exome Sequencing in Two Large Multi-Ancestry Studies\nUp to one of every six individuals diagnosed with one cancer will be diagnosed with a second primary cancer in their lifetime. Genetic factors contributing to the development of multiple primary cancers, beyond known cancer syndromes, have been underexplored. To characterize genetic susceptibility to multiple cancers, we conducted a pan-cancer, whole-exome sequencing study of individuals drawn from two large prospective cohorts (6,429 cases, 165,853 controls). We created two groupings of individuals diagnosed with multiple primary cancers: 1) an overall combined set with at least two cancers across any of 36 organ sites; and 2) cancer-specific sets defined by an index cancer at one of 16 organ sites with at least 50 cases from each study population. We then investigated whether variants identified from exome sequencing were associated with these sets of multiple cancer cases in comparison to individuals with one and, separately, no cancers. We identified 22 variant-phenotype associations, 10 of which have not been previously discovered and were significantly overrepresented among individuals with multiple cancers, compared to those with a single cancer. Overall, we describe variants and genes that may play a fundamental role in the development of multiple primary cancers and improve our understanding of shared mechanisms underlying carcinogenesis. Further investigation of these findings may lead to new screening strategies for individuals at risk for multiple primary cancers.","The acceptability of testing contacts of confirmed COVID-19 cases using serial, self-administered lateral flow devices as an alternative to self-isolation\nBackgroundTesting asymptomatic contacts of confirmed COVID-19 cases for the presence of SARS-CoV-2 could reduce onward transmission by improving case ascertainment and lessen the impact of self-isolation on un-infected individuals. This study investigated the feasibility and acceptability of implementing a test to enable approach as part of Englands tracing strategy.\n\nMethodsContacts of confirmed COVID-19 cases were offered serial testing as an alternative to self-isolation using daily self-performed lateral flow device (LFD) tests for the first 7 days post exposure. Asymptomatic participants with a negative LFD result were given 24 hours of freedom from self-isolation between each test. A self-collected confirmatory PCR test was performed on testing positive or at the end of the LFD testing period.\n\nResultsOf 1,760 contacts, 882 consented to daily testing, with 812 within 48 hours of exposure sent testing packs. Of those who declined to participate, 39.1% stated they had already accessed PCR testing. Of the 812 who were sent packs, 570 (70.2%) reported one or more LFD results; 102 (17.9%) tested positive. Concordance between reported LFD result and a supplied LFD image was 97.1%. 82.8% of PCR positive samples and 99.6% of PCR negative samples were correctly detected by LFD. The proportion of secondary cases from contacts of those who participated in the study and tested positive (6.3%; 95% CI: 3.4-11.1%) were comparable to a comparator group who self-isolated (7.6%; 95% CI: 7.3-7.8%).\n\nConclusionThis study shows a high acceptability, compliance and positivity rates when using self-administered LFDs among contacts of confirmed COVID-19 cases. Offering routine testing as a structured part of the contact tracing process is likely to be an effective method of case ascertainment.","Transcriptome analysis of PBMCs reveals distinct immune response in the asymptomatic and re-detectable positive COVID-19 patients\nThe existence of asymptomatic and re-detectable positive COVID-19 patients presents the disease control challenges of COVID-19. Most studies on immune response of COVID-19 have focused on the moderately or severely symptomatic patients, however little is known about the immune response in asymptomatic and re-detectable positive patients. Here we performed a comprehensive analysis of the transcriptomic profiles of PBMCs from 48 COVID-19 patients which include 8 asymptomatic, 13 symptomatic, 15 recovering and 12 RP patients. Our analysis revealed a down-regulation of IFN response and complement activation in the asymptomatic patients compared with the symptomatic, indicating a weaker immune response of the PBMCs in the asymptomatic patients. In addition, we observed a lower expression of the cytokines and chemokines in the PBMC of asymptomatic and symptomatic patients. In contrast, the cytokines and chemokines level in the RP patients are higher than the recovering. GSEA analysis showed the enrichment of TNFa/NF-{kappa}B and influenza infection in the RP patients compared with the recovering patients, indicating a flu-like, hyper-inflammatory immune response in the PBMC of RP patients. Thus our findings could extend our understanding of host immune response during the progression COVID-19 disease and help the clinical management and the immunotherapy development for COVID-19.","Multinational Prevalence of Neurological Phenotypes in Patients Hospitalized with COVID-19\nOBJECTIVENeurological complications can worsen outcomes in COVID-19. We defined the prevalence of a wide range of neurological conditions among patients hospitalized with COVID-19 in geographically diverse multinational populations.\n\nMETHODSUsing electronic health record (EHR) data from 348 participating hospitals across 6 countries and 3 continents between January and September 2020, we performed a cross-sectional study of hospitalized adult and pediatric patients with a positive SARS-CoV-2 reverse transcription polymerase chain reaction test, both with and without severe COVID-19. We assessed the frequency of each disease category and 3-character International Classification of Disease (ICD) code of neurological diseases by countries, sites, time before and after admission for COVID-19, and COVID-19 severity.\n\nRESULTSAmong the 35,177 hospitalized patients with SARS-CoV-2 infection, there was increased prevalence of disorders of consciousness (5.8%, 95% confidence interval [CI]: 3.7%-7.8%, pFDR<.001) and unspecified disorders of the brain (8.1%, 95%CI: 5.7%-10.5%, pFDR<.001), compared to pre-admission prevalence. During hospitalization, patients who experienced severe COVID-19 status had 22% (95%CI: 19%-25%) increase in the relative risk (RR) of disorders of consciousness, 24% (95%CI: 13%-35%) increase in other cerebrovascular diseases, 34% (95%CI: 20%-50%) increase in nontraumatic intracranial hemorrhage, 37% (95%CI: 17%-60%) increase in encephalitis and/or myelitis, and 72% (95%CI: 67%-77%) increase in myopathy compared to those who never experienced severe disease.\n\nINTERPRETATIONUsing an international network and common EHR data elements, we highlight an increase in the prevalence of central and peripheral neurological phenotypes in patients hospitalized with SARS-CoV-2 infection, particularly among those with severe disease.","SARS-CoV-2 responsive T cell numbers are associated with protection from COVID-19: A prospective cohort study in keyworkers\nImmune correlates of protection from COVID-19 are incompletely understood. 2,826 keyworkers had T-SPOT(R) Discovery SARS-CoV-2 tests (measuring interferon-{gamma} secreting, SARS-CoV-2 responsive T cells, Oxford Immunotec Ltd), and anti-Spike S1 domain IgG antibody levels (EuroImmun AG) performed on recruitment into a cohort study. 285/2,826 (10.1%) of participants had positive SARS-CoV-2 RT-PCR tests, predominantly associated with symptomatic illness, during 200 days followup. T cell responses to Spike, Nucleoprotein and Matrix proteins (SNM responses) were detected in some participants at recruitment, as were anti-Spike S1 IgG antibodies; higher levels of both were associated with protection from subsequent SARS-CoV-2 test positivity. In volunteers with moderate antibody responses, who represented 39% (252/654) of those with detectable anti-Spike IgG, protection was partial, and higher with higher circulating T cell SNM responses. SARS-CoV-2 responsive T cell numbers predict protection in individuals with low anti-Spike IgG responses; serology alone underestimates the proportion of the population protected after infection.","The contribution of common regulatory and protein-coding TYR variants in the genetic architecture of albinism\nGenetic diseases have been historically segregated into rare Mendelian and common complex conditions.1,2 Large-scale studies using genome sequencing are eroding this distinction and are gradually unmasking the underlying complexity of human traits.3-8 Aiming to gain insights into the genetic architecture of rare recessive disorders, we studied a cohort of 1,313 individuals with albinism, an archetypal Mendelian condition. We investigated the contribution of protein-coding and regulatory variants both rare and common. We focused on TYR, the gene encoding tyrosinase, and found that a high-frequency promoter variant, TYR c.-301C>T [rs4547091], modulates the penetrance of a prevalent, disease-associated missense change, TYR c.1205G>A [rs1126809]. We also found that homozygosity for a haplotype formed by three common, functionally-relevant variants, TYR c.[-301C;575C>A;1205G>A], is associated with a high probability of receiving an albinism diagnosis (OR>82). This genotype is also associated with reduced visual acuity and increased central retinal thickness in UK Biobank participants. Finally, we report how the combined analysis of rare and common variants increases diagnostic yield and informs genetic counselling in families with albinism.","Point-of-care semiquantitative test for adherence to tenofovir alafenamide or tenofovir disoproxil fumarate\nSynopsisO_ST_ABSObjectiveC_ST_ABSObjective measurement of antiretrovirals may aid clinical interventions for improving adherence to HIV prevention or treatment regimens. A point-of-care urine test could provide real-time information about recent adherence to regimens containing tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). We developed a lateral flow immunoassay (LFA) and enzyme-linked immunoassay (ELISA) for urinary tenofovir.\n\nMethodsIntensity of the LFA test line was quantified using an optical reader and visually scored 0 - 5 by two independent people, using a reference card. The sensitivity and specificity of both the ELISA and LFA were determined for two different tenofovir concentration cutoffs for TDF and TAF adherence--1,500 ng/mL and 150 ng/mL, respectively. To validate the assays, we measured 586 urine samples from 28 individuals collected as part of a study of tenofovir pharmacokinetics in adults, which were also measured by mass spectrometry as ground truth.\n\nResultsBoth the LFA signal and ELISA signal were each strongly correlated to drug concentrations (0.91 and 0.92 respectively). The LFA signal and ELISA were highly sensitive and specific at both thresholds (LFA se/sp TDF 89%/96%, TAF 90%/96%; ELISA se/sp TDF 94%/94%, TAF 92%/84%). Visual scoring of the LFA was also highly sensitive and specific at both the TDF and TAF thresholds (se/sp TDF 91%/94%, TAF 87%/90%).\n\nConclusionsOur rapid semi-quantitative test can measure TFV concentrations relevant to both TAF or TDF adherence, which may support adherence-promoting interventions across a range of HIV care settings.","Treatment of sarcoidosis with cutaneous involvement with tofacitinib\nSarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids and there are no approved steroid-sparing medications. There is emerging evidence that Janus kinase (JAK) inhibitors, which inhibit JAK-dependent cytokine activity, may hold promise in sarcoidosis. In this open-label trial, 10 patients with recalcitrant sarcoidosis with cutaneous involvement were treated with tofacitinib 5 mg twice daily. There was no washout period and patients were permitted to continue, taper, or discontinue other treatments. The primary outcome was the change in the Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI) activity score after 6 months. Change in internal organ disease activity was also assessed using total lesion glycolysis (TLG) determined by full-body positron emission tomography. A mean reduction in the CSAMI activity score of 82.7% was observed, with 6 patients showing a complete response. Internal organ response data was available in 8 patients; a decrease in TLG of [≥]50% was noted in 5 patients, with complete or near complete resolution in 3 (>98% reduction in TLG). Patients were generally able to significantly taper or discontinue their baseline immunosuppressive regimen, which included prednisone in 5 patients. Single cell RNA-sequencing, bulk RNA-sequencing, and high-throughput proteomic analyses were performed on skin and blood as a function of treatment in order to delineate changes in immunologic signals with therapy. We identified CD4+ T cell derived IFN-{gamma} as a central cytokine driver of sarcoidosis and inhibition of its activity was achieved with tofacitinib and correlated closely with clinical improvement. Tofacitinib appears to have impressive activity in treatment of sarcoidosis and likely acts by inhibiting IFN-{gamma}, larger, controlled studies are warranted.","Sexual Behaviours and Sexual Health Among Middle-Aged and Older Adults in Britain: A Latent Class Analysis of The Natsal-3\nObjectivesPopulation-representative studies of the sexual health of middle-aged and older adults are lacking in aging societies. This study aimed to identify latent patterns of sexual behaviours and health of people aged 45-74.\n\nMethodsWe conducted a latent class analysis of the National Attitudes and Sexual Lifestyles Survey (Natsal-3), a nationally representative survey conducted in Britain in 2011.\n\nResultsOf the 5260 respondents aged 45-74, 49% of men and 45% of women belonged to the Content Caseys class who reported good sexual health. The Infrequent Indigos (31% of men, 44% of women) were characterized by a lack of sexual activity, reported some dissatisfaction, and were more likely to have a disability. The Low-Functioning Lees (12% of men, 8% of women) reported some more disability and had issues with sexual functioning and higher levels of distress. The Multiple-Partnered Morgans (9% of men, 2% of women) were characterized by a greater number of sexual partners and several risk behaviours.\n\nConclusionsThe use of these four classes can aid in improved targeting of tailored sexual health services to improve sexual function, sexual satisfaction, reduce distress and risky behaviours among middle-aged and older adults. These services should be inclusive of the disabled community.\n\nBullet pointsO_LIAbout half of these respondents were classified as Content Caseys who reported few issues concerning their sex lives.\nC_LIO_LIOver a third who reported no recent sexual activity, the vast majority of whom are single, were classified as Infrequent Indigos.\nC_LIO_LINearly 10% were classified Low-Functioning Lees due to the greater probability of reporting sexual function issues and distress.\nC_LIO_LIThe rest were classified as Multiple Partner Morgans as a result of a high likelihood of having multiple partners and unsafe sex.\nC_LI","Lipid-Modulating Agents for Prevention or Treatment of COVID-19 in Randomized Trials\nCoronavirus disease 2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multi-organ manifestations. Lipid modulating agents may be useful in treating patients with COVID-19. They may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglycerides portends worse outcome in patients with COVID-19. Upon a systematic search, 40 RCTs with lipid modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrates RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for management or prevention of COVID-19. This manuscript summarizes the ongoing or completed randomized controlled trials (RCTs) of lipid modulating agents in COVID-19 and the implications of these trials for patient management.","Relationships between freezing of gait severity and cognitive deficits in Parkinson's disease\nObjectiveEvidence supports an association between freezing of gait (FOG) severity and cognitive functioning in patients with Parkinsons disease (PD); however, results are varied. Here we sought to explore the differences in cognitive measurements via multivariable statistical models in patients with PD.\n\nMethodsPD patients with (PDFOG+, n=41) and without FOG (PDFOG-, n=39) and control healthy subjects (n=41) participated in the study. The NIH toolbox cognition battery, Montreal cognitive assessment (MoCA), and interval timing task were used to test cognitive domains. Measurements were compared between groups using multivariable models and adjusting for covariates. Correlation analyses, linear regression, and mediation models were applied to examine relationships among disease duration and severity, FOG severity, and cognitive functioning.\n\nResultsSignificant differences were observed between controls and PD patients for all cognitive domains. PDFOG+ and PDFOG- exhibited differences in the dimensional change card sort (DCCS) test, interval timing task, and MoCA scores. After adjusting for covariates in two different models, PDFOG+ and PDFOG- differed in both MoCA and DCCS scores. In addition, significant relationships between FOG severity and cognitive function (MoCA, DCCS, and interval timing) were also found. Regression models suggest that FOG severity may be a predictor of cognitive impairment, and mediation models show the effects of cognitive impairment on the relationship between disease severity and FOG severity.\n\nConclusionsOverall, this study provides insight into the relationship between cognitive and FOG severity in patients with PD, which could aid in the development of therapeutic interventions to manage both.","A Quantitative Systems Pharmacology Model of the Pathophysiology and Treatment of COVID-19 Predicts Optimal Timing of Pharmacological Interventions\nA quantitative systems pharmacology (QSP) model of the pathogenesis and treatment of SARS-CoV-2 infection can streamline and accelerate the development of novel medicines to treat COVID-19. Simulation of clinical trials allows in silico exploration of the uncertainties of clinical trial design and can rapidly inform their protocols. We previously published a preliminary model of the immune response to SARS-CoV-2 infection. To further our understanding of COVID-19 and treatment we significantly updated the model by matching a curated dataset spanning viral load and immune responses in plasma and lung. We identified a population of parameter sets to generate heterogeneity in pathophysiology and treatment and tested this model against published reports from interventional SARS-CoV-2 targeting Ab and anti-viral trials. Upon generation and selection of a virtual population, we match both the placebo and treated responses in viral load in these trials. We extended the model to predict the rate of hospitalization or death within a population. Via comparison of the in silico predictions with clinical data, we hypothesize that the immune response to virus is log-linear over a wide range of viral load. To validate this approach, we show the model matches a published subgroup analysis, sorted by baseline viral load, of patients treated with neutralizing Abs. By simulating intervention at different timepoints post infection, the model predicts efficacy is not sensitive to interventions within five days of symptom onset, but efficacy is dramatically reduced if more than five days pass post-symptom onset prior to treatment.","The Effect of Convalescent Plasma Therapy on COVID-19 Patient Mortality: Systematic Review and Meta-analysis\nTo determine the effect of COVID-19 convalescent plasma on mortality, we aggregated patient outcome data from randomized clinical trials, matched control, case series, and case report studies. Fixed-effects analyses demonstrated that hospitalized COVID-19 patients transfused with convalescent plasma exhibited a ~57% reduction in mortality rate (10%) compared to matched-patients receiving standard treatments (22%; OR: 0.43, P < 0.001). These data provide evidence favouring the efficacy of human convalescent plasma as a therapeutic agent in hospitalized COVID-19 patients.","Waist circumference thresholds predicting incident dysglycemia and type 2 diabetes in Black African men and women\nObjectiveTo determine the waist circumference (WC) thresholds for the prediction of incident dysglycemia and type 2 diabetes in Black South African (SA) men and women and compare these to advocated International Diabetes Federation (IDF) Europid thresholds.\n\nResearch design and methodIn this prospective study, Black SA men (n=502) and women (n=527) from the Middle Aged Sowetan Cohort (MASC) study who had normal or impaired fasting glucose at baseline (2011-2015) were followed up through 2017-2018. Baseline measurements included anthropometry, blood pressure and fasting glucose, HDL-cholesterol and triglyceride concentrations. At follow-up, glucose tolerance was assessed using an oral glucose tolerance test. The Youden index was used to determine the optimal threshold of WC to predict incident dysglycemia and type 2 diabetes.\n\nResultsIn men, the optimal WC threshold was 96.8 cm for both dysglycemia and type 2 diabetes (sensitivity 56 and 70%, specificity 74 and 70%, respectively), which performed similarly to the IDF threshold of 94 cm. In women, the optimal WC threshold for incident dysglycemia was 91.8 cm (sensitivity 86%, specificity 37%) and for type 2 diabetes was 95.8 cm (sensitivity 85%, specificity 45%). In comparison, the IDF threshold of 80 cm in women had higher sensitivity (97 and 100%), but lower specificity (12 and 11%) to predict incident dysglycemia and type 2 diabetes, respectively.\n\nConclusionsIn this first prospective study of incident type 2 diabetes in Africa, we show that African-specific WC thresholds perform better than the IDF WC thresholds to predict incident dysglycemia and type 2 diabetes.","Comparing human and AI performance in medical machine learning: An open-source Python library for the statistical analysis of reader study data\nIn seeking to understand the potential effects of artificial intelligence (AI) on the practice of diagnostic medicine, many investigations involve collecting interpretations from several human experts on a common set of cases. In an effort to standardize the process of analyzing the data emerging from such studies, we have released an open-source Python library to perform applicable statistical procedures. The software implements the industry-standard Obuchowski-Rockette-Hillis (ORH) method for multi-reader multi-case (MRMC) studies. The tools can be used to compare a standalone algorithm against a panel of readers, or compare readers operating in two modalities (for example, with and without algorithmic assistance). The software supports both nonequivalence and noninferiority tests. Functions are also provided to simulate reader and model scores, useful for Monte Carlo power analysis. The code is publicly available in our Gitub repository at https://github.com/Google-Health/google-health/tree/master/analysis.","Super-Resolution of Magnetic Resonance Images Acquired Under Clinical Protocols using Deep Attention-based Method\nAO_SCPLOWBSTRACTC_SCPLOWVast quantities of Magnetic Resonance Images (MRI) are routinely acquired in clinical practice but, to speed up acquisition, these scans are typically of a quality that is sufficient for clinical diagnosis but sub-optimal for large-scale precision medicine, computational diagnostics, and large-scale neuroimaging research. Here, we present a critic-guided framework to upsample low-resolution (often 2D) MRI scans. In addition, we incorporated feature-importance and self-attention methods into our model to improve the interpretability of this work. We evaluate our framework on paired low- and high-resolution brain MRI structural full scans (i.e. T1-, T2-weighted and FLAIR sequences are simultaneously input) obtained in clinical and research settings from scanners manufactured by Siemens, Phillips and GE. We showed that the upsampled MRIs are qualitatively faithful to the ground-truth high-quality scans (PSNR = 35.39; MAE = 3.78E -3; NMSE = 4.32E -10; SSIM = 0.9852; mean normal-appearing grey/white matter ratio intensity differences ranging from 0.0363 to 0.0784 for FLAIR, from 0.0010 to 0.0138 for T1-weighted and from 0.0156 to 0.074 for T2-weighted sequences). The automatic raw segmentations of tissues and lesions using the super-resolved images have fewer false positives and higher accuracy than those obtained from interpolated images in protocols represented with more than three sets in the training sample, making our approach a strong candidate for practical application in clinical research."],"string":"[\n \"Reliability and validity of the Japanese version of the Mental Health Literacy Scale (MHLS) among undergraduate and graduate students in the medical field\\nObjectiveMental health literacy (MHL) is a fundamental basis of reducing stigma towards mental disorders and promoting early help-seeking. However, there is no internationally standardized scale covering all the attributes of MHL available in Japan. This study aimed to examine the reliability and validity of the Japanese version of the Mental Health Literacy Scale (MHLS) developed by OConnor et al. (2015).\\n\\nMethodsThe MHLS was translated in accordance with international guidelines. Japanese students in the medical field were invited to complete an online questionnaire twice at baseline and two-week follow-up. Using the data, Cronbachs alphas, intra-class correlation coefficient (ICC), and measurement errors were calculated for internal consistency and test-retest reliability. Correlations with mental health-related behavior (RIBS), accurate knowledge about mental disorders (MIDUS), intentions to seek help (GHSQ), and psychological distress (K6) were used to examine the convergent validity. Confirmatory factor analysis (CFA) and exploratory factor analysis (EFA) were performed to test structural validity.\\n\\nResultsA total of 183 and 150 students responded at baseline and follow-up. Cronbachs alpha coefficient was 0.76 and the ICC was 0.77 for the total score. The MHLS had a strong positive correlation with RIBS and moderate positive correlations with MIDUS and GHSQ. The CFA did not show a good fit either for one-or six-factor models, and the EFA yielded a four-factor structure.\\n\\nConclusionsThe Japanese version of the MHLS demonstrated adequate reliability and validity, while the factor structure did not fit previously proposed models. This scale may be useful for assessing the degree of MHL among medical field students in Japan.\",\n \"Antibody kinetics to SARS-CoV-2 at 13.5 months, by disease severity\\nBackgroundUnderstanding humoral responses and seroprevalence in SARS-CoV-2 infection is essential for guiding vaccination strategies in both infected and uninfected individuals.\\n\\nMethodsWe determine the kinetics of IgM against the nucleocapsid (N) and IgG against the spike (S) and N proteins of SARS-CoV-2 in a cohort of 860 health professionals (healthy and infected) in northern Barcelona. We model the kinetics of IgG and IgM at nine time points over 13.5 months from infection, using non-linear mixed models by sex and clinical disease severity.\\n\\nResultsOf the 781 participants who were followed up, 478 (61.2%) became infected with SARS-CoV-2. Significant differences were found for the three antibodies by disease severity and sex. At day 270 after diagnosis, median IgM(N) levels were already below the positivity threshold in patients with asymptomatic and mild-moderate disease, while IgG(N, S) levels remained positive to days 360 and 270, respectively. Kinetic modelling showed a general rise in both IgM(N) and IgG(N) levels up to day 30, followed by a decay whose rate depended on disease severity. IgG(S) levels increased at day 15 and remained relatively constant over time.\\n\\nConclusionsWe describe kinetic models of IgM(N) and IgG(N, S) SARS-CoV-2 antibodies at 13.5 months from infection and disease spectrum. Our analyses delineate differences in the kinetics of IgM and IgG over a year and differences in the levels of IgM and IgG as early as 15 days from symptoms onset in severe cases. These results can inform public health policies around vaccination criteria.\\n\\nFunded by the regional Ministry of Health of the Generalitat de Catalunya (Call COVID19-PoC SLT16_04; NCT04885478)\",\n \"Molecular diagnosis of causality in T cell mediated severe cutaneous adverse drug reactions\\nBackgroundOne of the most severe forms of T cell mediated cutaneous adverse drug reactions is drug reaction with eosinophilia and systemic symptoms (DRESS), hence subsequent avoidance of the causal drug is imperative. However, attribution of drug culpability in DRESS is challenging and standard skin allergy tests are not recommended due to for patient safety reasons. We sought to identify potential biomarkers for development of a diagnostic test.\\n\\nMethodsPeripheral blood mononuclear cells (PBMCs) from a discovery cohort (n=5) challenged to drug or control were analysed for transcriptomic profile. A signature panel of genes was then tested in a validation cohort (n=6), and compared to tolerant controls and other inflammatory conditions which can clinically mimic DRESS. A scoring system to identify presence of drug hypersensitivity was developed based on gene expression alterations of this panel.\\n\\nResultsWhole transcriptome analysis identified 4 major gene clusters including those regulating T cell activation via NFAT and cytokine receptor activity. 22 differentially expressed gene transcripts were identified as a DRESS signature including Type 1 interferon pathways and Th2 activation. The DRESS transcriptomic panel identified antibiotic-DRESS cases in a validation cohort but was not altered in other inflammatory conditions. Machine learning or differential expression selection of a biomarker panel showed high sensitivity and specificity (100% and 85.7-100% respectively) for identification of the culprit drug in DRESS.\\n\\nConclusionTranscriptomic analysis of DRESS revealed important insights into the key activated pathways and identified a transcriptional signature which shows potential as a test with high sensitivity for drug culpability attribution.\",\n \"Evaluation of the Implementation of the 4C Mortality Score in United Kingdom hospitals during the second pandemic wave\\nThe 4C Mortality Score (4C Score) was designed to risk stratify hospitalised patients with COVID-19. We assessed inclusion of 4C Score in COVID-19 management guidance and its documentation in patients case notes in January 2021 in UK hospitals. 4C Score was included within guidance by 50% of sites, though score documentation in case notes was highly variable. Higher documentation of 4C Score was associated with score integration within admissions proformas, inclusion of 4C Score variables or link to online calculator, and management decisions. Integration of 4C Score within clinical pathways may encourage more widespread use.\",\n \"Vagus nerve cross-sectional area in patients with Parkinsons Disease; an ultrasound case-control study\\nBackgroundVagal parasympathetic neurons are prone to degeneration in Parkinsons disease (PD). High-resolution ultrasound can precisely estimate the cross-sectional area (CSA) of peripheral nerves. Here, we tested the hypothesis that vagus CSA is reduced in PD.\\n\\nMethodsWe included 56 healthy controls (HCs) and 63 patients with PD. Using a high-end ultrasound system equipped with a high-frequency transducer, five images were obtained of each nerve. The hypoechoic neuronal tissue was delineated offline with dedicated software and the CSA extracted.\\n\\nResultsIn the initial PD vs. HC comparison, no statistically significant differences were observed in mean left vagus CSA (HC: 1.97mm2, PD: 1.89mm2, P=0.36) or in mean right vagus CSA (HC: 2.37mm2, PD: 2.23mm2, P=0.17). The right vagus CSA was significantly larger than the left vagus CSA in both groups (P<0.0001). Females were overrepresented in the HC group and presented with generally smaller vagus CSAs. Consequently, sex-adjusted CSA was significantly smaller for the right vagus nerve of the PD group (P=0.041), but not for the left.\\n\\nConclusionA small but significant reduction in sex-adjusted right vagus CSA was observed in patients with PD. The left vagus CSA was not significantly reduced in patients with PD. Ultrasound may not be a suitable method to detecting vagal axonal loss in individual patients.\",\n \"Performance evaluation of the BD SARS-CoV-2 reagents for the BD MAX™ system\\nBackgroundThe RT-qPCR assay for detecting SARS-CoV-2 virus is the favorable approach to test suspected COVID-19 cases. However, discordant results can occur when two or more assays are compared. Variability in analytical sensitivities between assays, among other factors, may account for these differences in reporting.\\n\\nMethodsThe limits of detection (LOD) for the BD SARS-CoV-2 Reagents for BD MAX System (\\\"MAX SARS-CoV-2 assay\\\"), the Biomerieux BioFire(R) Respiratory Panel 2.1 (\\\"BioFire SARS-CoV-2 assay\\\"), the Roche cobas SARS-CoV-2 assay (\\\"cobas SARS-CoV-2 assay\\\"), and the Hologic Aptima(R) SARS-CoV-2 assay Panther(R) (\\\"Aptima SARS-CoV-2 assay\\\") RT-qPCR systems were determined using a total of 84 contrived nasopharyngeal specimens with seven target levels for each comparator. The positive and negative percent agreement (PPA and NPA, respectively) for the MAX SARS-CoV-2 assay were compared to the Aptima SARS-CoV-2 assay in a post-market clinical study utilizing 708 paired nasopharyngeal specimens collected from suspected COVID-19 cases. Discordant results were further tested by the cobas and BioFire SARS-CoV-2 assays.\\n\\nResultsThe measured LOD for the MAX SARS-CoV-2 assay (251 copies/mL) was comparable to the cobas SARS-CoV-2 assay (298 copies/mL) and the BioFire SARS-CoV-2 assay (302 copies/mL); the Aptima SARS-CoV-2 assay had a LOD of 612 copies/mL. The MAX SARS-CoV-2 assay had a PPA of 100% (95%CI: [97.3%-100.0%]) and a NPA of 96.7% (95%CI: [94.9%-97.9%]) when compared to the Aptima SARS-CoV-2 assay.\\n\\nConclusionsThe MAX SARS-CoV-2 assay exhibited a high analytical sensitivity and specificity for SARS-CoV-2 detection. The clinical performance of the MAX SARS-CoV-2 assay agreed with another sensitive EUA cleared assay.\",\n \"Deceased donor kidney degradomics indicates cytoskeletal proteolytic alterations impacting post-transplant function.\\nBackgroundIn brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys that adversely impacts the quality of grafts. Here, we hypothesized that DBD kidneys may undergo proteolytic processes that renders grafts susceptible to post-transplant dysfunction.\\n\\nMaterial & MethodsUsing mass spectrometry and immunoblotting analyses, we profiled degradation patterns of cytoskeletal proteins in deceased (n=55) and living (n=10) donor kidneys.\\n\\nResultsWe found that in DBD kidneys, key podocyte cytoskeletal proteins had been proteolytically cleaved. Generated degradation profiles were not associated to donor related demographic and clinical factors but were associated to suboptimal post-transplant function. Strikingly, -actinin -4 and Talin-1 degradation profiles were not observed in circulatory-death or living-donor kidneys. As Talin-1 is a specific proteolytic target of Calpain-1, we investigated a potential trigger of Calpain activation and Talin-1 degradation using ex-vivo precision-cut human kidney slices and in-vitro immortalised human podocytes. Notably, we found that Transforming-Growth Factor-{beta} (TGF-{beta}) activated Calpain-1 and proteolytically cleaved Talin-1 to generate distinct peptide fragments. These peptide fragments were of similar size and matched the degradation patterns observed in DBD kidneys. Talin-1 degradation was prevented in vitro by Calpain-1 inhibition.\\n\\nConclusionsHere, we provide initial evidence that DBD kidneys are susceptible to cytoskeletal protein degradation that impacts posttransplant kidney function. Subsequent studies should aim to further investigate the link between brain death and activation of proteolytic pathways exploring new therapeutic opportunities.\",\n \"Upper Limb Motor Improvement after TBI: Systematic Review of Interventions\\nBackgroundTraumatic Brain Injury (TBI) is a leading cause of adult morbidity and mortality. Individuals with TBI have impairments in both cognitive and motor domains. Motor improvements post-TBI are attributable to adaptive neuroplasticity and motor learning. Majority of the studies focus on remediation of balance and mobility issues. There is limited understanding on the use of interventions for upper limb (UL) motor improvements in this population.\\n\\nObjectiveWe examined the evidence regarding the effectiveness of different interventions to augment UL motor improvement after a TBI.\\n\\nMethodsWe systematically examined the evidence published in English from 1990-2020. The modified Downs and Black checklist helped assess study quality (total score:28). Studies were classified as excellent:24-28, good:19-23, fair:14-18 and poor:[≤]13 in quality. Effect sizes helped quantify intervention effectiveness.\\n\\nResultsTwenty-three studies were retrieved. Study quality was excellent(n=1), good(n=5) or fair(n=17). Interventions used included strategies to decrease muscle tone (n=6), constraint induced movement therapy (n=4), virtual reality gaming (n=5), noninvasive stimulation (n=3), arm motor ability training (n=1), stem-cell transplant (n=1); task-oriented training (n=2) and feedback provision (n=1). Motor impairment outcomes included Fugl-Meyer Assessment, Modified Ashworth Scale, and kinematic outcomes (error and movement straightness). Activity limitation outcomes included Wolf Motor Function Test and Motor Activity Log. Effect sizes for majority of the interventions ranged from medium(0.5-0.79) to large([≥]0.8). Only ten studies included retention testing.\\n\\nConclusionThere is preliminary evidence that using some interventions may enhance UL motor improvement after a TBI. Answers to emergent questions can help select the most appropriate interventions in this population.\",\n \"A Deep Learning Method to Detect Opioid Prescription and Opioid Use Disorder from Electronic Health Records\\nObjectiveAs the opioid epidemic continues across the United States, methods are needed to accurately and quickly identify patients at risk for opioid use disorder (OUD). The purpose of this study is to develop two predictive algorithms: one to predict opioid prescription and one to predict OUD.\\n\\nMaterials and MethodsWe developed an informatics algorithm that trains two deep learning models over patient EHRs using the MIMIC-III database. We utilize both the structured and unstructured parts of the EHR and show that it is possible to predict both of these challenging outcomes.\\n\\nResultsOur deep learning models incorporate both structured and unstructured data elements from the EHRs to predict opioid prescription with an F1-score of 0.88 {+/-} 0.003 and an AUC-ROC of 0.93 {+/-} 0.002. We also constructed a model to predict OUD diagnosis achieving an F1-score of 0.82 {+/-} 0.05 and AUC-ROC of 0.94 {+/-} 0.008.\\n\\nDiscussionOur model for OUD prediction outperformed prior algorithms for specificity, F1 score and AUC-ROC while achieving equivalent sensitivity. This demonstrates the importance of a.) deep learning approaches in predicting OUD and b.) incorporating both structured and unstructured data for this prediction task. No prediction models for opioid prescription as an outcome were found in the literature and therefore this represents an important contribution of our work as opioid prescriptions are more common than OUDs.\\n\\nConclusionAlgorithms such as those described in this paper will become increasingly important to understand the drivers underlying this national epidemic.\",\n \"Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease\\nBackgroundOver 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target variants to improve lung function, but marked variability in response exists and current therapies do not address all CF-causing variants highlighting unmet needs. Alternative epithelial ion channel/transporters such as SLC26A9 could compensate for CFTR dysfunction, providing therapeutic targets that may benefit all individuals with CF.\\n\\nMethodWe investigate the relationship between rs7512462, a marker of SLC26A9 activity, and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD).\\n\\nResultsRs7512462 CC genotype is associated with greater lung function in CF individuals with minimal function variants (for which there are currently no approved therapies; p=0.008); and for gating (p=0.033) and p.Phe508del/ p.Phe508del (p=0.006) genotypes upon treatment with CFTR modulators. In parallel, human nasal epithelia with CC and p.Phe508del/p.Phe508del after Ussing chamber analysis of a combination of approved and experimental modulator treatments show greater CFTR function (p=0.0022). Beyond CF, rs7512462 is associated with lung function in a meta-analysis of the UK Biobank and Spirometa Consortium (min p=2.74x0-44) and provides p=0.0891 in an analysis of COPD case-control status in the UK Biobank defined by spirometry.\\n\\nConclusionThese findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases.\",\n \"Trajectories: a framework for detecting temporal clinical event sequences from health data standardized to the OMOP Common Data Model\\nObjectiveTo develop a framework for identifying prominent clinical event trajectories from OMOP-formatted observational healthcare data.\\n\\nMethodsA four-step framework based on significant temporal event pair detection is described and implemented as an open-source R package. It is used on a population-based Estonian dataset to first replicate a large Danish population-based study and second, to conduct a disease trajectory detection study for Type 2 Diabetes patients in the Estonian and Dutch databases as an example.\\n\\nResultsAs a proof of concept, we apply the methods in the Estonian database and provide a detailed breakdown of our findings. All Estonian population-based event pairs are shown. We compare the event pairs identified from Estonia to Danish and Dutch data and discuss the causes of the differences.\\n\\nConclusionsFor the first time, there is a complete software package for detecting disease trajectories in health data.\",\n \"Extubation generates lung volume inhomogeneity in preterm infants\\nObjectiveTo evaluate the feasibility of EIT to describe the regional tidal ventilation (VT) and change in end-expiratory lung volume (EELV) patterns in preterm infants during the process of extubation from invasive to non-invasive respiratory support.\\n\\nDesignProspective observational study\\n\\nSettingSingle-centre tertiary neonatal intensive care unit\\n\\nPatientsPreterm infants born <32 weeks gestation who were being extubated to nasal continuous positive airway pressure (nCPAP) as per clinician discretion.\\n\\nInterventionsElectrical Impedance Tomography measurements were taken in supine infants during elective extubation from synchronised positive pressure ventilation (SIPPV) before extubation, during and then at 2 and 20 minutes after commencing nCPAP. Extubation and pressure settings were determined by clinicians.\\n\\nMain outcome measuresGlobal and regional {Delta}EELV and {Delta}VT were measured. Heart rate, respiratory rate and oxygen saturation were measured throughout.\\n\\nResultsThirty infants of median (range) 2 (1, 21) days were extubated to a median (range) CPAP 7 (6, 8) cmH2O. SpO2/FiO2 ratio was mean (95% CI) 50 (35, 65) lower 20 minutes after nCPAP compared with SIPPV. EELV was lower at all points after extubation compared to SIPPV, and EELV loss was primarily in the ventral lung (p=0.04). VT was increased immediately after extubation, especially in the central and ventral regions of the lung, but the application of nCPAP returned VT to pre-extubation patterns.\\n\\nConclusionsLung behaviour during the transition from invasive positive pressure ventilation to CPAP at moderate distending pressures is variable and associated with lung volume loss in the ventral lung.\",\n \"Effectiveness of COVID-19 vaccines against hospitalization and death in Canada: A multiprovincial test-negative design study\\nBackgroundA major goal of COVID-19 vaccination is to prevent severe outcomes (hospitalizations and deaths). We estimated the effectiveness of mRNA and ChAdOx1 COVID-19 vaccines against severe outcomes in four Canadian provinces between December 2020 and September 2021.\\n\\nMethodsWe conducted this multiprovincial retrospective test-negative study among community-dwelling adults aged [≥]18 years in Ontario, Quebec, British Columbia, and Manitoba using linked provincial databases and a common study protocol. Multivariable logistic regression was used to estimate province-specific vaccine effectiveness against COVID-19 hospitalization and/or death. Estimates were pooled using random effects models.\\n\\nResultsWe included 2,508,296 tested subjects, with 31,776 COVID-19 hospitalizations and 5,842 deaths. Vaccine effectiveness was 83% after a first dose, and 98% after a second dose, against both hospitalization and death (separately). Against severe outcomes (hospitalization or death), effectiveness was 87% (95%CI: 71%-94%) [≥]84 days after a first dose of mRNA vaccine, increasing to 98% (95%CI: 96%-99%) [≥]112 days after a second dose. Vaccine effectiveness against severe outcomes for ChAdOx1 was 88% (95%CI: 75%-94%) [≥]56 days after a first dose, increasing to 97% (95%CI: 91%-99%) [≥]56 days after a second dose. Lower one-dose effectiveness was observed for adults aged [≥]80 years and those with comorbidities, but effectiveness became comparable after a second dose. Two doses of vaccines provided very high protection for both homologous and heterologous schedules, and against Alpha, Gamma, and Delta variants.\\n\\nConclusionsTwo doses of mRNA or ChAdOx1 vaccines provide excellent protection against severe outcomes of hospitalization and death.\",\n \"CNV-ClinViewer: Enhancing the clinical interpretation of large copy-number variants online\\nPurposeLarge copy number variants (CNVs) can cause a heterogeneous spectrum of rare and severe disorders. However, most CNVs are benign and are part of natural variation in human genomes. CNV pathogenicity classification, genotype-phenotype analyses, and therapeutic target identification are challenging and time-consuming tasks that require the integration and analysis of information from multiple scattered sources by experts.\\n\\nMethodsWe developed a web-application combining >250,000 patient and population CNVs together with a large set of biomedical annotations and provide tools for CNV classification based on ACMG/ClinGen guidelines and gene-set enrichment analyses.\\n\\nResultsHere, we introduce the CNV-ClinViewer (https://cnv-ClinViewer.broadinstitute.org), an open-source web-application for clinical evaluation and visual exploration of CNVs. The application enables real-time interactive exploration of large CNV datasets in a user-friendly designed interface.\\n\\nConclusionOverall, this resource facilitates semi-automated clinical CNV interpretation and genomic loci exploration and, in combination with clinical judgment, enables clinicians and researchers to formulate novel hypotheses and guide their decision-making process. Subsequently, the CNV-ClinViewer enhances for clinical investigators patient care and for basic scientists translational genomic research.\",\n \"Longitudinal prediction of motor dysfunction after stroke: a disconnectome study.\\nMotricity is the most commonly affected ability after a stroke. While many clinical studies attempt to predict motor symptoms at different chronic time points after a stroke, longitudinal acute-to-chronic studies remain scarce. Taking advantage of recent advances in mapping brain disconnections, we predict motor outcomes in 62 patients assessed longitudinally two weeks, three months, and one year after their stroke. Results indicate that brain disconnection patterns accurately predict motor impairments. However, disconnection patterns leading to impairment differ between the three time points and between left and right motor impairments. These results were cross-validated using resampling techniques. In sum, we demonstrated that while some neuroplasticity mechanisms exist changing the structure-function relationship, disconnection patterns prevail when predicting motor impairment at different time points after stroke.\",\n \"A seq2seq model to forecast the COVID-19 cases, deaths and reproductive R numbers in US counties\\nThe global pandemic of coronavirus disease 2019 (COVID-19) has killed almost two million people worldwide and over 400 thousand in the United States (US). As the pandemic evolves, informed policy-making and strategic resource allocation relies on accurate forecasts. To predict the spread of the virus within US counties, we curated an array of county-level demographic and COVID-19-relevant health risk factors. In combination with the county-level case and death numbers curated by John Hopkins university, we developed a forecasting model using deep learning (DL). We implemented an autoencoder-based Seq2Seq model with gated recurrent units (GRUs) in the deep recurrent layers. We trained the model to predict future incident cases, deaths and the reproductive number, R. For most counties, it makes accurate predictions of new incident cases, deaths and R values, up to 30 days in the future. Our framework can also be used to predict other targets that are useful indices for policymaking, for example hospitalization or the occupancy of intensive care units. Our DL framework is publicly available on GitHub and can be adapted for other indices of the COVID-19 spread. We hope that our forecasts and model can help local governments in the continued fight against COVID-19.\",\n \"An AI-based quantitative home-use framework for assessing fertility and identifying novel hormone trends by recording urine hormones\\nFertility testing using urinary hormones has been used to effectively improve the likelihood of pregnancy. To provide fertility scores, the existing home-use systems measure one or two hormones. However, the hormone profiles vary depending on cycle duration, fertility-related disorders, drugs and other treatments. Here, we introduce Inito, a mobile-phone connected reader that is scalable to multiple hormone tests. In this report, we assess the accuracy of the quantitative home-based fertility monitor, the Inito Fertility Monitor (IFM), and suggest using IFM as a device to monitor and analyse female hormone patterns. There were two aspects of the study: i. evaluation of the efficacy of IFM in quantifying urinary Estrone-3-glucuronide (E3G), pregnanediol glucuronide (PdG) and luteinizing hormone (LH), and ii. A retrospective study of patients hormone profiles using IFM. We observed that with all three hormones, IFM had an accurate recovery percentage and had a CV of less than 10 percent. Furthermore, in predicting the concentration of urinary hormones, IFM showed a high correlation with ELISA. Using Inito in clinical trials, we report a novel criterion for earlier confirmation of ovulation compared to existing criteria. We also present a novel hormone pattern consistent across most menstrual cycles included in the study. In conclusion, the Inito Fertility Monitor is an effective tool for calculating the urinary concentrations of E3G, PdG and LH and can also be used to provide accurate fertility scores and confirm ovulation. In addition, the sensitivity of IFM facilitates the monitoring of menstrual cycle-related hormone patterns, therefore also making it a great tool for physicians to track the hormones of their patients.\",\n \"Insights into genetic factors contributing to variability in SARS-CoV-2 susceptibility and COVID-19 disease severity\\nVariability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we applied colocalization to compare summary statistics for 16 GWASs from the COVID-19 Host Genetics Initiative to investigate similarities and differences in their genetic signals. We identified 9 loci associated with susceptibility (one with two independent GWAS signals; one with an ethnicity-specific signal), 14 associated with severity (one with two independent GWAS signals; two with ethnicity-specific signals) and one harboring two discrepant GWAS signals (one for susceptibility; one for severity). Utilizing colocalization we also identified 45 GTEx tissues that had eQTL(s) for 18 genes strongly associated with GWAS signals in eleven loci (1-4 genes per locus). Some of these genes showed tissue-specific altered expression and others showed altered expression in up to 41 different tissue types. Our study provides insights into the complex molecular mechanisms underlying inherited predispositions to COVID-19-disease phenotypes.\",\n \"One vaccine to counter many diseases? Modelling the economics of oral polio vaccine against child mortality and COVID-19\\nBackgroundRecent reviews summarize evidence that some vaccines have heterologous or non-specific effects (NSE), potentially offering protection against multiple pathogens. Numerous economic evaluations examine vaccines pathogen-specific effects, but we have found only two economic evaluations of NSE. This paper starts to fill this gap by reporting economic evaluations of the NSE of oral polio vaccine (OPV) against under-five mortality and COVID-19.\\n\\nMethodsWe studied two settings: (1) reducing child mortality in a high-mortality setting (Guinea-Bissau) and (2) preventing COVID-19 in India. In the former, the intervention involves three annual campaigns in which children receive OPV incremental to routine immunization. In the latter, a susceptible-exposed-infectious-recovered model was developed to estimate the population benefits of two scenarios, in which OPV would be co-administered alongside COVID-19 vaccines. Incremental cost-effectiveness and benefit-cost ratios were modelled for ranges of intervention effectiveness estimates to supplement the headline numbers and account for heterogeneity and uncertainty.\\n\\nResultsFor child mortality, headline cost-effectiveness was $650 per child death averted. For COVID-19, assuming OPV had 20% effectiveness, incremental cost per death averted was $23,000-65,000 if it were administered simultaneously with a COVID-19 vaccine less than 200 days into a wave of the epidemic. If the COVID-19 vaccine availability were delayed, the cost per averted death would decrease to $2600-6100. Estimated benefit-to-cost ratios vary but are consistently high.\\n\\nConclusionEconomic evaluation suggests the potential of OPV to efficiently reduce child mortality in high mortality environments. Likewise, within a broad range of assumed effect sizes OPV could play an economically attractive role against COVID-19.\",\n \"Knowledge and Impact of COVID-19 on Middle-Aged and Older People living with HIV in Lima, Peru\\nCOVID-19 has had an unprecedented worldwide impact, and Peru has had one of the highest COVID-19 case rates despite implementation of an early strict nationwide quarantine. Repercussions on Perus healthcare system may impact vulnerable populations, particularly people with HIV (PWH). We explored the knowledge of COVID-19 and the socioeconomic and health impact of the pandemic among middle-aged and older PWH. A cross-sectional telephone survey was administered to 156 PWH age [≥]40 years receiving care in one of two large HIV clinics in Lima, Peru. The majority of PWH (age 52{+/-}7.7 years, 41% female, 65% completed secondary school or less) were knowledgeable regarding COVID-19 symptoms and prevention methods. Nearly half of those employed prior to the pandemic reported job loss. Female sex (unadjusted prevalence ratio [PR] 1.85 [95%CI 1.27-2.69]), low educational level (PR 1.62 [1.06-2.48]) and informal work (PR 1.58 [1.06-2.36]) were risk factors for unemployment but not in adjusted models. Increased anxiety was reported in 64% and stress in 77%. COVID-19 has had a substantial socioeconomic and mental health impact on PWH living in Lima, Peru, particularly those with lower educational levels and informal workers. Efforts are needed to ensure continued medical care and socioeconomic support of PWH in Peru.\",\n \"Alcohol consumption and telomere length: observational and Mendelian randomization approaches\\nAlcohols impact on telomere length, a proposed marker of biological age, is unclear. We performed the largest observational study to date and compared findings with Mendelian randomization (MR) estimates. Two-sample MR used data from a recent genome-wide association study (GWAS) of telomere length. Genetic variants were selected on the basis of associations with alcohol consumption and alcohol use disorder (AUD). Non-linear MR employed UK Biobank individual data. MR analyses suggest a causal relationship between alcohol and telomere length: both genetically predicted alcohol traits were inversely associated with telomere length. 1 S.D. higher genetically-predicted log-transformed alcoholic drinks weekly had a -0.07 S.D. effect on telomere length (95% confidence interval [CI]:-0.14 to -0.01); genetically-predicted AUD - 0.06 S.D. effect (CI:-0.10 to -0.02). Results were consistent across methods and independent from smoking. Non-linear analyses indicated a potential threshold relationship between alcohol and telomere length. Our findings have implications for potential aging-related disease prevention strategies.\",\n \"Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity.\\nThe combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole exome sequencing data of about 4,000 SARS-CoV-2-positive individuals were used to define an interpretable machine learning model for predicting COVID-19 severity. Firstly, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthly, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management.\",\n \"Preliminary Rasch analysis of the Multidimensional Assessment of Interoceptive Awareness in adults with stroke\\nPurposeThe Multidimensional Assessment of Interoceptive Awareness (MAIA) measures interoceptive body awareness, which includes aspects such as attention regulation, self-regulation, and body listening. Our purpose was to validate the MAIA in adults with stroke using Rasch Measurement Theory.\\n\\nMethodsThe original MAIA has 32 items grouped into eight separately scored subscales that measure aspects of body awareness. Using Rasch Measurement Theory, we evaluated the unidimensionality of the entire scale and investigated person and item fit, person separation reliability, targeting, local item dependence, and principal components analysis of residuals.\\n\\nResultsForty-one adults with chronic stroke (average 3.8 years post-stroke, 13 women, and average age, 57{+/-}13 years) participated in the study. Overall fit (X2=62.26, p=0.26) and item fit were obtained after deleting 3 items and rescoring 26 items. One participant did not fit the model (2.44%). There were no floor (0.00%) or ceiling effects (0.00%). Local item dependence was found in 42 pairs. The person separation reliability was 0.91, and the person mean location was 0.06{+/-}1.12 logits.\\n\\nConclusionsThe MAIA demonstrated good targeting and reliability, as well as good item and person fit in adults with chronic stroke. A study with a larger sample size is needed to validate our findings.\",\n \"Immuno-proteomic profiling reveals abundant airway CD8 T cells and ongoing epithelial injury in prolonged post-COVD19 respiratory disease\\nSome patients hospitalized with acute COVID19 suffer respiratory symptoms that persist for many months. To characterize the local and systemic immune responses associated with this form of Long COVID, we delineated the immune and proteomic landscape in the airway and peripheral blood of normal volunteers and patients from 3 to 6 months after hospital discharge. The bronchoalveolar lavage (but not peripheral blood) proteome was abnormal in patients with post-COVID19 lung disease with significantly elevated concentration of proteins associated with apoptosis, tissue repair and epithelial injury. This correlated with an increase in cytotoxic lymphocytes (especially tissue resident CD8+ T cells), lactate dehydrogenase and albumin (biomarkers of cell death and barrier integrity). Follow-up of a subset of these patients greater than 1-year post-COVID19 indicated these abnormalities resolved over time. Collectively, these data indicate that COVID-19 results in a prolonged change to the airway immune landscape in those with persistent lung disease, with evidence of cell death and tissue repair linked to ongoing activation of cytotoxic T cells.\\n\\nHighlightsO_LIThe post-COVID19 airway is characterized by increased cytotoxic lymphocytes.\\nC_LIO_LIDistinct airway proteomes are associated with the airway immune cell landscape.\\nC_LIO_LIThe peripheral blood does not predict immune-proteome alterations in the airway post-COVID19.\\nC_LIO_LIPersistent abnormalities in the airway immune-proteome post-COVID19 airways correlate with ongoing epithelial damage.\\nC_LI\",\n \"Improvement of behavioural pattern and alpha-synuclein levels in autism spectrum disorder after consumption of a beta-glucan food supplement in a randomized, parallel-group pilot clinical study\\nBackgroundAutism spectrum disorders (ASDs) are a wide range of behavioural disabilities for which there are no definite interventional modalities available. Remedial therapies remain the only option but with varying outcomes. We have evaluated the childhood autism rating scale (CARS) and alpha-synuclein levels in this parallel-group, multiple-arm pilot clinical study after supplementation with a biological response modifier beta-glucan food supplement (Nichi Glucan).\\n\\nMethodsSix subjects with ASD (n = 6) Gr. 1 underwent conventional treatment comprising remedial behavioural therapies and L-carnosine 500 mg per day, and 12 subjects (n = 12) Gr. 2 underwent supplementation with the Nichi Glucan 0.5 g twice daily along with the conventional treatment.\\n\\nResultsThere was a significant decrease in the CARS score in all of the children of the Nichi Glucan Gr.2 compared to the control (p-value = 0.034517). Plasma levels of alpha-synuclein were significantly higher in Gr. 2 (Nichi Glucan) than in the control group Gr. 1 (p-value = 0.091701).\\n\\nConclusionImprovement of the behavioural pattern CARS score and a correlating alpha-synuclein level, followed by a safe beta-glucan food supplement, warrants further research on other parameters, such as gut-microbiota evaluation, and relevant neuronal biomarkers which is likely to cast light on novel solutions.\",\n \"Mortality audit of cancer patients with SARS-CoV-2 positivity or COVID-19\\nCoronavirus disease-2019 (COVID-19) has disrupted cancer care services globally. The present review of cause of deaths was conducted in a tertiary care cancer center in the North East India. In our institute, all cancer patients requiring admission for surgery, chemotherapy, and other daycare procedures require testing for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). From 09 July 2020 to 16 May 2021, 119 cancer patients with SARS-CoV-2 positive report or COVID-19 have been admitted at our institute Covid ward. A total of 19 cancer patients with COVID-19 succumbed. Of 19 deaths, 13 (68.4%) patients were men and 6 (31.6%) patients were women. The age range from 27 years to 74 years (median =55 years). Vomiting alone or with diarrhea was the most common symptom requiring admission after testing (4/19, 21.0%), followed by bleeding from primary tumour site (3/19, 15.7%). The antecedent and underlying cause of deaths in 19 (100%) patients was cancer. SARS-CoV-2 infection should not be a hindrance for cancer treatment and management.\",\n \"An expanded population of CD8dim T cells with features of mitochondrial dysfunction and senescence is associated with persistent HIV-associated Kaposis sarcoma under ART\\nHIV-associated Kaposis sarcoma (KS), which is caused by Kaposis sarcoma-associated herpesvirus, usually arises in the context of uncontrolled HIV replication and immunosuppression. However, disease occasionally persists in individuals with durable HIV viral suppression and CD4 T cell recovery under anti-retroviral therapy (ART). The underlying mechanisms associated with this persistence are unclear. Suppression of viral infections can be mediated by CD8 T cells that detect infected cells via their T cell receptor and the CD8 co-receptor. However, CD8 T cells exhibit signs of functional exhaustion in untreated HIV infection that may not be fully reversed under ART. To investigate whether persistent KS under ART was associated with phenotypic and functional perturbations of CD8 T cells, we performed a cross-sectional study comparing HIV-infected individuals with persistent KS under effective ART (HIV+ KS+) to HIV-infected individuals receiving effective ART with no documented history of KS (HIV+ KSneg). A subset of T cells with low cell surface expression of CD8 (\\\"CD8dim T cells\\\") was expanded in HIV+ KS+ compared with HIV+ KSneg participants. Relative to CD8bright T cells, CD8dim T cells exhibited signs of senescence (CD57) and mitochondrial perturbations (PGC-1, MitoTracker) ex vivo. Mitochondrial activity (MitoTracker) was also reduced in proliferating CD8dim T cells. These findings indicate that an expanded CD8dim T cell population displaying features of senescence and mitochondrial dysfunction is associated with KS persistence under ART. CD8 co-receptor down-modulation may be symptomatic of ongoing disease.\",\n \"Association between metabolic syndrome and humoral immune response to Pfizer BioNTech vaccine in healthcare workers\\nPurposeThe clustering of metabolic abnormalities may weaken vaccine-induced immunity, but epidemiological data regarding SARS-CoV-2 vaccines are scarce. The present study examined the cross-sectional association between metabolic syndrome (MetS) and humoral immune response to Pfizer-BioNTech vaccine among healthcare workers.\\n\\nMethodsParticipants were 946 healthcare workers, aged 21-75 years, who had completed the second dose of Pfizer-BioNTech vaccine 1-3 months before the survey. MetS was defined according to the Joint Interim Statement. SARS-CoV-2 spike immunoglobulin G (IgG) antibody was measured using quantitative assays. Multivariable linear regression was used to estimate the geometric mean titers (GMT) and geometric mean ratio (GMR) of IgG titers, relative to MetS status.\\n\\nResultsA total of 51 participants (5.4%) had MetS. Healthcare workers with MetS had a significantly lower IgG titer (GMT 3882; 95% confidence interval [CI], 3124-4824) than those without MetS (GMT 5033; 95% CI, 4395-5764); the GMR was 0.77 (95% CI 0.64-0.93). The GMR for IgG titers among those having 0 (reference group), 1, 2, 3, or [≥] 4 MetS components was 1.00, 1.00, 0.89, 0.86 and 0.61, respectively (Ptrend = 0.004).\\n\\nConclusionResults suggest that having MetS and a greater number of its components are associated with a weaker humoral immune response to the Pfizer-BioNTech vaccine.\",\n \"Evolution of SARS-CoV-2 immune responses in nursing home residents following full dose of the Comirnaty COVID-19 vaccine\\nObjectivesThere is scarce information as to the durability of immune responses elicited by the Comirnaty(R) COVID-19 vaccine in nursing home residents. Here, we assessed SARS-CoV-2-Spike (S)-targeted antibody and functional T cell responses at around 6 months after complete vaccination.\\n\\nMethodsThe sample comprised 46 residents (34 females; age, 60-100 years), of whom 10 had COVID-19 prior to vaccination. Baseline (median of 17.5 days after vaccination) and follow-up (median, 195 days) plasma specimens were available for quantitation of SARS-CoV-2-S antibodies and enumeration of SARS-CoV-2-S-reactive IFN-{gamma} CD4+ and CD8+ T cells by flow cytometry.\\n\\nResultsIn total, 44/45 participants had detectable SARS-CoV-2-S antibodies at follow-up. Overall, antibody levels were found to decrease (median, 4.8 fold). Antibodies waning was more frequent (P<0.001) in SARS-CoV-2 naive (29/35) than in recovered (1/10) residents. SARS-CoV-2-S IFN-{gamma} CD8+ T cells were detected in 33/46 and 24/46 at baseline and follow-up, respectively. The figures for CD4+ T cell counterparts were 12/46 and 30/46. Detectable SARS-CoV-2 IFN-{gamma} CD8+ and CD4+ T cell responses at follow-up were more common in recovered (8/10 and 7/10, respectively) than in naive residents (9/36 and 25/36, respectively). For those with detectable responses at both time points, SARS-CoV-2-S IFN-{gamma} CD8+ T cell frequencies decreased significantly (P=0.001) over time whereas the opposite (P=0.01) was observed in CD4+ T cells.\\n\\nConclusionAlmost all residents displayed detectable SARS-CoV-2-S-reactive antibodies and T cell responses, respectively, by around 6 months after complete vaccination with Comirnaty(R) COVID-19 vaccine, albeit generally waning in magnitude over time.\",\n \"Specific gait changes in prodromal hereditary spastic paraplegia type 4 - The preSPG4 study\\nBackgroundIn hereditary spastic paraplegia type 4 (SPG4), subclinical gait changes might occur years before patients realize gait disturbances. The prodromal phase of neurodegenerative disease is of particular interest to halt disease progression by future interventions before impairment has manifested.\\n\\nObjectivesIdentification of specific movement abnormalities before manifestation of gait impairment and quantification of disease progression in the prodromal phase.\\n\\nMethods70 subjects participated in gait assessment, including 30 prodromal SPAST mutation carriers, 17 patients with mild-to-moderate manifest SPG4, and 23 healthy controls. Gait was assessed by an infrared-camera-based motion capture system to analyze features like range of motion and continuous angle trajectories. Those features were correlated with disease severity as assessed by the Spastic Paraplegia Rating Scale (SPRS) and neurofilament light chain (NfL) as a fluid biomarker indicating neurodegeneration.\\n\\nResultsCompared to healthy controls, we found an altered gait pattern in prodromal mutation carriers during the swing phase in segmental angles of the lower leg (p<0.05) and foot (p<0.01), and in heel ground clearance (p<0.01). Furthermore, ranges of motion of segmental angles were reduced for foot (p<0.001) and lower leg (p<0.01). These changes occurred in prodromal mutation carriers without quantified leg spasticity in clinical examination. Gait features correlated with NfL levels and SPRS score.\\n\\nConclusionGait analysis can quantify changes in prodromal and mild-to-moderate manifest SPG4 patients. Thus, gait features constitute promising motor biomarkers characterizing the subclinical progression of spastic gait and might help to evaluate interventions in early disease stages.\",\n \"Large Registry Based Analysis of Genetic Predisposition to Tuberculosis Identifies Genetic Risk Factors at HLA\\nTuberculosis is a significant public health concern resulting in the death of over 1 million individuals each year worldwide. While treatment options and vaccines exist, a substantial number of infections still remain untreated or are caused by treatment resistant strains. Therefore, it is important to identify mechanisms that contribute to risk and prognosis of tuberculosis as this may provide tools to understand disease mechanisms and provide novel treatment options for those with severe infection. Our goal was to identify genetic risk factors that contribute to the risk of tuberculosis and to understand biological mechanisms and causality behind the risk of tuberculosis. A total of 1,895 individuals in the FinnGen study had ICD-based tuberculosis diagnosis. GWAS analysis identified genetic variants with statistically significant association with tuberculosis at the Human leukocyte antigen (HLA) region (p<5e-8) and at rs560595454 in gene INPP5A. Fine mapping the HLA-association provided evidence for one protective haplotype tagged by HLA DQB1*05:01 (p=1.82E-06, OR = 0.81 [CI 95 % 0.74-0.88]), and predisposing alleles tagged by HLA DRB1*13:02 (p=0.00011, OR = 1.35 [CI 95% 1.16-1.57]). Furthermore, genetic correlation analysis showed association with earlier reported risk factors including smoking (p<0.05). Mendelian randomization supported smoking as a risk factor for tuberculosis (inverse-variance weighted p<0.05, OR = 1.83 [CI 95 % 1.15-2.93]) with no significant evidence of pleiotropy. Our findings indicate that specific HLA alleles and INPP5A associate with the risk of tuberculosis. In addition, lifestyle risk factors such as smoking contribute to the risk of developing tuberculosis.\",\n \"Quantitative Digitography Solves the Remote Measurement Problem in Parkinson's disease\\nBackgroundAssessment of motor signs in Parkinsons disease (PD) has required an in-person examination. However, 50% of people with PD do not have access to a neurologist. Wearable sensors can provide remote measures of some motor signs but require continuous data acquisition for several days. A major unmet need is reliable metrics of all cardinal motor signs, including rigidity, from a simple short active task that can be performed remotely or in the clinic.\\n\\nObjectiveInvestigate whether thirty seconds of repetitive alternating finger tapping (RAFT) on a portable quantitative digitography (QDG) device, which measures amplitude and timing, produces reliable metrics of all cardinal motor signs in PD\\n\\nMethodsNinety-six individuals with PD and forty-two healthy controls performed a thirty-second QDG-RAFT task and clinical motor assessment. Eighteen individuals were followed longitudinally with repeated assessments for an average of three years and up to six years.\\n\\nResultsQDG-RAFT metrics differentiated individuals with PD from controls and provided validated metrics for total motor disability (MDS-UPDRS III) and for rigidity, bradykinesia, tremor, gait impairment and freezing of gait (FOG). Additionally, QDG-RAFT tracked disease progression over several years off therapy, and differentiated akinetic rigid from tremor dominant phenotypes, as well as people with from those without FOG.\\n\\nConclusionsQDG is a reliable technology, which will improve access to care, allows complex remote disease management, and accurate monitoring of disease progression over time in PD. QDG-RAFT also provides the comprehensive PD motor metrics needed for therapeutic trials.\",\n \"Seroconversion rate and socioeconomic and ethnic risk factors for SARS-CoV-2 infection in children in a population-based cohort\\nIntroductionSocioeconomic and ethnic background have been discussed as possible risk factors for SARS-CoV-2 infections in children. Improved knowledge could lead way to tailored prevention strategies and help to improve infection control.\\n\\nMethodsObservational population-based cohort study in children (6mo. - 18 ys.) scheduled for legally required preventive examination and their parents in a metropolitan region in Germany. Primary endpoint was the SARS-CoV-2 seroconversion rate during study period. Risk factors assessed included age, pre-existing medical conditions, socioeconomic factors, and ethnicity.\\n\\nResults2124 children and their parents were included. Seroconversion rates among children in all age groups increased by 3-4-fold from 06/2020 to 02/2021. Only 41% of seropositive children were symptomatic. In 51% of infected children at least one parent was also SARS-CoV-2 positive.\\n\\nLow level of parental education (OR 3.13 (0.72-13.69)) significantly increased the risk of infection. Of the total cohort, 38.5% had a migration background. Specifically, 9% were of Turkish and 5% of Middle Eastern origin. These children had the highest risk for SARS-CoV-2 infections (OR 6.24 (1.38-28.12) and 6.44 (1.14-36.45) after adjustment for other risk factors.\\n\\nDiscussionSeroprevalence of SARS-CoV-2 infections in children increased by 3-4-fold within the study period. Frequently, more than one family member was infected. Children from families with lower socioeconomic status were at higher risk. The highest risk for SARS-CoV-2 infection was identified in families with Turkish or Middle Eastern background. Culture sensitive approaches are essential to improve infection control and serve as a blueprint for vaccination strategies in this population.\\n\\nTrial RegistrationBMBF funding registration 01KI20173 (Corkid)\",\n \"Using Geographically Weighted Linear Regression for County-Level Breast Cancer Modeling in the United States\\nDue to the continued disparities in breast cancer, improved models are being needed to inform policy related to existing social disparities related to cancer. First ordinal least squares regression was used to determine the relationship of sociodemographic measures (i.e. poverty rate and social inequity) on breast cancer incidence in the United States. Gini coefficient was used as a measure of income inequality. Next, Geographically Weighted Regression (GWR), a local spatial model, was used to explore the impact location has on the relationship between sociodemographic measures and breast cancer. Mappings of the results are presented, which can assist policymakers to address inequities and social determinants when funding cancer interventions. The GWR model is then compared to linear regression models that do not take into consideration location, highlighting the benefits of spatial models in cancer policy research. More studies applying spatial regression techniques are needed in order to accurately inform policy.\",\n \"Microsampling for monitoring gentamicin in neonates.\\nGentamicin is recommended as first-line treatment of neonatal sepsis. The use of gentamicin is associated with toxicity which complicates neonatal dosing and necessitates therapeutic drug monitoring (TDM).\\n\\nIn a proof-of-concept investigation, we sought to compare (1) gentamicin concentrations obtained using volumetric absorptive microsampling (VAMS) to standard TDM plasma samples, and (2) the time taken to report results obtained using VAMS compared to standard TDM by the local hospital chemical pathology service.\\n\\nThe difference between gentamicin concentrations obtained from plasma collected for routine clinical care and calculated plasma concentrations, based on samples collected in whole blood using VAMS, was -18.0% and -0.4% for two patients. The research laboratory reported results within the time taken for the routine chemical pathology laboratory to report results. This proof-of-concept study demonstrates that the use of microsampling for TDM by pathology services can fulfil the requirements of providing an accurate gentamicin concentration in a timely manner.\",\n \"Proteomic deconvolution reveals distinct immune cell fractions in different body sites in SARS-Cov-2 positive individuals\\nBackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be a significant public health challenge globally. SARS-CoV-2 is a novel virus, and what constitutes immunological responses in different human body sites in infected individuals is yet to be presented. We set to determine the various immune cell fractions in gargle solution, bronchoalveolar lavage fluid, nasopharyngeal, and urine samples post-SARS-CoV-2 infection in humans.\\n\\nMaterials and methodsWe downloaded proteomics data from (https://www.ebi.ac.uk/pride/) with the following identifiers: PXD019423, n=3 (gargle solution), PXD018970, n=15 (urine), PXD022085, n=5 (Bronchoalveolar lavage fluid), PXD022889, n=18 (nasopharyngeal). MaxQuant was used for the peptide spectral matching using humans, and SARS-CoV-2 was downloaded from the UniProt database (Access date 9th January 2022). The protein count matrix was extracted from the proteins group file and used as an input for the cibersort for the immune cells fraction determination.\\n\\nResultsThe body of individuals infected with the SARS-CoV-2 virus is characterized by different fractions of immune cells in Bronchoalveolar lavage fluid (BALF), nasopharyngeal, urine, and gargle solution. BALF has more abundant memory B cells, CD8, activated mast cells, and resting macrophages than urine, nasopharyngeal, and gargle solution. Our analysis also demonstrates that each body site comprises different immune cell fractions post-SARS-CoV-2 infection in humans.\\n\\nConclusionDifferent body sites are characterized by different immune cells fractions in SARS-CoV-2 infected individuals. The findings in this study can inform public health policies and health professionals on treatment strategies and drive SARS-CoV-2 diagnosis procedures.\",\n \"Small Patient Datasets Reveal Genetic Drivers of Non-Small Cell Lung Cancer Subtypes using a Novel Machine Learning Approach\\nThere are many small datasets of significant value in the medical space that are being underutilized. Due to the heterogeneity of complex disorders found in oncology, systems capable of discovering patient subpopulations while elucidating etiologies is of great value as it can indicate leads for innovative drug discovery and development. Here, we report on a machine intelligence-based study that utilized a combination of two small non-small cell lung cancer (NSCLC) datasets consisting of 58 samples of adenocarcinoma (ADC) and squamous cell carcinoma (SCC) and 45 samples from the gene expression analysis of human lung cancer and control samples series (GSE18842). Utilizing a novel machine learning approach, we were able to uncover subpopulations of ADC and SCC while simultaneously extracting which genes, in combination, were significantly involved in defining the subpopulations. An interactive hypothesis-generating interface designed to work with machine learning methods allowed us to explore the hypotheses generated by the unsupervised components of the system. Using these methods, we were able to uncover genes implicated by other methods and accurately discover known subpopulations without being asked, such as different levels of aggressiveness within the SCC and ADC subtypes. Furthermore, PIGX was a novel gene implicated in this study that warrants further study due to its role in breast cancer proliferation. Here we demonstrate the ability to learn from small datasets and reveal well-established properties of NSCLC. These machine learning techniques can reveal the driving factors behind subpopulations of patients altering the approach to drug discovery and development by making precision medicine a reality.\",\n \"Surgical interventions targeting the nucleus caudalis for craniofacial pain: a systematic and historical review.\\nIntroductionChronic facial pain is a prevalent group of conditions and when refractory to common treatments poses a social and economic burden. The last decade has seen a multitude of advancements in the multimodal management of pain. Ablative or neuromodulatory interventions targeting the nucleus caudalis (NC) of the trigeminocervical complex is one such treatment that has remained underutilized.\\n\\nMethodsHere we present a systematic review of the literature and historical perspective regarding interventions targeting the NC. We examine the various intervention techniques, clinical indications, and procedural efficacy. A novel outcome reporting scheme was devised to allow comparison between studies using differing outcome reporting methods.\\n\\nResultsA review of the literature revealed 49 retrospective studies published over the last 80 years, reporting on 858 patients. The most common technique was the open NC dorsal root entry zone nucleotomy/tractotomy (n=515, 60.0%); however, there has been an emergence of novel approaches such as endoscopic (n=6, 0.7%) and spinal cord stimulation (n=20, 2.3%) in the last 10 years. Regardless of intervention technique or preoperative diagnosis, 90.4% of patients demonstrated some improvement from treatment.\\n\\nConclusionThis systematic review highlights recent advancements in NC intervention technique and the wide range of facial pain syndromes for which these interventions show promising efficacy. New and less invasive techniques continue to emerge, however prospective studies remain absent in the literature. Future work should address efficacy comparisons between intervention type and preoperative diagnosis.\",\n \"Frequent Cocaine Use is Associated with Larger HIV Latent Reservoir Size\\nBackgroundWith the success of combination antiretroviral therapy, HIV is now treated as a chronic disease, including among drug users. Cocaine--one of the most frequently abused illicit drugs among persons living with HIV (PLWH)-- slows the decline of viral production after ART, and is associated with higher HIV viral load, more rapid HIV progression, and increased mortality. We examined the impact of cocaine use on the CD4+ T-cell HIV Latent Reservoir (HLR) in virally suppressed PLWH.\\n\\nMethodsCD4+ T-cell genomic DNA was isolated from peripheral blood mononuclear cells collected from 434 women of diverse ancestry (i.e., 75% Black, 14% Hispanic, 12% White) who self-reported cocaine use (i.e., 160 cocaine users, 59 prior users, 215 non-users). Participants had to have an undetectable HIV RNA viral load measured by commercial assay for at least 6 months. The Intact Proviral HIV DNA Assay (IPDA) provided estimates of intact provirus per 106 CD4+ T-cells.\\n\\nResultsThe HLR size differed by cocaine use (i.e., median [interquartile range]: 72 [14, 193] for never users, for prior users 165 [63, 387], 184 [28, 502] for current users), which was statistically significantly larger in both prior (p=0.023) and current (p=0.001) cocaine users compared with never users.\\n\\nConclusionOur study is the first to provide evidence that cocaine use may contribute to a larger replication competent HLR in CD4* T-cells among virologically suppressed women living with HIV. Our findings are important, because women are under-represented in HIV reservoir studies and in studies of the impact of cocaine use on outcomes among PLWH.\",\n \"Decreased Immune Response to COVID-19 mRNA Vaccine in Patients with Inflammatory Bowel Diseases Treated with Anti TNFα\\nBackgroundPatients with inflammatory bowel diseases (IBD), specifically those treated with anti-tumor necrosis factor (TNF) biologics are at high risk for vaccine preventable infections. Their ability to mount adequate vaccine responses is unclear.\\n\\nAimto assess immune responses to mRNA-COVID-19 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared to healthy controls (HC).\\n\\nMethodsProspective, controlled, multi-center Israeli study. Subjects enrolled received two BNT162b2 (Pfizer/BioNTech) doses. Anti-spike (S) antibodies levels and functional activity, anti-TNF levels and adverse events (AEs) were detected longitudinaly.\\n\\nResultsOverall 258 subjects: 185 IBD (67 treated with anti-TNF), and 73 HC. After the first vaccine dose all HC were seropositive, while some patients with IBD, regardless of treatment, remained seronegative. After the second dose all subjects were seropositive, however anti-S levels were significantly lower in anti-TNF treated compared to untreated patients, and HC (p<0.001; p<0.001, respectively). Neutralizing and inhibitory functions were both lower in anti-TNF treated compared to untreated patients, and HC (p<0.03; p<0.0001, respectively). Anti-TNF drug levels and vaccine responses did not affect anti-S levels. Infection rate ([~]2%) and AEs were comparable in all groups. IBD activity did not change in response to BNT162b2.\\n\\nConclusionsIn this prospective study in patients with IBD stratified according to treatment all patients mounted an immune response to two doses of BNT162b2. However, its magnitude was significantly lower in patients treated with anti-TNF, regardless of administration timing and drug levels. Vaccine was safe. As vaccine immune response longevity in this group may be limited, vaccine booster dose should be considered.\",\n \"Head-to-head performance comparison of self-collected nasal versus professional-collected nasopharyngeal swab for a WHO-listed SARS-CoV-2 antigen-detecting rapid diagnostic test\\nBackgroundIn 2020, the World Health Organization (WHO) recommended two SARS-CoV-2 lateral flow antigen detecting rapid diagnostics tests (Ag-RDTs), both initially with nasopharyngeal (NP) sample collection. Independent head-to-head studies demonstrated for SARS-CoV-2 Ag-RDTs nasal sampling to be a comparable and reliable alternative for nasopharyngeal (NP) sampling.\\n\\nMethodsWe conducted a head-to-head comparison study of a supervised, self-collected nasal mid-turbinate (NMT) swab and a professional-collected NP swab, using the Panbio Ag-RDT (the second WHO-listed SARS-CoV-2 Ag-RDT, distributed by Abbott). We calculated positive and negative percent agreement and, compared to the reference standard reverse transcription polymerase chain reaction (RT-PCR), sensitivity and specificity for both sampling techniques.\\n\\nResultsA SARS-CoV-2 infection could be diagnosed by RT-PCR in 45 of 290 participants (15.5%). Comparing the NMT and NP sampling the positive percent agreement of the Ag-RDT was 88.1% (37/42 PCR positives detected; CI 75.0% - 94.8%). The negative percent agreement was 98.8% (245/248; CI 96.5% - 99.6%). The overall sensitivity of Panbio with NMT sampling was 84.4% (38/45; CI 71.2% - 92.3%) and 88.9% (40/45; CI 76.5% - 95.5%) with NP sampling. Specificity was 99.2% (243/245; CI 97.1% - 99.8%) for both, NP and NMT sampling. The sensitivity of the Panbio test in participants with high viral load (> 7 log10 SARS-CoV-2 RNA copies/mL) was 96.3% (CI 81.7% - 99.8%) for both, NMT and NP sampling.\\n\\nConclusionFor the Panbio Ag-RDT supervised NMT self-sampling yields to results comparable to NP sampling. This suggests that nasal self-sampling could be used for scale-up population testing.\",\n \"Lower probability and shorter duration of infections after Covid-19 vaccine correlate with anti-SARS-CoV-2 circulating IgGs\\nThe correlation between immune responses and protection from SARS-CoV-2 infections and its duration remains unclear. We performed a sanitary surveillance at the European Institute of Oncology (IEO) in Milan over a 17 months period. Pre-vaccination, in 1,493 participants, we scored 266 infections (17.8%) and 8 possible reinfections (3%). Post-vaccination, we identified 30 infections in 2,029 vaccinated individuals (1.5%). We report that the probability of infection post-vaccination is i) significantly lower compared to natural infection, ii) associated with a significantly shorter median duration of infection than that of first infection and reinfection, iii) anticorrelated with circulating antibody levels.\",\n \"Tau-PET and in vivo Braak-staging as a prognostic marker in Alzheimer's disease\\nINTRODUCTIONTau pathology in Alzheimers disease tracks clinical status more closely than beta-amyloid. Thus, tau-PET may be a promising prognostic marker for cognitive decline. Here, we systematically compared tau-PET and Braak-staging vs. amyloid-PET as predictors of cognitive decline.\\n\\nMETHODSWe included 396 cognitively normal to dementia subjects with 18F-Flutemetamol/18F-Florbetapir-amyloid-PET, 18F-Flortaucipir-tau-PET and ~2-year cognitive assessments. Annual cognitive change rates were calculated via linear-mixed models. We determined global amyloid-PET, global tau-PET, and tau-PET-based Braak-stage (Braak0/BraakI+/BraakI-IV+/BraakI-VI+/Braakatypical+). In bootstrapped linear regression, we assessed whether tau-PET outperformed amyloid-PET in predicting cognitive decline. Using ANCOVAs, we tested whether later Braak-stage predicted accelerated cognitive decline and determined Braak-stage-specific conversion risk to MCI or dementia.\\n\\nRESULTSGlobal tau-PET was a better predictor of cognitive decline than global amyloid-PET (p<0.001). Advanced Braak-stage was associated with faster cognitive decline (p<0.001) and elevated clinical conversion risk.\\n\\nDISCUSSIONTau-PET and Braak-staging show promise for predicting patient-specific risk of clinical AD progression.\",\n \"Atypical resting state functional connectivity in mild traumatic brain injury\\nObjectivesThis study aimed to investigate changes in three intrinsic functional connectivity networks (IFCNs; default mode (DMN), salience (SN), and task-positive networks (TPN)) in individuals who had sustained a mild traumatic brain injury (mTBI).\\n\\nMethodsResting-state functional magnetic resonance imaging (rs-fMRI) data was acquired from 27 mTBI patients with persistent post-concussive symptoms (PCS), along with 26 age- and sex-matched controls. These individuals were recruited from a Level-1 trauma centre, at least three months after a traumatic episode. IFCNs were established based on seed-to-voxel, region-of-interest (ROI) to ROI, and independent component analyses (ICA). Subsequently, we analyzed the relationship between functional connectivity and PCS.\\n\\nResultsSeed-to-voxel analysis of rs-fMRI demonstrated decreased functional connectivity in the right lateral parietal lobe, part of the DMN, and increased functional connectivity in the supramarginal gyrus, part of the SN. Our TPN showed both hypo- and hyperconnectivity, dependent on seed location. Within network hypoconnectivity was observed in the visual network, also using group comparison. Using an ICA, we identified altered network functional connectivity in regions within four IFCNs (sensorimotor, visual, DMN, and dorsal attentional). A significant negative correlation between dorsal attentional network connectivity and behavioural symptoms score was also found.\\n\\nConclusionsOur findings indicate that rs-fMRI may be of use clinically, in order to assess disrupted functional connectivity among IFCNs in mTBI patients. Improved mTBI diagnostic and prognostic information could be especially relevant for athletes looking to safely return to play, as well for individuals from the general population with persistent post-concussive symptoms months after injury, who hope to resume activity.\",\n \"ARE GEOGRAPHIC FACTORS ASSOCIATED WITH POORER OUTCOMES IN PATIENTS DIAGNOSED WITH COVID-19?\\nBackgroundThe prognosis of patients with COVID-19, with older age and comorbidities, is associated with a more severe course and higher fatality rates but no analysis has yet included factors related to the geographical area/municipality in which the affected patients live. So the objective of this study is to analyse the prognosis of patients with COVID-19 in terms of sex, age, comorbidities, and geographic variables.\\n\\nMethodsA retrospective cohort of 6286 patients diagnosed with COVID-19 was analysed, considering demographic data, previous comorbidities and geographic variables. The main study variables were hospital admission, Intensive Care Unit (ICU) admission and death due to worsening symptoms; and the secondary variables were sex, age, comorbidities and geographic variables (size of the area of residence, distance to the hospital and the driving time to the hospital). A comparison analysis and a multivariate Cox model were performed.\\n\\nResultsThe multivariate Cox model showed that women had a better prognosis in any type of analysed prognosis. Most of the comorbidities studied were related to a poorer prognosis except for dementia, which is related to lower admissions and higher mortality. Suburban areas were associated with greater mortality and with less hospital or ICU admission. Distance to the hospital was also associated with hospital admission.\\n\\nConclusionsFactors such as type of municipality and distance to hospital act as social health determinants. This fact must be taken account in order to stablish specifics prevention measures and treatment protocols.\",\n \"Comparison of clinical course and outcomes of critically ill patients with SARS-CoV2 infection managed in traditional ICU and \\\"Flex\\\" ICU during the surge of the pandemic in the Bronx.\\nBACKGROUNDAs part of the response to increase critical care capacity during the unprecedented surge of COVID-19 infections, NYC Health + Hospital systems identified and resourced areas in the hospital that could deliver critical care as \\\"Flex\\\" ICUs to complement the traditional ICUs to manage the rapid influx of critically ill patients.\\n\\nOBJECTIVEComparison of clinical features and outcomes of mechanically ventilated COVID-19 patients admitted to the traditional and \\\"Flex\\\" ICUs during the surge of the pandemic\\n\\nMETHODSRetrospective comparative cohort study of patients with confirmed SARS-CoV-2 infection on mechanical ventilation admitted to traditional ICU and Flex ICU. Univariate and multivariate analysis to detect factors associated with death from COVID-19 patients in mechanical ventilation were performed with the Cox proportional hazards regression model\\n\\nRESULTSOut of the 312 patients on mechanical ventilation, 111 were admitted to the traditional ICU and 201 to the Flex ICU. The mortality rate was higher in the Flex ICU compared with the traditional ICU, but the adjusted risk model was not significantly associated with increased mortality\\n\\nCONCLUSION\\\"Flex\\\" ICUs played a crucial role in the management of critically ill patients during the pandemic. Mortality risk of patients in the \\\"Flex\\\" ICUs were comparable to traditional ICUs in the adjusted analysis. While there is enough evidence for Intensivist managed ICUs to have better outcomes, our study demonstrates the feasibility of non-intensivist led Flex\\\" ICUs during a crisis.\",\n \"The Statistical Monitoring by Adaptive RMSTD Tests: an efficient, informative, and customizable method for the complete internal quality control intended for low-frequent sampling of control measures\\nTwo control mechanisms are relevant to perform an internal quality assurance: a permissible limit LSMC applied to single measures of control samples and a retrospective statistical analysis to detect increased imprecision and baseline drifts. A common statistical metric is the root mean square (total) deviation (RMSD/RMSTD). To focus on recent changes under low-frequent sampling conditions, the monitored amount of retrospective data is usually very small. Unfortunately, the calculated RMSTD of a small data set with n<50 samples has a significant statistical uncertainty that needs to be considered in adequate limit definitions. In particular, the minimum reasonable limit LRMSTD(n), applied to the RMSTD of a series of n samples, decreases from LSMC (e.g., 2.33*standard_deviation+bias) for n=1 towards Ltrue_RMSTD for n[->]{infty} (long-term statistics). Two mathematical approaches were derived to reliably estimate an optimal function to adjust LRMSTD(n) to small sample sizes.\\n\\nThis knowledge led to the development of a new quality-control method: the Statistical Monitoring by Adaptive RMSTD Tests (SMART). SMART requires just one mandatory limit (either LSMC or Ltrue_RMSTD) per analyte. By definition of up to 7 possible alert levels, SMART can early recognize and evaluate both the significance of a single outlier and establishing critical trends or shifts in recent SMC data. SMART is intended to efficiently monitor and evaluate small amounts of control data.\",\n \"Individualized diversity in the extracellular metabolome of live human gliomas\\nCancer metabolism is of increasing interest for drug development but few methods exist to evaluate live human malignancies. We utilized high molecular weight (HMW) microdialysis with elevated flow rate pumps under an investigational device exemption to sample the microenvironments of live human gliomas and adjacent brain during neurosurgical resections. Untargeted metabolic profiles spanning over 300 named metabolites were captured from 20{micro}L of microdialysate representing 10 minutes of intra-operative collection time. Five patients were each analyzed via 3 catheters with analysis of >300 named metabolites and 5 drugs. Rank-based analyses and machine learning highlighted metabolic heterogeneity across and between patients, as well as marked metabolic convergence within the most aggressive regions of molecularly diverse tumors. A novel glioma-associated metabolite, guanidinoacetatic acid (GAA), topped the list of extracellular glioma metabolites reflecting altered amino acid and energy metabolism. Intraoperative HMW microdialysis offers improved opportunities to accelerate individualized translational progress for glioma.\",\n \"Anthropometric measures and their relationship to corneal refractive power in the United States population\\nPurposeTo determine the relationship between anthropometric measures and corneal refractive power (CRP).\\n\\nMethodsParticipants from the 1999-2008 United States National Health and Nutrition Examination Survey (NHANES) visual exam with demographic, ocular, and anthropometric data (20,165 subjects) were included. Cases with steep cornea were defined by corneal power [≥] 48.0 diopters (n = 171) while controls had dioptric power < 48.0 D (n = 19,994). Multivariable analyses were performed for pooled and sex-stratified populations. Separate models assessed body mass index, height, and weight in relation to steep cornea.\\n\\nResultsA relationship between BMI and steep cornea in the pooled population was not detected (P for trend = 0.78). There was a strong inverse relationship between height and steep cornea in the pooled population (P for trend <0.0001) and women (P for trend <0.0001). For every 1-inch increase in height, there was a 16% reduced odds of steep cornea in the pooled population (OR, 0.84; 95% CI: 0.78-0.91). There was also a significant inverse relationship between weight and steep cornea in the pooled population (P for trend = 0.01) and in men (P for trend = 0.02). For each 10-pound increase in weight there was a 7% reduced odds of steep cornea (OR, 0.927; 95% CI: 0.882-0.975) in the pooled analysis.\\n\\nConclusionsGreater height and greater weight were associated with a lower risk of steep cornea. These findings can contribute to an improved understanding of the pathogenesis of corneal ectasias.\",\n \"A unique dexamethasone-dependent gene expression profile in the lungs of COVID-19 patients\\nLocal immunopathogenesis of COVID-19 acute respiratory distress syndrome (CARDS) and the effects of systemic dexamethasone (DXM) treatment on pulmonary immunity in COVID-19 remain insufficiently understood. To provide further insight into insight into immune regulatory mechanisms in the lungs of CARDS (with and without DXM treatment) and critically ill non-COVID-19 patients (without DXM treatment), transcriptomic RNA-seq analysis of bronchoalveolar lavage fluid (BALF) was performed in these patients. Functional analysis was performed using gene ontology and a blood transcription module, and gene expression of select pro-inflammatory cytokines, interferon-stimulated genes (ISGs) and auto-IFN antibodies were assessed. We found 550 and 2173 differentially expressed genes in patients with non-DXM-CARDS and DXM-CARDS, respectively. DXM-CARDS was characterized by upregulation of genes related to pulmonary innate and adaptive immunity, notably B-cell and complement pathway activation, antigen presentation, phagocytosis and FC-gamma receptor signalling. Pro-inflammatory genes were not differentially expressed in CARDS vs. non-COVID-19, nor did they differ according to DXM. Most ISGs were specifically upregulated in CARDS, particularly in non-DXM-CARDS. Auto-IFN autoantibodies were detectable in BALF of some CARDS patients. In conclusion, DXM treatment was not associated with regulation of pro-inflammatory pathways in CARDS but with regulation of other specific local innate and adaptive immune responses.\\n\\nsummaryThis study identifies differentially expressed genes in bronchoalveolar fluid of COVID-19 acute respiratory distress patients with a distinct RNA expression profile of those treated with dexamethasone. These results challenge the concept of a COVID-19 specific cytokine storm.\",\n \"Predicting longitudinal brain atrophy in Parkinson's disease using a Susceptible-Infected-Removed agent-based model\\nParkinsons disease (PD) is a progressive neurodegenerative disorder characterized by accumulation of abnormal isoforms of alpha-synuclein. Alpha-synuclein is proposed to act as a prion in PD: in its misfolded pathologic state it favours the misfolding of normal alpha-synuclein molecules, spreads trans-neuronally, and causes neuronal or synaptic damage as it accumulates. This theory remains controversial. We have previously developed a Susceptible-Infected-Removed (SIR) computational model that simulates the templating, propagation and toxicity of alpha-synuclein molecules in the brain. Here we test this model with longitudinal MRI collected over four years from the Parkinson Progression Markers Initiative (1068 T1 MRI scans, 790 PD, 278 matched controls). We find that brain deformation progresses in subcortical and cortical regions. The SIR model, using structural connectivity from diffusion MRI, recapitulates the spatiotemporal distribution of brain atrophy observed in PD. We show that connectome topology and geometry significantly contribute to model fit. We also show that the spatial expression of two genes implicated in alpha-synuclein synthesis and clearance, SNCA and GBA, also influences the atrophy pattern. We conclude that the progression of atrophy in PD is consistent with the prion-like hypothesis and that the SIR model is a promising tool to investigate multifactorial neurodegenerative diseases over time.\",\n \"Genomic answers for children: Dynamic analyses of >1000 pediatric rare disease genomes\\nPURPOSETo provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids (GA4K) program.\\n\\nMETHODSExtensive analyses of 960 families with suspected genetic disorders including short-read exome (ES) and genome sequencing (srGS); PacBio HiFi long-read GS (HiFi-GS); variant calling for small-nucleotide (SNV), structural (SV) and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants and pedigrees are stored in PhenoTips database, with data sharing through controlled access (dbGAP).\\n\\nRESULTSDiagnostic rates ranged from 11% for cases with prior negative genetic tests to 34.5% in naive patients. Incorporating SVs from GS added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with >4-fold more rare coding SVs than srGS. Variants and genes of unknown significance (VUS/GUS) remain the most common finding (58% of non-diagnostic cases).\\n\\nCONCLUSIONComputational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated by HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation, and by providing HiFi variant (SNV/SV) resources from >1,000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.\",\n \"Thyroid function and risk of anemia: a multivariable-adjusted and Mendelian Randomization analysis in the UK Biobank\\nContextThyroid dysfunction is associated with higher anemia prevalence, though causality remains unclear.\\n\\nObjectiveTo investigate a potential causal relationship between thyroid function and anemia.\\n\\nDesignCross-sectional and Mendelian Randomization study\\n\\nSettingEuropeans from UK Biobank\\n\\nParticipants445,482 participants, mean age 56.77 years (SD 8.0) and 54.2% were women. Self-reported clinical diagnosis of hypothyroidism was stated by 21,860 (4.9%); self-reported clinical diagnosis of hyperthyroidism by 3,431 (0.8%).\\n\\nMain Outcome MeasureAnemia, defined as hemoglobin level of <13 g/dL in men and <12 g/dL in women, was present in 18,717 (4.2%) participants.\\n\\nResultsIn cross-sectional logistic regression analyses, self-reported clinical diagnoses of hypo- and hyperthyroidism were associated with higher odds of anemia (OR 1.12, 95%CI 1.05-1.19 and OR 1.09, 95%CI 0.91-1.30), though with wide confidence intervals for hyperthyroidism. Although we considered a possible non-linear relationship, we did not observe an association of higher or lower genetically-influenced thyrotropin (TSH) with anemia (versus middle tertile: OR lowest tertile 0.98, 95% CI 0.95-1.02; highest tertile 1.02, 95% CI 0.98-1.06), nor of genetically-influenced free thyroxine (fT4) with anemia. Individuals with genetic variants in the DIO3OS gene implicated in intracellular regulation of thyroid hormones had a higher anemia risk (OR 1.05, 95% CI 1.02-1.10); no association was observed with variants in DIO1 or DIO2 genes.\\n\\nConclusionsWhile self-reported clinical diagnosis of hypothyroidism was associated with a higher prevalence of anemia, we did not found evidence supporting this association was causal. However, intracellular regulation of thyroid hormones might play a role in developing anemia.\",\n \"Accurate and reproducible prediction of ICU readmissions\\nReadmission in the intensive care unit (ICU) is associated with poor clinical outcomes and high costs. Traditional scoring methods to help clinicians deciding whether a patient is ready for discharge have failed to meet expectations, paving the way for machine learning based approaches. Freely available datasets such as MIMIC-III have served as benchmarking media to compare such tools. We used the OMOP-CDM version of MIMIC-III (MIMIC-OMOP) to train and evaluate a lightweight tree boosting method to predict readmission in ICU at different time points after discharge (3, 7 and 30 days), outperforming existing solutions with an AUROC of 0.805 for 3-days readmission.\",\n \"Choosing questions before methods in dementia research with competing events and causal goals\\nSeveral of the hypothesized or studied exposures that may affect dementia risk are known to increase the risk of death. This may explain counterintuitive results, where exposures that are known to be harmful for mortality risk sometimes seem protective for the risk of dementia. Authors have attempted to explain these counterintuitive results as biased, but the bias associated with a particular analytic method cannot be defined or assessed if the causal question is not explicitly specified. Indeed, we can consider several causal questions when competing events like death, which cannot be prevented by design, are present. Current dementia research guidelines have not explicitly considered what constitutes a meaningful causal question in this setting or, more generally, how this choice justifies and should drive particular analytic decisions. To contextualize current practices, we first perform a systematic review of the conduct and interpretation of longitudinal studies focused on dementia outcomes where death is a competing event. We then describe and demonstrate how to address different causal questions (referred here as \\\"the total effect\\\" and \\\"the controlled direct effect\\\") with traditional analytic approaches under explicit assumptions. Our application focuses on smoking cessation in late-midlife. To illustrate core concepts, we discuss this example both in terms of a hypothetical randomized trial and with an emulation of such a trial using observational data from the Rotterdam Study.\",\n \"Fed-GLMM: A Privacy-Preserving and Computation-Efficient Federated Algorithm for Generalized Linear Mixed Models to Analyze Correlated Electronic Health Records Data\\nLarge collaborative research networks provide opportunities to jointly analyze multicenter electronic health record (EHR) data, which can improve the sample size, diversity of the study population, and generalizability of the results. However, there are challenges to analyzing multicenter EHR data including privacy protection, large-scale computation, heterogeneity across sites, and correlated observations. In this paper, we propose a federated algorithm for generalized linear mixed models (Fed-GLMM), which can flexibly model multicenter longitudinal or correlated data while accounting for site-level heterogeneity. Fed-GLMM can be applied to both federated and centralized research networks to enable privacy-preserving data integration and improve computational efficiency. By communicating only a limited amount of summary statistics, Fed-GLMM can achieve nearly identical results as the gold-standard method where the GLMM is directly fitted on the pooled dataset. We demonstrate the performance of Fed-GLMM in both numerical experiments and an application to longitudinal EHR data from multiple healthcare facilities.\",\n \"Personalized Computational Heart Models with T1-Mapped Fibrotic Remodeling Predict Risk of Sudden Death Risk in Patients with Hypertrophic Cardiomyopathy\\nHypertrophic cardiomyopathy (HCM) causes sudden cardiac death (SCD) due to ventricular arrhythmias (VA) manifesting from myocardial fibrosis proliferation. Current clinical risk stratification criteria inadequately identify at-risk patients in need of primary prevention of VA. Here, we use mechanistic computational modeling of the heart to analyze how HCM-specific remodeling of the heart promotes arrhythmogenesis and to develop a personalized strategy to forecast risk of VAs in these patients. We combine contrast-enhanced cardiac magnetic-resonance (CMR) imaging and T1 mapping data to construct digital replicas of HCM patient hearts that represent the patient-specific distribution of focal and diffuse fibrosis and evaluate the substrate propensity to VA. Our analysis indicates that the presence of diffuse fibrosis, which is rarely assessed in these patients, increases arrhythmogenic propensity. In forecasting future VA events in HCM patients, the imaging-based computational heart approach achieved 84.6%, 76.9%, and 80.1% sensitivity, specificity, and accuracy, respectively, and significantly outperformed current clinical risk predictors. This novel VA risk assessment may have the potential to prevent SCD and help deploy primary prevention appropriately in HCM patients.\",\n \"Epidemiological characteristics of three SARS-CoV-2 variants of concern and implications for future COVID-19 pandemic outcomes\\nThree SARS-CoV-2 variants classified as variants of concern - B.1.1.7, B.1.351, and P.1 - have spread globally. To characterize their viral and epidemiological properties in support of public health planning, we develop and apply a model-inference system to estimate the changes in transmissibility and immune escape for each variant, based on case and mortality data from the country where each variant emerged. Accounting for under-detection of infection, disease seasonality, concurrent non-pharmaceutical interventions, and mass-vaccination, we estimate that B.1.1.7 has a 46.6% (95% CI: 32.3 - 54.6%) increase in transmissibility but nominal immune escape from protection induced by prior wild-type infection; B.1.351 has a 32.4% (95% CI: 14.6 - 48.0%) increase in transmissibility and 61.3% (95% CI: 42.6 - 85.8%) immune escape; and P.1 has a 43.3% (95% CI: 30.3 - 65.3%) increase in transmissibility and 52.5% (95% CI: 0 - 75.8%) immune escape. Model simulations indicate that B.1.351 and P.1 could supplant B.1.1.7 dominance and lead to increased infections. Our findings highlight the importance of preventing the spread of B.1.351 and P.1, in addition to B.1.1.7, via continued preventive measures, prompt mass-vaccination of all populations, continued monitoring of vaccine efficacy, and possible updating of vaccine formulations to ensure high efficacy.\",\n \"Differences in detected viral loads guide use of SARS-CoV-2 antigen-detection assays towards symptomatic college students and children.\\nLimitations in timely testing for SARS-CoV-2 drive the need for new approaches in suspected COVID-19 disease. We queried whether viral load (VL) in the upper airways at presentation could improve the management and diagnosis of patients. This study was conducted in a 9 hospital system in Allegheny County, Pennsylvania between March 1-August 31 2020. Viral load was determined by PCR assays for patients presenting to the Emergency Departments (ED), community pediatrics practices and college health service. We found that for the ED patients, VL did not vary substantially between those admitted and not. VL was relatively equivalent across ages, except for the under 25 age groups that tended to present with higher loads. To determine if rapid antigen testing (RAT) could aid diagnosis in certain populations, we compared BD Veritor and Quidel Sofia to SOC PCR-based tests. The antigen assay provided a disease-detection sensitivity of >90% in a selection of 32 positive students and was modeled to have an 80% sensitivity in all positive students. In the outpatient pediatric population, the antigen assay detected 70% of PCR-positives. Extrapolating these findings to viral loads in older hospitalized patients, a minority would be detected by RAT (40%). Higher loads did correlate with death, though the prognostic value was marginal (ROC AUC of only 0.66). VL did not distinguish between those needing mechanical ventilation and routine inpatients. We conclude that VL in upper airways, while not prognostic for disease management, may aid in selecting proper testing methodologies for certain patient populations.\",\n \"Assessing the contribution of rare-to-common protein-coding variants to circulating metabolic biomarker levels via 412,394 UK Biobank exome sequences\\nGenome-wide association studies have established the contribution of common and low frequency variants to metabolic biomarkers in the UK Biobank (UKB); however, the role of rare variants remains to be assessed systematically. We evaluated rare coding variants for 198 metabolic biomarkers, including metabolites assayed by Nightingale Health, using exome sequencing in participants from four genetically diverse ancestries in the UKB (N=412,394). Gene-level collapsing analysis - that evaluated a range of genetic architectures - identified a total of 1,303 significant relationships between genes and metabolic biomarkers (p<1x10-8), encompassing 207 distinct genes. These include associations between rare non-synonymous variants in GIGYF1 and glucose and lipid biomarkers, SYT7 and creatinine, and others, which may provide insights into novel disease biology. Comparing to a previous microarray-based genotyping study in the same cohort, we observed that 40% of gene-biomarker relationships identified in the collapsing analysis were novel. Finally, we applied Gene-SCOUT, a novel tool that utilises the gene-biomarker association statistics from the collapsing analysis to identify genes having similar biomarker fingerprints and thus expand our understanding of gene networks.\",\n \"In situ transcriptional profile of a germinal center plasmablastic burst hints at MYD88/CD79B mutants-enriched Diffuse Large B-cell Lymphomas.\\nThe germinal center (GC) reaction results in the selection of B-cells acquiring effector Ig secreting ability by progressing towards plasmablastic differentiation. This transition is associated with exclusion from the GC microenvironment. The aberrant expansion of plasmablastic elements within the GC fringes configures an atypical condition, the biological characteristics of which have not been defined yet. We investigated the in situ immunophenotypical and transcriptional characteristics of a non-clonal germinotropic expansion of plasmablastic elements (GEx) occurring in the tonsil of a young patient. Compared to neighboring GC and peri-follicular regions, the GEx showed a distinctive signature featuring key regulators of plasmacytic differentiation, cytokine signaling, and cell metabolism. The GEx signature was tested in the setting of diffuse large B-cell lymphoma (DLBCL) as a prototypical model of lymphomagenesis encompassing transformation at different stages of GC and post-GC functional differentiation. The signature outlined DLBCL clusters with different immune microenvironment composition and enrichment in genetic subtypes.\\n\\nSignificanceThis report represents the first insight into the transcriptional features of a germinotropic plasmablastic burst, shedding light into the molecular hallmarks of B cells undergoing plasmablastic differentiation and aberrant expansion within the non-canonical setting of the GC microenvironment.\",\n \"Developing and validating a multivariable prediction model for predicting costs of Colorectal Surgery\\nHospitals are faced with a burden to predict and therefore to calculate and also to manage various cost factors in regard to the patients and their treatments. Especially the increased costs which occur if a patient suffers from an anastomotic insufficiency. This can lead to an unavoidable deficit in the final revenue of these medical centers.\\n\\nThis study aims to determine whether machine learning (ML) algorithms can predict the cost factors based on patients with and without colon anastomosis after colorectal surgery. For the forecasting, multiple predictors will be taken into the model to provide a tool which can be helpful for hospitals to manage their costs which can end up in operating more cost effectively. This proof of principle will lay the groundwork for an efficient ML-based prediction tool based on multicenter data from a range of international centers in the subsequent phases of the study.\\n\\nWith a % MAPE result of 18 to 25.6 the prediction if our model showed decent results in order to forecast the costs in regard to various diagnosed factors and surgery approaches. There is an urgent need for further studies on predicting cost factors, especially for cases with and without anastomotic leakage to minimize unnecessary costs for the hospitals.\",\n \"The unmutated common ancestor of Gp41 conformational epitope targeting variable heavy chain 1-02 utilizing antibodies maintains antibody dependent cell cytotoxicity\\nIn studies on monoclonal Abs (mAbs) from long-term non-progressors (LTNPs), our laboratory has previously described highly mutated Abs against a complex conformational epitope with contributions from both gp41 heptad repeat regions. Despite using the VH1-02 gene segment, known to contribute to some of the broadest neutralizing Abs against HIV, members of these Abs, termed group 76C Abs, did not exhibit broad neutralization.\\n\\nBecause of the excessive mutations and use of VH1-02, our goal was to characterize the non-neutralizing functions of Abs of group 76C, to assess targeting of the epitope in various clinical presentations, and to assess the development of these Abs by comparison to their predicted common ancestor. Serum competition assays showed group 76C Abs were enriched in LTNPs, in comparison to VRC-01. Specific group 76C clones 6F5 and 6F11, expressed as recombinant Abs, both have robust ADCC activity, despite their sequence disparity. Sequence analysis predicted the common ancestor of this clonal group would utilize the germline non-mutated variable gene. We produced a recombinant ancestor Ab (76Canc) with a heavy chain utilizing the germline variable gene sequence paired to the 6F5 light chain. Competition with group 76C recombinant Ab 6F5 confirms 76Canc binds HIV envelope constructs near the original group C epitope. 76Canc demonstrates comparable ADCC to 6F5 and 6F11 when targeting both clade B and C HIV constructs. The functional capability of Abs utilizing germline VH1-02 has implications for disease control and vaccine development.\",\n \"COVID-19 mortality risk correlates inversely with vitamin D3 status, and a mortality rate close to zero could theoretically be achieved at 50 ng/ml 25(OH)D3: Results of a systematic review and meta-analysis\\nBackgroundMuch research shows that blood calcidiol (25(OH)D3) levels correlate strongly with SARS-CoV-2 infection severity. There is open discussion regarding whether low D3 is caused by the infection or if deficiency negatively affects immune defense. The aim of this study was to collect further evidence on this topic.\\n\\nMethodsSystematic literature search was performed to identify retrospective cohort as well as clinical studies on COVID-19 mortality rates versus D3 blood levels. Mortality rates from clinical studies were corrected for age, sex and diabetes. Data were analyzed using correlation and linear regression.\\n\\nResultsOne population study and seven clinical studies were identified, which reported D3 blood levels pre-infection or on the day of hospital admission. They independently showed a negative Pearson correlation of D3 levels and mortality risk (r(17)=-.4154, p=.0770/r(13)=-.4886, p=.0646). For the combined data, median (IQR) D3 levels were 23.2 ng/ml (17.4 - 26.8), and a significant Pearson correlation was observed (r(32)=-.3989, p=.0194). Regression suggested a theoretical point of zero mortality at approximately 50 ng/ml D3.\\n\\nConclusionsThe two datasets provide strong evidence that low D3 is a predictor rather than a side effect of the infection. Despite ongoing vaccinations, we recommend raising serum 25(OH)D levels to above 50 ng/ml to prevent or mitigate new outbreaks due to escape mutations or decreasing antibody activity.\\n\\nTrial registrationNot applicable.\",\n \"Post discharge persistent symptoms after COVID-19 in rheumatic and musculoskeletal diseases\\nOBJECTIVESTo describe persistent symptoms and consequences in Rheumatic and Musculoskeletal diseases (RMD) discharged from the hospital after Covid-19; to assess the roll of autoimmune rheumatic diseases (ARD) compared to and non-autoimmune rheumatic and musculoskeletal diseases (NARD) on persistent symptoms and consequences.\\n\\nMETHODSWe performed a cross-sectional observational study. RMD attended at a rheumatology outpatient clinic in Madrid with Covid-19 that required hospital admission were included. The main outcomes were persistence of symptoms and health consequences related to Covid19 after discharge. Independent variable was RMD group (ARD and NARD) and covariates were sociodemographic, clinical, and treatments. We ran a multivariable logistic regression model to assess the risk by RMD group on main outcomes.\\n\\nRESULTSWe included 105 patients and 51.5% had ARD. 68.57% reported at least one persistent symptom. The most frequent were dyspnea, fatigue, and chest pain. 31 patients had consequences. Lung damage was found in 11.4% of the patients, 18% had blood test abnormalities (10% lymphopenia), two died, one developed central retinal vein occlusion and one patient developed optic neuritis. 11 patients required readmission due to Covid-19 problems (16.7% ARD vs 3.9% NARD; p=0.053). No statistically significant differences by RMD groups were found in the final models.\\n\\nCONCLUSIONMany RMD patients have persistent symptoms, similar to other populations. This study also highlights that lung damage is the most frequent consequence. ARD compared to NARD does not seem to differ in terms of persistent symptoms or consequences, although ARD might have a greater number of readmissions due to Covid-19.\",\n \"Assessing the impact of race on glomerular filtration rate (GFR) prediction\\nBackgroundThe appropriate use and the implications of using variables that attempt to encode a patients race in clinical predictive algorithms remain unclear. The clinical algorithm for estimating glomerular filtration rate (GFR) adjusts for race, but the observed difference between Black and non-Black participants lacks biologically substantiated evidence. We investigated the impact of using a race variable on GFR prediction by race-stratified error analysis.\\n\\nMethodsWe implemented three predictive algorithms with varied amount of input information from an electronic health record database to estimate GFR. We compared the prediction error of the estimated GFR with and without the variable race between Black patients and White patients.\\n\\nResultsThe prediction error for patients coded as Black was higher than that for patients coded as White across all three algorithms. Removing race from the prediction algorithm did not lower the prediction error for patients coded as Black, neither did it decrease the difference in error between the two groups. The algorithm that included the most information with thousands of variables but excluding race produced the most accurate estimate for both groups and minimized the difference in performance between the two groups.\\n\\nConclusionThe prediction error for patients coded as Black was higher compared to those coded as White, regardless of inclusion of race as a variable. Using a large amount of information represented in electronic health record variables achieved a more accurate prediction of GFR and the least difference in prediction error across racial groups.\",\n \"Low-field thoracic magnetic stimulation increases peripheral oxygen saturation levels in coronavirus disease (COVID-19) patients: a single-blind, sham-controlled, crossover study\\nThe severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may cause low oxygen saturation (SpO2) and respiratory failure in coronavirus disease (COVID-19) patients. Hence the increase of SpO2 levels could be crucial for the quality of life and recovery of these patients. Here we introduce an electromagnetic device termed low-field thoracic magnetic stimulation (LF-ThMS) system. This device was designed to non-invasively deliver a pulsed magnetic field from 100 to 118 Hz and 10.5 to 13.1 mT (i.e., 105 to 131 Gauss) to the dorsal thorax. We show that these frequencies and magnetic flux densities are safe for the patients. We also present a proof-of-concept that a single session of LF-ThMS applied for 30 minutes to the dorsal thorax of 17 COVID-19 patients significantly increases their SpO2 levels. We designed a single-blind, sham-controlled, crossover study on 5 COVID-19 patients who underwent two sessions of the study (real and sham LF-ThMS) and 12 COVID-19 patients who underwent only the real LF-ThMS. We found a statistically significant correlation between magnetic flux density, frequency, or temperature associated with the real LF-ThMS and SpO2 levels in all COVID-19 patients. However, the five patients of the sham-controlled study did not exhibit a significant change in their SpO2 levels during sham stimulation. All the patients did not present adverse events after the LF-ThMS intervention.\\n\\nTrial registrationClinicalTrials.gov\\n\\nIdentifierNCT04895267\",\n \"Accounting for health inequities in the design of contact tracing interventions: a rapid review\\nContextContact tracing has been a central COVID-19 transmission control measure. However, without the consideration of the needs of specific populations, public health interventions can exacerbate health inequities.\\n\\nPurposeThe purpose of this rapid review was to determine if and how health inequities were included in the design of contact tracing interventions in epidemic settings.\\n\\nMethodWe conducted a search of the electronic databases MEDLINE and Web of Science. Our inclusion criteria included articles that: (i) described the design of contact tracing interventions, (ii) have been published between 2013 and 2020 in English, French, Spanish, Chinese, or Portuguese, (iii) and included at least 50% of empiricism, according to the Automated Classifier of Texts on Scientific Studies (ATCER) tool. We relied on various tools to extract data.\\n\\nResultFollowing the titles and abstracts screening of 230 articles, 39 articles met the inclusion criteria. Only seven references were retained after full text review. None of the selected studies considered health inequities in the design of contact tracing interventions.\\n\\nConclusionThe use of tools/concepts for incorporating health inequities, such as the REFLEX-ISS tool, and \\\"proportionate universalism\\\" when designing contact tracing interventions, would enable practitioners, decision makers, and researchers to better consider health inequities.\",\n \"Pathogens detected using a syndromic molecular diagnostic platform in patients hospitalized with severe respiratory illness in South Africa in 2017\\nBackgroundPneumonia continues to be a leading cause of death globally; however, in >50% of cases, an etiological agent is not identified. We describe the use of a multi-pathogen platform, TaqMan array card (TAC) real-time PCR, for the detection of pathogens in patients hospitalized with severe respiratory illness (SRI).\\n\\nMethodsWe conducted prospective hospital-based surveillance for SRI among patients at two sentinel sites in South Africa between January and December 2017. Patients were included in this study if a blood specimen and at least one respiratory specimen (naso- and oro-pharyngeal (NP/OP) swabs and/or sputum) were available for testing. We tested respiratory specimens for 21 respiratory pathogens and blood samples for nine bacteria using TAC. Pathogen detection was compared by age group and HIV status using the chi-squared test.\\n\\nResultsDuring 2017, 956 patients were enrolled in SRI surveillance, and of these, 637 (67%) patients were included in this study (637 blood, 487 NP/OP and 411 sputum specimens tested). At least one pathogen was detected in 83% (527/637) of patients. Common pathogens detected included H. influenzae (225/637; 35%), S. pneumoniae (224/637; 35%), rhinovirus (144/637; 23%), S. aureus (129/637; 20%), K. pneumoniae (85/637; 13%), M. tuberculosis (75/637; 12%), and respiratory syncytial virus (57/637; 9%). Multiple pathogens ([≥]2) were co-detected in 57% (364/637) of patients.\\n\\nConclusionWhile use of a multi-pathogen platform was useful in the detection of a pathogen in the majority of the patients, pathogen co-detections were common and would need clinical assessment for usefulness in individual-level treatment and management decisions.\",\n \"Safety Assessment of BNT162b2 Vaccine in Adolescents Aged 12-15 Years\\nPresent evidence of the safety of BNT162b2 Vaccine in adolescents of 12 to 15 years relies only on 2260 subjects involved in phase 3 study. Therefore, clinical and post-clinical safety assessment of BNT162b2 Vaccine in Age Group of 12 to 15 Years is urgently needed to make an accurate judgment for mass vaccination. A rapid systemic review was conducted to determine safety profile of BNT162b2 Vaccine in Age Group of 12 to 15 Years following the PRISMA guidelines. Published literature before August 15, 2021 were searched in PubMed, Scopus, Web of Science, Embase, the Cochrane library and MedRxiv, using the defined search words. 135 records found from 6 databases, of which 4 studies (2 studies from NEJM and 2 MMWR), total subject who received at least one dose of vaccine: 64969, were included in this systemic review per the inclusion criteria. The major events reported in clinical phase and post-authorisation observational studies are pain at injection site (local), fatigue (systemic), headache (systemic), chill (systemic), diarrhoea (systemic) and joint pain (systemic). Post-authorisation observational study (n = 62,709) reported about 50% lower major systemic events, specifically, fatigue, headache, chill, diarrhoea and join pain and about 25% lower major local event, specifically, pain at injection site, than phase 3 clinical study (n = 1,131). Our study suggest that higher adherence rate (>97 percent received second dose) in clinical phase 3 and significantly lower incident of major local and systemic events in post-authorisation observational study indicating that BNT162b2 vaccine has highly favourable safety profile.\",\n \"Polygenic risk vectors (PRV) improve genetic risk stratification for cardio-metabolic diseases\\n1.Accurate disease risk stratification can lead to more precise and personalized prevention and treatment of diseases. As an important component to disease risk, genetic risk factors can be utilized as an early and stable predictor for disease onset. Recently, the polygenic risk score (PRS) method has combined the effects from hundreds to millions of single nucleotide polymorphisms (SNPs) into a score that can be used for genetic risk stratification. However, current PRS approaches only utilize the additive associations between SNPs and disease risk in a one-dimensional score. Here, we show that leveraging multiple types of genetic effects in multi-dimensional risk vectors, or a polygenic risk vector (PRV), can improve the stratification of cardio-metabolic diseases risks. Using data from UK Biobank (UKBB) and Electronic Medical Records and Genomics (eMERGE) Network biobank linked electronic health records (EHR) as development and evaluation data, we found that the combined effects between the additive PRS and the dominant PRS outperformed either one in terms of disease risk stratification, especially for the individuals in the high-risk group. Our results demonstrate that disease risks are likely to be influenced by multiple types of genetic effects, and PRV could utilize these effects for better risk stratification while retaining the simplicity of the PRS method.\",\n \"Long-lasting neutralizing antibody responses in SARS-CoV-2 seropositive individuals are robustly boosted by immunization with the CoronaVac and BNT162b2 vaccines\\nThe durability of circulating neutralizing antibody (nAb) responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and their boosting by vaccination remains to be defined. We show that outpatient and hospitalized SARS-CoV-2 seropositive individuals mount a robust neutralizing antibody (nAb) response that peaks at days 23 and 27 post-symptom onset, respectively. Although nAb titers remained higher in hospitalized patients, both study groups showed long-lasting nAb responses that can persist for up to 12 months after natural infection. These nAb responses in previously seropositive individuals can be significantly boosted through immunization with two doses of the CoronaVac (Sinovac) or one dose of the BNT162b2 (BioNTech/Pfizer) vaccines, suggesting a substantial induction of B cell memory responses. Noteworthy, three obese previously seropositive individuals failed to mount a booster response upon vaccination, warranting further studies in this population. Immunization of naive individuals with two doses of the CoronaVac vaccine or one dose of the BNT162b2 vaccine elicited similar levels of nAbs compared to seropositive individuals 4.2 to 13.3 months post-infection with SARS-CoV-2. Thus, this preliminary evidence suggests that both, seropositive and naive individuals, require two doses of CoronaVac to ensure the induction of robust nAb titers.\",\n \"Spread of the SARS-CoV-2 UK-variant in the South East of France: impact on COVID-19 patients age, comorbidity profiles and clinical presentation, week 50 2020 to week 8 2021\\nObjectivesThe variant 20I/501Y.V1, associated to a higher risk of transmissibility, emerged in Nice city (South East of France, French Riviera) during January 2021. The pandemic has resumed late December 2020 in this aera. A high incidence rate together with a fast turn-over of the main circulating variants, provided us the opportunity to analyze modifications in clinical profile and outcome traits.\\n\\nMethodsObservational study in the University hospital of Nice from December 2020 to February 2021. We analyzed data of sequencing of SARS-CoV-2 from the sewage collector and PCR screening from all positive samples at the hospital. Then, we described the characteristics of all COVID-19 patients admitted in the emergency department (ED) (n=1247) and those hospitalized in the infectious diseases ward or ICU (n=232). Demographic data, clinical signs and severity were recorded by the NEWS-2, SAPS-2 and SOFA scores were recorded and analyzed.\\n\\nResultsthe UK-variant was absent in the area in December, then increasingly spread in January representing 59% of the PCR screening performed mid-February. The rate of patients over 65 years admitted to the ED decreased from 63% to 50% (p=0.001). The mean age of hospitalized patients in the infectious diseases ward decreased from 70.7 to 59.2 (p<0.001) while the proportion of patients without comorbidity increased from 16% to 42% (p=0.007). Neither the NEWS-2 score nor the main signs of clinical severity have changed over time.\\n\\nConclusionSpread of the UK-variant in the South East of France affects younger and healthier patients.\",\n \"A game theory based analysis of network connectivity reveals that state transition is crucial for epilepsy surgery outcome prediction\\nSeizures recur in half of patients who undergo epilepsy surgery. Presurgical workup mainly focuses on seizures, but only partially helps predicting outcomes, even after invasive electroencephalography. We conceived a generalizable model to detect epileptogenic networks through connectivity changes and identified the crucial role of the transition from pre-seizure to seizure, achieving the highest outcome prediction (93%) to date in a chronological cohort of 21 patients with 3-year follow-up or more.\",\n \"Age-specific effects of childhood BMI on multiple sclerosis risk: a Mendelian Randomisation study\\nObjectiveHigher Body Mass Index (BMI) during early life is thought to be a causal risk factor for Multiple Sclerosis (MS). We used longitudinal mendelian randomisation (MR) to determine whether there is a critical window during which BMI influences MS risk.\\n\\nMethodsSummary statistics for childhood BMI and for MS susceptibility were obtained from recent large GWAS. We generated exposure instruments for BMI during four non-overlapping epochs (< 3 months, 3 months-1.5 years, 2-5 years, and 7-8 years) and performed MR using the inverse-variance weighted method with standard sensitivity analyses. Multivariable MR was used to account for effects mediated via later-life BMI.\\n\\nResultsFor all time epochs other than birth, genetically determined higher BMI was associated with an increased liability to MS: Birth (OR 0.81, 95% CI 0.50-1.31, NSNPs=7, p=0.39), Infancy (OR 1.18, 95%CI 1.04-1.33, NSNPs=18, p=0.01), Early childhood (OR 1.31, 95%CI 1.03-1.66, NSNPs=4, p=0.03), Later childhood (OR 1.34, 95% CI 1.08-1.66, NSNPs=4, p=0.01). Multivariable MR suggested that these effects may be mediated by effects on adult BMI.\\n\\nConclusionWe provide evidence using MR that genetically-determined higher BMI during early life is associated with increased MS risk. This effect may be driven by shared genetic architecture with later-life BMI.\",\n \"Optical Genome Mapping And Single Nucleotide Polymorphism Microarray: An Integrated Approach For Investigating Challenging Cases Of Products Of Conception.\\nConventional cytogenetic analysis of products of conception (POC) is of limited utility because of failed cultures, microbial and maternal cell contamination (MCC). Optical genome mapping (OGM) is an emerging technology that has the potential to replace conventional cytogenetic methods. The use of OGM precludes the requirement for culturing (and related microbial contamination). However, a high percentage of MCC impedes a definitive diagnosis, which can be addressed by an additional pre-analytical quality control step that includes histological assessment of H&E stained slides from FFPE tissue with macro-dissection for Chorionic villi to enrich fetal tissue component for Single nucleotide polymorphism (SNP) microarray analysis. An internal audit of POC cases subjected to karyotype-only analysis showed a low yield on clinically actionable information that contributed to patient care. To improve the diagnostic yield, an integrated workflow was devised that included MCC characterization of POC tissue, followed by OGM for MCC negative cases or SNPM with histological assessment for MCC positive cases. A result was obtained in 93% (29/31) cases with a diagnostic yield of 45.1% (14/31) with proposed workflow compared to 9.6% (3/31) and 6.4% (2/31) with routine workflow, respectively. The integrated workflow with these technologies demonstrates the clinical utility and higher diagnostic yield in evaluating POC specimens.\",\n \"Mendelian randomization analyses reveal mediating factors of the causal effect of height on coronary artery disease\\nAn inverse correlation between stature and risk of coronary artery disease (CAD) has been observed in several epidemiologic studies, and recent Mendelian randomization (MR) experiments have suggested evidence that this association may be causal. However, the extent to which the effect estimated by MR can be explained by established cardiovascular risk factors is unclear, with a recent report suggesting that lung function traits could fully explain the height-CAD effect. To clarify this relationship, we utilized the largest set of genetic instruments for human stature to date, comprising >2,000 genetic variants for height and CAD. In univariable analysis, we confirmed that a one standard deviation decrease in height ([~]6.5 cm) was associated with a 12.0% increase in the risk of CAD, consistent with previous reports. In multivariable analysis accounting for effects from up to 12 established risk factors, we observed a >3-fold attenuation in the causal effect of height on CAD susceptibility (3.7%, p = 2.1x10-2). We observed minimal effects of lung function traits on CAD risk in our analyses, indicating that these traits are unlikely to explain the residual association between height and CAD risk. In sum, these results suggest that height does not add meaningful clinical impact on CAD risk prediction beyond established risk factors.\",\n \"Low-dose IL-2 reduces IL-21+ T cells and induces a long-lived anti-inflammatory gene expression signature inversely modulated in COVID-19 patients\\nDespite early clinical success, the mechanisms of action of low-dose interleukin-2 (LD-IL-2) immunotherapy remain only partly understood. Here, we examine the effects of interval administration of low-dose recombinant IL-2 (iLD-IL-2) using high-resolution, single-cell multiomics. We confirmed that iLD-IL-2 selectively expands thymic-derived FOXP3+HELIOS+ Tregs and CD56br NK cells, and provide new evidence for an IL-2-induced reduction of highly differentiated IL-21-producing CD4+ T cells. We also discovered that iLD-IL-2 induces an anti-inflammatory gene expression signature, which was detected in all T and NK cell subsets even one month after treatment. The same signature was present in COVID-19 patients, but in the opposite direction. These findings indicate that the sustained Treg and CD56br NK cell increases induced by our 4-week iLD-IL2 treatment create a long-lasting and global anti-inflammatory environment, warranting further investigations of the potential clinical benefits of iLD-IL-2 in immunotherapy, including the possibility of reversing the pro-inflammatory environment in COVID-19 patients.\",\n \"Metformin Is Associated with Favorable Outcomes in Patients with COVID-19 and Type 2 Diabetes Mellitus\\nAimCoronavirus disease 2019 (COVID-19) is a new pandemic the entire world is facing since December of 2019. In this retrospective study, we aim to address whether metformin use offers a low mortality on patients with COVID-19 and pre-existing type 2 diabetes mellitus (T2DM).\\n\\nMaterials and MethodsA cohort of 1356 hospitalized patients with COVID-19 and pre-existing T2DM was analyzed by multivariate regression. Covariates that potentially confound the association were further adjusted using propensity score matching or inverse probability of treatment weighting. A meta-analysis of the present study along with 5 published studies with metformin use prior to admission in patients with COVID-19 and T2DM was carried out.\\n\\nResultsWe found that metformin therapy prior to admission in patients with COVID-19 and T2DM was significantly associated with less primary outcome events including in-hospital mortality and hospice care enrollment with an odds ratio (OR) of 0.25 (95% CI, 0.06-0.74) and less in-hospital length of stay, compared to non-metformin group. There were no statistical differences between the metformin group and non-metformin group for all three inflammatory markers (ferritin, CRP, and IL-6) on admission or peak levels during hospitalization. Furthermore, meta-analysis demonstrated that metformin use was significantly correlated with reduced mortality with an OR of 0.73 (95% CI, 0.65-0.82) in the fixed effect model and 0.58 (95% CI, 0.42-0.80) for the random effect model.\\n\\nConclusionsOur results provide supporting evidence that metformin may confer increased survival in patients with COVID-19 and T2DM treated with Metformin prior to hospitalization.\",\n \"A functional TGFB1 polymorphism in the donor associates with long-term graft survival after kidney transplantation.\\nIntroductionImprovement of long-term outcomes in kidney transplantation remains one of the most pressing challenges, yet drug development is stagnating. Human genetics offers an opportunity for much-needed target validation in transplantation. Conflicting data exists about the effect of transforming growth factor-beta 1 (TGF-{beta}1) on kidney transplant survival, since TGF-{beta}1 has profibrotic and protective effects. We therefore the impact of a recently discovered functional TGBF1 polymorphism on long-term kidney graft survival.\\n\\nMethodsWe performed an observational cohort study analyzing recipient and donor DNA in 1,271 kidney transplant-pairs from the University Medical Center Groningen in The Netherlands and associated a low-producing TGBF1 polymorphism (rs1800472-C>T) with 5, 10, and 15-year death-censored kidney graft survival.\\n\\nResultsDonor genotype frequencies of s1800472 in TGBF1 differed significantly between patients with and without graft loss (P=0.042). Additionally, the low-producing TGBF1 polymorphism in the donor was associated with an increased risk of graft loss following kidney transplantation (HR 2.13 for the T-allele; 95%-CI 1.16-3.90; P=0.015). The incidence of graft loss within 15 years of follow-up 16.4% in the CC-genotype group and 28.9% in the CT-genotype group. After adjustment for transplant-related covariates, the association between the TGBF1 polymorphism in the donor and graft loss remained significant. In contrast, there was no association between the TGBF1 polymorphism in the recipient and graft loss.\\n\\nConclusionKidney allografts possessing a low-producing TGBF1 polymorphism have a higher risk of late graft loss. Our study adds to a growing body of evidence that TGF-{beta}1 is beneficial, rather than harmful, for kidney transplant survival.\",\n \"SARS-CoV-2 serostatus of healthcare worker in the Austrian state Vorarlberg between June 2020 and January 2021\\nBackgroundAustria, and particularly its westernmost federal state Vorarlberg, developed an extremely high COVID-19 incidence rate in November 2020. Health care workers (HCW) may be at higher risk of contracting the disease within the working environment and therefore the seroprevalence in this population is of particular interest. Here, we analyzed SARS-CoV-2-specific antibody response in Vorarlberg HCW in a prospective cohort study.\\n\\nMethodsA total of 395 HCW have been tested at three different time points for the prevalence of anti-SARS-CoV-2 IgG antibodies specific for NP and RBD. Enrollment started in June 2020 (t1), two months after the end of the first wave. Re-testing took place between October to November at the beginning of the second wave (t2), and again at the end of the second wave in January 2021 (t3).\\n\\nResultsAt t1, 3% of HCW showed a strong IgG-specific responses to either NP or RBD. At t2, the rate increased to 4%, and after the second wave in January 2021, 14% had a strong response, which was assessed to be stable for up to ten months. The amount of HCW with anti-SARS-CoV-2 IgG antibodies was 38% higher than the number of infections found by RT-PCR.\\n\\nConclusionWe found low numbers of SARS-CoV-2-seropositive HCW in a hotspot setting after the first wave but a very high increase during the second massive wave. Though the seroprevalence in HCW was comparable to the general population. Our findings offer support for the routine application of serological testing in management of the ongoing COVID-19 pandemic.\\n\\nMain summaryA relatively low percentage of 3% SARS-CoV-2 seropositive HCW with strong IgG-specific antibody responses was found in the Austrian federal state Vorarlberg after the first wave increasing to 14% after the second massive wave lasting until January 2021.\",\n \"Trans-ancestry genome-wide association study identifies novel genetic mechanisms in rheumatoid arthritis\\nTrans-ancestry genetic research promises to improve power to detect genetic signals, fine-mapping resolution, and performances of polygenic risk score (PRS). We here present a large-scale genome-wide association study (GWAS) of rheumatoid arthritis (RA) which includes 276,020 samples of five ancestral groups. We conducted a trans-ancestry meta-analysis and identified 124 loci (P < 5 x 10-8), of which 34 were novel. Candidate genes at the novel loci suggested essential roles of the immune system (e.g., TNIP2 and TNFRSF11A) and joint tissues (e.g., WISP1) in RA etiology. Trans-ancestry fine mapping identified putatively causal variants with biological insights (e.g., LEF1). Moreover, PRS based on trans-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between European and East Asian populations. Our study provides multiple insights into the etiology of RA and improves genetic predictability of RA.\",\n \"Analyzing Healthcare Safety Climate Through A Collaborative Filtering of Safety Attitudes Questionnaire for A Hospital Case Study\\nBackgroundPatient safety climate in healthcare is an important element to improve quality of current healthcare system globally. Safety Attitudes Questionnaire (SAQ), one of measurable tools for patient safety climate, is applied as an effective research survey to collect opinions and information from medical workers in a long term.\\n\\nMethodSAQ data in this study consists of medical employee scores to 46 questions in 8 aspects or dimensions and personal information during 2014 to 2017 from a teaching hospital. A quantitative analysis with a core user based collaborative filtering method is conducted to analyze the SAQ data for discovering the latent inter-related pattern among different SAQ aspects of sub-sectors in this hospital for four years.\\n\\nResultsThere are not interrelationships between these 8 independent aspects for wards at different level (A, B and C) consistently across 4 years. The correlation patterns of aspects are not strong consistent over years for wards.\\n\\nConclusionObservations in this study can be used to support understanding patient safety climate assessment. They are contributed to further study in this area and understand SAQ aspects dynamically in a real hospital case.\",\n \"Phenome-wide association analysis of substance use disorders in a deeply phenotyped sample\\nBackgroundSubstance use disorders (SUDs) are associated with a variety of co-occurring psychiatric disorders and other SUDs, which partly reflects genetic pleiotropy. Polygenic risk scores (PRS) and phenome-wide association studies (PheWAS) are useful in evaluating pleiotropic effects. The comparatively low prevalence of SUDs and lack of detailed information available in electronic health records limits their informativeness for such analyses.\\n\\nMethodsWe used the deeply-phenotyped Yale-Penn sample [(N=10,610; 46.3% African ancestry (AFR), 53.7% European ancestry (EUR)], recruited for genetic studies of substance dependence, to examine pleiotropy for 4 major substance-related traits: alcohol use disorder (AUD), opioid use disorder (OUD), smoking initiation (SMK), and lifetime cannabis use (CAN). The sample includes both affected and control subjects interviewed using the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA), a comprehensive psychiatric interview.\\n\\nResultsIn AFR individuals PRS for AUD, and in EUR individuals PRS for AUD, OUD, and SMK, were associated with their respective primary DSM diagnoses. These PRS were also associated with additional phenotypes involving the same substance. PheWAS analyses of PRS in EUR individuals identified associations across multiple phenotypic domains, including phenotypes not commonly assessed in PheWAS analyses, such as family environment and early childhood experiences.\\n\\nConclusionsSmaller, deeply-phenotyped samples can complement large biobank genetic studies with limited phenotyping by providing greater phenotypic granularity. These efforts allow associations to be identified between specific features of disorders and genetic liability for SUDs, which help to inform our understanding of the pleiotropic pathways underlying them.\",\n \"A Systematic Review of the Methodological Quality of Economic Evaluations in Genetic Screening and Testing for Monogenic Disorders\\nPurposeUnderstanding the value of genetic screening and testing for monogenic disorders requires high-quality, methodologically robust economic evaluations. This systematic review sought to assess the methodological quality among such studies and examine opportunities for improvement.\\n\\nMethodsWe searched Pubmed, Cochrane, Embase, and Web of Science for economic evaluations of genetic screening/testing (2013-2019). Methodological rigor and adherence to best practices were systematically assessed using the BMJ checklist.\\n\\nResultsAcross 47 identified studies, there was substantial variation in modeling approaches, reporting detail, and sophistication. Models ranged from simple decision trees to individual-level microsimulation, comparing between two and >20 alternative interventions. Many studies failed to report sufficient detail to enable replication or did not justify modeling assumptions, especially for costing methods and utility values. Meta-analyses, systematic reviews, or calibration were rarely used to derive parameter estimates. Nearly all studies conducted some sensitivity analysis, and more sophisticated studies implemented probabilistic sensitivity/uncertainty analysis, threshold analysis, and value of information analysis.\\n\\nConclusionWe describe a heterogeneous body of work and present recommendations and exemplar studies across the methodological domains of (1) perspective, scope, and parameter selection, (2) use of uncertainty/sensitivity analyses, and (3) reporting transparency for improvement in the economic evaluation of genetic screening/testing.\",\n \"Cardiovascular disease biomarkers derived from circulating cell-free DNA methylation\\nAcute coronary syndromes (ACS) remain a major cause of worldwide mortality. ACS diagnosis is done by a combination of factors, such as electrocardiogram and plasma biomarkers. These biomarkers, however, lack the power to accurately stratify patients into different risk groups. Instead, we used changes in the circulating cell-free DNA (ccfDNA) methylation profiles to estimate the extent of heart injury and the severity of ACS. Our approach relies on the fact that dying cells in acutely damaged tissue release DNA into the blood, causing an increase in the ccfDNA. In addition, each cell type has a distinct DNA methylation profile. We leverage cell type/state specificity of DNA methylation to deconvolute the cell types of origin for ccfDNA and also find DNA methylation-based biomarkers that stratify patient cohorts. The cohorts consisted of healthy subjects, and patients from three ACS conditions: ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina (UA). We have used two cohorts of patients - discovery, and validation, both consisting of the same conditions. We have sequenced the ccfDNA from the discovery cohort using Whole Bisulfite Genome Sequencing (WBGS), to obtain an unbiased overview of plasma DNA methylation profiles. We have found a total of 1,614 differential methylated regions (DMRs) in the three ACS groups. Many of the regions are associated with genes involved in cardiovascular conditions and inflammation. Using linear models, we were able to narrow down to 254 DMRs significantly associated with ACS severity. The reduced list of DMRs enabled a more accurate stratification of ACS patients. The predictive power of the DMRs was validated in the confirmation cohort using targeted methylation sequencing of the validation cohort.\",\n \"Alpha-1 adrenoreceptor antagonism mitigates extracellular mitochondrial DNA accumulation in lung fibrosis models and in patients with IPF\\nIdiopathic Pulmonary Fibrosis is increasingly associated with adrenergic innervation and endogenous innate immune ligands such as mitochondrial DNA (mtDNA). Interestingly, a connection between these entities has not been explored. Here we report that noradrenaline (NA) derived from the lungs adrenergic nerve supply drives the accumulation of SMA-expressing fibroblasts via a mechanism involving 1 adrenoreceptors and mtDNA. Using the bleomycin model of lung fibrosis we compared the effect of lung specific adrenergic denervation achieved via the inhalational administration of the sympathetic neurotoxin 6-hydroxydopamine to surgically mediated adrenal ablation and found that NA derived from local but not adrenal sources drives lung fibrosis. Bleomycin induced the appearance of a SMA+ fibroblast population co-expressing the adrenoreceptor alpha-1D (ADRA1D). Therapeutic delivery of the 1 adrenoreceptor antagonist terazosin reversed these changes and suppressed the accumulation of extracellular mtDNA. TGF{beta}1-stimulated normal human lung fibroblasts treated with TGF{beta}1 and Noradrenaline expressed ADRA1D and developed reduced SMA expression and extracellular mtDNA concentrations when treated with terazosin. IPF patients prescribed 1 adrenoreceptor antagonists for non-pulmonary indications showed improved survival and reduced concentrations of plasma mtDNA. These findings link nerve-derived NA and 1 adrenoreceptor antagonism with mtDNA accumulation and lung fibrogenesis in mouse models, cultured cells, and humans with IPF. Further study of this neuro-innate connection may yield new avenues for investigation in the clinical and basic science realms.\",\n \"Spatial covariance analysis of FDG-PET and HMPAO-SPECT for the differential diagnosis of dementia with Lewy bodies and Alzheimer's disease.\\nWe investigated diagnostic characteristics of spatial covariance analysis (SCA) of FDG-PET and HMPAO-SPECT scans in the differential diagnosis of dementia with Lewy bodies (DLB) and Alzheimers disease (AD), in comparison with visual ratings and region of interest (ROI) analysis. Sixty-seven patients (DLB 29, AD 38) had both HMPAO-SPECT and FDG-PET scans. Spatial covariance patterns were used to separate AD and DLB in an initial derivation group (DLB n=15, AD n=19), before being forward applied to an independent group (DLB n=14, AD n=19). Visual ratings were by consensus, with ROI analysis utilising medial occipital/medial temporal uptake ratios. SCA of HMPAO-SPECT performed poorly (AUC 0.59{+/-}0.10), whilst SCA of FDG-PET (AUC 0.83{+/-}0.07) was significantly better. For FDG-PET, SCA showed similar diagnostic performance to ROI analysis (AUC 0.84{+/-}0.08) and visual rating (AUC 0.82{+/-}0.08). In contrast to ROI analysis, there was little concordance between SCA and visual ratings of FDG-PET scans. We conclude that SCA of FDG-PET outperforms that of HMPAO-SPECT and performed similarly to other analytical approaches, with the potential to improve with larger derivation groups. Compared to visual rating, SCA of FDG-PET relies on different sources of group variance to separate DLB from AD.\",\n \"Comparative analysis unveils novel changes in serum metabolites and metabolomic networks of retinopathy of prematurity infants\\nBackgroundAdvances in mass spectrometry are providing new insights into the role of metabolomics in the aetiology of many diseases. Studies in retinopathy of prematurity (ROP), for instance, overlooked the role of metabolic alterations in disease development. Here, we employed comprehensive metabolic profiling and gold-standard metabolic analysis to explore major metabolites and metabolic pathways significantly affected in early stages of pathogenesis toward ROP.\\n\\nMethodsThis is a multicentre, retrospective case-control study. We collected serums from 57 ROP cases and 57 strictly baseline matched non-ROP controls. Non-targeted ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) from Metabolon, Inc. was used to detect the metabolites in serum samples. Machine learning was used to unravel most affected metabolites and pathways in ROP development.\\n\\nResultsCompared to non-ROP controls, we found a significant metabolic perturbation in the ROP serums, featured with an increase in lipid, nucleotide, carbohydrate metabolites and a lower level of peptides. Machine leaning helped to distinguish a cluster of metabolic pathways (glycometabolism, redox homeostasis, lipid metabolism and arginine pathway) that were strongly related to the development of ROP. In addition, we found that the severity of ROP was related to the level of creatinine and ribitol.\\n\\nConclusionIn the current study, our results suggested a strong link between metabolic profiling and retinal neovascularization during ROP pathogenesis. These findings provided an insight into identifying novel metabolic biomarkers for ROP diagnosis and prevention.\",\n \"Fitting the Reproduction number from UK coronavirus case data, and why it is close to 1\\nWe present a method for rapid calculation of coronavirus growth rates and R-numbers tailored to the publicly available data in the UK. The R-number is derived from time-series of case data, using bespoke data processing to remove systematic and errors and stochastic fluctuations. In principle, growth rate can be obtained by differentiating the reported case numbers, but in fact daily stochastic fluctuations disqualify this method. We therefore assume that the case data comprises a smooth, underlying trend which is differentiable and a noise term. The approach produces, up-to-date estimates of the R-number throughout the period of data availability. Our method is validated against published consensus R-numbers from the UK government, and shown to produce comparable results. A significant advantage of our method is that it is stable up to the most recent data, this enables us to make R-number estimates available over two weeks ahead of the published consensus. The short-lived peaks observed in the R-number and case data cannot be explained by a well-mixed model and are suggestive of spread on a localised network. Such a localised spread model tends to give an Rt number close to 1, regardless of how large R0 is. The case-driven approach is combined with Weight-Shift-Scale (WSS) methods to monitor trends in the epidemic and for medium term predictions. Using case-fatality ratios, we create a narrative for trends in the UK epidemic increased infectiousness of the alpha and delta variants, and the effectiveness of vaccination in reducing severity of infection.\",\n \"Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium\\nSchizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.64 years (95% CI: 3.01, 4.26; I2 = 55.28%) compared to controls, after adjusting for age and sex (Cohens d = 0.50). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.\",\n \"High incidence of pulmonary thromboembolism in hospitalized SARS-CoV-2 infected patients\\nIntroductionSARS-CoV-2 infected patients present thrombotic complications caused by direct endothelial cells injury of the microvessels. Pulmonary thromboembolism (PE) has been reported by Computed Tomography pulmonary angiogram (CTPA) in patients with COVID-19 pneumonia with high D-dimer levels.\\n\\nObjectivesWe present the characteristics of SARS-CoV-2 infected patients diagnosed of PE by CTPA in our hospital. We also present the comparison of these findings with non-infected patients with PE data.\\n\\nMethodsPatients 18 years of age or older with SARS-CoV2 virus infection, and patients with suspected infection at beginning of admission but with negative PCR, were studied with CTPA for suspicion of VTE, during their hospitalization.\\n\\nResultsDuring the study period, 52 CTPA were performed in our hospital, sixteen in SARS-CoV-2 infected patients. No significant differences in age (p=0.43) and sex (p=0.31) were found between the two groups, infected and non-infected patients. In the infected group, the patients who had PE had a much lower median age (47.8 years) than those without PE (73.3 years). No differences between infected and non-infected patients were detected in the diagnosis of PE with CTPA, 28.6% versus 27.8% (p=1.00). Overall patient mortality was 1.9%; one patient died (6.3%) in the infected group, and none in the non-infected group (p=0.31).\\n\\nConclusionA considerable incidence of PE diagnosed by CTPA in SARS-CoV-2 infected patients has been observed, despite thrombo-prophylaxis.\",\n \"Transmission blocking activity of low dose tafenoquine in healthy volunteers experimentally infected with Plasmodium falciparum\\nBackgroundBlocking the transmission of parasites from humans to mosquitoes is a key component of malaria control. Tafenoquine exhibits activity against all stages of the malaria parasite and may have utility as a transmission blocking agent. We aimed to characterize the transmission blocking activity of low dose tafenoquine.\\n\\nMethodsHealthy adults were inoculated with P. falciparum 3D7-infected erythrocytes on day 0. Piperaquine was administered on days 9 and 11 to clear asexual parasitemia while allowing gametocyte development. A single 50 mg oral dose of tafenoquine was administered on day 25. Transmission was determined by enriched membrane feeding assays pre-dose and at 1, 4 and 7 days post-dose. Artemether-lumefantrine was administered following the final assay. Outcomes were the reduction in mosquito infection and gametocytemia post-tafenoquine, and safety parameters.\\n\\nResultsSix participants were enrolled, and all were infective to mosquitoes pre-tafenoquine, with a median 86% (range: 22-98) of mosquitoes positive for oocysts and 57% (range: 4-92) positive for sporozoites. By day 4 post-tafenoquine, the oocyst and sporozoite positivity rate had reduced by a median 35% (IQR: 16-46) and 52% (IQR: 40-62), respectively, and by day 7, 81% (IQR 36-92) and 77% (IQR 52-98), respectively. The decline in gametocyte density post-tafenoquine was not significant. No significant participant safety concerns were identified.\\n\\nConclusionLow dose tafenoquine reduces P. falciparum transmission to mosquitoes, with a delay in effect.\\n\\nTrial registrationAustralian New Zealand Clinical Trials Registry (ACTRN12620000995976).\\n\\nFundingQIMR Berghofer Medical Research Institute.\",\n \"Dysbiosis in pre-cancerous mucosa may drive immune dysfunction: a study of immune system: microbiota interaction in familial adenomatous polyposis\\nObjectivesFamilial adenomatous polyposis (FAP) is a condition caused by a constitutional pathogenic variant of the adenomatous polyposis coli (APC) gene that results in intestinal adenoma formation and colorectal cancer (CRC), necessitating pre-emptive colectomy. We sought to examine interaction between the mucosal immune system and commensal bacteria in FAP to test for immune dysfunction that might accelerate tumorigenesis.\\n\\nMethodsColonic biopsies were obtained from macroscopically normal mucosal tissue from 14 healthy donors and 13 patients with FAP during endoscopy or from surgical specimens. Intraepithelial and lamina propria lymphocytes were phenotyped. Intraepithelial microbes were labelled with anti-IgA/IgG and analyzed by flow cytometry.\\n\\nResultsProportions of resident memory CD103-expressing CD8+ and {gamma}{delta} T cell receptor+ intraepithelial lymphocytes were dramatically reduced in both left and right colon of patients with FAP compared to healthy controls. In lamina propria, T-cells expressed less CD103 and CD4+ CD103+ cells expressed less CD73 ectonucleotidase. IgA coating of epithelia-associated bacteria, IgA+ peripheral B cells and CD4 T-cell memory responses to commensal bacteria were increased in FAP.\\n\\nConclusionsLoss of resident memory T-cells and {gamma}{delta} T-cells in mucosal tissue of patients with FAP accompanies intestinal microbial dysbiosis previously reported in this pre-cancerous state and suggests impaired cellular immunity and tumor surveillance. This may lead to barrier dysfunction, possible loss of regulatory T-cell function and excess IgA antibody secretion. Our data are the first to implicate mucosal immune dysfunction as a contributing factor in this genetically driven disease and identify potentially critical pathways in the etiology of CRC.\",\n \"Dynamic balance recovery in chronic Acquired Brain Injury participants following a perturbation training.\\nBackgroundAcquired Brain Injury (ABI) is defined as a damage to the brain that occurs after birth. Subjects post-ABI suffer from dynamic balance impairments that persist years after the injury.\\n\\nObjectiveTo explore the effect of a perturbation method which is consisted of unexpected balance perturbations using Re-Step technology on the recovery of dynamic balance and gait velocity in chronic ABI participants.\\n\\nMethodsIn a clinical trial, 35 chronic ABI participants (stroke and traumatic brain injury) participated in 22 sessions of perturbation-training, twice a week for 3 months. Dynamic balance was assessed pre and post-training using Community Balance and Mobility Scale (CB&M). Gait velocity was also assessed in the stroke participants using the 10-meter walk test (10MWT).\\n\\nResultsDynamic balance improved significantly post-training (p=0.001). This improvement was greater than the improvement that was observed in a sub-group that was tested twice before training (p=0.04). 16 participants (45.7%) out of 35 met or exceeded minimal detectable change (MDC) of the CB&M Scale. Self-paced velocity also improved significantly (p=0.02) but only 2 participants (9.5%) out of 21 exceeded the MDC of 10MWT post-stroke.\\n\\nConclusionsUnexpected balance perturbation-training using Re-Step technology led to an improvement in dynamic balance and gait velocity in chronic ABI participants. The advantage of Re-Step technology training compared to conventional balance training should be further examined.\",\n \"Torque teno virus load predicts allograft rejection but not viral infection after kidney transplantation\\nThe main challenge of immunosuppressive therapy after solid organ transplantation is to create a new immunological balance that prevents organ rejection and does not promote opportunistic infection. Torque teno virus (TTV) a ubiquitous and non-pathogenic single-stranded DNA virus has been proposed as a marker of functional immunity in immunocompromised patients. Here investigate whether TTV loads predict the risk of common viral infection and allograft rejection in kidney transplantation recipients.\\n\\nIn a retrospective cohort of 389 kidney transplantation recipients, individual TTV loads in were measured by qPCR in consecutive plasma samples during one year follow-up. The endpoints were allograft rejection, BK polyomavirus (BKPyV) viremia and cytomegalovirus (CMV) viremia. Repeated TTV measurements and rejection and infection survival data were analysed in a joint model.\\n\\nDuring follow-up, TTV DNA detection in the transplant recipients increased from 85 to 100%. The median viral load increased to 107 genome copies/ml within three months after transplantation. Rejection, BKPyV viremia and CMV viremia occurred in 23%, 27% and 17% of the patients, respectively. With every 10-fold TTV load-increase, the risk of rejection decreased considerably (HR: 0.74, CI 95%: 0.71-0.76), while the risk of BKPyV and CMV viremia remained the same (HR: 1.03, CI 95%: 1.03-1.04 and HR: 1.01, CI 95%: 1.01-1.01).\\n\\nIn conclusion, TTV load kinetics predict allograft rejection in kidney transplantation recipients, but not the BKPyV and CMV infection. The potential use of TTV load levels as a guide for optimal immunosuppressive drug dosage to prevent allograft rejection deserves further validation.\",\n \"Machine learning enabled subgroup analysis with real-world data to inform better clinical trial design\\nRestrictive eligibility criteria for clinical trials may limit the generalizability of treatment effectiveness and safety to real-world patients. In this paper, we propose a machine learning approach to derive patient subgroups from real-world data (RWD), such that the patients within the same subgroup share similar clinical characteristics and safety outcomes. The effectiveness of our approach was validated on two existing clinical trials with the electronic health records (EHRs) from a large clinical research network. One is the donepezil trial for Alzheimers disease (AD), and the other is the Bevacizumab trial on colon cancer (CRC). The results show that our proposed algorithm can identify patient subgroups with coherent clinical manifestations and similar risk levels of encountering severe adverse events (SAEs). We further exemplify that potential rules for describing the patient subgroups with less SAEs can be derived to inform the design of clinical trial eligibility criteria.\",\n \"Laboratory-Developed Test for SARS-CoV-2 Using Saliva Samples at the University of California, Riverside\\nHere we describe a relatively quick, simple, economical and accurate laboratory developed test (LDT) for detection of SARS-CoV-2 in heated and diluted saliva samples without RNA extraction. Our protocol is a variation of the University of Illinois Urbana-Champaign SHIELD LDT. Differences include chilling of the samples during dilution and using a reduced volume for the qRT-PCR reactions. The level of detection for our LDT is 3125 copies/ml, which compares favorably with other saliva-based tests. Initial validation studies with a limited number of patient samples have demonstrated excellent agreement between results using our LDT and those obtained from external laboratories. The cost of consumables for our test is under $8 and a throughput of 1000 tests/day can be achieved with 3-4 personnel.\",\n \"Longitudinal analysis shows durable and broad immune memory after SARS-CoV-2 infection with persisting antibody responses and memory B and T cells\\nEnding the COVID-19 pandemic will require long-lived immunity to SARS-CoV-2. Here, we evaluate 254 COVID-19 patients longitudinally up to eight months and find durable broad-based immune responses. SARS-CoV-2 spike binding and neutralizing antibodies exhibit a bi-phasic decay with an extended half-life of >200 days suggesting the generation of longer-lived plasma cells. SARS-CoV-2 infection also boosts antibody titers to SARS-CoV-1 and common betacoronaviruses. In addition, spike-specific IgG+ memory B cells persist, which bodes well for a rapid antibody response upon virus re-exposure or vaccination. Virus-specific CD4+ and CD8+ T cells are polyfunctional and maintained with an estimated half-life of 200 days. Interestingly, CD4+ T cell responses equally target several SARS-CoV-2 proteins, whereas the CD8+ T cell responses preferentially target the nucleoprotein, highlighting the potential importance of including the nucleoprotein in future vaccines. Taken together, these results suggest that broad and effective immunity may persist long-term in recovered COVID-19 patients.\",\n \"Predicting bloodstream infection outcome using machine learning\\nBloodstream infections (BSI) are a main cause of infectious disease morbidity and mortality world-wide. Early prediction of patients at high risk of poor outcomes of BSI is important for earlier decision making and effective patient stratification. We developed electronic medical record-based machine learning models that predict patient outcomes of BSI. The area under the receiver-operating characteristics curve was 0.82 for a full featured inclusive model, and 0.81 for a compact model using only 25 features. Our models were trained, using electronic medical records that include demographics, blood tests, and the medical and diagnosis history of 7,889 hospitalized patients diagnosed with BSI. Among the implications of this work is implementation of the models as a basis for selective rapid microbiological identification, toward earlier administration of appropriate antibiotic therapy. Additionally, our models may help reduce the development of BSI and its associated adverse health outcomes and complications.\",\n \"Distinct cellular dynamics associated with response to CAR-T therapy for refractory B-cell lymphoma\\nChimeric Antigen Receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies. Approximately half of patients with refractory large B-cell lymphomas achieve durable responses from CD19-targeting CAR-T treatment; however, failure mechanisms are identified in only a fraction of cases. To gain novel insights into the basis of clinical response, we performed single-cell transcriptome sequencing of 105 pre- and post-treatment peripheral blood mononuclear cell samples, and infusion products collected from 32 individuals with high-grade B cell lymphoma treated with either of two CD19 CAR-T products: axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel). Expansion of proliferative memory-like CD8 clones was a hallmark of tisa-cel response, whereas axi-cel responders displayed more heterogeneous populations. Elevations in CAR-T regulatory cells (CAR-Tregs) among non-responders to axi-cel were detected, and these populations were capable of suppressing conventional CAR-T cell expansion and driving late relapses in an in vivo model. Our analyses reveal the temporal dynamics of effective responses to CAR-T therapy, the distinct molecular phenotypes of CAR-T cells with differing designs, and the capacity for even small increases in CAR-Tregs to drive relapse.\",\n \"Peripheral optical coherence tomography assisted by scleral depression in retinopathy of prematurity\\nObjectiveTo determine whether handheld widefield optical coherence tomography (OCT) can be used to document retinopathy of prematurity (ROP) stage while using scleral depression to improve peripheral views.\\n\\nDesignProspective observational study\\n\\nParticipantsConsecutive neonates admitted to the neonatal intensive care unit (NICU) in a single academic medical center who also met criteria for ROP screening and consented for research imaging.\\n\\nMethodsScleral depression was combined with widefield OCT using an investigational 400-kHz, 55-degree field of view handheld OCT during ROP screening from October 28, 2020 to March 03, 2021.\\n\\nMain Outcome MeasuresAcquisition of en face and B-scan imaging of the peripheral retina to objectively assess early vitreoretinal pathology, including the demarcation between vascularized and anterior avascular retina, the presence of early ridge formation, and small neovascular tufts.\\n\\nResultsVarious stages of ROP were detected using a rapid acquisition OCT system. In one neonate, serial OCT imaging over a five-week period demonstrated accumulation of neovascular tufts with progression to stage 3 ROP with extraretinal fibrovascular proliferation along the ridge. Videography of this technique is included in this report for instructional purposes.\\n\\nConclusionsSerial examinations using widefield OCT and scleral depression may improve detection and documentation of ROP disease progression. Earlier detection of ROP-related proliferation may prevent vitreoretinal traction, retinal detachment, and blindness.\",\n \"The impact of population mobility on COVID-19 incidence and socioeconomic disparities at the sub-city level in 314 Latin American cities\\nBackgroundLittle is known about the impact of changes in mobility at the sub-city level on subsequent COVID-19 incidence or the contribution of mobility to socioeconomic disparities in COVID-19 incidence.\\n\\nMethodsWe compiled aggregated mobile phone location data, COVID-19 confirmed cases, and features of the urban and social environments to analyze linkages between population mobility, COVID-19 incidence, and educational attainment at the sub-city level among cities with >100,000 inhabitants in Argentina, Brazil, Colombia, Guatemala, and Mexico from March to August 2020. We used mixed effects negative binomial regression to examine longitudinal associations between changes in weekly mobility (lags 1-6 weeks) and subsequent COVID-19 incidence at the sub-city level, adjusting for urban environmental factors.\\n\\nFindingsAmong 1,031 sub-cities representing 314 cities in five Latin American countries, 10% higher weekly mobility was associated with 8.5% (95% CI 7.4% to 9.5%) higher weekly COVID-19 incidence the following week. This association gradually declined as the lag between mobility and COVID-19 incidence increased and was not different from the null at a six-week lag. We found evidence that suggests differences in mobility reductions are a driver of socioeconomic disparities in COVID-19 incidence.\\n\\nInterpretationLower population movement within a sub-city is associated with lower risk of subsequent COVID-19 incidence among residents of that sub-city. Implementing policies that reduce population mobility at the sub-city level may be an impactful COVID-19 mitigation strategy that takes equity into consideration and reduces economic and social disruption at the city or regional level.\\n\\nFundingWellcome Trust\",\n \"Breakthrough SARS-CoV-2 infections in MS patients on disease modifying therapies\\nBackgroundPatients with Multiple Sclerosis (pwMS) treated with anti-CD20 or fingolimod showed a reduced humoral response to SARS-CoV-2 vaccines. In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in pwMS on different Disease Modifying Therapy (DMT).\\n\\nMethodsData on number of vaccinated patients and of patients with a breakthrough infection were retrospectively collected in 27 Italian MS centers. We estimated the rate of breakthrough infections and of infection requiring hospitalization per DMT.\\n\\nFindings19641 vaccinated pwMS were included in the database. After a median follow-up of 8 months, we observed 137 breakthrough infections. As compared to the other DMTs, the rate of breakthrough infections was significantly higher on ocrelizumab (0.57% vs 2.00%, RR=3.55,95%CI=2.74-4.58, p<0.001) and fingolimod (0.58% vs 1.62%, RR=2.65,95%CI=1.75-4.00, p<0.001), while there were no significant differences in any other DMT group. In the ocrelizumab group the hospitalization rate was 16.7% vs 19.4% in the pre-vaccination era (RR=0.86,p=0.74) and it was 3.9% in all the other DMT groups vs 11.9% in the pre-vaccination period (RR=0.33,p=0.02).\\n\\nInterpretationThe risk of breakthrough SARS-CoV-2 infections is higher in patients treated with ocrelizumab and fingolimod, and the rate of severe infections was significantly reduced in all the DMTs excluding ocrelizumab.\",\n \"Assessment of Genetic Susceptibility to Multiple Primary Cancers through Whole-Exome Sequencing in Two Large Multi-Ancestry Studies\\nUp to one of every six individuals diagnosed with one cancer will be diagnosed with a second primary cancer in their lifetime. Genetic factors contributing to the development of multiple primary cancers, beyond known cancer syndromes, have been underexplored. To characterize genetic susceptibility to multiple cancers, we conducted a pan-cancer, whole-exome sequencing study of individuals drawn from two large prospective cohorts (6,429 cases, 165,853 controls). We created two groupings of individuals diagnosed with multiple primary cancers: 1) an overall combined set with at least two cancers across any of 36 organ sites; and 2) cancer-specific sets defined by an index cancer at one of 16 organ sites with at least 50 cases from each study population. We then investigated whether variants identified from exome sequencing were associated with these sets of multiple cancer cases in comparison to individuals with one and, separately, no cancers. We identified 22 variant-phenotype associations, 10 of which have not been previously discovered and were significantly overrepresented among individuals with multiple cancers, compared to those with a single cancer. Overall, we describe variants and genes that may play a fundamental role in the development of multiple primary cancers and improve our understanding of shared mechanisms underlying carcinogenesis. Further investigation of these findings may lead to new screening strategies for individuals at risk for multiple primary cancers.\",\n \"The acceptability of testing contacts of confirmed COVID-19 cases using serial, self-administered lateral flow devices as an alternative to self-isolation\\nBackgroundTesting asymptomatic contacts of confirmed COVID-19 cases for the presence of SARS-CoV-2 could reduce onward transmission by improving case ascertainment and lessen the impact of self-isolation on un-infected individuals. This study investigated the feasibility and acceptability of implementing a test to enable approach as part of Englands tracing strategy.\\n\\nMethodsContacts of confirmed COVID-19 cases were offered serial testing as an alternative to self-isolation using daily self-performed lateral flow device (LFD) tests for the first 7 days post exposure. Asymptomatic participants with a negative LFD result were given 24 hours of freedom from self-isolation between each test. A self-collected confirmatory PCR test was performed on testing positive or at the end of the LFD testing period.\\n\\nResultsOf 1,760 contacts, 882 consented to daily testing, with 812 within 48 hours of exposure sent testing packs. Of those who declined to participate, 39.1% stated they had already accessed PCR testing. Of the 812 who were sent packs, 570 (70.2%) reported one or more LFD results; 102 (17.9%) tested positive. Concordance between reported LFD result and a supplied LFD image was 97.1%. 82.8% of PCR positive samples and 99.6% of PCR negative samples were correctly detected by LFD. The proportion of secondary cases from contacts of those who participated in the study and tested positive (6.3%; 95% CI: 3.4-11.1%) were comparable to a comparator group who self-isolated (7.6%; 95% CI: 7.3-7.8%).\\n\\nConclusionThis study shows a high acceptability, compliance and positivity rates when using self-administered LFDs among contacts of confirmed COVID-19 cases. Offering routine testing as a structured part of the contact tracing process is likely to be an effective method of case ascertainment.\",\n \"Transcriptome analysis of PBMCs reveals distinct immune response in the asymptomatic and re-detectable positive COVID-19 patients\\nThe existence of asymptomatic and re-detectable positive COVID-19 patients presents the disease control challenges of COVID-19. Most studies on immune response of COVID-19 have focused on the moderately or severely symptomatic patients, however little is known about the immune response in asymptomatic and re-detectable positive patients. Here we performed a comprehensive analysis of the transcriptomic profiles of PBMCs from 48 COVID-19 patients which include 8 asymptomatic, 13 symptomatic, 15 recovering and 12 RP patients. Our analysis revealed a down-regulation of IFN response and complement activation in the asymptomatic patients compared with the symptomatic, indicating a weaker immune response of the PBMCs in the asymptomatic patients. In addition, we observed a lower expression of the cytokines and chemokines in the PBMC of asymptomatic and symptomatic patients. In contrast, the cytokines and chemokines level in the RP patients are higher than the recovering. GSEA analysis showed the enrichment of TNFa/NF-{kappa}B and influenza infection in the RP patients compared with the recovering patients, indicating a flu-like, hyper-inflammatory immune response in the PBMC of RP patients. Thus our findings could extend our understanding of host immune response during the progression COVID-19 disease and help the clinical management and the immunotherapy development for COVID-19.\",\n \"Multinational Prevalence of Neurological Phenotypes in Patients Hospitalized with COVID-19\\nOBJECTIVENeurological complications can worsen outcomes in COVID-19. We defined the prevalence of a wide range of neurological conditions among patients hospitalized with COVID-19 in geographically diverse multinational populations.\\n\\nMETHODSUsing electronic health record (EHR) data from 348 participating hospitals across 6 countries and 3 continents between January and September 2020, we performed a cross-sectional study of hospitalized adult and pediatric patients with a positive SARS-CoV-2 reverse transcription polymerase chain reaction test, both with and without severe COVID-19. We assessed the frequency of each disease category and 3-character International Classification of Disease (ICD) code of neurological diseases by countries, sites, time before and after admission for COVID-19, and COVID-19 severity.\\n\\nRESULTSAmong the 35,177 hospitalized patients with SARS-CoV-2 infection, there was increased prevalence of disorders of consciousness (5.8%, 95% confidence interval [CI]: 3.7%-7.8%, pFDR<.001) and unspecified disorders of the brain (8.1%, 95%CI: 5.7%-10.5%, pFDR<.001), compared to pre-admission prevalence. During hospitalization, patients who experienced severe COVID-19 status had 22% (95%CI: 19%-25%) increase in the relative risk (RR) of disorders of consciousness, 24% (95%CI: 13%-35%) increase in other cerebrovascular diseases, 34% (95%CI: 20%-50%) increase in nontraumatic intracranial hemorrhage, 37% (95%CI: 17%-60%) increase in encephalitis and/or myelitis, and 72% (95%CI: 67%-77%) increase in myopathy compared to those who never experienced severe disease.\\n\\nINTERPRETATIONUsing an international network and common EHR data elements, we highlight an increase in the prevalence of central and peripheral neurological phenotypes in patients hospitalized with SARS-CoV-2 infection, particularly among those with severe disease.\",\n \"SARS-CoV-2 responsive T cell numbers are associated with protection from COVID-19: A prospective cohort study in keyworkers\\nImmune correlates of protection from COVID-19 are incompletely understood. 2,826 keyworkers had T-SPOT(R) Discovery SARS-CoV-2 tests (measuring interferon-{gamma} secreting, SARS-CoV-2 responsive T cells, Oxford Immunotec Ltd), and anti-Spike S1 domain IgG antibody levels (EuroImmun AG) performed on recruitment into a cohort study. 285/2,826 (10.1%) of participants had positive SARS-CoV-2 RT-PCR tests, predominantly associated with symptomatic illness, during 200 days followup. T cell responses to Spike, Nucleoprotein and Matrix proteins (SNM responses) were detected in some participants at recruitment, as were anti-Spike S1 IgG antibodies; higher levels of both were associated with protection from subsequent SARS-CoV-2 test positivity. In volunteers with moderate antibody responses, who represented 39% (252/654) of those with detectable anti-Spike IgG, protection was partial, and higher with higher circulating T cell SNM responses. SARS-CoV-2 responsive T cell numbers predict protection in individuals with low anti-Spike IgG responses; serology alone underestimates the proportion of the population protected after infection.\",\n \"The contribution of common regulatory and protein-coding TYR variants in the genetic architecture of albinism\\nGenetic diseases have been historically segregated into rare Mendelian and common complex conditions.1,2 Large-scale studies using genome sequencing are eroding this distinction and are gradually unmasking the underlying complexity of human traits.3-8 Aiming to gain insights into the genetic architecture of rare recessive disorders, we studied a cohort of 1,313 individuals with albinism, an archetypal Mendelian condition. We investigated the contribution of protein-coding and regulatory variants both rare and common. We focused on TYR, the gene encoding tyrosinase, and found that a high-frequency promoter variant, TYR c.-301C>T [rs4547091], modulates the penetrance of a prevalent, disease-associated missense change, TYR c.1205G>A [rs1126809]. We also found that homozygosity for a haplotype formed by three common, functionally-relevant variants, TYR c.[-301C;575C>A;1205G>A], is associated with a high probability of receiving an albinism diagnosis (OR>82). This genotype is also associated with reduced visual acuity and increased central retinal thickness in UK Biobank participants. Finally, we report how the combined analysis of rare and common variants increases diagnostic yield and informs genetic counselling in families with albinism.\",\n \"Point-of-care semiquantitative test for adherence to tenofovir alafenamide or tenofovir disoproxil fumarate\\nSynopsisO_ST_ABSObjectiveC_ST_ABSObjective measurement of antiretrovirals may aid clinical interventions for improving adherence to HIV prevention or treatment regimens. A point-of-care urine test could provide real-time information about recent adherence to regimens containing tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). We developed a lateral flow immunoassay (LFA) and enzyme-linked immunoassay (ELISA) for urinary tenofovir.\\n\\nMethodsIntensity of the LFA test line was quantified using an optical reader and visually scored 0 - 5 by two independent people, using a reference card. The sensitivity and specificity of both the ELISA and LFA were determined for two different tenofovir concentration cutoffs for TDF and TAF adherence--1,500 ng/mL and 150 ng/mL, respectively. To validate the assays, we measured 586 urine samples from 28 individuals collected as part of a study of tenofovir pharmacokinetics in adults, which were also measured by mass spectrometry as ground truth.\\n\\nResultsBoth the LFA signal and ELISA signal were each strongly correlated to drug concentrations (0.91 and 0.92 respectively). The LFA signal and ELISA were highly sensitive and specific at both thresholds (LFA se/sp TDF 89%/96%, TAF 90%/96%; ELISA se/sp TDF 94%/94%, TAF 92%/84%). Visual scoring of the LFA was also highly sensitive and specific at both the TDF and TAF thresholds (se/sp TDF 91%/94%, TAF 87%/90%).\\n\\nConclusionsOur rapid semi-quantitative test can measure TFV concentrations relevant to both TAF or TDF adherence, which may support adherence-promoting interventions across a range of HIV care settings.\",\n \"Treatment of sarcoidosis with cutaneous involvement with tofacitinib\\nSarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids and there are no approved steroid-sparing medications. There is emerging evidence that Janus kinase (JAK) inhibitors, which inhibit JAK-dependent cytokine activity, may hold promise in sarcoidosis. In this open-label trial, 10 patients with recalcitrant sarcoidosis with cutaneous involvement were treated with tofacitinib 5 mg twice daily. There was no washout period and patients were permitted to continue, taper, or discontinue other treatments. The primary outcome was the change in the Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI) activity score after 6 months. Change in internal organ disease activity was also assessed using total lesion glycolysis (TLG) determined by full-body positron emission tomography. A mean reduction in the CSAMI activity score of 82.7% was observed, with 6 patients showing a complete response. Internal organ response data was available in 8 patients; a decrease in TLG of [≥]50% was noted in 5 patients, with complete or near complete resolution in 3 (>98% reduction in TLG). Patients were generally able to significantly taper or discontinue their baseline immunosuppressive regimen, which included prednisone in 5 patients. Single cell RNA-sequencing, bulk RNA-sequencing, and high-throughput proteomic analyses were performed on skin and blood as a function of treatment in order to delineate changes in immunologic signals with therapy. We identified CD4+ T cell derived IFN-{gamma} as a central cytokine driver of sarcoidosis and inhibition of its activity was achieved with tofacitinib and correlated closely with clinical improvement. Tofacitinib appears to have impressive activity in treatment of sarcoidosis and likely acts by inhibiting IFN-{gamma}, larger, controlled studies are warranted.\",\n \"Sexual Behaviours and Sexual Health Among Middle-Aged and Older Adults in Britain: A Latent Class Analysis of The Natsal-3\\nObjectivesPopulation-representative studies of the sexual health of middle-aged and older adults are lacking in aging societies. This study aimed to identify latent patterns of sexual behaviours and health of people aged 45-74.\\n\\nMethodsWe conducted a latent class analysis of the National Attitudes and Sexual Lifestyles Survey (Natsal-3), a nationally representative survey conducted in Britain in 2011.\\n\\nResultsOf the 5260 respondents aged 45-74, 49% of men and 45% of women belonged to the Content Caseys class who reported good sexual health. The Infrequent Indigos (31% of men, 44% of women) were characterized by a lack of sexual activity, reported some dissatisfaction, and were more likely to have a disability. The Low-Functioning Lees (12% of men, 8% of women) reported some more disability and had issues with sexual functioning and higher levels of distress. The Multiple-Partnered Morgans (9% of men, 2% of women) were characterized by a greater number of sexual partners and several risk behaviours.\\n\\nConclusionsThe use of these four classes can aid in improved targeting of tailored sexual health services to improve sexual function, sexual satisfaction, reduce distress and risky behaviours among middle-aged and older adults. These services should be inclusive of the disabled community.\\n\\nBullet pointsO_LIAbout half of these respondents were classified as Content Caseys who reported few issues concerning their sex lives.\\nC_LIO_LIOver a third who reported no recent sexual activity, the vast majority of whom are single, were classified as Infrequent Indigos.\\nC_LIO_LINearly 10% were classified Low-Functioning Lees due to the greater probability of reporting sexual function issues and distress.\\nC_LIO_LIThe rest were classified as Multiple Partner Morgans as a result of a high likelihood of having multiple partners and unsafe sex.\\nC_LI\",\n \"Lipid-Modulating Agents for Prevention or Treatment of COVID-19 in Randomized Trials\\nCoronavirus disease 2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multi-organ manifestations. Lipid modulating agents may be useful in treating patients with COVID-19. They may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglycerides portends worse outcome in patients with COVID-19. Upon a systematic search, 40 RCTs with lipid modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrates RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for management or prevention of COVID-19. This manuscript summarizes the ongoing or completed randomized controlled trials (RCTs) of lipid modulating agents in COVID-19 and the implications of these trials for patient management.\",\n \"Relationships between freezing of gait severity and cognitive deficits in Parkinson's disease\\nObjectiveEvidence supports an association between freezing of gait (FOG) severity and cognitive functioning in patients with Parkinsons disease (PD); however, results are varied. Here we sought to explore the differences in cognitive measurements via multivariable statistical models in patients with PD.\\n\\nMethodsPD patients with (PDFOG+, n=41) and without FOG (PDFOG-, n=39) and control healthy subjects (n=41) participated in the study. The NIH toolbox cognition battery, Montreal cognitive assessment (MoCA), and interval timing task were used to test cognitive domains. Measurements were compared between groups using multivariable models and adjusting for covariates. Correlation analyses, linear regression, and mediation models were applied to examine relationships among disease duration and severity, FOG severity, and cognitive functioning.\\n\\nResultsSignificant differences were observed between controls and PD patients for all cognitive domains. PDFOG+ and PDFOG- exhibited differences in the dimensional change card sort (DCCS) test, interval timing task, and MoCA scores. After adjusting for covariates in two different models, PDFOG+ and PDFOG- differed in both MoCA and DCCS scores. In addition, significant relationships between FOG severity and cognitive function (MoCA, DCCS, and interval timing) were also found. Regression models suggest that FOG severity may be a predictor of cognitive impairment, and mediation models show the effects of cognitive impairment on the relationship between disease severity and FOG severity.\\n\\nConclusionsOverall, this study provides insight into the relationship between cognitive and FOG severity in patients with PD, which could aid in the development of therapeutic interventions to manage both.\",\n \"A Quantitative Systems Pharmacology Model of the Pathophysiology and Treatment of COVID-19 Predicts Optimal Timing of Pharmacological Interventions\\nA quantitative systems pharmacology (QSP) model of the pathogenesis and treatment of SARS-CoV-2 infection can streamline and accelerate the development of novel medicines to treat COVID-19. Simulation of clinical trials allows in silico exploration of the uncertainties of clinical trial design and can rapidly inform their protocols. We previously published a preliminary model of the immune response to SARS-CoV-2 infection. To further our understanding of COVID-19 and treatment we significantly updated the model by matching a curated dataset spanning viral load and immune responses in plasma and lung. We identified a population of parameter sets to generate heterogeneity in pathophysiology and treatment and tested this model against published reports from interventional SARS-CoV-2 targeting Ab and anti-viral trials. Upon generation and selection of a virtual population, we match both the placebo and treated responses in viral load in these trials. We extended the model to predict the rate of hospitalization or death within a population. Via comparison of the in silico predictions with clinical data, we hypothesize that the immune response to virus is log-linear over a wide range of viral load. To validate this approach, we show the model matches a published subgroup analysis, sorted by baseline viral load, of patients treated with neutralizing Abs. By simulating intervention at different timepoints post infection, the model predicts efficacy is not sensitive to interventions within five days of symptom onset, but efficacy is dramatically reduced if more than five days pass post-symptom onset prior to treatment.\",\n \"The Effect of Convalescent Plasma Therapy on COVID-19 Patient Mortality: Systematic Review and Meta-analysis\\nTo determine the effect of COVID-19 convalescent plasma on mortality, we aggregated patient outcome data from randomized clinical trials, matched control, case series, and case report studies. Fixed-effects analyses demonstrated that hospitalized COVID-19 patients transfused with convalescent plasma exhibited a ~57% reduction in mortality rate (10%) compared to matched-patients receiving standard treatments (22%; OR: 0.43, P < 0.001). These data provide evidence favouring the efficacy of human convalescent plasma as a therapeutic agent in hospitalized COVID-19 patients.\",\n \"Waist circumference thresholds predicting incident dysglycemia and type 2 diabetes in Black African men and women\\nObjectiveTo determine the waist circumference (WC) thresholds for the prediction of incident dysglycemia and type 2 diabetes in Black South African (SA) men and women and compare these to advocated International Diabetes Federation (IDF) Europid thresholds.\\n\\nResearch design and methodIn this prospective study, Black SA men (n=502) and women (n=527) from the Middle Aged Sowetan Cohort (MASC) study who had normal or impaired fasting glucose at baseline (2011-2015) were followed up through 2017-2018. Baseline measurements included anthropometry, blood pressure and fasting glucose, HDL-cholesterol and triglyceride concentrations. At follow-up, glucose tolerance was assessed using an oral glucose tolerance test. The Youden index was used to determine the optimal threshold of WC to predict incident dysglycemia and type 2 diabetes.\\n\\nResultsIn men, the optimal WC threshold was 96.8 cm for both dysglycemia and type 2 diabetes (sensitivity 56 and 70%, specificity 74 and 70%, respectively), which performed similarly to the IDF threshold of 94 cm. In women, the optimal WC threshold for incident dysglycemia was 91.8 cm (sensitivity 86%, specificity 37%) and for type 2 diabetes was 95.8 cm (sensitivity 85%, specificity 45%). In comparison, the IDF threshold of 80 cm in women had higher sensitivity (97 and 100%), but lower specificity (12 and 11%) to predict incident dysglycemia and type 2 diabetes, respectively.\\n\\nConclusionsIn this first prospective study of incident type 2 diabetes in Africa, we show that African-specific WC thresholds perform better than the IDF WC thresholds to predict incident dysglycemia and type 2 diabetes.\",\n \"Comparing human and AI performance in medical machine learning: An open-source Python library for the statistical analysis of reader study data\\nIn seeking to understand the potential effects of artificial intelligence (AI) on the practice of diagnostic medicine, many investigations involve collecting interpretations from several human experts on a common set of cases. In an effort to standardize the process of analyzing the data emerging from such studies, we have released an open-source Python library to perform applicable statistical procedures. The software implements the industry-standard Obuchowski-Rockette-Hillis (ORH) method for multi-reader multi-case (MRMC) studies. The tools can be used to compare a standalone algorithm against a panel of readers, or compare readers operating in two modalities (for example, with and without algorithmic assistance). The software supports both nonequivalence and noninferiority tests. Functions are also provided to simulate reader and model scores, useful for Monte Carlo power analysis. The code is publicly available in our Gitub repository at https://github.com/Google-Health/google-health/tree/master/analysis.\",\n \"Super-Resolution of Magnetic Resonance Images Acquired Under Clinical Protocols using Deep Attention-based Method\\nAO_SCPLOWBSTRACTC_SCPLOWVast quantities of Magnetic Resonance Images (MRI) are routinely acquired in clinical practice but, to speed up acquisition, these scans are typically of a quality that is sufficient for clinical diagnosis but sub-optimal for large-scale precision medicine, computational diagnostics, and large-scale neuroimaging research. Here, we present a critic-guided framework to upsample low-resolution (often 2D) MRI scans. In addition, we incorporated feature-importance and self-attention methods into our model to improve the interpretability of this work. We evaluate our framework on paired low- and high-resolution brain MRI structural full scans (i.e. T1-, T2-weighted and FLAIR sequences are simultaneously input) obtained in clinical and research settings from scanners manufactured by Siemens, Phillips and GE. We showed that the upsampled MRIs are qualitatively faithful to the ground-truth high-quality scans (PSNR = 35.39; MAE = 3.78E -3; NMSE = 4.32E -10; SSIM = 0.9852; mean normal-appearing grey/white matter ratio intensity differences ranging from 0.0363 to 0.0784 for FLAIR, from 0.0010 to 0.0138 for T1-weighted and from 0.0156 to 0.074 for T2-weighted sequences). The automatic raw segmentations of tissues and lesions using the super-resolved images have fewer false positives and higher accuracy than those obtained from interpolated images in protocols represented with more than three sets in the training sample, making our approach a strong candidate for practical application in clinical research.\"\n]","isConversational":false},"cluster":{"kind":"number","value":10,"string":"10"}}},{"rowIdx":225,"cells":{"query":{"kind":"string","value":"Prophylactic Antibiotics in Arteriovenous Fistulae: A systematic Review\nBackgroundThe aim of this study is to establish and evaluate whether the use of prophylactic antibiotics in the creation of any autogenous arteriovenous fistula in hemodialysis patients is indicated, evidence-based and/or recommended.\n\nMethodsA systematic review and meta-aggregation of the literature from 1966 to August 2016 in the English language in Medline, Scopus, Embase and Cochrane Library was conducted.\n\nResultsThe search produced a total of n=94 articles. Following the application of the recruitment criteria in accordance to PRISMA one (n=1) article was found eligible with a population of n=611 patients undergoing autogenous fistula formation. A total of n=136 patients received prophylactic antibiotics with no incidence of surgical site infection (SSI). The reported incidence of SSI in the group of patients (n=475) that did not receive prophylactic antibiotics was 0.2% (n=1). The quality of the article was assessed by the Oxford Critical Appraisal Skills Programme (CASP) and their recommendation for practice was evaluated through National Institute for Health and Care Excellence (NICE).\n\nConclusionThe first systematic review of the literature demonstrates that the current use of prophylactic antibiotics in the creation of any autogenous AVF is not evidence-based and further research in this area is highly advocated."},"positive":{"kind":"list like","value":["Development of machine learning models for the prediction of complications after colorectal and small intestine surgery in psychiatric and non-psychiatric patient collectives (P-Study)\nPsychiatric and psychosomatic diseases are an increasingly cumbersome burden for the medical system. Indeed, hospital costs associated with mental health conditions have been constantly on the rise in recent years. Moreover, psychiatric conditions are likely to have a negative effect on the treatment of other medical conditions and surgical outcomes, in addition to their direct effects on the overall quality of life. Our study aims to investigate the impact of preoperative Risk factor, psychiatric and psychosomatic diseases on the outcomes of colorectal surgery and length of hospital stay via predictive modeling techniques.\n\nMethodPatient data will be collected from several participating national and international surgical centers The machine learning models will be calculated and coded, but also published according to the TRIPOD guidelines (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis).\n\nResultIt is conceivable to arrive at generalizable models predicting the abovementioned endpoints through large amounts of data from several centers. The models will be subsequently deployed as a free-to-use web-based prediction tool using the Shiny environment [47]. The cost for the hosting server and digital infrastructure will be covered by Dr. Anas Taha. The sponsor will store the data for ten years.","Impact of low-dose intrathecal morphine on orthopedic surgery: a protocol of a systematic review and meta-analysis of randomized controlled trials\nIntroductionPatients undergoing orthopedic surgery usually suffer considerably from peri-operative pain and intrathecal morphine (ITM) has recently been used as an effective analgesic method. The intrathecal morphine dose achieving optimal analgesia for orthopedic surgery while minimizing side effects has not yet been determined. There is currently a lack of literature synthesis on the safety and effects of low-dose ITM on orthopedic surgery.\n\nMethods and analysisA thorough literature search will be performed on multiple electronic databases and trial registries until January 11th 2022, and reference lists will be examined. Two independent reviewers will select studies, extract data and assess the risk of bias and quality of the included studies. We will select randomized controlled trials comparing low-dose ITM (<100g) with high-dose ITM (<200g) or placebo treatment or other comparatives. We will assess the risk of bias using the Cochrane risk of bias tool and Jadad score will be applied to assess the quality of each included trial. We will also use Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) to determine the confidence in effect estimates. Publication bias will be evaluated by visually inspecting funnel plots and Egger regression asymmetry test in estimations of more than 10 trials. Standard meta-analysis will be performed using R package meta.\n\nEthics and disseminationThe results of this systematic review and meta-analysis will be disseminated through peer-reviewed journal and related conferences. The data used in this meta-analysis will not contain individual patient data and ethical approval is therefore not required.","Predicting patient-reported outcomes following lumbar spine surgery: development and external validation of multivariable prediction models\nBackgroundThis study aimed to develop and externally validate prediction models of spinal surgery outcomes based on a retrospective review of a prospective clinical database, uniquely comparing multivariate regression and machine learning approaches, and identifying the most important predictors.\n\nMethodsOutcomes were change in back and leg pain intensity and Core Outcome Measures Index (COMI) from baseline to the last available postoperative follow-up (3-24 months), defined as minimal clinically important change (MCID) and continuous change score. Eligible patients underwent lumbar spine surgery for degenerative pathology between 2011 and 2021. Data were split by surgery date into development (N=2691) and validation (N=1616) sets. Multivariate logistic and linear regression, and random forest classification and regression models, were fit to the development data and validated on the external data.\n\nResultsAll models demonstrated good calibration in the validation data. Discrimination ability (area under the curve) for MCID ranged from 0.63 (COMI) to 0.72 (back pain) in regression, and from 0.62 (COMI) to 0.68 (back pain) in random forests. The explained variation in continuous change scores spanned 16%-28% in linear, and 15%-25% in random forests regression. The most important predictors included age, baseline scores on the respective outcome measures, type of degenerative pathology, previous spinal surgeries, smoking status, morbidity, and duration of hospital stay.\n\nConclusionsThe developed models appear robust and generalisable across different outcomes and modelling approaches but produced only borderline acceptable discrimination ability, suggesting the need to assess further prognostic factors. External validation showed no advantage of the machine learning approach.","No impact of sex on surgical site infections in abdominal surgery: A multi-center study\nObjectiveMale sex is controversially discussed as a risk factor for surgical site infections (SSI). The aim of the present study was to evaluate the impact of sex on SSI in abdominal surgery under elimination of relevant confounders.\n\nMethodsClinicopathological data of 6603 patients undergoing abdominal surgery from a multi-center prospective database of four Swiss hospitals including patients between 2015 and 2018 were assessed. Patients were stratified according to postoperative SSI and risk factors for SSI were assessed using univariate and multivariate analysis.\n\nResultsIn 649 of 6603 patients SSI was reported (9.8%). SSI was significantly associated with reoperation (22.7% vs. 3.4%, p <0.001), higher mortality rate (4.6% vs. 0.9%, p <0.001) and higher rate of length of hospital stay over the 75th percentile (57.0 % vs. 17.9 %, p <0.001). In univariate analysis male sex was a significant risk factor for SSI (p = 0.01). In multivariate analysis including multiple confounders such as comorbidities and perioperative factors there was no association between male sex and risk of SSI (odds ratio (OR) 1.1 [CI 0.8 - 1.4]). Independent risk factors for SSI in multivariate analysis were BMI [≥] 30 kg/m2 (OR 1.8 [CI 1.3 - 2.3]), duration of surgery > 75th percentile (OR 2.3 [1.8 - 2.9]), high contamination level (OR 1.3 [1.0 - 1.6]), laparotomy (OR 1.3 [1.0 - 1.7]), pervious laparotomy (OR 1.4 [1.1 - 1.7]), blood transfusion (OR 1.7 [1.2 - 2.4]), cancer (OR 1.3 [1.0-1.8], malnutrition (OR 2.5 [1.8 - 3.4]).\n\nConclusionUnder elimination of relevant confounders there is no significant correlation between sex and risk of SSI after abdominal surgery.","A Standardised Protocol for Neuro-endoscopic Lavage for Post-haemorrhagic Ventricular Dilatation: A Delphi Consensus Approach\nPurposeNeuro-endoscopic lavage (NEL) has shown promise as an emerging procedure for intraventricular haemorrhage (IVH) and post-haemorrhagic ventricular dilatation (PHVD). However, there is considerable variation with regards to the indications, objectives, and surgical technique in NEL. There is currently no randomised trial evidence that supports the use of NEL in the context of PHVD. This study aims to form a consensus on technical variations in the indications and procedural steps of NEL.\n\nMethodsA mixed methods modified Delphi consensus process was conducted between consultant paediatric neurosurgeons across the United Kingdom. Stages involved literature review, survey, focused online consultation and iterative revisions until > 80% consensus was achieved.\n\nResultsTwelve consultant paediatric neurosurgeons from 10 centres participated. A standardised protocol including indications, a 3-phase operative workflow (pre-ventricular, intraventricular, post-ventricular) and post-operative care was agreed upon by 100% of participants. Case- and surgeon-specific variation was considered and included through delineation of mandatory, optional, and not recommended steps.\n\nConclusionExpert consensus on a standardised protocol for NEL was achieved, delineating the surgical workflow into three phases: pre-ventricular, intraventricular, and post-ventricular, each consisting of mandatory, optional, and not recommended steps. The work provides a platform for future trials, training, and implementation of NEL.","One-year results of long femoropopliteal lesions stenting with fasciotomy lamina vastoadductoria\nObjectiveFasciotomy can increase the mobility of the superficial femoral artery and reduce the incidence of stent breakage. This study aimed to compare the long-term patency of drug-eluting nitinol stents with and without fasciotomy in patients with prolonged SFA occlusions.\n\nMethodsA randomized clinical trial was conducted in 60 (1:1) patients with long femoropopliteal steno-occlusive lesions more than 200 mm. Patients in group 1 (Zilver) underwent recanalization of occlusion of the femoropopliteal artery with stenting. In group 2 (ZilverFas), recanalization of the femoropopliteal occlusion with stenting and fasciotomy of Gunters canal were performed. The follow up evaluation of patency at 6, 12 months.\n\nResults12-month primary patency in Zilver and ZilverFas groups was 51% and 80%, respectively (p = 0.02). The freedom from target revascularization (TLR) in Zilver and ZilverFas groups was 50% and 76%, respectively (p = 0.04). At one-years, primary-assisted and secondary patency for the ZilverFas and Zilver groups were 83% versus 62% (p = 0.07), 86% versus 65% (p = 0.05), respectively. In groups Zilver and ZilverFas, the number of stents fracture was 14 and 7, respectively (p = 0.05). The Cox multivariables regression indicated that the stent fracture, diabetes mellitus were the independent predictor of restenosis and reocclusion. Fasciotomy reduced the chance of reocclusion and restenosis by 2.94 times.\n\nConclusionsOur study has shown that a decompressing the stented segment with fasciotomy significantly improves the patency of the femoropopliteal segment and significantly reduces the number and severity of stents fractures.","Early Carotid Revascularization Rates, Procedural Distribution, and Hospital Density\nEarly carotid revascularization (i.e. during the index hospitalization) may help reduce the risk of additional neurologic events without excess perioperative morbidity. We evaluated the relationship between rates of early carotid endarterectomy (CEA) or stenting (CAS) and hospital density/distribution within metropolitan areas of Texas. Patients with extracranial carotid artery stenosis and either stroke, transient ischemic attacks, or amaurosis were identified among all patients admitted from 2009 to 2013 to non-federal Texas hospitals within all 24 Texas metropolitan statistical areas (MSAs). Early CEA/CAS was defined as occurring during the index hospitalization. A Gini coefficient with bias correction factor was calculated to quantify the distribution of carotid procedures within an MSA. In total, 3,330 (15.4%) of the 21,665 metropolitan patients admitted to Texas hospitals with symptomatic carotid stenosis received early CEA/CAS. Only 263 (44%) of the 600 total hospitals where patients were admitted performed early CEA/CAS. An increasing proportion receiving early carotid CEA/CAS was inversely correlated with the procedural Gini coefficient (p=0.002) and directly correlated with the number of hospitals per 100K population (p=0.01). These two factors accounted for 51% of the variability among MSAs. Early CEA/CAS rates did not correlate with hospital volume or with level 1or 2 stroke centers within an MSA. Increasing the number of hospitals performing early carotid revascularization procedures (i.e. avoiding regionalization/concentration) may help increase the number of patients receiving early carotid revascularization for symptomatic carotid artery disease.","Genetic Risk Factors for Postoperative Atrial Fibrillation - a Nationwide Genome-Wide Association Study (GWAS)\nBackgroundAtrial fibrillation (AF) is a major cause of morbidity with a high prevalence among the elderly and has an established genetic disposition. Surgery is a well-known risk factor for AF; however, it is currently not recognized how much common genetic variants influence the postoperative risk. The purpose of this study was to identify Single Nucleotide Polymorphisms associated with postoperative AF.\n\nMethodsThe UK Biobank was utilized to conduct a Genome-Wide Association Study (GWAS) to identify variants associated with AF after surgery. An initial discovery GWAS was performed in patients that had undergone surgery with subsequent replication in a unique non-surgical cohort. In the surgical cohort, cases were defined as newly diagnosed AF within 30 days after surgery. The threshold for significance was set at 5 x 10-8.\n\nResultsAfter quality control, 144,196 surgical patients with 254,068 SNPs were left for analysis. Two variants (rs17042171 (p = 4.86 x 10-15) and rs17042081 (p = 7.12 x 10-15)) near the PITX2-gene reached statistical significance. These variants were replicated in the non-surgical cohort (1.39 x 10-101 and 1.27 x 10-93, respectively). Several other loci were significantly associated with AF in the non-surgical cohort.\n\nConclusionIn this GWAS-analysis of a large national biobank, we identified 2 variants that were significantly associated with postoperative AF. These variants were subsequently replicated in a unique non-surgical cohort. These findings bring new insight in the genetics of postoperative AF and may help identify at-risk patients and guide management."],"string":"[\n \"Development of machine learning models for the prediction of complications after colorectal and small intestine surgery in psychiatric and non-psychiatric patient collectives (P-Study)\\nPsychiatric and psychosomatic diseases are an increasingly cumbersome burden for the medical system. Indeed, hospital costs associated with mental health conditions have been constantly on the rise in recent years. Moreover, psychiatric conditions are likely to have a negative effect on the treatment of other medical conditions and surgical outcomes, in addition to their direct effects on the overall quality of life. Our study aims to investigate the impact of preoperative Risk factor, psychiatric and psychosomatic diseases on the outcomes of colorectal surgery and length of hospital stay via predictive modeling techniques.\\n\\nMethodPatient data will be collected from several participating national and international surgical centers The machine learning models will be calculated and coded, but also published according to the TRIPOD guidelines (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis).\\n\\nResultIt is conceivable to arrive at generalizable models predicting the abovementioned endpoints through large amounts of data from several centers. The models will be subsequently deployed as a free-to-use web-based prediction tool using the Shiny environment [47]. The cost for the hosting server and digital infrastructure will be covered by Dr. Anas Taha. The sponsor will store the data for ten years.\",\n \"Impact of low-dose intrathecal morphine on orthopedic surgery: a protocol of a systematic review and meta-analysis of randomized controlled trials\\nIntroductionPatients undergoing orthopedic surgery usually suffer considerably from peri-operative pain and intrathecal morphine (ITM) has recently been used as an effective analgesic method. The intrathecal morphine dose achieving optimal analgesia for orthopedic surgery while minimizing side effects has not yet been determined. There is currently a lack of literature synthesis on the safety and effects of low-dose ITM on orthopedic surgery.\\n\\nMethods and analysisA thorough literature search will be performed on multiple electronic databases and trial registries until January 11th 2022, and reference lists will be examined. Two independent reviewers will select studies, extract data and assess the risk of bias and quality of the included studies. We will select randomized controlled trials comparing low-dose ITM (<100g) with high-dose ITM (<200g) or placebo treatment or other comparatives. We will assess the risk of bias using the Cochrane risk of bias tool and Jadad score will be applied to assess the quality of each included trial. We will also use Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) to determine the confidence in effect estimates. Publication bias will be evaluated by visually inspecting funnel plots and Egger regression asymmetry test in estimations of more than 10 trials. Standard meta-analysis will be performed using R package meta.\\n\\nEthics and disseminationThe results of this systematic review and meta-analysis will be disseminated through peer-reviewed journal and related conferences. The data used in this meta-analysis will not contain individual patient data and ethical approval is therefore not required.\",\n \"Predicting patient-reported outcomes following lumbar spine surgery: development and external validation of multivariable prediction models\\nBackgroundThis study aimed to develop and externally validate prediction models of spinal surgery outcomes based on a retrospective review of a prospective clinical database, uniquely comparing multivariate regression and machine learning approaches, and identifying the most important predictors.\\n\\nMethodsOutcomes were change in back and leg pain intensity and Core Outcome Measures Index (COMI) from baseline to the last available postoperative follow-up (3-24 months), defined as minimal clinically important change (MCID) and continuous change score. Eligible patients underwent lumbar spine surgery for degenerative pathology between 2011 and 2021. Data were split by surgery date into development (N=2691) and validation (N=1616) sets. Multivariate logistic and linear regression, and random forest classification and regression models, were fit to the development data and validated on the external data.\\n\\nResultsAll models demonstrated good calibration in the validation data. Discrimination ability (area under the curve) for MCID ranged from 0.63 (COMI) to 0.72 (back pain) in regression, and from 0.62 (COMI) to 0.68 (back pain) in random forests. The explained variation in continuous change scores spanned 16%-28% in linear, and 15%-25% in random forests regression. The most important predictors included age, baseline scores on the respective outcome measures, type of degenerative pathology, previous spinal surgeries, smoking status, morbidity, and duration of hospital stay.\\n\\nConclusionsThe developed models appear robust and generalisable across different outcomes and modelling approaches but produced only borderline acceptable discrimination ability, suggesting the need to assess further prognostic factors. External validation showed no advantage of the machine learning approach.\",\n \"No impact of sex on surgical site infections in abdominal surgery: A multi-center study\\nObjectiveMale sex is controversially discussed as a risk factor for surgical site infections (SSI). The aim of the present study was to evaluate the impact of sex on SSI in abdominal surgery under elimination of relevant confounders.\\n\\nMethodsClinicopathological data of 6603 patients undergoing abdominal surgery from a multi-center prospective database of four Swiss hospitals including patients between 2015 and 2018 were assessed. Patients were stratified according to postoperative SSI and risk factors for SSI were assessed using univariate and multivariate analysis.\\n\\nResultsIn 649 of 6603 patients SSI was reported (9.8%). SSI was significantly associated with reoperation (22.7% vs. 3.4%, p <0.001), higher mortality rate (4.6% vs. 0.9%, p <0.001) and higher rate of length of hospital stay over the 75th percentile (57.0 % vs. 17.9 %, p <0.001). In univariate analysis male sex was a significant risk factor for SSI (p = 0.01). In multivariate analysis including multiple confounders such as comorbidities and perioperative factors there was no association between male sex and risk of SSI (odds ratio (OR) 1.1 [CI 0.8 - 1.4]). Independent risk factors for SSI in multivariate analysis were BMI [≥] 30 kg/m2 (OR 1.8 [CI 1.3 - 2.3]), duration of surgery > 75th percentile (OR 2.3 [1.8 - 2.9]), high contamination level (OR 1.3 [1.0 - 1.6]), laparotomy (OR 1.3 [1.0 - 1.7]), pervious laparotomy (OR 1.4 [1.1 - 1.7]), blood transfusion (OR 1.7 [1.2 - 2.4]), cancer (OR 1.3 [1.0-1.8], malnutrition (OR 2.5 [1.8 - 3.4]).\\n\\nConclusionUnder elimination of relevant confounders there is no significant correlation between sex and risk of SSI after abdominal surgery.\",\n \"A Standardised Protocol for Neuro-endoscopic Lavage for Post-haemorrhagic Ventricular Dilatation: A Delphi Consensus Approach\\nPurposeNeuro-endoscopic lavage (NEL) has shown promise as an emerging procedure for intraventricular haemorrhage (IVH) and post-haemorrhagic ventricular dilatation (PHVD). However, there is considerable variation with regards to the indications, objectives, and surgical technique in NEL. There is currently no randomised trial evidence that supports the use of NEL in the context of PHVD. This study aims to form a consensus on technical variations in the indications and procedural steps of NEL.\\n\\nMethodsA mixed methods modified Delphi consensus process was conducted between consultant paediatric neurosurgeons across the United Kingdom. Stages involved literature review, survey, focused online consultation and iterative revisions until > 80% consensus was achieved.\\n\\nResultsTwelve consultant paediatric neurosurgeons from 10 centres participated. A standardised protocol including indications, a 3-phase operative workflow (pre-ventricular, intraventricular, post-ventricular) and post-operative care was agreed upon by 100% of participants. Case- and surgeon-specific variation was considered and included through delineation of mandatory, optional, and not recommended steps.\\n\\nConclusionExpert consensus on a standardised protocol for NEL was achieved, delineating the surgical workflow into three phases: pre-ventricular, intraventricular, and post-ventricular, each consisting of mandatory, optional, and not recommended steps. The work provides a platform for future trials, training, and implementation of NEL.\",\n \"One-year results of long femoropopliteal lesions stenting with fasciotomy lamina vastoadductoria\\nObjectiveFasciotomy can increase the mobility of the superficial femoral artery and reduce the incidence of stent breakage. This study aimed to compare the long-term patency of drug-eluting nitinol stents with and without fasciotomy in patients with prolonged SFA occlusions.\\n\\nMethodsA randomized clinical trial was conducted in 60 (1:1) patients with long femoropopliteal steno-occlusive lesions more than 200 mm. Patients in group 1 (Zilver) underwent recanalization of occlusion of the femoropopliteal artery with stenting. In group 2 (ZilverFas), recanalization of the femoropopliteal occlusion with stenting and fasciotomy of Gunters canal were performed. The follow up evaluation of patency at 6, 12 months.\\n\\nResults12-month primary patency in Zilver and ZilverFas groups was 51% and 80%, respectively (p = 0.02). The freedom from target revascularization (TLR) in Zilver and ZilverFas groups was 50% and 76%, respectively (p = 0.04). At one-years, primary-assisted and secondary patency for the ZilverFas and Zilver groups were 83% versus 62% (p = 0.07), 86% versus 65% (p = 0.05), respectively. In groups Zilver and ZilverFas, the number of stents fracture was 14 and 7, respectively (p = 0.05). The Cox multivariables regression indicated that the stent fracture, diabetes mellitus were the independent predictor of restenosis and reocclusion. Fasciotomy reduced the chance of reocclusion and restenosis by 2.94 times.\\n\\nConclusionsOur study has shown that a decompressing the stented segment with fasciotomy significantly improves the patency of the femoropopliteal segment and significantly reduces the number and severity of stents fractures.\",\n \"Early Carotid Revascularization Rates, Procedural Distribution, and Hospital Density\\nEarly carotid revascularization (i.e. during the index hospitalization) may help reduce the risk of additional neurologic events without excess perioperative morbidity. We evaluated the relationship between rates of early carotid endarterectomy (CEA) or stenting (CAS) and hospital density/distribution within metropolitan areas of Texas. Patients with extracranial carotid artery stenosis and either stroke, transient ischemic attacks, or amaurosis were identified among all patients admitted from 2009 to 2013 to non-federal Texas hospitals within all 24 Texas metropolitan statistical areas (MSAs). Early CEA/CAS was defined as occurring during the index hospitalization. A Gini coefficient with bias correction factor was calculated to quantify the distribution of carotid procedures within an MSA. In total, 3,330 (15.4%) of the 21,665 metropolitan patients admitted to Texas hospitals with symptomatic carotid stenosis received early CEA/CAS. Only 263 (44%) of the 600 total hospitals where patients were admitted performed early CEA/CAS. An increasing proportion receiving early carotid CEA/CAS was inversely correlated with the procedural Gini coefficient (p=0.002) and directly correlated with the number of hospitals per 100K population (p=0.01). These two factors accounted for 51% of the variability among MSAs. Early CEA/CAS rates did not correlate with hospital volume or with level 1or 2 stroke centers within an MSA. Increasing the number of hospitals performing early carotid revascularization procedures (i.e. avoiding regionalization/concentration) may help increase the number of patients receiving early carotid revascularization for symptomatic carotid artery disease.\",\n \"Genetic Risk Factors for Postoperative Atrial Fibrillation - a Nationwide Genome-Wide Association Study (GWAS)\\nBackgroundAtrial fibrillation (AF) is a major cause of morbidity with a high prevalence among the elderly and has an established genetic disposition. Surgery is a well-known risk factor for AF; however, it is currently not recognized how much common genetic variants influence the postoperative risk. The purpose of this study was to identify Single Nucleotide Polymorphisms associated with postoperative AF.\\n\\nMethodsThe UK Biobank was utilized to conduct a Genome-Wide Association Study (GWAS) to identify variants associated with AF after surgery. An initial discovery GWAS was performed in patients that had undergone surgery with subsequent replication in a unique non-surgical cohort. In the surgical cohort, cases were defined as newly diagnosed AF within 30 days after surgery. The threshold for significance was set at 5 x 10-8.\\n\\nResultsAfter quality control, 144,196 surgical patients with 254,068 SNPs were left for analysis. Two variants (rs17042171 (p = 4.86 x 10-15) and rs17042081 (p = 7.12 x 10-15)) near the PITX2-gene reached statistical significance. These variants were replicated in the non-surgical cohort (1.39 x 10-101 and 1.27 x 10-93, respectively). Several other loci were significantly associated with AF in the non-surgical cohort.\\n\\nConclusionIn this GWAS-analysis of a large national biobank, we identified 2 variants that were significantly associated with postoperative AF. These variants were subsequently replicated in a unique non-surgical cohort. These findings bring new insight in the genetics of postoperative AF and may help identify at-risk patients and guide management.\"\n]","isConversational":false},"negative":{"kind":"list like","value":["Saving Lives with Pre-Financed Rules-Based Disaster Aid: Evidence from Mexico\nDeveloping economies are not disproportionately exposed to natural disasters, but they experience significantly more deaths. Exploiting a discontinuity in the eligibility rules to Mexicos pre-financed indexed disaster fund (Fonden), I show that accelerated reconstruction of public infrastructure can fully reduce postdisaster excess mortality in the short-run and up to 75 percent two years after. I also find that Fondens impact is concentrated in areas with medical infrastructure and among conditions responsive to basic medical interventions. These findings suggest that Fonden operates by restoring access to health services after a disaster. Annual benefits from Fonden amount to 197 thousand life-years saved. (JEL: G22, H12, H84, Q54, I15, O18.)","Whole genome sequencing identifies common and rare structural variants contributing to hematologic traits in the NHLBI TOPMed program\nGenome-wide association studies (GWAS) have identified thousands of single nucleotide variants and small indels that contribute to the genetic architecture of hematologic traits. While structural variants (SVs) are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of SVs to quantitative blood cell trait variation is unknown. Here we utilized SVs detected from whole genome sequencing (WGS) in ancestrally diverse participants of the NHLBI TOPMed program (N=50,675). Using single variant tests, we assessed the association of common and rare SVs with red cell-, white cell-, and platelet-related quantitative traits. The results show 33 independent SVs (23 common and 10 rare) reaching genome-wide significance. The majority of significant association signals (N=27) replicated in independent datasets from deCODE genetics and the UK BioBank. Moreover, most trait-associated SVs (N=24) are within 1Mb of previously-reported GWAS loci. SV analyses additionally discovered an association between a complex structural variant on 17p11.2 and white blood cell-related phenotypes. Based on functional annotation, the majority of significant SVs are located in non-coding regions (N=26) and predicted to impact regulatory elements and/or local chromatin domain boundaries in blood cells. We predict that several trait-associated SVs represent the causal variant. This is supported by genome-editing experiments which provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.","Proteasome inhibition enhances myeloma oncolytic reovirus therapy by suppressing monocytic anti-viral immune responses\nReovirus is an oncolytic virus with natural tropism for cancer cells. We previously showed that reovirus intravenous administration in myeloma patients was safe, but disease control associated with viral replication in the cancer cells was not observed. Here we show that ex vivo proteasome inhibitors (PIs) potentiate reovirus replication in circulating classical monocytes, increasing viral delivery to myeloma cells. We found that the anti-viral signals in monocytes primarily rely on the NF-kB activation and that this effect is impaired by the addition of PIs. Conversely, PIs improved reovirus-induced monocyte and T cell activation against cancer cells. Based on these preclinical data, we conducted a phase 1b trial of the reovirus Pelareorep together with the PI carfilzomib in 13 heavily pretreated bortezomib-resistant MM patients. Objective responses associated with reovirus active replication in MM cells, T cell activation and monocytic expansion were noted in 70% of patients.","Simultaneous evaluation of antibodies that inhibit SARS-CoV-2 RBD variants with a novel competitive multiplex assay\nThe SARS-CoV-2 Receptor Binding Domain (RBD) is both the principal target of neutralizing antibodies, and one of the most rapidly evolving domains, which can result in the emergence of immune escape mutations limiting the effectiveness of vaccines and antibody therapeutics. To facilitate surveillance, we developed a rapid, high-throughput, multiplex assay able to assess the inhibitory response of antibodies to 24 RBD natural variants simultaneously. We demonstrate that immune escape can occur through two mechanisms, antibodies that fail to recognize mutations, along with antibodies that have reduced inhibitory capacity due to enhanced variant RBD-ACE2 affinity. A competitive approach where antibodies simultaneously compete with ACE2 for binding to the RBD may therefore more accurately reflect the physiological dynamics of infection. We describe the enhanced affinity of RBD variants N439K, S477N, Q493L, S494P and N501Y to the ACE2 receptor, and demonstrate the ability of this assay to bridge a major gap for SARS-CoV-2 research; informing selection of complementary monoclonal antibody candidates and the rapid identification of immune escape to emerging RBD variants following vaccination or natural infection.","Racial Disparities in the SOFA Score Among Patients Hospitalized with COVID-19\nBackgroundSequential Organ Failure Assessment (SOFA) score predicts probability of in-hospital mortality. Many crisis standards of care use SOFA score to allocate medical resources during the COVID-19 pandemic.\n\nResearch QuestionAre SOFA scores disproportionately elevated among Non-Hispanic Black and Hispanic patients hospitalized with COVID-19, compared to Non-Hispanic White patients?\n\nStudy Design and MethodsRetrospective cohort study conducted in Yale New Haven Health System, including 5 hospitals with total of 2681 beds. Study population drawn from consecutive patients aged [≥]18 admitted with COVID-19 from March 29th to August 1st, 2020. Patients excluded from the analysis if not their first admission with COVID-19, if they did not have SOFA score recorded within 24 hours of admission, if race and ethnicity data were not Non-Hispanic Black, Non-Hispanic White, or Hispanic, or if they had other missing data. The primary outcomes was SOFA score, with peak score within 24 hours of admission dichotomized as <6 or [≥]6.\n\nResultsOf 2982 patients admitted with COVID-19, 2320 met inclusion criteria and were analyzed, of whom 1058 (45.6%) were Non-Hispanic White, 645 (27.8%) were Hispanic, and 617 (26.6%) were Non-Hispanic Black. Median age was 65.0 and 1226 (52.8%) were female. In univariate logistic screen and in full multivariate model, Non-Hispanic Black patients but not Hispanic patients had greater odds of an elevated SOFA score [≥]6 when compared to Non-Hispanic White patients (OR 1.49, 95%CI 1.11-1.99).\n\nInterpretationCrisis standards of care utilizing the SOFA score to allocate medical resources would be more likely to deny these resources to Non-Hispanic Black patients.","THEMIS: A Framework for Cost-Benefit Analysis of COVID-19 Non-Pharmaceutical Interventions\nSince December 2019, the world has been ravaged by the COVID-19 pandemic, with over 150 million confirmed cases and 3 million confirmed deaths worldwide. To combat the spread of COVID-19, governments have issued unprecedented non-pharmaceutical interventions (NPIs), ranging from mass gathering restrictions to complete lockdowns. Despite their proven effectiveness in reducing virus transmission, the policies often carry significant economic and humanitarian cost, ranging from unemployment to depression, PTSD, and anxiety. In this paper, we create a data-driven system dynamics framework, THEMIS, that allows us to compare the costs and benefits of a large class of NPIs in any geographical region across different cost dimensions. As a demonstration, we analyzed thousands of alternative policies across 5 countries (United States, Germany, Brazil, Singapore, Spain) and compared with the actual implemented policy.\n\nOur results show that moderate NPIs (such as restrictions on mass gatherings) usually produce the worst results, incurring significant cost while unable to sufficiently slow down the pandemic to prevent the virus from becoming endemic. Short but severe restrictions (complete lockdown for 4-5 weeks) generally produced the best results for developed countries, but only if the speed of reopening is slow enough to prevent a resurgence. Developing countries exhibited very different trade-off profiles from developed countries, and suggests that severe NPIs such as lockdowns might not be as suitable for developing countries in general.","The slower antibody response in myelofibrosis patients after two doses of mRNA SARS-CoV-2 vaccine calls for a third dose\nImmunization with mRNA SARS-CoV-2 vaccines has been highly recommended and prioritized in fragile categories with higher risk of mortality after COVID-19 disease compared to healthy people, including patients with myelofibrosis (MF). Available data on the vaccine immune response developed by MF patients, and the impact of the treatment with the inhibitor of JAK-STAT signaling ruxolitimib, are still fragmented to support an informed decision for a third dose for this category of subjects. Here, we show that 76% of MF patients develop spike-specific IgG after the second vaccine dose, but the response has a slower kinetic compared to healthy subjects, suggesting a reduced capability of their immune system to promptly react to vaccination. A reduced ACE2/RBD inhibition binding activity of spike-specific antibodies was also observed, especially in ruxolitimib treated patients. Our results contribute to answer the open question on the induction of the antibody responses in MF patients following vaccination with COVID-19 mRNA vaccines, showing a slow kinetic that support the need for a third dose of SARS-CoV-2 mRNA vaccines.","Toward a phenome-wide view of Parkinson's disease\nBackground and ObjectivesMany studies have examined the relation between PD and environmental variables serially --- one candidate association at a time. In the real world however, both environmental exposures and patients are much more complex, including correlated environmental exposures, polypharmacy, and complex comorbidities. Here we begin to characterize a holistic view of environmental, health, and pharmacological traits linked to patients with PD.\n\nMethodsThe Harvard Biomarkers Study (HBS) is a large case-control study of PD patients and healthy controls that includes an extensive questionnaire covering past medical and social history data and is thus well-suited for such an exploratory study. Sixty-four environmental, pharmacological, and clinical features were evaluated for associations with PD using logistic regression analysis with backward elimination.\n\nResultsMale gender, coronary artery disease, depression, anxiety, restless leg syndrome, head trauma, ibuprofen use, co-enzyme Q10 use, and vitamin D supplementation were significantly positively associated with PD. By contrast, asthma/chronic obstructive pulmonary disease (COPD), naproxen, ezetimibe, and smoking were significantly negatively associated with PD.\n\nDiscussionThis study shows that unbiased, data-rich exploration of the Parkinson phenome has the promise to uncover, prioritize, and clarify associations between environment, multi-system health phenotypes, and PD in a patient-centric manner. Associations with coronary artery disease, mood disorders, and the cholesterol-absorption inhibitor ezetimibe were revealed that have been largely neglected in traditional hypothesis-driven investigations. Interestingly, asthma/COPD was inversely associated with PD, and this was independent of smoking history. Furthermore, well-established associations were confirmed for male gender, smoking, head trauma, and restless legs syndrome.","Impact of Exercise-induced Dehydration on Perceived Exertion During Endurance Exercise: A Systematic Review with Meta-analysis\nUnderstanding the impact of stressors on the rating of perceived exertion (RPE) is relevant from a performance and exercise adherence/participation standpoint. Athletes and recreationally active individuals dehydrate during exercise. No attempt has been made to systematically determine the impact of exercise-induced dehydration (EID) on RPE. The present meta-analysis aimed to determine the effect of EID on RPE during endurance exercise and examine the moderating effect of potential confounders using a meta-analytical approach. Data analyses were performed on raw RPE values using random-effects models weighted mean effect summaries and meta-regressions with robust standard errors, and with a practical meaningful effect set at 1 point difference between euhydration (EUH) and EID. Only controlled crossover studies measuring RPE with a Borg scale in healthy adults performing [≥] 30 min of continuous endurance exercise while dehydrating or drinking to maintain EUH were included. Sixteen studies were included, representing 147 individuals. Mean body mass loss with EUH was 0.5 {+/-} 0.4%, compared to 2.3 {+/-} 0.5% with EID (range 1.7 to 3.1%). Within an EID of 0.5 to 3% body mass, a maximum difference in RPE of 0.81 points (95% CI: 0.36-1.27) was observed between conditions. A meta-regression revealed that RPE increases by 0.21 points for each 1% increase in EID (95% CI: 0.12-0.31). Humidity, ambient temperature and aerobic capacity did not alter the relationship between EID and RPE. Therefore, the effect of EID on RPE is unlikely to be practically meaningful until a body mass loss of at least 3%.","Covid-19 High Attack Rate Can Lead to High Case Fatality Rate\nBackgroundDuring the current Covid-19 pandemic case fatality rate (CFR) estimates were subjected to a lot of debates regarding the accuracy of its estimations, predictions, and the reason of across countries variances. In this context, we conduct this study to see the relationship between attack rate (AR) and CFR.\n\nThe study hypothesis is based on two: 1-evidence suggests that the mortality rate (MR) has a positive influence on case fatality ratio (CFR), 2- and increase number of Covid-19 cases leads to increased mortality rate (MR).\n\nMaterial and methodsThirty countries and territories were chosen. Inclusion criterion was > 500 Covid-19 reported cases per 10,000 population inhabitants. Data on covid-19 cases and deaths was selected as it was on March 10, 2021. Statistical methods used are descriptive and one-sample Kolmogorov-Smirnov (K-S), the one-way ANOVA, Levene, least significant different (LSD), and matched paired-samples T-tests.\n\nResultsANOVA test showed a significant difference at P<0.01 among all studied groups concerning AR and CFR mean values. Group of countries with MR [≥] 15 death / 104 inhabitants recorded the highest level of crude mean CFR and AR values, and recorded the highest gap with leftover groups, especially with countries reported MR of <10 death/ 104 inhabitants. There were independence 95% confidence intervals of mean CFR and AR values between countries with [≥] 15 death / 104 MR and countries with MR of <10 death /104. There was a significant difference between countries with MR [≥] 15 death / 104 inhabitants and countries with MR of <10 death / 10 4 inhabitants groups through least significant difference (LSD) test for CFR%(0.042 p-value) and Games Howell (GH) test for AR/104 (p-value 0.000).\n\nConclusionsTotal and mean AR and CFR are higher in high MR countries compared to low MR countries.","Evolution and emergence of multidrug-resistant Mycobacterium tuberculosis in Chisinau, Moldova\n1.BackgroundDrug-resistant tuberculosis is a high priority threat to global public health. There are still critical gaps in understanding how novel drug-resistant M. tuberculosis strains emerge and, once emergent, what drives the differential propagation of certain epidemiologically-successful strains over others. This study sought to describe the joint evolutionary and epidemiological histories of a novel multidrug-resistant M. tuberculosis strain recently identified in the capital city of the Republic of Moldova (MDR Ural/4.2).\n\nMethodsUsing whole genome sequence data and Bayesian phylogenomic methods, we reconstruct the stepwise acquisition of drug-resistance mutations in the MDR Ural/4.2 strain, estimate its historical bacterial population size over time, and infer the migration history of this strain between Eastern European countries.\n\nResultsWe infer that MDR Ural/4.2 likely evolved (via acquisition of rpoB S450L, which confers resistance to rifampin) in the early 1990s, during a period of social turmoil following Moldovan independence from the Soviet Union. This strain subsequently underwent substantial population size expansion in the early 2000s, at a time when national guidelines encouraged in hospital treatment of TB patients. We infer exportation of this strain and its INH-resistant ancestral precursor from Moldova to neighboring countries starting as early as 1985.\n\nConclusionsOur findings underscore how public health practice and social determinants of health shape the conditions under which M. tuberculosis evolves, and demonstrates how historical changes in these conditions shape present-day challenges in TB control. These findings underscore the need for regional coordination in TB control across Eastern Europe.","Human influenza virus infection elicits distinct patterns of monocyte and dendritic cell mobilization in blood and the nasopharynx\nDuring respiratory viral infections, the precise roles of monocytes and dendritic cells (DCs) in the nasopharynx in limiting infection and influencing disease severity are incompletely described. We studied circulating and nasopharyngeal monocytes and DCs in healthy individuals and in patients with mild respiratory infections (primarily influenza A virus, IAV). As compared to healthy controls (HCs), patients with acute IAV infection displayed reduced DC but increased intermediate monocytes frequencies in blood, and an accumulation of most monocyte and DC subsets in the nasopharynx. IAV patients had more mature monocytes and DCs in the nasopharynx, and higher levels of TNF, IL-6 and IFN in plasma and the nasopharynx. In blood, monocytes, the most frequent cellular source of TNF during IAV infection, remained responsive to additional stimulation with TLR7/8L. Immune responses in older patients skewed towards increased monocytes rather than DCs suggesting a contributory role for monocytes in disease severity. In patients with other respiratory virus infections, we observed changes in monocyte and DC frequencies in the nasopharynx distinct from IAV patients, while differences in blood were more similar across patient groups. Together, our findings demonstrate tissue-specific and pathogen-specific patterns of monocyte and DC function during human respiratory viral infections and highlight the importance of comparative investigations in blood and the nasopharynx.","High Speed Photographic Detection of Particle Distribution During Aerosol and Smoke Generating Surgical Procedures: Effects of Surgical Site Evacuation\nObjectiveDetermine the effectiveness of evacuation systems designed to clear bioaerosols and smoke from the surgical field.\n\nStudy designHigh-speed photographic evaluation of aerosol and smoke generated in simulated surgical fields.\n\nMaterials and methodsSurgical site aerosol clearance was evaluated using a model of the anterior neck and prototypes for surgical site evacuator ports created using 3D printing. A commercially available electrocautery handpiece fitted with an evacuator was tested on animal tissue for smoke clearance. Both systems were connected to a commercial vacuum powered evacuation system. High speed photography was used to record videos of the aerosols and plumes. Fields were recorded with and without evacuation.\n\nResultsEfficient aerosol clearance from an open surgical field using an evacuator port is dependent upon the port design, airflow velocity, and placement relative to the aerosol generating site. The size and surface geometry of the surgical field are also important.\n\nSurgical smoke generated with electrocautery is cleared from the field by the evacuation enclosure around the handpiece, even at high electrocautery power settings. Except for device noise, there appears to be no reason for using evacuator flow rates below the maximum setting.\n\nConclusionsBioaerosol and smoke generated during surgery are potential sources of respiratory pathogens and pose a threat to operating room personnel. Surgical site evacuation can significantly reduce the volume of airborne particles in the field but requires careful design and deployment considerations.x","Association of history of metformin use with delirium and mortality: A retrospective cohort study\nObjectiveTo investigate the relationship between history of metformin use and delirium risk, as well as long-term mortality.\n\nMethodsIn this retrospective cohort study, subjects recruited between January 2016 and March 2020 were analyzed. Logistic regression analysis was performed to investigate the relationship between metformin use and delirium. Log-rank analysis and Cox proportional hazards model were used to investigate the relationship between metformin use and 3-year mortality.\n\nResultsThe data from 1404 subjects were analyzed. 242 subjects were categorized into a DM-without-metformin group, and 264 subjects were categorized into a DM-with-metformin group. Prevalence of delirium was 36.0% in the DM-without-metformin group, and 29.2% in the DM-with-metformin group. A history of metformin use reduced the risk of delirium in patients with DM (OR, 0.50 [95% CI, 0.32 to 0.79]) after controlling for age, sex, and dementia status, body mass index (BMI), and insulin use. The 3-year mortality in the DM-without-metformin group (survival rate, 0.595 [95% CI, 0.512 to 0.669]) was higher than in the DM-with-metformin group (survival rate, 0.695 [95% CI, 0.604 to 0.770]) (p=0.035). A history of metformin use decreased the risk of 3-year mortality after adjustment for age, sex, Charlson Comorbidity Index, BMI, history of insulin use, and delirium status (HR, 0.69 [95% CI, 0.48 to 0.98]).\n\nConclusionsIt was found that metformin usage was associated with decreased delirium prevalence and lower 3-year mortality. The potential benefit of metformin on delirium risk and mortality were shown.","Standardized and optimized preservation, extraction and quantification techniques for detection of fecal SARS-CoV-2 RNA\nCOVID-19 patients shed SARS-CoV-2 viral RNA in their stool, sometimes well after they have cleared their respiratory infection. This feature of the disease may be significant for patient health, epidemiology, and diagnosis. However, to date, methods to preserve stool samples from COVID patients, and to extract and quantify viral RNA concentration have yet to be optimized. We sought to meet this urgent need by developing and benchmarking a standardized protocol for the fecal detection of SARS-CoV-2 RNA. We test three preservative conditions for their ability to yield detectable SARS-CoV-2 RNA: OMNIgene-GUT, Zymo DNA/RNA shield kit, and the most common condition, storage without any preservative. We test these in combination with three extraction kits: the QIAamp Viral RNA Mini Kit, Zymo Quick-RNA Viral Kit, and MagMAX Viral/Pathogen Kit. Finally, we also test the utility of two detection methods, ddPCR and RT-qPCR, for the robust quantification of SARS-CoV-2 viral RNA from stool. We identify that the Zymo DNA/RNA shield collection kit and the QiaAMP viral RNA mini kit yield more detectable RNA than the others, using both ddPCR and RT-qPCR assays. We also demonstrate key features of experimental design including the incorporation of appropriate controls and data analysis, and apply these techniques to effectively extract viral RNA from fecal samples acquired from COVID-19 outpatients enrolled in a clinical trial. Finally, we recommend a comprehensive methodology for future preservation, extraction and detection of RNA from SARS-CoV-2 and other coronaviruses in stool.","SplitStrains, a tool to identify and separate mixed Mycobacterium tuberculosis infections from WGS data\nThe occurrence of multiple strains of a bacterial pathogen such as M. tuberculosis or C. difficile within a single human host, referred to as a mixed infection, has important implications for both healthcare and public health. However, methods for detecting it, and especially determining the proportion and identities of the underlying strains, from WGS (whole-genome sequencing) data, have been limited.\n\nIn this paper we introduce SplitStrains, a novel method for addressing these challenges. Grounded in a rigorous statistical model, SplitStrains not only demonstrates superior performance in proportion estimation to other existing methods on both simulated as well as real M. tuberculosis data, but also successfully determines the identity of the underlying strains.\n\nWe conclude that SplitStrains is a powerful addition to the existing toolkit of analytical methods for data coming from bacterial pathogens, and holds the promise of enabling previously inaccessible conclusions to be drawn in the realm of public health microbiology.\n\nAuthor summaryWhen multiple strains of a pathogenic organism are present in a patient, it may be necessary to not only detect this, but also to identify the individual strains. However, this problem has not yet been solved for bacterial pathogens processed via whole-genome sequencing. In this paper, we propose the SplitStrains algorithm for detecting multiple strains in a sample, identifying their proportions, and inferring their sequences, in the case of Mycobacterium tuberculosis. We test it on both simulated and real data, with encouraging results. We believe that our work opens new horizons in public health microbiology by allowing a more precise detection, identification and quantification of multiple infecting strains within a sample.","The genetic architecture of human infectious diseases and pathogen-induced cellular phenotypes\nHere, we develop a genetics-anchored framework to decipher mechanisms of infectious disease (ID) risk and infer causal effect on potential complications. We perform transcriptome-wide association studies (TWAS) of 35 ID traits in 27,615 individuals in a broad collection of human tissues, identifying 70 gene-level associations with 26 ID traits, with replication in two large-scale biobanks. A phenome-scale scan and Mendelian Randomization of the 70 gene-level associations across 197 traits proposes a molecular basis for known complications of the ID traits. This rich resource of host genetic associations with pathogen cultures and 16S-rRNA-based microbiome variation provides a platform to investigate host-pathogen interactions. To identify relevant cellular processes, we develop a TWAS repository of 79 pathogen-exposure induced cellular phenotypes. Our study will facilitate mechanistic insights into the role of host genetic variation on ID risk and pathophysiology, with important implications for our molecular understanding of severe phenotypic outcomes.","Clinician and patient experience of neurology telephone consultations during the COVID-19 pandemic\nBackgroundTelephone consultations are already employed in specific neurological settings. At Cambridge University Hospitals, the COVID-19 pandemic initially prompted almost all face-to-face appointments to be delivered by telephone, providing a uniquely unselected population to assess.\n\nObjectivesWe explored patient and clinician experience of telephone consultations; and whether telephone consultations might be preferable for pre-identifiable subgroups of patients after the pandemic.\n\nMethodsClinicians delivering neurological consultations converted to telephone between April-July 2020 were invited to complete a questionnaire following each consult (430 respondents) and the corresponding patients were subsequently surveyed (290 respondents). The questionnaires assessed clinician and patient goal achievement (and the reasons for any dissatisfaction). Clinicians also described consultation duration (in comparison to face-to-face) while patients detailed comparative convenience and preference.\n\nResultsThe majority of clinicians (335/430, 78%) and patients (227/290, 78%) achieved their consultation goals by telephone, particularly during follow-up consultations (clinicians 272/329, 83%, patients 176/216, 81%) and in some disease subgroups (e.g. seizures/epilepsy (clinicians 114/122 (93%), patients 71/81 (88%)). 95% of telephone consultations were estimated to take the same or less time than an equivalent face-to-face consultation. Most patients found telephone consultations convenient (69%) with 149/211 (71%) indicating they would like telephone or video consultations to play some role in their future follow-up.\n\nConclusionTelephone consultations appear effective, convenient and popular in prespecified subgroups of neurological outpatients. Further work comparing telephone, video and face-to-face consultations across multiple centres is now needed.","Spillover Benefit of Pre-Exposure Prophylaxis for HIV Prevention: Evaluating the Importance of Effect Modification using an Agent-Based Model\nWe developed an agent-based model using a trial emulation approach to quantify effect measure modification of key variables on spillover effects of pre-exposure prophylaxis (PrEP) among men who have sex with men (MSM) in Atlanta, GA. PrEP may impact not only the individual prescribed, but also their partners and beyond, known as spillover. We simulated a two-stage randomized trial with eligible components ([≥]3 agents and [≥]1 HIV+ agent) first randomized to intervention or control (no PrEP). Within intervention components, agents were randomized to PrEP with intervention coverage of 70%, providing insight into a high PrEP coverage strategy. We evaluated effect modification by component level characteristics and estimated spillover effects using an extension of randomization-based estimators. We observed an attenuation of the spillover effect when agents were in components with a higher prevalence of either drug use or bridging potential (if an agent acts as a mediator between [≥]2 connected groups of agents). The estimated spillover effects were larger in magnitude among components with either higher HIV prevalence or greater density (number of existing compared to all possible partnerships). Consideration of effect modification is important when evaluating the spillover of PrEP among MSM.","Over- and under-estimation of vaccine effectiveness\nSARS-CoV-2 vaccines provide not just high protection against infection to the vaccinated individual but also provide indirect protection to its surroundings by blocking further transmission. Divergent results have been reported on the effectiveness of the SARS-CoV-2 vaccines. Here, we argue that this divergence is due to the fact that the analyses did not take into account the indirect protection. Using a novel heterogenous infection model and real-world data, we demonstrate that heterogeneous vaccination rates among families and communities, and the study design that is used, may significantly skew the vaccine effectiveness estimations. We show that estimations of a vaccine with 85% effectiveness will vary between marked underestimation of [~]70% and overestimation of [~]95% depending on the number of interactions between vaccinated and unvaccinated individuals.","Commercialized kit to assess T-cell responses against SARS-CoV-2 S peptides. A pilot study in Health Care Workers.\nBackgroundIt is crucial to assess the levels of protection generated by natural infection or SARS-CoV-2 vaccines, mainly in individuals professionally exposed and in vulnerable groups. Measuring T-cell responses may complement antibody tests currently in use as correlates of protection. Our aim was to assess the feasibility of a validated assay of T-cell responses.\n\nMethodsTwenty health-care-workers (HCW) were included. Antibody test to SARS-CoV-2 N and S-proteins in parallel with a commercially available whole-blood-interferon-gamma-release-assay (IGRA) to S-peptides and two detection methods, CLIA and ELISA were determined.\n\nResultsIGRA test detected T-cell responses in naturally exposed and vaccinated HCW already after first vaccination dose. The correlation by the two detection methods was very high (R>0.8) and sensitivity and specificity ranged between 100 and 86% and 100-73% respectively. Even though there was a very high concordance between specific antibody levels and the IGRA assay in the ability to detect immune response to SARS-CoV-2, there was a relatively low quantitative correlation. In the small group primed by natural infection, one vaccine dose was sufficient to reach immune response plateau. IGRA was positive in one, with Ig(S) antibody negative vaccinated immunosuppressed HCW illustrating another advantage of the IGRA-test.\n\nConclusionWhole-blood-IGRA-tests amenable to automation and constitutes a promising additional tool for measuring the state of the immune response to SARS-CoV-2; they are applicable to large number of samples and may become a valuable correlate of protection to COVID-19, particularly for vulnerable groups at risk of being re-exposed to infection, as are health-care-workers.","Convalescent Plasma and Improved Survival in Patients with Hematologic Malignancies and COVID-19\nConvalescent plasma may benefit immunocompromised individuals with COVID-19, including those with hematologic malignancy. We evaluated the association of convalescent plasma treatment with 30-day mortality in hospitalized adults with hematologic malignancy and COVID-19 from a multi-institutional cohort. 143 treated patients were compared to 823 untreated controls. After adjustment for potential confounding factors, convalescent plasma treatment was associated with improved 30-day mortality (hazard ratio, 0.60; 95% CI, 0.37-0.97). This association remained significant after propensity-score matching (hazard ratio, 0.52; 95% CI, 0.29-0.92). These findings suggest a potential survival benefit in the administration of convalescent plasma to patients with hematologic malignancy and COVID-19.","Do panic values cause panic? Reporting of critical laboratory results in a tertiary hospital in Kenya\nPrompt communication of critical laboratory results is important for patient safety. Various standardisation bodies have proposed procedures for handling critical results, with notification parameters outlined. However, few studies exist in low- and middle-income countries (LMIC) to document how critical results are handled. We tracked 12 types of laboratory tests over a three-week period in December 2018 and documented if and how critical test results were communicated, the time-frame for communication, and evidence of action taken on the results. During the period, 331 of 5,500 (6.1%) test results were identified as critical. Only 71 (21%) of the critical results were documented as having been communicated to the destination departments. Of the communicated results, clinicians were unaware of 21 (29.6%). Of the 12 test types, critical results were only communicated for three tests namely: potassium, haemoglobin and positive malaria tests. Communication of critical results to inpatient settings was significantly higher than to outpatient settings (p <0.05), with communication rates decreasing as the week progressed, during weekends and around holidays. The observed poor communication of critical results in an LMIC setting raise significant patient safety concerns. Laboratories in these settings need to adhere to international standards, like ISO 15189:2009, to assure safe practice. Training of staff, establishment of standard operating procedures guiding these results, and implementation of fail-proof critical result dissemination mechanisms are essential. It is important that all critical results are communicated within one hour of availability. Implementation of Order Entry and Laboratory systems should be highly considered.","High-intensity exercise is a risk factor for renal medullary carcinoma in individuals with sickle cell trait\nRenal medullary carcinoma (RMC) predominantly occurs in individuals with sickle cell trait (SCT). We found that patients with RMC more frequently participated in high-intensity exercise than matched controls, and renal medullary hypoxia significantly increased predominantly in the right kidney of mice with SCT following high-but not moderate-intensity exercise, consistent with the distinct predilection of RMC toward the right kidney. These results establish high-intensity exercise as a risk factor for RMC in individuals with SCT.","Cancer-associated Lactobacillus iners are genetically distinct and associated with chemoradiation resistance in cervical cancer\nThis study identifies a novel pathotype of cervical cancer-associated Lactobacillus iners (L. iners) that results in chemoradiation resistance in vitro and is associated with poor patient survival. Cervical cancer affects over half a million women a year around the world. Treatment for women with locally advanced cancer is delivered with definitive chemoradiation (CRT) but is curative for only 60% of patients. There are few validated molecular markers to identify patients who will respond poorly to treatment. Tumor microbiome features are associated with treatment resistance in patients with colon and pancreatic cancers, and thus we investigated their role in the response of cervical cancer to therapy. We identified a strong association between poor clinical response to CRT and tumors dominated by L. iners. Cancer-associated L. iners promoted in vitro resistance of cervical cancer cells and modified the local tumor immunologic microenvironment, while non-cancer-associated L. iners did not. Assembly of genomes from cancer-derived L. iners also demonstrated pathogenic, metabolic, and immune functions not found in healthy patients.","The spread and burden of the COVID-19 pandemic in sub-Saharan Africa: comparison between predictions and actual data and lessons learned.\nIntroductionSub-Saharan Africa (SSA) was predicted to be severely affected by the coronavirus disease 2019 (COVID-19) pandemic, but the actual data seem to have contradicted these forecasts. This study attempted to verify this observation by comparing predictions against actual data on the spread and burden of the COVID-19 pandemic in SSA.\n\nMethodsFocused on the period from March 1st to September 30th, 2020, we compared (1) the predicted interval dates when each SSA country would report 1 000 and 10 000 COVID-19 cases, to the actual dates when these numbers were attained, as well as (2) the daily number of predicted versus actual COVID-19 cases.\n\nFurther, we calculated the case fatality ratio of the COVID-19 infection in SSA, and the correlation coefficient between the weekly average number of confirmed COVID-19 cases reported by each country and the weekly average stringency index of its anti-COVID-19 policy measures.\n\nResults84.61% (33) and 100% (39) of the 39 SSA countries for which predictions were made did not reach a total of 1 000 and 10 000 confirmed COVID-19 cases at the predicted interval dates. The daily number of confirmed COVID-19 cases was lower than the one projected for all SSA countries. The case fatality ratio of the COVID-19 infection in SSA was 3.42%. Among the 44 SSA countries for which the correlation could be estimated, it was negative for 17 (38.6 %) of them.\n\nConclusionsThe natural characteristics of SSA and the public health measures implemented might partly explain that the actual data were lower than the predictions on the COVID-19 pandemic in SSA, but the low case ascertainment and the numerous asymptomatic cases did significantly influence this observation.","Neutralizing anti-DNase1L3 antibodies derive from autoreactive VH4-34+ B cells and associate with the interferon signature in SLE\nDNase1L3 deficiency is an inborn error of immunity that causes monogenic systemic lupus erythematosus (SLE) in humans. Here, we identified that one third of patients with sporadic SLE have antibodies to DNase1L3. Like DNase1L3 deficiency, we found that patients with anti-DNase1L3 antibodies have features associated with immune pathways activated by immunogenic self-DNA, including elevated antibodies to dsDNA and prominent expression of the interferon and myeloid/neutrophil signatures. Interestingly, 40-80% of anti-DNase1L3 antibodies in SLE serum contain the 9G4 idiotype, which is encoded by the autoreactive heavy-chain gene segment VH4-34. Sequence and functional analysis of four anti-DNase1L3 monoclonal antibodies generated from SLE patients experiencing disease-associated flares showed that these antibodies were derived from self-reactive 9G4+ switched memory B cells. These antibodies are highly enriched in somatic hypermutations, indicating that they originated from antigen-experienced cells, and have neutralizing activity against DNase1L3. Together, the data demonstrate that autoantibodies to DNase1L3 phenocopy pathogenic mechanisms associated with DNase1L3 deficiency. Moreover, the finding that autoreactive B cells bearing the 9G4 idiotype produce dominant serum autoantibodies, including antibodies to DNase1L3, underscores VH4-34+ B cells as sensible therapeutic targets for specific depletion of pathogenic B cells in SLE.","Predicting Prognosis in COVID-19 Patients using Machine Learning and Readily Available Clinical Data\nRationalePrognostic tools for aiding in the treatment of hospitalized COVID-19 patients could help improve outcome by identifying patients at higher or lower risk of severe disease.\n\nObjectivesThe study objective was to develop models to stratify patients by risk of severe outcomes during COVID-19 hospitalization using readily available information at hospital admission.\n\nMethodsHierarchical ensemble classification models were trained on a set of 229 patients hospitalized with COVID-19 to predict severe outcomes, including ICU admission, development of ARDS, or intubation, using easily attainable attributes including basic patient characteristics, vital signs at admission, and basic lab results collected at time of presentation. Each test stratifies patients into groups of increasing risk. An additional cohort of 330 patients was used for blinded, independent validation. Shapley value analysis evaluated which attributes contributed most to the models predictions of risk.\n\nMeasurements and Main ResultsTest performance was assessed using precision (positive predictive value) and recall (sensitivity) of the final risk groups. All test cut-offs were fixed prior to blinded validation. In both development and validation, the tests achieved precision in the lowest risk groups near or above 0.9. The proportion of patients with severe outcomes significantly increased across increasing risk groups. While the importance of attributes varied by test and patient, CRP, LDH, and D-dimer were often found to be important in the assignment of risk label.\n\nConclusionsRisk of severe outcomes for patients hospitalized with COVID-19 infection can be assessed using machine learning-based models based on attributes routinely collected at hospital admission.","Single-Blind and Double-Blind Peer Review: Effects on National Representation\nBackground/ObjectivesTo assess whether the type of peer-review (single-blinded vs double-blinded) has an impact on nationality representation in journals.\n\nMethodsA cross-sectional study analyzing the top ten nationalities contributing to the number of articles across 16 ophthalmology journals.\n\nResultsThere was no significant difference in the percentage of articles published from the journals country of origin between the top single-blind journals and top double-blind journals (SB= 42.0%, DB = 26.6%, p=0.49) but there was a significant difference between the percentage of articles from the US (SB=48.0%, DB=22.8%, p=0.02). However, there was no significant difference for both country of origin (SB =38.0%, DB =26.6%, p=0.43) and articles from the US (SB=35.0%, DB=22.8%, p=0.21) when assessing the top 8 double-blind journals matched with single-blind journals of a similar impact factor. The countries that most commonly made the top ten lists for highest number of articles were the US (n=16, 100%) and England (n=16, 100%). This held true even for journals established outside the United States (US=11/12, England=11/12).\n\nConclusionsThere was no statistically significant difference in country-of-origin representation between single-blind journals and double-blind journals. However, higher income countries contributed most often to the journals studied even among journals based outside the US.","The humoral response to BK polyomavirus in kidney transplant recipients is dominated by IgM antibodies that use a distinct repertoire compared to IgG against the same antigen\n1.The BK polyomavirus (BKPyV) persists asymptomatically in the kidney and active replication is only seen in immunosuppressed individuals, such as kidney transplant (KTx) recipients, in whom BKPyV reactivation can cause significant morbidity. KTx recipients with BKPyV reactivation mount a robust humoral response, but this often fails to clear the virus. In order to characterize the BKPyV-specific B-cell receptor (BCR) repertoire in KTx recipients, we used fluorescence-labeled BKPyV virus-like particles (VLPs) to sort with BKPyV-specific B-cells, then single-cell RNAseq to obtain paired heavy and light chain antibody sequences, and gene transcriptome data. The BCR repertoire was highly diverse in terms of both V-gene usage and clonotype diversity, with approximately 3% repertoire overlap between patients. The BKPyV-specific response was characterized by the presence of both memory IgG and memory IgM B-cells with extensive somatic hypermutation, which expressed distinct BCR repertoires within the same patient. The gene expression profile of IgG and IgM memory B-cells was highly similar, with only 19 genes, including CD83, CD79A and PARP1 showing significant differential expression. These results confirm that the IgM memory B-cells are a significant component of the BKPyV-specific humoral response, and show for the first time that IgG and IgM repertoires directed against the same antigen can have significant differences.","Design of optical cavity for air sanification through ultraviolet germicidal irradiation\nThe transmission of airborne pathogens represents a major issue to worldwide public health. Ultraviolet light irradiation can contribute to the sanification of air to reduce the pathogen transmission. This study concerns the design of a compact filter for airborne pathogen inactivation by means of UV-C LED sources, whose effective irradiance is enhanced thanks to high reflective surfaces. Ray-tracing and computational fluid dynamic simulations are both used to model the device and to maximize the performance inside the filter volume. Simulations foresee the inhibition of SARS-Cov 2 also in the case of high air fluxes. This study demonstrates that current available LED technology is effective for air sanification purposes.","Prediction of recessive inheritance for missense variants in human disease\nThe prediction of pathogenic human missense variants has improved in recent years, but a more granular level of variant characterization is required. Further axes of information need to be incorporated in order to advance the genotype-to-phenotype map. Recent efforts have developed mode of inheritance prediction tools; however, these lack robust validation and their discrimination performance does not support clinical utility, with evidence of them being fundamentally insensitive to recessive acting diseases. Here, we present MOI-Pred, a three-way variant-level mode of inheritance prediction tool aimed at recessive identification for missense variants. MOI-Pred shows strong ability to discriminate missense variants causing autosomal recessive disease (area under the receiver operating characteristic (AUROC)=0.99 and sensitivity=0.85) in an external validation set. Additionally, we introduce an electronic health record (EHR)-based validation approach using real-world clinical data and show that our recessive predictions are enriched for recessive associations with human diseases, demonstrating utility of our method. Mode of inheritance predictions - pathogenic for autosomal recessive (AR) disease, pathogenic for autosomal dominant (AD) disease, or benign - for all possible missense variants in the human genome are available at https://github.com/rondolab/MOI-Pred/.","A Clinical Feasibility Study of an Artificial Intelligence-Powered Clinical Decision Support System\nObjectiveWe examine the feasibility of an Artificial Intelligence (AI)-powered clinical decision support system (CDSS), which combines the operationalized 2016 Canadian Network for Mood and Anxiety Treatments guidelines with a neural-network based individualized treatment remission prediction.\n\nMethodsDue to COVID-19, the study was adapted to be completed entirely at a distance. Seven physicians recruited outpatients diagnosed with major depressive disorder (MDD) as per DSM-V criteria. Patients completed a minimum of one visit without the CDSS (baseline) and two subsequent visits where the CDSS was used by the physician (visit 1 and 2). The primary outcome of interest was change in session length after CDSS introduction, as a proxy for feasibility. Feasibility and acceptability data were collected through self-report questionnaires and semi-structured interviews.\n\nResultsSeventeen patients enrolled in the study; 14 completed. There was no significant difference between appointment length between visits (introduction of the tool did not increase session length). 92.31% of patients and 71.43% of physicians felt that the tool was easy to use. 61.54% of the patients and 71.43% of the physicians rated that they trusted the CDSS. 46.15% of patients felt that the patient-clinician relationship significantly or somewhat improved, while the other 53.85% felt that it did not change.\n\nConclusionsOur results confirm the primary hypothesis that the integration of the tool does not increase appointment length. Findings suggest the CDSS is easy to use and may have some positive effects on the patient-physician relationship. The CDSS is feasible and ready for effectiveness studies.","Amplicon-based nanopore minion sequencing of patients with COVID-19 omicron variant from India\nSARS-CoV-2 infection has been playing havoc with emerging omicron variants of concern (VoC). Here, we report sequencing of the omicron variant in 13 patients from India using Oxford Nanopore Technology (ONT) Minion, wherein a rapid amplicon based sequence analysis was performed to assess and compare with existing 34 mutations in spike glycoprotein. We highlight and discuss the nature of these mutations that are unique and common to other populations. This is perhaps the first report on omicron variants from India using a long read sequencing chemistry.","Improving prediction of amyloid deposition in Mild Cognitive Impairment with a timed motor task\nCortical amyloid deposition is one of the hallmark biomarkers of Alzheimers disease. However, given how cost- and time-intensive amyloid imaging can be, there is a continued need for a low-cost, non-invasive, and accessible enrichment strategy to pre-screen individuals for their likelihood of amyloid prior to imaging. Previous work supports the use of coordinated limb movement as a potential screening tool, even after controlling for cognitive and daily function. Thirty-six patients diagnosed with amnestic Mild Cognitive Impairment over the age of 65 underwent 18F-Flutemetamol amyloid-positron emission tomography imaging, then completed a timed motor task involving upper limb coordination. This task takes [~]5 minutes to administer and score. Multivariate linear regression and Receiver Operator Characteristic analyses showed that including motor task performance improved model prediction of amyloid burden. Results support the rationale for including functional upper extremity motor assessment as a cost- and time-effective means to screen participants for amyloid deposition.","Barriers to early initiation of breastfeeding in healthy neonates in an urban hospital setting.\nBackgroundBreastfeeding is a key intervention to improve global targets on nutrition, health and survival. The World Health Organization (WHO) recommends early initiation of breastfeeding to prevent infections in the newborn and achieve targets of exclusive breastfeeding for the first six months of life. Early initiation of breastfeeding improves neonatal-maternal bonding, reduces jaundice and prevents gastrointestinal and respiratory tract infections. Global prevalence of early initiation of breastfeeding is 45% and 51% for Tanzania. The recommended prevalence is at least 80% by WHO guidelines.\n\nObjectiveTo explore barriers to early initiation of breastfeeding in a hospital setting.\n\nMethodsA descriptive exploratory qualitative study with semi-structured individual interviews was employed to explore the barriers to early initiation of breastfeeding in a hospital setting. Three midwives and six mothers were interviewed. The interview topic guide covered experiences and challenges of early initiation of breastfeeding. Data was analyzed using Systematic Text Condensation as described by Malterud.\n\nResultsParticipants perceived that inadequate breastfeeding information especially on ideal time to start breastfeeding contributed to delayed initiation. The practices and environment post-delivery such as perineal tear repair and dirty labor room prevented women from initiating breastfeeding immediately.\n\nConclusionsThe barriers identified were related to gaps in knowledge, immediate postpartum practices and individual perceptions of a non-conducive environment.","Excess Serum Interleukin-18 Distinguishes Patients with Pathogenic Mutations in PSTPIP1\nObjectiveDominantly-inherited mutations in PSTPIP1 cause a family of monogenic autoinflammatory diseases epitomized by Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA) syndrome. The connections between PSTPIP1 and PAPA are poorly understood, although in vitro evidence suggests increased activation of the pyrin-inflammasome. We sought to identify biomarkers of potential mechanistic, diagnostic, and therapeutic utility specific to autoinflammatory diseases.\n\nMethodsClinical and genetic data and sera were obtained from patients referred with concern for PAPA syndrome, as well as relevant disease controls. Serum Interleukin-18 (IL-18) and related biomarkers were assessed by bead-based assay.\n\nResultsSymptoms in PSTPIP1 mutation-positive PAPA patients overlapped with those of mutation-negative PAPA-like patients, but the former were younger at onset and had more arthritis. We found uniform elevation of total IL-18 in PAPA patients at a level approaching NLRC4-associated Macrophage Activation Syndrome (MAS) and well beyond Familial Mediterranean Fever. IL-18 elevation in PAPA patients sera persisted despite fluctuations in disease activity. IL-18 Binding Protein (IL-18BP) was modestly elevated, and as such PAPA patients had detectable free IL-18. PAPA patients did not develop MAS, and CXCL9 (an indicator of Interferon-gamma activity) was rarely elevated in their sera.\n\nConclusionPAPA syndrome is a refractory, and often disabling monogenic autoinflammatory disease associated with chronic elevation of serum IL-18, but not risk for MAS. This finding instructs our understanding of the origins of excess IL-18, its potential spectrum of pathogenic effects, and the possible role for IL-18 blockade in refractory PAPA syndrome.","Dose-dependent effect of nuts on blood pressure: a systematic review and meta-analysis of randomized controlled trials\nObjectiveTraditional pairwise meta-analyses indicated that nuts consumption can improve blood pressure. We iamed to determine the dose-dependent effect of nuts on systolic (SBP) and diastolic blood pressure (DBP) in adults.\n\nMethodsA systematic search was undertaken in PubMed, Scopus, and ISI Web of Science till March 2021. Randomized controlled trials (RCT) evaluating the effects of nuts on SBP and DBP in adults were included. We estimated change in blood pressure for each 20 g/d increment in nut consumption in each trial and then, calculated mean difference (MD) and 95%CI using a random-effects model. We estimated dose-dependent effect using a dose-response meta-analysis of differences in means. The certainty of evidence was rated using the GRADE instrument, with the minimal clinically important difference being considered 2 mmHg.\n\nResultsA total of 31 RCTs with 2784 participants were included. Each 20 g/d increase in nut consumption reduced SBP (MD: -0.50 mmHg, 95%CI: -0.79, -0.21; I2 = 12%, n = 31; GRADE = moderate certainty) and DBP (MD: -0.23 mmHg, 95%CI: -0.38, -0.08; I2 = 0%, n = 31; GRADE = moderate certainty). The effect of nuts on SBP was more evident in patients with type 2 diabetes (MD: -1.31, 95%CI: -2.55, -0.05; I2 = 31%, n = 6). The results were robust in the subgroup of trials with low risk of bias. Levels of SBP decreased proportionally with the increase in nuts consumption up to 40 g/d (MD40g/d: -1.60, 95%CI: -2.63, -0.58), and then appeared to plateau with a slight upward curve. A linear dose-dependent reduction was seen for DBP, with the greatest reduction at 80 g/d (MD80g/d: -0.80, 95%CI: -1.55, -0.04).\n\nConclusionsThe available evidence provides a good indication that nut consumption can result in a small improvement in blood pressure in adults. Well-designed trials are needed to confirm the findings in long term follow-up.","Patients Experiences of Using Smartphone Apps to Manage their Gestational Diabetes Diagnosis: A Systematic Review - protocol (version 1)\nBackgroundGestational diabetes is a strong predictor of type 2 diabetes onset. However, women who make healthy dietary and lifestyle choices can significantly reduce their risk. There is a need to understand the factors facilitating or preventing women from using smartphone apps that may encourage these behaviours.\n\nMethodsWe plan to conduct a systematic review of patient experiences when using mobile health applications to manage gestational diabetes. We will include primary studies of qualitative data around patient experiences of using these applications, as well as the barriers and facilitators to using technologies. We will search the following electronic databases: Medline, Embase, PsycINFO, Global Health, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), AMED and CINAHL and manually search the reference lists of included studies. We will include primary studies involving direct user interviews and where the results have been analysed using qualitative methods. To assess the quality of included studies, we will use the CASP qualitative research checklist.\n\nExpected resultsWe intend to use summary tables to report the characteristics of the study population, the overarching themes that emerged, and recommendations for research and practice.","The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: A Mendelian randomization study\nDespite early interest, the evidence linking fatty acids to cardiovascular diseases remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the aetiology of several cardiovascular disease endpoints in up to 1,153,768 European and 212,453 East Asian ancestry individuals. As instruments, we selected single nucleotide polymorphisms (SNP) mapping to genes with well-known roles in PUFA (i.e. FADS1/2 and ELOVL2) and MUFA (i.e. SCD) biosynthesis. Our findings suggest that higher PUFA biosynthesis rate (proxied by rs174576 near FADS1/2) is related to higher odds of multiple cardiovascular diseases, particularly ischemic stroke, peripheral artery disease and venous thromboembolism, whereas higher MUFA biosynthesis rate (proxied by rs603424 near SCD) is related to lower odds of coronary artery disease among Europeans. Results were unclear for East Asians as most effect estimates were imprecise. By triangulating multiple approaches (i.e. uni-/multi-variable Mendelian randomization, a phenome-wide scan, genetic colocalization and within-sibling analyses), our results are compatible with higher low- density lipoprotein (LDL)-cholesterol (and possibly glucose) being a downstream effect of higher PUFA biosynthesis rate. Our findings indicate that genetically-determined PUFA and MUFA biosynthesis are involved in the aetiology of cardiovascular diseases and suggest LDL-cholesterol as a potential mediating trait between PUFA biosynthesis and cardiovascular diseases risk.","Intramuscular SARS-CoV-2 vaccines elicit varying degrees of plasma and salivary antibody responses as compared to natural infection\nVaccination induced antibody and T-cell immune responses are important for systemic protection from COVID-19. Because SARS-CoV-2 infects and is transmitted by oral-pharyngeal mucosa, we wished to test mucosal antibodies elicited by natural infection or intramuscular vaccine injection. In a non-randomized observational study, we measured antibodies against the SARS-CoV-2 RBD in plasma and saliva from convalescent or vaccinated individuals and tested their neutralizing potential using a replication competent rVSV-eGFP-SARS-CoV-2. We found IgG and IgA anti-RBD antibodies as well as neutralizing activity in convalescent plasma and saliva. Two doses of mRNA vaccination (BNT162b2 or mRNA-1273) induced high levels of IgG anti-RBD in saliva, a subset of whom also had IgA, and significant neutralizing activity. We detected anti-RBD IgG and IgA with significant neutralizing potential in the plasma of single dose Ad26.COV2.S vaccinated individuals, and we detected slight amounts of anti-RBD antibodies in matched saliva. The role of salivary antibodies in protection against SARS-CoV-2 infection is unknown and merits further investigation. This study was not designed to, nor did it study the full kinetics of the antibody response or protection from infection, nor did it address variants of SARS-CoV-2.","Design of an optimal combination therapy with broadly neutralizing antibodies to suppress HIV-1\nBroadly neutralizing antibodies (bNAbs) are promising targets for vaccination and therapy against HIV. Passive infusions of bNAbs have shown promise in clinical trials as a potential alternative for anti-retroviral therapy. A key challenge for the potential clinical application of bnAbs is the suppression of viral escape, which is more effectively achieved with a combination of bNAbs. However, identifying an optimal bNAb cocktail is combinatorially complex. Here, we propose a computational approach to predict the efficacy of a bNAb therapy trial based on the population genetics of HIV escape, which we parametrize using high-throughput HIV sequence data from a cohort of untreated bNAb-naive patients. By quantifying the mutational target size and the fitness cost of HIV-1 escape from bNAbs, we reliably predict the distribution of rebound times in three clinical trials. Importantly, we show that early rebounds are dominated by the pre-treatment standing variation of HIV-1 populations, rather than spontaneous mutations during treatment. Lastly, we show that a cocktail of three bNAbs is necessary to suppress the chances of viral escape below 1%, and we predict the optimal composition of such a bNAb cocktail. Our results offer a rational design for bNAb therapy against HIV-1, and more generally show how genetic data could be used to predict treatment outcomes and design new approaches to pathogenic control.","Competitive fitness of emerging SARS-CoV-2 variants is linked to their Distinctiveness relative to preceding lineages from that region\nThe COVID-19 pandemic has seen the persistent emergence of fitter Variants of Concern (VOCs) that have successfully out-competed circulating strains, but the determinants of viral fitness remain unknown. Here we define Distinctiveness of SARS-CoV-2 sequences based on a proteome-wide comparison with all prior sequences from the same geographical region. From the perspective of viral evolution, Distinctiveness captures \"regional herd exposure\" and has the advantage over the canonical concept of mutation, which relies foremost on the reference ancestral sequence that is invariant over time. By assessing the correlation between Distinctiveness and change in prevalence for all circulating lineages in each region when a new lineage is introduced, we find that the relative Distinctiveness of emergent SARS-CoV-2 lineages is associated with their competitive fitness (Pearson r = 0.67). Further, by assessing the Delta variant in India versus Brazil, we show that the same lineage can have different Distinctiveness-contributing positions in different geographical regions depending on the other variants that previously circulated in those regions. Finally, analysis of Omicron lineages in India and USA shows the BA.1 and BA.2 sub-lineages have comparable distinctiveness, suggesting that they may have similar levels of competitive fitness. Overall, our study proposes that augmenting the ongoing surveillance of highly mutated variants with real-time assessment of Distinctiveness can aid in achieving robust pandemic preparedness.","Comprehensive Joint Modeling of First-Line Therapeutics in Non-Small Cell Lung Cancer\nFirst-line antiproliferatives for non-small cell lung cancer (NSCLC) have a relatively high failure rate due to high intrinsic resistance rates and acquired resistance rates to therapy. 57% patients are diagnosed in late-stage disease due to the tendency of early-stage NSCLC to be asymptomatic. For patients first diagnosed with metastatic disease the 5-year survival rate is approximately 5%. To help accelerate the development of novel therapeutics and computer-based tools for optimizing individual therapy, we have collated data from 11 different clinical trials in NSCLC and developed a semi-mechanistic, clinical model of NSCLC growth and pharmacodynamics relative to the various therapeutics represented in the study. In this study, we have produced extremely precise estimates of clinical parameters fundamental to cancer modeling such as the rate of acquired resistance to various pharmaceuticals, the relationship between drug concentration and rate of cancer cell death, as well as the fine temporal dynamics of anti-VEGF therapy. In the simulation sets documented in this study, we have used the model to make meaningful descriptions of efficacy gain in making bevacizumab-antiproliferative combination therapy sequential, over a series of days, rather than concurrent.","Effects of Diet on the Microbiome and Serum Metabolome of South Asian Infants at 1 Year\nDiet is known to affect the gut microbiome and metabolome composition in adults, but this has not been fully explored in infants. Dietary patterns from 1 year-old infants (n=182) from the South Asian Birth Cohort (START) study were compared to gut microbiome alpha and beta diversity and to taxa abundance differences. Diet - serum metabolite associations were identified using multivariate analysis (partial least squares-discriminant analysis, PLS-DA) and univariate analysis (T-Test). Dietary biomarkers identified from START were also examined in a separate cohort of white Caucasian infants (CHILD Cohort Study, n=82). Lastly, the association of diet with gut microbiome and serum biomarkers, considering maternal, perinatal and infant characteristics was investigated using multivariate forward stepwise regression. A dietary pattern characterized by breastfeeding, supplemented by formula and dairy was the strongest predictor of the gut microbiome that also differentiated the serum metabolome of infants. The formula and dairy dietary pattern was associated with a panel of circulating metabolites in both cohorts, including: S-methylcysteine, branched-chain/aromatic amino acids, lysine, dimethylglycine, and methionine. Breastfeeding status, the prominent feature of the dietary pattern, was also associated with a sub-set of serum metabolites in both cohorts. In START, this diet pattern was associated with the metabolites tryptophan betaine, 2-hydroxybutyric acid, tyrosine, phenylalanine, and trimethyl-N-oxide. In the CHILD Cohort Study(CHILD), breastfeeding status was associated with the metabolites aminooctanoic acid, 3-hydroxybutyric acid, and methyl-proline. The results of our study suggest that breastfeeding has the largest effect on the composition of the gut microbiome and the serum metabolome at 1 year, even when solid food diet and other covariates are considered.","A 6-mRNA host response whole-blood classifier trained using patients with non-COVID-19 viral infections accurately predicts severity of COVID-19\nBackgroundDetermining the severity of COVID-19 remains an unmet medical need. Our objective was to develop a blood-based host-gene-expression classifier for the severity of viral infections and validate it in independent data, including COVID-19.\n\nMethodsWe developed the classifier for the severity of viral infections and validated it in multiple viral infection settings including COVID-19. We used training data (N=705) from 21 retrospective transcriptomic clinical studies of influenza and other viral illnesses looking at a preselected panel of host immune response messenger RNAs.\n\nResultsWe selected 6 host RNAs and trained logistic regression classifier with a cross-validation area under curve of 0.90 for predicting 30-day mortality in viral illnesses. Next, in 1,417 samples across 21 independent retrospective cohorts the locked 6-RNA classifier had an area under curve of 0.91 for discriminating patients with severe vs. non-severe infection. Next, in independent cohorts of prospectively (N=97) and retrospectively (N=100) enrolled patients with confirmed COVID-19, the classifier had an area under curve of 0.89 and 0.87, respectively, for identifying patients with severe respiratory failure or 30-day mortality. Finally, we developed a loop-mediated isothermal gene expression assay for the 6-messenger-RNA panel to facilitate implementation as a rapid assay.\n\nConclusionsWith further study, the classifier could assist in the risk assessment of COVID-19 and other acute viral infections patients to determine severity and level of care, thereby improving patient management and reducing healthcare burden.","Two Data-Driven Approaches to Identifying the Spectrum of Problematic Opioid Use: A Pilot Study within a Chronic Pain Cohort\nASTRACTO_ST_ABSBackgroundC_ST_ABSAlthough electronic health records (EHR) have significant potential for the study of opioid use disorders (OUD), detecting OUD in clinical data is challenging. Models using EHR data to predict OUD often rely on case/control classifications focused on extreme opioid use. There is a need to expand this work to characterize the spectrum of problematic opioid use.\n\nMethodsUsing a large academic medical center database, we developed 2 datadriven methods of OUD detection: (1) a Comorbidity Score developed from a Phenome-Wide Association Study of phenotypes associated with OUD and (2) a Textbased Score using natural language processing to identify OUD-related concepts in clinical notes. We evaluated the performance of both scores against a manual review with correlation coefficients, Wilcoxon rank sum tests, and area-under the receiver operating characteristic curves. Records with the highest Comorbidity and Text-based scores were re-evaluated by manual review to explore discrepancies.\n\nResultsBoth the Comorbidity and Text-based OUD risk scores were significantly elevated in the patients judged as High Evidence for OUD in the manual review compared to those with No Evidence (p = 1.3E-5 and 1.3E-6, respectively). The risk scores were positively correlated with each other (rho = 0.52, p < 0.001). AUCs for the Comorbidity and Text-based scores were high (0.79 and 0.76, respectively). Follow-up manual review of discrepant findings revealed strengths of data-driven methods over manual review, and opportunities for improvement in risk assessment.\n\nConclusionRisk scores comprising comorbidities and text offer differing but synergistic insights into characterizing problematic opioid use. This pilot project establishes a foundation for more robust work in the future.","Markers of brain and endothelial Injury and inflammation are acutely and sex specifically regulated in SARS-CoV-2 infection\nObjectiveTo investigate brain injury markers (BIM), endothelial injury markers (EIM) and cytokine/chemokine (CC) markers of systemic inflammation in coronavirus disease 2019 (COVID-19) and across sex.\n\nMethodsPlasma samples from 57 subjects at <48 hours of COVID-19 hospitalization, 14 subjects at 3 months of COVID-19 hospitalization and 20 matched controls were interrogated for the levels of six BIMs - including GFAP, S100B, Syndecan-1, UCHLI, MAP2 and NSE, two EIMs - including sICAM1 and sVCAM1 and thirty-eight CCs. Statistical and bioinformatics methods were used to measure differences in the marker profiles across (a) COVID-19 vs controls and (b) men vs women.\n\nResultsThree BIMs: MAP2, NSE and S100B, two EIMs: sICAM1 and sVCAM1 and seven CCs: GRO IL10, sCD40L, IP10, IL1Ra, MCP1 and TNF were significantly (p<0.05) elevated in the COVID-19 cohort compared to controls. Two CCs: MDC and MIP1 were significantly lower in the COVID-19 cohort. Bioinformatics analysis reveal a stronger positive association between BIM/CC/EIMs in the COVID-19 cohort. Analysis across sex revealed that several BIMs and CCs including NSE, IL10, IL15 and IL8 were significantly (p<0.05) higher in men compared to women. Men also expressed a more robust BIM/ EIM/CC association profile compared to women. At 3 months, BIMs and CCs were not significantly different in the COVID-19 cohort compared to controls.\n\nConclusionThe acute elevation of BIMs, CCs, and EIMs and the robust associations among them at COVID-19 hospitalization suggest that brain injury is mediated by endotheliopathy and inflammation. Higher BIM and inflammatory markers in men additionally suggest that men are more susceptible to the risk compared to women.","Genome-wide association study identifies two new loci associated with anti-NMDAR encephalitis\nObjectiveTo investigate the genetic determinants of the most common type of antibody-mediated autoimmune encephalitis, anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis.\n\nMethodsWe performed a genome-wide association study in 178 patients with anti-NMDAR encephalitis and 590 healthy controls followed by a colocalization analysis to identify putatively causal genes.\n\nResultsWe identified two independent risk loci harboring genome-wide significant variants (P < 5 x 10-8, OR [≤] 2.2), one on chromosome 15, harboring only the LRRK1 gene, and one on chromosome 11 centered on the ACP2 and NR1H3 genes in a larger region of high linkage-disequilibrium. Colocalization signals with expression quantitative trait loci (eQTL) for different brain regions and immune cell types suggested ACP2, NR1H3, MADD, DDB2, and C11orf49 as putatively causal genes. The best candidate genes in each region are LRRK1, encoding Leucine-Rich Repeat Kinase 1, a protein involved in B-cell development, and NR1H3 liver x receptor alpha, a transcription factor whose activation inhibits inflammatory processes.\n\nConclusionThis study provides evidence for relevant genetic determinants of antibody-mediated autoimmune encephalitides outside the HLA-region. The results suggest that future studies with larger sample sizes will successfully identify additional genetic determinants and contribute to the elucidation of the pathomechanism.","Parental attitudes towards mandatory vaccination; a systematic review\nWhile mandatory vaccination schemes can increase vaccine uptake rates, they can also cause backlash among some parents. We conducted a systematic review investigating parental beliefs about vaccine mandates and factors associated with support for mandatory vaccination schemes. We searched Embase, Ovid MEDLINE, Global Health, APA PsycINFO and Web of Science from inception to 17th September 2020. Seventeen studies (five qualitative, twelve quantitative) were eligible for inclusion. We synthesised results of qualitative and quantitative studies separately. Studies were heterogeneous with regard to schemes investigated and factors investigated. Quantitative studies found little evidence for any factors being consistently associated with support for mandatory vaccination. Qualitative studies found that parents perceived mandatory vaccination schemes as an infringement of their rights and that they preferred universal, compared to targeted, schemes. To optimise engagement with existing child mandatory vaccination legislation, schemes should be designed with parental beliefs in mind.","Infrared spectroscopy enables rapid, robust, portable COVID-19 saliva screening based on pathophysiological response to SARS-CoV-2\nFourier-transform infrared (FTIR) spectroscopy provides a (bio)chemical snapshot of the sample, and was recently proposed for COVID-19 saliva screening in proof-of-concept cohort studies. As a step towards translation of this technology, we conducted controlled validation experiments in multiple biological systems. SARS-CoV-2 or UV-inactivated SARS-CoV-2 were used to infect Vero E6 cells in vitro, and K18-hACE2 mice in vivo. Potentially infectious culture supernatant or mouse oral lavage samples were treated with ethanol or Trizol to 75% (v/v) for attenuated total reflectance (ATR)-FTIR spectroscopy, or RT-PCR, respectively. The control condition, UV-inactivated SARS-CoV-2 elicited strong biochemical changes in culture supernatant/oral lavage despite lack of replication determined by RT-PCR or cell culture infectious dose 50%. Crucially, we show that active SARS-CoV-2 infection induced additional FTIR signals over the UV-inactivated SARS-CoV-2 infection, which correspond to innate immune response, aggregated proteins, and RNA. For human patient cohort prediction, we achieved high sensitivity of 93.48% on leave-on-out cross validation (n=104 participants) for predicting COVID-19 positivity using a partial least squares discriminant analysis model, in agreement with recent studies. However, COVID-19 patients negative on follow-up (RT-PCR on day of saliva sampling) were poorly predicted in this model. Importantly, COVID-19 vaccination did not lead to mis-classification of COVID-19 negatives. Meta-analysis revealed SARS-CoV-2 induced increase in Amide II band in all arms of this study and recent studies, indicative of altered {beta}-sheet structures in secreted proteins. In conclusion, ATR-FTIR is a robust, simple, portable method for COVID-19 saliva screening based on detection of pathophysiological responses to SARS-CoV-2.","Whole Genome Sequencing identifies novel structural variant in a large Indian family affected with X - linked agammaglobulinemia\nBackgroundX - linked agammaglobulinemia (XLA, OMIM #300755) is a primary immunodeficiency disorder caused by pathogenic variations in the BTK gene, characterized by failure of development and maturation of B lymphocytes. The estimated prevalence worldwide is 1 in 190,000 male births. Recently, genome sequencing has been widely used in difficult to diagnose and familial cases. We report a large Indian family suffering from XLA with five affected individuals.\n\nMethodsWe performed complete blood count, immunoglobulin assay, and lymphocyte subset analysis for all patients and analyzed Btk expression for one patient and his mother. Whole exome sequencing (WES) for four patients, and whole genome sequencing (WGS) for two patients have been performed. Carrier screening was done for 17 family members using Multiplex Ligation-dependent Probe Amplification (MLPA) and haplotype ancestry mapping using fineSTRUCTURE was performed.\n\nResultsAll patients had hypogammaglobulinemia and low CD19+ B cells. One patient who underwent Btk estimation had low expression and his mother showed a mosaic pattern. On structural variant analysis of WGS data, we found a novel large deletion of 5,296 bp at loci chrX:100,624,323-100,629,619 encompassing exons 3-5 of the BTK gene. Family screening revealed seven carriers for the deletion. Two patients had a successful HSCT. Haplotype mapping revealed mainly South Asian ancestry.\n\nConclusionWhole genome sequencing led to identification of the accurate genetic mutation which could help in early diagnosis leading to improved outcomes, prevention of permanent organ damage and improved quality of life, as well as enabling prenatal diagnosis.","A Novel de novo TP63 Mutation in WholeExome Sequencing of a Syrian Family with Oral Cleft and Ectrodactyly\nOral clefts and ectrodactyly are common, heterogeneous birth defects. We performed whole exome sequencing (WES) analysis in a Syrian family. The proband presented with both orofacial clefting and ectrodactyly. A paternal side second-degree relative with only an oral cleft was deceased and unavailable for analysis. Variant annotation, Mendelian inconsistencies, and novel variants in known cleft genes were examined. Candidate variants were validated using Sanger sequencing. Twentyeight candidate de novo events were identified, one of which is in a known oral cleft and ectrodactyly gene, TP63 (c.956G>T, p.Arg319Leu), and confirmed by Sanger sequencing. A triallelic SNV was also found in HLA-DRB5, which is similar to and overlaps the known oral cleft gene HLA-DRB1.\n\nTP63 mutations are associated with multiple autosomal dominant orofacial clefting and limb malformation disorders. The p.Arg319Leu mutation seen in this patient is de novo but also novel. A known mutation 1bp upstream (rs121908839, c.955C>T, p.Arg319Cys) causes ectrodactyly, providing evidence that mutating this codon is deleterious. It is unclear whether this patients mutation is responsible for the entire phenotype. Generation and characterization of tp63 knockout zebrafish showed necrosis and rupture of the head at 3 days postfertilization. The embryonic phenotype could not be rescued by injection of zebrafish or human mRNA. Further functional analysis is needed to determine what proportion of the phenotype is due to this mutation.","Improving the Diagnosis of SIBO Using an At-Home Handheld App Connected Breath Analysis Device (AIRE)\nINTRODUCTIONSmall Intestinal Bacterial Overgrowth (SIBO) is a common yet underdiagnosed condition. Lactulose hydrogen breath tests (LHBT) are typically used to detect SIBO; however, current breath testing methods require specialised, expensive equipment and technical support and are either done at a point-of-care facility and/or have to be mailed to a central laboratory. To address these issues a novel hand-held breath analyzer (AIRE(R), FoodMarble) was tested. The aims of this study were first, to perform a technical assessment of the AIRE device, second to compare the performance of the AIRE device against a commercially available mail-in LHBT kit using a zero-inflated negative binomial mixed effect model.\n\nMETHODSThree AIRE devices were tested with certified test gases covering a diagnostically meaningful range (hydrogen mixed with air at 3 ppm, 10 ppm and 50 ppm). For the clinical study, 36 patients suspected to have SIBO presenting to a tertiary level clinic were provided with an AIRE device and performed concurrent LHBTs at home with a mail-in LHBT kit.\n\nRESULTSThe overall average readings (mean {+/-} SD) for the AIRE devices tested at 3 ppm, 10 ppm and 50 ppm H2 were: 3.5 {+/-} 0.7 ppm; 10.7 {+/-} 1.1 ppm and 49.5 {+/-} 2.6 ppm respectively. The overall mean absolute error across the tested devices was 1.2 ppm. A significant positive correlation (r = 0.78, p < 0.001) was demonstrated between AIRE and mail-in kit H2 values.\n\nDISCUSSIONThe AIRE device is a compelling alternative to mail-in LHBT kits for the diagnosis of SIBO. The AIRE device may also offer advantages over other traditional breath testing methods.","Accurate and reproducible prediction of ICU readmissions\nReadmission in the intensive care unit (ICU) is associated with poor clinical outcomes and high costs. Traditional scoring methods to help clinicians deciding whether a patient is ready for discharge have failed to meet expectations, paving the way for machine learning based approaches. Freely available datasets such as MIMIC-III have served as benchmarking media to compare such tools. We used the OMOP-CDM version of MIMIC-III (MIMIC-OMOP) to train and evaluate a lightweight tree boosting method to predict readmission in ICU at different time points after discharge (3, 7 and 30 days), outperforming existing solutions with an AUROC of 0.805 for 3-days readmission.","Searching for prognostic biomarkers of Parkinson's Disease development in the Spanish EPIC cohort through a multiplatform metabolomics approach\nObjectiveThe lack of knowledge about the onset and progression of Parkinsons disease (PD) hampers its early diagnosis and treatment. Our aim was to determine the biochemical remodeling induced by PD in a really early and pre-symptomatic stage and unveiling early potential diagnostic biomarkers adopting a multiplatform (LC-MS, GC-MS, CE-MS) untargeted metabolomics approach.\n\nMethods41,437 healthy volunteers from the European Prospective Study on Nutrition and Cancer (EPIC)-Spain cohort were followed for around 15 years to ascertain incident PD. For this study, baseline pre-clinical plasma samples of 39 randomly selected individuals (46% females, 41- 69 years old) that developed PD (Pre-PD group) and the corresponding control group (n=39, 46% females, 41-69 years old) were analyzed. The metabolic differences were investigated by univariate and multivariate data analyses, followed by pathway-based metabolite analyses to obtain possible clues on biological functions.\n\nResultsOur results exposed significantly lower levels of seven free fatty acids in the pre-PD subjects, together with alterations in other metabolite classes. Our finding revealed alterations in fatty acids metabolism, mitochondrial dysfunction, oxidative stress, and gut-brain axis dysregulation.\n\nConclusionsAlthough the biological purpose of these events is still unknown, the mechanisms involved in the remodelling of the suggested metabolic pathways seem to appear long before the development of PD hallmarks. These findings might be considered as worthy potential markers whose alteration might lead to the development of PD hallmarks in the future. Consequently, this study is of inestimable value since this is the first study conducted with samples collected many years before the disease development.","The Association of Stay-at-Home Orders and the Spread of COVID-19 in Rural and Urban United States\nBackgroundThroughout the spring of 2020, stay-at-home orders were imposed to curb the spread of COVID-19. There is limited data on the effectiveness of stay-at-home orders, particularly in rural as compared to urban areas.\n\nObjectiveTo examine the association between stay-at-home order implementation and the incidence of COVID-19 in rural vs. urban counties.\n\nDesignInterrupted time series analysis using a mixed effects zero-inflated Poisson model.\n\nParticipants3,142 U.S. counties.\n\nInterventionsStay-at-home orders.\n\nMain MeasuresCOVID-19 daily incidence (primary) and mobility (secondary and intermediate measure of stay-at-home effectiveness)\n\nKey ResultsStay-at-home orders were implemented later (median March 30 vs. March 28) and were shorter (median 35 vs. 54 days) in rural than urban counties. Indoor mobility was, on average, 2.6-6.9% higher in rural than urban counties both during and after stay-at-home orders. Compared to the baseline (pre-stay-at-home) period, the number of new COVID-19 cases increased under stay-at-home by IRR 1.60 (95% CI, 1.57-1.64) in rural and 1.36 (95% CI, 1.30-1.42) in urban counties. For each day under stay-at-home orders, the number of new cases changed by a factor of 0.982 (95% CI 0.981-0.982) in rural and 0.952 (95% CI, 0.951-0.953) in urban counties compared to prior to stay-at-home. Each day after stay-at-home orders expired, the number of new cases changed by a factor of 0.995 (95% CI, 0.994-0.995) in rural and 0.997 (95% CI, 0.995-0.999) in urban counties compared to prior to stay-at-home.\n\nConclusionStay-at-home orders decreased mobility and slowed the spread of COVID-19, but less effectively in rural than in urban counties. This necessitates a critical reevaluation of how stay-at-home orders are designed, communicated, and implemented in rural areas.","Association of the medical therapy with beta-blockers or inhibitors of renin-angiotensin system with clinical outcomes in patients with mildly reduced left ventricular ejection fraction after acute myocardial infarction\nIn the era of the initial optimal interventional and medical therapy for acute myocardial infarction (AMI), a number of patients with mildly reduced left ventricular ejection fraction (EF) (41 - 49%) have been increasing. This observational study aimed to investigate the association between the medical therapy with oral beta-blockers or inhibitors of renin-angiotensin system (RAS) and 2-year clinical outcomes in patients with mildly reduced EF after AMI. Among patients enrolled in the Korea Acute Myocardial Infarction Registry-National Institute of Health, propensity-score matched patients who survived the initial attack and had mildly reduced EF were selected according to beta-blocker or RAS inhibitor therapy at discharge. Beta-blocker therapy at discharge was associated with lower 2-year major adverse cardiac events which was a composite of cardiac death, myocardial infarction, revascularization and re-hospitalization due to heart failure (8.7 vs. 12.8/100 patient-years; hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.50-0.93; P=0.015), and no significant interaction between EF [≤]45% and >45% was observed (Pinteraction=0.354). This association was mainly driven by lower myocardial infarction in patients with beta-blockers (HR 0.50; 95% CI 0.26-0.95; P=0.035). Inhibitors of RAS at discharge were associated with lower re-hospitalization due to heart failure (1.8 vs. 3.5/100 patient-years; HR 0.53; 95% CI 0.33-0.86; P=0.010) without a significant interaction between EF [≤]45% and >45% (Pinteraction=0.333). In patients with mildly reduced EF after AMI, the medical therapy with beta-blockers or RAS inhibitors at discharge was associated with better 2-year clinical outcomes.","Development of ADAF screening tool for emotional and coping problems in cancer patients\nPurposePsychological screening in patient with cancer is recommended by clinical guidelines, however most of scales have large number of items, difficulty detection and refer from routine consultations. The specific objective of the study was to develop and validate the ADAF screening for anxiety, depression and coping.\n\nMethods/PatientsCross-sectional, multicenter study performed in the medical and radiotherapy oncology services of 5 hospitals in Madrid, coordinated by the Medical Oncology Service of the Hospital Clinico San Carlos (CEIC n{o}19 / 265-E). To determine the psychometric properties, the ADAF screening questionnaire ADAF was administered, including 5 items (one related to anxiety symptoms, two related to depressive symptoms, one for helplessness coping and one for avoidance coping), and as a gold-standard the HADS and the MiniMAC. Intraclass correlation coefficients and receiver operating characteristic curves were performed. The p value <0.05 was considered significant.\n\nResultsA total of 186 patients completed the evaluation. The correlation coefficients were significant for all dimensions (Anxiety, Depression, Helplessness coping, and Avoidance Coping), with p <0.001. The statistical analysis of ROC curves suggests that the cut-off point for screening is equivalent to a score > 2 points (3 in the case of depression, having two items), with a sensitivity and specificity between 62 and 90%, depending on the item, and an area under the curve above 0.8 for the first 4 items.\n\nConclusionsADAF screening has adequate reliability, good sensitivity and specificity. This instrument is useful and easy to use to identify emotional and coping problems in cancer patients.","Analysis of cutoff point estimation for determining seropositivity in the context of SARS-CoV-2 infections\nIn this work will apply mixture models based on distributions from the SMSN family to antibody data against four SARS-CoV-2 virus antigens. Furthermore, since the true infection status of individuals is known a priori, performance measures will be calculated for the methods proposed for cutoff point estimation such as sensitivity, specificity and accuracy. The results of a simulation study will also be presented.","Public Covid-19 X-ray datasets and their impact on model bias - a systematic review of a significant problem\nComputer-aided-diagnosis for COVID-19 based on chest X-ray suffers from weak bias assessment and limited quality-control. Undetected bias induced by inappropriate use of datasets, and improper consideration of confounders prevents the translation of prediction models into clinical practice. This study provides a systematic evaluation of publicly available COVID-19 chest X-ray datasets, determining their potential use and evaluating potential sources of bias.\n\nOnly 5 out of 256 identified datasets met at least the criteria for proper assessment of risk of bias and could be analysed in detail. Remarkably almost all of the datasets utilised in 78 papers published in peer-reviewed journals, are not among these 5 datasets, thus leading to models with high risk of bias. This raises concerns about the suitability of such models for clinical use.\n\nThis systematic review highlights the limited description of datasets employed for modelling and aids researchers to select the most suitable datasets for their task.","Wastewater and surface monitoring to detect COVID-19 in elementary school settings: The Safer at School Early Alert project\nSchools are high-risk settings for SARS-CoV-2 transmission, but necessary for childrens educational and social-emotional wellbeing. While wastewater monitoring has been implemented to mitigate outbreak risk in universities and residential settings, its effectiveness in community K-12 sites is unknown. We implemented a wastewater and surface monitoring system to detect SARS-CoV-2 in nine elementary schools in San Diego County. Ninety-three percent of identified cases were associated with either a positive wastewater or surface sample; 67% were associated with a positive wastewater sample, and 40% were associated with a positive surface sample. The techniques we utilized allowed for near-complete genomic sequencing of wastewater and surface samples. Passive environmental surveillance can complement approaches that require individual consent, particularly in communities with limited access and/or high rates of testing hesitancy.\n\nOne sentence summaryPassive wastewater and surface environmental surveillance can identify up to 93% of on-campus COVID-19 cases in public elementary schools; positive samples can be sequenced to monitor for variants of concerns with neighborhood level resolution.","Genomic profiling defines variable clonal relatedness between invasive breast cancer and primary ductal carcinoma in situ\nPure ductal carcinoma in situ (DCIS) is being diagnosed more frequently through breast screening programmes and is associated with an increased risk of developing invasive breast cancer. We assessed the clonal relatedness of 143 cases of pure DCIS and their subsequent events using a combination of whole exome, targeted and copy number sequencing, supplemented by single cell analysis. Unexpectedly, 18% of all invasive events after DCIS were clonally unrelated to the primary DCIS. Single cell sequencing of selected pairs confirmed our findings. In contrast, synchronous DCIS and invasive disease (n=44) were almost always (93%) clonally related. This challenges the dogma that almost all invasive events after DCIS represent invasive transformation of the initial DCIS and suggests that DCIS could be an independent risk factor for developing invasive disease as well as a precursor lesion. Our findings support a paradigm shift that confirms a more complex role for DCIS than previously recognized, and that the future management of DCIS should take into account both the precursor and risk factor implications of this diagnosis.","Overcoming the pitfalls of NGS-based molecular diagnosis of Shwachman-Diamond syndrome\nPurposeShwachman-Diamond syndrome (SDS) is predominately caused by biallelic mutations in the SBDS gene and is characterized by exocrine pancreatic insufficiency, skeletal abnormalities and pancytopenia. Gene conversion between SBDS and its pseudogene SBDSP1 is the major cause. We established an efficient approach, HapICE, to infer the haplotype of SBDS based on short-read next-generation sequencing (NGS).\n\nMethodsHapICE based on the Expectation-Maximization algorithm was developed to detect variants in exon 2 of SBDS arising from gene conversion. We retrospectively analyzed two common pathogenic variants (c.183_184delinsCT and c.258+2T>C) in suspected SDS patients and compared the results with those from conventional NGS analysis.\n\nResultsIn 47 SDS high-risk individuals and 64 available parents, HapICE improved the diagnostic rate by 27.7% compared with conventional methods and revealed 100% (95% CI: 92.5%-100%) concordance with Sanger sequencing. In addition to eighteen patients having consistent genetic results by both methods, HapICE further reported 8 patients with more accurate variant detection and 13 cases with the c.183_184delinsCT variant missing by conventional methods. HapICE also showed better performance in screening for carrier and wild-type status.\n\nConclusionWe have developed a novel SBDS variant detection tool through regular NGS data that demonstrated precise variant detection performance in clinical scenarios.","A Novel Abnormality Annotation Database for COVID-19 Affected Frontal Lung X-rays\nPurposeTo advance the usage of CXRs as a viable solution for efficient COVID-19 diagnostics by providing large-scale annotations of the abnormalities in frontal CXRs in BIMCV-COVID19+ database, and to provide a robust evaluation mechanism to facilitate its usage.\n\nMaterials and MethodsWe provide the abnormality annotations in frontal CXRs by creating bounding boxes. The frontal CXRs are a part of the existing BIMCV-COVID19+ database. We also define four different protocols for robust evaluation of semantic segmentation and classification algorithms. Finally, we benchmark the defined protocols and report the results using popular deep learning models as a part of this study.\n\nResultsFor semantic segmentation, Mask-RCNN performs the best among all the models with a DICE score of 0.43 {+/-} 0.01. For classification, we observe that MobileNetv2 yields the best results for 2-class and 3-class classification. We also observe that deep models report a lower performance for classifying other classes apart from the COVID class.\n\nConclusionBy making the annotated data and protocols available to the scientific community, we aim to advance the usage of CXRs as a viable solution for efficient COVID-19 diagnostics. This large-scale data will be useful for ML algorithms and can be used for learning radiological patterns observed in COVID-19 patients. Further, the protocols will facilitate ML practitioners for unified large-scale evaluation of their algorithms.\n\nData Availability StatementThe data associated with this work is available here : Radiologists Annotations on COVID-19+ X-rays https://osf.io/b35xu/ via @OSFramework and http://covbase4all.igib.res.in/.","Masking significantly reduces, but does not eliminate COVID-19 infection in a spatial agent-based simulation of a University dormitory floor\nCOVID-ADAPT is a stochastic, discrete-space, agent-based simulation model of airborne infection and public health interventions, capable of modeling SARS-CoV-2 transmission. Using a map of a real university dormitory floor, the model simulates agents moving about and potentially infecting each other. Health interventions tested are vaccination and masking, including whether the solitary initial infectious agent was masked. Universal masking with N95 masks and 100% vaccination of susceptible people resulted in significantly lower prevalence after 3 weeks compared to all other scenarios, but still led to a substantial number of infections. Increased vaccination levels from 52% to 100% by itself did not result in a significant difference in prevalence due to symptomatic and asymptomatic breakthrough infections. These results suggest that vaccination alone is insufficient to stem outbreaks, and the best way to reduce COVID-19 infections is to ensure that all infectious people are masked. However, because asymptomatic infections are common, the only way to ensure this is universal masking, which also reduces prevalence by protecting susceptible individuals from infection. Universal masking is the best way forward, especially under threat of the Delta variant, to keep facilities open and safe for occupants, while minimizing the number of infections.","A Dynamic Bayesian Model for Identifying High-Mortality Risk in Hospitalized COVID-19 Patients\nIntroductionAs COVID-19 hospitalization rates remain high, there is an urgent need to identify prognostic factors to improve treatment. Our analysis, to our knowledge, is one of the first to quantify the risk associated with dynamic clinical measurements taken throughout the course of hospitalization.\n\nMethodsWe collected data for 553 PCR-positive COVID-19 patients admitted to hospital whose eventual outcomes were known. The data collected for the patients included demographics, comorbidities and laboratory values taken at admission and throughout the course of hospitalization. We trained multivariate Markov prognostic models to identify high-risk patients at admission along with a dynamic measure of risk incorporating time-dependent changes in patients laboratory values.\n\nResultsFrom the set of factors available upon admission, the Markov model determined that age >80 years, history of coronary artery disease and chronic obstructive pulmonary disease increased mortality risk. The lab values upon admission most associated with mortality included neutrophil percentage, RBC, RDW, protein levels, platelets count, albumin levels and MCHC. Incorporating dynamic changes in lab values throughout hospitalization lead to dramatic gains in the predictive accuracy of the model and indicated a catalogue of variables for determining high-risk patients including eosinophil percentage, WBC, platelets, pCO2, RDW, LUC count, alkaline phosphatase and albumin.\n\nConclusionOur prognostic model highlights the nuance of determining risk for COVID-19 patients and indicates that, rather than a single variable, a range of factors (at different points in hospitalization) are needed for effective risk stratification.","Can prognostic factors for indirect muscle injuries in elite football (soccer) players be identified using data from preseason screening? An exploratory analysis using routinely-collected periodic health examination records.\nThis study used periodic health examination (PHE) data from 134 outfield elite male football players, over 5 seasons (1st July 2013 to 19th May 2018). Univariable and multivariable logistic regression models were used to determine prognostic associations between 36 variables and time-loss, lower extremity index indirect muscle injuries (I-IMIs). Non-linear associations were explored using fractional polynomials. During 317 participant-seasons, 138 I-IMIs were recorded. Univariable associations were determined for previous calf indirect muscle injury (IMI) frequency (OR=1.80, 95% confidence interval (CI) = 1.09 to 2.97), hamstring IMI frequency (OR=1.56, 95% CI=1.17 to 2.09), if the most recent hamstring IMI occurred > 12 months but < 3 years prior to PHE (OR= 2.95, 95% CI = 1.51 to 5.73) and age (OR =1.12 per 1-year increase, 95% CI = 1.06 to 1.18). Multivariable analyses demonstrated that if a players most recent previous hamstring IMI was >12 months but <3 years prior to PHE (OR= 2.24, 95% CI = 1.11 to 4.53), then this was the only variable with added prognostic value over and above age (OR=1.12 per 1-year increase, 95%CI = 1.05 to 1.18). Allowing non-linear associations conferred no advantage over linear ones. Therefore, PHE has limited use for injury risk prediction.","Machine Learning Based Prediction of COVID-19 Mortality Suggests Repositioning of Anticancer Drug for Treating Severe Cases\nDespite available vaccinations COVID-19 case numbers around the world are still growing, and effective medications against severe cases are lacking. In this work, we developed a machine learning model which predicts mortality for COVID-19 patients using data from the multi-center Lean European Open Survey on SARS-CoV-2-infected patients (LEOSS) observational study (>100 active sites in Europe, primarily in Germany), resulting into an AUC of almost 80%. We showed that molecular mechanisms related to dementia, one of the relevant predictors in our model, intersect with those associated to COVID-19. Most notably, among these molecules was tyrosine kinase 2 (TYK2), a protein that has been patented as drug target in Alzheimers Disease but also genetically associated with severe COVID-19 outcomes. We experimentally verified that anti-cancer drugs Sorafenib and Regorafenib showed a clear anti-cytopathic effect in Caco2 and VERO-E6 cells and can thus be regarded as potential treatments against COVID-19. Altogether, our work demonstrates that interpretation of machine learning based risk models can point towards drug targets and new treatment options, which are strongly needed for COVID-19.","Wastewater surveillance for SARS-CoV-2 on college campuses: Initial efforts, lessons learned and research needs\nBackgroundWastewater surveillance for SARS-CoV-2 is an emerging approach to help identify the risk of a COVID-19 outbreak. This tool can contribute to public health surveillance at both community (wastewater treatment system) and institutional (e.g., colleges, prisons, nursing homes) scales.\n\nObjectivesThis research aims to understand the successes, challenges, and lessons learned from initial wastewater surveillance efforts at colleges and university systems to inform future research, development and implementation.\n\nMethodsThis paper presents the experiences of 25 college and university systems in the United States that monitored campus wastewater for SARS-CoV-2 during the fall 2020 academic period. We describe the broad range of approaches, findings, resource needs, and lessons learned from these initial efforts. These institutions range in size, social and political geographies, and include both public and private institutions.\n\nDiscussionOur analysis suggests that wastewater monitoring at colleges requires consideration of information needs, local sewage infrastructure, resources for sampling and analysis, college and community dynamics, approaches to interpretation and communication of results, and follow-up actions. Most colleges reported that a learning process of experimentation, evaluation, and adaptation was key to progress. This process requires ongoing collaboration among diverse stakeholders including decision-makers, researchers, faculty, facilities staff, students, and community members.","Irremediable psychiatric suffering in the context of physician assisted death: a Delphi-study\nBackgroundPatients with a psychiatric disorder (PPD) are eligible to request physician assisted death (PAD) in a small but growing number of jurisdictions, including the Netherlands and Belgium. For this request to be granted, most of these jurisdictions demand that the patient is competent in her request, and that the suffering experienced is unbearable and irremediable. Especially the criterion of irremediability is challenging to establish in patients with psychiatric disorders.\n\nAimsTo establish what criteria Dutch and Belgian experts agree to be essential in characterising irremediable psychiatric suffering (IPS) in the context of PAD.\n\nMethodA two round Delphi procedure among psychiatrists with relevant experience.\n\nResultsThirteen consensus-criteria were established: five diagnostic and eight treatment-related criteria. Diagnostically, the participants deem a narrative description and attention to contextual and systemic elements necessary. Also, a mandatory second opinion is required. The criteria concerning treatment show that extensive biopsychosocial treatment is needed, and the suffering must be present for several years. Finally, in the case of treatment refusal, the participants agree that there are limits to the number of diagnostic procedures or treatments a patient must undergo.\n\nConclusionsConsensus was found among a Dutch and Belgian expert group on essential criteria for establishing IPS in the context of PAD. These criteria can be used in clinical decision making and can inform future procedural demands and research.","LAMP-BEAC: Detection of SARS-CoV-2 RNA Using RT-LAMP and Molecular Beacons\nBackgroundRapid spread of SARS-CoV-2 has led to a global pandemic, resulting in the need for rapid assays to allow diagnosis and prevention of transmission. Reverse Transcription-Polymerase Chain Reaction (RT-PCR) provides a gold standard assay for SARS-CoV-2 RNA, but tests are expensive and supply chains are potentially fragile, motivating interest in additional assay methods. Reverse Transcription and Loop-Mediated Isothermal Amplification (RT-LAMP) provides an alternative that uses orthogonal and often less expensive reagents without the need for thermocyclers. The presence of SARS-CoV-2 RNA is typically detected using dyes to report bulk amplification of DNA; however, a common artifact is nonspecific DNA amplification, which complicates detection.\n\nResultsHere we describe the design and testing of molecular beacons, which allow sequence-specific detection of SARS-CoV-2 genomes with improved discrimination in simple reaction mixtures. To optimize beacons for RT-LAMP, multiple locked nucleic acid monomers were incorporated to elevate melting temperatures. We also show how beacons with different fluorescent labels can allow convenient multiplex detection of several amplicons in \"single pot\" reactions, including incorporation of a human RNA LAMP-BEAC assay to confirm sample integrity. Comparison of LAMP-BEAC and RT-qPCR on clinical saliva samples showed good concordance between assays. To facilitate implementation, we developed custom polymerases for LAMP-BEAC and inexpensive purification procedures, which also facilitates increasing sensitivity by increasing reaction volumes.\n\nConclusionsLAMP-BEAC thus provides an affordable and simple SARS-CoV-2 RNA assay suitable for population screening; implementation of the assay has allowed robust screening of thousands of saliva samples per week.","Feasibility of an online antigen self-testing strategy for SARS-CoV-2 addressed to health care and education professionals in Catalonia (Spain). The TESTAT- COVID Project\nWe aimed to implement a pilot intervention based on offering online COVID-19 selftest kits addressed to healthcare and education professionals in Spain during the peak of the 6th wave caused by Omicron variant. Kits were ordered online and sent by mail, participants answered an online acceptability/usability survey and uploaded the picture of results. 492 participants ordered a test, 304 uploaded the picture (61.8%). Eighteen positive cases were detected (5.9%). 92.2% were satisfied/very satisfied with the intervention; and 92.5% found performing the test easy/very easy. We demonstrated that implementing online COVID-19 self-testing in schools and healthcare settings in Spain is feasible.\n\nKey findingsO_LIWe implemented a pilot intervention based on offering online COVID-19 selftest kits in Spain.\nC_LIO_LIWe demonstrated the feasibility of the intervention during the peak of the 6th wave caused by Omicron variant.\nC_LIO_LIThe intervention counted with high acceptability among healthcare and education professionals in Spain.\nC_LIO_LIOur results may contribute to define screening strategies addressed to key populations, particularly during peaks of high community transmission of SARS-CoV-2.\nC_LI","Exploring potential causal genes for uterine leiomyomas: A summary data-based Mendelian randomization and FUMA analysis\nObjectiveTo explore potential causal genetic variants and genes underlying the pathogenesis of uterine leiomyomas (ULs).\n\nMethodsWe conducted the summary data-based Mendelian randomization (SMR) analysis and performed functional mapping and annotation using FUMA to examine genetic variants and genes that are potentially involved in the pathogenies of ULs.\n\nBoth analyses used summarized data of a recent genome-wide association study (GWAS) on ULs, which has a total sample size of 244,324 (20,406 cases and 223,918 controls). For the SMR analysis, we performed separate analysis using CAGE and GTEx eQTL data.\n\nResultsUsing the CAGE eQTL data, our SMR analysis identified 13 probes tagging 10 unique genes that were pleiotropically/potentially causally associated with ULs, with the top three probes being ILMN_1675156 (tagging CDC42, PSMR=8.03x10-9), ILMN_1705330 (tagging CDC42, PSMR=1.02x10-7) and ILMN_2343048 (tagging ABCB9, PSMR=9.37x10-7). Using GTEx eQTL data, our SMR analysis did not identify any significant genes after correction for multiple testing. FUMA analysis identified 106 independent SNPs, 24 genomic loci and 137 genes that are potentially involved in the pathogenesis of ULs, seven of which were also identified by the SMR analysis.\n\nConclusionsWe identified many genetic variants, genes, and genomic loci that are potentially involved in the pathogenesis of ULs. More studies are needed to explore the exact underlying mechanisms in the etiology of ULs.","Assessing the nationwide impact of COVID-19 mitigation policies on the transmission rate of SARS-CoV-2 in Brazil\nCOVID-19 is now identified in almost all countries in the world, with poorer regions being particularly more disadvantaged to efficiently mitigate the impacts of the pandemic. In the absence of efficient therapeutics or vaccines, control strategies are currently based on non-pharmaceutical interventions, comprising changes in population behavior and governmental interventions, among which the prohibition of mass gatherings, closure of non-essential establishments, quarantine and movement restrictions. In this work we analyzed the effects of 707 published governmental interventions, and population adherence thereof, on the dynamics of COVID-19 cases across all 27 Brazilian states, with emphasis on state capitals and remaining inland cities. A generalized SEIR (Susceptible, Exposed, Infected and Removed) model with a time-varying transmission rate (TR), that considers transmission by asymptomatic individuals, is presented. We analyze the effect of both the extent of enforced measures across Brazilian states and population movement on the changes in the TR and effective reproduction number. The social mobility reduction index, a measure of population movement, together with the stringency index, adapted to incorporate the degree of restrictions imposed by governmental regulations, were used in conjunction to quantify and compare the effects of varying degrees of policy strictness across Brazilian states. Our results show that population adherence to social distance recommendations plays an important role for the effectiveness of interventions and represents a major challenge to the control of COVID-19 in low- and middle-income countries.","A high content microscopy-based platform for detecting antibodies to the nucleocapsid, spike and membrane proteins of SARS-CoV-2\nThe strong humoral immune response produced against the SARS-CoV-2 nucleocapsid (N) and spike (S) proteins has underpinned serological testing but the prevalence of antibody responses to other SARS-CoV-2 proteins, which may be of use as further serological markers, is still unclear. Cell-based serological screening platforms can fulfil a crucial niche in the identification of antibodies which recognise more complex folded epitopes or those incorporating post-translation modifications which may be undetectable by other methods used to investigate the antigenicity of the SARS-CoV-2 proteome. Here, we employed automated high content immunofluorescence microscopy (AHCIM) to assess the viability of such an approach as a method capable of assaying humoral immune responses against full length SARS-CoV-2 proteins in their native cellular state. We first demonstrate that AHCIM provides high sensitivity and specificity in the detection of SARS-CoV-2 N and S IgG. Assessing the prevalence of antibody responses to the SARS-CoV-2 structural membrane protein (M), we further find that 85% of COVID-19 patients within our sample set developed detectable M IgG responses (M sensitivity 85%, N sensitivity 93%, combined N + M sensitivity 95%). The identification of M as a serological marker of high prevalence may be of value in detecting additional COVID-19 cases during the era of mass SARS-CoV-2 vaccinations, where serological screening for SARS CoV-2 infections in vaccinated individuals is dependent on detection of antibodies against N. These findings highlight the advantages of using cell-based systems as serological screening platforms and raise the possibility of using M as a widespread serological marker alongside N and S.","Cost effective sequencing enables longitudinal profiling of clonal hematopoiesis\nClonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of mutant hematopoietic stem cells, confers risk for multiple diseases of aging including hematologic cancer and cardiovascular disease. Whole-exome or genome sequencing can detect CHIP, but due to its high cost, most population studies have been cross-sectional, sequencing only a single timepoint. Here we describe a cost-effective sequencing assay for detecting CHIP. We validate this technology on a set of 548 longitudinal and multi-timepoint samples from 182 participants in the Womens Health Initiative cohort over median 16 years, including 85 participants with [≥]3 timepoints assayed. The majority (52.1%) of clonal mutations expanded over time (with a median doubling period of 7.43 years), with the others remaining static or decreasing in size in the absence of any cytotoxic therapy. This assay provides a cost-effective and sensitive platform for investigating the associations between CHIP dynamics and health outcomes at a biobank scale.","Expert Opinion on COVID-19 Vaccination and the Use of Cladribine Tablets in Clinical Practice\nBackgroundGaps in current evidence and guidance leave clinicians with unanswered questions on the use of cladribine tablets for the treatment of multiple sclerosis (MS) in the era of the COVID-19 pandemic, in particular relating to COVID-19 vaccination.\n\nObjectiveWe describe a consensus-based program led by international MS experts with the aim of supplementing current guidelines and treatment labels by providing timely recommendations relating to COVID-19 vaccination and the use of cladribine tablets in clinical practice.\n\nMethodsA steering committee (SC) of 10 international MS experts identified seven clinical questions to answer concerning the use of cladribine tablets and COVID-19 vaccination, which addressed issues relating to patient selection, timing and efficacy, and safety. Clinical recommendations to address each question were drafted using available evidence combined with expert opinion from the SC. An extended faculty of 28 MS experts, representing 19 countries, in addition to the 10 SC members, voted on the recommendations. Consensus on recommendations was achieved when [≥]75% of respondents expressed an agreement score of 7-9, on a 9-point scale.\n\nResultsConsensus was achieved on all 13 recommendations. Clinical recommendations are provided on whether all patients with MS receiving cladribine tablets should be vaccinated against COVID-19, and whether they should be prioritized; the timing of vaccination around dosing of cladribine tablets (i.e., before and after a treatment course); and the safety of COVID-19 vaccination for these patients.\n\nConclusionsThese expert recommendations provide timely guidance on COVID-19 vaccination in patients receiving cladribine tablets, which is relevant to everyday clinical practice.","COVID-19 Vaccine Efficacy in a Diverse Urban Healthcare Worker Population\nObjectiveTo investigate COVID-19 vaccine efficacy (VE) among healthcare workers (HCWs) in an ethnically diverse community healthcare system, during its initial immunization campaign.\n\nMethodsHCWs of the system were retrospectively included from the beginning of a COVID-19 vaccination program (December 16, 2020) until March 31, 2021. Those with a prior COVID-19 infection before December 15 were excluded. The Occupational Health department of the system ran a COVID-19 screening and testing referral program for workers, consistently throughout the study period. A master database had been established and updated comprising of the demographics, COVID-19 PCR assays, and vaccinations of each HCW. Andersen-Gill extension of the Cox models were built to estimate the VE of fully/partially vaccinated person-days at risk.\n\nResultsAmong the 4317 eligible HCWs, 3249 (75%) received any vaccination during the study period. Vaccinated HCWs were older, less likely to be Black/African American, Hispanic/Latino or identify as two or more races, and more likely to be medical providers. After adjusting for age, sex, race, and the statewide background incidence at the time of vaccination, we observed a VE of 80.2% (95% CI: 57.5-90.8%) for [greater double equals]14 days after the first dose of Pfizer/Moderna, and 95.5% (95% CI: 88.2-98.3%) among those fully vaccinated (i.e. [greater double equals]14 days after the second dose of Pfizer/Moderna or the single dose of J&J/Janssen).\n\nConclusionCOVID-19 vaccine effectiveness in the real world is promising, and these data in concert with culturally appropriate may decrease vaccine hesitancy.","Metabolomics and a Breath Sensor Identify Acetone as a Biomarker for Heart Failure\nBackgroundMultiomics delivers more biological insight than targeted investigations. We applied multiomics to patients with heart failure with reduced ejection fraction (HFrEF).\n\nMethods46 patients with HFrEF and 20 controls underwent metabolomic profiling, including liquid/gas chromatography mass spectrometry (LCMS/GCMS) and solid-phase microextraction (SPME) volatilomics in plasma and urine. HFrEF was defined using left ventricular global longitudinal strain, ejection fraction and NTproBNP. A consumer breath acetone (BrACE) sensor validated results in n=73.\n\nResults28 metabolites were identified by GCMS, 35 by LCMS and 4 volatiles by SPME in plasma and urine. Alanine, aspartate and glutamate, citric acid cycle, arginine biosynthesis, glyoxylate and dicarboxylate metabolism were altered in HFrEF. Plasma acetone correlated with NT-proBNP (r = 0.59, 95% CI 0.4 to 0.7), 2-oxovaleric and cis-aconitic acid, involved with ketone metabolism and mitochondrial energetics. BrACE> 1.5 ppm discriminated HF from other cardiac pathology (AUC 0.8, 95% CI 0.61 to 0.92, P < 0.0001).\n\nConclusionBreath acetone discriminated HFrEF from other cardiac pathology using a consumer sensor, but was not cardiac specific.","Genetic liability for substance use associated with medical comorbidities in electronic health records of African- and European-ancestry individuals\nPolygenic risk scores (PRS) represent an individuals summed genetic risk for a trait and can serve as biomarkers for disease. Less is known about the utility of PRS as a means to quantify genetic risk for substance use disorders (SUDs) than for many other traits. Nonetheless, the growth of large, electronic health record-based biobanks makes it possible to evaluate the association of SUD PRS with other traits. We calculated PRS for smoking initiation, alcohol use disorder (AUD), and opioid use disorder (OUD) using summary statistics from the Million Veteran Program sample. We then tested the association of each PRS with its primary phenotype in the Penn Medicine BioBank (PMBB) using all available genotyped participants of African or European ancestry (AFR and EUR, respectively) (N=18,612). Finally, we conducted phenome-wide association analyses (PheWAS) separately by ancestry and sex to test for associations across disease categories. Tobacco use disorder was the most common SUD in the PMBB, followed by AUD and OUD, consistent with the population prevalence of these disorders. All PRS were associated with their primary phenotype in both ancestry groups. PheWAS results yielded cross-trait associations across multiple domains, including psychiatric disorders and medical conditions. SUD PRS were associated with their primary phenotypes, however they are not yet predictive enough to be useful diagnostically. The cross-trait associations of the SUD PRS are indicative of a broader genetic liability. Future work should extend findings to additional population groups and for other substances of abuse.","Development and validation of a multiple-choice question-based delirium care knowledge quiz for critical care nurses\nAimsTo develop and psychometrically test a multiple choice questions (MCQs)-based quiz of delirium care knowledge for critical care nurses.\n\nDesignInstrument development and psychometric evaluation study.\n\nMethodsThe development and validation process including two phases. Phase I focused on the quiz development, conducted by the following steps: (1) generated initial 20-item pool; (2) examined content validity and (3) face validity; (4) conducted pilot testing, data were collected from 217 critical care nurses via online survey during 01 October to 07 November, 2020; (5) performed item analysis and eliminated items based on the item difficulty and discrimination indices. The MCQs quiz was finalised through the development process. Then, phases II emphasised the quiz validation, to estimate the internal consistency, split-half and test-retest reliability, and construct validity using parallel analysis with the exploratory factor analysis (EFA).\n\nResultsA final 16-item MCQs quiz was emerged from the item analysis. The Kuder- Richardson Formula 20 coefficient for the overall quiz showed good internal consistency (0.85), and the intraclass correlation coefficient with a 30-day interval also indicated that the questionnaire had satisfactory stability (0.96). The EFA confirmed appropriate construct validity for the quiz, four factors could explain the total variance of 60.87%.\n\nConclusionThis study developed the first MCQs quiz for delirium care knowledge and it is a reliable and valid tool that can be implemented to assess the level of delirium care knowledge.\n\nImpactThis study offers an evidence-based quiz designed for future research and education purposes in delirium care that has significant implications for knowledge test by using MCQs in clinical practice.","Passive Detection of COVID-19 with Wearable Sensors and Explainable Machine Learning Algorithms\nIndividual smartwatch or fitness band sensor data in the setting of COVID-19 has shown promise to identify symptomatic and pre-symptomatic infection or the need for hospitalization, correlations between peripheral temperature and self-reported fever, and an association between changes in heart-rate-variability and infection. In our study, a total of 38,911 individuals (61% female, 15% over 65) have been enrolled between March 25, 2020 and April 3, 2021, with 1,118 reported testing positive and 7,032 negative for COVID-19 by nasopharyngeal PCR swab test. We propose an explainable gradient boosting prediction model based on decision trees for the detection of COVID-19 infection that can adapt to the absence of self-reported symptoms and to the available sensor data, and that can explain the importance of each feature and the post-test-behavior for the individuals. We tested it in a cohort of symptomatic individuals who exhibited an AUC of 0.83 [0.81-0.85], or AUC=0.78 [0.75-0.80] when considering only data before the test date, outperforming state-of-the-art algorithm in these conditions. The analysis of all individuals (including asymptomatic and pre-symptomatic) when self-reported symptoms were excluded provided an AUC of 0.78 [0.76-0.79], or AUC of 0.70 [0.69-0.72] when considering only data before the test date. Extending the use of predictive algorithms for detection of COVID-19 infection based only on passively monitored data from any device, we showed that it is possible to scale up this platform and apply the algorithm in other settings where self-reported symptoms can not be collected.","Low CD4/CD8 ratio predicts cancer risk among adults with HIV\nBackgroundIndependent of CD4 cell count, low CD4/CD8 ratio in people with HIV (PWH) is associated with deleterious immune senescence, activation, and inflammation, which may contribute to carcinogenesis and excess cancer risk. We examined whether low CD4/CD8 ratios predicted cancer among PWH in the USA and Canada.\n\nMethodsWe examined all cancer-free PWH with one or more CD4/CD8 values from NA-ACCORD observational cohorts with validated cancer diagnoses between 1998-2016. We evaluated the association between time-lagged CD4/CD8 ratio and risk of specific cancers in multivariable, time-updated Cox proportional hazard models using restricted cubic spines.\n\nModels were adjusted for age, sex, race/ethnicity, hepatitis C virus, and time-updated CD4 cell count, HIV RNA, and history of AIDS-defining illness.\n\nResultsAmong 83,893 PWH, there were 5,628 incident cancers, including lung cancer (n=755), Kaposi sarcoma (KS, n=501), non-Hodgkin lymphoma (NHL, n=497), and anal cancer (n=439). Median age at cohort entry was 43 years, 87% were male, and 43% were white. Overall median six-month lagged CD4/CD8 ratio was 0.52 (interquartile range: 0.30-0.82). Compared with six-month lagged CD4/CD8=0.80, CD4/CD8=0.30 was associated with increased risk of any incident cancer (adjusted hazard ratio = 1.24 [95% confidence interval: 1.14-1.35]). CD4/CD8 ratio was also inversely associated with NHL, KS, lung cancer, anal cancer, and colorectal cancer in adjusted analyses (all p<0.05). Results were similar using 12-, 18-, and 24-month lagged CD4/CD8 values.\n\nConclusionsLow CD4/CD8 ratio up to 24 months prior to cancer diagnosis was independently associated with increased cancer risk in PWH and may serve as a clinical biomarker.","Distinct patterns of treatment response using the Early Start Denver Model with young children with autism spectrum disorder: a cluster analysis\nEvidence-based, early intervention significantly improves developmental outcome in young children with autism. Nonetheless, there is high interindividual heterogeneity in developmental trajectories during the therapy. It is currently not possible to predict a childs developmental outcome after receiving an early intervention based on his skills and symptoms at baseline. In this study, we analyze developmental trajectories of preschoolers with autism who received 2 years of intervention using the Early Start Denver Model (ESDM) approach in Geneva, Switzerland (n = 47). Our aim was to identify early predictors of response to treatment. We applied a cluster analysis to distinguish between 3 subgroups based on their cognitive level at intake, and rates of cognitive change over the course of treatment. The first subgroup of children only had a mild cognitive delay at intake, and nearly no cognitive delay by the end of treatment (Higher Cognitive at baseline: HC). The children in the two other subgroups all presented with severe cognitive delay at baseline, however, they had two very different patterns of response to treatment. The majority significantly improved developmental scores within their first year of intervention (Optimal Responders: OptR). Whereas a minority of children showed little to no improvement over the course of treatment (Minimal Responders: MinR). Our findings suggest that children who end up having an optimal two-year treatment outcome show rapid developmental improvement. Inversely, less significant progress by the sixth month of intervention may predict a less optimal response to treatment.","Evaluation of SIGLEC1 in the diagnosis of suspected systemic lupus erythematosus\nObjectivesTo evaluate and compare the diagnostic accuracy of SIGLEC1, a surrogate marker of type I IFN, with established biomarkers in an inception cohort of systemic lupus erythematosus (SLE).\n\nMethodsSIGLEC1 was analysed by flow cytometry in 232 patients referred to our institution with suspected SLE between October 2015 and September 2020.\n\nResultsSLE was confirmed in 76 of 232 patients (32.8%) according to the 2019 EULAR/ACR classification criteria and their SIGLEC1 values were significantly higher compared to patients without SLE (p<0.0001). A sensitivity of 98.7 %, a specificity of 82.1 %, a negative predictive value (NPV) of 99.2 % and a positive predictive value (PPV) of 72.8 % were calculated for SIGLEC1. Adjusted to the highest reported prevalence of SLE, the NPV and PPV were > 99.9 % and 0.1 %, respectively. Using ROC analysis and Delong testing, the area under the curve (AUC) for SIGLEC1 (AUC=0.95) was significantly higher than for ANA (AUC=0.88, p=0.031), C3 (AUC=0.83, p=0.001) and C4 (AUC=0.83, p=0.002) but not for anti-dsDNA antibodies (AUC=0.90, p=0.163).\n\nConclusionIFN-I pathway activation is detectable in almost all newly diagnosed SLE patients. Thus, a negative test result for SIGLEC1 is powerful to exclude SLE in suspected cases.","Partial recovery of amblyopia following fellow eye ischemic optic neuropathy\nBackgroundRecovery from amblyopia in adulthood following fellow eye (FE) vision loss is a well-known phenomenon. Incidence of recovery varies widely following different FE pathologies and rate of recovery following FE ischemic optic neuropathy (ION) has not been examined. We aimed to determine frequency and degree of improvement in amblyopic eye (AE) visual function following ION in the FE.\n\nMethodsWe performed a retrospective chart review of patients between 2007-2021 confirmed to have amblyopia and ischemic optic neuropathy in different eyes. Patients with unstable ocular pathology potentially limiting vision were excluded. We compared best-corrected visual acuity (VA) in each eye before and after FE ION over time. For patients with available data, we examined change in perimetric performance over time.\n\nResultsAmong the 12 patients who met inclusion criteria (mean age 67{+/-}8 years), 9 (75%) improved [≥]1 line and 2 (17%) improved [≥]3 lines. Median time from ION symptom onset to maximal improvement was 6 months (range: 2-101 months). Reliable perimetric data were available for 6 patients. Mean sensitivity improved in the amblyopic eye for all patients, with a mean improvement of 1.9{+/-}1.1 dB. There was no correspondence between foci of ION-related field loss and gains in field sensitivity in the AE.\n\nConclusionA high proportion of patients with amblyopia and contralateral ION experience improvement in their amblyopic eye. Modest gains in perimetric sensitivity in the AE may accompany FE ION. These findings support the view that residual plasticity in the adult visual cortex can be tapped to support functional improvement in amblyopia.","Donor race has no role in predicting allograft and patient survival among kidney transplant recipients\nA heated debate in creatinine-based estimated glomerular filtration rate (eGFR) calculation is the inclusion of race alongside biological factors, such as age and gender. Similarly, the race variable was included in the calculation of the Kidney Donor Risk Index (KDRI) as deceased donor kidneys from black donors have historically been shown to be associated with lower allograft or patient survival. Given the current climate of uncertainty with the use of race in nephrology, we sought to answer the question of whether removing the donor race variable from the KDRI would alter its validity to assess allograft and patient survival. Our modeling and analysis showed that removing donor race from the original KDRI did not alter the overall model predictability of allograft failure or patient mortality. Clinical risk factors included in the KDRI have largely accounted for differential risk between black and other donors. Adding donor race into the KDRI only shifts how risk is attributed to these clinical risk factors, without yielding better prediction of outcomes than the model without race.","Transcriptional patterns of coexpression across autism risk genes converge on established and novel signatures of neurodevelopment\nAutism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and communication. Protein function altering variants in many genes have been shown to contribute to ASD risk; however, understanding the biological convergence across so many genes has been difficult. Here, we demonstrate that coexpression patterns from human post-mortem brain samples (N=993) are significantly correlated with the transcriptional consequences of CRISPR perturbations (gene editing, interference and activation) of 15 neurodevelopmental genes in neuronal cell models. We find that across 70 ASD risk genes, there is significant tissue-specific transcriptional convergence that implicates synaptic pathways. We further show that the degree of convergence is significantly correlated with the level of association to ASD from sequencing studies (rho = -0.14, P = 4.75x10-63) as well as differential expression from transcription studies in post-mortem ASD brains (rho = -0.22, P = 3.62x10-41). After removing genes with minimal evidence of association with ASD, the remaining positively convergent genes are intolerant to mutation, have shorter coding lengths and are enriched for genes with suggestive evidence of contribution to ASD. These results indicate that leveraging convergent coexpression can identify novel ASD risk genes that are more likely to be underpowered and therefore missed by current large-scale sequencing studies. This work ultimately provides a simple approach to functionally proxy CRISPR perturbation, demonstrates significant context-specific transcriptional convergence among known ASD risk genes, and proposes several novel ASD risk gene candidates.","#AstraZeneca vaccine disinformation on Twitter\nWe analyzed 50,080 tweets about # AstraZeneca in English from 2021. We found that the news most common in the frequently retweeted tweets abound in negative information, and in many cases come from media sources well-known for disinformation. Also, we found that RT, a Russian state-sponsored news website, as well as Al Arabiya, a Saudi-owned news website, are frequently retweeted with information about the vaccine. Our analysis identified large coordination networks involved in political astroturfing and vaccine diplomacy in South Asia but also vaccine advocacy networks associated with European Commission employees. Our results show that Twitter discourse about # AstraZeneca is filled with disinformation and bad press, and may be distributed not only organically by anti-vaxxer activists, but also systematically by professional sources.\n\nHighlightsO_LIMost commonly retweeted media news links abound in negative information\nC_LIO_LIWell established disinformation media sources are retweeted more\nC_LIO_LIState coordinated networks are active in # AstraZeneca astroturfing\nC_LI","Patients at risk of pulmonary fibrosis Post Covid-19: Epidemiology, pulmonary sequelaes and humoral response\nBackgroundThe COVID-19 pandemic is one of the greatest public health problems. Our aims were to describe epidemiological characteristics, know the amount of protective antibodies and their permanence after a COVID-19 primary infection in patients with risk of pulmonary fibrosis.\n\nMethodsDescriptive epidemiological and follow-up study of the humoral response in patients at risk of pulmonary fibrosis Post-Covid-19 hospitalized, between March and October 2020, and who were followed up for a one year after hospital discharge.\n\nResults72 patients participated in the study, 52 showed pre-existing chronic comorbidities. COVID-19 clinical severity was rated in 6% mild, 58% as moderate and 36% as severe. After a year of follow-up, the forty percent had pulmonary sequelae, the most frequent (20%) was mild pulmonary fibrosis. Any case of reinfection was detected. All patients presented RBD IgG antibodies and 88% presented IgA antibodies after 8-9 months. The amount of RBD IgG was similar at 4-5 and 8-9 months post-Covid. There was no difference when level of RBD IgG according to the severity of the COVID-19 (p=0.441, p=0.594).\n\nConclusionsMild pulmonary fibrosis sequelae is exceptional but was detected in a high percentage. The amount of RBD IgG is maintained throughout the convalescent phase and seems to protect against new reinfections despite of emerging viral variants. However, seems not predict the developed or not of pulmonary fibrosis.","Asymptomatic carriers of the p.A53T SNCA mutation: data from the PPMI study\nIntroductionThere has been great interest in the prodromal phase of Parkinsons disease (PD), especially in subjects who are asymptomatic carriers of genetic mutations leading to PD because of the high risk to convert to PD. The objective of the present study was to assess non motor characteristics of asymptomatic p.A53T mutation carriers (A53T-AC) compared with healthy controls (HC).\n\nMethodsWe compared 12 A53T-AC with 36 matched HC enrolled into in the Parkinsons Progression Markers Initiative (PPMI) study. Baseline data extracted from the PPMI database, contained demographics and non-motor symptoms (e.g. the Montreal Cognitive Assessment (MOCA) for cognition, the University of Pennsylvania Smell Identification Test (UPSIT) for olfaction, MDS-UPDRS I etc.)\n\nResultsThe mean UPSIT score was lower in A53T-AC vs HC (p =0.000). MoCA test showed a trend towards lower scores in A53T AC. We found a significant positive correlation between UPSIT score and MOCA in A53T-AC (rs = 0,68, p=0,021) but not in HC. Total scores for MDS-UPDRS I did not differ between the groups but the subscore of anxiety was more prevalent in A53T-AC.\n\nConclusionThe more affected olfaction in A53T-AC may indicate that olfactory function is affected quite early in A53T carriers. The strong positive correlation between UPSIT and MOCA in the A53T-AC group may indicate that cognitive dysfunction and olfactory impairment progress alongside, prior to nigrostriatal degeneration. Anxiety was also more prevalent in A53T-AC and may represent an additional prodromal feature in this group of subjects.","Development of an explicit and implicit knowledge identification tool for the analysis of the decision-making process of traditional Asian medicine doctors\nBackground and objectivesWhile pattern identification (PI) is an essential process for diagnosis and treatment in traditional Asian medicine (TAM), it is difficult to objectify since it relies heavily on implicit knowledge. Here, we propose a machine learning-based analysis tool to objectify and evaluate the clinical decision-making process of PI in terms of explicit and implicit knowledge.\n\nMethodsClinical data for the development of the analysis tool were collected using a questionnaire administered to allergic rhinitis (AR) patients and the diagnosis and prescription results of TAM doctors based on the completed AR questionnaires. Explicit knowledge and implicit knowledge were defined based on the explicit and implicit importance scores of the AR questionnaire, which were obtained through doctors explicit scoring and feature evaluations of machine learning models, respectively. The analysis tool consists of eight evaluation indicators used to compare, analyze and visualize the explicit and implicit knowledge of TAM doctors.\n\nResultsThe analysis results for 8 doctors showed that our tool could successfully identify explicit and implicit knowledge in the PI process. We also conducted a postquestionnaire study with the doctors who participated to evaluate the applicability of our tool.\n\nConclusionsThis study proposed a tool to evaluate and compare decision-making processes of TAM doctors in terms of their explicit and implicit knowledge. We identified the differences between doctors own explicit and implicit knowledge and the differences among TAM doctors. The proposed tool would be helpful for the clinical standardization of TAM, doctors own clinical practice, and intern/resident training.","A novel RT-LAMP workflow for rapid salivary diagnostics of COVID-19 and effects of age, gender and time from symptom onset\nObjectivesRapid diagnostics is pivotal to curb SARS-CoV-2 transmission, and saliva has emerged as a practical alternative to naso/oropharyngeal (NOP) specimens. We aimed to develop a direct RT-LAMP workflow for viral detection in saliva, and to provide more information regarding its potential in COVID-19 diagnostics.\n\nMethodsClinical and contrived specimens were used to screen/optimize formulations and sample processing protocols. Salivary viral load was determined in symptomatic patients to evaluate clinical performance (n = 90) and to characterize saliva based on age, gender and time from onset of symptoms (n = 49).\n\nResultsThe devised workflow achieved 93.2% sensitivity, 97% specificity, and 0.895 Kappa for salivas containing >102 copies/L. Further analyses in saliva showed peak viral load in the first days of symptoms and lower viral loads in females, particularly among young individuals (<38 years). NOP RT-PCR data did not yield relevant associations.\n\nConclusionsThis novel saliva RT-LAMP workflow can be applied to point-of-care testing. This work reinforces that saliva better correlates with transmission dynamics than NOP specimens, and reveals gender differences that may reflect higher transmission by males. To maximize detection, testing should be done immediately after symptom onset, especially in females.\n\nHIGHLIGHTS- Development of DGS, a dithiothreitol/guanidine-based solution for stabilization of the viral genome that increases sensitivity for SARS-CoV-2 detection in saliva;\n- Rapid, cost-effective RT-LAMP assay workflow for viral detection in saliva without need of RNA extraction;\n- Insights into the differences in viral load between saliva and naso-oropharyngeal specimens, and correlation with age, gender and time from symptom onset;","Blood cytokine analysis suggests that SARS-CoV-2 infection results in a sustained tumour promoting environment in cancer patients\nCytokines, chemokines and (angiogenic) growth factors (CCGs) have been shown to play an intricate role in the progression of both solid and haematological malignancies. Recent studies have shown that SARS-CoV-2 infection leads to worse outcome in cancer patients, especially in haematological malignancy patients. Here, we investigated how SARS-CoV-2 infection impacts the already altered CCG levels in solid or haematological malignancies, specifically whether there is a protective effect or rather a potentially higher risk for major COVID-19 complications in cancer patients due to elevated CCGs linked to cancer progression. Serially analysing immune responses with 55 CCGs in cancer patients under active treatment with or without SARS-CoV-2 infection, we first showed that cancer patients without SARS-CoV-2 infection (n=54) demonstrate elevated levels of 35 CCGs compared to the non-cancer, non-infected control group of health care workers (n=42). Of the 35 CCGs, 19 were common to both solid and haematological malignancy groups and comprised previously described cytokines such as IL-6, TNF-, IL-1Ra, IL-17A, and VEGF, but also several less well described cytokines/chemokines such as Fractalkine, Tie-2, and T cell chemokine CTACK. Importantly, we show here that 7 CCGs are significantly altered in SARS-CoV-2 exposed cancer patients (n=52). Of these TNF-, IFN-{beta}, TSLP and sVCAM-1, identified to be elevated in haematological cancers, are also known tumour-promoting factors. Longitudinal analysis conducted over 3 months showed persistence of several tumour-promoting CCGs in SARS-CoV-2 exposed cancer patients. These data urge for increased vigilance for haematological malignancy patients as a part of long COVID follow-up.","Duration of COVID-19 mRNA Vaccine Effectiveness against Severe Disease\nBackgroundWaning immunity following administration of mRNA based COVID-19 vaccines remains a concern for many health systems. We undertook a study of SARS-CoV-2 infections, with and without requirement for intensive care to shed more light on the duration of vaccine effectiveness for protection against the need for intensive care.\n\nMethodsWe used a matched case-control study design with the study base being all individuals with first infection with SARS-CoV-2 reported in the State of Qatar between 1 Jan 2021 and 20 Feb 2022. Cases were those requiring intensive care while controls were those who recovered without need for intensive care. Vaccine effectiveness against requiring intensive care and number needed to vaccinate (NNV) to prevent one more case of COVID-19 requiring intensive care were computed for the mRNA (BNT162b2 / mRNA-1273) vaccines.\n\nResultsVaccine effectiveness against requiring intensive care was 59% (95% confidence interval [CI], 50 to 76) between the first and second dose and strengthened to 89% (95% CI, 85 to 92) between the second dose and 4 months post the second dose in persons who received a primary course of the vaccine. There was no waning of vaccine effectiveness in the period from 4 to 12 months after the second dose.\n\nConclusionsThis study demonstrates that vaccine effectiveness against requiring intensive care remains robust till at least 12 months after the second dose of mRNA based vaccines.","The Microbiome in Adult Acute Appendicitis\nAcute appendicitis is a common acute surgical emergency; however, the pathogenesis of adult appendicitis remains poorly understood. The microbiome is increasingly thought to play a key role in inflammatory disease of the bowel and similarly, may play a role in appendicitis.\n\nAimThis study aimed to characterize the microbiome of adult acute appendicitis in a prospective cohort.\n\nMethodWe recruited 60 adults with acute appendicitis and 20 healthy controls. Rectal swabs were taken from each patient. After DNA extraction, 16S rRNA amplicon sequencing was carried out for analysis of diversity and taxonomic abundance.\n\nResultsPhylogenetic sequencing of the samples indicated that there is a difference between the microbial composition of those with acute appendicitis and healthy controls, with a statistically significant decrease in alpha diversity in rectal swabs of appendicitis patients compared to healthy controls. At the genus level, we saw an increased abundance of potential pathogens, e.g. Parvimonas and Acinetobacter, and a decrease in commensal taxa such as Faecalibacterium, Blautia and Lachnospiraceae in appendicitis patients compared to healthy controls.\n\nConclusionAn imbalance in the gut microbiome may contribute to the pathogenesis of adult acute appendicitis.","TreatmentPatterns: An R package to analyze treatment patterns of a study population of interest\nBackground and objectivesThere is an increasing interest to use real-world data to illustrate how patients with specific medical conditions are treated in real life. Insight in the current treatment practices helps to improve and tailor patient care. We aim to provide an easy tool to support the development and analysis of treatment pathways for a wide variety of medical conditions.\n\nMethodsWe formally defined the process of constructing treatment pathways and developed an open-source R package TreatmentPatterns (https://github.com/mi-erasmusmc/TreatmentPatterns) to enable a reproducible and timely analysis of treatment patterns.\n\nResultsThe developed package supports the analysis of treatment patterns of specific populations of interest. We demonstrate the functionality of the package by analyzing the treatment patterns of three common chronic diseases (type II diabetes mellitus, hypertension, and depression) in the Dutch Integrated Primary Care Information (IPCI) database.\n\nConclusionTreatmentPatterns is a tool to make the analysis of treatment patterns more accessible, more standardized, and more interpretation friendly. This tool can facilitate and contribute to the accumulation of knowledge on real-world treatment patterns across disease domains. We encourage researchers to further adjust and add custom analysis to the package based on their research needs.","A pipeline for tabular dataset formation from unstructured data provided by ACR Appropriateness Criteria guidelines\nCurrently, data performns a critical concept for disparate human activities, from law to technology. Among data-centric technologies, clinical decision support systems (CDSS) figures out as one of the most promising for healthcare. Despite the technological advances facilitating its implementation, the maintainance of knowledge base for CDSS remains open to improvements. Here, we argue that the Appropriateness Criteria provided by ACR guidelines can be used as a open data-source that, combined with appropriate algorithms, can push forward basic research and technological developments regarding knowledge base for CDSS. Therefore, we developed a pipeline capable of forming tabular datasets from ACR guidelines, stored in a web site as textual PDF files. We also experimentally demonstrate that the proposed pipeline successfully recorvers the interested contents, and the best composition, in terms of its component algorithms, is discussed. Future research focused on algorithms flexibility in the face of PDF template updates could improve our work.","Safety and immunogenicity of the third booster dose with inactivated, viral vector, and mRNA COVID-19 vaccines in fully immunized healthy adults with inactivated vaccine\nThe coronavirus disease-2019 (COVID-19) pandemic has become a severe healthcare problem worldwide since the first outbreak in late December 2019. Currently, the COVID-19 vaccine has been used in many countries, but it is still unable to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection despite patients receiving full vaccination doses. Therefore, we aimed to appraise the booster effect of the different platforms of vaccines, including inactivated vaccine (BBIBP), viral vector vaccine (AZD122), and mRNA vaccine (BNT162b2) in healthy adults who received the full dose of inactivated vaccine (CoronaVac). The booster dose was safe with no serious adverse events. Moreover, the immunogenicity indicated that the booster dose with viral vector and mRNA vaccine achieved a significant proportion of Ig anti-receptor binding domain (RBD), IgG anti-RBD, and IgA anti-S1 booster response. In contrast, inactivated vaccine achieved a lower booster response than others. Consequently, the neutralization activity of vaccinated serum had a high inhibition of over 90% against SARS-CoV-2 wild-type and their variants (B.1.1.7-alpha, B.1.351-beta, and B.1.617.2-delta). In addition, IgG anti-nucleocapsid was observed only among the group that received the BBIBP booster. Our study found a significant increase in levels of interferon gamma-secreting T-cell response after the additional viral vector or mRNA booster vaccination. This study showed that administration with either viral vector (AZD1222) or mRNA (BNT162b2) boosters in individuals with a history of two doses of inactivated vaccine (CoronaVac) obtained great immunogenicity with acceptable adverse events.","Pre-conceptional maternal vitamin B12 supplementation improves offspring neurodevelopment at 2 years of age: PRIYA trial\nBackgroundNutritional interventions during the first 1000 days of life improves lifelong health. Better pre-conceptional maternal nutrition improves the nutrition of the early embryo. Vitamins B12 and folate are important for fetal neural development. Vitamin B12 deficiency is common in India.\n\nMethodsIn the Pune Rural Intervention in Young Adolescents (PRIYA) adolescents (N=557, 226 females) were provided with vitamin B12 (2{micro}g/day) with or without multiple micronutrients, or a placebo, from preconception until delivery. All groups received mandatory iron and folic acid. We used the Bayleys Scale of Infant Development (BSID-III) at 24-42 months of age to investigate effects on offspring neurodevelopment. We examined cord blood concentrations of brain-derived neurotropic factor (BDNF).\n\nResultsParticipants in the three groups had similar baseline B12 levels. These improved in the B12 supplemented groups at pre-conceptional and pregnancy (28 weeks gestation) measurements, reflected in higher cord holo-TC levels compared to the placebo. Neurodevelopmental outcomes are available for 74 children. Offspring in the B12 alone group (n=21) performed better than the placebo (n=27) on cognition (p=0.044) and language (p=0.020) domains (adjusted for maternal baseline B12 levels). There were no differences between the B12+MMN (n=26) and placebo group. Cord blood BDNF levels were highest in the B12 alone group (not statistically significant).\n\nConclusionPre-conceptional vitamin B12 supplementation improved maternal B12 status and offspring neurodevelopment at 2 years of age. The usefulness of cord BDNF as a marker of brain development needs further investigation. Our results highlight the importance of intervening in the pre-conceptional period.","Detecting cryptic clinically-relevant structural variation in exome sequencing data increases diagnostic yield for developmental disorders\nStructural Variation (SV) describes a broad class of genetic variation greater than 50bps in size. SVs can cause a wide range of genetic diseases and are prevalent in rare developmental disorders (DD). Patients presenting with DD are often referred for diagnostic testing with chromosomal microarrays (CMA) to identify large copy-number variants (CNVs) and/or with single gene, gene-panel, or exome sequencing (ES) to identify single nucleotide variants, small insertions/deletions, and CNVs. However, patients with pathogenic SVs undetectable by conventional analysis often remain undiagnosed. Consequently, we have developed the novel tool InDelible, which interrogates short-read sequencing data for split-read clusters characteristic of SV breakpoints. We applied InDelible to 13,438 probands with severe DD recruited as part of the Deciphering Developmental Disorders (DDD) study and discovered 64 rare, damaging variants in genes previously associated with DD missed by standard SNV, InDel or CNV discovery approaches. Clinical review of these 64 variants determined that about half (30/64) were plausibly pathogenic. InDelible was particularly effective at ascertaining variants between 21-500 bps in size, and increased the total number of potentially pathogenic variants identified by DDD in this size range by 42.3%. Of particular interest were seven confirmed de novo variants in MECP2 which represent 35.0% of all de novo protein truncating variants in MECP2 among DDD patients. InDelible provides a framework for the discovery of pathogenic SVs that are likely missed by standard analytical workflows and has the potential to improve the diagnostic yield of ES across a broad range of genetic diseases.","Antibodies against type-I Interferon: detection and association with severe clinical outcome in COVID-19 patients\nObjectivesImpairment of type I interferon (IFN-I) immunity has been reported in critically-ill COVID-19 patients. This defect can be explained in a subset of patients by the presence of circulating autoantibodies (auto-Abs) against IFN-I. We set out to improve the detection and the quantification of IFN-I auto-Abs in a cohort of critically-ill COVID-19 patients, in order to better evaluate the prevalence of these Abs as the pandemic progresses, and how they correlate with the clinical course of the disease.\n\nMethodsThe concentration of anti-IFN-2 Abs was determined in the serum of 84 critically-ill COVID-19 patients who were admitted to ICU in Hospices Civils de Lyon, France using a commercially available kit (Thermo-Fisher, Catalog #BMS217).\n\nResultsA total of 21/84 (25%) critically-ill COVID-19 patients had circulating anti-IFN-2 Abs above cut-off (>34 ng.mL-1). Among them, 15/21 had Abs with neutralizing activity against IFN-2, i.e. 15/84 (18%) of critically-ill patients. In addition, we noticed an impairment of the IFN-I response in the majority of patients with neutralizing anti-IFN-2 Abs. There was no significant difference in the clinical characteristics or outcome of with or without neutralizing anti-IFN-2 auto-Abs. We detected anti-IFN-2 auto-Abs in COVID-19 patients sera throughout their ICU stay. Finally, we also found auto-Abs against multiple subtypes of IFN-I including IFN-{omega}.\n\nConclusionsWe reported that 18% of critically-ill COVID-19 patients were positive for IFN-I auto-Abs, confirming that the presence of these antibodies is associated with higher risk of developing a criticall COVID-19 form.","ELF5 is a respiratory epithelial cell-specific risk gene for severe COVID-19\nDespite two years of intense global research activity, host genetic factors that predispose to a poorer prognosis and severe course of COVID-19 infection remain poorly understood. Here, we identified eight candidate protein mediators of COVID-19 outcomes by establishing a shared genetic architecture at protein-coding loci using large-scale human genetic studies. The transcription factor ELF5 (ELF5) showed robust and directionally consistent associations across different outcome definitions, including a >4-fold higher risk (odds ratio: 4.85; 95%-CI: 2.65-8.89; p-value<3.1x10-7) for severe COVID-19 per 1 s.d. higher genetically predicted plasma ELF5. We show that ELF5 is specifically expressed in epithelial cells of the respiratory system, such as secretory and alveolar type 2 cells, using single-cell RNA sequencing and immunohistochemistry. These cells are also likely targets of SARS-CoV-2 by colocalisation with key host factors, including ACE2 and TMPRSS2. We also observed a 25% reduced risk of severe COVID-19 per 1 s.d. higher genetically predicted plasma G-CSF, a finding corroborated by a clinical trial of recombinant human G-CSF in COVID-19 patients with lymphopenia reporting a lower number of patients developing critical illness and death. In summary, large-scale human genetic studies together with gene expression at single-cell resolution highlight ELF5 as a novel risk gene for COVID-19 prognosis, supporting a role of epithelial cells of the respiratory system in the adverse host response to SARS-CoV-2.","SynTL: A synthetic-data-based transfer learning approach for multi-center risk prediction\nObjectivesWe propose a synthetic-data-based transfer learning approach (SynTL) to incorporate multi-center healthcare data for improving the risk prediction of a target population, accounting for challenges including heterogeneity, data sharing, and privacy constraints.\n\nMethodsSynTL combines locally trained risk prediction models from each source population with the target population to adjust for the data heterogeneity through a flexible distance-based transfer learning approach. Heterogeneity-adjusted synthetic data are then generated for source populations where individual-level data are not shareable. The synthetic data are then combined with the target and source data for joint training of the target model. We evaluate SynTL via extensive simulation studies and an application to multi-center data from the electronic Medical Records and Genomics (eMERGE) Network to predict extreme obesity.\n\nResultsSimulation studies show that SynTL outperforms methods without adjusting for the data heterogeneity and methods that are trained in a single population over a wide spectrum of settings. SynTL has low communication costs where each participating site only needs to share parameter estimates to the target, requiring only one round of communication. SynTL protects against negative transfer when some source populations are highly different from the target. Using eMERGE data, SynTL achieves an area under the receiver operating characteristic curve (AUC) around 0.79, which outperforms other benchmark methods (0.50 - 0.67).\n\nConclusionSynTL improves the risk prediction performance of the target population, and is robust to the level of heterogeneity between the target and source populations. It protects patient-level information and is highly communication efficient.","Addressing Extreme Imbalance for Detecting Medications Mentioned in Twitter User Timelines\nTweets mentioning medications are valuable for efforts in digital epidemiology to supplement traditional methods of monitoring public health. A major obstacle, however, is to differentiate them from the large majority of tweets on other topics posted in a users timeline: solving the infamous needle in a haystack problem. While deep learning models have significantly improved classification, their performance and inference processing time remain low on extremely imbalanced corpora where the tweets of interest are less than 1% of all tweets. In this study, we empirically evaluate under-sampling, fine-tuning, and filtering heuristics to train such classifiers. Using a corpus of 212 Twitter timelines (181,607 tweets with only 0.2% tweets mentioning a medication), our results show that combining these heuristics is necessary to impact the classifiers performance. In our intrinsic evaluation, a classifier based on a lexicon and a BERT-base neural network achieved a 0.838 F1-score, a score similar to the ones of the best existing classifier, but it processed the corpus 28 times faster - a positive result, since processing speed is still a roadblock to deploying classifiers on large cohorts of Twitter users needed for pharmacovigilance. In our extrinsic evaluation, our classifier helped a labeler to extract the spans of medications more accurately and achieved a 0.76 Strict F1-score. To the best of our knowledge, this is the first evaluation of medications extraction in Twitter timelines and it establishes the first benchmark for future studies.","Characterization of Autonomic Symptom Burden in Long COVID: A Global Survey of 2,314 Adults\nBackgroundAutonomic dysfunction is a common complication of post-acute sequalae of SARS-CoV-2 (PASC)/long COVID, however prevalence and severity rates are unknown.\n\nObjectiveThe primary goal of this study was to assess the frequency and severity of autonomic symptoms in PASC. We also aimed to assess symptom burden in PASC though well-validated questionnaires, evaluate which pre-existing conditions are associated with an increased risk of developing autonomic dysfunction, and determine whether the severity of acute COVID-19 illness is associated with the severity of autonomic dysfunction in this population.\n\nMethodsWe conducted an online survey of 2,314 adults with PASC using several validated questionnaires including the COMPASS-31 to evaluate for autonomic dysfunction. We included both participants who had tested positive for COVID-19 (test-confirmed) and participants who were diagnosed with COVID-19 based on clinical symptoms alone (test-unconfirmed). Additional analyses were performed on test-confirmed participants, comparing hospitalized to non-hospitalized participants.\n\nResults67% of PASC patients had a COMPASS-31 score >20, suggestive of moderate to severe autonomic dysfunction. COMPASS-31 scores did not differ between test-confirmed hospitalized and non-hospitalized participants (28.95{+/-}30.98 vs 26.4{+/-}28.35, p=0.06). Both hospitalized and non-hospitalized participants reported significant functional disability across all quality-of-life domains.\n\nConclusionsModerate to severe autonomic dysfunction was seen in all PASC groups in our study, independent of hospitalization status, suggesting that autonomic dysfunction is highly prevalent in the PASC population and not necessarily dependent on the severity of acute COVID illness.","Polygenic risk scores for psychiatric, inflammatory, and cardio-metabolic traits and diseases highlight possible genetic overlaps with suicide attempt and treatment-emergent suicidal ideation\nSuicide is the second leading cause of death among young people. Genetics may contribute to suicidal phenotypes and their co-occurrence in other psychiatric and medical conditions. Our study aimed to investigate the association of polygenic risk scores (PRSs) for 22 psychiatric, inflammatory, and cardio-metabolic traits and diseases with suicide attempt (SA) or treatment-worsening/emergent suicidal ideation (TWESI).\n\nPRSs were computed based on summary statistics of genome-wide association studies. Regression analyses were performed between PRSs and SA or TWESI in four clinical cohorts, including up to 3,834 individuals, and results were meta-analyzed across samples. Stratified genetic covariance analyses were performed to investigate the biology underlying cross-phenotype PRS associations. After Bonferroni correction, PRS for major depressive disorder (MDD) was positively associated with SA (p=1.7e-4). Nominal associations were shown between PRSs for coronary artery disease (CAD) (p=4.6e-3) or loneliness (p=0.009) and SA, PRSs for MDD or CAD and TWESI (p=0.033 and p=0.032, respectively). Genetic covariance between MDD and SA was shown in 35 gene sets related to drugs having anti-suicidal effects.\n\nA higher genetic liability for MDD may underlie a higher risk of SA. Further, but milder, possible modulatory factors are genetic risk for loneliness and CAD.","A Simplified Point-of-Care Lung Ultrasound Protocol to Detect Coronavirus Disease 2019 in Inpatients: A Prospective Observational Study\nObjectivesTo assess the diagnostic performance of lung point-of-care ultrasound (POCUS) compared to either a positive nucleic acid test (NAT) or a COVID-19-typical pattern on computed tomography (CT) and to evaluate opportunities to simplify a POCUS algorithm.\n\nMethodsHospital-admitted adult inpatients with (1) either confirmed or suspected COVID-19 and (2) a completed or ordered CT within the preceding 24 hours were recruited. Twelve lung zones were scanned with a handheld POCUS machine. POCUS, CT, and X-ray (CXR) images were reviewed independently by blinded experts. A simplified POCUS algorithm was developed via machine learning.\n\nResultsOf 79 enrolled subjects, 26.6% had a positive NAT and 31.6% had a CT typical for COVID-19. The receiver operator curve (ROC) for a 12-zone POCUS protocol had an area under the curve (AUC) of 0.787 for positive NAT and 0.820 for typical CT. A simplified four-zone protocol had an AUC of 0.862 for typical CT and 0.862 for positive NAT. CT had an AUC of 0.815 for positive NAT; CXR had AUCs of 0.793 for positive NAT and 0.733 for typical CT. Performance of the four-zone protocol was superior to CXR for positive NAT (p=0.0471). Using a two-point cutoff system, the four-zone POCUS protocol had a sensitivity of 0.920 and 0.904 compared to CT and NAT, respectively, at the lower cutoff; it had a specificity of 0.926 and 0.948 at the higher cutoff, respectively.\n\nConclusionPOCUS outperformed CXR to predict positive NAT. POCUS could potentially replace other chest imaging for persons under investigation for COVID-19.","Factors Associated with Antenatal Care Service Utilization among Mothers with Children under five years in Sunyani Municipality, Ghana\nBackgroundMaternal and neonatal mortality remains a public health burden around the globe most especially in developing countries. A well utilized antenatal care (ANC) is however among the identified interventions to reduce this burden of maternal and neonatal mortality rates. A lot of factors therefore predispose, enable and cause mothers to identify the need to utilize this service (ANC).\n\nAims/objectivesThe aim of this study was to determine factors associated with the utilization of ANC service among postpartum mothers in the Sunyani municipality.\n\nMethodsThis study employed descriptive cross-sectional survey design. A semi-structured questionnaire consisting of demographic profile of the respondents, their knowledge about ANC services and the level of ANC utilization. Logistic regression analysis techniques and chi-square were used for the categorical variables to examine the associations between the dependent and independent variables. Data analysis was done using the Statistical Package for Social Science software (SPSS) version 22.\n\nResultsMajority (87%) of postpartum mothers in the Sunyani municipality attended ANC at least once during their last pregnancy of which 95.6% had four or more visits and 77.1% initiated their ANC attendance within their first trimester. It was further observed that 97.3% of the mothers had good knowledge about ANC. Marital status and ANC knowledge were found to be significantly associated with ANC attendance. Husbands were found to be poorly involved in ANC services in the Sunyani municipality.\n\nConclusionMarital status and ANC knowledge predisposes most mothers to utilize ANC services. Hence, health education activities about ANC services and its importance should be channeled more to areas where ANC utilization is low.","Study design: Validation of clinical acceptability of deep-learning-based automated segmentation of organs-at-risk for head-and-neck radiotherapy treatment planning.\nThis document reports the design of a retrospective study to validate the clinical acceptability of a deep-learning-based model for the autosegmentation of organs-at-risk (OARs) for use in radiotherapy treatment planning for head & neck (H&N) cancer patients.","A One-Step open RT-qPCR for SARS-CoV-2 detection\nThe Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), etiological agent of the coronavirus disease 2019 (COVID-19), is currently detected by reverse transcription followed by quantitative polymerase chain reaction (RT-qPCR) of its viral RNA genome. Within the available alternatives, One-Step procedures are preferred since they are fast and significantly decrease preanalytical errors, minimizing the risk of diagnostic errors.\n\nIncreasing the testing capacity and tracing contacts are essential steps to control the pandemic. However, high-cost commercial reagents subject to shortage and poor scalability have hindered the use of these technologies and their adoption for a wide population-scale testing, being even more critical in developing countries. In the current context, open-source initiatives have promoted global collaboration to promote accessible solutions for rapid local deployment. As a result, open protocols are being developed for the local production of SARS-CoV-2 diagnostics.\n\nThis work aimed to produce an open-source system for SARS-CoV-2 diagnostic tests in RNA clinical samples. We provide guidelines for standardizing an open One-Step RT-qPCR master mix using recombinant M-MLV reverse transcriptase together with either Pfu-Sso7d or Taq DNA polymerase. Both were tested on synthetic RNA and clinical samples, observing a good correlation when compared to commercial RT-qPCR kits. Nevertheless, the best results were obtained using M-MLV RT combined with Taq DNA polymerase in a probe-based RT-qPCR assay, allowing successful discrimination between positive and negative samples with accuracies comparable to a CDC-recommended commercial kit.\n\nHere, we demonstrate that these open RT-qPCR systems can be successfully used to identify SARS-CoV-2 in clinical samples and potentially be implemented in any molecular diagnostic laboratory.","Determinants and causes of early neonatal mortality: Hospital based retrospective cohort study in Somali region of Ethiopia\nBackgroundEarly neonatal mortality occurs when a newborn dies within the first seven days of life. Despite interventions, newborn mortality in Ethiopia has grown over time (33 death per 1000 live births). Determinants varies on level of neonatal mortality. The studys goal was to determine magnitude of early newborn death, as well as its causes and drivers, in Newborn Intensive Care Unit of Referral hospital in Ethiopias Somali region.\n\nMethodsHealth facility based retrospective study review was conducted between May 2019 to May 2021 in Shiek Hassan Yabare Referral Hospital of Jigjiga University of Ethiopia. All neonates between 0 to 7 days admitted at NICU and get registered using the new NICU registration book from May 2019 to May 2021 with complete data were included. Kobo toolkit was used for data collection and analyzed in SPSS 20. Logistic regression model was used to estimate determinants.\n\nResultThe magnitude of early neonatal mortality rate (defined as death between 0-7 days) of Ethiopias Somali region is estimated to be 130 per 1000 live births--That is say 130 newborn couldnt celebrate their seventh day in every 1000 live births. Hypothermia, prematurity, maternal death at birth and shorter length of stay in NICU were increasing the chance of neonatal mortality at early stage while neonatal resuscitation had shown protective effect against neonatal mortality. Similarly birth asphyxia, preterm, sepsis, and congenital abnormalities were major causes of admission and death in the NICU.\n\nConclusionThe magnitude of early neonatal mortality is considerable and causes are preventable. Enhancing quality of care including infection prevention and hypothermia through mentorship and encouraging the Kangaroo Mother Care practice is necessary at childbirth and NICU of the Hospital.","Quantifying the role of naturally- and vaccine-derived neutralizing antibodies as a correlate of protection against COVID-19 variants\nThe functional relationship between neutralizing antibodies (NAbs) and protection against SARS-CoV-2 infection and disease remains unclear. We jointly estimated protection against infection and disease progression following natural infection and vaccination from meta-study data. We find that NAbs are strongly correlated with prevention of infection and that any history of NAbs will stimulate immune memory to moderate disease progression. We also find that natural infection provides stronger protection than vaccination for the same level of NAbs, noting that infection itself, unlike vaccination, carries risk of morbidity and mortality, and that our most potent vaccines induce much higher NAb levels than natural infection. These results suggest that while sterilizing immunity may decay, we expect protection against severe disease to be robust over time and in the face of immune-evading variants.","METHYLATION BIOMARKERS ASSOCIATED WITH DRUG-RESISTANT EPILEPSY\nEpilepsy is a disabling neurological disease that affects 2% of the population. Drug-resistant epilepsy (DRE) affects 25-30% of epilepsy patients. Understanding its underlying mechanisms is key to adequately manage this condition. To analyze the main epigenetic marks of DRE an epigenome-wide association study was carried out including samples from different regions of DRE patients brain and peripheral blood. An Illumina Infinium MethylationEPIC BeadChip array including cortex, hippocampus, amygdala, and peripheral blood from DRE subjected to neurosurgical resection of the epileptogenic zone was used. Overall, 32, 59, 3210, and 6 differentially methylated probes (DMPs) associated with DRE were found in the hippocampus, amygdala, cortex, and peripheral blood, respectively. These DMPs harbored 19, 28, 1574, and 7 genes, respectively, which play different roles in processes such as neurotrophic or calcium signaling. Three of the top DMPs observed in cortex were validated with methylation specific qPCR. Moreover, 163 DMPs associated with neurosurgery response at 6 months were found in the hippocampus. Genes located on these DMPs were involved in diverse processes such as synaptic signaling and central nervous system development. Besides 3 DMPs in blood samples were associated with response to neurosurgery at 12 months. In conclusion, the present study reports genome-wide DNA methylation changes across different regions of the DRE brain. These changes could be useful for further studies to disentangle the bases of DRE to search for therapeutic alternatives for this disease. Furthermore, they could also help identify patients likely to respond to neurosurgery.","Integrating Multiple Imaging Modalities does not Boost Prediction of Carotid Artery Intima-Media Thickness in Midlife Adults\nBackgroundHuman neuroimaging evidence suggests that cardiovascular disease (CVD) risk may relate to functional and structural features of the brain. The present study tested whether combining functional and structural (multimodal) brain measures, derived from magnetic resonance imaging (MRI), would yield a multivariate brain biomarker that reliably predicts a subclinical marker of CVD risk, carotid-artery intima-media thickness (CA-IMT).\n\nMethodsNeuroimaging, cardiovascular, and demographic data were assessed in 324 midlife and otherwise healthy adults who were free of (a) clinical CVD and (b) use of medications for chronic illness (aged 30-51 years, 49% female). We implemented a prediction stacking algorithm that combined multimodal brain imaging measures and Framingham Risk Scores (FRS) to predict CA-IMT. We included imaging measures that could be easily obtained in clinical settings: resting state functional connectivity and structural morphology measures from T1-weighted images.\n\nResultsOur models reliably predicted CA-IMT using FRS, as well as for several individual MRI measures; however, none of the individual MRI measures outperformed FRS. Moreover, stacking functional and structural brain measures with FRS did not boost prediction accuracy above that of FRS alone.\n\nConclusionsCombining multimodal functional and structural brain measures through a stacking algorithm does not appear to yield a reliable brain biomarker of subclinical CVD, as reflected by CA-IMT.","Predictors for participation in DNA self-sampling of childhood cancer survivors in Switzerland\nResearch on germline genetic variants relies on a sufficient number of eligible participants which is difficult to achieve for rare diseases such as childhood cancer. With self-collection kits using saliva or buccal swabs, participants can contribute genetic samples conveniently from their home. We identified determinants of participation in DNA self-collection in this cross-sectional study.\n\nWe invited 928 childhood cancer survivors in Switzerland with a median age of 26.5 years (interquartile range 18.8-36.5), of which 463 (50%) participated. Foreign nationality (odds ratio [OR] 0.5, 95%-confidence interval [CI] 0.4-0.7), survivors aged 30-39 years at study versus other age groups (OR 0.5, CI 0.4-0.8), and those with a known cancer predisposition syndrome (OR 0.5, CI 0.3-1.0) participated less. Survivors with a second primary neoplasm (OR 1.9, CI 1.0-3.8) or those living in a French or Italian speaking region (OR 1.3, 1.0-1.8) tended to participate more.\n\nWe showed that half of survivors participate in germline DNA self-sampling relying completely on mailing of sample kits. Foreign nationality, age 30-39 years, and cancer predisposition syndromes were associated with less participation. More targeted recruitment strategies may be advocated for these subgroups. To increase participation in DNA self-sampling, understanding and perceptions of survivors need to be better understood.","Ammonium Sulfate Addition Reduces the Need for Guanidinium Isothiocyanate in the Denaturing Transport Medium Used for SARS-COV-2 RNA Detection\nRapid identification of SARS-CoV-2 infected individuals through viral RNA detection followed by effective personal isolation remains the most effective way to prevent the spread of this virus. Large-scale RNA detection involves mass specimen collection and transportation. For biosafety reasons, denaturing viral transport medium has been extensively used during the pandemic. But the high concentrations of guanidinium isothiocyanate (GITC) in such media have raised issues around sufficient GITC supply and laboratory safety. Here, we tested whether supplementing media containing low concentrations of GITC with ammonium sulfate (AS) would affect the throat-swab detection of SARS-CoV-2 pseudovirus or a viral inactivation assay targeting both enveloped and non-enveloped viruses. Adding AS to the denaturing transport media reduced the need for high levels of GITC and improved SARS-COV-2 RNA detection without compromising virus inactivation.","Quantification of T- and B-cell immune receptor distribution diversity characterizes immune cell infiltration and lymphocyte heterogeneity in clear cell renal cell carcinoma\nImmune-modulating systemic therapies are often used to treat advanced cancer such as metastatic clear cell renal cell carcinoma (ccRCC). Used alone, sequence-based biomarkers neither accurately capture patient dynamics nor the tumor immune microenvironment. To better understand the tumor ecology of this immune microenvironment, we quantified tumor infiltration across two distinct ccRCC patient tumor cohorts using complementarity determining region-3 (CDR3) sequence recovery counts in tumor-infiltrating lymphocytes and a generalized diversity index (GDI) for CDR3 sequence distributions. GDI can be understood as a curve over a continuum of diversity scales which allows sensitive characterization of distributions to capture sample richness, evenness, and subsampling uncertainty, along with other important metrics that characterize tumor heterogeneity. For example, richness quantified the total unique sequence count, while evenness quantified similarities across sequence frequencies. Significant differences in receptor sequence diversity across gender and race revealed that patients with larger and more clinically aggressive tumors had increased richness of recovered tumoral CDR3 sequences, specifically in those from T-cell receptor alpha and B-cell immunoglobulin lambda light chain. The GDI inflection point (IP) allowed for a novel and robust measure of distribution evenness. High IP values associated with improved overall survival, suggesting that normal-like sequence distributions lead to better outcomes. These results propose a new quantitative tool that can be used to better characterize patient-specific differences related to immune cell infiltration, and to identify unique characteristics of tumor-infiltrating lymphocyte heterogeneity in ccRCC and other malignancies.","PRACTICE OF EARLY BREASTFEEDING INITIATION ON PRIMIGRAVIDA WITH A CULTURAL PERSPECTIVE: A SYSTEMATIC REVIEW\nOne of the health aspects in the development process is the development of human resource potential (HR). What plays a role in this potential of human resources is good nutritional status from an early age. In addition to these factors, the quality of human resource formation is also influenced by the environment that shapes human character. namely the socio-cultural environment (Soekirman, 2005). One of the cultural interactions that affect nutritional status as a condition for the formation of quality human resources is the practice of breastfeeding and the practice of early breastfeeding initiation (IMD). There have been many previous studies that have written that there are still many mothers who do not practice IMD, where one of the reasons mentioned is the belief that the first milk that comes out is dirty and unhealthy, so it is not suitable to be given to babies (Roesli, 2008). The purpose of this literature study is to determine the influence of culture in the practice of early breastfeeding initiation.\n\nThe articles used in the literature review were obtained through databases of international journal providers such as Proquest, Google Scholar and Science Direct. The journal was taken from 2019 to 2021. Researchers used keywords, namely transcultural nursing, breastfeeding (according to MESH/Medical Subject Heading) and 20 articles were analyzed using PRISMA diagrams. The analysis found that most mothers did not practice early breastfeeding because of certain beliefs about early breastfeeding, such as early breastfeeding was not as good as exclusive breastfeeding, dirty early breast milk, unhealthy early breastfeeding given to babies and the habit of mothers who immediately gave additional food immediately. after the baby is born."],"string":"[\n \"Saving Lives with Pre-Financed Rules-Based Disaster Aid: Evidence from Mexico\\nDeveloping economies are not disproportionately exposed to natural disasters, but they experience significantly more deaths. Exploiting a discontinuity in the eligibility rules to Mexicos pre-financed indexed disaster fund (Fonden), I show that accelerated reconstruction of public infrastructure can fully reduce postdisaster excess mortality in the short-run and up to 75 percent two years after. I also find that Fondens impact is concentrated in areas with medical infrastructure and among conditions responsive to basic medical interventions. These findings suggest that Fonden operates by restoring access to health services after a disaster. Annual benefits from Fonden amount to 197 thousand life-years saved. (JEL: G22, H12, H84, Q54, I15, O18.)\",\n \"Whole genome sequencing identifies common and rare structural variants contributing to hematologic traits in the NHLBI TOPMed program\\nGenome-wide association studies (GWAS) have identified thousands of single nucleotide variants and small indels that contribute to the genetic architecture of hematologic traits. While structural variants (SVs) are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of SVs to quantitative blood cell trait variation is unknown. Here we utilized SVs detected from whole genome sequencing (WGS) in ancestrally diverse participants of the NHLBI TOPMed program (N=50,675). Using single variant tests, we assessed the association of common and rare SVs with red cell-, white cell-, and platelet-related quantitative traits. The results show 33 independent SVs (23 common and 10 rare) reaching genome-wide significance. The majority of significant association signals (N=27) replicated in independent datasets from deCODE genetics and the UK BioBank. Moreover, most trait-associated SVs (N=24) are within 1Mb of previously-reported GWAS loci. SV analyses additionally discovered an association between a complex structural variant on 17p11.2 and white blood cell-related phenotypes. Based on functional annotation, the majority of significant SVs are located in non-coding regions (N=26) and predicted to impact regulatory elements and/or local chromatin domain boundaries in blood cells. We predict that several trait-associated SVs represent the causal variant. This is supported by genome-editing experiments which provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.\",\n \"Proteasome inhibition enhances myeloma oncolytic reovirus therapy by suppressing monocytic anti-viral immune responses\\nReovirus is an oncolytic virus with natural tropism for cancer cells. We previously showed that reovirus intravenous administration in myeloma patients was safe, but disease control associated with viral replication in the cancer cells was not observed. Here we show that ex vivo proteasome inhibitors (PIs) potentiate reovirus replication in circulating classical monocytes, increasing viral delivery to myeloma cells. We found that the anti-viral signals in monocytes primarily rely on the NF-kB activation and that this effect is impaired by the addition of PIs. Conversely, PIs improved reovirus-induced monocyte and T cell activation against cancer cells. Based on these preclinical data, we conducted a phase 1b trial of the reovirus Pelareorep together with the PI carfilzomib in 13 heavily pretreated bortezomib-resistant MM patients. Objective responses associated with reovirus active replication in MM cells, T cell activation and monocytic expansion were noted in 70% of patients.\",\n \"Simultaneous evaluation of antibodies that inhibit SARS-CoV-2 RBD variants with a novel competitive multiplex assay\\nThe SARS-CoV-2 Receptor Binding Domain (RBD) is both the principal target of neutralizing antibodies, and one of the most rapidly evolving domains, which can result in the emergence of immune escape mutations limiting the effectiveness of vaccines and antibody therapeutics. To facilitate surveillance, we developed a rapid, high-throughput, multiplex assay able to assess the inhibitory response of antibodies to 24 RBD natural variants simultaneously. We demonstrate that immune escape can occur through two mechanisms, antibodies that fail to recognize mutations, along with antibodies that have reduced inhibitory capacity due to enhanced variant RBD-ACE2 affinity. A competitive approach where antibodies simultaneously compete with ACE2 for binding to the RBD may therefore more accurately reflect the physiological dynamics of infection. We describe the enhanced affinity of RBD variants N439K, S477N, Q493L, S494P and N501Y to the ACE2 receptor, and demonstrate the ability of this assay to bridge a major gap for SARS-CoV-2 research; informing selection of complementary monoclonal antibody candidates and the rapid identification of immune escape to emerging RBD variants following vaccination or natural infection.\",\n \"Racial Disparities in the SOFA Score Among Patients Hospitalized with COVID-19\\nBackgroundSequential Organ Failure Assessment (SOFA) score predicts probability of in-hospital mortality. Many crisis standards of care use SOFA score to allocate medical resources during the COVID-19 pandemic.\\n\\nResearch QuestionAre SOFA scores disproportionately elevated among Non-Hispanic Black and Hispanic patients hospitalized with COVID-19, compared to Non-Hispanic White patients?\\n\\nStudy Design and MethodsRetrospective cohort study conducted in Yale New Haven Health System, including 5 hospitals with total of 2681 beds. Study population drawn from consecutive patients aged [≥]18 admitted with COVID-19 from March 29th to August 1st, 2020. Patients excluded from the analysis if not their first admission with COVID-19, if they did not have SOFA score recorded within 24 hours of admission, if race and ethnicity data were not Non-Hispanic Black, Non-Hispanic White, or Hispanic, or if they had other missing data. The primary outcomes was SOFA score, with peak score within 24 hours of admission dichotomized as <6 or [≥]6.\\n\\nResultsOf 2982 patients admitted with COVID-19, 2320 met inclusion criteria and were analyzed, of whom 1058 (45.6%) were Non-Hispanic White, 645 (27.8%) were Hispanic, and 617 (26.6%) were Non-Hispanic Black. Median age was 65.0 and 1226 (52.8%) were female. In univariate logistic screen and in full multivariate model, Non-Hispanic Black patients but not Hispanic patients had greater odds of an elevated SOFA score [≥]6 when compared to Non-Hispanic White patients (OR 1.49, 95%CI 1.11-1.99).\\n\\nInterpretationCrisis standards of care utilizing the SOFA score to allocate medical resources would be more likely to deny these resources to Non-Hispanic Black patients.\",\n \"THEMIS: A Framework for Cost-Benefit Analysis of COVID-19 Non-Pharmaceutical Interventions\\nSince December 2019, the world has been ravaged by the COVID-19 pandemic, with over 150 million confirmed cases and 3 million confirmed deaths worldwide. To combat the spread of COVID-19, governments have issued unprecedented non-pharmaceutical interventions (NPIs), ranging from mass gathering restrictions to complete lockdowns. Despite their proven effectiveness in reducing virus transmission, the policies often carry significant economic and humanitarian cost, ranging from unemployment to depression, PTSD, and anxiety. In this paper, we create a data-driven system dynamics framework, THEMIS, that allows us to compare the costs and benefits of a large class of NPIs in any geographical region across different cost dimensions. As a demonstration, we analyzed thousands of alternative policies across 5 countries (United States, Germany, Brazil, Singapore, Spain) and compared with the actual implemented policy.\\n\\nOur results show that moderate NPIs (such as restrictions on mass gatherings) usually produce the worst results, incurring significant cost while unable to sufficiently slow down the pandemic to prevent the virus from becoming endemic. Short but severe restrictions (complete lockdown for 4-5 weeks) generally produced the best results for developed countries, but only if the speed of reopening is slow enough to prevent a resurgence. Developing countries exhibited very different trade-off profiles from developed countries, and suggests that severe NPIs such as lockdowns might not be as suitable for developing countries in general.\",\n \"The slower antibody response in myelofibrosis patients after two doses of mRNA SARS-CoV-2 vaccine calls for a third dose\\nImmunization with mRNA SARS-CoV-2 vaccines has been highly recommended and prioritized in fragile categories with higher risk of mortality after COVID-19 disease compared to healthy people, including patients with myelofibrosis (MF). Available data on the vaccine immune response developed by MF patients, and the impact of the treatment with the inhibitor of JAK-STAT signaling ruxolitimib, are still fragmented to support an informed decision for a third dose for this category of subjects. Here, we show that 76% of MF patients develop spike-specific IgG after the second vaccine dose, but the response has a slower kinetic compared to healthy subjects, suggesting a reduced capability of their immune system to promptly react to vaccination. A reduced ACE2/RBD inhibition binding activity of spike-specific antibodies was also observed, especially in ruxolitimib treated patients. Our results contribute to answer the open question on the induction of the antibody responses in MF patients following vaccination with COVID-19 mRNA vaccines, showing a slow kinetic that support the need for a third dose of SARS-CoV-2 mRNA vaccines.\",\n \"Toward a phenome-wide view of Parkinson's disease\\nBackground and ObjectivesMany studies have examined the relation between PD and environmental variables serially --- one candidate association at a time. In the real world however, both environmental exposures and patients are much more complex, including correlated environmental exposures, polypharmacy, and complex comorbidities. Here we begin to characterize a holistic view of environmental, health, and pharmacological traits linked to patients with PD.\\n\\nMethodsThe Harvard Biomarkers Study (HBS) is a large case-control study of PD patients and healthy controls that includes an extensive questionnaire covering past medical and social history data and is thus well-suited for such an exploratory study. Sixty-four environmental, pharmacological, and clinical features were evaluated for associations with PD using logistic regression analysis with backward elimination.\\n\\nResultsMale gender, coronary artery disease, depression, anxiety, restless leg syndrome, head trauma, ibuprofen use, co-enzyme Q10 use, and vitamin D supplementation were significantly positively associated with PD. By contrast, asthma/chronic obstructive pulmonary disease (COPD), naproxen, ezetimibe, and smoking were significantly negatively associated with PD.\\n\\nDiscussionThis study shows that unbiased, data-rich exploration of the Parkinson phenome has the promise to uncover, prioritize, and clarify associations between environment, multi-system health phenotypes, and PD in a patient-centric manner. Associations with coronary artery disease, mood disorders, and the cholesterol-absorption inhibitor ezetimibe were revealed that have been largely neglected in traditional hypothesis-driven investigations. Interestingly, asthma/COPD was inversely associated with PD, and this was independent of smoking history. Furthermore, well-established associations were confirmed for male gender, smoking, head trauma, and restless legs syndrome.\",\n \"Impact of Exercise-induced Dehydration on Perceived Exertion During Endurance Exercise: A Systematic Review with Meta-analysis\\nUnderstanding the impact of stressors on the rating of perceived exertion (RPE) is relevant from a performance and exercise adherence/participation standpoint. Athletes and recreationally active individuals dehydrate during exercise. No attempt has been made to systematically determine the impact of exercise-induced dehydration (EID) on RPE. The present meta-analysis aimed to determine the effect of EID on RPE during endurance exercise and examine the moderating effect of potential confounders using a meta-analytical approach. Data analyses were performed on raw RPE values using random-effects models weighted mean effect summaries and meta-regressions with robust standard errors, and with a practical meaningful effect set at 1 point difference between euhydration (EUH) and EID. Only controlled crossover studies measuring RPE with a Borg scale in healthy adults performing [≥] 30 min of continuous endurance exercise while dehydrating or drinking to maintain EUH were included. Sixteen studies were included, representing 147 individuals. Mean body mass loss with EUH was 0.5 {+/-} 0.4%, compared to 2.3 {+/-} 0.5% with EID (range 1.7 to 3.1%). Within an EID of 0.5 to 3% body mass, a maximum difference in RPE of 0.81 points (95% CI: 0.36-1.27) was observed between conditions. A meta-regression revealed that RPE increases by 0.21 points for each 1% increase in EID (95% CI: 0.12-0.31). Humidity, ambient temperature and aerobic capacity did not alter the relationship between EID and RPE. Therefore, the effect of EID on RPE is unlikely to be practically meaningful until a body mass loss of at least 3%.\",\n \"Covid-19 High Attack Rate Can Lead to High Case Fatality Rate\\nBackgroundDuring the current Covid-19 pandemic case fatality rate (CFR) estimates were subjected to a lot of debates regarding the accuracy of its estimations, predictions, and the reason of across countries variances. In this context, we conduct this study to see the relationship between attack rate (AR) and CFR.\\n\\nThe study hypothesis is based on two: 1-evidence suggests that the mortality rate (MR) has a positive influence on case fatality ratio (CFR), 2- and increase number of Covid-19 cases leads to increased mortality rate (MR).\\n\\nMaterial and methodsThirty countries and territories were chosen. Inclusion criterion was > 500 Covid-19 reported cases per 10,000 population inhabitants. Data on covid-19 cases and deaths was selected as it was on March 10, 2021. Statistical methods used are descriptive and one-sample Kolmogorov-Smirnov (K-S), the one-way ANOVA, Levene, least significant different (LSD), and matched paired-samples T-tests.\\n\\nResultsANOVA test showed a significant difference at P<0.01 among all studied groups concerning AR and CFR mean values. Group of countries with MR [≥] 15 death / 104 inhabitants recorded the highest level of crude mean CFR and AR values, and recorded the highest gap with leftover groups, especially with countries reported MR of <10 death/ 104 inhabitants. There were independence 95% confidence intervals of mean CFR and AR values between countries with [≥] 15 death / 104 MR and countries with MR of <10 death /104. There was a significant difference between countries with MR [≥] 15 death / 104 inhabitants and countries with MR of <10 death / 10 4 inhabitants groups through least significant difference (LSD) test for CFR%(0.042 p-value) and Games Howell (GH) test for AR/104 (p-value 0.000).\\n\\nConclusionsTotal and mean AR and CFR are higher in high MR countries compared to low MR countries.\",\n \"Evolution and emergence of multidrug-resistant Mycobacterium tuberculosis in Chisinau, Moldova\\n1.BackgroundDrug-resistant tuberculosis is a high priority threat to global public health. There are still critical gaps in understanding how novel drug-resistant M. tuberculosis strains emerge and, once emergent, what drives the differential propagation of certain epidemiologically-successful strains over others. This study sought to describe the joint evolutionary and epidemiological histories of a novel multidrug-resistant M. tuberculosis strain recently identified in the capital city of the Republic of Moldova (MDR Ural/4.2).\\n\\nMethodsUsing whole genome sequence data and Bayesian phylogenomic methods, we reconstruct the stepwise acquisition of drug-resistance mutations in the MDR Ural/4.2 strain, estimate its historical bacterial population size over time, and infer the migration history of this strain between Eastern European countries.\\n\\nResultsWe infer that MDR Ural/4.2 likely evolved (via acquisition of rpoB S450L, which confers resistance to rifampin) in the early 1990s, during a period of social turmoil following Moldovan independence from the Soviet Union. This strain subsequently underwent substantial population size expansion in the early 2000s, at a time when national guidelines encouraged in hospital treatment of TB patients. We infer exportation of this strain and its INH-resistant ancestral precursor from Moldova to neighboring countries starting as early as 1985.\\n\\nConclusionsOur findings underscore how public health practice and social determinants of health shape the conditions under which M. tuberculosis evolves, and demonstrates how historical changes in these conditions shape present-day challenges in TB control. These findings underscore the need for regional coordination in TB control across Eastern Europe.\",\n \"Human influenza virus infection elicits distinct patterns of monocyte and dendritic cell mobilization in blood and the nasopharynx\\nDuring respiratory viral infections, the precise roles of monocytes and dendritic cells (DCs) in the nasopharynx in limiting infection and influencing disease severity are incompletely described. We studied circulating and nasopharyngeal monocytes and DCs in healthy individuals and in patients with mild respiratory infections (primarily influenza A virus, IAV). As compared to healthy controls (HCs), patients with acute IAV infection displayed reduced DC but increased intermediate monocytes frequencies in blood, and an accumulation of most monocyte and DC subsets in the nasopharynx. IAV patients had more mature monocytes and DCs in the nasopharynx, and higher levels of TNF, IL-6 and IFN in plasma and the nasopharynx. In blood, monocytes, the most frequent cellular source of TNF during IAV infection, remained responsive to additional stimulation with TLR7/8L. Immune responses in older patients skewed towards increased monocytes rather than DCs suggesting a contributory role for monocytes in disease severity. In patients with other respiratory virus infections, we observed changes in monocyte and DC frequencies in the nasopharynx distinct from IAV patients, while differences in blood were more similar across patient groups. Together, our findings demonstrate tissue-specific and pathogen-specific patterns of monocyte and DC function during human respiratory viral infections and highlight the importance of comparative investigations in blood and the nasopharynx.\",\n \"High Speed Photographic Detection of Particle Distribution During Aerosol and Smoke Generating Surgical Procedures: Effects of Surgical Site Evacuation\\nObjectiveDetermine the effectiveness of evacuation systems designed to clear bioaerosols and smoke from the surgical field.\\n\\nStudy designHigh-speed photographic evaluation of aerosol and smoke generated in simulated surgical fields.\\n\\nMaterials and methodsSurgical site aerosol clearance was evaluated using a model of the anterior neck and prototypes for surgical site evacuator ports created using 3D printing. A commercially available electrocautery handpiece fitted with an evacuator was tested on animal tissue for smoke clearance. Both systems were connected to a commercial vacuum powered evacuation system. High speed photography was used to record videos of the aerosols and plumes. Fields were recorded with and without evacuation.\\n\\nResultsEfficient aerosol clearance from an open surgical field using an evacuator port is dependent upon the port design, airflow velocity, and placement relative to the aerosol generating site. The size and surface geometry of the surgical field are also important.\\n\\nSurgical smoke generated with electrocautery is cleared from the field by the evacuation enclosure around the handpiece, even at high electrocautery power settings. Except for device noise, there appears to be no reason for using evacuator flow rates below the maximum setting.\\n\\nConclusionsBioaerosol and smoke generated during surgery are potential sources of respiratory pathogens and pose a threat to operating room personnel. Surgical site evacuation can significantly reduce the volume of airborne particles in the field but requires careful design and deployment considerations.x\",\n \"Association of history of metformin use with delirium and mortality: A retrospective cohort study\\nObjectiveTo investigate the relationship between history of metformin use and delirium risk, as well as long-term mortality.\\n\\nMethodsIn this retrospective cohort study, subjects recruited between January 2016 and March 2020 were analyzed. Logistic regression analysis was performed to investigate the relationship between metformin use and delirium. Log-rank analysis and Cox proportional hazards model were used to investigate the relationship between metformin use and 3-year mortality.\\n\\nResultsThe data from 1404 subjects were analyzed. 242 subjects were categorized into a DM-without-metformin group, and 264 subjects were categorized into a DM-with-metformin group. Prevalence of delirium was 36.0% in the DM-without-metformin group, and 29.2% in the DM-with-metformin group. A history of metformin use reduced the risk of delirium in patients with DM (OR, 0.50 [95% CI, 0.32 to 0.79]) after controlling for age, sex, and dementia status, body mass index (BMI), and insulin use. The 3-year mortality in the DM-without-metformin group (survival rate, 0.595 [95% CI, 0.512 to 0.669]) was higher than in the DM-with-metformin group (survival rate, 0.695 [95% CI, 0.604 to 0.770]) (p=0.035). A history of metformin use decreased the risk of 3-year mortality after adjustment for age, sex, Charlson Comorbidity Index, BMI, history of insulin use, and delirium status (HR, 0.69 [95% CI, 0.48 to 0.98]).\\n\\nConclusionsIt was found that metformin usage was associated with decreased delirium prevalence and lower 3-year mortality. The potential benefit of metformin on delirium risk and mortality were shown.\",\n \"Standardized and optimized preservation, extraction and quantification techniques for detection of fecal SARS-CoV-2 RNA\\nCOVID-19 patients shed SARS-CoV-2 viral RNA in their stool, sometimes well after they have cleared their respiratory infection. This feature of the disease may be significant for patient health, epidemiology, and diagnosis. However, to date, methods to preserve stool samples from COVID patients, and to extract and quantify viral RNA concentration have yet to be optimized. We sought to meet this urgent need by developing and benchmarking a standardized protocol for the fecal detection of SARS-CoV-2 RNA. We test three preservative conditions for their ability to yield detectable SARS-CoV-2 RNA: OMNIgene-GUT, Zymo DNA/RNA shield kit, and the most common condition, storage without any preservative. We test these in combination with three extraction kits: the QIAamp Viral RNA Mini Kit, Zymo Quick-RNA Viral Kit, and MagMAX Viral/Pathogen Kit. Finally, we also test the utility of two detection methods, ddPCR and RT-qPCR, for the robust quantification of SARS-CoV-2 viral RNA from stool. We identify that the Zymo DNA/RNA shield collection kit and the QiaAMP viral RNA mini kit yield more detectable RNA than the others, using both ddPCR and RT-qPCR assays. We also demonstrate key features of experimental design including the incorporation of appropriate controls and data analysis, and apply these techniques to effectively extract viral RNA from fecal samples acquired from COVID-19 outpatients enrolled in a clinical trial. Finally, we recommend a comprehensive methodology for future preservation, extraction and detection of RNA from SARS-CoV-2 and other coronaviruses in stool.\",\n \"SplitStrains, a tool to identify and separate mixed Mycobacterium tuberculosis infections from WGS data\\nThe occurrence of multiple strains of a bacterial pathogen such as M. tuberculosis or C. difficile within a single human host, referred to as a mixed infection, has important implications for both healthcare and public health. However, methods for detecting it, and especially determining the proportion and identities of the underlying strains, from WGS (whole-genome sequencing) data, have been limited.\\n\\nIn this paper we introduce SplitStrains, a novel method for addressing these challenges. Grounded in a rigorous statistical model, SplitStrains not only demonstrates superior performance in proportion estimation to other existing methods on both simulated as well as real M. tuberculosis data, but also successfully determines the identity of the underlying strains.\\n\\nWe conclude that SplitStrains is a powerful addition to the existing toolkit of analytical methods for data coming from bacterial pathogens, and holds the promise of enabling previously inaccessible conclusions to be drawn in the realm of public health microbiology.\\n\\nAuthor summaryWhen multiple strains of a pathogenic organism are present in a patient, it may be necessary to not only detect this, but also to identify the individual strains. However, this problem has not yet been solved for bacterial pathogens processed via whole-genome sequencing. In this paper, we propose the SplitStrains algorithm for detecting multiple strains in a sample, identifying their proportions, and inferring their sequences, in the case of Mycobacterium tuberculosis. We test it on both simulated and real data, with encouraging results. We believe that our work opens new horizons in public health microbiology by allowing a more precise detection, identification and quantification of multiple infecting strains within a sample.\",\n \"The genetic architecture of human infectious diseases and pathogen-induced cellular phenotypes\\nHere, we develop a genetics-anchored framework to decipher mechanisms of infectious disease (ID) risk and infer causal effect on potential complications. We perform transcriptome-wide association studies (TWAS) of 35 ID traits in 27,615 individuals in a broad collection of human tissues, identifying 70 gene-level associations with 26 ID traits, with replication in two large-scale biobanks. A phenome-scale scan and Mendelian Randomization of the 70 gene-level associations across 197 traits proposes a molecular basis for known complications of the ID traits. This rich resource of host genetic associations with pathogen cultures and 16S-rRNA-based microbiome variation provides a platform to investigate host-pathogen interactions. To identify relevant cellular processes, we develop a TWAS repository of 79 pathogen-exposure induced cellular phenotypes. Our study will facilitate mechanistic insights into the role of host genetic variation on ID risk and pathophysiology, with important implications for our molecular understanding of severe phenotypic outcomes.\",\n \"Clinician and patient experience of neurology telephone consultations during the COVID-19 pandemic\\nBackgroundTelephone consultations are already employed in specific neurological settings. At Cambridge University Hospitals, the COVID-19 pandemic initially prompted almost all face-to-face appointments to be delivered by telephone, providing a uniquely unselected population to assess.\\n\\nObjectivesWe explored patient and clinician experience of telephone consultations; and whether telephone consultations might be preferable for pre-identifiable subgroups of patients after the pandemic.\\n\\nMethodsClinicians delivering neurological consultations converted to telephone between April-July 2020 were invited to complete a questionnaire following each consult (430 respondents) and the corresponding patients were subsequently surveyed (290 respondents). The questionnaires assessed clinician and patient goal achievement (and the reasons for any dissatisfaction). Clinicians also described consultation duration (in comparison to face-to-face) while patients detailed comparative convenience and preference.\\n\\nResultsThe majority of clinicians (335/430, 78%) and patients (227/290, 78%) achieved their consultation goals by telephone, particularly during follow-up consultations (clinicians 272/329, 83%, patients 176/216, 81%) and in some disease subgroups (e.g. seizures/epilepsy (clinicians 114/122 (93%), patients 71/81 (88%)). 95% of telephone consultations were estimated to take the same or less time than an equivalent face-to-face consultation. Most patients found telephone consultations convenient (69%) with 149/211 (71%) indicating they would like telephone or video consultations to play some role in their future follow-up.\\n\\nConclusionTelephone consultations appear effective, convenient and popular in prespecified subgroups of neurological outpatients. Further work comparing telephone, video and face-to-face consultations across multiple centres is now needed.\",\n \"Spillover Benefit of Pre-Exposure Prophylaxis for HIV Prevention: Evaluating the Importance of Effect Modification using an Agent-Based Model\\nWe developed an agent-based model using a trial emulation approach to quantify effect measure modification of key variables on spillover effects of pre-exposure prophylaxis (PrEP) among men who have sex with men (MSM) in Atlanta, GA. PrEP may impact not only the individual prescribed, but also their partners and beyond, known as spillover. We simulated a two-stage randomized trial with eligible components ([≥]3 agents and [≥]1 HIV+ agent) first randomized to intervention or control (no PrEP). Within intervention components, agents were randomized to PrEP with intervention coverage of 70%, providing insight into a high PrEP coverage strategy. We evaluated effect modification by component level characteristics and estimated spillover effects using an extension of randomization-based estimators. We observed an attenuation of the spillover effect when agents were in components with a higher prevalence of either drug use or bridging potential (if an agent acts as a mediator between [≥]2 connected groups of agents). The estimated spillover effects were larger in magnitude among components with either higher HIV prevalence or greater density (number of existing compared to all possible partnerships). Consideration of effect modification is important when evaluating the spillover of PrEP among MSM.\",\n \"Over- and under-estimation of vaccine effectiveness\\nSARS-CoV-2 vaccines provide not just high protection against infection to the vaccinated individual but also provide indirect protection to its surroundings by blocking further transmission. Divergent results have been reported on the effectiveness of the SARS-CoV-2 vaccines. Here, we argue that this divergence is due to the fact that the analyses did not take into account the indirect protection. Using a novel heterogenous infection model and real-world data, we demonstrate that heterogeneous vaccination rates among families and communities, and the study design that is used, may significantly skew the vaccine effectiveness estimations. We show that estimations of a vaccine with 85% effectiveness will vary between marked underestimation of [~]70% and overestimation of [~]95% depending on the number of interactions between vaccinated and unvaccinated individuals.\",\n \"Commercialized kit to assess T-cell responses against SARS-CoV-2 S peptides. A pilot study in Health Care Workers.\\nBackgroundIt is crucial to assess the levels of protection generated by natural infection or SARS-CoV-2 vaccines, mainly in individuals professionally exposed and in vulnerable groups. Measuring T-cell responses may complement antibody tests currently in use as correlates of protection. Our aim was to assess the feasibility of a validated assay of T-cell responses.\\n\\nMethodsTwenty health-care-workers (HCW) were included. Antibody test to SARS-CoV-2 N and S-proteins in parallel with a commercially available whole-blood-interferon-gamma-release-assay (IGRA) to S-peptides and two detection methods, CLIA and ELISA were determined.\\n\\nResultsIGRA test detected T-cell responses in naturally exposed and vaccinated HCW already after first vaccination dose. The correlation by the two detection methods was very high (R>0.8) and sensitivity and specificity ranged between 100 and 86% and 100-73% respectively. Even though there was a very high concordance between specific antibody levels and the IGRA assay in the ability to detect immune response to SARS-CoV-2, there was a relatively low quantitative correlation. In the small group primed by natural infection, one vaccine dose was sufficient to reach immune response plateau. IGRA was positive in one, with Ig(S) antibody negative vaccinated immunosuppressed HCW illustrating another advantage of the IGRA-test.\\n\\nConclusionWhole-blood-IGRA-tests amenable to automation and constitutes a promising additional tool for measuring the state of the immune response to SARS-CoV-2; they are applicable to large number of samples and may become a valuable correlate of protection to COVID-19, particularly for vulnerable groups at risk of being re-exposed to infection, as are health-care-workers.\",\n \"Convalescent Plasma and Improved Survival in Patients with Hematologic Malignancies and COVID-19\\nConvalescent plasma may benefit immunocompromised individuals with COVID-19, including those with hematologic malignancy. We evaluated the association of convalescent plasma treatment with 30-day mortality in hospitalized adults with hematologic malignancy and COVID-19 from a multi-institutional cohort. 143 treated patients were compared to 823 untreated controls. After adjustment for potential confounding factors, convalescent plasma treatment was associated with improved 30-day mortality (hazard ratio, 0.60; 95% CI, 0.37-0.97). This association remained significant after propensity-score matching (hazard ratio, 0.52; 95% CI, 0.29-0.92). These findings suggest a potential survival benefit in the administration of convalescent plasma to patients with hematologic malignancy and COVID-19.\",\n \"Do panic values cause panic? Reporting of critical laboratory results in a tertiary hospital in Kenya\\nPrompt communication of critical laboratory results is important for patient safety. Various standardisation bodies have proposed procedures for handling critical results, with notification parameters outlined. However, few studies exist in low- and middle-income countries (LMIC) to document how critical results are handled. We tracked 12 types of laboratory tests over a three-week period in December 2018 and documented if and how critical test results were communicated, the time-frame for communication, and evidence of action taken on the results. During the period, 331 of 5,500 (6.1%) test results were identified as critical. Only 71 (21%) of the critical results were documented as having been communicated to the destination departments. Of the communicated results, clinicians were unaware of 21 (29.6%). Of the 12 test types, critical results were only communicated for three tests namely: potassium, haemoglobin and positive malaria tests. Communication of critical results to inpatient settings was significantly higher than to outpatient settings (p <0.05), with communication rates decreasing as the week progressed, during weekends and around holidays. The observed poor communication of critical results in an LMIC setting raise significant patient safety concerns. Laboratories in these settings need to adhere to international standards, like ISO 15189:2009, to assure safe practice. Training of staff, establishment of standard operating procedures guiding these results, and implementation of fail-proof critical result dissemination mechanisms are essential. It is important that all critical results are communicated within one hour of availability. Implementation of Order Entry and Laboratory systems should be highly considered.\",\n \"High-intensity exercise is a risk factor for renal medullary carcinoma in individuals with sickle cell trait\\nRenal medullary carcinoma (RMC) predominantly occurs in individuals with sickle cell trait (SCT). We found that patients with RMC more frequently participated in high-intensity exercise than matched controls, and renal medullary hypoxia significantly increased predominantly in the right kidney of mice with SCT following high-but not moderate-intensity exercise, consistent with the distinct predilection of RMC toward the right kidney. These results establish high-intensity exercise as a risk factor for RMC in individuals with SCT.\",\n \"Cancer-associated Lactobacillus iners are genetically distinct and associated with chemoradiation resistance in cervical cancer\\nThis study identifies a novel pathotype of cervical cancer-associated Lactobacillus iners (L. iners) that results in chemoradiation resistance in vitro and is associated with poor patient survival. Cervical cancer affects over half a million women a year around the world. Treatment for women with locally advanced cancer is delivered with definitive chemoradiation (CRT) but is curative for only 60% of patients. There are few validated molecular markers to identify patients who will respond poorly to treatment. Tumor microbiome features are associated with treatment resistance in patients with colon and pancreatic cancers, and thus we investigated their role in the response of cervical cancer to therapy. We identified a strong association between poor clinical response to CRT and tumors dominated by L. iners. Cancer-associated L. iners promoted in vitro resistance of cervical cancer cells and modified the local tumor immunologic microenvironment, while non-cancer-associated L. iners did not. Assembly of genomes from cancer-derived L. iners also demonstrated pathogenic, metabolic, and immune functions not found in healthy patients.\",\n \"The spread and burden of the COVID-19 pandemic in sub-Saharan Africa: comparison between predictions and actual data and lessons learned.\\nIntroductionSub-Saharan Africa (SSA) was predicted to be severely affected by the coronavirus disease 2019 (COVID-19) pandemic, but the actual data seem to have contradicted these forecasts. This study attempted to verify this observation by comparing predictions against actual data on the spread and burden of the COVID-19 pandemic in SSA.\\n\\nMethodsFocused on the period from March 1st to September 30th, 2020, we compared (1) the predicted interval dates when each SSA country would report 1 000 and 10 000 COVID-19 cases, to the actual dates when these numbers were attained, as well as (2) the daily number of predicted versus actual COVID-19 cases.\\n\\nFurther, we calculated the case fatality ratio of the COVID-19 infection in SSA, and the correlation coefficient between the weekly average number of confirmed COVID-19 cases reported by each country and the weekly average stringency index of its anti-COVID-19 policy measures.\\n\\nResults84.61% (33) and 100% (39) of the 39 SSA countries for which predictions were made did not reach a total of 1 000 and 10 000 confirmed COVID-19 cases at the predicted interval dates. The daily number of confirmed COVID-19 cases was lower than the one projected for all SSA countries. The case fatality ratio of the COVID-19 infection in SSA was 3.42%. Among the 44 SSA countries for which the correlation could be estimated, it was negative for 17 (38.6 %) of them.\\n\\nConclusionsThe natural characteristics of SSA and the public health measures implemented might partly explain that the actual data were lower than the predictions on the COVID-19 pandemic in SSA, but the low case ascertainment and the numerous asymptomatic cases did significantly influence this observation.\",\n \"Neutralizing anti-DNase1L3 antibodies derive from autoreactive VH4-34+ B cells and associate with the interferon signature in SLE\\nDNase1L3 deficiency is an inborn error of immunity that causes monogenic systemic lupus erythematosus (SLE) in humans. Here, we identified that one third of patients with sporadic SLE have antibodies to DNase1L3. Like DNase1L3 deficiency, we found that patients with anti-DNase1L3 antibodies have features associated with immune pathways activated by immunogenic self-DNA, including elevated antibodies to dsDNA and prominent expression of the interferon and myeloid/neutrophil signatures. Interestingly, 40-80% of anti-DNase1L3 antibodies in SLE serum contain the 9G4 idiotype, which is encoded by the autoreactive heavy-chain gene segment VH4-34. Sequence and functional analysis of four anti-DNase1L3 monoclonal antibodies generated from SLE patients experiencing disease-associated flares showed that these antibodies were derived from self-reactive 9G4+ switched memory B cells. These antibodies are highly enriched in somatic hypermutations, indicating that they originated from antigen-experienced cells, and have neutralizing activity against DNase1L3. Together, the data demonstrate that autoantibodies to DNase1L3 phenocopy pathogenic mechanisms associated with DNase1L3 deficiency. Moreover, the finding that autoreactive B cells bearing the 9G4 idiotype produce dominant serum autoantibodies, including antibodies to DNase1L3, underscores VH4-34+ B cells as sensible therapeutic targets for specific depletion of pathogenic B cells in SLE.\",\n \"Predicting Prognosis in COVID-19 Patients using Machine Learning and Readily Available Clinical Data\\nRationalePrognostic tools for aiding in the treatment of hospitalized COVID-19 patients could help improve outcome by identifying patients at higher or lower risk of severe disease.\\n\\nObjectivesThe study objective was to develop models to stratify patients by risk of severe outcomes during COVID-19 hospitalization using readily available information at hospital admission.\\n\\nMethodsHierarchical ensemble classification models were trained on a set of 229 patients hospitalized with COVID-19 to predict severe outcomes, including ICU admission, development of ARDS, or intubation, using easily attainable attributes including basic patient characteristics, vital signs at admission, and basic lab results collected at time of presentation. Each test stratifies patients into groups of increasing risk. An additional cohort of 330 patients was used for blinded, independent validation. Shapley value analysis evaluated which attributes contributed most to the models predictions of risk.\\n\\nMeasurements and Main ResultsTest performance was assessed using precision (positive predictive value) and recall (sensitivity) of the final risk groups. All test cut-offs were fixed prior to blinded validation. In both development and validation, the tests achieved precision in the lowest risk groups near or above 0.9. The proportion of patients with severe outcomes significantly increased across increasing risk groups. While the importance of attributes varied by test and patient, CRP, LDH, and D-dimer were often found to be important in the assignment of risk label.\\n\\nConclusionsRisk of severe outcomes for patients hospitalized with COVID-19 infection can be assessed using machine learning-based models based on attributes routinely collected at hospital admission.\",\n \"Single-Blind and Double-Blind Peer Review: Effects on National Representation\\nBackground/ObjectivesTo assess whether the type of peer-review (single-blinded vs double-blinded) has an impact on nationality representation in journals.\\n\\nMethodsA cross-sectional study analyzing the top ten nationalities contributing to the number of articles across 16 ophthalmology journals.\\n\\nResultsThere was no significant difference in the percentage of articles published from the journals country of origin between the top single-blind journals and top double-blind journals (SB= 42.0%, DB = 26.6%, p=0.49) but there was a significant difference between the percentage of articles from the US (SB=48.0%, DB=22.8%, p=0.02). However, there was no significant difference for both country of origin (SB =38.0%, DB =26.6%, p=0.43) and articles from the US (SB=35.0%, DB=22.8%, p=0.21) when assessing the top 8 double-blind journals matched with single-blind journals of a similar impact factor. The countries that most commonly made the top ten lists for highest number of articles were the US (n=16, 100%) and England (n=16, 100%). This held true even for journals established outside the United States (US=11/12, England=11/12).\\n\\nConclusionsThere was no statistically significant difference in country-of-origin representation between single-blind journals and double-blind journals. However, higher income countries contributed most often to the journals studied even among journals based outside the US.\",\n \"The humoral response to BK polyomavirus in kidney transplant recipients is dominated by IgM antibodies that use a distinct repertoire compared to IgG against the same antigen\\n1.The BK polyomavirus (BKPyV) persists asymptomatically in the kidney and active replication is only seen in immunosuppressed individuals, such as kidney transplant (KTx) recipients, in whom BKPyV reactivation can cause significant morbidity. KTx recipients with BKPyV reactivation mount a robust humoral response, but this often fails to clear the virus. In order to characterize the BKPyV-specific B-cell receptor (BCR) repertoire in KTx recipients, we used fluorescence-labeled BKPyV virus-like particles (VLPs) to sort with BKPyV-specific B-cells, then single-cell RNAseq to obtain paired heavy and light chain antibody sequences, and gene transcriptome data. The BCR repertoire was highly diverse in terms of both V-gene usage and clonotype diversity, with approximately 3% repertoire overlap between patients. The BKPyV-specific response was characterized by the presence of both memory IgG and memory IgM B-cells with extensive somatic hypermutation, which expressed distinct BCR repertoires within the same patient. The gene expression profile of IgG and IgM memory B-cells was highly similar, with only 19 genes, including CD83, CD79A and PARP1 showing significant differential expression. These results confirm that the IgM memory B-cells are a significant component of the BKPyV-specific humoral response, and show for the first time that IgG and IgM repertoires directed against the same antigen can have significant differences.\",\n \"Design of optical cavity for air sanification through ultraviolet germicidal irradiation\\nThe transmission of airborne pathogens represents a major issue to worldwide public health. Ultraviolet light irradiation can contribute to the sanification of air to reduce the pathogen transmission. This study concerns the design of a compact filter for airborne pathogen inactivation by means of UV-C LED sources, whose effective irradiance is enhanced thanks to high reflective surfaces. Ray-tracing and computational fluid dynamic simulations are both used to model the device and to maximize the performance inside the filter volume. Simulations foresee the inhibition of SARS-Cov 2 also in the case of high air fluxes. This study demonstrates that current available LED technology is effective for air sanification purposes.\",\n \"Prediction of recessive inheritance for missense variants in human disease\\nThe prediction of pathogenic human missense variants has improved in recent years, but a more granular level of variant characterization is required. Further axes of information need to be incorporated in order to advance the genotype-to-phenotype map. Recent efforts have developed mode of inheritance prediction tools; however, these lack robust validation and their discrimination performance does not support clinical utility, with evidence of them being fundamentally insensitive to recessive acting diseases. Here, we present MOI-Pred, a three-way variant-level mode of inheritance prediction tool aimed at recessive identification for missense variants. MOI-Pred shows strong ability to discriminate missense variants causing autosomal recessive disease (area under the receiver operating characteristic (AUROC)=0.99 and sensitivity=0.85) in an external validation set. Additionally, we introduce an electronic health record (EHR)-based validation approach using real-world clinical data and show that our recessive predictions are enriched for recessive associations with human diseases, demonstrating utility of our method. Mode of inheritance predictions - pathogenic for autosomal recessive (AR) disease, pathogenic for autosomal dominant (AD) disease, or benign - for all possible missense variants in the human genome are available at https://github.com/rondolab/MOI-Pred/.\",\n \"A Clinical Feasibility Study of an Artificial Intelligence-Powered Clinical Decision Support System\\nObjectiveWe examine the feasibility of an Artificial Intelligence (AI)-powered clinical decision support system (CDSS), which combines the operationalized 2016 Canadian Network for Mood and Anxiety Treatments guidelines with a neural-network based individualized treatment remission prediction.\\n\\nMethodsDue to COVID-19, the study was adapted to be completed entirely at a distance. Seven physicians recruited outpatients diagnosed with major depressive disorder (MDD) as per DSM-V criteria. Patients completed a minimum of one visit without the CDSS (baseline) and two subsequent visits where the CDSS was used by the physician (visit 1 and 2). The primary outcome of interest was change in session length after CDSS introduction, as a proxy for feasibility. Feasibility and acceptability data were collected through self-report questionnaires and semi-structured interviews.\\n\\nResultsSeventeen patients enrolled in the study; 14 completed. There was no significant difference between appointment length between visits (introduction of the tool did not increase session length). 92.31% of patients and 71.43% of physicians felt that the tool was easy to use. 61.54% of the patients and 71.43% of the physicians rated that they trusted the CDSS. 46.15% of patients felt that the patient-clinician relationship significantly or somewhat improved, while the other 53.85% felt that it did not change.\\n\\nConclusionsOur results confirm the primary hypothesis that the integration of the tool does not increase appointment length. Findings suggest the CDSS is easy to use and may have some positive effects on the patient-physician relationship. The CDSS is feasible and ready for effectiveness studies.\",\n \"Amplicon-based nanopore minion sequencing of patients with COVID-19 omicron variant from India\\nSARS-CoV-2 infection has been playing havoc with emerging omicron variants of concern (VoC). Here, we report sequencing of the omicron variant in 13 patients from India using Oxford Nanopore Technology (ONT) Minion, wherein a rapid amplicon based sequence analysis was performed to assess and compare with existing 34 mutations in spike glycoprotein. We highlight and discuss the nature of these mutations that are unique and common to other populations. This is perhaps the first report on omicron variants from India using a long read sequencing chemistry.\",\n \"Improving prediction of amyloid deposition in Mild Cognitive Impairment with a timed motor task\\nCortical amyloid deposition is one of the hallmark biomarkers of Alzheimers disease. However, given how cost- and time-intensive amyloid imaging can be, there is a continued need for a low-cost, non-invasive, and accessible enrichment strategy to pre-screen individuals for their likelihood of amyloid prior to imaging. Previous work supports the use of coordinated limb movement as a potential screening tool, even after controlling for cognitive and daily function. Thirty-six patients diagnosed with amnestic Mild Cognitive Impairment over the age of 65 underwent 18F-Flutemetamol amyloid-positron emission tomography imaging, then completed a timed motor task involving upper limb coordination. This task takes [~]5 minutes to administer and score. Multivariate linear regression and Receiver Operator Characteristic analyses showed that including motor task performance improved model prediction of amyloid burden. Results support the rationale for including functional upper extremity motor assessment as a cost- and time-effective means to screen participants for amyloid deposition.\",\n \"Barriers to early initiation of breastfeeding in healthy neonates in an urban hospital setting.\\nBackgroundBreastfeeding is a key intervention to improve global targets on nutrition, health and survival. The World Health Organization (WHO) recommends early initiation of breastfeeding to prevent infections in the newborn and achieve targets of exclusive breastfeeding for the first six months of life. Early initiation of breastfeeding improves neonatal-maternal bonding, reduces jaundice and prevents gastrointestinal and respiratory tract infections. Global prevalence of early initiation of breastfeeding is 45% and 51% for Tanzania. The recommended prevalence is at least 80% by WHO guidelines.\\n\\nObjectiveTo explore barriers to early initiation of breastfeeding in a hospital setting.\\n\\nMethodsA descriptive exploratory qualitative study with semi-structured individual interviews was employed to explore the barriers to early initiation of breastfeeding in a hospital setting. Three midwives and six mothers were interviewed. The interview topic guide covered experiences and challenges of early initiation of breastfeeding. Data was analyzed using Systematic Text Condensation as described by Malterud.\\n\\nResultsParticipants perceived that inadequate breastfeeding information especially on ideal time to start breastfeeding contributed to delayed initiation. The practices and environment post-delivery such as perineal tear repair and dirty labor room prevented women from initiating breastfeeding immediately.\\n\\nConclusionsThe barriers identified were related to gaps in knowledge, immediate postpartum practices and individual perceptions of a non-conducive environment.\",\n \"Excess Serum Interleukin-18 Distinguishes Patients with Pathogenic Mutations in PSTPIP1\\nObjectiveDominantly-inherited mutations in PSTPIP1 cause a family of monogenic autoinflammatory diseases epitomized by Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA) syndrome. The connections between PSTPIP1 and PAPA are poorly understood, although in vitro evidence suggests increased activation of the pyrin-inflammasome. We sought to identify biomarkers of potential mechanistic, diagnostic, and therapeutic utility specific to autoinflammatory diseases.\\n\\nMethodsClinical and genetic data and sera were obtained from patients referred with concern for PAPA syndrome, as well as relevant disease controls. Serum Interleukin-18 (IL-18) and related biomarkers were assessed by bead-based assay.\\n\\nResultsSymptoms in PSTPIP1 mutation-positive PAPA patients overlapped with those of mutation-negative PAPA-like patients, but the former were younger at onset and had more arthritis. We found uniform elevation of total IL-18 in PAPA patients at a level approaching NLRC4-associated Macrophage Activation Syndrome (MAS) and well beyond Familial Mediterranean Fever. IL-18 elevation in PAPA patients sera persisted despite fluctuations in disease activity. IL-18 Binding Protein (IL-18BP) was modestly elevated, and as such PAPA patients had detectable free IL-18. PAPA patients did not develop MAS, and CXCL9 (an indicator of Interferon-gamma activity) was rarely elevated in their sera.\\n\\nConclusionPAPA syndrome is a refractory, and often disabling monogenic autoinflammatory disease associated with chronic elevation of serum IL-18, but not risk for MAS. This finding instructs our understanding of the origins of excess IL-18, its potential spectrum of pathogenic effects, and the possible role for IL-18 blockade in refractory PAPA syndrome.\",\n \"Dose-dependent effect of nuts on blood pressure: a systematic review and meta-analysis of randomized controlled trials\\nObjectiveTraditional pairwise meta-analyses indicated that nuts consumption can improve blood pressure. We iamed to determine the dose-dependent effect of nuts on systolic (SBP) and diastolic blood pressure (DBP) in adults.\\n\\nMethodsA systematic search was undertaken in PubMed, Scopus, and ISI Web of Science till March 2021. Randomized controlled trials (RCT) evaluating the effects of nuts on SBP and DBP in adults were included. We estimated change in blood pressure for each 20 g/d increment in nut consumption in each trial and then, calculated mean difference (MD) and 95%CI using a random-effects model. We estimated dose-dependent effect using a dose-response meta-analysis of differences in means. The certainty of evidence was rated using the GRADE instrument, with the minimal clinically important difference being considered 2 mmHg.\\n\\nResultsA total of 31 RCTs with 2784 participants were included. Each 20 g/d increase in nut consumption reduced SBP (MD: -0.50 mmHg, 95%CI: -0.79, -0.21; I2 = 12%, n = 31; GRADE = moderate certainty) and DBP (MD: -0.23 mmHg, 95%CI: -0.38, -0.08; I2 = 0%, n = 31; GRADE = moderate certainty). The effect of nuts on SBP was more evident in patients with type 2 diabetes (MD: -1.31, 95%CI: -2.55, -0.05; I2 = 31%, n = 6). The results were robust in the subgroup of trials with low risk of bias. Levels of SBP decreased proportionally with the increase in nuts consumption up to 40 g/d (MD40g/d: -1.60, 95%CI: -2.63, -0.58), and then appeared to plateau with a slight upward curve. A linear dose-dependent reduction was seen for DBP, with the greatest reduction at 80 g/d (MD80g/d: -0.80, 95%CI: -1.55, -0.04).\\n\\nConclusionsThe available evidence provides a good indication that nut consumption can result in a small improvement in blood pressure in adults. Well-designed trials are needed to confirm the findings in long term follow-up.\",\n \"Patients Experiences of Using Smartphone Apps to Manage their Gestational Diabetes Diagnosis: A Systematic Review - protocol (version 1)\\nBackgroundGestational diabetes is a strong predictor of type 2 diabetes onset. However, women who make healthy dietary and lifestyle choices can significantly reduce their risk. There is a need to understand the factors facilitating or preventing women from using smartphone apps that may encourage these behaviours.\\n\\nMethodsWe plan to conduct a systematic review of patient experiences when using mobile health applications to manage gestational diabetes. We will include primary studies of qualitative data around patient experiences of using these applications, as well as the barriers and facilitators to using technologies. We will search the following electronic databases: Medline, Embase, PsycINFO, Global Health, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), AMED and CINAHL and manually search the reference lists of included studies. We will include primary studies involving direct user interviews and where the results have been analysed using qualitative methods. To assess the quality of included studies, we will use the CASP qualitative research checklist.\\n\\nExpected resultsWe intend to use summary tables to report the characteristics of the study population, the overarching themes that emerged, and recommendations for research and practice.\",\n \"The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: A Mendelian randomization study\\nDespite early interest, the evidence linking fatty acids to cardiovascular diseases remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the aetiology of several cardiovascular disease endpoints in up to 1,153,768 European and 212,453 East Asian ancestry individuals. As instruments, we selected single nucleotide polymorphisms (SNP) mapping to genes with well-known roles in PUFA (i.e. FADS1/2 and ELOVL2) and MUFA (i.e. SCD) biosynthesis. Our findings suggest that higher PUFA biosynthesis rate (proxied by rs174576 near FADS1/2) is related to higher odds of multiple cardiovascular diseases, particularly ischemic stroke, peripheral artery disease and venous thromboembolism, whereas higher MUFA biosynthesis rate (proxied by rs603424 near SCD) is related to lower odds of coronary artery disease among Europeans. Results were unclear for East Asians as most effect estimates were imprecise. By triangulating multiple approaches (i.e. uni-/multi-variable Mendelian randomization, a phenome-wide scan, genetic colocalization and within-sibling analyses), our results are compatible with higher low- density lipoprotein (LDL)-cholesterol (and possibly glucose) being a downstream effect of higher PUFA biosynthesis rate. Our findings indicate that genetically-determined PUFA and MUFA biosynthesis are involved in the aetiology of cardiovascular diseases and suggest LDL-cholesterol as a potential mediating trait between PUFA biosynthesis and cardiovascular diseases risk.\",\n \"Intramuscular SARS-CoV-2 vaccines elicit varying degrees of plasma and salivary antibody responses as compared to natural infection\\nVaccination induced antibody and T-cell immune responses are important for systemic protection from COVID-19. Because SARS-CoV-2 infects and is transmitted by oral-pharyngeal mucosa, we wished to test mucosal antibodies elicited by natural infection or intramuscular vaccine injection. In a non-randomized observational study, we measured antibodies against the SARS-CoV-2 RBD in plasma and saliva from convalescent or vaccinated individuals and tested their neutralizing potential using a replication competent rVSV-eGFP-SARS-CoV-2. We found IgG and IgA anti-RBD antibodies as well as neutralizing activity in convalescent plasma and saliva. Two doses of mRNA vaccination (BNT162b2 or mRNA-1273) induced high levels of IgG anti-RBD in saliva, a subset of whom also had IgA, and significant neutralizing activity. We detected anti-RBD IgG and IgA with significant neutralizing potential in the plasma of single dose Ad26.COV2.S vaccinated individuals, and we detected slight amounts of anti-RBD antibodies in matched saliva. The role of salivary antibodies in protection against SARS-CoV-2 infection is unknown and merits further investigation. This study was not designed to, nor did it study the full kinetics of the antibody response or protection from infection, nor did it address variants of SARS-CoV-2.\",\n \"Design of an optimal combination therapy with broadly neutralizing antibodies to suppress HIV-1\\nBroadly neutralizing antibodies (bNAbs) are promising targets for vaccination and therapy against HIV. Passive infusions of bNAbs have shown promise in clinical trials as a potential alternative for anti-retroviral therapy. A key challenge for the potential clinical application of bnAbs is the suppression of viral escape, which is more effectively achieved with a combination of bNAbs. However, identifying an optimal bNAb cocktail is combinatorially complex. Here, we propose a computational approach to predict the efficacy of a bNAb therapy trial based on the population genetics of HIV escape, which we parametrize using high-throughput HIV sequence data from a cohort of untreated bNAb-naive patients. By quantifying the mutational target size and the fitness cost of HIV-1 escape from bNAbs, we reliably predict the distribution of rebound times in three clinical trials. Importantly, we show that early rebounds are dominated by the pre-treatment standing variation of HIV-1 populations, rather than spontaneous mutations during treatment. Lastly, we show that a cocktail of three bNAbs is necessary to suppress the chances of viral escape below 1%, and we predict the optimal composition of such a bNAb cocktail. Our results offer a rational design for bNAb therapy against HIV-1, and more generally show how genetic data could be used to predict treatment outcomes and design new approaches to pathogenic control.\",\n \"Competitive fitness of emerging SARS-CoV-2 variants is linked to their Distinctiveness relative to preceding lineages from that region\\nThe COVID-19 pandemic has seen the persistent emergence of fitter Variants of Concern (VOCs) that have successfully out-competed circulating strains, but the determinants of viral fitness remain unknown. Here we define Distinctiveness of SARS-CoV-2 sequences based on a proteome-wide comparison with all prior sequences from the same geographical region. From the perspective of viral evolution, Distinctiveness captures \\\"regional herd exposure\\\" and has the advantage over the canonical concept of mutation, which relies foremost on the reference ancestral sequence that is invariant over time. By assessing the correlation between Distinctiveness and change in prevalence for all circulating lineages in each region when a new lineage is introduced, we find that the relative Distinctiveness of emergent SARS-CoV-2 lineages is associated with their competitive fitness (Pearson r = 0.67). Further, by assessing the Delta variant in India versus Brazil, we show that the same lineage can have different Distinctiveness-contributing positions in different geographical regions depending on the other variants that previously circulated in those regions. Finally, analysis of Omicron lineages in India and USA shows the BA.1 and BA.2 sub-lineages have comparable distinctiveness, suggesting that they may have similar levels of competitive fitness. Overall, our study proposes that augmenting the ongoing surveillance of highly mutated variants with real-time assessment of Distinctiveness can aid in achieving robust pandemic preparedness.\",\n \"Comprehensive Joint Modeling of First-Line Therapeutics in Non-Small Cell Lung Cancer\\nFirst-line antiproliferatives for non-small cell lung cancer (NSCLC) have a relatively high failure rate due to high intrinsic resistance rates and acquired resistance rates to therapy. 57% patients are diagnosed in late-stage disease due to the tendency of early-stage NSCLC to be asymptomatic. For patients first diagnosed with metastatic disease the 5-year survival rate is approximately 5%. To help accelerate the development of novel therapeutics and computer-based tools for optimizing individual therapy, we have collated data from 11 different clinical trials in NSCLC and developed a semi-mechanistic, clinical model of NSCLC growth and pharmacodynamics relative to the various therapeutics represented in the study. In this study, we have produced extremely precise estimates of clinical parameters fundamental to cancer modeling such as the rate of acquired resistance to various pharmaceuticals, the relationship between drug concentration and rate of cancer cell death, as well as the fine temporal dynamics of anti-VEGF therapy. In the simulation sets documented in this study, we have used the model to make meaningful descriptions of efficacy gain in making bevacizumab-antiproliferative combination therapy sequential, over a series of days, rather than concurrent.\",\n \"Effects of Diet on the Microbiome and Serum Metabolome of South Asian Infants at 1 Year\\nDiet is known to affect the gut microbiome and metabolome composition in adults, but this has not been fully explored in infants. Dietary patterns from 1 year-old infants (n=182) from the South Asian Birth Cohort (START) study were compared to gut microbiome alpha and beta diversity and to taxa abundance differences. Diet - serum metabolite associations were identified using multivariate analysis (partial least squares-discriminant analysis, PLS-DA) and univariate analysis (T-Test). Dietary biomarkers identified from START were also examined in a separate cohort of white Caucasian infants (CHILD Cohort Study, n=82). Lastly, the association of diet with gut microbiome and serum biomarkers, considering maternal, perinatal and infant characteristics was investigated using multivariate forward stepwise regression. A dietary pattern characterized by breastfeeding, supplemented by formula and dairy was the strongest predictor of the gut microbiome that also differentiated the serum metabolome of infants. The formula and dairy dietary pattern was associated with a panel of circulating metabolites in both cohorts, including: S-methylcysteine, branched-chain/aromatic amino acids, lysine, dimethylglycine, and methionine. Breastfeeding status, the prominent feature of the dietary pattern, was also associated with a sub-set of serum metabolites in both cohorts. In START, this diet pattern was associated with the metabolites tryptophan betaine, 2-hydroxybutyric acid, tyrosine, phenylalanine, and trimethyl-N-oxide. In the CHILD Cohort Study(CHILD), breastfeeding status was associated with the metabolites aminooctanoic acid, 3-hydroxybutyric acid, and methyl-proline. The results of our study suggest that breastfeeding has the largest effect on the composition of the gut microbiome and the serum metabolome at 1 year, even when solid food diet and other covariates are considered.\",\n \"A 6-mRNA host response whole-blood classifier trained using patients with non-COVID-19 viral infections accurately predicts severity of COVID-19\\nBackgroundDetermining the severity of COVID-19 remains an unmet medical need. Our objective was to develop a blood-based host-gene-expression classifier for the severity of viral infections and validate it in independent data, including COVID-19.\\n\\nMethodsWe developed the classifier for the severity of viral infections and validated it in multiple viral infection settings including COVID-19. We used training data (N=705) from 21 retrospective transcriptomic clinical studies of influenza and other viral illnesses looking at a preselected panel of host immune response messenger RNAs.\\n\\nResultsWe selected 6 host RNAs and trained logistic regression classifier with a cross-validation area under curve of 0.90 for predicting 30-day mortality in viral illnesses. Next, in 1,417 samples across 21 independent retrospective cohorts the locked 6-RNA classifier had an area under curve of 0.91 for discriminating patients with severe vs. non-severe infection. Next, in independent cohorts of prospectively (N=97) and retrospectively (N=100) enrolled patients with confirmed COVID-19, the classifier had an area under curve of 0.89 and 0.87, respectively, for identifying patients with severe respiratory failure or 30-day mortality. Finally, we developed a loop-mediated isothermal gene expression assay for the 6-messenger-RNA panel to facilitate implementation as a rapid assay.\\n\\nConclusionsWith further study, the classifier could assist in the risk assessment of COVID-19 and other acute viral infections patients to determine severity and level of care, thereby improving patient management and reducing healthcare burden.\",\n \"Two Data-Driven Approaches to Identifying the Spectrum of Problematic Opioid Use: A Pilot Study within a Chronic Pain Cohort\\nASTRACTO_ST_ABSBackgroundC_ST_ABSAlthough electronic health records (EHR) have significant potential for the study of opioid use disorders (OUD), detecting OUD in clinical data is challenging. Models using EHR data to predict OUD often rely on case/control classifications focused on extreme opioid use. There is a need to expand this work to characterize the spectrum of problematic opioid use.\\n\\nMethodsUsing a large academic medical center database, we developed 2 datadriven methods of OUD detection: (1) a Comorbidity Score developed from a Phenome-Wide Association Study of phenotypes associated with OUD and (2) a Textbased Score using natural language processing to identify OUD-related concepts in clinical notes. We evaluated the performance of both scores against a manual review with correlation coefficients, Wilcoxon rank sum tests, and area-under the receiver operating characteristic curves. Records with the highest Comorbidity and Text-based scores were re-evaluated by manual review to explore discrepancies.\\n\\nResultsBoth the Comorbidity and Text-based OUD risk scores were significantly elevated in the patients judged as High Evidence for OUD in the manual review compared to those with No Evidence (p = 1.3E-5 and 1.3E-6, respectively). The risk scores were positively correlated with each other (rho = 0.52, p < 0.001). AUCs for the Comorbidity and Text-based scores were high (0.79 and 0.76, respectively). Follow-up manual review of discrepant findings revealed strengths of data-driven methods over manual review, and opportunities for improvement in risk assessment.\\n\\nConclusionRisk scores comprising comorbidities and text offer differing but synergistic insights into characterizing problematic opioid use. This pilot project establishes a foundation for more robust work in the future.\",\n \"Markers of brain and endothelial Injury and inflammation are acutely and sex specifically regulated in SARS-CoV-2 infection\\nObjectiveTo investigate brain injury markers (BIM), endothelial injury markers (EIM) and cytokine/chemokine (CC) markers of systemic inflammation in coronavirus disease 2019 (COVID-19) and across sex.\\n\\nMethodsPlasma samples from 57 subjects at <48 hours of COVID-19 hospitalization, 14 subjects at 3 months of COVID-19 hospitalization and 20 matched controls were interrogated for the levels of six BIMs - including GFAP, S100B, Syndecan-1, UCHLI, MAP2 and NSE, two EIMs - including sICAM1 and sVCAM1 and thirty-eight CCs. Statistical and bioinformatics methods were used to measure differences in the marker profiles across (a) COVID-19 vs controls and (b) men vs women.\\n\\nResultsThree BIMs: MAP2, NSE and S100B, two EIMs: sICAM1 and sVCAM1 and seven CCs: GRO IL10, sCD40L, IP10, IL1Ra, MCP1 and TNF were significantly (p<0.05) elevated in the COVID-19 cohort compared to controls. Two CCs: MDC and MIP1 were significantly lower in the COVID-19 cohort. Bioinformatics analysis reveal a stronger positive association between BIM/CC/EIMs in the COVID-19 cohort. Analysis across sex revealed that several BIMs and CCs including NSE, IL10, IL15 and IL8 were significantly (p<0.05) higher in men compared to women. Men also expressed a more robust BIM/ EIM/CC association profile compared to women. At 3 months, BIMs and CCs were not significantly different in the COVID-19 cohort compared to controls.\\n\\nConclusionThe acute elevation of BIMs, CCs, and EIMs and the robust associations among them at COVID-19 hospitalization suggest that brain injury is mediated by endotheliopathy and inflammation. Higher BIM and inflammatory markers in men additionally suggest that men are more susceptible to the risk compared to women.\",\n \"Genome-wide association study identifies two new loci associated with anti-NMDAR encephalitis\\nObjectiveTo investigate the genetic determinants of the most common type of antibody-mediated autoimmune encephalitis, anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis.\\n\\nMethodsWe performed a genome-wide association study in 178 patients with anti-NMDAR encephalitis and 590 healthy controls followed by a colocalization analysis to identify putatively causal genes.\\n\\nResultsWe identified two independent risk loci harboring genome-wide significant variants (P < 5 x 10-8, OR [≤] 2.2), one on chromosome 15, harboring only the LRRK1 gene, and one on chromosome 11 centered on the ACP2 and NR1H3 genes in a larger region of high linkage-disequilibrium. Colocalization signals with expression quantitative trait loci (eQTL) for different brain regions and immune cell types suggested ACP2, NR1H3, MADD, DDB2, and C11orf49 as putatively causal genes. The best candidate genes in each region are LRRK1, encoding Leucine-Rich Repeat Kinase 1, a protein involved in B-cell development, and NR1H3 liver x receptor alpha, a transcription factor whose activation inhibits inflammatory processes.\\n\\nConclusionThis study provides evidence for relevant genetic determinants of antibody-mediated autoimmune encephalitides outside the HLA-region. The results suggest that future studies with larger sample sizes will successfully identify additional genetic determinants and contribute to the elucidation of the pathomechanism.\",\n \"Parental attitudes towards mandatory vaccination; a systematic review\\nWhile mandatory vaccination schemes can increase vaccine uptake rates, they can also cause backlash among some parents. We conducted a systematic review investigating parental beliefs about vaccine mandates and factors associated with support for mandatory vaccination schemes. We searched Embase, Ovid MEDLINE, Global Health, APA PsycINFO and Web of Science from inception to 17th September 2020. Seventeen studies (five qualitative, twelve quantitative) were eligible for inclusion. We synthesised results of qualitative and quantitative studies separately. Studies were heterogeneous with regard to schemes investigated and factors investigated. Quantitative studies found little evidence for any factors being consistently associated with support for mandatory vaccination. Qualitative studies found that parents perceived mandatory vaccination schemes as an infringement of their rights and that they preferred universal, compared to targeted, schemes. To optimise engagement with existing child mandatory vaccination legislation, schemes should be designed with parental beliefs in mind.\",\n \"Infrared spectroscopy enables rapid, robust, portable COVID-19 saliva screening based on pathophysiological response to SARS-CoV-2\\nFourier-transform infrared (FTIR) spectroscopy provides a (bio)chemical snapshot of the sample, and was recently proposed for COVID-19 saliva screening in proof-of-concept cohort studies. As a step towards translation of this technology, we conducted controlled validation experiments in multiple biological systems. SARS-CoV-2 or UV-inactivated SARS-CoV-2 were used to infect Vero E6 cells in vitro, and K18-hACE2 mice in vivo. Potentially infectious culture supernatant or mouse oral lavage samples were treated with ethanol or Trizol to 75% (v/v) for attenuated total reflectance (ATR)-FTIR spectroscopy, or RT-PCR, respectively. The control condition, UV-inactivated SARS-CoV-2 elicited strong biochemical changes in culture supernatant/oral lavage despite lack of replication determined by RT-PCR or cell culture infectious dose 50%. Crucially, we show that active SARS-CoV-2 infection induced additional FTIR signals over the UV-inactivated SARS-CoV-2 infection, which correspond to innate immune response, aggregated proteins, and RNA. For human patient cohort prediction, we achieved high sensitivity of 93.48% on leave-on-out cross validation (n=104 participants) for predicting COVID-19 positivity using a partial least squares discriminant analysis model, in agreement with recent studies. However, COVID-19 patients negative on follow-up (RT-PCR on day of saliva sampling) were poorly predicted in this model. Importantly, COVID-19 vaccination did not lead to mis-classification of COVID-19 negatives. Meta-analysis revealed SARS-CoV-2 induced increase in Amide II band in all arms of this study and recent studies, indicative of altered {beta}-sheet structures in secreted proteins. In conclusion, ATR-FTIR is a robust, simple, portable method for COVID-19 saliva screening based on detection of pathophysiological responses to SARS-CoV-2.\",\n \"Whole Genome Sequencing identifies novel structural variant in a large Indian family affected with X - linked agammaglobulinemia\\nBackgroundX - linked agammaglobulinemia (XLA, OMIM #300755) is a primary immunodeficiency disorder caused by pathogenic variations in the BTK gene, characterized by failure of development and maturation of B lymphocytes. The estimated prevalence worldwide is 1 in 190,000 male births. Recently, genome sequencing has been widely used in difficult to diagnose and familial cases. We report a large Indian family suffering from XLA with five affected individuals.\\n\\nMethodsWe performed complete blood count, immunoglobulin assay, and lymphocyte subset analysis for all patients and analyzed Btk expression for one patient and his mother. Whole exome sequencing (WES) for four patients, and whole genome sequencing (WGS) for two patients have been performed. Carrier screening was done for 17 family members using Multiplex Ligation-dependent Probe Amplification (MLPA) and haplotype ancestry mapping using fineSTRUCTURE was performed.\\n\\nResultsAll patients had hypogammaglobulinemia and low CD19+ B cells. One patient who underwent Btk estimation had low expression and his mother showed a mosaic pattern. On structural variant analysis of WGS data, we found a novel large deletion of 5,296 bp at loci chrX:100,624,323-100,629,619 encompassing exons 3-5 of the BTK gene. Family screening revealed seven carriers for the deletion. Two patients had a successful HSCT. Haplotype mapping revealed mainly South Asian ancestry.\\n\\nConclusionWhole genome sequencing led to identification of the accurate genetic mutation which could help in early diagnosis leading to improved outcomes, prevention of permanent organ damage and improved quality of life, as well as enabling prenatal diagnosis.\",\n \"A Novel de novo TP63 Mutation in WholeExome Sequencing of a Syrian Family with Oral Cleft and Ectrodactyly\\nOral clefts and ectrodactyly are common, heterogeneous birth defects. We performed whole exome sequencing (WES) analysis in a Syrian family. The proband presented with both orofacial clefting and ectrodactyly. A paternal side second-degree relative with only an oral cleft was deceased and unavailable for analysis. Variant annotation, Mendelian inconsistencies, and novel variants in known cleft genes were examined. Candidate variants were validated using Sanger sequencing. Twentyeight candidate de novo events were identified, one of which is in a known oral cleft and ectrodactyly gene, TP63 (c.956G>T, p.Arg319Leu), and confirmed by Sanger sequencing. A triallelic SNV was also found in HLA-DRB5, which is similar to and overlaps the known oral cleft gene HLA-DRB1.\\n\\nTP63 mutations are associated with multiple autosomal dominant orofacial clefting and limb malformation disorders. The p.Arg319Leu mutation seen in this patient is de novo but also novel. A known mutation 1bp upstream (rs121908839, c.955C>T, p.Arg319Cys) causes ectrodactyly, providing evidence that mutating this codon is deleterious. It is unclear whether this patients mutation is responsible for the entire phenotype. Generation and characterization of tp63 knockout zebrafish showed necrosis and rupture of the head at 3 days postfertilization. The embryonic phenotype could not be rescued by injection of zebrafish or human mRNA. Further functional analysis is needed to determine what proportion of the phenotype is due to this mutation.\",\n \"Improving the Diagnosis of SIBO Using an At-Home Handheld App Connected Breath Analysis Device (AIRE)\\nINTRODUCTIONSmall Intestinal Bacterial Overgrowth (SIBO) is a common yet underdiagnosed condition. Lactulose hydrogen breath tests (LHBT) are typically used to detect SIBO; however, current breath testing methods require specialised, expensive equipment and technical support and are either done at a point-of-care facility and/or have to be mailed to a central laboratory. To address these issues a novel hand-held breath analyzer (AIRE(R), FoodMarble) was tested. The aims of this study were first, to perform a technical assessment of the AIRE device, second to compare the performance of the AIRE device against a commercially available mail-in LHBT kit using a zero-inflated negative binomial mixed effect model.\\n\\nMETHODSThree AIRE devices were tested with certified test gases covering a diagnostically meaningful range (hydrogen mixed with air at 3 ppm, 10 ppm and 50 ppm). For the clinical study, 36 patients suspected to have SIBO presenting to a tertiary level clinic were provided with an AIRE device and performed concurrent LHBTs at home with a mail-in LHBT kit.\\n\\nRESULTSThe overall average readings (mean {+/-} SD) for the AIRE devices tested at 3 ppm, 10 ppm and 50 ppm H2 were: 3.5 {+/-} 0.7 ppm; 10.7 {+/-} 1.1 ppm and 49.5 {+/-} 2.6 ppm respectively. The overall mean absolute error across the tested devices was 1.2 ppm. A significant positive correlation (r = 0.78, p < 0.001) was demonstrated between AIRE and mail-in kit H2 values.\\n\\nDISCUSSIONThe AIRE device is a compelling alternative to mail-in LHBT kits for the diagnosis of SIBO. The AIRE device may also offer advantages over other traditional breath testing methods.\",\n \"Accurate and reproducible prediction of ICU readmissions\\nReadmission in the intensive care unit (ICU) is associated with poor clinical outcomes and high costs. Traditional scoring methods to help clinicians deciding whether a patient is ready for discharge have failed to meet expectations, paving the way for machine learning based approaches. Freely available datasets such as MIMIC-III have served as benchmarking media to compare such tools. We used the OMOP-CDM version of MIMIC-III (MIMIC-OMOP) to train and evaluate a lightweight tree boosting method to predict readmission in ICU at different time points after discharge (3, 7 and 30 days), outperforming existing solutions with an AUROC of 0.805 for 3-days readmission.\",\n \"Searching for prognostic biomarkers of Parkinson's Disease development in the Spanish EPIC cohort through a multiplatform metabolomics approach\\nObjectiveThe lack of knowledge about the onset and progression of Parkinsons disease (PD) hampers its early diagnosis and treatment. Our aim was to determine the biochemical remodeling induced by PD in a really early and pre-symptomatic stage and unveiling early potential diagnostic biomarkers adopting a multiplatform (LC-MS, GC-MS, CE-MS) untargeted metabolomics approach.\\n\\nMethods41,437 healthy volunteers from the European Prospective Study on Nutrition and Cancer (EPIC)-Spain cohort were followed for around 15 years to ascertain incident PD. For this study, baseline pre-clinical plasma samples of 39 randomly selected individuals (46% females, 41- 69 years old) that developed PD (Pre-PD group) and the corresponding control group (n=39, 46% females, 41-69 years old) were analyzed. The metabolic differences were investigated by univariate and multivariate data analyses, followed by pathway-based metabolite analyses to obtain possible clues on biological functions.\\n\\nResultsOur results exposed significantly lower levels of seven free fatty acids in the pre-PD subjects, together with alterations in other metabolite classes. Our finding revealed alterations in fatty acids metabolism, mitochondrial dysfunction, oxidative stress, and gut-brain axis dysregulation.\\n\\nConclusionsAlthough the biological purpose of these events is still unknown, the mechanisms involved in the remodelling of the suggested metabolic pathways seem to appear long before the development of PD hallmarks. These findings might be considered as worthy potential markers whose alteration might lead to the development of PD hallmarks in the future. Consequently, this study is of inestimable value since this is the first study conducted with samples collected many years before the disease development.\",\n \"The Association of Stay-at-Home Orders and the Spread of COVID-19 in Rural and Urban United States\\nBackgroundThroughout the spring of 2020, stay-at-home orders were imposed to curb the spread of COVID-19. There is limited data on the effectiveness of stay-at-home orders, particularly in rural as compared to urban areas.\\n\\nObjectiveTo examine the association between stay-at-home order implementation and the incidence of COVID-19 in rural vs. urban counties.\\n\\nDesignInterrupted time series analysis using a mixed effects zero-inflated Poisson model.\\n\\nParticipants3,142 U.S. counties.\\n\\nInterventionsStay-at-home orders.\\n\\nMain MeasuresCOVID-19 daily incidence (primary) and mobility (secondary and intermediate measure of stay-at-home effectiveness)\\n\\nKey ResultsStay-at-home orders were implemented later (median March 30 vs. March 28) and were shorter (median 35 vs. 54 days) in rural than urban counties. Indoor mobility was, on average, 2.6-6.9% higher in rural than urban counties both during and after stay-at-home orders. Compared to the baseline (pre-stay-at-home) period, the number of new COVID-19 cases increased under stay-at-home by IRR 1.60 (95% CI, 1.57-1.64) in rural and 1.36 (95% CI, 1.30-1.42) in urban counties. For each day under stay-at-home orders, the number of new cases changed by a factor of 0.982 (95% CI 0.981-0.982) in rural and 0.952 (95% CI, 0.951-0.953) in urban counties compared to prior to stay-at-home. Each day after stay-at-home orders expired, the number of new cases changed by a factor of 0.995 (95% CI, 0.994-0.995) in rural and 0.997 (95% CI, 0.995-0.999) in urban counties compared to prior to stay-at-home.\\n\\nConclusionStay-at-home orders decreased mobility and slowed the spread of COVID-19, but less effectively in rural than in urban counties. This necessitates a critical reevaluation of how stay-at-home orders are designed, communicated, and implemented in rural areas.\",\n \"Association of the medical therapy with beta-blockers or inhibitors of renin-angiotensin system with clinical outcomes in patients with mildly reduced left ventricular ejection fraction after acute myocardial infarction\\nIn the era of the initial optimal interventional and medical therapy for acute myocardial infarction (AMI), a number of patients with mildly reduced left ventricular ejection fraction (EF) (41 - 49%) have been increasing. This observational study aimed to investigate the association between the medical therapy with oral beta-blockers or inhibitors of renin-angiotensin system (RAS) and 2-year clinical outcomes in patients with mildly reduced EF after AMI. Among patients enrolled in the Korea Acute Myocardial Infarction Registry-National Institute of Health, propensity-score matched patients who survived the initial attack and had mildly reduced EF were selected according to beta-blocker or RAS inhibitor therapy at discharge. Beta-blocker therapy at discharge was associated with lower 2-year major adverse cardiac events which was a composite of cardiac death, myocardial infarction, revascularization and re-hospitalization due to heart failure (8.7 vs. 12.8/100 patient-years; hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.50-0.93; P=0.015), and no significant interaction between EF [≤]45% and >45% was observed (Pinteraction=0.354). This association was mainly driven by lower myocardial infarction in patients with beta-blockers (HR 0.50; 95% CI 0.26-0.95; P=0.035). Inhibitors of RAS at discharge were associated with lower re-hospitalization due to heart failure (1.8 vs. 3.5/100 patient-years; HR 0.53; 95% CI 0.33-0.86; P=0.010) without a significant interaction between EF [≤]45% and >45% (Pinteraction=0.333). In patients with mildly reduced EF after AMI, the medical therapy with beta-blockers or RAS inhibitors at discharge was associated with better 2-year clinical outcomes.\",\n \"Development of ADAF screening tool for emotional and coping problems in cancer patients\\nPurposePsychological screening in patient with cancer is recommended by clinical guidelines, however most of scales have large number of items, difficulty detection and refer from routine consultations. The specific objective of the study was to develop and validate the ADAF screening for anxiety, depression and coping.\\n\\nMethods/PatientsCross-sectional, multicenter study performed in the medical and radiotherapy oncology services of 5 hospitals in Madrid, coordinated by the Medical Oncology Service of the Hospital Clinico San Carlos (CEIC n{o}19 / 265-E). To determine the psychometric properties, the ADAF screening questionnaire ADAF was administered, including 5 items (one related to anxiety symptoms, two related to depressive symptoms, one for helplessness coping and one for avoidance coping), and as a gold-standard the HADS and the MiniMAC. Intraclass correlation coefficients and receiver operating characteristic curves were performed. The p value <0.05 was considered significant.\\n\\nResultsA total of 186 patients completed the evaluation. The correlation coefficients were significant for all dimensions (Anxiety, Depression, Helplessness coping, and Avoidance Coping), with p <0.001. The statistical analysis of ROC curves suggests that the cut-off point for screening is equivalent to a score > 2 points (3 in the case of depression, having two items), with a sensitivity and specificity between 62 and 90%, depending on the item, and an area under the curve above 0.8 for the first 4 items.\\n\\nConclusionsADAF screening has adequate reliability, good sensitivity and specificity. This instrument is useful and easy to use to identify emotional and coping problems in cancer patients.\",\n \"Analysis of cutoff point estimation for determining seropositivity in the context of SARS-CoV-2 infections\\nIn this work will apply mixture models based on distributions from the SMSN family to antibody data against four SARS-CoV-2 virus antigens. Furthermore, since the true infection status of individuals is known a priori, performance measures will be calculated for the methods proposed for cutoff point estimation such as sensitivity, specificity and accuracy. The results of a simulation study will also be presented.\",\n \"Public Covid-19 X-ray datasets and their impact on model bias - a systematic review of a significant problem\\nComputer-aided-diagnosis for COVID-19 based on chest X-ray suffers from weak bias assessment and limited quality-control. Undetected bias induced by inappropriate use of datasets, and improper consideration of confounders prevents the translation of prediction models into clinical practice. This study provides a systematic evaluation of publicly available COVID-19 chest X-ray datasets, determining their potential use and evaluating potential sources of bias.\\n\\nOnly 5 out of 256 identified datasets met at least the criteria for proper assessment of risk of bias and could be analysed in detail. Remarkably almost all of the datasets utilised in 78 papers published in peer-reviewed journals, are not among these 5 datasets, thus leading to models with high risk of bias. This raises concerns about the suitability of such models for clinical use.\\n\\nThis systematic review highlights the limited description of datasets employed for modelling and aids researchers to select the most suitable datasets for their task.\",\n \"Wastewater and surface monitoring to detect COVID-19 in elementary school settings: The Safer at School Early Alert project\\nSchools are high-risk settings for SARS-CoV-2 transmission, but necessary for childrens educational and social-emotional wellbeing. While wastewater monitoring has been implemented to mitigate outbreak risk in universities and residential settings, its effectiveness in community K-12 sites is unknown. We implemented a wastewater and surface monitoring system to detect SARS-CoV-2 in nine elementary schools in San Diego County. Ninety-three percent of identified cases were associated with either a positive wastewater or surface sample; 67% were associated with a positive wastewater sample, and 40% were associated with a positive surface sample. The techniques we utilized allowed for near-complete genomic sequencing of wastewater and surface samples. Passive environmental surveillance can complement approaches that require individual consent, particularly in communities with limited access and/or high rates of testing hesitancy.\\n\\nOne sentence summaryPassive wastewater and surface environmental surveillance can identify up to 93% of on-campus COVID-19 cases in public elementary schools; positive samples can be sequenced to monitor for variants of concerns with neighborhood level resolution.\",\n \"Genomic profiling defines variable clonal relatedness between invasive breast cancer and primary ductal carcinoma in situ\\nPure ductal carcinoma in situ (DCIS) is being diagnosed more frequently through breast screening programmes and is associated with an increased risk of developing invasive breast cancer. We assessed the clonal relatedness of 143 cases of pure DCIS and their subsequent events using a combination of whole exome, targeted and copy number sequencing, supplemented by single cell analysis. Unexpectedly, 18% of all invasive events after DCIS were clonally unrelated to the primary DCIS. Single cell sequencing of selected pairs confirmed our findings. In contrast, synchronous DCIS and invasive disease (n=44) were almost always (93%) clonally related. This challenges the dogma that almost all invasive events after DCIS represent invasive transformation of the initial DCIS and suggests that DCIS could be an independent risk factor for developing invasive disease as well as a precursor lesion. Our findings support a paradigm shift that confirms a more complex role for DCIS than previously recognized, and that the future management of DCIS should take into account both the precursor and risk factor implications of this diagnosis.\",\n \"Overcoming the pitfalls of NGS-based molecular diagnosis of Shwachman-Diamond syndrome\\nPurposeShwachman-Diamond syndrome (SDS) is predominately caused by biallelic mutations in the SBDS gene and is characterized by exocrine pancreatic insufficiency, skeletal abnormalities and pancytopenia. Gene conversion between SBDS and its pseudogene SBDSP1 is the major cause. We established an efficient approach, HapICE, to infer the haplotype of SBDS based on short-read next-generation sequencing (NGS).\\n\\nMethodsHapICE based on the Expectation-Maximization algorithm was developed to detect variants in exon 2 of SBDS arising from gene conversion. We retrospectively analyzed two common pathogenic variants (c.183_184delinsCT and c.258+2T>C) in suspected SDS patients and compared the results with those from conventional NGS analysis.\\n\\nResultsIn 47 SDS high-risk individuals and 64 available parents, HapICE improved the diagnostic rate by 27.7% compared with conventional methods and revealed 100% (95% CI: 92.5%-100%) concordance with Sanger sequencing. In addition to eighteen patients having consistent genetic results by both methods, HapICE further reported 8 patients with more accurate variant detection and 13 cases with the c.183_184delinsCT variant missing by conventional methods. HapICE also showed better performance in screening for carrier and wild-type status.\\n\\nConclusionWe have developed a novel SBDS variant detection tool through regular NGS data that demonstrated precise variant detection performance in clinical scenarios.\",\n \"A Novel Abnormality Annotation Database for COVID-19 Affected Frontal Lung X-rays\\nPurposeTo advance the usage of CXRs as a viable solution for efficient COVID-19 diagnostics by providing large-scale annotations of the abnormalities in frontal CXRs in BIMCV-COVID19+ database, and to provide a robust evaluation mechanism to facilitate its usage.\\n\\nMaterials and MethodsWe provide the abnormality annotations in frontal CXRs by creating bounding boxes. The frontal CXRs are a part of the existing BIMCV-COVID19+ database. We also define four different protocols for robust evaluation of semantic segmentation and classification algorithms. Finally, we benchmark the defined protocols and report the results using popular deep learning models as a part of this study.\\n\\nResultsFor semantic segmentation, Mask-RCNN performs the best among all the models with a DICE score of 0.43 {+/-} 0.01. For classification, we observe that MobileNetv2 yields the best results for 2-class and 3-class classification. We also observe that deep models report a lower performance for classifying other classes apart from the COVID class.\\n\\nConclusionBy making the annotated data and protocols available to the scientific community, we aim to advance the usage of CXRs as a viable solution for efficient COVID-19 diagnostics. This large-scale data will be useful for ML algorithms and can be used for learning radiological patterns observed in COVID-19 patients. Further, the protocols will facilitate ML practitioners for unified large-scale evaluation of their algorithms.\\n\\nData Availability StatementThe data associated with this work is available here : Radiologists Annotations on COVID-19+ X-rays https://osf.io/b35xu/ via @OSFramework and http://covbase4all.igib.res.in/.\",\n \"Masking significantly reduces, but does not eliminate COVID-19 infection in a spatial agent-based simulation of a University dormitory floor\\nCOVID-ADAPT is a stochastic, discrete-space, agent-based simulation model of airborne infection and public health interventions, capable of modeling SARS-CoV-2 transmission. Using a map of a real university dormitory floor, the model simulates agents moving about and potentially infecting each other. Health interventions tested are vaccination and masking, including whether the solitary initial infectious agent was masked. Universal masking with N95 masks and 100% vaccination of susceptible people resulted in significantly lower prevalence after 3 weeks compared to all other scenarios, but still led to a substantial number of infections. Increased vaccination levels from 52% to 100% by itself did not result in a significant difference in prevalence due to symptomatic and asymptomatic breakthrough infections. These results suggest that vaccination alone is insufficient to stem outbreaks, and the best way to reduce COVID-19 infections is to ensure that all infectious people are masked. However, because asymptomatic infections are common, the only way to ensure this is universal masking, which also reduces prevalence by protecting susceptible individuals from infection. Universal masking is the best way forward, especially under threat of the Delta variant, to keep facilities open and safe for occupants, while minimizing the number of infections.\",\n \"A Dynamic Bayesian Model for Identifying High-Mortality Risk in Hospitalized COVID-19 Patients\\nIntroductionAs COVID-19 hospitalization rates remain high, there is an urgent need to identify prognostic factors to improve treatment. Our analysis, to our knowledge, is one of the first to quantify the risk associated with dynamic clinical measurements taken throughout the course of hospitalization.\\n\\nMethodsWe collected data for 553 PCR-positive COVID-19 patients admitted to hospital whose eventual outcomes were known. The data collected for the patients included demographics, comorbidities and laboratory values taken at admission and throughout the course of hospitalization. We trained multivariate Markov prognostic models to identify high-risk patients at admission along with a dynamic measure of risk incorporating time-dependent changes in patients laboratory values.\\n\\nResultsFrom the set of factors available upon admission, the Markov model determined that age >80 years, history of coronary artery disease and chronic obstructive pulmonary disease increased mortality risk. The lab values upon admission most associated with mortality included neutrophil percentage, RBC, RDW, protein levels, platelets count, albumin levels and MCHC. Incorporating dynamic changes in lab values throughout hospitalization lead to dramatic gains in the predictive accuracy of the model and indicated a catalogue of variables for determining high-risk patients including eosinophil percentage, WBC, platelets, pCO2, RDW, LUC count, alkaline phosphatase and albumin.\\n\\nConclusionOur prognostic model highlights the nuance of determining risk for COVID-19 patients and indicates that, rather than a single variable, a range of factors (at different points in hospitalization) are needed for effective risk stratification.\",\n \"Can prognostic factors for indirect muscle injuries in elite football (soccer) players be identified using data from preseason screening? An exploratory analysis using routinely-collected periodic health examination records.\\nThis study used periodic health examination (PHE) data from 134 outfield elite male football players, over 5 seasons (1st July 2013 to 19th May 2018). Univariable and multivariable logistic regression models were used to determine prognostic associations between 36 variables and time-loss, lower extremity index indirect muscle injuries (I-IMIs). Non-linear associations were explored using fractional polynomials. During 317 participant-seasons, 138 I-IMIs were recorded. Univariable associations were determined for previous calf indirect muscle injury (IMI) frequency (OR=1.80, 95% confidence interval (CI) = 1.09 to 2.97), hamstring IMI frequency (OR=1.56, 95% CI=1.17 to 2.09), if the most recent hamstring IMI occurred > 12 months but < 3 years prior to PHE (OR= 2.95, 95% CI = 1.51 to 5.73) and age (OR =1.12 per 1-year increase, 95% CI = 1.06 to 1.18). Multivariable analyses demonstrated that if a players most recent previous hamstring IMI was >12 months but <3 years prior to PHE (OR= 2.24, 95% CI = 1.11 to 4.53), then this was the only variable with added prognostic value over and above age (OR=1.12 per 1-year increase, 95%CI = 1.05 to 1.18). Allowing non-linear associations conferred no advantage over linear ones. Therefore, PHE has limited use for injury risk prediction.\",\n \"Machine Learning Based Prediction of COVID-19 Mortality Suggests Repositioning of Anticancer Drug for Treating Severe Cases\\nDespite available vaccinations COVID-19 case numbers around the world are still growing, and effective medications against severe cases are lacking. In this work, we developed a machine learning model which predicts mortality for COVID-19 patients using data from the multi-center Lean European Open Survey on SARS-CoV-2-infected patients (LEOSS) observational study (>100 active sites in Europe, primarily in Germany), resulting into an AUC of almost 80%. We showed that molecular mechanisms related to dementia, one of the relevant predictors in our model, intersect with those associated to COVID-19. Most notably, among these molecules was tyrosine kinase 2 (TYK2), a protein that has been patented as drug target in Alzheimers Disease but also genetically associated with severe COVID-19 outcomes. We experimentally verified that anti-cancer drugs Sorafenib and Regorafenib showed a clear anti-cytopathic effect in Caco2 and VERO-E6 cells and can thus be regarded as potential treatments against COVID-19. Altogether, our work demonstrates that interpretation of machine learning based risk models can point towards drug targets and new treatment options, which are strongly needed for COVID-19.\",\n \"Wastewater surveillance for SARS-CoV-2 on college campuses: Initial efforts, lessons learned and research needs\\nBackgroundWastewater surveillance for SARS-CoV-2 is an emerging approach to help identify the risk of a COVID-19 outbreak. This tool can contribute to public health surveillance at both community (wastewater treatment system) and institutional (e.g., colleges, prisons, nursing homes) scales.\\n\\nObjectivesThis research aims to understand the successes, challenges, and lessons learned from initial wastewater surveillance efforts at colleges and university systems to inform future research, development and implementation.\\n\\nMethodsThis paper presents the experiences of 25 college and university systems in the United States that monitored campus wastewater for SARS-CoV-2 during the fall 2020 academic period. We describe the broad range of approaches, findings, resource needs, and lessons learned from these initial efforts. These institutions range in size, social and political geographies, and include both public and private institutions.\\n\\nDiscussionOur analysis suggests that wastewater monitoring at colleges requires consideration of information needs, local sewage infrastructure, resources for sampling and analysis, college and community dynamics, approaches to interpretation and communication of results, and follow-up actions. Most colleges reported that a learning process of experimentation, evaluation, and adaptation was key to progress. This process requires ongoing collaboration among diverse stakeholders including decision-makers, researchers, faculty, facilities staff, students, and community members.\",\n \"Irremediable psychiatric suffering in the context of physician assisted death: a Delphi-study\\nBackgroundPatients with a psychiatric disorder (PPD) are eligible to request physician assisted death (PAD) in a small but growing number of jurisdictions, including the Netherlands and Belgium. For this request to be granted, most of these jurisdictions demand that the patient is competent in her request, and that the suffering experienced is unbearable and irremediable. Especially the criterion of irremediability is challenging to establish in patients with psychiatric disorders.\\n\\nAimsTo establish what criteria Dutch and Belgian experts agree to be essential in characterising irremediable psychiatric suffering (IPS) in the context of PAD.\\n\\nMethodA two round Delphi procedure among psychiatrists with relevant experience.\\n\\nResultsThirteen consensus-criteria were established: five diagnostic and eight treatment-related criteria. Diagnostically, the participants deem a narrative description and attention to contextual and systemic elements necessary. Also, a mandatory second opinion is required. The criteria concerning treatment show that extensive biopsychosocial treatment is needed, and the suffering must be present for several years. Finally, in the case of treatment refusal, the participants agree that there are limits to the number of diagnostic procedures or treatments a patient must undergo.\\n\\nConclusionsConsensus was found among a Dutch and Belgian expert group on essential criteria for establishing IPS in the context of PAD. These criteria can be used in clinical decision making and can inform future procedural demands and research.\",\n \"LAMP-BEAC: Detection of SARS-CoV-2 RNA Using RT-LAMP and Molecular Beacons\\nBackgroundRapid spread of SARS-CoV-2 has led to a global pandemic, resulting in the need for rapid assays to allow diagnosis and prevention of transmission. Reverse Transcription-Polymerase Chain Reaction (RT-PCR) provides a gold standard assay for SARS-CoV-2 RNA, but tests are expensive and supply chains are potentially fragile, motivating interest in additional assay methods. Reverse Transcription and Loop-Mediated Isothermal Amplification (RT-LAMP) provides an alternative that uses orthogonal and often less expensive reagents without the need for thermocyclers. The presence of SARS-CoV-2 RNA is typically detected using dyes to report bulk amplification of DNA; however, a common artifact is nonspecific DNA amplification, which complicates detection.\\n\\nResultsHere we describe the design and testing of molecular beacons, which allow sequence-specific detection of SARS-CoV-2 genomes with improved discrimination in simple reaction mixtures. To optimize beacons for RT-LAMP, multiple locked nucleic acid monomers were incorporated to elevate melting temperatures. We also show how beacons with different fluorescent labels can allow convenient multiplex detection of several amplicons in \\\"single pot\\\" reactions, including incorporation of a human RNA LAMP-BEAC assay to confirm sample integrity. Comparison of LAMP-BEAC and RT-qPCR on clinical saliva samples showed good concordance between assays. To facilitate implementation, we developed custom polymerases for LAMP-BEAC and inexpensive purification procedures, which also facilitates increasing sensitivity by increasing reaction volumes.\\n\\nConclusionsLAMP-BEAC thus provides an affordable and simple SARS-CoV-2 RNA assay suitable for population screening; implementation of the assay has allowed robust screening of thousands of saliva samples per week.\",\n \"Feasibility of an online antigen self-testing strategy for SARS-CoV-2 addressed to health care and education professionals in Catalonia (Spain). The TESTAT- COVID Project\\nWe aimed to implement a pilot intervention based on offering online COVID-19 selftest kits addressed to healthcare and education professionals in Spain during the peak of the 6th wave caused by Omicron variant. Kits were ordered online and sent by mail, participants answered an online acceptability/usability survey and uploaded the picture of results. 492 participants ordered a test, 304 uploaded the picture (61.8%). Eighteen positive cases were detected (5.9%). 92.2% were satisfied/very satisfied with the intervention; and 92.5% found performing the test easy/very easy. We demonstrated that implementing online COVID-19 self-testing in schools and healthcare settings in Spain is feasible.\\n\\nKey findingsO_LIWe implemented a pilot intervention based on offering online COVID-19 selftest kits in Spain.\\nC_LIO_LIWe demonstrated the feasibility of the intervention during the peak of the 6th wave caused by Omicron variant.\\nC_LIO_LIThe intervention counted with high acceptability among healthcare and education professionals in Spain.\\nC_LIO_LIOur results may contribute to define screening strategies addressed to key populations, particularly during peaks of high community transmission of SARS-CoV-2.\\nC_LI\",\n \"Exploring potential causal genes for uterine leiomyomas: A summary data-based Mendelian randomization and FUMA analysis\\nObjectiveTo explore potential causal genetic variants and genes underlying the pathogenesis of uterine leiomyomas (ULs).\\n\\nMethodsWe conducted the summary data-based Mendelian randomization (SMR) analysis and performed functional mapping and annotation using FUMA to examine genetic variants and genes that are potentially involved in the pathogenies of ULs.\\n\\nBoth analyses used summarized data of a recent genome-wide association study (GWAS) on ULs, which has a total sample size of 244,324 (20,406 cases and 223,918 controls). For the SMR analysis, we performed separate analysis using CAGE and GTEx eQTL data.\\n\\nResultsUsing the CAGE eQTL data, our SMR analysis identified 13 probes tagging 10 unique genes that were pleiotropically/potentially causally associated with ULs, with the top three probes being ILMN_1675156 (tagging CDC42, PSMR=8.03x10-9), ILMN_1705330 (tagging CDC42, PSMR=1.02x10-7) and ILMN_2343048 (tagging ABCB9, PSMR=9.37x10-7). Using GTEx eQTL data, our SMR analysis did not identify any significant genes after correction for multiple testing. FUMA analysis identified 106 independent SNPs, 24 genomic loci and 137 genes that are potentially involved in the pathogenesis of ULs, seven of which were also identified by the SMR analysis.\\n\\nConclusionsWe identified many genetic variants, genes, and genomic loci that are potentially involved in the pathogenesis of ULs. More studies are needed to explore the exact underlying mechanisms in the etiology of ULs.\",\n \"Assessing the nationwide impact of COVID-19 mitigation policies on the transmission rate of SARS-CoV-2 in Brazil\\nCOVID-19 is now identified in almost all countries in the world, with poorer regions being particularly more disadvantaged to efficiently mitigate the impacts of the pandemic. In the absence of efficient therapeutics or vaccines, control strategies are currently based on non-pharmaceutical interventions, comprising changes in population behavior and governmental interventions, among which the prohibition of mass gatherings, closure of non-essential establishments, quarantine and movement restrictions. In this work we analyzed the effects of 707 published governmental interventions, and population adherence thereof, on the dynamics of COVID-19 cases across all 27 Brazilian states, with emphasis on state capitals and remaining inland cities. A generalized SEIR (Susceptible, Exposed, Infected and Removed) model with a time-varying transmission rate (TR), that considers transmission by asymptomatic individuals, is presented. We analyze the effect of both the extent of enforced measures across Brazilian states and population movement on the changes in the TR and effective reproduction number. The social mobility reduction index, a measure of population movement, together with the stringency index, adapted to incorporate the degree of restrictions imposed by governmental regulations, were used in conjunction to quantify and compare the effects of varying degrees of policy strictness across Brazilian states. Our results show that population adherence to social distance recommendations plays an important role for the effectiveness of interventions and represents a major challenge to the control of COVID-19 in low- and middle-income countries.\",\n \"A high content microscopy-based platform for detecting antibodies to the nucleocapsid, spike and membrane proteins of SARS-CoV-2\\nThe strong humoral immune response produced against the SARS-CoV-2 nucleocapsid (N) and spike (S) proteins has underpinned serological testing but the prevalence of antibody responses to other SARS-CoV-2 proteins, which may be of use as further serological markers, is still unclear. Cell-based serological screening platforms can fulfil a crucial niche in the identification of antibodies which recognise more complex folded epitopes or those incorporating post-translation modifications which may be undetectable by other methods used to investigate the antigenicity of the SARS-CoV-2 proteome. Here, we employed automated high content immunofluorescence microscopy (AHCIM) to assess the viability of such an approach as a method capable of assaying humoral immune responses against full length SARS-CoV-2 proteins in their native cellular state. We first demonstrate that AHCIM provides high sensitivity and specificity in the detection of SARS-CoV-2 N and S IgG. Assessing the prevalence of antibody responses to the SARS-CoV-2 structural membrane protein (M), we further find that 85% of COVID-19 patients within our sample set developed detectable M IgG responses (M sensitivity 85%, N sensitivity 93%, combined N + M sensitivity 95%). The identification of M as a serological marker of high prevalence may be of value in detecting additional COVID-19 cases during the era of mass SARS-CoV-2 vaccinations, where serological screening for SARS CoV-2 infections in vaccinated individuals is dependent on detection of antibodies against N. These findings highlight the advantages of using cell-based systems as serological screening platforms and raise the possibility of using M as a widespread serological marker alongside N and S.\",\n \"Cost effective sequencing enables longitudinal profiling of clonal hematopoiesis\\nClonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of mutant hematopoietic stem cells, confers risk for multiple diseases of aging including hematologic cancer and cardiovascular disease. Whole-exome or genome sequencing can detect CHIP, but due to its high cost, most population studies have been cross-sectional, sequencing only a single timepoint. Here we describe a cost-effective sequencing assay for detecting CHIP. We validate this technology on a set of 548 longitudinal and multi-timepoint samples from 182 participants in the Womens Health Initiative cohort over median 16 years, including 85 participants with [≥]3 timepoints assayed. The majority (52.1%) of clonal mutations expanded over time (with a median doubling period of 7.43 years), with the others remaining static or decreasing in size in the absence of any cytotoxic therapy. This assay provides a cost-effective and sensitive platform for investigating the associations between CHIP dynamics and health outcomes at a biobank scale.\",\n \"Expert Opinion on COVID-19 Vaccination and the Use of Cladribine Tablets in Clinical Practice\\nBackgroundGaps in current evidence and guidance leave clinicians with unanswered questions on the use of cladribine tablets for the treatment of multiple sclerosis (MS) in the era of the COVID-19 pandemic, in particular relating to COVID-19 vaccination.\\n\\nObjectiveWe describe a consensus-based program led by international MS experts with the aim of supplementing current guidelines and treatment labels by providing timely recommendations relating to COVID-19 vaccination and the use of cladribine tablets in clinical practice.\\n\\nMethodsA steering committee (SC) of 10 international MS experts identified seven clinical questions to answer concerning the use of cladribine tablets and COVID-19 vaccination, which addressed issues relating to patient selection, timing and efficacy, and safety. Clinical recommendations to address each question were drafted using available evidence combined with expert opinion from the SC. An extended faculty of 28 MS experts, representing 19 countries, in addition to the 10 SC members, voted on the recommendations. Consensus on recommendations was achieved when [≥]75% of respondents expressed an agreement score of 7-9, on a 9-point scale.\\n\\nResultsConsensus was achieved on all 13 recommendations. Clinical recommendations are provided on whether all patients with MS receiving cladribine tablets should be vaccinated against COVID-19, and whether they should be prioritized; the timing of vaccination around dosing of cladribine tablets (i.e., before and after a treatment course); and the safety of COVID-19 vaccination for these patients.\\n\\nConclusionsThese expert recommendations provide timely guidance on COVID-19 vaccination in patients receiving cladribine tablets, which is relevant to everyday clinical practice.\",\n \"COVID-19 Vaccine Efficacy in a Diverse Urban Healthcare Worker Population\\nObjectiveTo investigate COVID-19 vaccine efficacy (VE) among healthcare workers (HCWs) in an ethnically diverse community healthcare system, during its initial immunization campaign.\\n\\nMethodsHCWs of the system were retrospectively included from the beginning of a COVID-19 vaccination program (December 16, 2020) until March 31, 2021. Those with a prior COVID-19 infection before December 15 were excluded. The Occupational Health department of the system ran a COVID-19 screening and testing referral program for workers, consistently throughout the study period. A master database had been established and updated comprising of the demographics, COVID-19 PCR assays, and vaccinations of each HCW. Andersen-Gill extension of the Cox models were built to estimate the VE of fully/partially vaccinated person-days at risk.\\n\\nResultsAmong the 4317 eligible HCWs, 3249 (75%) received any vaccination during the study period. Vaccinated HCWs were older, less likely to be Black/African American, Hispanic/Latino or identify as two or more races, and more likely to be medical providers. After adjusting for age, sex, race, and the statewide background incidence at the time of vaccination, we observed a VE of 80.2% (95% CI: 57.5-90.8%) for [greater double equals]14 days after the first dose of Pfizer/Moderna, and 95.5% (95% CI: 88.2-98.3%) among those fully vaccinated (i.e. [greater double equals]14 days after the second dose of Pfizer/Moderna or the single dose of J&J/Janssen).\\n\\nConclusionCOVID-19 vaccine effectiveness in the real world is promising, and these data in concert with culturally appropriate may decrease vaccine hesitancy.\",\n \"Metabolomics and a Breath Sensor Identify Acetone as a Biomarker for Heart Failure\\nBackgroundMultiomics delivers more biological insight than targeted investigations. We applied multiomics to patients with heart failure with reduced ejection fraction (HFrEF).\\n\\nMethods46 patients with HFrEF and 20 controls underwent metabolomic profiling, including liquid/gas chromatography mass spectrometry (LCMS/GCMS) and solid-phase microextraction (SPME) volatilomics in plasma and urine. HFrEF was defined using left ventricular global longitudinal strain, ejection fraction and NTproBNP. A consumer breath acetone (BrACE) sensor validated results in n=73.\\n\\nResults28 metabolites were identified by GCMS, 35 by LCMS and 4 volatiles by SPME in plasma and urine. Alanine, aspartate and glutamate, citric acid cycle, arginine biosynthesis, glyoxylate and dicarboxylate metabolism were altered in HFrEF. Plasma acetone correlated with NT-proBNP (r = 0.59, 95% CI 0.4 to 0.7), 2-oxovaleric and cis-aconitic acid, involved with ketone metabolism and mitochondrial energetics. BrACE> 1.5 ppm discriminated HF from other cardiac pathology (AUC 0.8, 95% CI 0.61 to 0.92, P < 0.0001).\\n\\nConclusionBreath acetone discriminated HFrEF from other cardiac pathology using a consumer sensor, but was not cardiac specific.\",\n \"Genetic liability for substance use associated with medical comorbidities in electronic health records of African- and European-ancestry individuals\\nPolygenic risk scores (PRS) represent an individuals summed genetic risk for a trait and can serve as biomarkers for disease. Less is known about the utility of PRS as a means to quantify genetic risk for substance use disorders (SUDs) than for many other traits. Nonetheless, the growth of large, electronic health record-based biobanks makes it possible to evaluate the association of SUD PRS with other traits. We calculated PRS for smoking initiation, alcohol use disorder (AUD), and opioid use disorder (OUD) using summary statistics from the Million Veteran Program sample. We then tested the association of each PRS with its primary phenotype in the Penn Medicine BioBank (PMBB) using all available genotyped participants of African or European ancestry (AFR and EUR, respectively) (N=18,612). Finally, we conducted phenome-wide association analyses (PheWAS) separately by ancestry and sex to test for associations across disease categories. Tobacco use disorder was the most common SUD in the PMBB, followed by AUD and OUD, consistent with the population prevalence of these disorders. All PRS were associated with their primary phenotype in both ancestry groups. PheWAS results yielded cross-trait associations across multiple domains, including psychiatric disorders and medical conditions. SUD PRS were associated with their primary phenotypes, however they are not yet predictive enough to be useful diagnostically. The cross-trait associations of the SUD PRS are indicative of a broader genetic liability. Future work should extend findings to additional population groups and for other substances of abuse.\",\n \"Development and validation of a multiple-choice question-based delirium care knowledge quiz for critical care nurses\\nAimsTo develop and psychometrically test a multiple choice questions (MCQs)-based quiz of delirium care knowledge for critical care nurses.\\n\\nDesignInstrument development and psychometric evaluation study.\\n\\nMethodsThe development and validation process including two phases. Phase I focused on the quiz development, conducted by the following steps: (1) generated initial 20-item pool; (2) examined content validity and (3) face validity; (4) conducted pilot testing, data were collected from 217 critical care nurses via online survey during 01 October to 07 November, 2020; (5) performed item analysis and eliminated items based on the item difficulty and discrimination indices. The MCQs quiz was finalised through the development process. Then, phases II emphasised the quiz validation, to estimate the internal consistency, split-half and test-retest reliability, and construct validity using parallel analysis with the exploratory factor analysis (EFA).\\n\\nResultsA final 16-item MCQs quiz was emerged from the item analysis. The Kuder- Richardson Formula 20 coefficient for the overall quiz showed good internal consistency (0.85), and the intraclass correlation coefficient with a 30-day interval also indicated that the questionnaire had satisfactory stability (0.96). The EFA confirmed appropriate construct validity for the quiz, four factors could explain the total variance of 60.87%.\\n\\nConclusionThis study developed the first MCQs quiz for delirium care knowledge and it is a reliable and valid tool that can be implemented to assess the level of delirium care knowledge.\\n\\nImpactThis study offers an evidence-based quiz designed for future research and education purposes in delirium care that has significant implications for knowledge test by using MCQs in clinical practice.\",\n \"Passive Detection of COVID-19 with Wearable Sensors and Explainable Machine Learning Algorithms\\nIndividual smartwatch or fitness band sensor data in the setting of COVID-19 has shown promise to identify symptomatic and pre-symptomatic infection or the need for hospitalization, correlations between peripheral temperature and self-reported fever, and an association between changes in heart-rate-variability and infection. In our study, a total of 38,911 individuals (61% female, 15% over 65) have been enrolled between March 25, 2020 and April 3, 2021, with 1,118 reported testing positive and 7,032 negative for COVID-19 by nasopharyngeal PCR swab test. We propose an explainable gradient boosting prediction model based on decision trees for the detection of COVID-19 infection that can adapt to the absence of self-reported symptoms and to the available sensor data, and that can explain the importance of each feature and the post-test-behavior for the individuals. We tested it in a cohort of symptomatic individuals who exhibited an AUC of 0.83 [0.81-0.85], or AUC=0.78 [0.75-0.80] when considering only data before the test date, outperforming state-of-the-art algorithm in these conditions. The analysis of all individuals (including asymptomatic and pre-symptomatic) when self-reported symptoms were excluded provided an AUC of 0.78 [0.76-0.79], or AUC of 0.70 [0.69-0.72] when considering only data before the test date. Extending the use of predictive algorithms for detection of COVID-19 infection based only on passively monitored data from any device, we showed that it is possible to scale up this platform and apply the algorithm in other settings where self-reported symptoms can not be collected.\",\n \"Low CD4/CD8 ratio predicts cancer risk among adults with HIV\\nBackgroundIndependent of CD4 cell count, low CD4/CD8 ratio in people with HIV (PWH) is associated with deleterious immune senescence, activation, and inflammation, which may contribute to carcinogenesis and excess cancer risk. We examined whether low CD4/CD8 ratios predicted cancer among PWH in the USA and Canada.\\n\\nMethodsWe examined all cancer-free PWH with one or more CD4/CD8 values from NA-ACCORD observational cohorts with validated cancer diagnoses between 1998-2016. We evaluated the association between time-lagged CD4/CD8 ratio and risk of specific cancers in multivariable, time-updated Cox proportional hazard models using restricted cubic spines.\\n\\nModels were adjusted for age, sex, race/ethnicity, hepatitis C virus, and time-updated CD4 cell count, HIV RNA, and history of AIDS-defining illness.\\n\\nResultsAmong 83,893 PWH, there were 5,628 incident cancers, including lung cancer (n=755), Kaposi sarcoma (KS, n=501), non-Hodgkin lymphoma (NHL, n=497), and anal cancer (n=439). Median age at cohort entry was 43 years, 87% were male, and 43% were white. Overall median six-month lagged CD4/CD8 ratio was 0.52 (interquartile range: 0.30-0.82). Compared with six-month lagged CD4/CD8=0.80, CD4/CD8=0.30 was associated with increased risk of any incident cancer (adjusted hazard ratio = 1.24 [95% confidence interval: 1.14-1.35]). CD4/CD8 ratio was also inversely associated with NHL, KS, lung cancer, anal cancer, and colorectal cancer in adjusted analyses (all p<0.05). Results were similar using 12-, 18-, and 24-month lagged CD4/CD8 values.\\n\\nConclusionsLow CD4/CD8 ratio up to 24 months prior to cancer diagnosis was independently associated with increased cancer risk in PWH and may serve as a clinical biomarker.\",\n \"Distinct patterns of treatment response using the Early Start Denver Model with young children with autism spectrum disorder: a cluster analysis\\nEvidence-based, early intervention significantly improves developmental outcome in young children with autism. Nonetheless, there is high interindividual heterogeneity in developmental trajectories during the therapy. It is currently not possible to predict a childs developmental outcome after receiving an early intervention based on his skills and symptoms at baseline. In this study, we analyze developmental trajectories of preschoolers with autism who received 2 years of intervention using the Early Start Denver Model (ESDM) approach in Geneva, Switzerland (n = 47). Our aim was to identify early predictors of response to treatment. We applied a cluster analysis to distinguish between 3 subgroups based on their cognitive level at intake, and rates of cognitive change over the course of treatment. The first subgroup of children only had a mild cognitive delay at intake, and nearly no cognitive delay by the end of treatment (Higher Cognitive at baseline: HC). The children in the two other subgroups all presented with severe cognitive delay at baseline, however, they had two very different patterns of response to treatment. The majority significantly improved developmental scores within their first year of intervention (Optimal Responders: OptR). Whereas a minority of children showed little to no improvement over the course of treatment (Minimal Responders: MinR). Our findings suggest that children who end up having an optimal two-year treatment outcome show rapid developmental improvement. Inversely, less significant progress by the sixth month of intervention may predict a less optimal response to treatment.\",\n \"Evaluation of SIGLEC1 in the diagnosis of suspected systemic lupus erythematosus\\nObjectivesTo evaluate and compare the diagnostic accuracy of SIGLEC1, a surrogate marker of type I IFN, with established biomarkers in an inception cohort of systemic lupus erythematosus (SLE).\\n\\nMethodsSIGLEC1 was analysed by flow cytometry in 232 patients referred to our institution with suspected SLE between October 2015 and September 2020.\\n\\nResultsSLE was confirmed in 76 of 232 patients (32.8%) according to the 2019 EULAR/ACR classification criteria and their SIGLEC1 values were significantly higher compared to patients without SLE (p<0.0001). A sensitivity of 98.7 %, a specificity of 82.1 %, a negative predictive value (NPV) of 99.2 % and a positive predictive value (PPV) of 72.8 % were calculated for SIGLEC1. Adjusted to the highest reported prevalence of SLE, the NPV and PPV were > 99.9 % and 0.1 %, respectively. Using ROC analysis and Delong testing, the area under the curve (AUC) for SIGLEC1 (AUC=0.95) was significantly higher than for ANA (AUC=0.88, p=0.031), C3 (AUC=0.83, p=0.001) and C4 (AUC=0.83, p=0.002) but not for anti-dsDNA antibodies (AUC=0.90, p=0.163).\\n\\nConclusionIFN-I pathway activation is detectable in almost all newly diagnosed SLE patients. Thus, a negative test result for SIGLEC1 is powerful to exclude SLE in suspected cases.\",\n \"Partial recovery of amblyopia following fellow eye ischemic optic neuropathy\\nBackgroundRecovery from amblyopia in adulthood following fellow eye (FE) vision loss is a well-known phenomenon. Incidence of recovery varies widely following different FE pathologies and rate of recovery following FE ischemic optic neuropathy (ION) has not been examined. We aimed to determine frequency and degree of improvement in amblyopic eye (AE) visual function following ION in the FE.\\n\\nMethodsWe performed a retrospective chart review of patients between 2007-2021 confirmed to have amblyopia and ischemic optic neuropathy in different eyes. Patients with unstable ocular pathology potentially limiting vision were excluded. We compared best-corrected visual acuity (VA) in each eye before and after FE ION over time. For patients with available data, we examined change in perimetric performance over time.\\n\\nResultsAmong the 12 patients who met inclusion criteria (mean age 67{+/-}8 years), 9 (75%) improved [≥]1 line and 2 (17%) improved [≥]3 lines. Median time from ION symptom onset to maximal improvement was 6 months (range: 2-101 months). Reliable perimetric data were available for 6 patients. Mean sensitivity improved in the amblyopic eye for all patients, with a mean improvement of 1.9{+/-}1.1 dB. There was no correspondence between foci of ION-related field loss and gains in field sensitivity in the AE.\\n\\nConclusionA high proportion of patients with amblyopia and contralateral ION experience improvement in their amblyopic eye. Modest gains in perimetric sensitivity in the AE may accompany FE ION. These findings support the view that residual plasticity in the adult visual cortex can be tapped to support functional improvement in amblyopia.\",\n \"Donor race has no role in predicting allograft and patient survival among kidney transplant recipients\\nA heated debate in creatinine-based estimated glomerular filtration rate (eGFR) calculation is the inclusion of race alongside biological factors, such as age and gender. Similarly, the race variable was included in the calculation of the Kidney Donor Risk Index (KDRI) as deceased donor kidneys from black donors have historically been shown to be associated with lower allograft or patient survival. Given the current climate of uncertainty with the use of race in nephrology, we sought to answer the question of whether removing the donor race variable from the KDRI would alter its validity to assess allograft and patient survival. Our modeling and analysis showed that removing donor race from the original KDRI did not alter the overall model predictability of allograft failure or patient mortality. Clinical risk factors included in the KDRI have largely accounted for differential risk between black and other donors. Adding donor race into the KDRI only shifts how risk is attributed to these clinical risk factors, without yielding better prediction of outcomes than the model without race.\",\n \"Transcriptional patterns of coexpression across autism risk genes converge on established and novel signatures of neurodevelopment\\nAutism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and communication. Protein function altering variants in many genes have been shown to contribute to ASD risk; however, understanding the biological convergence across so many genes has been difficult. Here, we demonstrate that coexpression patterns from human post-mortem brain samples (N=993) are significantly correlated with the transcriptional consequences of CRISPR perturbations (gene editing, interference and activation) of 15 neurodevelopmental genes in neuronal cell models. We find that across 70 ASD risk genes, there is significant tissue-specific transcriptional convergence that implicates synaptic pathways. We further show that the degree of convergence is significantly correlated with the level of association to ASD from sequencing studies (rho = -0.14, P = 4.75x10-63) as well as differential expression from transcription studies in post-mortem ASD brains (rho = -0.22, P = 3.62x10-41). After removing genes with minimal evidence of association with ASD, the remaining positively convergent genes are intolerant to mutation, have shorter coding lengths and are enriched for genes with suggestive evidence of contribution to ASD. These results indicate that leveraging convergent coexpression can identify novel ASD risk genes that are more likely to be underpowered and therefore missed by current large-scale sequencing studies. This work ultimately provides a simple approach to functionally proxy CRISPR perturbation, demonstrates significant context-specific transcriptional convergence among known ASD risk genes, and proposes several novel ASD risk gene candidates.\",\n \"#AstraZeneca vaccine disinformation on Twitter\\nWe analyzed 50,080 tweets about # AstraZeneca in English from 2021. We found that the news most common in the frequently retweeted tweets abound in negative information, and in many cases come from media sources well-known for disinformation. Also, we found that RT, a Russian state-sponsored news website, as well as Al Arabiya, a Saudi-owned news website, are frequently retweeted with information about the vaccine. Our analysis identified large coordination networks involved in political astroturfing and vaccine diplomacy in South Asia but also vaccine advocacy networks associated with European Commission employees. Our results show that Twitter discourse about # AstraZeneca is filled with disinformation and bad press, and may be distributed not only organically by anti-vaxxer activists, but also systematically by professional sources.\\n\\nHighlightsO_LIMost commonly retweeted media news links abound in negative information\\nC_LIO_LIWell established disinformation media sources are retweeted more\\nC_LIO_LIState coordinated networks are active in # AstraZeneca astroturfing\\nC_LI\",\n \"Patients at risk of pulmonary fibrosis Post Covid-19: Epidemiology, pulmonary sequelaes and humoral response\\nBackgroundThe COVID-19 pandemic is one of the greatest public health problems. Our aims were to describe epidemiological characteristics, know the amount of protective antibodies and their permanence after a COVID-19 primary infection in patients with risk of pulmonary fibrosis.\\n\\nMethodsDescriptive epidemiological and follow-up study of the humoral response in patients at risk of pulmonary fibrosis Post-Covid-19 hospitalized, between March and October 2020, and who were followed up for a one year after hospital discharge.\\n\\nResults72 patients participated in the study, 52 showed pre-existing chronic comorbidities. COVID-19 clinical severity was rated in 6% mild, 58% as moderate and 36% as severe. After a year of follow-up, the forty percent had pulmonary sequelae, the most frequent (20%) was mild pulmonary fibrosis. Any case of reinfection was detected. All patients presented RBD IgG antibodies and 88% presented IgA antibodies after 8-9 months. The amount of RBD IgG was similar at 4-5 and 8-9 months post-Covid. There was no difference when level of RBD IgG according to the severity of the COVID-19 (p=0.441, p=0.594).\\n\\nConclusionsMild pulmonary fibrosis sequelae is exceptional but was detected in a high percentage. The amount of RBD IgG is maintained throughout the convalescent phase and seems to protect against new reinfections despite of emerging viral variants. However, seems not predict the developed or not of pulmonary fibrosis.\",\n \"Asymptomatic carriers of the p.A53T SNCA mutation: data from the PPMI study\\nIntroductionThere has been great interest in the prodromal phase of Parkinsons disease (PD), especially in subjects who are asymptomatic carriers of genetic mutations leading to PD because of the high risk to convert to PD. The objective of the present study was to assess non motor characteristics of asymptomatic p.A53T mutation carriers (A53T-AC) compared with healthy controls (HC).\\n\\nMethodsWe compared 12 A53T-AC with 36 matched HC enrolled into in the Parkinsons Progression Markers Initiative (PPMI) study. Baseline data extracted from the PPMI database, contained demographics and non-motor symptoms (e.g. the Montreal Cognitive Assessment (MOCA) for cognition, the University of Pennsylvania Smell Identification Test (UPSIT) for olfaction, MDS-UPDRS I etc.)\\n\\nResultsThe mean UPSIT score was lower in A53T-AC vs HC (p =0.000). MoCA test showed a trend towards lower scores in A53T AC. We found a significant positive correlation between UPSIT score and MOCA in A53T-AC (rs = 0,68, p=0,021) but not in HC. Total scores for MDS-UPDRS I did not differ between the groups but the subscore of anxiety was more prevalent in A53T-AC.\\n\\nConclusionThe more affected olfaction in A53T-AC may indicate that olfactory function is affected quite early in A53T carriers. The strong positive correlation between UPSIT and MOCA in the A53T-AC group may indicate that cognitive dysfunction and olfactory impairment progress alongside, prior to nigrostriatal degeneration. Anxiety was also more prevalent in A53T-AC and may represent an additional prodromal feature in this group of subjects.\",\n \"Development of an explicit and implicit knowledge identification tool for the analysis of the decision-making process of traditional Asian medicine doctors\\nBackground and objectivesWhile pattern identification (PI) is an essential process for diagnosis and treatment in traditional Asian medicine (TAM), it is difficult to objectify since it relies heavily on implicit knowledge. Here, we propose a machine learning-based analysis tool to objectify and evaluate the clinical decision-making process of PI in terms of explicit and implicit knowledge.\\n\\nMethodsClinical data for the development of the analysis tool were collected using a questionnaire administered to allergic rhinitis (AR) patients and the diagnosis and prescription results of TAM doctors based on the completed AR questionnaires. Explicit knowledge and implicit knowledge were defined based on the explicit and implicit importance scores of the AR questionnaire, which were obtained through doctors explicit scoring and feature evaluations of machine learning models, respectively. The analysis tool consists of eight evaluation indicators used to compare, analyze and visualize the explicit and implicit knowledge of TAM doctors.\\n\\nResultsThe analysis results for 8 doctors showed that our tool could successfully identify explicit and implicit knowledge in the PI process. We also conducted a postquestionnaire study with the doctors who participated to evaluate the applicability of our tool.\\n\\nConclusionsThis study proposed a tool to evaluate and compare decision-making processes of TAM doctors in terms of their explicit and implicit knowledge. We identified the differences between doctors own explicit and implicit knowledge and the differences among TAM doctors. The proposed tool would be helpful for the clinical standardization of TAM, doctors own clinical practice, and intern/resident training.\",\n \"A novel RT-LAMP workflow for rapid salivary diagnostics of COVID-19 and effects of age, gender and time from symptom onset\\nObjectivesRapid diagnostics is pivotal to curb SARS-CoV-2 transmission, and saliva has emerged as a practical alternative to naso/oropharyngeal (NOP) specimens. We aimed to develop a direct RT-LAMP workflow for viral detection in saliva, and to provide more information regarding its potential in COVID-19 diagnostics.\\n\\nMethodsClinical and contrived specimens were used to screen/optimize formulations and sample processing protocols. Salivary viral load was determined in symptomatic patients to evaluate clinical performance (n = 90) and to characterize saliva based on age, gender and time from onset of symptoms (n = 49).\\n\\nResultsThe devised workflow achieved 93.2% sensitivity, 97% specificity, and 0.895 Kappa for salivas containing >102 copies/L. Further analyses in saliva showed peak viral load in the first days of symptoms and lower viral loads in females, particularly among young individuals (<38 years). NOP RT-PCR data did not yield relevant associations.\\n\\nConclusionsThis novel saliva RT-LAMP workflow can be applied to point-of-care testing. This work reinforces that saliva better correlates with transmission dynamics than NOP specimens, and reveals gender differences that may reflect higher transmission by males. To maximize detection, testing should be done immediately after symptom onset, especially in females.\\n\\nHIGHLIGHTS- Development of DGS, a dithiothreitol/guanidine-based solution for stabilization of the viral genome that increases sensitivity for SARS-CoV-2 detection in saliva;\\n- Rapid, cost-effective RT-LAMP assay workflow for viral detection in saliva without need of RNA extraction;\\n- Insights into the differences in viral load between saliva and naso-oropharyngeal specimens, and correlation with age, gender and time from symptom onset;\",\n \"Blood cytokine analysis suggests that SARS-CoV-2 infection results in a sustained tumour promoting environment in cancer patients\\nCytokines, chemokines and (angiogenic) growth factors (CCGs) have been shown to play an intricate role in the progression of both solid and haematological malignancies. Recent studies have shown that SARS-CoV-2 infection leads to worse outcome in cancer patients, especially in haematological malignancy patients. Here, we investigated how SARS-CoV-2 infection impacts the already altered CCG levels in solid or haematological malignancies, specifically whether there is a protective effect or rather a potentially higher risk for major COVID-19 complications in cancer patients due to elevated CCGs linked to cancer progression. Serially analysing immune responses with 55 CCGs in cancer patients under active treatment with or without SARS-CoV-2 infection, we first showed that cancer patients without SARS-CoV-2 infection (n=54) demonstrate elevated levels of 35 CCGs compared to the non-cancer, non-infected control group of health care workers (n=42). Of the 35 CCGs, 19 were common to both solid and haematological malignancy groups and comprised previously described cytokines such as IL-6, TNF-, IL-1Ra, IL-17A, and VEGF, but also several less well described cytokines/chemokines such as Fractalkine, Tie-2, and T cell chemokine CTACK. Importantly, we show here that 7 CCGs are significantly altered in SARS-CoV-2 exposed cancer patients (n=52). Of these TNF-, IFN-{beta}, TSLP and sVCAM-1, identified to be elevated in haematological cancers, are also known tumour-promoting factors. Longitudinal analysis conducted over 3 months showed persistence of several tumour-promoting CCGs in SARS-CoV-2 exposed cancer patients. These data urge for increased vigilance for haematological malignancy patients as a part of long COVID follow-up.\",\n \"Duration of COVID-19 mRNA Vaccine Effectiveness against Severe Disease\\nBackgroundWaning immunity following administration of mRNA based COVID-19 vaccines remains a concern for many health systems. We undertook a study of SARS-CoV-2 infections, with and without requirement for intensive care to shed more light on the duration of vaccine effectiveness for protection against the need for intensive care.\\n\\nMethodsWe used a matched case-control study design with the study base being all individuals with first infection with SARS-CoV-2 reported in the State of Qatar between 1 Jan 2021 and 20 Feb 2022. Cases were those requiring intensive care while controls were those who recovered without need for intensive care. Vaccine effectiveness against requiring intensive care and number needed to vaccinate (NNV) to prevent one more case of COVID-19 requiring intensive care were computed for the mRNA (BNT162b2 / mRNA-1273) vaccines.\\n\\nResultsVaccine effectiveness against requiring intensive care was 59% (95% confidence interval [CI], 50 to 76) between the first and second dose and strengthened to 89% (95% CI, 85 to 92) between the second dose and 4 months post the second dose in persons who received a primary course of the vaccine. There was no waning of vaccine effectiveness in the period from 4 to 12 months after the second dose.\\n\\nConclusionsThis study demonstrates that vaccine effectiveness against requiring intensive care remains robust till at least 12 months after the second dose of mRNA based vaccines.\",\n \"The Microbiome in Adult Acute Appendicitis\\nAcute appendicitis is a common acute surgical emergency; however, the pathogenesis of adult appendicitis remains poorly understood. The microbiome is increasingly thought to play a key role in inflammatory disease of the bowel and similarly, may play a role in appendicitis.\\n\\nAimThis study aimed to characterize the microbiome of adult acute appendicitis in a prospective cohort.\\n\\nMethodWe recruited 60 adults with acute appendicitis and 20 healthy controls. Rectal swabs were taken from each patient. After DNA extraction, 16S rRNA amplicon sequencing was carried out for analysis of diversity and taxonomic abundance.\\n\\nResultsPhylogenetic sequencing of the samples indicated that there is a difference between the microbial composition of those with acute appendicitis and healthy controls, with a statistically significant decrease in alpha diversity in rectal swabs of appendicitis patients compared to healthy controls. At the genus level, we saw an increased abundance of potential pathogens, e.g. Parvimonas and Acinetobacter, and a decrease in commensal taxa such as Faecalibacterium, Blautia and Lachnospiraceae in appendicitis patients compared to healthy controls.\\n\\nConclusionAn imbalance in the gut microbiome may contribute to the pathogenesis of adult acute appendicitis.\",\n \"TreatmentPatterns: An R package to analyze treatment patterns of a study population of interest\\nBackground and objectivesThere is an increasing interest to use real-world data to illustrate how patients with specific medical conditions are treated in real life. Insight in the current treatment practices helps to improve and tailor patient care. We aim to provide an easy tool to support the development and analysis of treatment pathways for a wide variety of medical conditions.\\n\\nMethodsWe formally defined the process of constructing treatment pathways and developed an open-source R package TreatmentPatterns (https://github.com/mi-erasmusmc/TreatmentPatterns) to enable a reproducible and timely analysis of treatment patterns.\\n\\nResultsThe developed package supports the analysis of treatment patterns of specific populations of interest. We demonstrate the functionality of the package by analyzing the treatment patterns of three common chronic diseases (type II diabetes mellitus, hypertension, and depression) in the Dutch Integrated Primary Care Information (IPCI) database.\\n\\nConclusionTreatmentPatterns is a tool to make the analysis of treatment patterns more accessible, more standardized, and more interpretation friendly. This tool can facilitate and contribute to the accumulation of knowledge on real-world treatment patterns across disease domains. We encourage researchers to further adjust and add custom analysis to the package based on their research needs.\",\n \"A pipeline for tabular dataset formation from unstructured data provided by ACR Appropriateness Criteria guidelines\\nCurrently, data performns a critical concept for disparate human activities, from law to technology. Among data-centric technologies, clinical decision support systems (CDSS) figures out as one of the most promising for healthcare. Despite the technological advances facilitating its implementation, the maintainance of knowledge base for CDSS remains open to improvements. Here, we argue that the Appropriateness Criteria provided by ACR guidelines can be used as a open data-source that, combined with appropriate algorithms, can push forward basic research and technological developments regarding knowledge base for CDSS. Therefore, we developed a pipeline capable of forming tabular datasets from ACR guidelines, stored in a web site as textual PDF files. We also experimentally demonstrate that the proposed pipeline successfully recorvers the interested contents, and the best composition, in terms of its component algorithms, is discussed. Future research focused on algorithms flexibility in the face of PDF template updates could improve our work.\",\n \"Safety and immunogenicity of the third booster dose with inactivated, viral vector, and mRNA COVID-19 vaccines in fully immunized healthy adults with inactivated vaccine\\nThe coronavirus disease-2019 (COVID-19) pandemic has become a severe healthcare problem worldwide since the first outbreak in late December 2019. Currently, the COVID-19 vaccine has been used in many countries, but it is still unable to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection despite patients receiving full vaccination doses. Therefore, we aimed to appraise the booster effect of the different platforms of vaccines, including inactivated vaccine (BBIBP), viral vector vaccine (AZD122), and mRNA vaccine (BNT162b2) in healthy adults who received the full dose of inactivated vaccine (CoronaVac). The booster dose was safe with no serious adverse events. Moreover, the immunogenicity indicated that the booster dose with viral vector and mRNA vaccine achieved a significant proportion of Ig anti-receptor binding domain (RBD), IgG anti-RBD, and IgA anti-S1 booster response. In contrast, inactivated vaccine achieved a lower booster response than others. Consequently, the neutralization activity of vaccinated serum had a high inhibition of over 90% against SARS-CoV-2 wild-type and their variants (B.1.1.7-alpha, B.1.351-beta, and B.1.617.2-delta). In addition, IgG anti-nucleocapsid was observed only among the group that received the BBIBP booster. Our study found a significant increase in levels of interferon gamma-secreting T-cell response after the additional viral vector or mRNA booster vaccination. This study showed that administration with either viral vector (AZD1222) or mRNA (BNT162b2) boosters in individuals with a history of two doses of inactivated vaccine (CoronaVac) obtained great immunogenicity with acceptable adverse events.\",\n \"Pre-conceptional maternal vitamin B12 supplementation improves offspring neurodevelopment at 2 years of age: PRIYA trial\\nBackgroundNutritional interventions during the first 1000 days of life improves lifelong health. Better pre-conceptional maternal nutrition improves the nutrition of the early embryo. Vitamins B12 and folate are important for fetal neural development. Vitamin B12 deficiency is common in India.\\n\\nMethodsIn the Pune Rural Intervention in Young Adolescents (PRIYA) adolescents (N=557, 226 females) were provided with vitamin B12 (2{micro}g/day) with or without multiple micronutrients, or a placebo, from preconception until delivery. All groups received mandatory iron and folic acid. We used the Bayleys Scale of Infant Development (BSID-III) at 24-42 months of age to investigate effects on offspring neurodevelopment. We examined cord blood concentrations of brain-derived neurotropic factor (BDNF).\\n\\nResultsParticipants in the three groups had similar baseline B12 levels. These improved in the B12 supplemented groups at pre-conceptional and pregnancy (28 weeks gestation) measurements, reflected in higher cord holo-TC levels compared to the placebo. Neurodevelopmental outcomes are available for 74 children. Offspring in the B12 alone group (n=21) performed better than the placebo (n=27) on cognition (p=0.044) and language (p=0.020) domains (adjusted for maternal baseline B12 levels). There were no differences between the B12+MMN (n=26) and placebo group. Cord blood BDNF levels were highest in the B12 alone group (not statistically significant).\\n\\nConclusionPre-conceptional vitamin B12 supplementation improved maternal B12 status and offspring neurodevelopment at 2 years of age. The usefulness of cord BDNF as a marker of brain development needs further investigation. Our results highlight the importance of intervening in the pre-conceptional period.\",\n \"Detecting cryptic clinically-relevant structural variation in exome sequencing data increases diagnostic yield for developmental disorders\\nStructural Variation (SV) describes a broad class of genetic variation greater than 50bps in size. SVs can cause a wide range of genetic diseases and are prevalent in rare developmental disorders (DD). Patients presenting with DD are often referred for diagnostic testing with chromosomal microarrays (CMA) to identify large copy-number variants (CNVs) and/or with single gene, gene-panel, or exome sequencing (ES) to identify single nucleotide variants, small insertions/deletions, and CNVs. However, patients with pathogenic SVs undetectable by conventional analysis often remain undiagnosed. Consequently, we have developed the novel tool InDelible, which interrogates short-read sequencing data for split-read clusters characteristic of SV breakpoints. We applied InDelible to 13,438 probands with severe DD recruited as part of the Deciphering Developmental Disorders (DDD) study and discovered 64 rare, damaging variants in genes previously associated with DD missed by standard SNV, InDel or CNV discovery approaches. Clinical review of these 64 variants determined that about half (30/64) were plausibly pathogenic. InDelible was particularly effective at ascertaining variants between 21-500 bps in size, and increased the total number of potentially pathogenic variants identified by DDD in this size range by 42.3%. Of particular interest were seven confirmed de novo variants in MECP2 which represent 35.0% of all de novo protein truncating variants in MECP2 among DDD patients. InDelible provides a framework for the discovery of pathogenic SVs that are likely missed by standard analytical workflows and has the potential to improve the diagnostic yield of ES across a broad range of genetic diseases.\",\n \"Antibodies against type-I Interferon: detection and association with severe clinical outcome in COVID-19 patients\\nObjectivesImpairment of type I interferon (IFN-I) immunity has been reported in critically-ill COVID-19 patients. This defect can be explained in a subset of patients by the presence of circulating autoantibodies (auto-Abs) against IFN-I. We set out to improve the detection and the quantification of IFN-I auto-Abs in a cohort of critically-ill COVID-19 patients, in order to better evaluate the prevalence of these Abs as the pandemic progresses, and how they correlate with the clinical course of the disease.\\n\\nMethodsThe concentration of anti-IFN-2 Abs was determined in the serum of 84 critically-ill COVID-19 patients who were admitted to ICU in Hospices Civils de Lyon, France using a commercially available kit (Thermo-Fisher, Catalog #BMS217).\\n\\nResultsA total of 21/84 (25%) critically-ill COVID-19 patients had circulating anti-IFN-2 Abs above cut-off (>34 ng.mL-1). Among them, 15/21 had Abs with neutralizing activity against IFN-2, i.e. 15/84 (18%) of critically-ill patients. In addition, we noticed an impairment of the IFN-I response in the majority of patients with neutralizing anti-IFN-2 Abs. There was no significant difference in the clinical characteristics or outcome of with or without neutralizing anti-IFN-2 auto-Abs. We detected anti-IFN-2 auto-Abs in COVID-19 patients sera throughout their ICU stay. Finally, we also found auto-Abs against multiple subtypes of IFN-I including IFN-{omega}.\\n\\nConclusionsWe reported that 18% of critically-ill COVID-19 patients were positive for IFN-I auto-Abs, confirming that the presence of these antibodies is associated with higher risk of developing a criticall COVID-19 form.\",\n \"ELF5 is a respiratory epithelial cell-specific risk gene for severe COVID-19\\nDespite two years of intense global research activity, host genetic factors that predispose to a poorer prognosis and severe course of COVID-19 infection remain poorly understood. Here, we identified eight candidate protein mediators of COVID-19 outcomes by establishing a shared genetic architecture at protein-coding loci using large-scale human genetic studies. The transcription factor ELF5 (ELF5) showed robust and directionally consistent associations across different outcome definitions, including a >4-fold higher risk (odds ratio: 4.85; 95%-CI: 2.65-8.89; p-value<3.1x10-7) for severe COVID-19 per 1 s.d. higher genetically predicted plasma ELF5. We show that ELF5 is specifically expressed in epithelial cells of the respiratory system, such as secretory and alveolar type 2 cells, using single-cell RNA sequencing and immunohistochemistry. These cells are also likely targets of SARS-CoV-2 by colocalisation with key host factors, including ACE2 and TMPRSS2. We also observed a 25% reduced risk of severe COVID-19 per 1 s.d. higher genetically predicted plasma G-CSF, a finding corroborated by a clinical trial of recombinant human G-CSF in COVID-19 patients with lymphopenia reporting a lower number of patients developing critical illness and death. In summary, large-scale human genetic studies together with gene expression at single-cell resolution highlight ELF5 as a novel risk gene for COVID-19 prognosis, supporting a role of epithelial cells of the respiratory system in the adverse host response to SARS-CoV-2.\",\n \"SynTL: A synthetic-data-based transfer learning approach for multi-center risk prediction\\nObjectivesWe propose a synthetic-data-based transfer learning approach (SynTL) to incorporate multi-center healthcare data for improving the risk prediction of a target population, accounting for challenges including heterogeneity, data sharing, and privacy constraints.\\n\\nMethodsSynTL combines locally trained risk prediction models from each source population with the target population to adjust for the data heterogeneity through a flexible distance-based transfer learning approach. Heterogeneity-adjusted synthetic data are then generated for source populations where individual-level data are not shareable. The synthetic data are then combined with the target and source data for joint training of the target model. We evaluate SynTL via extensive simulation studies and an application to multi-center data from the electronic Medical Records and Genomics (eMERGE) Network to predict extreme obesity.\\n\\nResultsSimulation studies show that SynTL outperforms methods without adjusting for the data heterogeneity and methods that are trained in a single population over a wide spectrum of settings. SynTL has low communication costs where each participating site only needs to share parameter estimates to the target, requiring only one round of communication. SynTL protects against negative transfer when some source populations are highly different from the target. Using eMERGE data, SynTL achieves an area under the receiver operating characteristic curve (AUC) around 0.79, which outperforms other benchmark methods (0.50 - 0.67).\\n\\nConclusionSynTL improves the risk prediction performance of the target population, and is robust to the level of heterogeneity between the target and source populations. It protects patient-level information and is highly communication efficient.\",\n \"Addressing Extreme Imbalance for Detecting Medications Mentioned in Twitter User Timelines\\nTweets mentioning medications are valuable for efforts in digital epidemiology to supplement traditional methods of monitoring public health. A major obstacle, however, is to differentiate them from the large majority of tweets on other topics posted in a users timeline: solving the infamous needle in a haystack problem. While deep learning models have significantly improved classification, their performance and inference processing time remain low on extremely imbalanced corpora where the tweets of interest are less than 1% of all tweets. In this study, we empirically evaluate under-sampling, fine-tuning, and filtering heuristics to train such classifiers. Using a corpus of 212 Twitter timelines (181,607 tweets with only 0.2% tweets mentioning a medication), our results show that combining these heuristics is necessary to impact the classifiers performance. In our intrinsic evaluation, a classifier based on a lexicon and a BERT-base neural network achieved a 0.838 F1-score, a score similar to the ones of the best existing classifier, but it processed the corpus 28 times faster - a positive result, since processing speed is still a roadblock to deploying classifiers on large cohorts of Twitter users needed for pharmacovigilance. In our extrinsic evaluation, our classifier helped a labeler to extract the spans of medications more accurately and achieved a 0.76 Strict F1-score. To the best of our knowledge, this is the first evaluation of medications extraction in Twitter timelines and it establishes the first benchmark for future studies.\",\n \"Characterization of Autonomic Symptom Burden in Long COVID: A Global Survey of 2,314 Adults\\nBackgroundAutonomic dysfunction is a common complication of post-acute sequalae of SARS-CoV-2 (PASC)/long COVID, however prevalence and severity rates are unknown.\\n\\nObjectiveThe primary goal of this study was to assess the frequency and severity of autonomic symptoms in PASC. We also aimed to assess symptom burden in PASC though well-validated questionnaires, evaluate which pre-existing conditions are associated with an increased risk of developing autonomic dysfunction, and determine whether the severity of acute COVID-19 illness is associated with the severity of autonomic dysfunction in this population.\\n\\nMethodsWe conducted an online survey of 2,314 adults with PASC using several validated questionnaires including the COMPASS-31 to evaluate for autonomic dysfunction. We included both participants who had tested positive for COVID-19 (test-confirmed) and participants who were diagnosed with COVID-19 based on clinical symptoms alone (test-unconfirmed). Additional analyses were performed on test-confirmed participants, comparing hospitalized to non-hospitalized participants.\\n\\nResults67% of PASC patients had a COMPASS-31 score >20, suggestive of moderate to severe autonomic dysfunction. COMPASS-31 scores did not differ between test-confirmed hospitalized and non-hospitalized participants (28.95{+/-}30.98 vs 26.4{+/-}28.35, p=0.06). Both hospitalized and non-hospitalized participants reported significant functional disability across all quality-of-life domains.\\n\\nConclusionsModerate to severe autonomic dysfunction was seen in all PASC groups in our study, independent of hospitalization status, suggesting that autonomic dysfunction is highly prevalent in the PASC population and not necessarily dependent on the severity of acute COVID illness.\",\n \"Polygenic risk scores for psychiatric, inflammatory, and cardio-metabolic traits and diseases highlight possible genetic overlaps with suicide attempt and treatment-emergent suicidal ideation\\nSuicide is the second leading cause of death among young people. Genetics may contribute to suicidal phenotypes and their co-occurrence in other psychiatric and medical conditions. Our study aimed to investigate the association of polygenic risk scores (PRSs) for 22 psychiatric, inflammatory, and cardio-metabolic traits and diseases with suicide attempt (SA) or treatment-worsening/emergent suicidal ideation (TWESI).\\n\\nPRSs were computed based on summary statistics of genome-wide association studies. Regression analyses were performed between PRSs and SA or TWESI in four clinical cohorts, including up to 3,834 individuals, and results were meta-analyzed across samples. Stratified genetic covariance analyses were performed to investigate the biology underlying cross-phenotype PRS associations. After Bonferroni correction, PRS for major depressive disorder (MDD) was positively associated with SA (p=1.7e-4). Nominal associations were shown between PRSs for coronary artery disease (CAD) (p=4.6e-3) or loneliness (p=0.009) and SA, PRSs for MDD or CAD and TWESI (p=0.033 and p=0.032, respectively). Genetic covariance between MDD and SA was shown in 35 gene sets related to drugs having anti-suicidal effects.\\n\\nA higher genetic liability for MDD may underlie a higher risk of SA. Further, but milder, possible modulatory factors are genetic risk for loneliness and CAD.\",\n \"A Simplified Point-of-Care Lung Ultrasound Protocol to Detect Coronavirus Disease 2019 in Inpatients: A Prospective Observational Study\\nObjectivesTo assess the diagnostic performance of lung point-of-care ultrasound (POCUS) compared to either a positive nucleic acid test (NAT) or a COVID-19-typical pattern on computed tomography (CT) and to evaluate opportunities to simplify a POCUS algorithm.\\n\\nMethodsHospital-admitted adult inpatients with (1) either confirmed or suspected COVID-19 and (2) a completed or ordered CT within the preceding 24 hours were recruited. Twelve lung zones were scanned with a handheld POCUS machine. POCUS, CT, and X-ray (CXR) images were reviewed independently by blinded experts. A simplified POCUS algorithm was developed via machine learning.\\n\\nResultsOf 79 enrolled subjects, 26.6% had a positive NAT and 31.6% had a CT typical for COVID-19. The receiver operator curve (ROC) for a 12-zone POCUS protocol had an area under the curve (AUC) of 0.787 for positive NAT and 0.820 for typical CT. A simplified four-zone protocol had an AUC of 0.862 for typical CT and 0.862 for positive NAT. CT had an AUC of 0.815 for positive NAT; CXR had AUCs of 0.793 for positive NAT and 0.733 for typical CT. Performance of the four-zone protocol was superior to CXR for positive NAT (p=0.0471). Using a two-point cutoff system, the four-zone POCUS protocol had a sensitivity of 0.920 and 0.904 compared to CT and NAT, respectively, at the lower cutoff; it had a specificity of 0.926 and 0.948 at the higher cutoff, respectively.\\n\\nConclusionPOCUS outperformed CXR to predict positive NAT. POCUS could potentially replace other chest imaging for persons under investigation for COVID-19.\",\n \"Factors Associated with Antenatal Care Service Utilization among Mothers with Children under five years in Sunyani Municipality, Ghana\\nBackgroundMaternal and neonatal mortality remains a public health burden around the globe most especially in developing countries. A well utilized antenatal care (ANC) is however among the identified interventions to reduce this burden of maternal and neonatal mortality rates. A lot of factors therefore predispose, enable and cause mothers to identify the need to utilize this service (ANC).\\n\\nAims/objectivesThe aim of this study was to determine factors associated with the utilization of ANC service among postpartum mothers in the Sunyani municipality.\\n\\nMethodsThis study employed descriptive cross-sectional survey design. A semi-structured questionnaire consisting of demographic profile of the respondents, their knowledge about ANC services and the level of ANC utilization. Logistic regression analysis techniques and chi-square were used for the categorical variables to examine the associations between the dependent and independent variables. Data analysis was done using the Statistical Package for Social Science software (SPSS) version 22.\\n\\nResultsMajority (87%) of postpartum mothers in the Sunyani municipality attended ANC at least once during their last pregnancy of which 95.6% had four or more visits and 77.1% initiated their ANC attendance within their first trimester. It was further observed that 97.3% of the mothers had good knowledge about ANC. Marital status and ANC knowledge were found to be significantly associated with ANC attendance. Husbands were found to be poorly involved in ANC services in the Sunyani municipality.\\n\\nConclusionMarital status and ANC knowledge predisposes most mothers to utilize ANC services. Hence, health education activities about ANC services and its importance should be channeled more to areas where ANC utilization is low.\",\n \"Study design: Validation of clinical acceptability of deep-learning-based automated segmentation of organs-at-risk for head-and-neck radiotherapy treatment planning.\\nThis document reports the design of a retrospective study to validate the clinical acceptability of a deep-learning-based model for the autosegmentation of organs-at-risk (OARs) for use in radiotherapy treatment planning for head & neck (H&N) cancer patients.\",\n \"A One-Step open RT-qPCR for SARS-CoV-2 detection\\nThe Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), etiological agent of the coronavirus disease 2019 (COVID-19), is currently detected by reverse transcription followed by quantitative polymerase chain reaction (RT-qPCR) of its viral RNA genome. Within the available alternatives, One-Step procedures are preferred since they are fast and significantly decrease preanalytical errors, minimizing the risk of diagnostic errors.\\n\\nIncreasing the testing capacity and tracing contacts are essential steps to control the pandemic. However, high-cost commercial reagents subject to shortage and poor scalability have hindered the use of these technologies and their adoption for a wide population-scale testing, being even more critical in developing countries. In the current context, open-source initiatives have promoted global collaboration to promote accessible solutions for rapid local deployment. As a result, open protocols are being developed for the local production of SARS-CoV-2 diagnostics.\\n\\nThis work aimed to produce an open-source system for SARS-CoV-2 diagnostic tests in RNA clinical samples. We provide guidelines for standardizing an open One-Step RT-qPCR master mix using recombinant M-MLV reverse transcriptase together with either Pfu-Sso7d or Taq DNA polymerase. Both were tested on synthetic RNA and clinical samples, observing a good correlation when compared to commercial RT-qPCR kits. Nevertheless, the best results were obtained using M-MLV RT combined with Taq DNA polymerase in a probe-based RT-qPCR assay, allowing successful discrimination between positive and negative samples with accuracies comparable to a CDC-recommended commercial kit.\\n\\nHere, we demonstrate that these open RT-qPCR systems can be successfully used to identify SARS-CoV-2 in clinical samples and potentially be implemented in any molecular diagnostic laboratory.\",\n \"Determinants and causes of early neonatal mortality: Hospital based retrospective cohort study in Somali region of Ethiopia\\nBackgroundEarly neonatal mortality occurs when a newborn dies within the first seven days of life. Despite interventions, newborn mortality in Ethiopia has grown over time (33 death per 1000 live births). Determinants varies on level of neonatal mortality. The studys goal was to determine magnitude of early newborn death, as well as its causes and drivers, in Newborn Intensive Care Unit of Referral hospital in Ethiopias Somali region.\\n\\nMethodsHealth facility based retrospective study review was conducted between May 2019 to May 2021 in Shiek Hassan Yabare Referral Hospital of Jigjiga University of Ethiopia. All neonates between 0 to 7 days admitted at NICU and get registered using the new NICU registration book from May 2019 to May 2021 with complete data were included. Kobo toolkit was used for data collection and analyzed in SPSS 20. Logistic regression model was used to estimate determinants.\\n\\nResultThe magnitude of early neonatal mortality rate (defined as death between 0-7 days) of Ethiopias Somali region is estimated to be 130 per 1000 live births--That is say 130 newborn couldnt celebrate their seventh day in every 1000 live births. Hypothermia, prematurity, maternal death at birth and shorter length of stay in NICU were increasing the chance of neonatal mortality at early stage while neonatal resuscitation had shown protective effect against neonatal mortality. Similarly birth asphyxia, preterm, sepsis, and congenital abnormalities were major causes of admission and death in the NICU.\\n\\nConclusionThe magnitude of early neonatal mortality is considerable and causes are preventable. Enhancing quality of care including infection prevention and hypothermia through mentorship and encouraging the Kangaroo Mother Care practice is necessary at childbirth and NICU of the Hospital.\",\n \"Quantifying the role of naturally- and vaccine-derived neutralizing antibodies as a correlate of protection against COVID-19 variants\\nThe functional relationship between neutralizing antibodies (NAbs) and protection against SARS-CoV-2 infection and disease remains unclear. We jointly estimated protection against infection and disease progression following natural infection and vaccination from meta-study data. We find that NAbs are strongly correlated with prevention of infection and that any history of NAbs will stimulate immune memory to moderate disease progression. We also find that natural infection provides stronger protection than vaccination for the same level of NAbs, noting that infection itself, unlike vaccination, carries risk of morbidity and mortality, and that our most potent vaccines induce much higher NAb levels than natural infection. These results suggest that while sterilizing immunity may decay, we expect protection against severe disease to be robust over time and in the face of immune-evading variants.\",\n \"METHYLATION BIOMARKERS ASSOCIATED WITH DRUG-RESISTANT EPILEPSY\\nEpilepsy is a disabling neurological disease that affects 2% of the population. Drug-resistant epilepsy (DRE) affects 25-30% of epilepsy patients. Understanding its underlying mechanisms is key to adequately manage this condition. To analyze the main epigenetic marks of DRE an epigenome-wide association study was carried out including samples from different regions of DRE patients brain and peripheral blood. An Illumina Infinium MethylationEPIC BeadChip array including cortex, hippocampus, amygdala, and peripheral blood from DRE subjected to neurosurgical resection of the epileptogenic zone was used. Overall, 32, 59, 3210, and 6 differentially methylated probes (DMPs) associated with DRE were found in the hippocampus, amygdala, cortex, and peripheral blood, respectively. These DMPs harbored 19, 28, 1574, and 7 genes, respectively, which play different roles in processes such as neurotrophic or calcium signaling. Three of the top DMPs observed in cortex were validated with methylation specific qPCR. Moreover, 163 DMPs associated with neurosurgery response at 6 months were found in the hippocampus. Genes located on these DMPs were involved in diverse processes such as synaptic signaling and central nervous system development. Besides 3 DMPs in blood samples were associated with response to neurosurgery at 12 months. In conclusion, the present study reports genome-wide DNA methylation changes across different regions of the DRE brain. These changes could be useful for further studies to disentangle the bases of DRE to search for therapeutic alternatives for this disease. Furthermore, they could also help identify patients likely to respond to neurosurgery.\",\n \"Integrating Multiple Imaging Modalities does not Boost Prediction of Carotid Artery Intima-Media Thickness in Midlife Adults\\nBackgroundHuman neuroimaging evidence suggests that cardiovascular disease (CVD) risk may relate to functional and structural features of the brain. The present study tested whether combining functional and structural (multimodal) brain measures, derived from magnetic resonance imaging (MRI), would yield a multivariate brain biomarker that reliably predicts a subclinical marker of CVD risk, carotid-artery intima-media thickness (CA-IMT).\\n\\nMethodsNeuroimaging, cardiovascular, and demographic data were assessed in 324 midlife and otherwise healthy adults who were free of (a) clinical CVD and (b) use of medications for chronic illness (aged 30-51 years, 49% female). We implemented a prediction stacking algorithm that combined multimodal brain imaging measures and Framingham Risk Scores (FRS) to predict CA-IMT. We included imaging measures that could be easily obtained in clinical settings: resting state functional connectivity and structural morphology measures from T1-weighted images.\\n\\nResultsOur models reliably predicted CA-IMT using FRS, as well as for several individual MRI measures; however, none of the individual MRI measures outperformed FRS. Moreover, stacking functional and structural brain measures with FRS did not boost prediction accuracy above that of FRS alone.\\n\\nConclusionsCombining multimodal functional and structural brain measures through a stacking algorithm does not appear to yield a reliable brain biomarker of subclinical CVD, as reflected by CA-IMT.\",\n \"Predictors for participation in DNA self-sampling of childhood cancer survivors in Switzerland\\nResearch on germline genetic variants relies on a sufficient number of eligible participants which is difficult to achieve for rare diseases such as childhood cancer. With self-collection kits using saliva or buccal swabs, participants can contribute genetic samples conveniently from their home. We identified determinants of participation in DNA self-collection in this cross-sectional study.\\n\\nWe invited 928 childhood cancer survivors in Switzerland with a median age of 26.5 years (interquartile range 18.8-36.5), of which 463 (50%) participated. Foreign nationality (odds ratio [OR] 0.5, 95%-confidence interval [CI] 0.4-0.7), survivors aged 30-39 years at study versus other age groups (OR 0.5, CI 0.4-0.8), and those with a known cancer predisposition syndrome (OR 0.5, CI 0.3-1.0) participated less. Survivors with a second primary neoplasm (OR 1.9, CI 1.0-3.8) or those living in a French or Italian speaking region (OR 1.3, 1.0-1.8) tended to participate more.\\n\\nWe showed that half of survivors participate in germline DNA self-sampling relying completely on mailing of sample kits. Foreign nationality, age 30-39 years, and cancer predisposition syndromes were associated with less participation. More targeted recruitment strategies may be advocated for these subgroups. To increase participation in DNA self-sampling, understanding and perceptions of survivors need to be better understood.\",\n \"Ammonium Sulfate Addition Reduces the Need for Guanidinium Isothiocyanate in the Denaturing Transport Medium Used for SARS-COV-2 RNA Detection\\nRapid identification of SARS-CoV-2 infected individuals through viral RNA detection followed by effective personal isolation remains the most effective way to prevent the spread of this virus. Large-scale RNA detection involves mass specimen collection and transportation. For biosafety reasons, denaturing viral transport medium has been extensively used during the pandemic. But the high concentrations of guanidinium isothiocyanate (GITC) in such media have raised issues around sufficient GITC supply and laboratory safety. Here, we tested whether supplementing media containing low concentrations of GITC with ammonium sulfate (AS) would affect the throat-swab detection of SARS-CoV-2 pseudovirus or a viral inactivation assay targeting both enveloped and non-enveloped viruses. Adding AS to the denaturing transport media reduced the need for high levels of GITC and improved SARS-COV-2 RNA detection without compromising virus inactivation.\",\n \"Quantification of T- and B-cell immune receptor distribution diversity characterizes immune cell infiltration and lymphocyte heterogeneity in clear cell renal cell carcinoma\\nImmune-modulating systemic therapies are often used to treat advanced cancer such as metastatic clear cell renal cell carcinoma (ccRCC). Used alone, sequence-based biomarkers neither accurately capture patient dynamics nor the tumor immune microenvironment. To better understand the tumor ecology of this immune microenvironment, we quantified tumor infiltration across two distinct ccRCC patient tumor cohorts using complementarity determining region-3 (CDR3) sequence recovery counts in tumor-infiltrating lymphocytes and a generalized diversity index (GDI) for CDR3 sequence distributions. GDI can be understood as a curve over a continuum of diversity scales which allows sensitive characterization of distributions to capture sample richness, evenness, and subsampling uncertainty, along with other important metrics that characterize tumor heterogeneity. For example, richness quantified the total unique sequence count, while evenness quantified similarities across sequence frequencies. Significant differences in receptor sequence diversity across gender and race revealed that patients with larger and more clinically aggressive tumors had increased richness of recovered tumoral CDR3 sequences, specifically in those from T-cell receptor alpha and B-cell immunoglobulin lambda light chain. The GDI inflection point (IP) allowed for a novel and robust measure of distribution evenness. High IP values associated with improved overall survival, suggesting that normal-like sequence distributions lead to better outcomes. These results propose a new quantitative tool that can be used to better characterize patient-specific differences related to immune cell infiltration, and to identify unique characteristics of tumor-infiltrating lymphocyte heterogeneity in ccRCC and other malignancies.\",\n \"PRACTICE OF EARLY BREASTFEEDING INITIATION ON PRIMIGRAVIDA WITH A CULTURAL PERSPECTIVE: A SYSTEMATIC REVIEW\\nOne of the health aspects in the development process is the development of human resource potential (HR). What plays a role in this potential of human resources is good nutritional status from an early age. In addition to these factors, the quality of human resource formation is also influenced by the environment that shapes human character. namely the socio-cultural environment (Soekirman, 2005). One of the cultural interactions that affect nutritional status as a condition for the formation of quality human resources is the practice of breastfeeding and the practice of early breastfeeding initiation (IMD). There have been many previous studies that have written that there are still many mothers who do not practice IMD, where one of the reasons mentioned is the belief that the first milk that comes out is dirty and unhealthy, so it is not suitable to be given to babies (Roesli, 2008). The purpose of this literature study is to determine the influence of culture in the practice of early breastfeeding initiation.\\n\\nThe articles used in the literature review were obtained through databases of international journal providers such as Proquest, Google Scholar and Science Direct. The journal was taken from 2019 to 2021. Researchers used keywords, namely transcultural nursing, breastfeeding (according to MESH/Medical Subject Heading) and 20 articles were analyzed using PRISMA diagrams. The analysis found that most mothers did not practice early breastfeeding because of certain beliefs about early breastfeeding, such as early breastfeeding was not as good as exclusive breastfeeding, dirty early breast milk, unhealthy early breastfeeding given to babies and the habit of mothers who immediately gave additional food immediately. after the baby is born.\"\n]","isConversational":false},"cluster":{"kind":"number","value":6,"string":"6"}}},{"rowIdx":226,"cells":{"query":{"kind":"string","value":"How hostile is prolonged brain death for donor organs in transplantation? A time course analysis using clinical samples\nOrgan donation after brain death (DBD) is an important source of transplanted organs, as chronic undersupply means many patients die whilst awaiting transplant. Improving organ quality and graft survival is key to reducing waiting lists: the interval between brain death (BD) confirmation and organ procurement offers an opportunity to reduce injury or encourage repair, yet data are lacking. Here, we developed a novel method of studying time-course changes in serum proteins in a DBD cohort from a UK biobank. Individual donor trajectories were combined into a mathematical model to allow us to determine changes in pro-inflammatory (TNF-alpha, IL-6, Complement) mediators and markers of central nervous injury (NSE, GFAP) after BD. Surprisingly, we found no evidence of a rise of TNF-alpha, NSE, IL-6 or C5a with prolonged BD, questioning the consensus view of progressively pro-inflammatory environment, and identified complement as a potential target for therapeutic intervention to improve organ quality."},"positive":{"kind":"list like","value":["Human cytomegalovirus strain diversity and dynamics reveal the donor lung as a major contributor after transplantation\nMixed human cytomegalovirus (HCMV) strain infections are frequent in lung transplant recipients (LTRs). To date, the influence of the donor (D) and recipient (R) HCMV-serostatus on intra-host HCMV strain composition and replication dynamics after transplantation is only poorly understood.\n\nHere, we investigated ten pre-transplant lungs from HCMV-seropositive donors, and 163 sequential HCMV-DNA positive plasma and bronchoalveolar lavage samples from 50 LTRs with multiviremic episodes post-transplantation. The study cohort included D+R+ (38%), D+R- (36%), and D-R+ (26%) patients. All samples were subjected to quantitative genotyping by short amplicon deep sequencing, and 24 thereof were additionally PacBio long-read sequenced for genotype linkages.\n\nWe find that D+R+ patients show a significantly elevated intra-host strain diversity compared to D+R- and D-R+ patients (P=0.0089). Both D+ patient groups display significantly higher replication dynamics than D- patients (P=0.0061). Five out of ten pre-transplant donor lungs were HCMV-DNA positive, whereof in three multiple HCMV strains were detected, indicating that multi-strain transmission via lung transplantation is likely. Using long reads, we show that intra-host haplotypes can share distinctly linked genotypes, which limits overall intra-host diversity in mixed infections. Together, our findings demonstrate donor-derived strains as a main source for increased HCMV strain diversity and dynamics post-transplantation, while a relatively limited number of intra-host strains may facilitate rapid adaptation to changing environments in the host. These results foster targeted strategies to mitigate the potential transmission of the donor strain reservoir with the allograft.","Afucosylation of HLA-specific IgG1 as a potential predictor of antibody pathogenicity in kidney transplantation\nAntibody-mediated rejection (AMR) is the leading cause of graft failure. While donor-specific antibodies (DSA) are associated with a higher risk of AMR, not all patients with DSA develop rejection suggesting that the characteristics of alloantibodies that determine their pathogenicity remain undefined. Using human leukocyte antigen (HLA)-A2-specific antibodies as a model, we applied systems serology tools to investigate qualitative features of immunoglobulin G (IgG) alloantibodies including Fc-glycosylation patterns and Fc{gamma}R binding properties. The levels of afucosylation of anti-A2 antibodies were elevated in all seropositive patients and were significantly higher in AMR patients, suggesting potential cytotoxicity via Fc{gamma}RIII-mediated mechanisms. Afucosylation of both glycoengineered monoclonal and naturally glycovariant polyclonal serum IgG specific to HLA-A2 exhibited potentiated binding to, slower dissociation from, and enhanced signaling through Fc{gamma}RIII, a receptor widely expressed on innate effector cells. Collectively, these results suggest that afucosylated DSA may be a biomarker of AMR and could contribute to its pathogenesis.\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=62 SRC=\"FIGDIR/small/22272152v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (24K):\norg.highwire.dtl.DTLVardef@55413dorg.highwire.dtl.DTLVardef@12e1532org.highwire.dtl.DTLVardef@71938eorg.highwire.dtl.DTLVardef@8e8847_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO Potential influence of HLA-A2-specific IgG1 afucosylation, Fc{gamma}RIIIa binding and activation on ADCC and graft rejection.Illustration created with https://BioRender.com.\n\nC_FIG","Seasonality in living kidney donation in the United States from 1995-2019\nFor nearly two decades, the annual number of US living kidney donors has been characterized by worrying patterns of decline and no factors have been identified to explain and reverse these patterns. Evidence suggests that there is seasonality in living kidney donation; herein we investigate whether potentially modifiable social, economic, and structural issues might explain this seasonality. Using donor-registry data from the Scientific Registry of Transplant Recipients, we described this seasonality in living kidney donation and used Poisson regression stratified by both donor-recipient biological relationship and estimated household income tertile to quantify these trends. In every decade from 1980-2020, there was a summer-only surge in living kidney donations (13%-25% for biologically related donors and 10%-17% for unrelated donors). This summer-only surge was evident for the months of June, July, and August when compared with January for each given year and statistically significant in some groups (range of incidence rate ratio [IRR] for related donors: 1.05-1.34; IRR for unrelated donors: 1.08-1.19). We observed this summer-only surge across all three income tertiles ($73,544+, $52,635- $73,544, and <$52,635) and regardless of donor-recipient relationship. Seasonal variation in donation is associated with structural factors, which may serve as potential targets for interventions to increase donation.","Risk of ESKD in related older living kidney donors\nLiving kidney donors who are biologically related to the recipient have higher risk for end-stage kidney disease (ESKD) compared with those who are unrelated to the recipient. This risk is greater for first-degree relatives than more distant relatives. To understand if this holds true for older donors, who were cleared for donation and might be past the peak-age for hereditary disease, we used donor data (SRTR) linked to ESKD registry data (CMS) and stratified donors by age (younger vs older [[≥]50 years]) and race (black, Hispanic, and white). Younger related donors of all racial groups had higher risk of ESKD compared with younger unrelated donors; however, only older related white and Hispanic donors had higher risk of ESRD compared with unrelated older donors (2.3-fold for white full-siblings and 1.9-fold for white parents/offspring; 3.3-fold for Hispanic full-siblings and 2.0-fold for Hispanic parents/offspring). Older related black donors did not have higher risk compared to older unrelated black donors (0.8-fold for black full-siblings and 0.5-fold for black parents/offspring). Our study points to an earlier age of onset of kidney disease in black donors with a family history of ESKD. Our findings call for programs that promote living donation among related older black donor candidates.","Validation of a rapid potency assay for cord blood stem cells using phospho flow cytometry: the IL-3-pSTAT5 assay\nPublic cord blood banks (CBBs) are required to measure cord blood units (CBUs) potency before their release, allowing for the identification of units that may be unsuitable for hematopoietic transplantation. We have developed a rapid flow cytometry assay based on the measurement of STAT-5 phosphorylation of CD34+ stem cells in response to IL-3 stimulation: the IL-3-pSTAT5 assay.\n\nTo adapt the assay from a research setting to its implementation within our CBB regulated operations, we proceeded with a full method validation and a correlation comparison of the IL-3-pSTAT5 assay results with the colony-forming unit assay (CFU) results. A total of 60 CBUs cryopreserved in vials were analyzed by flow cytometry to determine the sensitivity, specificity, intra-assay precision, robustness, reproducibility and inter-laboratory agreement of the assay. The CFU assay was also done on the same samples for comparison purposes.\n\nThe assay threshold was established at 50% CD34+CD45+pSTAT5+, which provides a 100% sensitivity and a 98.3% specificity. An average intra-assay CV of 7.3% was determined. All results met our qualitative results acceptance criteria regarding the inter-user and inter-laboratory agreements, IL-3 stimulation time, post-thaw incubation delay and staining time. The IL-3-pSTAT5 assay results correlated well with the total CFU determined using the CFU assay (r2 = 0.82, n = 56).\n\nThis study shows that our rapid flow cytometry assay can be successfully validated and that the potency data obtained display good sensitivity, specificity and robustness. These results demonstrate the feasibility of implementing this assay within CBB operations, as a validated CB potency assay.","Patient Perceptions by Race of Educational Animations About Living Kidney Donation Made for a Diverse Population\nIntroductionThis qualitative study sought to identify potential design and delivery alterations to inform cultural adaptation of educational animations about living donor kidney transplantation (LDKT) - previously developed for a diverse population - to better fit Black Americans needs.\n\nMethodsWe conducted a secondary analysis of 88 transcripts derived from interviews and focus groups conducted with diverse target users (62 kidney failure patients, 36 prior/potential donors, and 11 care partners) to develop 12 animations about LDKT, named KidneyTIME. Statements were abstracted and coded pertaining to cognitive and communication barriers to LDKT, and the perceived value of using the videos to learn and share the information with social network members using content analysis. Incidence counts of each content code were also calculated to assess differences between Black and non-Black patients.\n\nResultsCognitive barrier codes included lack of knowledge, ambivalence, and concern for donor. Communication barrier codes included reluctance and difficulty talking about LDKT. Cognitive facilitating codes included attention-getting, efficient learning, manageable content, emotional impact, and new knowledge. Communication facilitating codes included delivery through many dissemination channels and broadly shareable. Compared to non-black patients (n=33) Black patients (n=29) more often stated concern for donor and reluctance/difficulty talking about LDKT as barriers, and less often stated efficient learning and manageable content as facilitators.\n\nConclusionFindings highlight the value of LDKT informational content that is visually appealing, digestible, non-threatening, and highly shareable. Heterogeneity may exist when considering access and intervention preferences in using KidneyTIME videos and highlight a potential for further cultural targeting or tailoring.","Predicting Clinical Endpoints and Visual Changes with Quality-Weighted Tissue-based Histological Features\nTwo common obstacles limiting the performance of data-driven algorithms in digital histopathology classification tasks are the lack of expert annotations and the narrow diversity of datasets. Multi-instance learning (MIL) can be used to address the former challenge for the analysis of whole slide images (WSI) but performance is often inferior to full supervision. We show that the inclusion of weak annotations can significantly enhance the effectiveness of MIL while keeping the approach scalable.\n\nAn analysis framework was developed to process periodic acid-Schiff (PAS) and Sirius Red (SR) slides of renal biopsies. The workflow segments tissues into coarse tissue classes. Handcrafted and deep features were extracted from these tissues and combined using a soft attention model to predict several slide-level labels: delayed graft function (DGF), acute tubular injury (ATI), and Remuzzi grade components. A tissue segmentation quality metric was also developed to reduce the adverse impact of poorly segmented instances. The soft attention model was trained using 5-fold cross-validation on a mixed dataset and tested on the QUOD dataset containing n=373 PAS and n=195 SR biopsies.\n\nThe average ROC-AUC over different prediction tasks was found to be 0.598{+/-}0.011, significantly higher than using only ResNet50 (0.545{+/-}0.012), only handcrafted features (0.542 {+/-} 0.011), and the baseline (0.532 {+/-} 0.012) of state-of-the-art performance. Weighting tissues by segmentation quality in conjunction with the soft attention has led to further improvement (AUC = 0.618 {+/-} 0.010). Using an intuitive visualisation scheme, we show that our approach may also be used to support clinical decision making as it allows pinpointing individual tissues relevant to the predictions.","Extracellular vesicle-bound DNA in urine is indicative of kidney allograft injury\nExtracellular vesicle-bound DNA (evDNA) is an understudied extracellular vesicle (EV) cargo, particularly in cancer-unrelated fundamental and biomarker research. Although evDNA has been detected in urine, little is known about its characteristics, localization, and biomarker potential for kidney pathologies. To address this, we enriched EVs from urine of well-characterized kidney transplant recipients undergoing allograft biopsy, characterized their evDNA and its association to allograft injury. Using DNase treatment and immunogold labelling TEM, we show that DNA is bound to the surface of urinary EVs. Although the urinary evDNA and cell-free DNA correlated in several characteristics, the DNA integrity index showed evDNA was less fragmented (P < 0.001). Urinary EVs from patients with rejection and non-rejection allograft injury were significantly larger (mean: P = 0.045, median: P = 0.031) and have bound more DNA as measured by normalized evDNA yield (P = 0.018) and evDNA copy number (P = 0.007), compared to patients with normal histology. Urinary evDNA characteristics associated with the degree of interstitial inflammation, combined glomerulitis and peritubular capillaritis, and inflammation in areas of fibrosis (all P < 0.050). The normalized dd-evDNA copy numbers differed between the antibody- and T cell-mediated rejection (P = 0.036). Our study supports the importance of DNA as urine EV cargo, especially as potential non-invasive kidney allograft injury biomarker.","Racial Disparities in Post-Transplant Stroke and Mortality Following Stroke in Adult Cardiac Transplant Recipients in the United States\nBackgroundBlack heart transplant recipients have a higher mortality rate than white recipients 6-12 months after transplant. Whether there are racial disparities in post-transplant stroke incidence and all-cause mortality following post-transplant stroke among cardiac transplant recipients is unknown.\n\nMethods and FindingsUsing a nationwide transplant registry, we assessed the association between race and incident post-transplant stroke using logistic regression and the association between race and mortality among adults who survived a post-transplant stroke using Cox proportional hazards regression. We found no evidence of an association between race and the odds of post-transplant stroke (OR = 1.00, 95% CI: 0.83 - 1.21). The median survival time of those with a post-transplant stroke in this cohort was 4.1 years (95% CI: 3.0, 5.4). There were 726 deaths among the 1139 patients with post-transplant stroke, including 127 deaths among 203 Black patients and 599 deaths among 936 white patients. Among post-transplant stroke survivors, Black transplant recipients experienced a 27% higher rate of mortality compared to white recipients (HR = 1.27, 95% CI: 1.03 - 1.57). This disparity is strongest in the period beyond the first 6 months and appears to be mediated by differences in the post-transplant setting of care between Black and white patients. The racial disparity in mortality outcomes was not evident in the past decade.\n\nConclusionsThe improved survival of Black patients in the recent decade may reflect overall protocol improvements for heart transplant recipients irrespective of race, such as advancements in surgical techniques and immediate postoperative care as well as increased awareness about reducing racial disparities."],"string":"[\n \"Human cytomegalovirus strain diversity and dynamics reveal the donor lung as a major contributor after transplantation\\nMixed human cytomegalovirus (HCMV) strain infections are frequent in lung transplant recipients (LTRs). To date, the influence of the donor (D) and recipient (R) HCMV-serostatus on intra-host HCMV strain composition and replication dynamics after transplantation is only poorly understood.\\n\\nHere, we investigated ten pre-transplant lungs from HCMV-seropositive donors, and 163 sequential HCMV-DNA positive plasma and bronchoalveolar lavage samples from 50 LTRs with multiviremic episodes post-transplantation. The study cohort included D+R+ (38%), D+R- (36%), and D-R+ (26%) patients. All samples were subjected to quantitative genotyping by short amplicon deep sequencing, and 24 thereof were additionally PacBio long-read sequenced for genotype linkages.\\n\\nWe find that D+R+ patients show a significantly elevated intra-host strain diversity compared to D+R- and D-R+ patients (P=0.0089). Both D+ patient groups display significantly higher replication dynamics than D- patients (P=0.0061). Five out of ten pre-transplant donor lungs were HCMV-DNA positive, whereof in three multiple HCMV strains were detected, indicating that multi-strain transmission via lung transplantation is likely. Using long reads, we show that intra-host haplotypes can share distinctly linked genotypes, which limits overall intra-host diversity in mixed infections. Together, our findings demonstrate donor-derived strains as a main source for increased HCMV strain diversity and dynamics post-transplantation, while a relatively limited number of intra-host strains may facilitate rapid adaptation to changing environments in the host. These results foster targeted strategies to mitigate the potential transmission of the donor strain reservoir with the allograft.\",\n \"Afucosylation of HLA-specific IgG1 as a potential predictor of antibody pathogenicity in kidney transplantation\\nAntibody-mediated rejection (AMR) is the leading cause of graft failure. While donor-specific antibodies (DSA) are associated with a higher risk of AMR, not all patients with DSA develop rejection suggesting that the characteristics of alloantibodies that determine their pathogenicity remain undefined. Using human leukocyte antigen (HLA)-A2-specific antibodies as a model, we applied systems serology tools to investigate qualitative features of immunoglobulin G (IgG) alloantibodies including Fc-glycosylation patterns and Fc{gamma}R binding properties. The levels of afucosylation of anti-A2 antibodies were elevated in all seropositive patients and were significantly higher in AMR patients, suggesting potential cytotoxicity via Fc{gamma}RIII-mediated mechanisms. Afucosylation of both glycoengineered monoclonal and naturally glycovariant polyclonal serum IgG specific to HLA-A2 exhibited potentiated binding to, slower dissociation from, and enhanced signaling through Fc{gamma}RIII, a receptor widely expressed on innate effector cells. Collectively, these results suggest that afucosylated DSA may be a biomarker of AMR and could contribute to its pathogenesis.\\n\\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=62 SRC=\\\"FIGDIR/small/22272152v1_ufig1.gif\\\" ALT=\\\"Figure 1\\\">\\nView larger version (24K):\\norg.highwire.dtl.DTLVardef@55413dorg.highwire.dtl.DTLVardef@12e1532org.highwire.dtl.DTLVardef@71938eorg.highwire.dtl.DTLVardef@8e8847_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO Potential influence of HLA-A2-specific IgG1 afucosylation, Fc{gamma}RIIIa binding and activation on ADCC and graft rejection.Illustration created with https://BioRender.com.\\n\\nC_FIG\",\n \"Seasonality in living kidney donation in the United States from 1995-2019\\nFor nearly two decades, the annual number of US living kidney donors has been characterized by worrying patterns of decline and no factors have been identified to explain and reverse these patterns. Evidence suggests that there is seasonality in living kidney donation; herein we investigate whether potentially modifiable social, economic, and structural issues might explain this seasonality. Using donor-registry data from the Scientific Registry of Transplant Recipients, we described this seasonality in living kidney donation and used Poisson regression stratified by both donor-recipient biological relationship and estimated household income tertile to quantify these trends. In every decade from 1980-2020, there was a summer-only surge in living kidney donations (13%-25% for biologically related donors and 10%-17% for unrelated donors). This summer-only surge was evident for the months of June, July, and August when compared with January for each given year and statistically significant in some groups (range of incidence rate ratio [IRR] for related donors: 1.05-1.34; IRR for unrelated donors: 1.08-1.19). We observed this summer-only surge across all three income tertiles ($73,544+, $52,635- $73,544, and <$52,635) and regardless of donor-recipient relationship. Seasonal variation in donation is associated with structural factors, which may serve as potential targets for interventions to increase donation.\",\n \"Risk of ESKD in related older living kidney donors\\nLiving kidney donors who are biologically related to the recipient have higher risk for end-stage kidney disease (ESKD) compared with those who are unrelated to the recipient. This risk is greater for first-degree relatives than more distant relatives. To understand if this holds true for older donors, who were cleared for donation and might be past the peak-age for hereditary disease, we used donor data (SRTR) linked to ESKD registry data (CMS) and stratified donors by age (younger vs older [[≥]50 years]) and race (black, Hispanic, and white). Younger related donors of all racial groups had higher risk of ESKD compared with younger unrelated donors; however, only older related white and Hispanic donors had higher risk of ESRD compared with unrelated older donors (2.3-fold for white full-siblings and 1.9-fold for white parents/offspring; 3.3-fold for Hispanic full-siblings and 2.0-fold for Hispanic parents/offspring). Older related black donors did not have higher risk compared to older unrelated black donors (0.8-fold for black full-siblings and 0.5-fold for black parents/offspring). Our study points to an earlier age of onset of kidney disease in black donors with a family history of ESKD. Our findings call for programs that promote living donation among related older black donor candidates.\",\n \"Validation of a rapid potency assay for cord blood stem cells using phospho flow cytometry: the IL-3-pSTAT5 assay\\nPublic cord blood banks (CBBs) are required to measure cord blood units (CBUs) potency before their release, allowing for the identification of units that may be unsuitable for hematopoietic transplantation. We have developed a rapid flow cytometry assay based on the measurement of STAT-5 phosphorylation of CD34+ stem cells in response to IL-3 stimulation: the IL-3-pSTAT5 assay.\\n\\nTo adapt the assay from a research setting to its implementation within our CBB regulated operations, we proceeded with a full method validation and a correlation comparison of the IL-3-pSTAT5 assay results with the colony-forming unit assay (CFU) results. A total of 60 CBUs cryopreserved in vials were analyzed by flow cytometry to determine the sensitivity, specificity, intra-assay precision, robustness, reproducibility and inter-laboratory agreement of the assay. The CFU assay was also done on the same samples for comparison purposes.\\n\\nThe assay threshold was established at 50% CD34+CD45+pSTAT5+, which provides a 100% sensitivity and a 98.3% specificity. An average intra-assay CV of 7.3% was determined. All results met our qualitative results acceptance criteria regarding the inter-user and inter-laboratory agreements, IL-3 stimulation time, post-thaw incubation delay and staining time. The IL-3-pSTAT5 assay results correlated well with the total CFU determined using the CFU assay (r2 = 0.82, n = 56).\\n\\nThis study shows that our rapid flow cytometry assay can be successfully validated and that the potency data obtained display good sensitivity, specificity and robustness. These results demonstrate the feasibility of implementing this assay within CBB operations, as a validated CB potency assay.\",\n \"Patient Perceptions by Race of Educational Animations About Living Kidney Donation Made for a Diverse Population\\nIntroductionThis qualitative study sought to identify potential design and delivery alterations to inform cultural adaptation of educational animations about living donor kidney transplantation (LDKT) - previously developed for a diverse population - to better fit Black Americans needs.\\n\\nMethodsWe conducted a secondary analysis of 88 transcripts derived from interviews and focus groups conducted with diverse target users (62 kidney failure patients, 36 prior/potential donors, and 11 care partners) to develop 12 animations about LDKT, named KidneyTIME. Statements were abstracted and coded pertaining to cognitive and communication barriers to LDKT, and the perceived value of using the videos to learn and share the information with social network members using content analysis. Incidence counts of each content code were also calculated to assess differences between Black and non-Black patients.\\n\\nResultsCognitive barrier codes included lack of knowledge, ambivalence, and concern for donor. Communication barrier codes included reluctance and difficulty talking about LDKT. Cognitive facilitating codes included attention-getting, efficient learning, manageable content, emotional impact, and new knowledge. Communication facilitating codes included delivery through many dissemination channels and broadly shareable. Compared to non-black patients (n=33) Black patients (n=29) more often stated concern for donor and reluctance/difficulty talking about LDKT as barriers, and less often stated efficient learning and manageable content as facilitators.\\n\\nConclusionFindings highlight the value of LDKT informational content that is visually appealing, digestible, non-threatening, and highly shareable. Heterogeneity may exist when considering access and intervention preferences in using KidneyTIME videos and highlight a potential for further cultural targeting or tailoring.\",\n \"Predicting Clinical Endpoints and Visual Changes with Quality-Weighted Tissue-based Histological Features\\nTwo common obstacles limiting the performance of data-driven algorithms in digital histopathology classification tasks are the lack of expert annotations and the narrow diversity of datasets. Multi-instance learning (MIL) can be used to address the former challenge for the analysis of whole slide images (WSI) but performance is often inferior to full supervision. We show that the inclusion of weak annotations can significantly enhance the effectiveness of MIL while keeping the approach scalable.\\n\\nAn analysis framework was developed to process periodic acid-Schiff (PAS) and Sirius Red (SR) slides of renal biopsies. The workflow segments tissues into coarse tissue classes. Handcrafted and deep features were extracted from these tissues and combined using a soft attention model to predict several slide-level labels: delayed graft function (DGF), acute tubular injury (ATI), and Remuzzi grade components. A tissue segmentation quality metric was also developed to reduce the adverse impact of poorly segmented instances. The soft attention model was trained using 5-fold cross-validation on a mixed dataset and tested on the QUOD dataset containing n=373 PAS and n=195 SR biopsies.\\n\\nThe average ROC-AUC over different prediction tasks was found to be 0.598{+/-}0.011, significantly higher than using only ResNet50 (0.545{+/-}0.012), only handcrafted features (0.542 {+/-} 0.011), and the baseline (0.532 {+/-} 0.012) of state-of-the-art performance. Weighting tissues by segmentation quality in conjunction with the soft attention has led to further improvement (AUC = 0.618 {+/-} 0.010). Using an intuitive visualisation scheme, we show that our approach may also be used to support clinical decision making as it allows pinpointing individual tissues relevant to the predictions.\",\n \"Extracellular vesicle-bound DNA in urine is indicative of kidney allograft injury\\nExtracellular vesicle-bound DNA (evDNA) is an understudied extracellular vesicle (EV) cargo, particularly in cancer-unrelated fundamental and biomarker research. Although evDNA has been detected in urine, little is known about its characteristics, localization, and biomarker potential for kidney pathologies. To address this, we enriched EVs from urine of well-characterized kidney transplant recipients undergoing allograft biopsy, characterized their evDNA and its association to allograft injury. Using DNase treatment and immunogold labelling TEM, we show that DNA is bound to the surface of urinary EVs. Although the urinary evDNA and cell-free DNA correlated in several characteristics, the DNA integrity index showed evDNA was less fragmented (P < 0.001). Urinary EVs from patients with rejection and non-rejection allograft injury were significantly larger (mean: P = 0.045, median: P = 0.031) and have bound more DNA as measured by normalized evDNA yield (P = 0.018) and evDNA copy number (P = 0.007), compared to patients with normal histology. Urinary evDNA characteristics associated with the degree of interstitial inflammation, combined glomerulitis and peritubular capillaritis, and inflammation in areas of fibrosis (all P < 0.050). The normalized dd-evDNA copy numbers differed between the antibody- and T cell-mediated rejection (P = 0.036). Our study supports the importance of DNA as urine EV cargo, especially as potential non-invasive kidney allograft injury biomarker.\",\n \"Racial Disparities in Post-Transplant Stroke and Mortality Following Stroke in Adult Cardiac Transplant Recipients in the United States\\nBackgroundBlack heart transplant recipients have a higher mortality rate than white recipients 6-12 months after transplant. Whether there are racial disparities in post-transplant stroke incidence and all-cause mortality following post-transplant stroke among cardiac transplant recipients is unknown.\\n\\nMethods and FindingsUsing a nationwide transplant registry, we assessed the association between race and incident post-transplant stroke using logistic regression and the association between race and mortality among adults who survived a post-transplant stroke using Cox proportional hazards regression. We found no evidence of an association between race and the odds of post-transplant stroke (OR = 1.00, 95% CI: 0.83 - 1.21). The median survival time of those with a post-transplant stroke in this cohort was 4.1 years (95% CI: 3.0, 5.4). There were 726 deaths among the 1139 patients with post-transplant stroke, including 127 deaths among 203 Black patients and 599 deaths among 936 white patients. Among post-transplant stroke survivors, Black transplant recipients experienced a 27% higher rate of mortality compared to white recipients (HR = 1.27, 95% CI: 1.03 - 1.57). This disparity is strongest in the period beyond the first 6 months and appears to be mediated by differences in the post-transplant setting of care between Black and white patients. The racial disparity in mortality outcomes was not evident in the past decade.\\n\\nConclusionsThe improved survival of Black patients in the recent decade may reflect overall protocol improvements for heart transplant recipients irrespective of race, such as advancements in surgical techniques and immediate postoperative care as well as increased awareness about reducing racial disparities.\"\n]","isConversational":false},"negative":{"kind":"list like","value":["Mortality among Care Home Residents in England during the first and second waves of the COVID-19 pandemic: an analysis of 4.3 million adults over the age of 65\nBackgroundResidents in care homes have been severely impacted by the COVID-19 pandemic. We describe trends in risk of mortality among care home residents compared to residents in private homes in England.\n\nMethodsOn behalf of NHS England, we used OpenSAFELY-TPP, an analytics platform running across the linked electronic health records of approximately a third of the English population, to calculate monthly age-standardised risks of death due to all causes and COVID-19 among adults aged >=65 years between 1/2/2019 and 31/03/2021. Care home residents were identified using linkage to the Care and Quality Commission.\n\nFindingsWe included 4,329,078 people aged 65 years or older on the 1st of February 2019, 2.2% of whom were classified as residing in a care or nursing home. Age-standardised mortality risks were approximately 10 times higher among care home residents compared to non-residents in February 2019 residents (CMF = 10.59, 95%CI = 9.51, 11.81 among women, CMF = 10.82, 95%CI = 9.89, 11.84 among men). This increased to more than 17 times in April 2020 (CMF = 17.52, 95%CI = 16.38, 18.74 among women, CMF = 18.12, 95%CI = 17.17 - 19.12 among men) before returning to pre-pandemic levels in June 2020. CMFs did not increase during the second wave, despite a rise in the absolute age-standardised COVID-19 mortality risks.\n\nInterpretationThe first COVID-19 wave had a disproportionate impact on care home residents in England compared to older private home residents. A degree of immunity, improved protective measures or changes in the underlying frailty of the populations may explain the lack of an increase in the relative mortality risks during the second wave. The care home population should be prioritised for measures aimed at controlling the spread of COVID-19.\n\nFundingMedical Research Council MR/V015737/1","Use of multiple Polygenic Risk Scores for distinguishing Schizophrenia-spectrum disorder and Affective psychosis categories; the EUGEI study\nSchizophrenia (SZ), Bipolar Disorder (BD) and Depression (D) run in families. This susceptibility is partly due to hundreds or thousands of common genetic variants, each conferring a fractional risk. The cumulative effects of the associated variants can be summarised as a polygenic risk score (PRS). Using data from the EUGEI case-control study, we aimed to test whether PRSs for three major psychiatric disorders (SZ, BD, D) and for intelligent quotient (IQ) as a neurodevelopmental proxy, can discriminate affective psychosis (AP) from schizophrenia-spectrum disorder (SSD). Participants (573 cases, 1005 controls) of european ancestry from 17 sites as part of the EUGEI study were successfully genotyped following standard quality control procedures. Using standardised PRS for SZ, BD, D, and IQ built from the latest available summary statistics, we performed simple or multinomial logistic regression models adjusted for 10 principal components for the different clinical comparisons. In case-control comparisons PRS-SZ, PRS-BD and PRS-D distributed differentially across psychotic subcategories. In case-case comparison, both PRS-SZ (OR=0.7, 95 %CI 0.53-0.92) and PRS-D (OR=1.29, 95%CI 1.05-1.6) differentiated global AP from SSD; and within AP categories, only PRS-SZ differentiated BD from psychotic depression (OR=2.38, 95%CI 1.32-4.29). Combining PRS for severe psychiatric disorders in prediction models for psychosis phenotypes can increase discriminative ability and improve our understanding of these phenotypes. Our results point towards potential usefulness of PRSs for diagnostic prediction in specific populations such as high-risk or early psychosis phases.","Reduction in left frontal alpha oscillations by transcranial alternating current stimulation in major depressive disorder is context-dependent in a randomized-clinical trial\nBackgroundLeft frontal alpha oscillations are associated with decreased approach motivation and have been proposed as a target for non-invasive brain stimulation for the treatment of depression and anhedonia. Indeed, transcranial alternating current stimulation (tACS) at the alpha frequency reduced left frontal alpha power and was associated with a higher response rate than placebo stimulation in patients with major depressive disorder (MDD) in a recent double-blind placebo controlled clinical trial.\n\nMethodsIn this current study, we aimed to replicate such successful target engagement by delineating the effects of a single session of bifrontal tACS at the individualized alpha frequency (IAF-tACS) on alpha oscillations in patients with MDD. Electrical brain activity was recorded during rest and while viewing emotionally-salient images before and after stimulation to investigate if the modulation of alpha oscillation by tACS exhibited specificity with regards to valence.\n\nResultsIn agreement with the previous study of tACS in MDD, we found that a single session of bifrontal IAF-tACS reduced left frontal alpha power during the resting state when compared to placebo. Furthermore, the reduction of left frontal alpha oscillation by tACS was specific for stimuli with positive valence. In contrast, these effects on left frontal alpha power were not found in healthy control participants.\n\nConclusionTogether these results support an important role of tACS in reducing left frontal alpha oscillations as a future treatment for MDD.\n\nNational Clinical TrialNCT03449979, \"Single Session of tACS in a Depressive Episode (SSDE)\" https://www.clinicaltrials.gov/ct2/show/NCT03449979","Predictive Machine Learning for Personalised Medicine in Major Depressive Disorder\nDepression is a common psychiatric disorder with substantial recurrence risk. Accurate prediction from easily collected data would aid in diagnosis, treatment and prevention. We used machine learning in the Generation Scotland cohort to predict lifetime risk of depression and, among cases, recurrent depression. Rank aggregation was used to combine results across ten different algorithms and identify highly predictive variables. The model containing all but the cardiometabolic predictors had the highest predictive ability on independent data. Rank aggregation produced a reduced set of predictors without decreasing predictive performance (lifetime: 20 out of 154 predictors and Receiver Operating Characteristic area under the curve (AUC)=0{middle dot}84, recurrent: 10 out of 180 predictors and AUC=0{middle dot}76). Here we develop a pipeline which leads to a small set of highly predictive variables. This information can be easily collected with a smartphone application to help diagnosis and treatment, while longitudinal tracking may help patients in self-management.\n\nSignificanceDepression is the most common psychiatric disorder and a leading cause of disability worldwide. Patients are often diagnosed and treated by non-specialist clinicians who have limited time available to assess them. We present a novel methodology which allowed us to identify a small set of highly predictive variables for a diagnosis of depression, or recurrent depression in patients. This information can easily be collected using a tablet or smartphone application in the clinic to aid diagnosis.","Prediction of gestational diabetes mellitus using early oral glucose tolerance test\nIntroductionGestational Diabetes Mellitus (GDM) is defined as diabetes first detected at the second or third trimester of pregnancy, excluding preexisting diabetes. We aimed to build a predictive model of GDM using booking oral glucose tolerance test (OGTT) values.\n\nMaterials and MethodsSeventy-five healthy mothers who underwent 75g OGTT at 12-14 weeks and at 24-28 weeks were recruited. GDM was diagnosed at 28 weeks by cutoffs proposed by the Hyperglycemia and Adverse Pregnancy Outcomes study.\n\nSensitivities and specificities for diagnosing GDM using different cut-offs for each of the three booking OGTT variables were measured. A series of multivariate binary logistic regression models were fitted using different combinations of the three booking OGTT variables. In-sample sensitivities and specificities for different cutoff probabilities of the models were calculated and Receiver Operating Characteristic (ROC) curves were constructed. The Area Under the Curve (AUC) of the ROC curve and the best cutoff value which maximized the sum of sensitivity and specificity of each model were computed.\n\nResultsAUC of ROC curves for isolated fasting, 1 hour and 2 hour booking OGTT values for the prediction of GDM were 69.8%, 67.1% and 61.0% respectively. However, the logistic regression model with fasting and 1 hour booking OGTT values as predictors out-performed all other models with an AUC of 76.3%, in-sample sensitivity of 87.5% and a negative predictive value of 95.12%.\n\nConclusionsThe future occurrence of GDM can be predicted utilizing a logistic model with fasting and 1 hour booking OGTT variables, which enables early identification and intervention.","Consistency of performance of adverse outcome prediction models for hospitalized COVID-19 patients\nBackgroundWe previously reported and validated a risk prediction tool based on COVID-19 hospitalizations prior to June 2020. Here, we report performance of that model on subsequent data from 6 hospitals and among individual patient subgroups.\n\nMethodWe included individuals age 18 or older hospitalized at one of 2 academic medical centers and 4 community hospitals from 6/7/2020 through 1/22/2021 with positive PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within 5 days of admission. Coefficients from our previously reported least absolute shrinkage and selection operator (Lasso) risk models were applied to estimate probability of a mortality, as well as a composite severe illness outcome, including admission to the ICU, mechanical ventilation or mortality.\n\nResultsOverall model performance for mortality included AUC of 0.83 (95% CI:0.80-0.87) for mortality, with a PPV 0.55 and NPV of 0.95 when using a cutoff corresponding to the highest 20% of predicted risk derived in the training set. For all adverse outcomes, AUC was 0.79 (95% CI:0.75-0.81) and PPV 0.48 and NPV 0.98 in the top 20% risk group. Model discrimination was generally similar between genders and race/ethnicity groups, but markedly poorer for younger age groups.\n\nConclusionAlthough the population of individuals hospitalized for COVID-19 has shifted and outcomes have improved overall, prediction models derived earlier in the pandemic may maintain utility.","Analysis of cutoff point estimation for determining seropositivity in the context of SARS-CoV-2 infections\nIn this work will apply mixture models based on distributions from the SMSN family to antibody data against four SARS-CoV-2 virus antigens. Furthermore, since the true infection status of individuals is known a priori, performance measures will be calculated for the methods proposed for cutoff point estimation such as sensitivity, specificity and accuracy. The results of a simulation study will also be presented.","Experiences of staff providing specialist palliative care during COVID-19: A multiple qualitative case study.\nObjectivesTo explore the experiences of, and impact on, staff working in palliative care during the COVID-19 pandemic.\n\nDesignQualitative multiple case study using semi-structured interviews between November 2020 and April 2021 as part of the CovPall study. Data were analysed using thematic framework analysis.\n\nSettingOrganisations providing specialist palliative services in any setting.\n\nParticipantsStaff working in specialist palliative care, purposefully sampled by the criteria of role, care setting and COVID-19 experience.\n\nMain outcome measuresExperiences of working in palliative care during the COVID-19 pandemic.\n\nResultsFive cases and 24 participants were recruited (n=12 nurses, 4 clinical managers, 4 doctors, 2 senior managers, 1 healthcare assistant, 1 allied healthcare professional). Central themes demonstrate how infection control constraints prohibited and diluted participants ability to provide care that reflected their core values, resulting in experiences of moral distress. Despite organisational, team, and individual support strategies, continually managing these constraints led to a crescendo effect in which the impacts of moral distress accumulated over time, sometimes leading to burnout. Solidarity with colleagues and making a valued contribution provided moral comfort for some.\n\nConclusionsThis study provides a unique insight into why and how healthcare staff have experienced moral distress during the pandemic, and how organisations have responded. Despite their experience of dealing with death and dying, the mental health and well-being of palliative care staff was affected by the pandemic. Organisational, structural, and policy changes are urgently required to mitigate and manage these impacts.","Evaluation of determinants of the serological response to the split-inactivated influenza vaccine\nThe seasonal influenza vaccine is only effective in half of the vaccinated population. To identify determinants of vaccine efficacy, we used data from >1,300 vaccination events to predict the response to vaccination measured as seroconversion as well as hemagglutination inhibition (HAI) levels one year after. We evaluated the predictive capabilities of age, body mass index (BMI), sex, race, comorbidities, prevaccination history, and baseline HAI titers, as well as vaccination month and vaccine dose in multiple linear regression models. The models predicted the categorical response for >75% of the cases in all subsets with one exception. Prior vaccination, baseline titer level, and age were the strongest determinants on seroconversion, all of which had negative effects. Further, we identified a gender effect in older participants, and an effect of vaccination month. BMI played a surprisingly small role, likely due to its correlation with age. Comorbidities, vaccine dose, and race had negligible effects. Our models can generate a new seroconversion score that is corrected for the impact of these factors which can facilitate future biomarker identification.","Modelling the effectiveness and social costs of daily lateral flow antigen tests versus quarantine in preventing onward transmission of COVID-19 from traced contacts\nQuarantining close contacts of individuals infected with SARS-CoV-2 for 10 to 14 days is a key strategy in reducing transmission. However, quarantine requirements are often unpopular, with low adherence, especially when a large fraction of the population has been vaccinated. Daily contact testing (DCT), in which contacts are required to isolate only if they test positive, is an alternative to quarantine for mitigating the risk of transmission from traced contacts. In this study, we developed an integrated model of COVID-19 transmission dynamics and compared the strategies of quarantine and DCT with regard to reduction in transmission and social/economic costs (days of quarantine/self-isolation). Specifically, we compared 10-day quarantine to 7 days of self-testing using rapid lateral flow antigen tests, starting 3 days after exposure to a case. We modelled both incomplete adherence to quarantine and incomplete adherence to DCT. We found that DCT reduces transmission from contacts with similar effectiveness, at much lower social/economic costs, especially for highly vaccinated populations. The findings were robust across a spectrum of scenarios with varying assumptions on the speed of contact tracing, sensitivity of lateral flow antigen tests, adherence to quarantine and uptake of testing. Daily tests would also allow rapid initiation of a new round of tracing from infected contacts.","Tracking mutational semantics of SARS-CoV-2 genomes\nGenomes have an inherent context dictated by the order in which the nucleotides and higher order genomic elements are arranged in the DNA/RNA. Learning this context is a daunting task, governed by the combinatorial complexity of interactions possible between ordered elements of genomes. Can natural language processing be employed on these orderly, complex and also evolving datatypes (genomic sequences) to reveal the latent patterns or context of genomic elements (e.g Mutations)? Here we present an approach to understand the mutational landscape of Covid-19 by treating the temporally changing (continuously mutating) SARS-CoV-2 genomes as documents. We demonstrate how the analogous interpretation of evolving genomes to temporal literature corpora provides an opportunity to use dynamic topic modeling (DTM) and temporal Word2Vec models to delineate mutation signatures corresponding to different Variants-of-Concerns and tracking the semantic drift of Mutations-of-Concern (MoC). We identified and studied characteristic mutations affiliated to Covid-infection severity and tracked their relationship with MoCs. Our ground work on utility of such temporal NLP models in genomics could supplement ongoing efforts in not only understanding the Covid pandemic but also provide alternative strategies in studying dynamic phenomenon in biological sciences through data science (especially NLP, AI/ML).","Grey and white matter volume changes after preterm birth: A meta-analytic approach\nObjectiveLower brain grey matter volumes (GMV) and white matter volumes (WMV) have been reported at single time points in preterm-born individuals. While large MRI studies in the normative population have led to a better understanding of brain growth trajectories across the lifespan, such results remain elusive for preterm-born individuals since large, aggregated datasets of preterm-born individuals do not exist. To close this gap, we investigated GMV and WMV in preterm-born individuals as reported in the literature and contrasted it against individual volumetric data and trajectories from the general population.\n\nStudy designSystematic database search of PubMed and Web of Science in March 2021 and extraction of outcome measures by two independent reviewers. Individual data on full-term controls was extracted from freely available databases. Mean GMV, WMV, total intracranial volume (TIV), and mean age at scan were the main outcome measures.\n\nResultsOf 532 identified records, nine studies were included with 538 preterm-born subjects between 1.1 and 28.5 years of age. Reference data was generated from 880 full-term controls between 1 and 30 years of age. GMV was consistently lower in preterm-born individuals from infancy to early adulthood with no evidence for catch-up growth. While GMV changes followed a similar trajectory as full-term controls, WMV was particularly low in adolescence after preterm birth.\n\nConclusionsResults demonstrate altered brain volumes after premature birth across the first half of lifespan with particularly low white matter volumes in adolescence. Future studies should address this issue in large aggregated datasets of preterm-born individuals.","External Validation Of A Novel Signature Of Illness In Continuous Cardiorespiratory Monitoring To Detect Early Respiratory Deterioration Of ICU Patients\nThe goal of predictive analytics monitoring is the early detection of patients at high risk of subacute potentially catastrophic illnesses. An excellent example of a targeted illness is respiratory failure leading to urgent unplanned intubation, where early detection might lead to interventions that improve patient outcomes. Previously, we identified signatures of this illness in the continuous cardiorespiratory monitoring data of Intensive Care Unit patients and devised algorithms to identify patients at rising risk. Here, we externally validated three logistic regression models to estimate the risk of emergency intubation developed in Medical and Surgical ICUs at the University of Virginia. We calculated the model outputs for more than 8000 patients in the University of California - San Francisco ICUs, 240 of whom underwent emergency intubation as determined by individual chart review. We found that the AUC of the models exceeded 0.75 in this external population, and that the risk rose appreciably over the 12 hours before the event. We conclude that there are generalizable physiological signatures of impending respiratory failure in the continuous cardiorespiratory monitoring data.","WHAT ABOUT USING SNIFFIN STICKS 12 SCREENING TEST TO IDENTIFY POST-COVID-19 OLFACTORY DISORDERS?\nBackgroundOlfactory impairment is a major sequela of SARS-CoV-2 infection and has a negative impact on daily life quality. Olfactory loss can be assessed in many ways but seems to be little realized in a daily clinical practice. The sniffin Sticks test - 12 items (SST-12) can be used in quick olfactory disorders screening. Its use in a post-covid19 situation was the main objective of this work.\n\nMethodologyConsecutive patients consulting to the ENT department with post-Covid-19 olfactory loss were included. The clinical examination included an analog scale for the self-assessment of olfactory recovery (VAS), self-reported salt and sugar intake, a nasofibroscopy, the complete Sniffin Stick Test (SST) and the SST-12.\n\nResultsAmong the 54 patients included, based on the SST-12, 14,8% (n=8) of the patients could be classified as normosmic (SST-12[≥]11), 48,1% (n=26) as hyposmic (6< SST-12<10) and 37% (n=20) as functional anosmic (SST-12[≤]6). We report excellent and significant correlations between SST-12 and SST or VAS assessments. Salt and Sugar increased intake seems significantly related to SST-12 results.\n\nConclusionsSST-12 is a reliable way to screen post-COVID-19 olfactory disorders could be used in a daily clinical practice and might be used to prevent bad diet habits and so cardiovascular risk.","Analysis of 200,000 exome-sequenced UK Biobank subjects implicates genes involved in increased and decreased risk of hypertension\nBackgroundPrevious analyses have identified common variants along with some specific genes and rare variants which are associated with risk of hypertension but much remains to be discovered.\n\nMethods and ResultsExome-sequenced UK Biobank participants were phenotyped based on having a diagnosis of hypertension or taking anti-hypertensive medication to produce a sample of 66,123 cases and 134,504 controls. Variants with minor allele frequency (MAF) < 0.01 were subjected to a gene-wise weighted burden analysis, with higher weights assigned to variants which are rarer and/or predicted to have more severe effects. Of 20,384 genes analysed, two genes were exome-wide significant, DNMT3A and FES. Also strongly implicated were GUCY1A1 and GUCY1B1, which code for the subunits of soluble guanylate cyclase. There was further support for the previously reported effects of variants in NPR1 and protective effects of variants in DBH. An inframe deletion in CACNA1D with MAF = 0.005, rs72556363, is associated with modestly increased risk of hypertension. Other biologically plausible genes highlighted consist of CSK, AGTR1, ZYX and PREP. All variants implicated were rare and cumulatively they are not predicted to make a large contribution to the population risk of hypertension.\n\nConclusionsThis approach confirms and clarifies previously reported findings and also offers novel insights into biological processes influencing hypertension risk, potentially facilitating the development of improved therapeutic interventions. This research has been conducted using the UK Biobank Resource.","Rapid and Sensitive Detection of SARS-CoV-2 Infection Using Quantitative Peptide Enrichment LC-MS Analysis\nReliable, robust, large-scale molecular testing for SARS-CoV-2 is essential for monitoring the ongoing Covid-19 pandemic. We have developed a scalable analytical approach to detect viral proteins based on peptide immunoaffinity enrichment combined with liquid chromatography - mass spectrometry (LC-MS). This is a multiplexed strategy, based on targeted proteomics analysis and read-out by LC-MS, capable of precisely quantifying and confirming the presence of SARS-CoV-2 in PBS swab media from combined throat/nasopharynx/saliva samples.\n\nThe results reveal that the levels of SARS-CoV-2 measured by LC-MS correlate well with their corresponding RT-PCR readout (r=0.79). The analytical workflow shows similar turnaround times as regular RT-PCR instrumentation with a quantitative readout of viral proteins corresponding to cycle thresholds (Ct) equivalents ranging from 21 to 34. Using RT-PCR as a reference, we demonstrate that the LC-MS-based method has 100% negative percent agreement (estimated specificity) and 95% positive percent agreement (estimated sensitivity) when analyzing clinical samples collected from asymptomatic individuals with a Ct within the limit of detection of the mass spectrometer (Ct [≤]30). These results suggest that a scalable analytical method based on LC-MS has a place in future pandemic preparedness centers to complement current virus detection technologies.","Clinical features of UK Biobank subjects carrying protein truncating variants in genes implicated in schizophrenia pathogenesis\nThe SCHEMA consortium has identified ten genes in which protein truncating variants (PTVs) confer substantial risk of schizophrenia. Exome-sequenced participants in the UK Biobank who carried PTVs in these genes were studied to determine to what extent they demonstrated features of schizophrenia or had neuropsychiatric impairment. Following automated quality control and visual inspection of reads, 251 subjects were identified as having well-supported PTVs in one of these genes. The frequency of PTVs in CACNA1G was higher than had been observed in SCHEMA cases, casting doubt on its role in schizophrenia pathogenesis, but otherwise rates were similar to those observed in SCHEMA controls. Numbers were too small to allow formal statistical analysis but in general carriers of PTVs did not appear to have high rates of psychiatric illness or reduced educational or occupational functioning. One subject with a PTV in SETD1A had a diagnosis of schizophrenia. one with a PTV in HERC1 had psychotic depression and two subjects seemed to have developmental disorders, one with a PTV in GRIN2A and one with a PTV in RBCC1. There seemed to be somewhat increased rates of affective disorders among carriers of PTVs in HERC1 and RB1CC1. Carriers of PTVs did not appear to have subclinical manifestations of schizophrenia. Although PTVs in these genes can substantially increase schizophrenia risk, their effect seems to be dichotomous and most carriers appear psychiatrically well.\n\nThis research has been conducted using the UK Biobank Resource.","Gout, rheumatoid arthritis and the risk of death from COVID-19: an analysis of the UK Biobank\nObjectivesTo assess whether gout and / or rheumatoid arthritis (RA) are risk factors for coronavirus disease 19 (COVID-19) diagnosis. To assess whether gout and / or RA are risk factors for death with COVID-19.\n\nMethodsWe used data from the UK Biobank. Multivariable-adjusted logistic regression was employed in the following analyses: Analysis A, to test for association between gout or RA and COVID-19 diagnosis (n=473,139); Analysis B, to test for association between gout or RA and death with COVID-19 in a case-control cohort of people who died or survived with COVID-19 (n=2,059); Analysis C, to test for association with gout or RA and death with COVID-19 in the entire UK Biobank cohort (n=473,139)\n\nResultsRA, but not gout, associated with COVID-19 diagnosis in analysis A. Neither RA nor gout associated with risk of death in the COVID-19-diagnosed group in analysis B. However RA associated with risk of death related to COVID-19 using the UK Biobank cohort in analysis C independent of comorbidities and other measured risk factors (OR=1.9 [95% CI 1.2 ; 3.0]). Gout was not associated with death related to COVID-19 in the same UK Biobank analysis (OR=1.2 [95% CI 0.8 ; 1.7]).\n\nConclusionRheumatoid arthritis is a risk factor for death with COVID-19 using the UK Biobank cohort. These findings require replication in larger data sets that also allow inclusion of a wider range of factors.\n\nKey messagesInformation on the risk of death from COVID-19 for people with gout and rheumatoid arthritis is scarce.\n\nIn an analysis of the UK Biobank there is an increased risk of death related to COVID-19 for people with rheumatoid arthritis independent of included co-morbidities, but not gout.\n\nThe findings need to be replicated in other datasets where the influence of therapies for rheumatoid arthritis can be tested.","Human blood DNA methylation patterns reflect individual lifestyle\nObesity is driven by modifiable lifestyle factors whose effects may be mediated by epigenetics. Therefore, we investigated lifestyle effects (diet, physical activity, smoking and alcohol) on blood DNA methylation in participants of the LIFE-Adult study, a well-characterized population-based cohort from Germany. Fifty subjects with an extremely healthy and 50 with an extremely unhealthy lifestyle were selected for genome-wide DNA methylation analysis in blood samples. Whereas obesity was only marginally related to variability in DNA methylation pattern, comparisons between lifestyle categories resulted in 145 Differentially Methylated Positions (DMPs) and 4682 Differentially Methylated Regions (DMRs) annotated to 4426 unique genes. Intersection analysis showed that diet, physical activity, smoking and alcohol intake are equally contributing to the observed differences, which particularly affects pathways related to glutamatergic synapse and axon guidance. DNA methylation patterns help discriminate individuals with a healthy vs. unhealthy lifestyle, which may mask subtle methylation differences derived from obesity.","Population-split-based risk assessment model of venous thromboembolism in Chinese medical inpatients\nAbstractsO_ST_ABSObjectiveC_ST_ABSInpatients with high risk of venous thromboembolism (VTE) usually face serious threats to their health and economic conditions. Many studies using machine learning (ML) models to predict VTE risk neglected an important statistical phenomenon, fuzzy feature, and achieved inferior results. Considering the effect of fuzzy feature, our study aims to develop a VTE risk assessment model suitable for Chinese medical inpatients.\n\nMaterials and MethodsInpatients in the medical department of Peking Union Medical College Hospital (PUMCH) from January 2014 to June 2016 were collected. A new ML VTE risk assessment model was built through population splitting. First patients were classified into different groups based on values of VTE risk factors, then trustless groups were filtered out, and finally ML models were built on training data in unit of groups. Predictive performances of our method, five traditional ML models, and the Padua model were compared.\n\nResultsThe fuzzy feature was verified on the whole dataset. Compared with the Padua model, the proposed model showed higher sensitivities and specificities on training data, and higher specificities and similar sensitivities on test data. Standard deviations of predictive validity of five ML models were larger than the proposed model.\n\nDiscussionThe proposed model was the only one which showed advantages on both sensitivity and specificity over Padua model. Its robustness was better than traditional ML models.\n\nConclusionThis study built a population-split-based ML model of VTE for Chinese medical inpatients and it may help clinicians stratify VTE risk and guide prevention more efficiently.","Development of reference equations for the six-minute walk distance of school-aged Nigerian children\nBackgroundThe six-minute walk test (6MWT), a simple, reliable and valid test that uses the distance walked in six minutes (six-minute walk distance, 6MWD) to quantify functional capacity, is widely used in chronic cardiopulmonary and non-cardiopulmonary disorders. However, absence of reference standards for Nigerian school-age children limits its use in this age group.\n\nObjectivesTo develop normative values and equations for the 6MWT of school-aged Nigerian children.\n\nMethodsIn a cross-sectional study, healthy children aged 6-11 years in Lagos, Nigeria, completed 6MWT on 20-meter straight outdoor courses in their schools following standardized guidelines. Potential predictors: demographic (age, sex), anthropometric (height, weight, chest circumference, leg length) and physiologic data [pre-walk, immediate post-walk and 5th minute-post-walk heart rate (HR), oxygen saturation (SpO2), systolic pressure (SBP), diastolic blood pressure (DBP) and rating of perceived exertion (RPE)] and difference between pre-walk and post-walk HR ({Delta}HR), SpO2 (({Delta}SpO2), SBP ({Delta}SBP), DBP ({Delta}DBP) and RPE ({Delta}RPE). Primary outcome: six-minute walk distance (6MWD) in metres.\n\nResultsOverall, 627 pupils (52.1% girls) walked 504.6 {+/-} 66.6 m (95% CI: 499.4, 509.8), ranging from 326.6 m to 673.0 m; 16 m longer in boys (p=0.002). Stepwise linear regression yielded: 6MWD (m) = 347.9 + 14 (Age) + 1.6 ({Delta}HR) + 17.6 (Sex) + 1.2 ({Delta}SBP); R2 =0.25. Previously published reference equations over-estimated Nigerian childrens 6MWD.\n\nConclusionThe reference values and prediction equations, after validation in other Nigerian populations, may be useful for functional evaluation of Nigerian children aged 6-11 years with chronic childhood disorders.","Maternal underweight and obesity are associated with placental pathologies in human pregnancy\nIntroductionMaternal underweight and obesity are prevalent conditions, associated with chronic, low-grade inflammation, poor fetal development, and long-term adverse outcomes for the child. The placenta senses and adapts to the pregnancy environment in an effort to support optimal fetal development. However, the mechanisms driving these adaptations, and the resulting placental phenotypes, are poorly understood. We hypothesised that maternal underweight and obesity would be associated with increased prevalence of placental pathologies in term and preterm pregnancies.\n\nMethodsData from 12,154 pregnancies were obtained from the Collaborative Perinatal Project, a prospective cohort study conducted from 1959 to 1974. Macro and microscopic placental pathologies were analysed across maternal prepregnancy body mass index (BMI) to assess differences in the presence of pathologies among underweight, overweight, and obese BMI groups compared to normal weight reference BMI at term and preterm. Placental pathologies were also assessed across fetal sex.\n\nResultsPregnancies complicated by obesity had placentae with increased fetal inflammation at preterm, and increased inflammation of maternal gestational tissues at term. In term pregnancies, increasing maternal BMI associated with increased maternal vascular malperfusion (MVM), odds of an appropriate mature placenta for gestational age, and placental weight, and decreased placental efficiency. Male placentae, independent of maternal BMI, had increased inflammation, MVM, and placental efficiency than female placentae, particularly at term.\n\nDiscussionMaternal underweight and obesity are not inert conditions for the placenta, and the histomorphological changes driven by suboptimal maternal BMI may serve as indicators of adversities experienced in utero and potential predictors of future health trajectories.","Association of Visual Impairment with Brain Structure\nObjectiveTo investigate the association of visual impairment (VI) with brain structures in the UK Biobank Study.\n\nMethodsThe UK Biobank Study is a large prospective study that recruited more than 500,000 participants aged 40-69 from 2006 to 2010 across the UK. Visual acuity (VA) of worse than 0.3 LogMAR units (Snellen 20/40) was defined as VI. Structural magnetic resonance imaging (MRI) data were obtained using a 3.0-T MRI imager. Volumetric measures of five global brain volumes (total brain volume, total grey matter, total white matter, cerebrospinal fluid (CSF), brain stem) and the volumes of seven specific brain region (thalamus, caudate nucleus, basal ganglia, pallidum, hippocampus, amygdala and nucleus accumbens) were included in the present analysis. Multivariable linear regression was used to investigate the association of VI with global and specific brain volumes.\n\nResultsA total of 8976 participants free of neurological disorders at baseline assessment were included for the present analysis. The prevalence of VI was 0.02% (n=181). After adjusting for a range of cofounding factors, VI was significantly associated with decreased volumes of the total brain ({beta} = -0.12, 95% confidence interval (CI) -0.23 to 0.00, P = 0.049), thalamus ({beta} = -0.16, 95% CI -0.18 to -0.04, P = 0.010), caudatenucleus ({beta} = -0.14, 95% CI -0.27 to 0.00, P = 0.046), pallidum ({beta} = -0.15, 95% CI-0.27 to -0.02, P = 0.028) and amygdala ({beta} = -0.18, 95% CI -0.31 to -0.04, P = 0.012).\n\nInterpretationWe found that VI is associated with a decrease in total brain volumes and the volumes of specific brain regions implicated in neurodegenerative diseases.","Examining the Association between the COVID-19 Pandemic and Self-Harm Death Counts in Four Canadian Provinces\nGovernments implemented lockdowns and other physical distancing measures to stop the spread of SARS-CoV-2 (COVID-19). Resulting unemployment, income loss, poverty, and social isolation, coupled with daily reports of dire news about the COVID-19 pandemic, could serve as catalysts for increased self-harm deaths (SHD). This ecological study examined whether observed SHD counts were higher than predicted SHD counts during the pandemic period in the Canadian provinces of Alberta, British Columbia, Ontario, and Quebec. The study also explored whether SHD counts during the pandemic were affected by lockdown severity (measured using the lockdown stringency index [LSI]) and COVID-19 case numbers. We utilized publicly available SHD data from January 2018 through November 2020, and employed AutoRegressive Integrated Moving Average (ARIMA) modelling, to predict SHD during the COVID-19 period (March 21 to November 28, 2020). We used Poisson and negative binomial regression to assess ecological associations between the LSI and COVID-19 case numbers, controlling for seasonality, and SHD counts during the COVID-19 period. On average, observed SHD counts were lower than predicted counts during this period (p < 0.05 [except Alberta]). Additionally, LSI and COVID-19 case numbers were not statistically significantly associated with SHD counts.","A Single Dose of COVID-19 mRNA Vaccine Induces Airway Immunity in COVID-19 Convalescent Patients\nBackgroundMucosal antibodies can prevent virus entry and replication in mucosal epithelial cells and hence virus shedding. Preclinical and clinical studies have shown that a parenteral booster injection of a vaccine against a mucosal pathogen promotes stronger mucosal immune responses following prior infection compared to two injections of a parenteral vaccine. We investigated whether this was also the case for a COVID-19 mRNA vaccine.\n\nMethodsTwenty-three COVID-19 convalescent patients and 20 SARS-CoV-2-naive subjects were vaccinated with respectively one and two doses of the Pfizer-BioNTech COVID-19 RNA vaccine. Nasal Epithelial Lining Fluid (NELF) and plasma were collected before and after vaccination and assessed for Immunoglobulin (Ig)G and IgA to Spike and for their ability to inhibit the binding of Spike to its ACE-2 receptor. Blood was analyzed one week after vaccination for the number of Spike-specific Antibody Secreting Cells (ASCs) with a mucosal tropism.\n\nResultsIn COVID-19 convalescent patients, a single dose of vaccine amplified pre-existing Spike-specific IgG and IgA antibody responses in both NELF and blood against both vaccine homologous and variant strains, including delta. These responses were associated with Spike-specific IgG and IgA ASCs with a mucosal tropism in blood. Nasal IgA and IgG antibody responses were lower in magnitude in SARS-CoV-2-naive subjects after two vaccine doses\n\nConclusionThis study showed that a parenteral booster injection of a COVID-19 RNA vaccine promoted stronger mucosal immune responses in COVID-19 convalescent patients compared to SARS-CoV-2 naive subjects who had received a first vaccine dose.","Parent-of-origin effects in the life-course evolution of cardio-metabolic traits\nObjectiveHuman traits are heritable, and some of these including metabolic and lipid phenotypes show preferential parental transmissions, or parent-of-origin effects. These have been mostly studied in populations comprising adults. We aimed to investigate heritability and parent-of-origin effects on cardiometabolic and anthropometric traits in a birth-cohort with serial measurements to assess if these effects manifested at an early age.\n\nResearch design and methodsWe investigated heritability and parent-of-origin effects on cardiometabolic and anthropometric traits in the Pune Maternal Nutrition Study (PMNS) wherein offspring and parents were studied from birth and followed-up for 18 years. Heritability was estimated by calculating association between mid-parental phenotypes and offspring. Maternal and paternal effects on offspring phenotype were modelled by regression after adjusting for age, sex and BMI. Parent-of-origin effects were calculated by the difference between maternal and paternal effects.\n\nResultsAnthropomorphic traits and cardiometabolic traits were robustly heritable. Parent-of-origin effects were observed for glycemic traits at both 6- and 12-years, with a paternal effect at 6-years which transitioned to a maternal effect at 12-years. For insulin and HOMA-S, a negative maternal effect transitioned to a positive one at 12-years. For HOMA-B, a paternal effect at 6-years transitioned to a maternal one at 12-years. Lipid traits consistently showed stronger maternal influence while anthropometric traits did not show any parental biases.\n\nConclusionsOur study highlights that parental programming of cardiometabolic traits is evident from early childhood and can transition during puberty. Further studies are needed to determine the mechanisms of underlying such effects.","DNA methylation and general psychopathology in childhood: An epigenome-wide meta-analysis from the PACE consortium\nThe general psychopathology factor (GPF) has been proposed as a way to capture variance shared between psychiatric symptoms. Despite a growing body of evidence showing both genetic and environmental influences on GPF, the biological mechanisms underlying these influences remain unclear. In the current study, we conducted epigenome-wide meta-analyses to identify both probe- and region-level associations of DNA methylation (DNAm) with school-age general psychopathology in six cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. DNAm was examined both at birth (cord blood; prospective analysis) and during school-age (peripheral whole blood; cross-sectional analysis) in total samples of N=2,178 and N=2,190, respectively. At school-age, we identified one probe (cg11945228) located in the Bromodomain-containing protein 2 gene (BRD2) that negatively associated with GPF (p=8.58x10-8). We also identified a significant DMR at school-age (p=1.63x10-8), implicating the SHC Adaptor Protein 4 (SHC4) gene that has been previously implicated in multiple types of psychiatric disorders in adulthood, including obsessive compulsive disorder and major depressive disorder. In contrast, no prospective associations were identified with DNAm at birth. Taken together, results of this study revealed some evidence of an association between DNAm at school-age and GPF. Future research with larger samples is needed to further assess DNAm variation associated with GPF.","The locus coeruleus shows a spatial pattern of structural disintegration in Parkinson's disease.\nBackgroundParkinsons disease (PD) leads to a loss of neuromelanin positive, noradrenergic neurons in the locus coeruleus (LC) which has been implicated in non-motor dysfunction. \"Neuromelanin sensitive\" magnetic resonance imaging (MRI) has emerged as a promising tool for mapping the structural integrity of LC in vivo.\n\nObjectivesTo identify spatial patterns of structural LC disintegration in PD and regions in the LC where structural disintegration is associated with specific non-motor dysfunctions.\n\nMethods42 patients with PD and 24 age-matched healthy volunteers underwent ultra-high field MRI of the LC using a \"neuromelanin sensitive\" magnetization transfer weighted (MTw) sequence. The contrast-to-noise ratio of the MTw signal (CNRMTw) served as an estimate of structural integrity, slice- and voxel-wise analyses of CNRMTw were performed to map the spatial pattern of structural disintegration, complemented by Principal Component Analysis (PCA). We also tested for correlations between CNRMTw and the severity of non-motor symptoms.\n\nResultsMean CNRMTw of LC was reduced in patients relative to controls. The attenuation of CNRMTw was not uniformly expressed in LC, but confined to the middle and caudal LC. CNRMTw attenuation in caudal LC scaled with the orthostatic drop in systolic blood pressure and apathy ratings. PCA identified a bilaterally expressed component that was more weakly expressed in patients. This component was characterized by a gradual change in CNRMTw along the rostro-caudal and dorso-ventral axes of the nucleus. The individual expression score of this component reflected the overall severity of non-motor symptoms.\n\nConclusionPD related structural disintegration of LC mainly affects its caudal part and may determine the individual expression of specific non-motor symptoms such as orthostatic dysregulation or apathy.","Factors associated with severe sepsis in diarrheal adults and their outcome at an urban hospital, Bangladesh: A retrospective analysis\nBackgroundClinical features of sepsis and severe diarrhea often overlap and create a dilemma among the clinicians. To describe factors associated with severe sepsis in diarrheal adults and their outcomes to understand their interplay as clinical features of sepsis and severe diarrhea often overlap.\n\nMethods and resultsWe used this retrospective chart analysis employing a case-control design to study critically ill diarrheal adults aged [≥] 18 years treated in ICU Dhaka hospital, icddr,b between January 2011 to December 2015. Diarrheal adults with a diagnosis of severe sepsis were cases and an equal number of randomly selected non-septic patients were the controls. Of 8,863 in-patient adults, 350 fulfilled the criteria of cases. Cases died significantly more (9% vs 3%, p=0.002) than controls. 69% of the cases progressed to septic shock. In logistic regression analysis, steroid intake, ileus, acute kidney injury, metabolic acidosis, and hypocalcemia were significantly associated with severe sepsis in diarrheal adults (all, p<0.05). 12% of cases (40/335) had bacteremia. Streptococcus pneumoniae [9 (22.5%)] was the single most common pathogen and gram-negatives [27 (67.5%)] were prevailing as a group.\n\nConclusionDiarrheal adults who had ileus, AKI, metabolic acidosis, hypocalcemia, and also took steroids were prone to have severe sepsis. Strikingly, gram-negatives were the predominant bacteria among the diarrheal adults having severe sepsis.","Detection of choroidal hypoperfusion in giant cell arteritis using swept-source optical coherence tomographic angiography\nObjectiveTo determine whether swept-source optical coherence tomographic angiography (SS-OCTA) can demonstrate choroidal perfusion abnormalities seen on fluorescein angiography (FA) in giant cell arteritis (GCA).\n\nDesignObservational case series.\n\nParticipantsSix eyes of 3 patients with bilateral ischemic optic neuropathy secondary to GCA, and one control patient without ocular involvement from biopsy-confirmed GCA.\n\nMethodsEn face SS-OCTA (DRI OCT Triton, Topcon, Tokyo, Japan) and FA centered on the macula were obtained at presentation. SS-OCTA was segmented into superficial and deep retinal capillary plexuses and the choriocapillaris laminae. SS-OCTA images were independently analyzed for perfusion abnormalities and compared with corresponding FA images.\n\nMain Outcome MeasuresCorrespondence of choroidal angiographic abnormalities on SS-OCTA and FA.\n\nResultsSS-OCTA showed decreased angiographic signal within the choriocapillaris in 5/6 eyes and corresponded to hypoperfusion abnormalities on FA in similar geographic distributions in 5/5 eyes. SS-OCTA also showed dilation of the deep retinal capillary plexus overlying the area of choroidal hypoperfusion in one eye. In the one eye without angiographic signal abnormalities on SS-OCTA, no perfusion changes were noted on FA. One control patient without ocular involvement from biopsy-confirmed GCA did not show choroidal perfusion changes on SS-OCTA or FA.\n\nConclusionsThis case series demonstrates comparability between SS-OCTA and FA in detection and characterization of choroidal hypoperfusion secondary to GCA. As a rapid and non-invasive tool, SS-OCTA may serve as a viable alternative to FA in the diagnostic evaluation of GCA.","Polygenic risk scores for psychiatric, inflammatory, and cardio-metabolic traits and diseases highlight possible genetic overlaps with suicide attempt and treatment-emergent suicidal ideation\nSuicide is the second leading cause of death among young people. Genetics may contribute to suicidal phenotypes and their co-occurrence in other psychiatric and medical conditions. Our study aimed to investigate the association of polygenic risk scores (PRSs) for 22 psychiatric, inflammatory, and cardio-metabolic traits and diseases with suicide attempt (SA) or treatment-worsening/emergent suicidal ideation (TWESI).\n\nPRSs were computed based on summary statistics of genome-wide association studies. Regression analyses were performed between PRSs and SA or TWESI in four clinical cohorts, including up to 3,834 individuals, and results were meta-analyzed across samples. Stratified genetic covariance analyses were performed to investigate the biology underlying cross-phenotype PRS associations. After Bonferroni correction, PRS for major depressive disorder (MDD) was positively associated with SA (p=1.7e-4). Nominal associations were shown between PRSs for coronary artery disease (CAD) (p=4.6e-3) or loneliness (p=0.009) and SA, PRSs for MDD or CAD and TWESI (p=0.033 and p=0.032, respectively). Genetic covariance between MDD and SA was shown in 35 gene sets related to drugs having anti-suicidal effects.\n\nA higher genetic liability for MDD may underlie a higher risk of SA. Further, but milder, possible modulatory factors are genetic risk for loneliness and CAD.","Unveiling Sex-based Differences in Parkinson's Disease: A Comprehensive Meta-analysis of Transcriptomic Studies\nIn recent decades, increasing longevity (among other factors) has fostered a rise in Parkinsons disease (PD) incidence. Although not exhaustively studied in this devastating disease, the impact of sex represents a critical variable in PD as epidemiological and clinical features differ between males and females. To study sex bias in PD, we conducted a systematic review, tissue-specific meta-analyses of transcriptomic data from the frontal cortex (FC), striatum tissue (ST), and substantia nigra (SN), and a global meta-analysis of all 3 brain regions. We selected 7 PD studies that included sex information, analyzing 267 samples. The tissue-specific meta-analyses linked PD to the enhanced expression of MED31 in the female FC and the dysregulation of 237 genes in the SN. The global meta-analysis detected 15 genes with sex-differential patterns in PD, which participate in mitochondrial function, oxidative stress, neuronal degeneration, and cell death. Furthermore, functional analyses identified pathways, protein-protein interaction networks, and transcription factors that differed by sex. While male PD patients exhibited changes in oxidative stress based on metal ions, inflammation, and angiogenesis, female PD patients exhibited dysfunctions in mitochondrial and lysosomal activity, antigen processing and presentation functions, and glutamic and purine metabolism. Overall, we believe that our findings will provide new insight into the perspective of sex in PD, thereby underscoring the importance of including sex information in future PD studies.","The genetic architecture of Alzheimer disease risk in the Ohio and Indiana Amish\nAlzheimer disease (AD) is the most common type of dementia and is currently estimated to affect 6.2 million Americans. It ranks as the sixth leading cause of death in the United States and the proportion of deaths due to AD has been increasing since the year 2000 while the proportion of many other leading causes of deaths have decreased or remained constant. The risk for AD is multifactorial, including genetic and environmental risk factors. Though APOE remains the largest genetic risk factor for AD, more than 26 other loci have been associated with AD risk. Here, we recruited from a population of Amish adults from Ohio and Indiana to investigate AD risk and protective genetic effects. With slightly lower incidence and later age of onset, it is thought that the Amish may hold protective genetic variants for AD. As a founder population that typically practices endogamy, variants that are rare in the general population may be at higher frequency in the Amish population. We characterized the genetic architecture of AD risk in the Amish and compared this to a non-Amish population, elucidating the lower relative importance of APOE and differing genetic architecture of the Amish compared to a general European ancestry population.","Decoding mitochondrial genes in pediatric AML and development of a novel prognostic mitochondrial gene signature\nBackgroundGene expression profile of mitochondrial-related genes is not well deciphered in pediatric acute myeloid leukaemia (AML). We aimed to identify mitochondria-related differentially expressed genes (DEGs) in pediatric AML with their prognostic significance.\n\nMethodsChildren with de novo AML were included prospectively between July 2016-December 2019. Transcriptomic profiling was done for a subset of samples, stratified by mtDNA copy number. Top mitochondria-related DEGs were identified and validated by real-time PCR. A prognostic gene signature risk score was formulated using DEGs independently predictive of overall survival (OS) in multivariable analysis. Predictive ability of the risk score was estimated along with external validation in The Tumor Genome Atlas (TCGA) AML dataset.\n\nResultsIn 143 children with AML, twenty mitochondria-related DEGs were selected for validation, of which 16 were found to be significantly dysregulated. Upregulation of SDHC (p<0.001), CLIC1 (p=0.013) and downregulation of SLC25A29 (p<0.001) were independently predictive of inferior OS, and included for developing prognostic risk score. The risk score model was independently predictive of survival over and above ELN risk categorization (Harrells c-index: 0.675). High-risk patients (risk score above median) had significantly inferior OS (p<0.001) and event free survival (p<0.001); they were associated with poor-risk cytogenetics (p=0.021), ELN intermediate/poor risk group (p=0.016), absence of RUNX1-RUNX1T1 (p=0.027), and not attaining remission (p=0.016). On external validation, the risk score also predicted OS (p=0.019) in TCGA dataset.\n\nConclusionWe identified and validated mitochondria-related DEGs with prognostic impact in pediatric AML and also developed a novel 3-gene based externally validated gene signature predictive of survival.","Multi-state network meta-analysis of cause-specific survival data\nMultiple randomized controlled trials, each comparing a subset of competing interventions, can be synthesized by means of a network meta-analysis to estimate relative treatment effects between all interventions in the evidence base. Often there is an interest in estimating the relative treatment effects regarding time-to-event outcomes. Cancer treatment effectiveness is frequently quantified by analyzing overall survival (OS) and progression-free survival (PFS). In this paper we introduce a method for the joint network meta-analysis of PFS and OS that is based on a time-inhomogeneous tri-state (stable, progression, and death) Markov model where time-varying transition rates and relative treatment effects are modeled with known parametric survival functions or fractional polynomials. The data needed to run these analyses can be extracted directly from published survival curves. We demonstrate use by applying the methodology to a network of trials for the treatment of non-small-cell lung cancer. The proposed approach allows the joint synthesis of OS and PFS, relaxes the proportional hazards assumption, extends to a network of more than two treatments, and simplifies the parameterization of decision and cost-effectiveness analyses.","Epidemiological cutoff values for a 96-well broth microdilution plate for high throughput research antibiotic susceptibility testing of M. tuberculosis\nDrug susceptibility testing of M. tuberculosis is rooted in a binary susceptible/resistant paradigm.\n\nWhilst there are considerable advantages in measuring the minimum inhibitory concentrations (MICs) of a panel of drugs for an isolate it is n ecessary to measure the epidemiological cutoff values (ECOFF/ECVs) to permit comparison with qualitative data. Here we present ECOFF/ECVs for 13 anti-TB compounds, including bedaquiline and delamanid, derived from 20,637 clinical isolates collected by 14 laboratories based in 11 countries on five continents. Each isolate was incubated for 14 days on a dry 96-well broth microdilution plate and then read. Resistance to most of the drugs due to prior exposure is expected and the MIC distributions for many of the compounds are complex and therefore a phenotypically wild-type population could not be defined. Since a majority of samples also underwent genetic sequencing, we defined a genotypically wild-type population and measured the MIC of the 99th percentile by direct measurement and via fitting a Gaussian using interval regression.\n\nThe proposed ECOFF/ECV values were then validated by comparing to the MIC distributions of high-confidence genetic variants that confer resistance and to qualitative drug susceptibility tests obtained via Mycobacterial Growth Indicator Tube and the Microscopic-Observation Drug-Susceptibility assay.\n\nThese ECOFF/ECV values will inform and encourage the more widespread adoption of broth microdilution - this is a cheap culture-based method that tests the susceptibility of 12-14 antibiotics on a single 96-well plate and so could help personalise the treatment of tuberculosis.","A strategy to assess spillover risk of bat SARS-related coronaviruses in Southeast Asia\nEmerging diseases caused by coronaviruses of likely bat origin (e.g. SARS, MERS, SADS and COVID-19) have disrupted global health and economies for two decades.\n\nEvidence suggests that some bat SARS-related coronaviruses (SARSr-CoVs) could infect people directly, and that their spillover is more frequent than previously recognized. Each zoonotic spillover of a novel virus represents an opportunity for evolutionary adaptation and further spread; therefore, quantifying the extent of this \"hidden\" spillover may help target prevention programs. We derive biologically realistic range distributions for known bat SARSr-CoV hosts and quantify their overlap with human populations. We then use probabilistic risk assessment and data on human-bat contact, human SARSr-CoV seroprevalence, and antibody duration to estimate that [~]400,000 people (median: [~]50,000) are infected with SARSr-CoVs annually in South and Southeast Asia. These data on the geography and scale of spillover can be used to target surveillance and prevention programs for potential future bat-CoV emergence.","Clinical, neuroimaging and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability\nPURPOSEBi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus.\n\nMETHODSThrough an international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms.\n\nRESULTSA cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections and central/nocturnal hypopnea as core manifestations. A review of brain MRI scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing {beta}-propeller repeats. Despite constituting nearly half of disease associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1,221 in the general and 1/155 in the Jewish Ashkenazi populations.\n\nCONCLUSIONBased on clinical, neuroimaging and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2-associated disorder. This sets the stage for future prospective natural history studies.\n\nCONFLICTS OF INTERESTAll authors involved in the study declare no conflicts of interest relevant to this study.","Proton pump inhibitor use is not associated with severe COVID-19 related outcomes: A propensity score weighted analysis of a national veteran cohort\nBackground and AimsLow pH deactivates most pathogens, including coronaviruses. Proton pump inhibitors (PPIs) are potent gastric acid suppressing medications. Whether PPI use vs non-use is associated with severe Coronavirus disease-2019 (COVID-19) outcomes remains uncertain. We aimed to compare severe COVID-19 outcomes between current outpatient PPI users and non-users.\n\nMethodsWe conducted a retrospective propensity score-weighted analysis of a national cohort of US veterans with established care who tested positive for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) through January 9, 2021, and who had 60 days of follow-up. The positive test date was the index date. Current outpatient PPI use up to and including the index date (primary exposure) was compared to non-use, defined as no PPI prescription fill in the 365 days prior to the index date. The primary outcome was a composite of use of mechanical ventilation or death within 60 days. Weighted logistic regression models evaluated severe COVID-19 outcomes between current PPI users vs non-users.\n\nResultsOf 97,674 Veterans with SARS-CoV-2 testing, 14,958 tested positive (6262 [41.9%] current PPI users, 8696 [58.1%] non-users) and comprised the analytic cohort. After weighting, all covariates were well-balanced. In the weighted cohort, there was no difference in the primary composite outcome (8.2% vs 8.0%; OR 1.03, 95% CI 0.91-1.16), secondary composite outcome, nor individual component outcomes between current PPI users and non-users. There was no significant interaction between age and PPI use on outcomes.\n\nConclusionAmong patients with SARS-CoV-2 infection, current PPI use vs non-use is not associated with severe COVID-19 outcomes.","A cautionary note on recall vaccination in ex-COVID-19 subjects\nCurrently approved COVID-19 vaccines based on mRNA or adenovirus require a first jab followed by recall immunization. There is no indication as to whether individuals who have recovered from COVID-19 should be vaccinated, and if so, if they should receive one or two vaccine doses. Here, we tested the antibody response developed after the first dose of the mRNA based vaccine encoding the SARS-CoV-2 full-length spike protein (BNT162b2) in 124 healthcare professionals of which 57 had a previous history of COVID-19 (ExCOVID). Post-vaccine antibodies in ExCOVID individuals increase exponentially within 7-15 days after the first dose compared to naive subjects (p<0.0001). We developed a multivariate Linear Regression (LR) model with l2 regularization to predict the IgG response for SARS-COV-2 vaccine. We found that the antibody response of ExCOVID patients depends on the IgG pre-vaccine titer and on the symptoms that they developed during the disorder, with anosmia/dysgeusia and gastrointestinal disorders being the most significantly positively correlated in the LR. Thus, one vaccine dose is sufficient to induce a good antibody response in ExCOVID subjects. This poses caution for ExCOVID subjects to receive a second jab both because they may have a overreaction of the inflammatory response and also in light of the current vaccine shortage.","High definition analyses of single cohort, whole genome sequencing data provides a direct route to defining sub-phenotypes and personalising medicine\nPossession of a clinical or molecular disease label alters the context in which life-course events operate, but rarely explains the phenotypic variability observed by clinicians. Whole genome sequencing of unselected endothelial vasculopathy patients demonstrated more than a third had rare, likely deleterious variants in clinically-relevant genes unrelated to their vasculopathy (1 in 10 within platelet genes; 1 in 8 within coagulation genes; and 1 in 4 within erythrocyte hemolytic genes). High erythrocyte membrane variant rates paralleled genomic damage and prevalence indices in the general population. In blinded analyses, patients with greater hemorrhagic severity that had been attributed solely to their vasculopathy had more deleterious variants in platelet (Spearman {rho}=0.25, p=0.008) and coagulation (Spearman {rho}=0.21, p=0.024) genes. We conclude that rare diseases can provide insights for medicine beyond their primary pathophysiology, and propose a framework based on rare variants to inform interpretative approaches to accelerate clinical impact from whole genome sequencing.","Evaluating Vaccine Efficacy Against SARS-CoV-2 Infection\nAlthough interim results from several large placebo-controlled phase 3 trials demonstrated high vaccine efficacy (VE) against symptomatic COVID-19, it is unknown how effective the vaccines are in preventing people from becoming asymptomatically infected and potentially spreading the virus unwittingly. It is more difficult to evaluate VE against SARS-CoV-2 infection than against symptomatic COVID-19 because infection is not observed directly but rather is known to occur between two antibody or RT-PCR tests. Additional challenges arise as community transmission changes over time and as participants are vaccinated on different dates because of staggered enrollment or crossover before the end of the study. Here, we provide valid and efficient statistical methods for estimating potentially waning VE against SARS-CoV-2 infection with blood or nasal samples under time-varying community transmission, staggered enrollment, and blinded or unblinded crossover. We demonstrate the usefulness of the proposed methods through numerical studies mimicking the BNT162b2 phase 3 trial and the Prevent COVID U study. In addition, we assess how crossover and the frequency of diagnostic tests affect the precision of VE estimates.\n\nSummaryWe show how to estimate potentially waning efficacy of COVID-19 vaccines against SARS-CoV-2 infection using blood or nasal samples collected periodically from clinical trials with staggered enrollment of participants and crossover of placebo recipients.","Within-Day Variability of SARS-CoV-2 RNA in Municipal Wastewater Influent During Periods of Varying COVID-19 Prevalence and Positivity\nWastewater surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA is being used to monitor Coronavirus Disease 2019 (COVID-19) trends in communities; however, within-day variation in primary influent concentrations of SARS-CoV-2 RNA remain largely uncharacterized. In the current study, grab sampling of primary influent was performed every 2 hours over two different 24-hour periods at two wastewater treatment plants (WWTPs) in northern Indiana, USA. In primary influent, uncorrected, recovery-corrected, and pepper mild mottle virus (PMMoV)-normalized SARS-CoV-2 RNA concentrations demonstrated ordinal agreement with increasing clinical COVID-19 positivity, but not COVID-19 cases. Primary influent SARS-CoV-2 RNA concentrations exhibited greater variation than PMMoV RNA concentrations as expected for lower shedding prevalence. The bovine respiratory syncytial virus (BRSV) process control recovery efficiency was low (mean: 0.91%) and highly variable (coefficient of variation: 51% - 206%) over the four sampling events with significant differences between the two WWTPs (p <0.0001). The process control recovery was similar to the independently assessed SARS-CoV-2 RNA recovery efficiency, which was also significantly different between the two WWTPs (p <0.0001). Recovery-corrected SARS-CoV-2 RNA concentrations better reflected within-day changes in primary influent flow rate and fecal content, as indicated by PMMoV concentrations. These observations highlight the importance of assessing the process recovery efficiency, which is highly variable, using an appropriate process control. Despite large variations, both recovery-corrected and PMMoV-normalized SARS-CoV-2 RNA concentrations in primary influent demonstrate potential for monitoring COVID-19 positivity trends in WWTPs serving peri-urban and rural areas.","London Ramadan Fasting Study (LORANS): Rationale, design, and methods\nBackgroundHundreds of millions of Muslims fast during the month of Ramadan. The London Ramadan Fasting Study (LORANS) aims to assess the lifestyle changes during this month and investigate the effect of Ramadan fasting on health.\n\nMethodsLORANS is an observational study of participants that follow religious fasting in Ramadan. We advertised, recruited, and visited participants in five mosques in London, United Kingdom. In total, 146 individuals were recruited before Ramadan in May 2019 of which 85 participated in the follow up visit after Ramadan. The study protocol was approved by the ethics committee affiliated to Imperial College London. A written informed consent was signed by all the participants. Every participant completed a questionnaire, a physical examination, and gave blood samples at each visit. Moreover, they completed a 3-day food diary before Ramadan and once again during Ramadan to record dietary changes during the month of fasting.\n\nResultsThe mean age of participants was 45.6{+/-} 15.9 years. 47.1% of the participants were females, 25.5% were obese, 4.7% were smokers, 14% were diabetic, 24% were hypertensive, and 5.2% had cardiovascular diseases. Data collection covered demographics, lifestyle, food intake, blood pressure, anthropometric measurements, body composition, and metabolic biomarker profiling.\n\nConclusionBy engaging with mosques, proper introduction of the study aims and convenient recruitment in the mosque, we were able to recruit a balanced population regarding age and sex and collected valuable data on Ramadan fasting using high-quality techniques.","Safety and Efficacy of Navigational Bronchoscopy with Archimedes Virtual Bronchoscopic Platform in Patients with Advanced Pulmonary Disease\nBackgroundPatients with advanced lung disease who present with suspicious pulmonary nodules (SPNs) undergoing transthoracic needle aspiration pose a diagnostic challenge given risk for complications. Virtual bronchoscopic navigation (VBN) is an alternative means to biopsy patients.\n\nStudy DesignThe study was a retrospective chart review of all patients who underwent VBN with the Archimedes platform. Demographic information, radiographic evidence of parenchymal lung disease and pulmonary function testing were gathered. Peri-procedure complications and clinical data on biopsy results were gathered to assist in determining both adequate tissue sample (defined if adequate specimen was obtained as per pathology/cytology report) and diagnostic yield (defined as if after further testing/CT imaging from 1 year post-procedure the diagnosis did not change). Univariate analysis was performed to determine the impact of clinical factors on diagnostic yield.\n\nResultsNinety-six patients with 110 nodules underwent VBN. Eight-eight patients (92%) had radiographic emphysema with 56% having moderate to severe. Fourteen patients (17%) had radiographic ILD. Adequate tissue sample at time of VBN was 93%. Overall diagnostic yield in 80 patients (excluding 16 patients who were initially benign/non-diagnostic that were lost to follow-up) was 72%. Overall complication rate was 7% with 1-pneumothorax (1%), 3-significant bleeding and 3-hospitalized for respiratory failure.\n\nConclusionIn our cohort of patients the diagnostic yield and complication rate were comparable to other studies where there were fewer patients with advanced lung disease. This data suggests that VBN-guided bronchoscopic biopsy of SPNs is a viable diagnostic option with an acceptable safety profile.","Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits\nImmunoglobulin A (IgA) mediates mucosal responses to food antigens and the intestinal microbiome and has a known role in susceptibility to mucosal pathogens, celiac disease, inflammatory bowel disease, and IgA nephropathy. We performed genetic analyses of serum IgA levels in 41,263 individuals of diverse ancestries. We observed unexpected variability in IgA levels across major ancestral populations, with African ancestry being reproducibly associated with higher serum IgA levels compared to other ancestries. The trans-ethnic GWAS analysis identified 20 genome-wide significant loci associated with serum IgA levels, including nine known and 11 novel loci. Systematic co-localization analysis with blood and primary immune cell expression QTLs prioritized candidate genes for 14 of 20 loci. Most GWAS loci encoded genes that produce immune defects and IgA abnormalities when genetically manipulated in mice. We uncovered positive genetic correlations of serum IgA levels with IgA nephropathy, type 2 diabetes and body mass index, as well as negative genetic correlations with celiac disease, inflammatory bowel disease, several infections, and intestinal microbiome diversity. Our findings provide novel insights into the genetic regulation of IgA production and its potential role in human disease.","Determinants of adolescent lung function in Indians: race, nutrition and systemic inflammation\nRationaleWhile determining normal variation of spirometric volumes, the geo-political construct of Indian inadequately captures the diverse racial structure and varied lifestyles that exist for 1 in 5 people globally. It is necessary to determine the degree of racial heterogeneity and other underlying factors to know whether lower spirometric volumes of Indians is normal or abnormal.\n\nObjectivesTo investigate the differences in spirometric volumes and their associations with overall health parameters, for adolescent children and young adults, across geo-ethnic regions within India.\n\nMethodsData was analyzed for 2338 healthy subjects aged 9-19 years with acceptable spirometry from SOLID cohort. Associations between lung function and potential determinants (Race, anthropometry, nutrition, family/life history, airway oscillometric parameters and systemic inflammation) were examined by using multiple regression. Latent profile analysis (LPA) was performed for 903 subjects to uncover hidden sub-phenotypes.\n\nResultsFEV1 and FVC varied significantly between Indian genetic ancestries, being highest in Tibeto-Burmans and lowest in Dravidians. After statistical adjustments, FEV1 and FVC were positively correlated with waist-height-ratio, shoulder-height-ratio, normalized BMI, and blood hemoglobin. Lower FVC was associated with lower expiratory flows (PEF and FEF25-75), higher lung reactance (X5), higher airway resistance (R10 and R15), gastro-intestinal symptoms, and higher inflammation (IL-8 and IL-17). A sub-phenotype of thinness, higher inflammation (IFN-gamma, IL-17, TNF-alpha, IL-8) and lower FVC was identified on LPA for 35% of the sample.\n\nConclusionsSpirometric volumes in Indians are different between major racial subgroups but may also be abnormally low due to prevalent nutritional or environmental adversity. Care must be taken while establishing normative standards.","Multi-task deep learning-based survival analysis on the prognosis of late AMD using the longitudinal data in AREDS\nAge-related macular degeneration (AMD) is the leading cause of vision loss. Some patients experience vision loss over a delayed timeframe, others at a rapid pace. Physicians analyze time-of-visit fundus photographs to predict patient risk of developing late-AMD, the most severe form of AMD. Our study hypothesizes that 1) incorporating historical data improves predictive strength of developing late-AMD and 2) state-of-the-art deep-learning techniques extract more predictive image features than clinicians do. We incorporate longitudinal data from the Age-Related Eye Disease Studies and deep-learning extracted image features in survival settings to predict development of late-AMD. To extract image features, we used multi-task learning frameworks to train convolutional neural networks. Our findings show 1) incorporating longitudinal data improves prediction of late-AMD for clinical standard features, but only the current visit is informative when using complex features and 2) \"deep-features\" are more informative than clinician derived features. We make codes publicly available at https://github.com/bionlplab/AMD_prognosis_amia2021.","Possibility of SARS-CoV-2 infection in metastatic microenvironment of cancer\nAccording to a report from the World Health Organization, the mortality and severity rates among patients with cancer infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are significantly higher than those of individuals infected with SARS-CoV-2 without complications. Common and cancer-specific risk factors may be involved in the mortality and severity rates of coronavirus disease 2019 (COVID-19). Various factors have been determined to contribute to the aggravation of COVID-19 in patients with cancer. However, on the basis of current research, the factors involved in the aggravation of COVID-19 in patients with cancer have not been fully investigated. In the general course of treatment for patients with cancer, the detection of the formation of metastases in other organs is common. Therefore, the present study investigates the association between lung metastatic lesion formation and SARS-CoV-2 infectivity. On the basis of the results obtained, in the pulmonary micrometastatic niche of patients with ovarian cancer, alveolar epithelial stem-like cells adjacent to the ovarian cancer were observed. Moreover, it was revealed that angiotensin-converting enzyme 2, a host-side receptor for SARS-CoV-2, was expressed in alveolar epithelial stem-like cells adjacent to the ovarian cancer in the pulmonary micrometastatic niche. Furthermore, it was also observed that the SARS-CoV-2 spike glycoprotein receptor-binding domain binds to alveolar epithelial stem-like cells. In other words, it was suggested that patients with cancer and pulmonary micrometastases may be more susceptible to SARS-CoV-2. The prevention of de novo niche formation in metastatic disease may be a new strategy for the clinical treatment of COVID-19 for patients with cancer.","Transdiagnostic connectome-based prediction of craving\nCraving is a central construct in the study of motivation and human behavior and is also a clinical symptom of substance and non-substance-related addictive disorders. Thus, craving represents a target for transdiagnostic modeling. We applied connectome-based predictive modeling (CPM) to functional connectivity data in a large (N=274) transdiagnostic sample of individuals with and without substance-use-related conditions, to predict self-reported craving. CPM is a machine-learning approach used to identify neural signatures in functional connectivity data related to a specific phenotype. Functional connectomes were derived from three guided imagery conditions of personalized appetitive, stress, and neutral-relaxing experiences. Craving was rated before and after each imagery condition. CPM successfully predicted craving, thereby identifying a transdiagnostic craving network comprised primarily of the posterior cingulate cortex, hippocampus, visual cortex, and primary sensory areas. Findings suggest that craving may be associated with difficulties directing attention away from internal self-related processing, represented in the default mode network.","Analysis of cell-specific peripheral blood biomarkers in severe allergic asthma identifies innate immune dysfunction\nAsthma is a disease of complex origin and multiple pathologies. There are currently very few biomarkers of proven utility in its diagnosis, management or response to treatment. Recent studies have identified multiple asthma phenotypes following biofluid analysis; however, such findings may be driven by the well-characterised alterations in immune cell populations in asthma. We present a study designed to identify cell type-specific gene signatures of severe allergic asthma in peripheral blood samples. Using transcriptomic profiling of four magnetically purified peripheral blood cell types, we identify significant gene expression changes in monocytes and NK cells but not T lymphocytes in severe asthmatics. Pathway analysis indicates dysfunction of immune cell regulation and bacterial suppression in the NK cells. These gene expression changes may be useful on their own as prognostic peripheral blood cell markers of severe asthma, but also may indicate novel cell pathways for therapeutic intervention.","Causes, Predictors, and Costs of Unplanned 30-Day Readmissions in Patients with Right Heart Failure.\nOBJECTIVESThe aim of this study was to describe the frequency, causes, factors, and costs associated with right heart failure encounters.\n\nBACKGROUNDMultiple studies have looked into heart failure readmissions but there is no study to our knowledge specifically analyzing patients with right heart failure.\n\nMETHODSPatients with right heart failure diagnosis were identified using the 2017 Nationwide Readmission Database (NRD) and were evaluated for the rates, predictors, and costs of unplanned 30 days readmission. Weighted analysis was performed to obtain nationally representative data.\n\nRESULTSWe identified 7142 patients with right heart failure of whom 21% had an unplanned readmission within 30 days of the index discharge. Patients with history of Coronary artery bypass grafting (p=0.033; OR 2.359; 95% CI 1.071 - 5.197), Chronic kidney disease (p<0.001; OR 1.607; 95% CI 1.402 - 1.843), atrial fibrillation (p=0.014; OR 1.417; 95% CI 1.072-1.873) had high odds of unplanned 30 day readmissions while obesity (p<0.001; OR 0.686; 95% CI 0.594 - 0.792) had negative odds of such readmissions.\n\nCONCLUSIONSThirty-day unplanned readmissions remain a significant issue affecting over 1 in 5 patients with right heart failure. Early unplanned readmissions are associated with significant mortality and financial burden in these patients.","Tumour volume distribution can yield information on tumour growth and tumour control\nBackgroundIt is shown that tumour volume distributions, can yield information on two aspects of cancer research: tumour induction and tumour control.\n\nMaterials and methodsFrom the hypothesis that the intrinsic distribution of breast cancer volumes follows an exponential distribution, firstly the probability density function of tumour growth time was deduced via a mathematical transformation of the probability density functions of tumour volumes. In a second step, the distribution of tumour volumes was used to model the variation of the clonogenic cell number between patients in order to determine tumour control probabilities for radiotherapy patients.\n\nResultsDistribution of lag times, i.e. the time from the appearance of the first fully malignant cell until a clinicaly observable cancer, can be used to deduce the probability of tumour induction as a function of patient age. The integration of the volume variation with a Poisson-TCP model results in a logistic function which explains population-averaged survival data of radiotherapy patients.\n\nConclusionsThe inclusion of tumour volume distributions into the TCP formalism enables a direct link to be deduced between a cohort TCP model (logistic) and a TCP model for individual patients (Poisson). The TCP model can be applied to non-uniform tumour dose distributions.","Patient and physician shared decision making behaviors in oncology: Evidence on adequate measurement properties of the iSHARE questionnaires\nObjectivesWe have developed two questionnaires to assess the shared decision making (SDM) process in oncology; the iSHAREpatient and iSHAREphysician. In this study, we aimed to determine: scores, construct validity, test-retest agreement (iSHAREpatient), and inter-rater (iSHAREpatient-iSHAREphysician) agreement.\n\nMethodsPhysicians from seven Dutch hospitals recruited cancer patients, and completed the iSHAREphysician and SDM-Questionnaire-physician version. Their patients completed the: iSHAREpatient, 9-item SDM-Questionnaire, Decisional Conflict Scale, Combined Outcome Measure for Risk communication And treatment Decision making Effectiveness, and Perceived Efficacy in Patient-Physician Interactions. We formulated, respectively, one (iSHAREphysician) and 10 (iSHAREpatient) a priori hypotheses regarding correlations between the iSHARE questionnaires and questionnaires assessing related constructs. To assess test-retest agreement patients completed the iSHAREpatient again 1-2 weeks later.\n\nResultsIn total, 151 treatment decision making processes with unique patients were rated. Dimension and total iSHARE scores were high both in patients and physicians. The hypothesis on the iSHAREphysician and 9/10 hypotheses on the iSHAREpatient were confirmed. Test-retest and inter-rater agreement were >.60 for most items.\n\nConclusionsThe iSHARE questionnaires show high scores, have good construct validity, substantial test-retest agreement, and moderate inter-rater agreement.\n\nPractice implicationsResults from the iSHARE questionnaires can inform both physician- and patient-directed efforts to improve SDM in clinical practice.","AnmO2l: An open-source pulse-dose oxygen conserving device for the COVID-19 crisis\nThe surge of COVID-19 cases in India and around the world has resulted in acute oxygen shortage. Oxygen therapy through nasal cannula with flow rates of 1-6 L/min is an effective treatment for many COVID-19 patients in non-critical conditions and may help prevent disease progression. The same treatment is also used in post-acute care for recovering COVID-19 patients. Here we describe a simple, open source, and rapidly manufacturable oxygen conservation device for use with dual-port nasal cannula that can extend the life of current oxygen supply by almost two to three times, which we hope will help towards coping with the ongoing crisis.","Using Whole Genome Sequencing to Characterize Clinically Significant Blood Groups Among Healthy Older Australians\nThere have been no comprehensive studies of a full range of blood group polymorphisms within the Australian population. The problem is compounded by the absence of any databases carrying genomic information on chronically transfused patients and low frequency blood group antigens in Australia. Here, we use RBCeq, a web server-based blood group genotyping software, to identify unique blood group variants among Australians and compare the variation detected versus global data. Whole genome sequencing data was analysed from for 2796 healthy older Australians from the Medical Genome Reference Bank and compared with data from 1000G phase 3 (1KGP3) databases comprising 661 African, 347 American, 503 European, 504 East Asian, and 489 South Asian participants. There were 688 rare variants detected in this Australian sample population, including nine variants that had clinical associations. Notably, we identified 149 variants that were computationally predicted to be novel and deleterious. No clinically significant rare or novel variants were found associated with the genetically complex ABO blood group system. For the Rh blood group system, one novel and 16 rare variants were found. Our detailed blood group profiling results provide a starting point for the creation of an Australian blood group variant database.\n\nKey pointsO_LIWe identified unique blood group variants among the healthy older Australian population compared with global data using RBCeq software.\nC_LIO_LIOur detailed blood group profiling result may be a starting point for the creation of an Australian blood group variant database.\nC_LI","Association of Egg Consumption, Metabolic Markers, and Risk of Cardiovascular Diseases: A Nested Case-control Study\nObjectiveTo simultaneously explore the associations of self-reported egg consumption with plasma metabolic markers and these markers with CVD risk.\n\nMethodsTotally 4,778 participants (3,401 CVD cases subdivided into subtypes and 1,377 controls) aged 30-79 were selected from a nested case-control study based on the China Kadoorie Biobank. Targeted nuclear magnetic resonance was used to quantify 225 metabolites and derived traits in baseline plasma samples. Linear regression was conducted to assess associations between self-reported egg consumption and metabolic markers, which were further compared with associations between metabolic markers and CVD risk.\n\nResultsEgg consumption was associated with 24 out of 225 markers, including positive associations for apolipoprotein A1, acetate, mean HDL diameter, and lipid profiles of very large and large HDL, and inverse associations for total cholesterol and cholesterol esters in small VLDL. Among these 24 markers, 14 of them were associated with CVD risk. In general, the associations of metabolic markers with egg consumption and of metabolic markers with CVD risk showed opposite patterns.\n\nConclusionsIn the Chinese population, egg consumption is associated with several metabolic markers, which may partially explain the protective effect of egg consumption on CVD.","Role of physiotherapy team in critically ill COVID-19 patients pronation: can a multidisciplinary management reduce the complications rate?\nObjectivesDuring the pandemic, critically ill COVID-19 patients management presented an increased workload for Intensive Care Unit (ICU) nursing staff, particularly during pronation maneuvers, with high risk of complications. In this scenario, a support during pronation by the ICU Physiotherapy Team was introduced.\n\nResearch methodologyRetrospective analysis. Consecutive critically ill COVID-19 patients.\n\nSettingA COVID-19 Center in southern Switzerland, between March 16th and April 30th, 2020.\n\nMain Outcome MeasuresRates and characteristics of pronation-related complications.\n\nResultsForty-two patients on mechanical ventilation (MV) were treated; 296 standard prone/supine positioning were performed, with 3.52 cycles/patient. One (0.3%) major complication was observed, while fourteen (33.3%) patients developed minor complications, e.g. pressure injuries. The incidence of pressure sores was related to ICU length-of-stay (LOS) (p = 0.029) and MV days (p = 0.015), while their number (n = 27) further correlated with ICU LOS (p = 0.001) and MV days (p = 0.001). The propensity matching score analysis did not show any protective factor of pronation regarding pressure injuries (p = 0.448). No other significant correlation was found.\n\nConclusionThe specific pronation team determined a low rate of major complications in critically ill COVID19 patients. The high rate of minor complications appeared to be related to disease severity, rather than from pronation.","Voice of the patient: Emergence of new motor and non-motor symptoms in early Parkinsons Disease?\nObjectiveTo explore the utility of using patient reported emergence of new symptoms (ES) as an outcome measure during the early phase of the disease.\n\nMethodsWe analyzed data from MDS-UPDRS Part IB and Part II from the Safety, Tolerability, and Efficacy Assessment of Isradipine for PD (STEADY-PD3) study, with at least one annual follow-up over two years. We divided the sample into categories of follow-up visit (between 0 and 12-months, and 13 and 24-months) and the number of ES for each part of the scale between participants who started symptomatic treatment and those who did not (STx-yes/no). We assessed ES differences between participants STx in each follow-up visit using Mann-Whitney U test, and the Kaplan-Meier analyses.\n\nResultsOf 331 participants observed for months 0 to 12, 288 (87%) developed ES, and 182 (55%) started STx. For Part IB, the median number of ES did not significantly differ between the STx groups (Z=-0.86, p = 0.39), while for Part 2, the number of ES was significantly higher for the STx-yes group (Z=-2.38, p=0.02). Of 148 participants who continued to be observed for months 13 to 24, 114 (77%) developed ES, and 62 (42%) started STx. For Part IB, the median number of ES did not significantly differ between the STx groups (Z=-0.33, p = 0.74), while for Part 2, the number of ES was significantly higher for the STx-yes group (Z=-2.25, p=0.02).\n\nConclusionsAssessing ES among patient-reported experiences of daily living may provide a useful marker for tracking PD progression.","Deep Learning based Intraretinal Layer Segmentation using Cascaded Compressed U-Net\nAO_SCPLOWBSTRACTC_SCPLOWIntraretinal layer segmentation on macular optical coherence tomography (OCT) images generates non invasive biomarkers querying neuronal structures with near cellular resolution. While first deep learning methods have delivered promising results with high computing power demands, a reliable, power efficient and reproducible intraretinal layer segmentation is still an unmet need. We propose a cascaded two-stage network for intraretinal layer segmentation, with both networks being compressed versions of U-Net (CCU-INSEG). The first network is responsible for retinal tissue segmentation from OCT B-scans. The second network segments 8 intraretinal layers with high fidelity. By compressing U-Net, we achieve 392- and 26-time reductions in model size and parameters in the first and second network, respectively. Still, our method delivers almost similar accuracy compared to U-Net without additional constraints of computation and memory resources. At the post-processing stage, we introduce Laplacian-based outlier detection with layer surface hole filling by adaptive non-linear interpolation. We trained our method using 17,458 B-scans from patients with autoimmune optic neuropathies, i.e. multiple sclerosis, and healthy controls. Voxel-wise comparison against manual segmentation produces a mean absolute error of 2.3m, which is 2.5x better than the devices own segmentation. Voxel-wise comparison against external multicenter data leads to a mean absolute error of 2.6m for glaucoma data using the same gold standard segmentation approach, and 3.7m mean absolute error compared against an externally segmented reference data set. In 20 macular volume scans from patients with severe disease, 3.5% of B-scan segmentation results were rejected by an experienced grader, whereas this was the case in 41.4% of B-scans segmented with a graph-based reference method.","A high-throughput microfluidic nano-immunoassay for detecting anti-SARS-CoV-2 antibodies in serum or ultra-low volume dried blood samples\nNovel technologies are needed to facilitate large-scale detection and quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specific antibodies in human blood samples. Such technologies are essential to support seroprevalence studies, vaccine clinical trials, and to monitor quality and duration of immunity. We developed a microfluidic nano-immunnoassay for the detection of anti-SARS-CoV-2 IgG antibodies in 1024 samples per device. The method achieved a specificity of 100% and a sensitivity of 98% based on the analysis of 289 human serum samples. To eliminate the need for venipuncture, we developed low-cost, ultra-low volume whole blood sampling methods based on two commercial devices and repurposed a blood glucose test strip. The glucose test strip permits the collection, shipment, and analysis of 0.6 {micro}L whole blood easily obtainable from a simple fingerprick. The nano-immunoassay platform achieves high-throughput, high sensitivity and specificity, negligible reagent consumption, and a decentralized and simple approach to blood sample collection. We expect this technology to be immediately applicable to current and future SARS-CoV-2 related serological studies and to protein biomarker diagnostics in general.","Association between comorbidities and death from COVID-19 in different age groups\nBackgroundThis new COVID-19 pandemic challenges health systems around the world; therefore, it is extremely important to determine which patients with COVID-19 can evolve to more severe outcomes. Accordingly, we decided to assess the role that comorbidities play in death from COVID-19.\n\nMethodsTwo age groups (<60 and [≥] 60 years) were defined for analysis. Decision trees were made to identify which comorbidities had the highest fatality rate (FR). Multiple logistic regressions were performed to measure the association between comorbidities and death.\n\nResultsA significant difference was found between the FR of <60 group and [≥] 60 group. The most frequent comorbidity were cardiac diseases and diabetes. The combination of comorbidities with the highest FR was diabetes with kidney disease. Combinations of more than two comorbidities presented higher FR. The comorbidities had higher Odd ratios in the younger group than in the older group.\n\nConclusionsComorbidities seem to play a greater role in death from COVID-19 in the younger group, while in the> 60 group; age seems to be the most important factor. We assigned a score to the comorbidities and their combinations for both age groups to help the health personnel make decisions.","Evaluating the effects of second-dose vaccine-delay policies in European countries: A simulation study based on data from Greece\nThe results of a simulation-based evaluation of several policies for vaccine rollout are reported, particularly focusing on the effects of delaying the second dose of two-dose vaccines. In the presence of limited vaccine supply, the specific policy choice is a pressing issue for several countries worldwide, and the adopted course of action will affect the extension or easing of non-pharmaceutical interventions in the next months. We employ a suitably generalised, age-structure, stochastic SEIR (Susceptible [->] Exposed [->] Infectious [->] Removed) epidemic model that can accommodate quantitative descriptions of the major effects resulting from distinct vaccination strategies. The different rates of social contacts among distinct age-groups (as well as some other model parameters) are informed by a recent survey conducted in Greece, but the conclusions are much more widely applicable. The results are summarised and evaluated in terms of the total number of deaths and infections as well as life years lost. The optimal strategy is found to be one based on fully vaccinating the elderly/at risk as quickly as possible, while extending the time-interval between the two vaccine doses to 12 weeks for all individuals below 75 years old, in agreement with epidemic theory which suggests targeting a combination of susceptibility and infectivity. This policy, which is similar to the approaches adopted in the UK and in Canada, is found to be effective in reducing deaths and life years lost in the period while vaccination is still being carried out.","High Brain-Derived Neurotrophic Factor (BDNF) and Negative Psychological Flexibility associate with Early Fatigue Syndrome in healthy females\nBackgroundRecent studies showed that enhancing psychological flexibility could improve fatigue interference. Brain-Derived Neurotrophic Factor (BDNF), Heart Rate Variability (HRV), and Cortisol were proposed to involve biomarkers in psychological flexibility. Our study aims to explore the association of fatigue with psychological flexibility and related biomarkers.\n\nMethodA cross-sectional study gathered data from a baseline characteristic mindful volunteer. Each participant was self-evaluated with the questionnaire of fatigue and psychological flexibility. The participants were evaluated potential biomarkers related to psychological flexibility including HRV, serum cortisol, and BDNF within one week after responding to the questionnaire.\n\nResultsThe 47 healthy females including 22 nurses and 25 occupational therapy students, mean age 29.70 {+/-} 12.55 years. The prevalence of fatigue is 38.30%. The multivariate analysis showed the independent factors associated with fatigue including negative psychological flexibility (OR 1.31, p=0.03) and high BDNF (OR 1.33, p=0.05).\n\nConclusionOur study found that psychological flexibility and high BDNF was independent factors associate with fatigue. This result provide insight that intervention that increase either psychological flexibility may prevent fatigue symptoms. The high BDNF may reflex the adaptive response of fatigue person and may be potential biomarkers for detecting early fatigue conditions.","Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study: Study Design\nThe Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults at risk for coronavirus disease 2019 (COVID-19) comprising 14 established United States (US) prospective cohort studies. For decades, C4R cohorts have collected extensive data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R will link this pre-COVID phenotyping to information on SARS-CoV-2 infection and acute and post-acute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and broadly reflects the racial, ethnic, socioeconomic, and geographic diversity of the US. C4R is ascertaining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations, and high-quality events surveillance. Extensive pre-pandemic data minimize referral, survival, and recall bias. Data are being harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these will be pooled and shared widely to expedite collaboration and scientific findings. This unique resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including post-acute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term trajectories of health and aging.","The role of the uncinate fasciculus in the risk-architecture of bipolar disorders: A meta-analysis\nBackgroundBipolar disorder (BD) is a severe mental disorder, characterized by prominent mood swings and emotion regulation (ER) deficits. The uncinate fasciculus (UF), a white matter tract connecting the amygdala and the ventral prefrontal cortex, has been implicated in ER. Aberrancies in UF microstructure may be an endophenotype associated with increased risk for BD. However, findings in individuals with BD and at familial risk for BD (AR) have yielded inconsistent findings. This meta-analysis takes a region-of-interest approach to consolidate the available evidence and elucidate the role of the UF in the risk-architecture of BD.\n\nMethodsUsing web-based search engines, we identified diffusion tensor imaging studies focusing on the left and right UF and conducted meta-analyses comparing fractional anisotropy (FA) and radial diffusivity (RD) between BD or AR to healthy volunteers (HV).\n\nResultsWe included 32 studies (nBD=1186, nHV=2001; nAR=289, nHV=314). Compared to HV, individuals with BD showed lower FA in the right (p<.0001) and left UF (p=.010), and higher RD in the right UF (p=.009). We found no significant differences between AR and HV. In the right but not the left UF, AR individuals showed higher FA than BD (p=.043).\n\nConclusionComparable UF microstructure between AR and HV and higher FA in the right UF in AR compared to BD suggest that aberrancies in UF microstructure is not an endophenotype for BD. Longitudinal studies are needed to determine when UF abnormalities emerge in the context of BD.","Preexisting diabetes and COVID-associated hyperglycaemia in patients with COVID-19 pneumonia\nAO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSAimC_ST_ABSThe aim of the current study was to compare clinical characteristics, laboratory findings and major outcomes of patients hospitalized for COVID-19 pneumonia with COVID-associated hyperglycaemia or preexisting diabetes.\n\nMethodsA cohort of 176 adult patients with a diagnosis of pre-existing diabetes (n=112) or COVID-associated hyperglycaemia (n=55) was studied. Clinical outcomes and laboratory findings were analysed according to the presence of the two conditions. The time to viral clearance was assessed during the follow-up after hospital discharge.\n\nResultPatients with COVID-associated hyperglycaemia had lower BMI, significantly less comorbidities and higher levels of inflammatory markers and indicators of multi-organ injury than those with preexisting diabetes. No differences between preexisting diabetes and COVID-associated hyperglycaemia were evident for symptoms at admission, humoral response against SARS-CoV-2 or autoantibodies to glutamic acid decarboxylase or interferon alpha-4. COVID-associated hyperglycaemia was independently associated with the risk of adverse clinical outcome defined as ICU admission or death (HR 2.11, 95% CI 1.34-3.31; p=0.001), even after adjustment for age, sex and other selected variables associated with COVID-19 severity. Furthermore, we documented a negative association (HR 0.661, 95% CI 0.43-1.02; p=0.063) between COVID-associated hyperglycaemia and the time to swab negativization.\n\nConclusionsThe recognition of hyperglycaemia as a specific clinical entity associated with COVID-19 pneumonia is relevant for early and appropriate patient management and close monitoring for the progression of disease severity.","Rapid Screening of COVID-19 Disease Directly from Clinical Nasopharyngeal Swabs using the MasSpec Pen Technology\nThe outbreak of COVID-19 has created an unprecedent global crisis. While PCR is the gold standard method for detecting active SARS-CoV-2 infection, alternative high-throughput diagnostic tests are of significant value to meet universal testing demands. Here, we describe a new design of the MasSpec Pen technology integrated to electrospray ionization (ESI) for direct analysis of clinical swabs and investigate its use for COVID-19 screening. The redesigned MasSpec Pen system incorporates a disposable sampling device refined for uniform and efficient analysis of swab tips via liquid extraction directly coupled to a ESI source. Using this system, we analyzed nasopharyngeal swabs from 244 individuals including symptomatic COVID-19 positive, symptomatic negative, and asymptomatic negative individuals, enabling rapid detection of rich lipid profiles. Two statistical classifiers were generated based on the lipid information aquired. Classifier 1 was built to distinguish symptomatic PCR-positive from asymptomatic PCR-negative individuals, yielding cross-validation accuracy of 83.5%, sensitivity of 76.6%, and specificity of 86.6%, and validation set accuracy of 89.6%, sensitivity of 100%, and specificity of 85.3%. Classifier 2 was built to distinguish symptomatic PCR-positive patients from negative individuals including symptomatic PCR-negative patients with moderate to severe symptoms and asymptomatic individuals, yielding a cross-validation accuracy of 78.4% accuracy, specificity of 77.21%, and sensitivity of 81.8%. Collectively, this study suggests that the lipid profiles detected directly from nasopharyngeal swabs using MasSpec Pen-ESI MS allows fast (under a minute) screening of COVID-19 disease using minimal operating steps and no specialized reagents, thus representing a promising alternative high-throughput method for screening of COVID-19.","How Timing of Stay-home Orders and Mobility Reductions Impacted First-Wave COVID-19 Deaths in US Counties\nAs SARS-CoV-2 transmission continues to evolve, understanding how location-specific variations in non-pharmaceutical interventions and behaviors contributed to disease transmission during the initial epidemic wave will be key for future control strategies. We offer a rigorous statistical analysis of the relative effectiveness of the timing of both official stay-at-home orders and population mobility reductions during the initial stage of the US epidemic. We use a Bayesian hierarchical regression to fit county-level mortality data from the first case on Jan 21 2020 through Apr 20 2020 and quantify associations between the timing of stay-at-home orders and population mobility with epidemic control. We find that among 882 counties with an early local epidemic, a 10-day delay in the enactment of stay-at-home orders would have been associated with 14,700 additional deaths by Apr 20 (95% credible interval: 9,100, 21,500), whereas shifting orders 10 days earlier would have been associated with nearly 15,700 fewer lives lost (95% credible interval: 11,350, 18,950). Analogous estimates are available for reductions in mobility--which typically occurred before stay-at-home orders--and are also stratified by county urbanicity, showing significant heterogeneity. Results underscore the importance of timely policy and behavioral action for early-stage epidemic control.","epiLiver a novel tumor specific, high throughput and cost-effective blood test for specific detection of liver cancer (HCC)\nRobust cost effective and high-throughput tests for early detection of cancer in otherwise healthy people could potentially revolutionize public-health and the heavy personal and public burden of the morbidity and mortality from cancer. Several studies have delineated tumor specific DNA methylation profiles that could serve as biomarkers for early detection of Hepatocellular Carcinoma (HCC) as well as other cancers in liquid biopsies. Several published DNA methylation markers fail to distinguish HCC DNA from DNA from other tissues and other cancers that are potentially present in plasma. We describe a set of DNA methylation signatures in HCC that are \"categorically\" distinct from normal tissues and blood DNA methylation profiles. We develop a classifier combined of 4 CG sites that is sufficient to detect HCC in TCGA HCC data set at high accuracy. A single CG site at the F12 gene is sufficient to differentiate HCC samples from thousands of other blood samples, normal tissues and 31 tumors in the TCGA and Gene Expression Omnibus (GEO) data repository (n=11,704). A \"next generation sequencing\"-targeted-multiplexed high-throughput assay was developed, which was used to examine in a clinical study plasma samples from HCC, chronic hepatitis B (CHB) patients and healthy controls (n=398). The sensitivity for HCC detection was 84.5% at a specificity of 95% and AUC of 0.94. Applying this assay for routine follow up of people who are at high risk for developing HCC could have a significant impact on reducing the morbidity and mortality from HCC.","Feasibility of Continuous Distal Body Temperature for Passive, Early Pregnancy Detection\nThe majority of American women become aware of pregnancy ~3-7 weeks after conception, and all must seek testing to confirm their pregnant status. The delay between conception and awareness is often a time in which contraindicated behaviors take place. However, there is long standing evidence that passive, early pregnancy detection may be possible using body temperature. To address this possibility, we analyzed 30 individuals continuous distal body temperature (DBT) in the 180 days surrounding self-reported conception in comparison to self-reported pregnancy confirmation. Features of DBT nightly maxima changed rapidly following self-reported conception, reaching uniquely elevated values after a median of 5.5 {+/-} 3.5 days, whereas individuals reported a positive pregnancy test result at a median of 14.5 {+/-} 4.2 days. Together, we were able to generate a retrospective, hypothetical alert a median of 9 {+/-} 3.9 days prior to the date at which individuals received a positive pregnancy test. Continuous temperature-derived features can provide early, passive indication of pregnancy onset. We propose these features for testing and refinement in clinical settings, and for exploration in large, diverse cohorts. The development of pregnancy detection using DBT may reduce the delay from conception to awareness and increase the agency of pregnant individuals.","Longitudinal changes in physical activity during and after the first national lockdown due to the COVID-19 pandemic in England\nBackgroundRecent studies have shown reduced physical activity at early stages of the COVID-19 pandemic. However, there is a lack of investigation on longitudinal changes in physical activity beyond lockdowns and stay at home orders. Moreover, it is unclear if there is heterogeneity in physical activity growth trajectories. This study aimed to explore longitudinal patterns of physical activity and factors associated with them.\n\nMethodsData were from the UCL COVID -19 Social Study. The analytical sample consisted of 35,915 adults in England who were followed up for 22 weeks from 24th March to 23rd August 2020. Data were analysed using growth mixture models.\n\nFindingsOur analyses identified six classes of growth trajectories, including three stable classes showing little change over time (62.4% in total), two classes showing decreasing physical activity (28.6%), and one class showing increasing physical activity over time (9%). A range of factors were found to be associated the class membership of physical activity trajectories, such as age, gender, education, income, employment status, and health.\n\nInterpretationThere is substantial heterogeneity in longitudinal changes in physical activity during the COVID-19 pandemic. However, a substantial proportion of our sample showed persistent physical inactivity or decreasing physical activity. Given the well-established linked between physical activity and health, persistent or increased physical inactivity is likely to have both immediate and long-term implications for peoples physical and mental health, as well as general wellbeing. More efforts are needed to promote physical activity during the pandemic and beyond.\n\nFundingNuffield Foundation, UK Research and Innovation, Wellcome Trust","Single cell sequencing reveals expanded cytotoxic CD4+ T cells and two states of peripheral helper T cells in synovial fluid of ACPA+ RA patients\nRheumatoid arthritis is an autoimmune disease affecting the synovial joints where different subsets of CD4+ T cells are suspected to play a pathogenic role. So far, our understanding of the contribution of cytotoxic CD4+ T cells is incomplete, particularly in the context of the recently described peripheral helper T-cell subset (TPH). Here, using single cell sequencing and multi-parameter flow cytometry, we show that cytotoxic CD4+ T cells are enriched in synovial fluid of anti-citrullinated peptides antibody (ACPA)-positive RA patients. We identify two distinct TPH states differentially characterized by the expression of CXCL13 and PRDM1, respectively. Our data reveal that the adhesion G-Protein Coupled Receptor 56 (GPR56), a marker of circulating cytotoxic cells, delineates the synovial TPH CD4+ T-cell subset. At the site of inflammation, GPR56+CD4+ T cells expressed the tissue-resident memory markers LAG-3, CXCR6 and CD69. Further, TCR clonality analysis revealed that most expanded clones in SF are contained within the cytotoxic and the CXCL13+ TPH CD4+ T-cell populations. Finally, the detection of common TCRs between the two TPH and cytotoxic CD4+ T-cell clusters suggest a shared differentiation. Our study provides comprehensive immunoprofiling of the heterogenous T-cell subsets at the site of inflammation in ACPA+ RA and suggests GPR56 as a therapeutic target to modulate TPH cells and cytotoxic CD4+ T cell function.","Amyloid-associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer\nFor optimal design of anti-amyloid-{beta} (A{beta}) and anti-tau clinical trials, it is important to understand how A{beta} and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with PET and subsequent cognitive decline across the Alzheimers disease (AD) continuum. In early stages of AD, increased concentration of soluble CSF p-tau was the main driver of accumulation of insoluble tau aggregates across the brain, and mediated the effect of A{beta} on tau aggregation. Further, higher soluble p-tau concentrations were mainly related to faster accumulation of tau aggregates in the regions with strong functional connectivity to individual tau epicenters. In this early stage, higher soluble p-tau concentrations were associated with cognitive decline, which was mediated by faster increase of tau aggregates. In AD dementia, when A{beta} fibrils and soluble p-tau levels have plateaued, cognitive decline was driven by the accumulation rate of insoluble tau aggregates. Our data suggest that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD.","Simulating the impact of different vaccination policies on the COVID-19 pandemic in New York City\nPurposeTo analyze potential COVID-19 epidemic outcomes in New York City under different SARS-CoV-2 virus circulation scenarios and vaccine rollout policies from early Jan 2021 to end of June 2021.\n\nKey findingsIn anticipation of the potential arrival and dominance of the more infectious SARS-CoV-2 variant:\n\nO_LIMass-vaccination would be critical to mitigating epidemic severity (26-52% reduction in infections, hospitalizations, and deaths, compared to no vaccination, provided the new UK variant supplants currently circulating variants).\nC_LIO_LIPrioritizing key risk groups for earlier vaccination would lead to greater reductions in hospitalizations and deaths than infections. Thus, in general this would be a good strategy.\nC_LIO_LICurrent vaccination prioritization policy is suboptimal. To avert more hospitalizations and deaths, mass-vaccination of all individuals 65 years or older should be done as soon as possible. For groups listed in the same phase, 65+ year-olds should be given first priority ahead of others.\nC_LIO_LIAvailable vaccine doses should be given to the next priority groups as soon as possible without awaiting hesitant up-stream groups.\nC_LIO_LIWhile efficacy of vaccination off-protocol is unknown, provided immune response following a first vaccine dose persists, delaying the 2nd vaccine dose by [~]1 month (i.e. administer the two doses 8 weeks apart) can substantially reduce infections, hospitalizations, and deaths compared to the 3-week apart regimen. Across all scenarios tested here, delaying the 2nd vaccine dose leads to the largest reduction in severe epidemic outcomes (e.g. hospitalizations and deaths). Therefore, to protect as many people as possible, this strategy should be considered if rapid increases in infections, hospitalization or deaths and/or shortages in vaccines were to occur.\nC_LI","Social relationships and activities following elimination of SARS-CoV-2: a qualitative cross-sectional study\nObjectivesTo investigate how successfully SARS-CoV-2 elimination strategies fulfil their promise of allowing a return to a normal social life, and to identify obstacles and challenges that may inhibit the realisation of this goal.\n\nDesignQualitative cross-sectional survey.\n\nSettingNew Zealand community cohort.\n\nParticipants1040 respondents entered the study (18-90 years, M = 48.18.11, SD = 15.52, 76% women). 966 completed the questions relevant to this article. Participants were recruited via online advertisement campaigns designed to maximise variation in the sample as far as practicably possible.\n\nMain outcome measuresThematic analysis of participants narratives.\n\nResultsA majority of participants reported that the elimination of SARS-CoV-2 had allowed their life to go back to being more or less the same as before the pandemic. A small number indicated the pandemic had inspired them to become more social following elimination. Nevertheless, a sizeable minority of respondents reported being less social, even many months after SARS-CoV-2 had been eliminated. This was often because of fears that the virus might be circulating undetected, or because the March-May 2020 lockdown had led to changes in relationships and personal habits that were not easily reversed. Becoming less social was associated with having an underlying health condition that heightened ones vulnerability to COVID-19 (p = 0.00005) and older age (p = 0.007).\n\nConclusionsElimination strategies can successfully allow the public to return to a pre-pandemic normal - or reinvent and improve their social lives should they wish. However, such outcomes are not inevitable. Re-establishing social connections after elimination can sometimes be a challenging process, with which people may need support. Plans for providing such support should be an integral part of elimination strategies.","Effects of Diabetes and Blood Glucose on COVID-19 Mortality: A Retrospective Observational Study\nOBJECTIVETo investigate the association of diabetes and blood glucose on mortality of patients with Coronavirus Disease 2019 (COVID-19).\n\nRESEARCH DESIGN AND METHODSThis was a retrospective observational study of all patients with COVID-19 admitted to Huo-Shen-Shan Hospital, Wuhan, China. The hospital was built only for treating COVID-19 and opened on February 5, 2020. The primary endpoint was all-cause mortality during hospitalization.\n\nRESULTSAmong 2877 hospitalized patients, 13.5% (387/2877) had a history of diabetes and 1.9% (56/2877) died in hospital. After adjustment for confounders, patients with diabetes had a 2-fold increase in the hazard of mortality as compared to patients without diabetes (adjusted HR 2.11, 95%CI: 1.16-3.83, P=0.014). The on-admission glucose (per mmol/L[≥]4mmol/L) was significantly associated with subsequent mortality on COVID-19 (adjusted HR 1.17, 95%CI: 1.10-1.24, P<0.001).\n\nCONCLUSIONSDiabetes and on-admission glucose (per mmol/L[≥]4mmol/L) are associated with increased mortality in patients with COVID-19. These data support that blood glucose should be properly controlled for possibly better survival outcome in patients with COVID-19.","Functional implications of aging-related lncRNAs for predicting prognosis and immune status in glioma patients\nGlioma, is the most prevalent intracranial tumor with high recurrence and mortality rate. Long noncoding RNAs (lncRNAs) play a critical role in the occurrence and progression of tumors as well as in aging regulation. Our study aimed to establish a new glioma prognosis model by integrating aging-related lncRNAs expression profiles and clinical parameters in glioma patients from the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) datasets. The Pearson correlation analysis (|R|> 0.6, P<0.001) was performed to explore the aging-related lncRNAs, and univariate cox tregresion and least absolute shrinkage and selection operator (LASSO) regression were used to screening prognostic signature in glioma patients. Based on the fifteen lncRNAs, we can divide glioma patients into three subtypes, and developed a prognostic model. Kaplan-Meier survival curve analysis showed that low-risk patients had longer survival time than high-risk group. Principal component analysis indicated that aging-related lncRNAs signature had a clear distinction between high- and low-risk groups. We also found that fifteen target lncRNAs were closely correlated with 119 genes by establishing a co-expression network. In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis displayed different function and pathways enrichment in high-and low-risk groups. The different missense mutations were observed in two groups, and the most frequent variant types were single nucleotide polymorphism (SNP). This study demonstrated that the novel aging-related lncRNAs signature had an important prognosis prediction and may contribute to individual treatment for glioma.","Comparison of Phase Angle Using Bioelectrical Impedance Analysis According to Device Type and Examination Posture\nBackgroundBioelectrical impedance analysis (BIA) is gaining popularity as a body composition assessment tool for patients. Although it has been studied and validated in different populations, age groups, and clinical settings, including critically ill patients, there are concerns about BIA reproducibility and reliability in different device types and postures. This study aimed to evaluate the reliability of BIA according to different devices, postures, and lead types.\n\nMethodsCross-sectional observational data of 74 healthy volunteers (32 women and 42 men) were collected. We used two types of devices, three types of postures (standing, sitting, and lying), and two lead types (clamp lead and adhesive lead) to measure the whole-body phase angle (phA) at a single frequency of 50 kHz. The measurements were validated using the intraclass correlation coefficient (ICC) and Bland-Altman plot analysis.\n\nResultsAll phA measurements recorded with two types of devices, three different postures, and two types of leads were equivalent to each other (mean ICC = 0.9932, 95% confidence interval (CI) 0.9905-0.0053). The average mean difference in phA was 0.31 (95% CI 0.16- 0.46). The largest phA value was measured using BWA with an adhesive-type lead in the lying position. There were no differences between standing and sitting positions.\n\nConclusionThis is the first study to show the consistency and reliability of BIA in measuring phA using different devices, lead types, and postures. This could provide the confidence that BIA can be used in various clinical settings.","Validation of motor and functional scales for the evaluation of adult patients with 5q spinal muscular atrophy\nObjectiveTo assess in adult spinal muscular atrophy (SMA) patients the construct validity and responsiveness of several outcome measures.\n\nMethodsPatients older than 15 years and followed-up at least for 6 months, between October 2015 and August 2020, with one motor function scale (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb module, RULM) in five referral centers were included. Bedside functional scales (Egen Klassification, EK2; Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, ALSFRS-R) were also collected when available. Correlations and regression models were performed to evaluate the construct validity. The monthly slopes of change were used to calculate their responsiveness.\n\nResultsThe study included 79 SMA patients, followed up for a mean of 16 months. All scales showed strong or very strong correlations with each other. A floor effect in motor function scales was found in weakest patients (HFMSE < 5 and RULM<10), and a ceiling effect in stronger patients (with HFMSE >55 and RULM > 35), when compared with other scales. ALSFRS-R (B=0.72) showed a strong discriminating ability between walkers, sitters, and non-sitters, and HFMSE (B=0.86) between walkers and sitters. The responsiveness was overall low, although in treated patients a moderate responsiveness was found for ALSFRS-R and HFMSE in walkers (0.69 and 0.61 respectively), and for EK2 in sitters (0.65) and non-sitters (0.60).\n\nConclusionsThis study shows the validity in SMA adult patients of commonly used scales. Overall, bedside functional scales showed some advantages over motor function scales, although all scales showed low responsiveness in untreated patients.","HAVAs: Alzheimer s Disease Detection using Normative and Pathological Lifespan Models\nIn this paper, we present an innovative MRI-based method for Alzheimers Disease (AD) detection and mild cognitive impairment (MCI) prognostic, using lifespan trajectories of brain structures. After a full screening of the most discriminant structures between AD and normal aging based on MRI volumetric analysis of 3032 subjects, we propose a novel Hippocampal-Amygdalo-Ventricular Alzheimer score (HAVAs) based on normative lifespan models and AD lifespan models. During a validation on three external datasets on 1039 subjects, our approach showed very accurate detection (AUC [≥] 94%) of patients with AD compared to control subjects and accurate discrimination (AUC=78%) between progressive MCI and stable MCI (during a 3 years follow-up). Compared to normative modelling and recent state-of-the-art deep learning methods, our method demonstrated better classification performance. Moreover, HAVAs simplicity makes it fully understandable and thus well-suited for clinical practice or future pharmaceutical trials.","A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank\nGenome-first approaches to analyzing rare variants can reveal new insights into human biology and disease. Because pathogenic variants are often rare, new discovery requires aggregating rare coding variants into gene burdens for sufficient power. However, a major challenge is deciding which variants to include in gene burden tests. Pathogenic variants in MYBPC3 and MYH7 are well-known causes of hypertrophic cardiomyopathy (HCM), and focusing on these positive control genes in a genome-first approach could help inform variant selection methods and gene burdening strategies for other genes and diseases. Integrating exome sequences with electronic health records among 41,759 participants in the Penn Medicine BioBank, we evaluated the performance of aggregating predicted loss-of-function (pLOF) and/or predicted deleterious missense (pDM) variants in MYBPC3 and MYH7 for gene burden phenome-wide association studies (PheWAS). The approach to grouping rare variants for these two genes produced very different results: pLOFs but not pDM variants in MYBPC3 were strongly associated with HCM, whereas the opposite was true for MYH7. Detailed review of clinical charts revealed that only 38.5% of patients with HCM diagnoses carrying an HCM-associated variant in MYBPC3 or MYH7 had a clinical genetic test result. Additionally, 26.7% of MYBPC3 pLOF carriers without HCM diagnoses had clear evidence of left atrial enlargement and/or septal/LV hypertrophy on echocardiography. Our study shows the importance of evaluating both pLOF and pDM variants for gene burden testing in future studies to uncover novel gene-disease relationships and identify new pathogenic loss-of-function variants across the human genome through genome-first analyses of healthcare-based populations.","Distinct microRNA expression signatures of primary and secondary central nervous system lymphomas\nCentral nervous system (CNS) lymphoma is a rare and aggressive non-Hodgkin lymphoma that might arise in the CNS (primary CNS lymphoma, PCNSL) or disseminates from a systemic lymphoma to the CNS (secondary CNS lymphoma, SCNSL). Dysregulated expression of microRNAs (miRNAs) is associated with various pathological processes and miRNA expression patterns may have diagnostic, prognostic and therapeutic implications. However, miRNA expression is understudied in CNS lymphomas. Here, we performed expression analysis of 798 miRNAs in 73 CNS lymphoma samples using the NanoString platform, followed by a detailed statistical analysis to identify potential novel biomarkers characterizing subgroups and to examine differences based on their primary and secondary nature, molecular subtype, mutational patterns and survival. We describe the general expression patterns of miRNAs across CNS lymphoma samples and identified 31 differentially expressed miRNAs between primary and secondary groups. Additionally, we identified 7 more miRNAs associated with a molecular subtype and 25 associated with mutation status. Using unsupervised clustering methods, we defined a small but distinct primary CNS lymphoma subgroup, with characteristically different expression patterns compared to the rest of the cases. Finally, we identified differentially regulated pathways in the above comparisons and assessed the utility of miRNA expression patterns in predicting survival. Our study identifies a novel CNS lymphoma subgroup defined by distinct miRNAs, proves the importance of specific miRNAs and pathways in their pathogenesis, and provides the basis for future research.","Death, Demography and the Denominator: Age-Adjusted Influenza-18 Mortality in Ireland\nUsing the Irish experience of the Spanish flu, we demonstrate that pandemic mortality statistics are sensitive to the demographic composition of a country. We build a population database for Irelands 32 counties with vital statistics on births, ageing, migration and deaths. We show how age-at-death statistics in 1918 and 1919 should be used to construct the age-adjusted mortality statistics necessary to make comparisons across time and space. We conclude that studies of the economic consequences of Influenza-18 and Covid-19 must better control for demographic factors if they are to yield useful policy-relevant results. For example, while Northern Ireland has a higher crude death rate in the current pandemic, it also has an older population; age-adjusted mortality paints a very different picture.","Structural disconnectome mapping of cognitive function in post-stroke patients\nSequalae following stroke represents a significant challenge in current rehabilitation. The location and size of focal lesions are only moderately predictive of the diverse cognitive outcome after stroke. One explanation building on recent work on brain networks proposes that the cognitive consequences of focal lesions are caused by damages to anatomically distributed brain networks supporting cognition rather than specific lesion locations. To investigate the association between post-stroke structural disconnectivity and cognitive performance, we estimated individual level whole-brain disconnectivity probability maps based on lesion maps from 102 stroke patients using normative data from healthy controls. Cognitive performance was assessed in the whole sample using Montreal Cognitive Assessment, and a more comprehensive computerized test protocol was performed on a subset (n=82). Multivariate analysis using Partial Least Squares on the disconnectome maps revealed that higher disconnectivity in right insular and frontal operculum, superior temporal gyrus and putamen was associated with poorer MoCA performance, indicating that lesions in regions connected with these brain regions are more likely to cause cognitive impairment. Furthermore, our results indicated that disconnectivity within these clusters was associated with poorer performance across multiple cognitive domains. These findings demonstrate that the extent and distribution of structural disconnectivity following stroke are sensitive to cognitive deficits and may provide important clinical information predicting post stroke cognitive sequalae.","Molecular portrait of prostate tissue probed by MALDI Imaging Mass Spectrometry\nBenign prostatic hyperplasia (BPH) is the most common condition in aging men, associated with lower urinary tract symptoms. BPH has been suggested to be a risk factor for certain urologic cancers, but the current evidence is inconsistent. The gold-standard method for the diagnosis of BPH is histopathology. Histopathology displays the cellular morphologies of tissues wherein characteristic changes pertaining specifically to BPH can be identified. However, the onset of BPH might be associated with minimal phenotypic changes in cellular morphologies in tissues that histopathology might not be able to detect successfully. Therefore, to understand the onset of a disease and its pathogenesis it is important to investigate the detailed molecular profiles associated with the disease that might help in the diagnosis and to understand the insights of the disease pathogenesis. Over the last decade, imaging mass spectrometry has been used to explore the spatial distribution and expression profiles of several molecules with their two-dimensional heterogeneity retained across the tissues. In the present study, using MALDI mass spectrometry based tissue imaging platform, we observed the expression of several proteins across human prostate tissue sections diagnosed with BPH. The proteins were identified and characterized using tissue proteomics approach. We could successfully identify the on-tissue distribution of ribonuclease T2, vinculin, isoform 2 of tropomyosin alpha-3 chain and mitochondrial citrate synthase proteins using this approach. Therefore, imaging mass spectrometry might be a potential tool to complement the findings of histopathology in diagnosis of BPH in human prostate tissues.","Title: Health and Healthcare Variables Associated with Italy's Excess Mortality during the First Wave of the COVID-19 pandemic: An Ecological Study.\nBackgroundHealthcare factors have strongly influenced the propagation of COVID-19. The present study aims to examine whether excess mortality during the first phase of the COVID-19 outbreak in Italy was associated with health, healthcare, demographic, and socioeconomic indicators measured at a provincial level.\n\nMethodsThe present ecological study concerns the raw number of deaths from Jan. 1 to Apr. 30, 2020 and the mean number of deaths in the same months of 2015 to 2019, per province. Information on socioeconomic factors and healthcare settings were extracted from the most recently updated databases on the ISTAT website. Two multilevel, multivariate models were constructed to test whether excess mortality was associated with the indicators across 107 provinces in Italy.\n\nResultsOn linear multilevel, multivariate analysis, AIDS mortality rate (p-value <0.05) correlates positively with excess mortality, while a higher density of General Practitioners (number of GPs per 1,000 population) is associated with lower excess mortality (p-value <0.05). After controlling for the diffusion of COVID-19 in each province, the significance of GP density increases (p-value <0.001) and the rate of hospitalization in long-term care wards is positively associated (p-value <0.05) with excess mortality.\n\nConclusionSome health and healthcare variables are strongly associated with excess mortality caused by COVID-19 in Italy and should be considered to implement mitigation policies and increase healthcare resilience.","Transdiagnostic neurocognitive deficits in patients with type 2 diabetes mellitus, major depressive disorder, bipolar disorder, and schizophrenia: A 1-year follow-up study\nBackgroundImpairments in neurocognition are critical factors in patients with major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ), and also in those with somatic diseases such as type 2 diabetes mellitus (T2DM). Intriguingly, these severe mental illnesses are associated with an increased co-occurrence of diabetes (direct comorbidity). This study sought to investigate the neurocognition and social functioning across T2DM, MDD, BD, and SZ using a transdiagnostic and longitudinal approach.\n\nMethodsA total of 165 subjects, including 30 with SZ, 42 with BD, 35 with MDD, 30 with T2DM, and 28 healthy controls (HC), were assessed twice at a 1-year interval using a comprehensive, integrated test battery on neuropsychological and social functioning.\n\nResultsCommon neurocognitive impairments in somatic and psychiatric disorders were identified, including deficits in short-term memory and cognitive reserve (p < 0.01; {eta}2p = 0.08-0.31). Social functioning impairments were observed in almost all the disorders (p < 0.0001; {eta}2p = 0.29-0.49). Transdiagnostic deficits remained stable across the 1-year follow-up (p < 0.001; {eta}2p = 0.13-0.43) and could accurately differentiate individuals with somatic and psychiatric disorders ({chi}2 = 48.0, p < 0.0001).\n\nConclusionsThis longitudinal study provides evidence of the overlap in neurocognition deficits across somatic and psychiatric diagnostic categories, such as T2DM, MDD, BD, and SZ, which have high comorbidity. This overlap may be a result of shared genetic and environmental etiological factors. The findings further lay forth promising avenues for research on transdiagnostic phenotypes of neurocognition in these disorders, in addition to their biological bases.","Lack of latent tuberculosis screening in HIV patients and delay in Anti-Retroviral Therapy initiation in HIV-TB co-infection: A 11-year study in an intermediate TB-burden country\nObjectivesTuberculosis (TB) is a common infection in HIV patients. Our study aims to determine the prevalence and characteristics of HIV-TB co-infected patients in Singapore, a high-income, intermediate TB-burden country.\n\nMethodsRetrospective data of 11-years was obtained from the National University Hospital (NUH), a quaternary care hospital and the National Centre for Infectious Diseases, the national HIV centre.\n\nResultsFrom December 2005 to December 2016, 48 out of 819 HIV patients and 272 out of 3,196 HIV patients who were managed in NUH and TTSH respectively, were diagnosed with TB. 89.1% (n=285) were males and 2 (0.6%) were screened for latent TB on HIV diagnosis. The median age at TB diagnosis was 47.3 years old (Interquartile range, IQR 41-57). Mean CD4 count at TB diagnosis was 125.0 {+/-} 153.9 cells/mm3. 124 (38.6%) patients had CD4 < 50 cells/mm3. 41.3% (n=132) of patients had HIV diagnosed at least 6 weeks before TB diagnosis, indicating an opportunity to initiate latent TB preventive therapy. 55.0% (n=176) had HIV and TB concomitantly diagnosed within 6 weeks whilst 2.25% (n=7) had TB diagnosed before HIV. Of those HIV-TB co-infected patients with CD4 [≤] 50 cells/mm3, 18 (14.2%) had anti-retroviral therapy (ART) started <2 weeks. TB-related mortality was 5.3% (n=17) and 3.75% (n=12) were lost to follow-up.\n\nConclusionThere is a lack of latent TB screening in HIV patients and a delay in initiation of ART in HIV-TB patients with low CD4 counts in our study. Clinical practices can be further improved for the benefit of outcomes in HIV-TB patients.","Characterization of the gene expression profile in younger and older low-grade glioma patients\nLow-grade gliomas (LGG) are the slowest growing type of brain cancer that often affects young adults. Of all LGG cases, older patients were associated with the poor prognosis compared to younger patients. However, the molecular mechanism underlying this association remains unclear. Here, we compared genes expression profiles between younger (age[≤]50) and older (age > 50) patients from The Cancer Genome Atlas (TCGA) and demonstrate the age-related gene expressions. Pathway and gene set enrichment analysis reveal that differentially expressed genes (DEGs) between tumors of older and younger patients have been involved in cancer-related biological procedures, such as, transcriptional misregulation in cancer, nucleotide synthesis, mTOR, and DNA damage repair signaling. We also demonstrated that older patients have higher expression of Mitosis Kinase Score (MKS) and Tumor Inflammation Signature (TIS) which reflects high cell proliferation and high immune cell activity; respectively. The comprehensive characterization of gene-expression profiles in younger versus older LGG may explain the age-related prognosis and facilitate the development of potential therapeutic biomarkers for LGG.","Effective connectivity during faces processing in major depression: Distinguishing markers of pathology, risk, and resilience\nBackgroundAberrant brain connectivity during emotional processing, especially within the fronto-limbic pathway, is one of the hallmarks of major depressive disorder (MDD). However, a lack of systematic approaches in previous studies made it difficult to determine whether a specific alteration in brain connectivity reflects a cause, correlate, or effect of the disorder. The current study aimed to investigate neural mechanisms that correspond to disease, risk and resilience in major depression during implicit processing of emotion cues.\n\nMethodsForty-eight patients with MDD, 49 first-degree relatives of patients with MDD and 103 healthy controls performed a face-matching task during functional magnetic resonance imaging. We used dynamic causal modelling to estimate task-dependent effective connectivity at the subject level. Parametric empirical Bayes was then performed to quantify group differences in effective connectivity.\n\nResultsDepressive pathology was associated with decreased effective connectivity from the left amygdala and left dorsolateral prefrontal cortex to the right fusiform gyrus, whereas familial risk for depression corresponded to decreased connectivity from the right orbitofrontal cortex to the left insula and from the left orbitofrontal cortex to the right fusiform gyrus. Resilience for depression was related to increased connectivity from the anterior cingulate cortex to the left dorsolateral prefrontal cortex.\n\nConclusionsOur results suggest that the depressive state alters top-down control of higher visual regions during the processing of emotional faces, whereas increased connectivity within the cognitive control network promotes resilience to depression.","Early estimates of SARS-CoV-2 Omicron variant severity based on a matched cohort study, Ontario, Canada\nWhile it is now evident that Omicron is rapidly replacing Delta, largely due to immune escape, it is less clear how the severity of Omicron compares to Delta. In Ontario, we sought to examine hospitalization and death associated with Omicron, as compared to cases infected with Delta. We conducted a matched cohort study, considering time to hospitalization or death as the outcome. Cases were matched on gender, age, vaccination status, health region and onset date. We identified 29,594 Omicron cases that met eligibility criteria, of which 11,622 could be matched with at least one Delta case (N=14,181). There were 59 (0.51%) hospitalizations and 3 (0.03%) deaths among matched Omicron cases, compared to 221 (1.6%) hospitalizations and 17 (0.12%) deaths among matched Delta cases. The risk of hospitalization or death was 65% lower (hazard ratio, HR=0.35, 95%CI: 0.26, 0.46) among Omicron cases compared to Delta cases, while risk of intensive care unit admission or death was 83% lower (HR=0.17, 95%CI: 0.08, 0.37). While severity is likely to be reduced, the absolute number of hospitalizations and impact on the healthcare system may nevertheless be significant due to the increased transmissibility of Omicron.","BinomiRare: A carriers-only test for association of rare genetic variants with a binary outcome for mixed models and any case-control proportion\nWhole genome and exome sequencing studies have become increasingly available and are being used to identify rare genetic variants associated with health and disease outcomes. Investigators routinely use mixed models to account for genetic relatedness or other clustering variables (e.g. family or household) when testing genetic associations. However, no existing tests of the association of a rare variant association with a binary outcome in the presence of correlated data controls the Type 1 error where there are (1) few carriers of the rare allele, (2) a small proportion of cases relative to controls, and (3) covariates to adjust for. Here, we address all three issues in developing the carriers-only test framework for testing rare variant association with a binary trait. In this framework, we estimate outcome probabilities under the null hypothesis, and then use them, within the carriers, to test variant associations. We extend the BinomiRare test, which was previously proposed for independent observations, and develop the Conway-Maxwell-Poisson (CMP) test, and study their properties in simulations. We show that the BinomiRare test always controls the type 1 error, while the CMP test sometimes does not. We then use the BinomiRare test to test the association of rare genetic variants in target genes with small vessel disease stroke, short sleep, and venous thromboembolism, in whole-genome sequence data from the Trans-Omics for Precision Medicine program.","Behavioral Markers for Deficits in Speed of Processing in Cerebrovascular Disease\nObjectiveTo assess overlap and uniqueness of established behavioral markers of speed of processing for different aspects of visual information within a cerebrovascular disease cohort, and to examine the link between these speed of processing markers and functional behavior, specifically walking.\n\nMethodsA cohort of 161 participants with cerebrovascular disease recruited to the Ontario Neurodegenerative Disease Research Initiative (ONDRI) were examined with three types of assessments: neuropsychology, saccadic eye movement and gait. Principal component analysis (PCA) and canonical correlation analysis (CCA) were performed on select variables from these assessments to reveal commonalities and discrepancies among the measures.\n\nResultsPCA analysis revealed different variable patterns between neuropsychology and saccade assessments, with the first component characterized primarily by neuropsychology, and the second and third components more influenced by the saccade assessments. CCA analysis did not reveal association between different types of assessments with the exception of a modest, but significant, positive association between speed of processing measures from the neuropsychological assessments and gait speed.\n\nDiscussionNeuropsychological tests and the pro-saccade task can be used for assessment of speed of processing for two major features of visual information, visual perception vs. spatial location. Despite a general lack of association between different types of assessments, combining gait speed as an important contributor to the models reinforces the idea of the link between speed of processing and complex function such as walking, and provides support for the importance of attending to the potential consequences of changes in speed of processing after neurologic injury.","Effect of Digoxin on Interstage Outcomes following Stage I Palliation for Functionally Univentricular Hearts: A Systematic Review and Meta-Analysis\nObjectivesThe goal of this systematic review and meta-analysis is to investigate the effects of digoxin on outcomes following stage I palliation for functionally univentricular hearts.\n\nData SourcesWe conducted electronic searches of PubMed, Ovid and Cochrane.\n\nStudy SelectionInclusion criteria included publication dates 1970-2018, children with functionally univentricular hearts between stage I and stage II palliation who received digoxin were compared to those who did not.\n\nData ExtractionWe identified 148 unique citations; 5 full-text articles were included in the final review. Data from 4 studies was pooled for meta-analysis.\n\nData SynthesisA total of 4 studies with 1,498 patients were included in the final analyses. Patient enrollment occurred between 2003 and 2013. A majority of patients were born full-term and approximately 25% were diagnosed with a syndrome. The most common cardiac diagnosis was hypoplastic left heart syndrome (70%). The most common initial surgical palliation was the Norwood procedure with a right ventricle to pulmonary artery conduit. The total amount of deaths was 121 (12 digoxin group versus 109 no digoxin group). The interstage mortality was reduced in the digoxin group [OR 0.25(95% CI 0.14 to 0.47)]. There was no statistically significant difference in the presence of arrhythmias or other complications.\n\nConclusionsThis systematic review and meta-analysis suggests that digoxin significantly decreases interstage period mortality with a concurrent significant decrease in weight for age. The odds of arrhythmia or other complications are not significantly different with digoxin based on current data.","A brain structural connectivity biomarker for diagnosis of autism spectrum disorder in early childhood\nObjectiveAutism spectrum disorder (ASD) is associated with altered brain development, but it is unclear which specific structural changes may serve as potential diagnostic markers. This study aimed to identify and model brain-wide differences in structural connectivity using MRI diffusion tensor imaging (DTI) in young ASD and typically developing (TD) children (3{middle dot}5-6 years old).\n\nMethodsNinety-three ASD and 26 TD children were included in a discovery dataset and 12 ASD and 9 TD children from different sites included as independent validation datasets. Brain-wide (294 regions) structural connectivity was measured using DTI (fractional anisotropy, FA) under sedation together with symptom severity and behavioral and cognitive development. A connection matrix was constructed for each child for comparisons between ASD and TD groups. Pattern classification was performed and the resulting model tested on two independent datasets.\n\nResultsThirty-three structural connections showed increased FA in ASD compared to TD children and associated with both symptom severity and general cognitive development. The majority (29/33) involved the frontal lobe and comprised five different networks with functional relevance to default mode, motor control, social recognition, language and reward. Overall, classification accuracy is very high in the discovery dataset 96.77%, and 91{middle dot}67% and 88{middle dot}89% in the two independent validation datasets.\n\nConclusionsIdentified structural connectivity differences primarily involving the frontal cortex can very accurately distinguish individual ASD from TD children and may therefore represent a robust early brain biomarker.","Automation of plate inoculation and reading reduces process time in the clinical microbiology laboratory, compared to a manual workflow\nWe evaluated the benefits of automation for clinical microbiology laboratory workflow and compared the time required for culture inoculation and plate reading between manual processes and BD Kiestra (but Kiestra) automation. Kiestra automation consists of different modules, each of which facilitate different tasks and work together from specimen inoculation to results reporting. We tracked the steps and measured the associated times-to-completion for both manual and automated workflows, including number of plate touches, hands-on-time (HOT), total technologist time (TTT), and walk-away time (WAT). Manual and automated processes both included 90 samples, and a total of 180 agar plates. There were three media quantity protocols used to mimic common laboratory samples: 1) 30 urine specimens on one biplate; 2) 30 urine specimens divided across two plates; and 3) 30 blood or wound specimens divided across three plates; all cultures incubated for a minimum of 18 hours prior to reading or imaging. Automation reduced HOT by 85% and overall plate touches by 88%. Automated inoculation (through implementation of the BD InoqulA module) resulted in a 100% reduction in plate touches and created 81.5-minutes of WAT. Automation of culture reading (through implementation of the BD ReadA incubation/plate imaging module and BD Synapsys Informatics) reduced HOT by 53%. Overall, laboratory automation resulted in shorter TTT and created WAT when compared to manual processes. Automation can facilitate increased processing capacity, more efficient use of the labor force, and reduced time to results in the clinical microbiology laboratory.","Predicting COVID-19 Vaccine Efficacy from Neutralizing Antibody Levels\nRecent studies using data accrued from global SARS-CoV-2 vaccination efforts have demonstrated that breakthrough infections are correlated with levels of neutralizing antibodies. The decrease in neutralizing antibody titers of vaccinated individuals over time, combined with the emergence of more infectious variants of concern has resulted in waning vaccine efficacy against infection and a rise in breakthrough infections. Here we use a combination of neutralizing antibody measurements determined by a high throughput surrogate viral neutralization test (sVNT) together with published data from vaccine clinical trials and comparative plaque reduction neutralization test (PRNT) between SARS-CoV-2 variants to develop a model for vaccine efficacy (VE) against symptomatic infection. Vaccine efficacy estimates using this model show good concordance with real world data from the US and Israel. Our work demonstrates that appropriately calibrated neutralizing antibody measurements determined by high throughput sVNT can be used to provide a semi-quantitative estimate of protection against infection. Given the highly variable antibody levels among the vaccinated population, this model may be of use in identification of individuals with an elevated risk of breakthrough infections.","Similar Rates of AKI during the First Two Waves of COVID-19 in Northern Italy: a single-center study\nIntroductionTwo waves of COVID-19 cases have overwhelmed most European countries during 2020. It is unclear if the incidence of acute kidney injury (AKI) has changed during the COVID-19 outbreaks. This study aims to evaluate the differences in incidence, risk factors and outcome of AKI in patients with SARS-CoV-2 infection during the first and second wave of COVID-19.\n\nMethodWe reviewed the health medical records of 792 consecutive patients with COVID-19 hospitalized at the University Hospital of Modena, Italy, from February 25 to December 14, 2020.\n\nResultsAKI was diagnosed in 122 (15.4%) patients. Incidence of AKI remained steady rate during wave-1 (15.9%) and wave-2 (14.7%) (P=0.89). AKI patients were older (P=<0.001) and had a more severe respiratory impairment (PO2/FO2) (P=[≤]0.001) than their non-AKI counterparts. AKI led to a longer hospital stay (P=0.001), complicated with a higher rate of ICU admission. COVID-19-related AKI was associate with 59.7% of deaths during wave-1 and 70.6% during wave-2. At the end of the period of observation, 24% (wave-1) and 46.7% (wave-2) of survivors were discharged with a not fully recovered kidney function. Risk factors for AKI in patients with COVID-19 were diuretics (HR=5.3; 95%CI, 1.2-23.3; P=0.025) and cardiovascular disease (HR, 2.23; 95%CI, 1.05-5.1; P=0.036).\n\nConclusionThe incidence of AKI (about 15%) remained unchanged during 2020, regardless of the trend of COVID-19. AKI occurred in patients with severe COVID-19 symptoms and was associated with a higher incidence of deaths than non-AKI patients. The risk factors of COVID-19-related AKI were diuretic therapy and cardiovascular disease.","High-Throughput Clinical Trial Emulation with Real World Data and Machine Learning: A Case Study of Drug Repurposing for Alzheimer's Disease\nClinical trial emulation, which is the process of mimicking targeted randomized controlled trials (RCT) with real-world data (RWD), has attracted growing attention and interest in recent years from the pharmaceutical industry. Different from RCTs which have stringent eligibility criteria for recruiting participants, RWD are more representative of real-world patients to whom the drugs will be prescribed. One technical challenge for trial emulation is how to conduct effective confounding control with complex RWD so that the treatment effects can be objectively derived. Recently many approaches, including deep learning algorithms, have been proposed for this goal, but there is still no systematic evaluation and practical guidance on them. In this paper, we emulate 430, 000 trials from two large-scale RWD warehouses, covering both electronic health records (EHR) and general claims, over 170 million patients spanning more than 10 years, aiming to identify new indications of approved drugs for Alzheimers disease (AD). We have investigated the behaviors of multiple different approaches including logistic regression and deep learning models, and propose a new model selection strategy that can significantly improve the performance of confounding balance of the participants in different arms of emulated trials. We demonstrate that regularized logistic regression-based propensity score (PS) model outperforms the deep learning-based PS model and others, which contradicts with our intuitions to a certain extent. Finally, we identified 8 drugs whose original indications are not AD (pantoprazole, gabapentin, acetaminophen, atorvastatin, albuterol, fluticasone, amoxicillin, and omeprazole), hold great potential of being beneficial to AD patients.","One Shot Model For The Prediction of COVID-19 and Lesions Segmentation In Chest CT Scans Through The Affinity Among Lesion Mask Features\nWe introduce a model that segments lesions and predicts COVID-19 from chest CT scans through the derivation of an affinity matrix between lesion masks. The novelty of the methodology is based on the computation of the affinity between the lesion masks features extracted from the image. First, a batch of vectorized lesion masks is constructed. Then, the model learns the parameters of the affinity matrix that captures the relationship between features in each vector. Finally, the affinity is expressed as a single vector of pre-defined length. Without any complicated data manipulation, class balancing tricks, and using only a fraction of the training data, we achieve a 91.74% COVID-19 sensitivity, 85.35% common pneumonia sensitivity, 97.26% true negative rate and 91.94% F1-score. Ablation studies show that the method can quickly generalize to new datasets. All source code, models and results are publicly available on https://github.com/AlexTS1980/COVID-Affinity-Model.","Retinal fundus photographs capture hemoglobin loss after blood donation\nRecently it was shown that blood hemoglobin concentration could be predicted from retinal fundus photographs by deep learning models. However, it is unclear whether the models were quantifying current blood hemoglobin level, or estimating based on subjects pretest probability of having anemia. Here, we conducted an observational study with 14 volunteers who donated blood at an on site blood drive held by the local blood center (ie, at which time approximately 10% of their blood was removed). When the deep learning model was applied to retinal fundus photographs taken before and after blood donation, it detected a decrease in blood hemoglobin concentration within each subject at 2-3 days after donation, suggesting that the model was quantifying subacute hemoglobin changes instead of predicting subjects risk. Additional randomized or controlled studies can further validate this finding.","The common H202D variant in GDF-15 does not affect its bioactivity but can significantly interfere with measurement of its circulating levels\nGenetic variants in proteins can interfere with measurement of their circulating concentrations. Given the growing biomedical importance of GDF-15, we wished to establish whether a common histidine to aspartate variant present in position 6 of the mature GDF-15 protein (H202D variant) interfered with its measurement by two commonly used immunoassays. We first examined the detectability of recombinant monomers, homodimers and heterodimers of GDF-15 by assays and/or reagents used in two widely used immunoassays (Roche Elecsys(R) GDF-15 and the R&D antibody combinations used in their Quantikine(R) and DuoSet(R) ELISAs). The Roche assay detected the H and D containing peptides similarly but the assays based on the R&D reagents consistently underreported concentrations of the D-containing variant peptide. Measurements of plasma concentrations of GDF-15 in genotyped human participants showed that the R&D reagents reported values in heterozygotes were [~]25% lower, and in homozygotes, 50% lower than the Roche assay. We finally studied the activation of the GDF-15 receptor, GFRAL-Ret, in a cell based assay and found that the activities of the HH and DD containing GDF-15 peptide were indistinguishable. These results have implications for the interpretation of genetic epidemiological studies which have used the R&D reagents to measure GDF-15, and for the emerging clinical use of GDF-15 as a diagnostic and prognostic biomarker. We provide correction equations, which may be of utility for the analysis of data generated with the R&D reagents where the genotype of the participants is known.","Longitudinal changes in brain diffusion MRI indices during and after proton beam therapy in a child with pilocytic astrocytoma: a case report\nBackgroundProton beam therapy (PBT) is an effective pediatric brain tumor treatment. However, resulting microstructural changes within and around irradiated tumors are unknown. We retrospectively applied Diffusion-Tensor-Imaging (DTI) and Free-Water-Imaging (FWI) on diffusion-weighted Magnetic Resonance Imaging (dMRI) data to monitor microstructural changes during-PBT and after 8 months, in a pilocytic astrocytoma (PA) and normal-appearing white matter (NAWM).\n\nMethodsWe evaluated conventional MRI and dMRI-derived indices from six MRI sessions in a child with a hypothalamic PA: at baseline (t0), during-PBT (t1-t4), and after 8 months (t5). Tumor voxels were classified as \"solid\" or \"fluid\" based on FWI.\n\nResultsWhile during PBT tumor volume remained stable, dMRI analyses identified two different response patterns: i) an increase in fluid content and diffusivity with anisotropy reductions in solid voxels at t1, followed by ii) smaller variations in fluid content but higher anisotropy in solid voxels at t2-t4. At follow-up (t5), tumor volume, its fluid content, and diffusivity in solid voxels increased. NAWM showed dose-dependent microstructural changes.\n\nConclusionsThe use of dMRI and FWI showed complex dynamic microstructural changes in the irradiated mass during PBT and at follow-up, opening new avenues in our understanding of radiation-induced pathophysiologic mechanisms in tumor and surrounding tissues.","A claims-based score for the prediction of bleeding in a contemporary cohort of patients receiving oral anticoagulation for venous thromboembolism\nBackgroundCurrent scores for bleeding risk assessment in patients with venous thromboembolism (VTE) undergoing oral anticoagulation (OAC) have limited predictive capacity. We developed and internally validated a bleeding prediction model using healthcare claims data.\n\nMethods and ResultsWe selected patients with incident VTE in the 2011-2017 MarketScan databases initiating OAC. Hospitalized bleeding events were identified using validated algorithms in the 180 days after VTE diagnosis. We evaluated demographic factors, comorbidities, and medication use prior to OAC initiation as potential predictors of bleeding using stepwise selection of variables in Cox models ran on 1000 bootstrap samples of the patient population. Variables included in >60% of all models were selected for the final analysis. We internally validated the model using bootstrapping and correcting for optimism. We included 165,434 VTE patients initiating OAC, of which 2,294 had a bleeding event. After undergoing the variable selection process, the final model included 20 terms (15 main effects and 5 interactions). The c-statistic for the final model was 0.68 (95% confidence interval [CI] 0.67-0.69). The internally validated c-statistic corrected for optimism was 0.68 (95%CI 0.67-0.69). For comparison, the c-statistic of the HAS-BLED score in this population was 0.62 (95%CI 0.61-0.63).\n\nConclusionWe have developed a novel model for bleeding prediction in VTE using large healthcare claims databases. Performance of the model was moderately good, highlighting the urgent need to identify better predictors of bleeding to inform treatment decisions.","Rapid, High-Throughput, Cost Effective Whole Genome Sequencing of SARS-CoV-2 Using a Condensed One Hour Library Preparation of the Illumina DNA Prep Kit\nThe ongoing COVID-19 pandemic necessitates cost-effective, high-throughput, and timely genomic sequencing of SARS-CoV-2 viruses for outbreak investigations, identifying variants of concern (VoC), characterizing vaccine breakthrough infections, and public health surveillance. Additionally, the enormous demand of genomic sequencing on supply chains and the resulting shortages of laboratory supplies necessitate the use of low-reagent and low-consumable methods. Here, we report an optimized library preparation method where the same protocol can be used in a STAT scenario, from sample to sequencer in as little as eight hours, and a high-throughput scenario, where one technologist can perform 576 library preparations over the course of one 8-hour shift. This new method uses Freed et al.s 1200 bp primer sets (Biol Methods Protoc 5:bpaa014, 2020, https://doi.org/10.1093/biomethods/bpaa014) and a modified and truncated Illumina DNA Prep workflow (Illumina, CA, USA). Compared to the original, application of this new method in hundreds of clinical specimens demonstrated equivalent results to the full-length DNA Prep workflow at 45% the cost, 15% of consumables required (such as pipet tips), 25% of manual hands-on time, and 15% of on-instrument time if performing on a liquid handler, with no compromise in sequence quality. Results suggest that this new method is a rapid, simple, cost-effective, and high-quality SARS-CoV-2 whole genome sequencing protocol.","The fragility index in randomised controlled trials of interventions for aneurysmal subarachnoid haemorrhage: a systematic review\nBackgroundFragility analysis supplements the p-value and risk of bias assessment in the interpretation of results of randomised controlled trials. In this systematic review we determine the fragility index (FI) and fragility quotient (FQ) of randomized trials in aneurysmal subarachnoid haemorrhage.\n\nMethodsThis is a systematic review registered with PROSPERO (ID: CRD42020173604). Randomised controlled trials in adults with aneurysmal subarachnoid haemorrhage were analysed if they reported a statistically significant primary outcome of mortality, function (e.g. modified Rankin Scale), vasospasm or delayed neurological deterioration.\n\nResultsWe identified 3809 records with 17 randomized trials selected for analysis. The median fragility index was 3 (inter-quartile range 0-5) and the median fragility quotient was 0.012 (IQR 0-0.034). Six of nineteen trial outcomes (31.6%) had an fragility index of 0. In seven trials (36.8%), the number of participants lost to follow-up was greater than or equal to the fragility index. Only 17.6% of trials are at low risk of bias.\n\nConclusionsRandomised controlled trial evidence supporting management of aneurysmal subarachnoid haemorrhage is weaker than indicated by conventional analysis using p-values alone. Increased use of fragility analysis by clinicians and researchers could improve the translation of evidence to practice.","Effects of bariatric surgery on functional connectivity of the reward and default mode network: a pre-registered analysis\nObesity imposes serious health risks and involves alterations in resting-state functional connectivity of brain networks involved in eating behavior. Bariatric surgery is an effective treatment, but its effects on functional connectivity are still under debate. In this pre-registered study, we aimed to determine the effects of bariatric surgery on major resting-state brain networks (reward and default mode network) in a longitudinal controlled design. 33 bariatric surgery patients and 15 obese waiting-list control patients (37 females; aged 44.15 {+/-} 11.86 SD years (range 21-68)) underwent magnetic resonance imaging at baseline, after 6 and 12 months. We conducted a pre-registered whole-brain time-by-group interaction analysis, and a time-by-group interaction analysis on within-network connectivity (https://osf.io/f8tpn/, https://osf.io/59bh7/). In exploratory analyses, we investigated the effects of weight loss and head motion. Bariatric surgery compared to waiting did not significantly affect functional connectivity (FWE-corrected p > 0.05), neither whole-brain nor within-network. In exploratory analyses, surgery-related BMI decrease (FWE-corrected p = 0.041) and higher average head motion (FWE-corrected p = 0.021) resulted in significantly stronger connectivity of the reward network with medial posterior frontal regions. This pre-registered well-controlled study did not support a strong effect of bariatric surgery, compared to waiting, on major resting-state brain networks after 6 months. Exploratory analyses indicated that head motion might have confounded the effects. Data pooling and more rigorous control of within-scanner head motion during data acquisition are needed to substantiate effects of bariatric surgery on brain organization.","Polygenic basis and biomedical consequences of telomere length variation\nTelomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence1. Here we characterize the genetic architecture of naturally-occurring variation in leucocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized participants in UK Biobank2. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 novel). Genetically-determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular, and inflammatory pathologies. Finally, we estimated that at age 40 years, people with >1-SD shorter compared to [≥]1-SD longer LTL than the population mean had 2.5 years lower life expectancy. Overall, we furnish novel insights into the genetic regulation of LTL, reveal LTLs wide-ranging influences on physiological traits, diseases, and longevity, and provide a powerful resource available to the global research community.","Estimating the risk reduction of isolation on COVID-19 non-household transmission and severe/critical illness in non-immune individuals: September to November 2021\nIn the fall 2021, immunity mandates/passports for COVID-19 started to be discussed and implemented globally. In addition to increasing vaccination levels, these interventions isolate non-immune individuals from various settings to reduce non-household transmission and severe/critical illness. This is based on the hypothesis that the non-immune are at high absolute risk of these outcomes. However, these absolute risks were not quantified in the literature such that the absolute risk reductions of isolation on these outcomes remain unknown. This study estimated these absolute risks from September to November 2021 prior to the emergence of Omicron (B.1.1.529) using known data on the risk of infection, transmission in non-household settings, and age-stratified severe/critical illness in non-immune individuals for the Delta (B.1.617.2) variant, focusing on the European Union, United Kingdom, United States, Canada, Australia, and Israel. This allowed us to quantify the absolute risk reductions of isolation on (1) non-household transmission from the non-immune and (2) severe/critical illness amongst the non-immune in these regions during this period. We observed that on any given day the absolute risk reductions of isolation were typically small for transmission in most types of non-household settings and severe/critical illness in most age-groups, especially those aged <40. During a wave or sustained higher infection risks, the risk reductions were modest only for transmission in intimate social gatherings and severe/critical illness in adults aged [≥]50-60. The limitations of this study and the implications for the expected benefits of isolating non-immune individuals on reducing these outcomes are discussed.","Trends in clinical characteristics and associations of severe non-respiratory events related to SARS-CoV-2\nBackgroundThe 2019 novel coronavirus (SARS-CoV-2) is reported to result in both respiratory and non-respiratory severe health outcomes, but quantitative assessment of the risk - while adjusting for underlying risk driven by comorbidities - is not yet established.\n\nMethodsA retrospective observational study using electronic health records of 9,344,021 individuals across the U.S. with at-least 1 year of clinical history and followed up throughout 2020.\n\nResults131,329 individuals were associated with SARS-CoV-2 infection by January 6, 2021 in three distinct surges. While the age and number of preexisting conditions had decreased throughout the pandemic, the characteristics of those who experienced severe health events did not.\n\nDuring the second surge, between June 7 and November 18, 2020, 425,988 individuals in the base cohort were admitted to emergency rooms or hospitals. Among them, 15,486 were detected with SAR-CoV-2 within few days of admission. Significant adjusted odds ratios were observed between SARS-CoV-2 infection and the following severe health events: respiratory (4.38, 95% confidence interval 4.16- 4.62), bacterial pneumonia (3.25, 2.76-3.83), sepsis (1.71, 1.53-1.91), renal (1.69, 1.57-1.83), hematologic/immune (1.32, 1.20-1.45), neurological (1.23, 1.09-1.38).\n\nConclusionsSARS-CoV-2 infection among hospitalized patients is associated with non-negligible increased risk of severe events including multiple non-respiratory ones. These associations, which complement recent studies, are persistent even after accounting for sources of selection and confounding bias, increasing the confidence they are not spurious.","Seroresponse to third doses of SARS-CoV-2 vaccine among patients receiving maintenance dialysis\nGiven the increased morbidity and mortality from COVID-19 among patients undergoing maintenance dialysis, we examined the seroresponse to an additional dose of SARS-CoV-2 mRNA vaccine, using a hypothesized protective anti-spike protein IgG antibody threshold of 7 based on prior work. Among 395 patients, 384 (97%) had seroresponse [≥]7 following administration of the third dose. Among those with suboptimal (peak <7) and minimal (peak <1) seroresponse to an initial mRNA vaccine regimen, the rate of seroresponse [≥]7 following a third dose was 97% (36 of 37) and 64% (14 of 22), respectively. Given ongoing high rates of COVID-19 and rapidly waning immunity after an initial vaccine series, we recommend a third mRNA vaccine dose be standard for all patients receiving maintenance dialysis.","Bayesian approach to comparing the left ventricular volume in myocardial infarction and in normal cases\nIntroductionPost-contrast delayed-enhancement MRI helps to show the extent of myocardial infarction (MI), as well as allowing the morphometric analysis of the heart structure, e.g., left ventricular volume (LVV). Here the author deployed Bayesian implementation of statistical inference to determine the difference between the LVV in MI cases and in normal controls.\n\nMethodsSixty-seven MI patients and thirty-three controls from the EMIDEC dataset challenge were used. These were acquired at the University Hospital of Dijon (France). A cardiologist with 10 years of experience in cardiology and MRI and a biophysicist with 20 years of experience of cardiovascular MRI supervised the acquisition and annotated the images. ITK-Snap was used to extract the LVV and Bayesian inference were used to investigate the data.\n\nResultsPatients with MI were younger than the controls (58.3 {+/-} 11.5 vs. 66.5 {+/-} 12.9 years; BF10 = 17.9). With age taken into consideration, the patients showed larger LVV relative to the controls (128.1 {+/-} 46.3 vs. 83.4 {+/-} 24.4 cm3; post-hoc BF10 = 12663.8).\n\nSummaryUsing Bayesian approach, we can conclude decisively that there is volumetric difference or remodeling in individuals with MI.","Treatment of Early Hypertension among Persons Living with HIV in Haiti: protocol for a randomized controlled trial\nBackgroundPeople living with HIV (PLWH) are at increased risk of cardiovascular disease (CVD) and death, with greater burdens of both HIV and CVD in lower-middle income countries. Treating prehypertension in PLWH may reduce progression to hypertension, CVD risk and potentially mortality. However, no trial has evaluated earlier blood pressure treatment for PLWH. We propose a randomized controlled trial to assess the feasibility, benefits, and risks of initiating antihypertensive treatment among PLWH with prehypertension, comparing prehypertension treatment to standard of care following current WHO guidelines.\n\nMethodsA total of 250 adults 18-65 years and living with HIV (PLWH) with viral suppression in the past 12 months, who have prehypertension will be randomized to prehypertension treatment versus standard of care. Prehypertension is defined as having a systolic blood pressure (SBP) 120-139 mmHg or diastolic blood pressure (DBP) 80-89 mmHg. In the prehypertension treatment arm, participants will initiate amlodipine 5 mg daily immediately. In the standard of care arm, participants will initiate amlodipine only if they develop hypertension defined as SBP [≥] 140 mmHg or DBP [≥] 90 mmHg. The primary outcome is the difference in mean change of SBP from enrollment to 12 months. Secondary outcomes include feasibility, acceptability, adverse effects, HIV viral suppression, and medication adherence. Qualitative in-depth interviews with providers and participants will explore attitudes about initiating amlodipine, satisfaction, perceived CVD risk, and implementation challenges.\n\nDiscussionPLWH have a higher CVD risk and may benefit from a lower BP threshold for initiation of antihypertensive treatment.\n\nTrial registrationClinicaltrials.gov registration number NCT04692467, registration date December 15, 2020, protocol ID 20-03021735.","Building Prediction Models for 30-Day Readmissions Among ICU Patients Using Both Structured and Unstructured Data in Electronic Health Records\nICU readmissions are associated with poor outcomes for patients and poor performance of hospitals. Patients who are readmitted have an increased risk of in-hospital deaths; hospitals with a higher readmission rate have a reduced profitability, due to an increase in cost and reduced payments from Medicare and Medicaid programs. Predicting a patients likelihood of being readmitted to the ICU can help reduce early discharges, the risk of in-hospital deaths, and help increase profitability. In this study, we built and evaluated multiple machine learning models to predict 30-day readmission rates of ICU patients in the MIMIC-III database. We used both the structured data including demographics, laboratory tests, comorbidities, and unstructured discharge summaries as the predictors and evaluated different combinations of features. The best performing model in this study Logistic Regression achieved an AUROC of 75.7%. This study shows the potential of leveraging machine learning and deep learning for predicting ICU readmissions.","Development and Pilot Testing of a Five Item Traumatic Stress Screener for Use with Adolescents in Pediatric Primary Care\nObjectivesTo develop and assess the psychometric properties of the Adolescent Primary Care Traumatic Stress Screen (APCTSS), a five-item yes/no screener for PTSD symptoms in adolescents, and the first developed for pediatric primary care.\n\nStudy DesignThe APCTSS was developed by combining and adapting the UCLA PTSD Reaction Index for DSM-5 with the adult Primary Care PTSD Screen for DSM-5. Adolescent medicine patients were universally approached during clinic visits. With a response rate of 83.6%, 178 patients aged 13-22 (M=18.4, SD=2.3), 64.4% female; 62.1% Black or African-American and 20.7% Hispanic/Latinx, were enrolled. Patients completed APCTSS, Patient Health Questionnaire for Adolescents (PHQ-A), and Child PTSD Symptom Scale for DSM-5 Interview (CPSS-5-I), and 61 completed the Traumatic Events Screening Inventory for Children (TESI-C).\n\nResults56.7% reported a criterion A trauma, 30.1% met criteria for PTSD, 7.4% met criteria for subsyndromal PTSD, and 19.0% for post-event impairing symptoms. Scores [≥] 2 on the APCTSS optimized sensitivity (.79; 95% CI=.66 to .89) and specificity (.68; 95% CI=.55 to .76) for PTSD, with an area under the curve (AUC) of .79. Sensitivity (.86; 95% CI=.65 to .90), specificity (.77; 95% CI=.60 to .90), and AUC (.86) were even stronger when the TESI-C was used to assess criterion A for PTSD diagnosis. Over half (56.0%) of patients who screened positive on the APCTSS were missed by the PHQ-A.\n\nConclusionsThe APCTSS shows promise as an internally consistent, valid, and effective tool for identifying adolescents at high risk of PTSD and traumatic stress.","RESISTANCE CONFERRING MUTATIONS IN SARS-CoV-2 DELTA FOLLOWING SOTROVIMAB INFUSION\nSeveral Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) neutralising monoclonal antibodies (mAbs) have received emergency use authorisation by regulatory agencies for treatment and prevention of Coronavirus Disease 2019 (COVID-19), including in patients at risk for progression to severe disease. Here we report the persistence of viable SARS-CoV-2 in patients treated with sotrovimab and the rapid development of spike gene mutations that have been shown to confer high level resistance to sotrovimab in vitro. We highlight the need for SARS-CoV-2 genomic surveillance in at risk individuals to inform stewardship of mAbs use and prevent potential treatment failures.","Assessing the performance of a serological point-of-care test in measuring detectable antibodies against SARS-CoV-2\nObjectiveTo investigate the performance of a rapid point-of-care antibody test, the BioMedomics COVID-19 IgM/IgG Rapid Test, in comparison with a high-quality, validated, laboratory-based platform, the Roche Elecsys Anti-SARS-CoV-2 assay.\n\nMethodsSerological testing was conducted on 708 individuals. Concordance metrics were estimated. Logistic regression was used to assess associations with seropositivity.\n\nResultsSARS-CoV-2 seroprevalence was 63.4% (449/708; 95% CI 59.8%-66.9%) using the BioMedomics assay and 71.9% (509/708; 95% CI 68.5%-75.1%) using the Elecsys assay. There were 62 discordant results between the two assays. One specimen was seropositive in the BioMedomics assay, but seronegative in the Elecsys assay, while 61 specimens were seropositive in the Elecsys assay, but seronegative in the BioMedomics assay. Positive, negative, and overall percent agreements between the two assays were 88.0% (95% CI 84.9%-90.6%), 99.5% (95% CI 97.2%-99.9%), and 91.2% (95% CI 88.9%-93.1%), respectively, with a Cohens kappa of 0.80 (95% CI 0.77-0.83), indicating excellent agreement. Excluding specimens with lower antibody titers, the agreement improved with positive, negative, and overall percent concordance of 91.2% (95% CI 88.2%-93.6%), 99.5% (95% CI 97.2%-99.9%), and 93.9% (95% CI 91.7%-95.5%), respectively, and a Cohens kappa of 0.87 (95% CI 0.84-0.89). Logistic regression confirmed better agreement with higher antibody titers.\n\nConclusionThe BioMedomics COVID-19 IgM/IgG Rapid Test demonstrated excellent performance in measuring detectable antibodies against SARS-CoV-2, supporting the utility of such rapid point-of-care serological testing to guide the public health responses and possible vaccine prioritization.","A comprehensive analysis of outcomes between COVID-19 patients with an elevated serum lipase compared to those with pancreatitis.\nBackground and AimsCOVID-19 patients may have asymptomatic hyperlipasemia without abdominal imaging findings or abdominal pain. In addition, primary and secondary pancreatitis have been described in COVID-19 patients. There is limited information on how the groups compare in outcomes. The aim is to compare outcomes among these groups.\n\nMethodsThis is a retrospective study from 12 hospitals within one healthcare system examining outcomes between hospitalized COVID-19 patients with a lipase <3x upper limit of normal (ULN), asymptomatic hyperlipasemia (>3x ULN), secondary pancreatitis (typical respiratory COVID-19 symptoms and found to have pancreatitis), and primary pancreatitis (presenting with pancreatitis).\n\nResultsOf 11,883 patients admitted with COVID-19, 1,560 patients were included: 1,155 COVID-19 patients with a normal serum lipase (control group), 270 with an elevated lipase <3x ULN, 46 patients with asymptomatic hyperlipasemia with a lipase 3xULN, 57 patients with secondary pancreatitis, and 32 patients with primary pancreatitis. On adjusted multivariate analysis, the elevated lipase <3x ULN and asymptomatic hyperlipasemia groups had worse outcomes. The mortality was OR1.6 (95% CI 1.2-2.2) and 1.1 (95% CI 0.5-2.3), respectively. The need for mechanical ventilation was OR 2.8 (95% CI 1.2-2.1) and 2.8 (95% CI 1.5-5.2), respectively. Longer length of stay was OR 1.5 (95%CI 1.1-2.0) and 3.16 (95%CI 1.5-6.5), respectively.\n\nConclusionCOVID-19 patients with an elevated lipase< 3x ULN and asymptomatic hyperlipasemia have generally worse outcomes than those with pancreatitis. This could be attributed to extrapancreatic causes (liver failure, renal failure, enteritis, etc), which may signify a more severe course of clinical disease.","Tele-Rapid Response Team (Tele-RRT): Implementation and outcomes of Safety Network System. Before and after cohort study.\nBackgroundRapid Response Teams were developed to provide interventions for deteriorating patients. Their activation depends on timely detection of deterioration. Automated calculation of warning signs may lead to early recognition, and improvement of RRT effectiveness.\n\nMethodThis was a \"Before\" and \"After\" study, in the \"Before\" period ward nurses activated RRT after manually recording vital signs and calculating warning scores. In the \"After\" period, vital signs and warning calculations were automatically relayed to RRT through a wireless monitoring network.\n\nResultsThe \"After\" group had significantly lower incidence and rates of cardiopulmonary resuscitation compared to the \"Before\" group (2.3 / 1000 inpatient days versus 3.8 / 1000 inpatient days respectively, p = 0.01), the \"Before\" group had a significantly higher hospital length of stay, and significantly fewer visits by the RRT. In multivariable logistic regression model, being in the \"After\" group decreases odds of CPR by 30% (OR = 0.7 [95% CI: 0.44 - 0.97]; p = 0.02). There was no difference between groups in unplanned ICU admission or readmission.\n\nConclusionAutomated activation of the RRT resulted in significant reduction of CPR events and rate, reduction of hospital length of stay, and increase in the number of visits by the RRT. There was no difference in unplanned ICU admission or readmission."],"string":"[\n \"Mortality among Care Home Residents in England during the first and second waves of the COVID-19 pandemic: an analysis of 4.3 million adults over the age of 65\\nBackgroundResidents in care homes have been severely impacted by the COVID-19 pandemic. We describe trends in risk of mortality among care home residents compared to residents in private homes in England.\\n\\nMethodsOn behalf of NHS England, we used OpenSAFELY-TPP, an analytics platform running across the linked electronic health records of approximately a third of the English population, to calculate monthly age-standardised risks of death due to all causes and COVID-19 among adults aged >=65 years between 1/2/2019 and 31/03/2021. Care home residents were identified using linkage to the Care and Quality Commission.\\n\\nFindingsWe included 4,329,078 people aged 65 years or older on the 1st of February 2019, 2.2% of whom were classified as residing in a care or nursing home. Age-standardised mortality risks were approximately 10 times higher among care home residents compared to non-residents in February 2019 residents (CMF = 10.59, 95%CI = 9.51, 11.81 among women, CMF = 10.82, 95%CI = 9.89, 11.84 among men). This increased to more than 17 times in April 2020 (CMF = 17.52, 95%CI = 16.38, 18.74 among women, CMF = 18.12, 95%CI = 17.17 - 19.12 among men) before returning to pre-pandemic levels in June 2020. CMFs did not increase during the second wave, despite a rise in the absolute age-standardised COVID-19 mortality risks.\\n\\nInterpretationThe first COVID-19 wave had a disproportionate impact on care home residents in England compared to older private home residents. A degree of immunity, improved protective measures or changes in the underlying frailty of the populations may explain the lack of an increase in the relative mortality risks during the second wave. The care home population should be prioritised for measures aimed at controlling the spread of COVID-19.\\n\\nFundingMedical Research Council MR/V015737/1\",\n \"Use of multiple Polygenic Risk Scores for distinguishing Schizophrenia-spectrum disorder and Affective psychosis categories; the EUGEI study\\nSchizophrenia (SZ), Bipolar Disorder (BD) and Depression (D) run in families. This susceptibility is partly due to hundreds or thousands of common genetic variants, each conferring a fractional risk. The cumulative effects of the associated variants can be summarised as a polygenic risk score (PRS). Using data from the EUGEI case-control study, we aimed to test whether PRSs for three major psychiatric disorders (SZ, BD, D) and for intelligent quotient (IQ) as a neurodevelopmental proxy, can discriminate affective psychosis (AP) from schizophrenia-spectrum disorder (SSD). Participants (573 cases, 1005 controls) of european ancestry from 17 sites as part of the EUGEI study were successfully genotyped following standard quality control procedures. Using standardised PRS for SZ, BD, D, and IQ built from the latest available summary statistics, we performed simple or multinomial logistic regression models adjusted for 10 principal components for the different clinical comparisons. In case-control comparisons PRS-SZ, PRS-BD and PRS-D distributed differentially across psychotic subcategories. In case-case comparison, both PRS-SZ (OR=0.7, 95 %CI 0.53-0.92) and PRS-D (OR=1.29, 95%CI 1.05-1.6) differentiated global AP from SSD; and within AP categories, only PRS-SZ differentiated BD from psychotic depression (OR=2.38, 95%CI 1.32-4.29). Combining PRS for severe psychiatric disorders in prediction models for psychosis phenotypes can increase discriminative ability and improve our understanding of these phenotypes. Our results point towards potential usefulness of PRSs for diagnostic prediction in specific populations such as high-risk or early psychosis phases.\",\n \"Reduction in left frontal alpha oscillations by transcranial alternating current stimulation in major depressive disorder is context-dependent in a randomized-clinical trial\\nBackgroundLeft frontal alpha oscillations are associated with decreased approach motivation and have been proposed as a target for non-invasive brain stimulation for the treatment of depression and anhedonia. Indeed, transcranial alternating current stimulation (tACS) at the alpha frequency reduced left frontal alpha power and was associated with a higher response rate than placebo stimulation in patients with major depressive disorder (MDD) in a recent double-blind placebo controlled clinical trial.\\n\\nMethodsIn this current study, we aimed to replicate such successful target engagement by delineating the effects of a single session of bifrontal tACS at the individualized alpha frequency (IAF-tACS) on alpha oscillations in patients with MDD. Electrical brain activity was recorded during rest and while viewing emotionally-salient images before and after stimulation to investigate if the modulation of alpha oscillation by tACS exhibited specificity with regards to valence.\\n\\nResultsIn agreement with the previous study of tACS in MDD, we found that a single session of bifrontal IAF-tACS reduced left frontal alpha power during the resting state when compared to placebo. Furthermore, the reduction of left frontal alpha oscillation by tACS was specific for stimuli with positive valence. In contrast, these effects on left frontal alpha power were not found in healthy control participants.\\n\\nConclusionTogether these results support an important role of tACS in reducing left frontal alpha oscillations as a future treatment for MDD.\\n\\nNational Clinical TrialNCT03449979, \\\"Single Session of tACS in a Depressive Episode (SSDE)\\\" https://www.clinicaltrials.gov/ct2/show/NCT03449979\",\n \"Predictive Machine Learning for Personalised Medicine in Major Depressive Disorder\\nDepression is a common psychiatric disorder with substantial recurrence risk. Accurate prediction from easily collected data would aid in diagnosis, treatment and prevention. We used machine learning in the Generation Scotland cohort to predict lifetime risk of depression and, among cases, recurrent depression. Rank aggregation was used to combine results across ten different algorithms and identify highly predictive variables. The model containing all but the cardiometabolic predictors had the highest predictive ability on independent data. Rank aggregation produced a reduced set of predictors without decreasing predictive performance (lifetime: 20 out of 154 predictors and Receiver Operating Characteristic area under the curve (AUC)=0{middle dot}84, recurrent: 10 out of 180 predictors and AUC=0{middle dot}76). Here we develop a pipeline which leads to a small set of highly predictive variables. This information can be easily collected with a smartphone application to help diagnosis and treatment, while longitudinal tracking may help patients in self-management.\\n\\nSignificanceDepression is the most common psychiatric disorder and a leading cause of disability worldwide. Patients are often diagnosed and treated by non-specialist clinicians who have limited time available to assess them. We present a novel methodology which allowed us to identify a small set of highly predictive variables for a diagnosis of depression, or recurrent depression in patients. This information can easily be collected using a tablet or smartphone application in the clinic to aid diagnosis.\",\n \"Prediction of gestational diabetes mellitus using early oral glucose tolerance test\\nIntroductionGestational Diabetes Mellitus (GDM) is defined as diabetes first detected at the second or third trimester of pregnancy, excluding preexisting diabetes. We aimed to build a predictive model of GDM using booking oral glucose tolerance test (OGTT) values.\\n\\nMaterials and MethodsSeventy-five healthy mothers who underwent 75g OGTT at 12-14 weeks and at 24-28 weeks were recruited. GDM was diagnosed at 28 weeks by cutoffs proposed by the Hyperglycemia and Adverse Pregnancy Outcomes study.\\n\\nSensitivities and specificities for diagnosing GDM using different cut-offs for each of the three booking OGTT variables were measured. A series of multivariate binary logistic regression models were fitted using different combinations of the three booking OGTT variables. In-sample sensitivities and specificities for different cutoff probabilities of the models were calculated and Receiver Operating Characteristic (ROC) curves were constructed. The Area Under the Curve (AUC) of the ROC curve and the best cutoff value which maximized the sum of sensitivity and specificity of each model were computed.\\n\\nResultsAUC of ROC curves for isolated fasting, 1 hour and 2 hour booking OGTT values for the prediction of GDM were 69.8%, 67.1% and 61.0% respectively. However, the logistic regression model with fasting and 1 hour booking OGTT values as predictors out-performed all other models with an AUC of 76.3%, in-sample sensitivity of 87.5% and a negative predictive value of 95.12%.\\n\\nConclusionsThe future occurrence of GDM can be predicted utilizing a logistic model with fasting and 1 hour booking OGTT variables, which enables early identification and intervention.\",\n \"Consistency of performance of adverse outcome prediction models for hospitalized COVID-19 patients\\nBackgroundWe previously reported and validated a risk prediction tool based on COVID-19 hospitalizations prior to June 2020. Here, we report performance of that model on subsequent data from 6 hospitals and among individual patient subgroups.\\n\\nMethodWe included individuals age 18 or older hospitalized at one of 2 academic medical centers and 4 community hospitals from 6/7/2020 through 1/22/2021 with positive PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within 5 days of admission. Coefficients from our previously reported least absolute shrinkage and selection operator (Lasso) risk models were applied to estimate probability of a mortality, as well as a composite severe illness outcome, including admission to the ICU, mechanical ventilation or mortality.\\n\\nResultsOverall model performance for mortality included AUC of 0.83 (95% CI:0.80-0.87) for mortality, with a PPV 0.55 and NPV of 0.95 when using a cutoff corresponding to the highest 20% of predicted risk derived in the training set. For all adverse outcomes, AUC was 0.79 (95% CI:0.75-0.81) and PPV 0.48 and NPV 0.98 in the top 20% risk group. Model discrimination was generally similar between genders and race/ethnicity groups, but markedly poorer for younger age groups.\\n\\nConclusionAlthough the population of individuals hospitalized for COVID-19 has shifted and outcomes have improved overall, prediction models derived earlier in the pandemic may maintain utility.\",\n \"Analysis of cutoff point estimation for determining seropositivity in the context of SARS-CoV-2 infections\\nIn this work will apply mixture models based on distributions from the SMSN family to antibody data against four SARS-CoV-2 virus antigens. Furthermore, since the true infection status of individuals is known a priori, performance measures will be calculated for the methods proposed for cutoff point estimation such as sensitivity, specificity and accuracy. The results of a simulation study will also be presented.\",\n \"Experiences of staff providing specialist palliative care during COVID-19: A multiple qualitative case study.\\nObjectivesTo explore the experiences of, and impact on, staff working in palliative care during the COVID-19 pandemic.\\n\\nDesignQualitative multiple case study using semi-structured interviews between November 2020 and April 2021 as part of the CovPall study. Data were analysed using thematic framework analysis.\\n\\nSettingOrganisations providing specialist palliative services in any setting.\\n\\nParticipantsStaff working in specialist palliative care, purposefully sampled by the criteria of role, care setting and COVID-19 experience.\\n\\nMain outcome measuresExperiences of working in palliative care during the COVID-19 pandemic.\\n\\nResultsFive cases and 24 participants were recruited (n=12 nurses, 4 clinical managers, 4 doctors, 2 senior managers, 1 healthcare assistant, 1 allied healthcare professional). Central themes demonstrate how infection control constraints prohibited and diluted participants ability to provide care that reflected their core values, resulting in experiences of moral distress. Despite organisational, team, and individual support strategies, continually managing these constraints led to a crescendo effect in which the impacts of moral distress accumulated over time, sometimes leading to burnout. Solidarity with colleagues and making a valued contribution provided moral comfort for some.\\n\\nConclusionsThis study provides a unique insight into why and how healthcare staff have experienced moral distress during the pandemic, and how organisations have responded. Despite their experience of dealing with death and dying, the mental health and well-being of palliative care staff was affected by the pandemic. Organisational, structural, and policy changes are urgently required to mitigate and manage these impacts.\",\n \"Evaluation of determinants of the serological response to the split-inactivated influenza vaccine\\nThe seasonal influenza vaccine is only effective in half of the vaccinated population. To identify determinants of vaccine efficacy, we used data from >1,300 vaccination events to predict the response to vaccination measured as seroconversion as well as hemagglutination inhibition (HAI) levels one year after. We evaluated the predictive capabilities of age, body mass index (BMI), sex, race, comorbidities, prevaccination history, and baseline HAI titers, as well as vaccination month and vaccine dose in multiple linear regression models. The models predicted the categorical response for >75% of the cases in all subsets with one exception. Prior vaccination, baseline titer level, and age were the strongest determinants on seroconversion, all of which had negative effects. Further, we identified a gender effect in older participants, and an effect of vaccination month. BMI played a surprisingly small role, likely due to its correlation with age. Comorbidities, vaccine dose, and race had negligible effects. Our models can generate a new seroconversion score that is corrected for the impact of these factors which can facilitate future biomarker identification.\",\n \"Modelling the effectiveness and social costs of daily lateral flow antigen tests versus quarantine in preventing onward transmission of COVID-19 from traced contacts\\nQuarantining close contacts of individuals infected with SARS-CoV-2 for 10 to 14 days is a key strategy in reducing transmission. However, quarantine requirements are often unpopular, with low adherence, especially when a large fraction of the population has been vaccinated. Daily contact testing (DCT), in which contacts are required to isolate only if they test positive, is an alternative to quarantine for mitigating the risk of transmission from traced contacts. In this study, we developed an integrated model of COVID-19 transmission dynamics and compared the strategies of quarantine and DCT with regard to reduction in transmission and social/economic costs (days of quarantine/self-isolation). Specifically, we compared 10-day quarantine to 7 days of self-testing using rapid lateral flow antigen tests, starting 3 days after exposure to a case. We modelled both incomplete adherence to quarantine and incomplete adherence to DCT. We found that DCT reduces transmission from contacts with similar effectiveness, at much lower social/economic costs, especially for highly vaccinated populations. The findings were robust across a spectrum of scenarios with varying assumptions on the speed of contact tracing, sensitivity of lateral flow antigen tests, adherence to quarantine and uptake of testing. Daily tests would also allow rapid initiation of a new round of tracing from infected contacts.\",\n \"Tracking mutational semantics of SARS-CoV-2 genomes\\nGenomes have an inherent context dictated by the order in which the nucleotides and higher order genomic elements are arranged in the DNA/RNA. Learning this context is a daunting task, governed by the combinatorial complexity of interactions possible between ordered elements of genomes. Can natural language processing be employed on these orderly, complex and also evolving datatypes (genomic sequences) to reveal the latent patterns or context of genomic elements (e.g Mutations)? Here we present an approach to understand the mutational landscape of Covid-19 by treating the temporally changing (continuously mutating) SARS-CoV-2 genomes as documents. We demonstrate how the analogous interpretation of evolving genomes to temporal literature corpora provides an opportunity to use dynamic topic modeling (DTM) and temporal Word2Vec models to delineate mutation signatures corresponding to different Variants-of-Concerns and tracking the semantic drift of Mutations-of-Concern (MoC). We identified and studied characteristic mutations affiliated to Covid-infection severity and tracked their relationship with MoCs. Our ground work on utility of such temporal NLP models in genomics could supplement ongoing efforts in not only understanding the Covid pandemic but also provide alternative strategies in studying dynamic phenomenon in biological sciences through data science (especially NLP, AI/ML).\",\n \"Grey and white matter volume changes after preterm birth: A meta-analytic approach\\nObjectiveLower brain grey matter volumes (GMV) and white matter volumes (WMV) have been reported at single time points in preterm-born individuals. While large MRI studies in the normative population have led to a better understanding of brain growth trajectories across the lifespan, such results remain elusive for preterm-born individuals since large, aggregated datasets of preterm-born individuals do not exist. To close this gap, we investigated GMV and WMV in preterm-born individuals as reported in the literature and contrasted it against individual volumetric data and trajectories from the general population.\\n\\nStudy designSystematic database search of PubMed and Web of Science in March 2021 and extraction of outcome measures by two independent reviewers. Individual data on full-term controls was extracted from freely available databases. Mean GMV, WMV, total intracranial volume (TIV), and mean age at scan were the main outcome measures.\\n\\nResultsOf 532 identified records, nine studies were included with 538 preterm-born subjects between 1.1 and 28.5 years of age. Reference data was generated from 880 full-term controls between 1 and 30 years of age. GMV was consistently lower in preterm-born individuals from infancy to early adulthood with no evidence for catch-up growth. While GMV changes followed a similar trajectory as full-term controls, WMV was particularly low in adolescence after preterm birth.\\n\\nConclusionsResults demonstrate altered brain volumes after premature birth across the first half of lifespan with particularly low white matter volumes in adolescence. Future studies should address this issue in large aggregated datasets of preterm-born individuals.\",\n \"External Validation Of A Novel Signature Of Illness In Continuous Cardiorespiratory Monitoring To Detect Early Respiratory Deterioration Of ICU Patients\\nThe goal of predictive analytics monitoring is the early detection of patients at high risk of subacute potentially catastrophic illnesses. An excellent example of a targeted illness is respiratory failure leading to urgent unplanned intubation, where early detection might lead to interventions that improve patient outcomes. Previously, we identified signatures of this illness in the continuous cardiorespiratory monitoring data of Intensive Care Unit patients and devised algorithms to identify patients at rising risk. Here, we externally validated three logistic regression models to estimate the risk of emergency intubation developed in Medical and Surgical ICUs at the University of Virginia. We calculated the model outputs for more than 8000 patients in the University of California - San Francisco ICUs, 240 of whom underwent emergency intubation as determined by individual chart review. We found that the AUC of the models exceeded 0.75 in this external population, and that the risk rose appreciably over the 12 hours before the event. We conclude that there are generalizable physiological signatures of impending respiratory failure in the continuous cardiorespiratory monitoring data.\",\n \"WHAT ABOUT USING SNIFFIN STICKS 12 SCREENING TEST TO IDENTIFY POST-COVID-19 OLFACTORY DISORDERS?\\nBackgroundOlfactory impairment is a major sequela of SARS-CoV-2 infection and has a negative impact on daily life quality. Olfactory loss can be assessed in many ways but seems to be little realized in a daily clinical practice. The sniffin Sticks test - 12 items (SST-12) can be used in quick olfactory disorders screening. Its use in a post-covid19 situation was the main objective of this work.\\n\\nMethodologyConsecutive patients consulting to the ENT department with post-Covid-19 olfactory loss were included. The clinical examination included an analog scale for the self-assessment of olfactory recovery (VAS), self-reported salt and sugar intake, a nasofibroscopy, the complete Sniffin Stick Test (SST) and the SST-12.\\n\\nResultsAmong the 54 patients included, based on the SST-12, 14,8% (n=8) of the patients could be classified as normosmic (SST-12[≥]11), 48,1% (n=26) as hyposmic (6< SST-12<10) and 37% (n=20) as functional anosmic (SST-12[≤]6). We report excellent and significant correlations between SST-12 and SST or VAS assessments. Salt and Sugar increased intake seems significantly related to SST-12 results.\\n\\nConclusionsSST-12 is a reliable way to screen post-COVID-19 olfactory disorders could be used in a daily clinical practice and might be used to prevent bad diet habits and so cardiovascular risk.\",\n \"Analysis of 200,000 exome-sequenced UK Biobank subjects implicates genes involved in increased and decreased risk of hypertension\\nBackgroundPrevious analyses have identified common variants along with some specific genes and rare variants which are associated with risk of hypertension but much remains to be discovered.\\n\\nMethods and ResultsExome-sequenced UK Biobank participants were phenotyped based on having a diagnosis of hypertension or taking anti-hypertensive medication to produce a sample of 66,123 cases and 134,504 controls. Variants with minor allele frequency (MAF) < 0.01 were subjected to a gene-wise weighted burden analysis, with higher weights assigned to variants which are rarer and/or predicted to have more severe effects. Of 20,384 genes analysed, two genes were exome-wide significant, DNMT3A and FES. Also strongly implicated were GUCY1A1 and GUCY1B1, which code for the subunits of soluble guanylate cyclase. There was further support for the previously reported effects of variants in NPR1 and protective effects of variants in DBH. An inframe deletion in CACNA1D with MAF = 0.005, rs72556363, is associated with modestly increased risk of hypertension. Other biologically plausible genes highlighted consist of CSK, AGTR1, ZYX and PREP. All variants implicated were rare and cumulatively they are not predicted to make a large contribution to the population risk of hypertension.\\n\\nConclusionsThis approach confirms and clarifies previously reported findings and also offers novel insights into biological processes influencing hypertension risk, potentially facilitating the development of improved therapeutic interventions. This research has been conducted using the UK Biobank Resource.\",\n \"Rapid and Sensitive Detection of SARS-CoV-2 Infection Using Quantitative Peptide Enrichment LC-MS Analysis\\nReliable, robust, large-scale molecular testing for SARS-CoV-2 is essential for monitoring the ongoing Covid-19 pandemic. We have developed a scalable analytical approach to detect viral proteins based on peptide immunoaffinity enrichment combined with liquid chromatography - mass spectrometry (LC-MS). This is a multiplexed strategy, based on targeted proteomics analysis and read-out by LC-MS, capable of precisely quantifying and confirming the presence of SARS-CoV-2 in PBS swab media from combined throat/nasopharynx/saliva samples.\\n\\nThe results reveal that the levels of SARS-CoV-2 measured by LC-MS correlate well with their corresponding RT-PCR readout (r=0.79). The analytical workflow shows similar turnaround times as regular RT-PCR instrumentation with a quantitative readout of viral proteins corresponding to cycle thresholds (Ct) equivalents ranging from 21 to 34. Using RT-PCR as a reference, we demonstrate that the LC-MS-based method has 100% negative percent agreement (estimated specificity) and 95% positive percent agreement (estimated sensitivity) when analyzing clinical samples collected from asymptomatic individuals with a Ct within the limit of detection of the mass spectrometer (Ct [≤]30). These results suggest that a scalable analytical method based on LC-MS has a place in future pandemic preparedness centers to complement current virus detection technologies.\",\n \"Clinical features of UK Biobank subjects carrying protein truncating variants in genes implicated in schizophrenia pathogenesis\\nThe SCHEMA consortium has identified ten genes in which protein truncating variants (PTVs) confer substantial risk of schizophrenia. Exome-sequenced participants in the UK Biobank who carried PTVs in these genes were studied to determine to what extent they demonstrated features of schizophrenia or had neuropsychiatric impairment. Following automated quality control and visual inspection of reads, 251 subjects were identified as having well-supported PTVs in one of these genes. The frequency of PTVs in CACNA1G was higher than had been observed in SCHEMA cases, casting doubt on its role in schizophrenia pathogenesis, but otherwise rates were similar to those observed in SCHEMA controls. Numbers were too small to allow formal statistical analysis but in general carriers of PTVs did not appear to have high rates of psychiatric illness or reduced educational or occupational functioning. One subject with a PTV in SETD1A had a diagnosis of schizophrenia. one with a PTV in HERC1 had psychotic depression and two subjects seemed to have developmental disorders, one with a PTV in GRIN2A and one with a PTV in RBCC1. There seemed to be somewhat increased rates of affective disorders among carriers of PTVs in HERC1 and RB1CC1. Carriers of PTVs did not appear to have subclinical manifestations of schizophrenia. Although PTVs in these genes can substantially increase schizophrenia risk, their effect seems to be dichotomous and most carriers appear psychiatrically well.\\n\\nThis research has been conducted using the UK Biobank Resource.\",\n \"Gout, rheumatoid arthritis and the risk of death from COVID-19: an analysis of the UK Biobank\\nObjectivesTo assess whether gout and / or rheumatoid arthritis (RA) are risk factors for coronavirus disease 19 (COVID-19) diagnosis. To assess whether gout and / or RA are risk factors for death with COVID-19.\\n\\nMethodsWe used data from the UK Biobank. Multivariable-adjusted logistic regression was employed in the following analyses: Analysis A, to test for association between gout or RA and COVID-19 diagnosis (n=473,139); Analysis B, to test for association between gout or RA and death with COVID-19 in a case-control cohort of people who died or survived with COVID-19 (n=2,059); Analysis C, to test for association with gout or RA and death with COVID-19 in the entire UK Biobank cohort (n=473,139)\\n\\nResultsRA, but not gout, associated with COVID-19 diagnosis in analysis A. Neither RA nor gout associated with risk of death in the COVID-19-diagnosed group in analysis B. However RA associated with risk of death related to COVID-19 using the UK Biobank cohort in analysis C independent of comorbidities and other measured risk factors (OR=1.9 [95% CI 1.2 ; 3.0]). Gout was not associated with death related to COVID-19 in the same UK Biobank analysis (OR=1.2 [95% CI 0.8 ; 1.7]).\\n\\nConclusionRheumatoid arthritis is a risk factor for death with COVID-19 using the UK Biobank cohort. These findings require replication in larger data sets that also allow inclusion of a wider range of factors.\\n\\nKey messagesInformation on the risk of death from COVID-19 for people with gout and rheumatoid arthritis is scarce.\\n\\nIn an analysis of the UK Biobank there is an increased risk of death related to COVID-19 for people with rheumatoid arthritis independent of included co-morbidities, but not gout.\\n\\nThe findings need to be replicated in other datasets where the influence of therapies for rheumatoid arthritis can be tested.\",\n \"Human blood DNA methylation patterns reflect individual lifestyle\\nObesity is driven by modifiable lifestyle factors whose effects may be mediated by epigenetics. Therefore, we investigated lifestyle effects (diet, physical activity, smoking and alcohol) on blood DNA methylation in participants of the LIFE-Adult study, a well-characterized population-based cohort from Germany. Fifty subjects with an extremely healthy and 50 with an extremely unhealthy lifestyle were selected for genome-wide DNA methylation analysis in blood samples. Whereas obesity was only marginally related to variability in DNA methylation pattern, comparisons between lifestyle categories resulted in 145 Differentially Methylated Positions (DMPs) and 4682 Differentially Methylated Regions (DMRs) annotated to 4426 unique genes. Intersection analysis showed that diet, physical activity, smoking and alcohol intake are equally contributing to the observed differences, which particularly affects pathways related to glutamatergic synapse and axon guidance. DNA methylation patterns help discriminate individuals with a healthy vs. unhealthy lifestyle, which may mask subtle methylation differences derived from obesity.\",\n \"Population-split-based risk assessment model of venous thromboembolism in Chinese medical inpatients\\nAbstractsO_ST_ABSObjectiveC_ST_ABSInpatients with high risk of venous thromboembolism (VTE) usually face serious threats to their health and economic conditions. Many studies using machine learning (ML) models to predict VTE risk neglected an important statistical phenomenon, fuzzy feature, and achieved inferior results. Considering the effect of fuzzy feature, our study aims to develop a VTE risk assessment model suitable for Chinese medical inpatients.\\n\\nMaterials and MethodsInpatients in the medical department of Peking Union Medical College Hospital (PUMCH) from January 2014 to June 2016 were collected. A new ML VTE risk assessment model was built through population splitting. First patients were classified into different groups based on values of VTE risk factors, then trustless groups were filtered out, and finally ML models were built on training data in unit of groups. Predictive performances of our method, five traditional ML models, and the Padua model were compared.\\n\\nResultsThe fuzzy feature was verified on the whole dataset. Compared with the Padua model, the proposed model showed higher sensitivities and specificities on training data, and higher specificities and similar sensitivities on test data. Standard deviations of predictive validity of five ML models were larger than the proposed model.\\n\\nDiscussionThe proposed model was the only one which showed advantages on both sensitivity and specificity over Padua model. Its robustness was better than traditional ML models.\\n\\nConclusionThis study built a population-split-based ML model of VTE for Chinese medical inpatients and it may help clinicians stratify VTE risk and guide prevention more efficiently.\",\n \"Development of reference equations for the six-minute walk distance of school-aged Nigerian children\\nBackgroundThe six-minute walk test (6MWT), a simple, reliable and valid test that uses the distance walked in six minutes (six-minute walk distance, 6MWD) to quantify functional capacity, is widely used in chronic cardiopulmonary and non-cardiopulmonary disorders. However, absence of reference standards for Nigerian school-age children limits its use in this age group.\\n\\nObjectivesTo develop normative values and equations for the 6MWT of school-aged Nigerian children.\\n\\nMethodsIn a cross-sectional study, healthy children aged 6-11 years in Lagos, Nigeria, completed 6MWT on 20-meter straight outdoor courses in their schools following standardized guidelines. Potential predictors: demographic (age, sex), anthropometric (height, weight, chest circumference, leg length) and physiologic data [pre-walk, immediate post-walk and 5th minute-post-walk heart rate (HR), oxygen saturation (SpO2), systolic pressure (SBP), diastolic blood pressure (DBP) and rating of perceived exertion (RPE)] and difference between pre-walk and post-walk HR ({Delta}HR), SpO2 (({Delta}SpO2), SBP ({Delta}SBP), DBP ({Delta}DBP) and RPE ({Delta}RPE). Primary outcome: six-minute walk distance (6MWD) in metres.\\n\\nResultsOverall, 627 pupils (52.1% girls) walked 504.6 {+/-} 66.6 m (95% CI: 499.4, 509.8), ranging from 326.6 m to 673.0 m; 16 m longer in boys (p=0.002). Stepwise linear regression yielded: 6MWD (m) = 347.9 + 14 (Age) + 1.6 ({Delta}HR) + 17.6 (Sex) + 1.2 ({Delta}SBP); R2 =0.25. Previously published reference equations over-estimated Nigerian childrens 6MWD.\\n\\nConclusionThe reference values and prediction equations, after validation in other Nigerian populations, may be useful for functional evaluation of Nigerian children aged 6-11 years with chronic childhood disorders.\",\n \"Maternal underweight and obesity are associated with placental pathologies in human pregnancy\\nIntroductionMaternal underweight and obesity are prevalent conditions, associated with chronic, low-grade inflammation, poor fetal development, and long-term adverse outcomes for the child. The placenta senses and adapts to the pregnancy environment in an effort to support optimal fetal development. However, the mechanisms driving these adaptations, and the resulting placental phenotypes, are poorly understood. We hypothesised that maternal underweight and obesity would be associated with increased prevalence of placental pathologies in term and preterm pregnancies.\\n\\nMethodsData from 12,154 pregnancies were obtained from the Collaborative Perinatal Project, a prospective cohort study conducted from 1959 to 1974. Macro and microscopic placental pathologies were analysed across maternal prepregnancy body mass index (BMI) to assess differences in the presence of pathologies among underweight, overweight, and obese BMI groups compared to normal weight reference BMI at term and preterm. Placental pathologies were also assessed across fetal sex.\\n\\nResultsPregnancies complicated by obesity had placentae with increased fetal inflammation at preterm, and increased inflammation of maternal gestational tissues at term. In term pregnancies, increasing maternal BMI associated with increased maternal vascular malperfusion (MVM), odds of an appropriate mature placenta for gestational age, and placental weight, and decreased placental efficiency. Male placentae, independent of maternal BMI, had increased inflammation, MVM, and placental efficiency than female placentae, particularly at term.\\n\\nDiscussionMaternal underweight and obesity are not inert conditions for the placenta, and the histomorphological changes driven by suboptimal maternal BMI may serve as indicators of adversities experienced in utero and potential predictors of future health trajectories.\",\n \"Association of Visual Impairment with Brain Structure\\nObjectiveTo investigate the association of visual impairment (VI) with brain structures in the UK Biobank Study.\\n\\nMethodsThe UK Biobank Study is a large prospective study that recruited more than 500,000 participants aged 40-69 from 2006 to 2010 across the UK. Visual acuity (VA) of worse than 0.3 LogMAR units (Snellen 20/40) was defined as VI. Structural magnetic resonance imaging (MRI) data were obtained using a 3.0-T MRI imager. Volumetric measures of five global brain volumes (total brain volume, total grey matter, total white matter, cerebrospinal fluid (CSF), brain stem) and the volumes of seven specific brain region (thalamus, caudate nucleus, basal ganglia, pallidum, hippocampus, amygdala and nucleus accumbens) were included in the present analysis. Multivariable linear regression was used to investigate the association of VI with global and specific brain volumes.\\n\\nResultsA total of 8976 participants free of neurological disorders at baseline assessment were included for the present analysis. The prevalence of VI was 0.02% (n=181). After adjusting for a range of cofounding factors, VI was significantly associated with decreased volumes of the total brain ({beta} = -0.12, 95% confidence interval (CI) -0.23 to 0.00, P = 0.049), thalamus ({beta} = -0.16, 95% CI -0.18 to -0.04, P = 0.010), caudatenucleus ({beta} = -0.14, 95% CI -0.27 to 0.00, P = 0.046), pallidum ({beta} = -0.15, 95% CI-0.27 to -0.02, P = 0.028) and amygdala ({beta} = -0.18, 95% CI -0.31 to -0.04, P = 0.012).\\n\\nInterpretationWe found that VI is associated with a decrease in total brain volumes and the volumes of specific brain regions implicated in neurodegenerative diseases.\",\n \"Examining the Association between the COVID-19 Pandemic and Self-Harm Death Counts in Four Canadian Provinces\\nGovernments implemented lockdowns and other physical distancing measures to stop the spread of SARS-CoV-2 (COVID-19). Resulting unemployment, income loss, poverty, and social isolation, coupled with daily reports of dire news about the COVID-19 pandemic, could serve as catalysts for increased self-harm deaths (SHD). This ecological study examined whether observed SHD counts were higher than predicted SHD counts during the pandemic period in the Canadian provinces of Alberta, British Columbia, Ontario, and Quebec. The study also explored whether SHD counts during the pandemic were affected by lockdown severity (measured using the lockdown stringency index [LSI]) and COVID-19 case numbers. We utilized publicly available SHD data from January 2018 through November 2020, and employed AutoRegressive Integrated Moving Average (ARIMA) modelling, to predict SHD during the COVID-19 period (March 21 to November 28, 2020). We used Poisson and negative binomial regression to assess ecological associations between the LSI and COVID-19 case numbers, controlling for seasonality, and SHD counts during the COVID-19 period. On average, observed SHD counts were lower than predicted counts during this period (p < 0.05 [except Alberta]). Additionally, LSI and COVID-19 case numbers were not statistically significantly associated with SHD counts.\",\n \"A Single Dose of COVID-19 mRNA Vaccine Induces Airway Immunity in COVID-19 Convalescent Patients\\nBackgroundMucosal antibodies can prevent virus entry and replication in mucosal epithelial cells and hence virus shedding. Preclinical and clinical studies have shown that a parenteral booster injection of a vaccine against a mucosal pathogen promotes stronger mucosal immune responses following prior infection compared to two injections of a parenteral vaccine. We investigated whether this was also the case for a COVID-19 mRNA vaccine.\\n\\nMethodsTwenty-three COVID-19 convalescent patients and 20 SARS-CoV-2-naive subjects were vaccinated with respectively one and two doses of the Pfizer-BioNTech COVID-19 RNA vaccine. Nasal Epithelial Lining Fluid (NELF) and plasma were collected before and after vaccination and assessed for Immunoglobulin (Ig)G and IgA to Spike and for their ability to inhibit the binding of Spike to its ACE-2 receptor. Blood was analyzed one week after vaccination for the number of Spike-specific Antibody Secreting Cells (ASCs) with a mucosal tropism.\\n\\nResultsIn COVID-19 convalescent patients, a single dose of vaccine amplified pre-existing Spike-specific IgG and IgA antibody responses in both NELF and blood against both vaccine homologous and variant strains, including delta. These responses were associated with Spike-specific IgG and IgA ASCs with a mucosal tropism in blood. Nasal IgA and IgG antibody responses were lower in magnitude in SARS-CoV-2-naive subjects after two vaccine doses\\n\\nConclusionThis study showed that a parenteral booster injection of a COVID-19 RNA vaccine promoted stronger mucosal immune responses in COVID-19 convalescent patients compared to SARS-CoV-2 naive subjects who had received a first vaccine dose.\",\n \"Parent-of-origin effects in the life-course evolution of cardio-metabolic traits\\nObjectiveHuman traits are heritable, and some of these including metabolic and lipid phenotypes show preferential parental transmissions, or parent-of-origin effects. These have been mostly studied in populations comprising adults. We aimed to investigate heritability and parent-of-origin effects on cardiometabolic and anthropometric traits in a birth-cohort with serial measurements to assess if these effects manifested at an early age.\\n\\nResearch design and methodsWe investigated heritability and parent-of-origin effects on cardiometabolic and anthropometric traits in the Pune Maternal Nutrition Study (PMNS) wherein offspring and parents were studied from birth and followed-up for 18 years. Heritability was estimated by calculating association between mid-parental phenotypes and offspring. Maternal and paternal effects on offspring phenotype were modelled by regression after adjusting for age, sex and BMI. Parent-of-origin effects were calculated by the difference between maternal and paternal effects.\\n\\nResultsAnthropomorphic traits and cardiometabolic traits were robustly heritable. Parent-of-origin effects were observed for glycemic traits at both 6- and 12-years, with a paternal effect at 6-years which transitioned to a maternal effect at 12-years. For insulin and HOMA-S, a negative maternal effect transitioned to a positive one at 12-years. For HOMA-B, a paternal effect at 6-years transitioned to a maternal one at 12-years. Lipid traits consistently showed stronger maternal influence while anthropometric traits did not show any parental biases.\\n\\nConclusionsOur study highlights that parental programming of cardiometabolic traits is evident from early childhood and can transition during puberty. Further studies are needed to determine the mechanisms of underlying such effects.\",\n \"DNA methylation and general psychopathology in childhood: An epigenome-wide meta-analysis from the PACE consortium\\nThe general psychopathology factor (GPF) has been proposed as a way to capture variance shared between psychiatric symptoms. Despite a growing body of evidence showing both genetic and environmental influences on GPF, the biological mechanisms underlying these influences remain unclear. In the current study, we conducted epigenome-wide meta-analyses to identify both probe- and region-level associations of DNA methylation (DNAm) with school-age general psychopathology in six cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. DNAm was examined both at birth (cord blood; prospective analysis) and during school-age (peripheral whole blood; cross-sectional analysis) in total samples of N=2,178 and N=2,190, respectively. At school-age, we identified one probe (cg11945228) located in the Bromodomain-containing protein 2 gene (BRD2) that negatively associated with GPF (p=8.58x10-8). We also identified a significant DMR at school-age (p=1.63x10-8), implicating the SHC Adaptor Protein 4 (SHC4) gene that has been previously implicated in multiple types of psychiatric disorders in adulthood, including obsessive compulsive disorder and major depressive disorder. In contrast, no prospective associations were identified with DNAm at birth. Taken together, results of this study revealed some evidence of an association between DNAm at school-age and GPF. Future research with larger samples is needed to further assess DNAm variation associated with GPF.\",\n \"The locus coeruleus shows a spatial pattern of structural disintegration in Parkinson's disease.\\nBackgroundParkinsons disease (PD) leads to a loss of neuromelanin positive, noradrenergic neurons in the locus coeruleus (LC) which has been implicated in non-motor dysfunction. \\\"Neuromelanin sensitive\\\" magnetic resonance imaging (MRI) has emerged as a promising tool for mapping the structural integrity of LC in vivo.\\n\\nObjectivesTo identify spatial patterns of structural LC disintegration in PD and regions in the LC where structural disintegration is associated with specific non-motor dysfunctions.\\n\\nMethods42 patients with PD and 24 age-matched healthy volunteers underwent ultra-high field MRI of the LC using a \\\"neuromelanin sensitive\\\" magnetization transfer weighted (MTw) sequence. The contrast-to-noise ratio of the MTw signal (CNRMTw) served as an estimate of structural integrity, slice- and voxel-wise analyses of CNRMTw were performed to map the spatial pattern of structural disintegration, complemented by Principal Component Analysis (PCA). We also tested for correlations between CNRMTw and the severity of non-motor symptoms.\\n\\nResultsMean CNRMTw of LC was reduced in patients relative to controls. The attenuation of CNRMTw was not uniformly expressed in LC, but confined to the middle and caudal LC. CNRMTw attenuation in caudal LC scaled with the orthostatic drop in systolic blood pressure and apathy ratings. PCA identified a bilaterally expressed component that was more weakly expressed in patients. This component was characterized by a gradual change in CNRMTw along the rostro-caudal and dorso-ventral axes of the nucleus. The individual expression score of this component reflected the overall severity of non-motor symptoms.\\n\\nConclusionPD related structural disintegration of LC mainly affects its caudal part and may determine the individual expression of specific non-motor symptoms such as orthostatic dysregulation or apathy.\",\n \"Factors associated with severe sepsis in diarrheal adults and their outcome at an urban hospital, Bangladesh: A retrospective analysis\\nBackgroundClinical features of sepsis and severe diarrhea often overlap and create a dilemma among the clinicians. To describe factors associated with severe sepsis in diarrheal adults and their outcomes to understand their interplay as clinical features of sepsis and severe diarrhea often overlap.\\n\\nMethods and resultsWe used this retrospective chart analysis employing a case-control design to study critically ill diarrheal adults aged [≥] 18 years treated in ICU Dhaka hospital, icddr,b between January 2011 to December 2015. Diarrheal adults with a diagnosis of severe sepsis were cases and an equal number of randomly selected non-septic patients were the controls. Of 8,863 in-patient adults, 350 fulfilled the criteria of cases. Cases died significantly more (9% vs 3%, p=0.002) than controls. 69% of the cases progressed to septic shock. In logistic regression analysis, steroid intake, ileus, acute kidney injury, metabolic acidosis, and hypocalcemia were significantly associated with severe sepsis in diarrheal adults (all, p<0.05). 12% of cases (40/335) had bacteremia. Streptococcus pneumoniae [9 (22.5%)] was the single most common pathogen and gram-negatives [27 (67.5%)] were prevailing as a group.\\n\\nConclusionDiarrheal adults who had ileus, AKI, metabolic acidosis, hypocalcemia, and also took steroids were prone to have severe sepsis. Strikingly, gram-negatives were the predominant bacteria among the diarrheal adults having severe sepsis.\",\n \"Detection of choroidal hypoperfusion in giant cell arteritis using swept-source optical coherence tomographic angiography\\nObjectiveTo determine whether swept-source optical coherence tomographic angiography (SS-OCTA) can demonstrate choroidal perfusion abnormalities seen on fluorescein angiography (FA) in giant cell arteritis (GCA).\\n\\nDesignObservational case series.\\n\\nParticipantsSix eyes of 3 patients with bilateral ischemic optic neuropathy secondary to GCA, and one control patient without ocular involvement from biopsy-confirmed GCA.\\n\\nMethodsEn face SS-OCTA (DRI OCT Triton, Topcon, Tokyo, Japan) and FA centered on the macula were obtained at presentation. SS-OCTA was segmented into superficial and deep retinal capillary plexuses and the choriocapillaris laminae. SS-OCTA images were independently analyzed for perfusion abnormalities and compared with corresponding FA images.\\n\\nMain Outcome MeasuresCorrespondence of choroidal angiographic abnormalities on SS-OCTA and FA.\\n\\nResultsSS-OCTA showed decreased angiographic signal within the choriocapillaris in 5/6 eyes and corresponded to hypoperfusion abnormalities on FA in similar geographic distributions in 5/5 eyes. SS-OCTA also showed dilation of the deep retinal capillary plexus overlying the area of choroidal hypoperfusion in one eye. In the one eye without angiographic signal abnormalities on SS-OCTA, no perfusion changes were noted on FA. One control patient without ocular involvement from biopsy-confirmed GCA did not show choroidal perfusion changes on SS-OCTA or FA.\\n\\nConclusionsThis case series demonstrates comparability between SS-OCTA and FA in detection and characterization of choroidal hypoperfusion secondary to GCA. As a rapid and non-invasive tool, SS-OCTA may serve as a viable alternative to FA in the diagnostic evaluation of GCA.\",\n \"Polygenic risk scores for psychiatric, inflammatory, and cardio-metabolic traits and diseases highlight possible genetic overlaps with suicide attempt and treatment-emergent suicidal ideation\\nSuicide is the second leading cause of death among young people. Genetics may contribute to suicidal phenotypes and their co-occurrence in other psychiatric and medical conditions. Our study aimed to investigate the association of polygenic risk scores (PRSs) for 22 psychiatric, inflammatory, and cardio-metabolic traits and diseases with suicide attempt (SA) or treatment-worsening/emergent suicidal ideation (TWESI).\\n\\nPRSs were computed based on summary statistics of genome-wide association studies. Regression analyses were performed between PRSs and SA or TWESI in four clinical cohorts, including up to 3,834 individuals, and results were meta-analyzed across samples. Stratified genetic covariance analyses were performed to investigate the biology underlying cross-phenotype PRS associations. After Bonferroni correction, PRS for major depressive disorder (MDD) was positively associated with SA (p=1.7e-4). Nominal associations were shown between PRSs for coronary artery disease (CAD) (p=4.6e-3) or loneliness (p=0.009) and SA, PRSs for MDD or CAD and TWESI (p=0.033 and p=0.032, respectively). Genetic covariance between MDD and SA was shown in 35 gene sets related to drugs having anti-suicidal effects.\\n\\nA higher genetic liability for MDD may underlie a higher risk of SA. Further, but milder, possible modulatory factors are genetic risk for loneliness and CAD.\",\n \"Unveiling Sex-based Differences in Parkinson's Disease: A Comprehensive Meta-analysis of Transcriptomic Studies\\nIn recent decades, increasing longevity (among other factors) has fostered a rise in Parkinsons disease (PD) incidence. Although not exhaustively studied in this devastating disease, the impact of sex represents a critical variable in PD as epidemiological and clinical features differ between males and females. To study sex bias in PD, we conducted a systematic review, tissue-specific meta-analyses of transcriptomic data from the frontal cortex (FC), striatum tissue (ST), and substantia nigra (SN), and a global meta-analysis of all 3 brain regions. We selected 7 PD studies that included sex information, analyzing 267 samples. The tissue-specific meta-analyses linked PD to the enhanced expression of MED31 in the female FC and the dysregulation of 237 genes in the SN. The global meta-analysis detected 15 genes with sex-differential patterns in PD, which participate in mitochondrial function, oxidative stress, neuronal degeneration, and cell death. Furthermore, functional analyses identified pathways, protein-protein interaction networks, and transcription factors that differed by sex. While male PD patients exhibited changes in oxidative stress based on metal ions, inflammation, and angiogenesis, female PD patients exhibited dysfunctions in mitochondrial and lysosomal activity, antigen processing and presentation functions, and glutamic and purine metabolism. Overall, we believe that our findings will provide new insight into the perspective of sex in PD, thereby underscoring the importance of including sex information in future PD studies.\",\n \"The genetic architecture of Alzheimer disease risk in the Ohio and Indiana Amish\\nAlzheimer disease (AD) is the most common type of dementia and is currently estimated to affect 6.2 million Americans. It ranks as the sixth leading cause of death in the United States and the proportion of deaths due to AD has been increasing since the year 2000 while the proportion of many other leading causes of deaths have decreased or remained constant. The risk for AD is multifactorial, including genetic and environmental risk factors. Though APOE remains the largest genetic risk factor for AD, more than 26 other loci have been associated with AD risk. Here, we recruited from a population of Amish adults from Ohio and Indiana to investigate AD risk and protective genetic effects. With slightly lower incidence and later age of onset, it is thought that the Amish may hold protective genetic variants for AD. As a founder population that typically practices endogamy, variants that are rare in the general population may be at higher frequency in the Amish population. We characterized the genetic architecture of AD risk in the Amish and compared this to a non-Amish population, elucidating the lower relative importance of APOE and differing genetic architecture of the Amish compared to a general European ancestry population.\",\n \"Decoding mitochondrial genes in pediatric AML and development of a novel prognostic mitochondrial gene signature\\nBackgroundGene expression profile of mitochondrial-related genes is not well deciphered in pediatric acute myeloid leukaemia (AML). We aimed to identify mitochondria-related differentially expressed genes (DEGs) in pediatric AML with their prognostic significance.\\n\\nMethodsChildren with de novo AML were included prospectively between July 2016-December 2019. Transcriptomic profiling was done for a subset of samples, stratified by mtDNA copy number. Top mitochondria-related DEGs were identified and validated by real-time PCR. A prognostic gene signature risk score was formulated using DEGs independently predictive of overall survival (OS) in multivariable analysis. Predictive ability of the risk score was estimated along with external validation in The Tumor Genome Atlas (TCGA) AML dataset.\\n\\nResultsIn 143 children with AML, twenty mitochondria-related DEGs were selected for validation, of which 16 were found to be significantly dysregulated. Upregulation of SDHC (p<0.001), CLIC1 (p=0.013) and downregulation of SLC25A29 (p<0.001) were independently predictive of inferior OS, and included for developing prognostic risk score. The risk score model was independently predictive of survival over and above ELN risk categorization (Harrells c-index: 0.675). High-risk patients (risk score above median) had significantly inferior OS (p<0.001) and event free survival (p<0.001); they were associated with poor-risk cytogenetics (p=0.021), ELN intermediate/poor risk group (p=0.016), absence of RUNX1-RUNX1T1 (p=0.027), and not attaining remission (p=0.016). On external validation, the risk score also predicted OS (p=0.019) in TCGA dataset.\\n\\nConclusionWe identified and validated mitochondria-related DEGs with prognostic impact in pediatric AML and also developed a novel 3-gene based externally validated gene signature predictive of survival.\",\n \"Multi-state network meta-analysis of cause-specific survival data\\nMultiple randomized controlled trials, each comparing a subset of competing interventions, can be synthesized by means of a network meta-analysis to estimate relative treatment effects between all interventions in the evidence base. Often there is an interest in estimating the relative treatment effects regarding time-to-event outcomes. Cancer treatment effectiveness is frequently quantified by analyzing overall survival (OS) and progression-free survival (PFS). In this paper we introduce a method for the joint network meta-analysis of PFS and OS that is based on a time-inhomogeneous tri-state (stable, progression, and death) Markov model where time-varying transition rates and relative treatment effects are modeled with known parametric survival functions or fractional polynomials. The data needed to run these analyses can be extracted directly from published survival curves. We demonstrate use by applying the methodology to a network of trials for the treatment of non-small-cell lung cancer. The proposed approach allows the joint synthesis of OS and PFS, relaxes the proportional hazards assumption, extends to a network of more than two treatments, and simplifies the parameterization of decision and cost-effectiveness analyses.\",\n \"Epidemiological cutoff values for a 96-well broth microdilution plate for high throughput research antibiotic susceptibility testing of M. tuberculosis\\nDrug susceptibility testing of M. tuberculosis is rooted in a binary susceptible/resistant paradigm.\\n\\nWhilst there are considerable advantages in measuring the minimum inhibitory concentrations (MICs) of a panel of drugs for an isolate it is n ecessary to measure the epidemiological cutoff values (ECOFF/ECVs) to permit comparison with qualitative data. Here we present ECOFF/ECVs for 13 anti-TB compounds, including bedaquiline and delamanid, derived from 20,637 clinical isolates collected by 14 laboratories based in 11 countries on five continents. Each isolate was incubated for 14 days on a dry 96-well broth microdilution plate and then read. Resistance to most of the drugs due to prior exposure is expected and the MIC distributions for many of the compounds are complex and therefore a phenotypically wild-type population could not be defined. Since a majority of samples also underwent genetic sequencing, we defined a genotypically wild-type population and measured the MIC of the 99th percentile by direct measurement and via fitting a Gaussian using interval regression.\\n\\nThe proposed ECOFF/ECV values were then validated by comparing to the MIC distributions of high-confidence genetic variants that confer resistance and to qualitative drug susceptibility tests obtained via Mycobacterial Growth Indicator Tube and the Microscopic-Observation Drug-Susceptibility assay.\\n\\nThese ECOFF/ECV values will inform and encourage the more widespread adoption of broth microdilution - this is a cheap culture-based method that tests the susceptibility of 12-14 antibiotics on a single 96-well plate and so could help personalise the treatment of tuberculosis.\",\n \"A strategy to assess spillover risk of bat SARS-related coronaviruses in Southeast Asia\\nEmerging diseases caused by coronaviruses of likely bat origin (e.g. SARS, MERS, SADS and COVID-19) have disrupted global health and economies for two decades.\\n\\nEvidence suggests that some bat SARS-related coronaviruses (SARSr-CoVs) could infect people directly, and that their spillover is more frequent than previously recognized. Each zoonotic spillover of a novel virus represents an opportunity for evolutionary adaptation and further spread; therefore, quantifying the extent of this \\\"hidden\\\" spillover may help target prevention programs. We derive biologically realistic range distributions for known bat SARSr-CoV hosts and quantify their overlap with human populations. We then use probabilistic risk assessment and data on human-bat contact, human SARSr-CoV seroprevalence, and antibody duration to estimate that [~]400,000 people (median: [~]50,000) are infected with SARSr-CoVs annually in South and Southeast Asia. These data on the geography and scale of spillover can be used to target surveillance and prevention programs for potential future bat-CoV emergence.\",\n \"Clinical, neuroimaging and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability\\nPURPOSEBi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus.\\n\\nMETHODSThrough an international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms.\\n\\nRESULTSA cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections and central/nocturnal hypopnea as core manifestations. A review of brain MRI scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing {beta}-propeller repeats. Despite constituting nearly half of disease associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1,221 in the general and 1/155 in the Jewish Ashkenazi populations.\\n\\nCONCLUSIONBased on clinical, neuroimaging and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2-associated disorder. This sets the stage for future prospective natural history studies.\\n\\nCONFLICTS OF INTERESTAll authors involved in the study declare no conflicts of interest relevant to this study.\",\n \"Proton pump inhibitor use is not associated with severe COVID-19 related outcomes: A propensity score weighted analysis of a national veteran cohort\\nBackground and AimsLow pH deactivates most pathogens, including coronaviruses. Proton pump inhibitors (PPIs) are potent gastric acid suppressing medications. Whether PPI use vs non-use is associated with severe Coronavirus disease-2019 (COVID-19) outcomes remains uncertain. We aimed to compare severe COVID-19 outcomes between current outpatient PPI users and non-users.\\n\\nMethodsWe conducted a retrospective propensity score-weighted analysis of a national cohort of US veterans with established care who tested positive for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) through January 9, 2021, and who had 60 days of follow-up. The positive test date was the index date. Current outpatient PPI use up to and including the index date (primary exposure) was compared to non-use, defined as no PPI prescription fill in the 365 days prior to the index date. The primary outcome was a composite of use of mechanical ventilation or death within 60 days. Weighted logistic regression models evaluated severe COVID-19 outcomes between current PPI users vs non-users.\\n\\nResultsOf 97,674 Veterans with SARS-CoV-2 testing, 14,958 tested positive (6262 [41.9%] current PPI users, 8696 [58.1%] non-users) and comprised the analytic cohort. After weighting, all covariates were well-balanced. In the weighted cohort, there was no difference in the primary composite outcome (8.2% vs 8.0%; OR 1.03, 95% CI 0.91-1.16), secondary composite outcome, nor individual component outcomes between current PPI users and non-users. There was no significant interaction between age and PPI use on outcomes.\\n\\nConclusionAmong patients with SARS-CoV-2 infection, current PPI use vs non-use is not associated with severe COVID-19 outcomes.\",\n \"A cautionary note on recall vaccination in ex-COVID-19 subjects\\nCurrently approved COVID-19 vaccines based on mRNA or adenovirus require a first jab followed by recall immunization. There is no indication as to whether individuals who have recovered from COVID-19 should be vaccinated, and if so, if they should receive one or two vaccine doses. Here, we tested the antibody response developed after the first dose of the mRNA based vaccine encoding the SARS-CoV-2 full-length spike protein (BNT162b2) in 124 healthcare professionals of which 57 had a previous history of COVID-19 (ExCOVID). Post-vaccine antibodies in ExCOVID individuals increase exponentially within 7-15 days after the first dose compared to naive subjects (p<0.0001). We developed a multivariate Linear Regression (LR) model with l2 regularization to predict the IgG response for SARS-COV-2 vaccine. We found that the antibody response of ExCOVID patients depends on the IgG pre-vaccine titer and on the symptoms that they developed during the disorder, with anosmia/dysgeusia and gastrointestinal disorders being the most significantly positively correlated in the LR. Thus, one vaccine dose is sufficient to induce a good antibody response in ExCOVID subjects. This poses caution for ExCOVID subjects to receive a second jab both because they may have a overreaction of the inflammatory response and also in light of the current vaccine shortage.\",\n \"High definition analyses of single cohort, whole genome sequencing data provides a direct route to defining sub-phenotypes and personalising medicine\\nPossession of a clinical or molecular disease label alters the context in which life-course events operate, but rarely explains the phenotypic variability observed by clinicians. Whole genome sequencing of unselected endothelial vasculopathy patients demonstrated more than a third had rare, likely deleterious variants in clinically-relevant genes unrelated to their vasculopathy (1 in 10 within platelet genes; 1 in 8 within coagulation genes; and 1 in 4 within erythrocyte hemolytic genes). High erythrocyte membrane variant rates paralleled genomic damage and prevalence indices in the general population. In blinded analyses, patients with greater hemorrhagic severity that had been attributed solely to their vasculopathy had more deleterious variants in platelet (Spearman {rho}=0.25, p=0.008) and coagulation (Spearman {rho}=0.21, p=0.024) genes. We conclude that rare diseases can provide insights for medicine beyond their primary pathophysiology, and propose a framework based on rare variants to inform interpretative approaches to accelerate clinical impact from whole genome sequencing.\",\n \"Evaluating Vaccine Efficacy Against SARS-CoV-2 Infection\\nAlthough interim results from several large placebo-controlled phase 3 trials demonstrated high vaccine efficacy (VE) against symptomatic COVID-19, it is unknown how effective the vaccines are in preventing people from becoming asymptomatically infected and potentially spreading the virus unwittingly. It is more difficult to evaluate VE against SARS-CoV-2 infection than against symptomatic COVID-19 because infection is not observed directly but rather is known to occur between two antibody or RT-PCR tests. Additional challenges arise as community transmission changes over time and as participants are vaccinated on different dates because of staggered enrollment or crossover before the end of the study. Here, we provide valid and efficient statistical methods for estimating potentially waning VE against SARS-CoV-2 infection with blood or nasal samples under time-varying community transmission, staggered enrollment, and blinded or unblinded crossover. We demonstrate the usefulness of the proposed methods through numerical studies mimicking the BNT162b2 phase 3 trial and the Prevent COVID U study. In addition, we assess how crossover and the frequency of diagnostic tests affect the precision of VE estimates.\\n\\nSummaryWe show how to estimate potentially waning efficacy of COVID-19 vaccines against SARS-CoV-2 infection using blood or nasal samples collected periodically from clinical trials with staggered enrollment of participants and crossover of placebo recipients.\",\n \"Within-Day Variability of SARS-CoV-2 RNA in Municipal Wastewater Influent During Periods of Varying COVID-19 Prevalence and Positivity\\nWastewater surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA is being used to monitor Coronavirus Disease 2019 (COVID-19) trends in communities; however, within-day variation in primary influent concentrations of SARS-CoV-2 RNA remain largely uncharacterized. In the current study, grab sampling of primary influent was performed every 2 hours over two different 24-hour periods at two wastewater treatment plants (WWTPs) in northern Indiana, USA. In primary influent, uncorrected, recovery-corrected, and pepper mild mottle virus (PMMoV)-normalized SARS-CoV-2 RNA concentrations demonstrated ordinal agreement with increasing clinical COVID-19 positivity, but not COVID-19 cases. Primary influent SARS-CoV-2 RNA concentrations exhibited greater variation than PMMoV RNA concentrations as expected for lower shedding prevalence. The bovine respiratory syncytial virus (BRSV) process control recovery efficiency was low (mean: 0.91%) and highly variable (coefficient of variation: 51% - 206%) over the four sampling events with significant differences between the two WWTPs (p <0.0001). The process control recovery was similar to the independently assessed SARS-CoV-2 RNA recovery efficiency, which was also significantly different between the two WWTPs (p <0.0001). Recovery-corrected SARS-CoV-2 RNA concentrations better reflected within-day changes in primary influent flow rate and fecal content, as indicated by PMMoV concentrations. These observations highlight the importance of assessing the process recovery efficiency, which is highly variable, using an appropriate process control. Despite large variations, both recovery-corrected and PMMoV-normalized SARS-CoV-2 RNA concentrations in primary influent demonstrate potential for monitoring COVID-19 positivity trends in WWTPs serving peri-urban and rural areas.\",\n \"London Ramadan Fasting Study (LORANS): Rationale, design, and methods\\nBackgroundHundreds of millions of Muslims fast during the month of Ramadan. The London Ramadan Fasting Study (LORANS) aims to assess the lifestyle changes during this month and investigate the effect of Ramadan fasting on health.\\n\\nMethodsLORANS is an observational study of participants that follow religious fasting in Ramadan. We advertised, recruited, and visited participants in five mosques in London, United Kingdom. In total, 146 individuals were recruited before Ramadan in May 2019 of which 85 participated in the follow up visit after Ramadan. The study protocol was approved by the ethics committee affiliated to Imperial College London. A written informed consent was signed by all the participants. Every participant completed a questionnaire, a physical examination, and gave blood samples at each visit. Moreover, they completed a 3-day food diary before Ramadan and once again during Ramadan to record dietary changes during the month of fasting.\\n\\nResultsThe mean age of participants was 45.6{+/-} 15.9 years. 47.1% of the participants were females, 25.5% were obese, 4.7% were smokers, 14% were diabetic, 24% were hypertensive, and 5.2% had cardiovascular diseases. Data collection covered demographics, lifestyle, food intake, blood pressure, anthropometric measurements, body composition, and metabolic biomarker profiling.\\n\\nConclusionBy engaging with mosques, proper introduction of the study aims and convenient recruitment in the mosque, we were able to recruit a balanced population regarding age and sex and collected valuable data on Ramadan fasting using high-quality techniques.\",\n \"Safety and Efficacy of Navigational Bronchoscopy with Archimedes Virtual Bronchoscopic Platform in Patients with Advanced Pulmonary Disease\\nBackgroundPatients with advanced lung disease who present with suspicious pulmonary nodules (SPNs) undergoing transthoracic needle aspiration pose a diagnostic challenge given risk for complications. Virtual bronchoscopic navigation (VBN) is an alternative means to biopsy patients.\\n\\nStudy DesignThe study was a retrospective chart review of all patients who underwent VBN with the Archimedes platform. Demographic information, radiographic evidence of parenchymal lung disease and pulmonary function testing were gathered. Peri-procedure complications and clinical data on biopsy results were gathered to assist in determining both adequate tissue sample (defined if adequate specimen was obtained as per pathology/cytology report) and diagnostic yield (defined as if after further testing/CT imaging from 1 year post-procedure the diagnosis did not change). Univariate analysis was performed to determine the impact of clinical factors on diagnostic yield.\\n\\nResultsNinety-six patients with 110 nodules underwent VBN. Eight-eight patients (92%) had radiographic emphysema with 56% having moderate to severe. Fourteen patients (17%) had radiographic ILD. Adequate tissue sample at time of VBN was 93%. Overall diagnostic yield in 80 patients (excluding 16 patients who were initially benign/non-diagnostic that were lost to follow-up) was 72%. Overall complication rate was 7% with 1-pneumothorax (1%), 3-significant bleeding and 3-hospitalized for respiratory failure.\\n\\nConclusionIn our cohort of patients the diagnostic yield and complication rate were comparable to other studies where there were fewer patients with advanced lung disease. This data suggests that VBN-guided bronchoscopic biopsy of SPNs is a viable diagnostic option with an acceptable safety profile.\",\n \"Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits\\nImmunoglobulin A (IgA) mediates mucosal responses to food antigens and the intestinal microbiome and has a known role in susceptibility to mucosal pathogens, celiac disease, inflammatory bowel disease, and IgA nephropathy. We performed genetic analyses of serum IgA levels in 41,263 individuals of diverse ancestries. We observed unexpected variability in IgA levels across major ancestral populations, with African ancestry being reproducibly associated with higher serum IgA levels compared to other ancestries. The trans-ethnic GWAS analysis identified 20 genome-wide significant loci associated with serum IgA levels, including nine known and 11 novel loci. Systematic co-localization analysis with blood and primary immune cell expression QTLs prioritized candidate genes for 14 of 20 loci. Most GWAS loci encoded genes that produce immune defects and IgA abnormalities when genetically manipulated in mice. We uncovered positive genetic correlations of serum IgA levels with IgA nephropathy, type 2 diabetes and body mass index, as well as negative genetic correlations with celiac disease, inflammatory bowel disease, several infections, and intestinal microbiome diversity. Our findings provide novel insights into the genetic regulation of IgA production and its potential role in human disease.\",\n \"Determinants of adolescent lung function in Indians: race, nutrition and systemic inflammation\\nRationaleWhile determining normal variation of spirometric volumes, the geo-political construct of Indian inadequately captures the diverse racial structure and varied lifestyles that exist for 1 in 5 people globally. It is necessary to determine the degree of racial heterogeneity and other underlying factors to know whether lower spirometric volumes of Indians is normal or abnormal.\\n\\nObjectivesTo investigate the differences in spirometric volumes and their associations with overall health parameters, for adolescent children and young adults, across geo-ethnic regions within India.\\n\\nMethodsData was analyzed for 2338 healthy subjects aged 9-19 years with acceptable spirometry from SOLID cohort. Associations between lung function and potential determinants (Race, anthropometry, nutrition, family/life history, airway oscillometric parameters and systemic inflammation) were examined by using multiple regression. Latent profile analysis (LPA) was performed for 903 subjects to uncover hidden sub-phenotypes.\\n\\nResultsFEV1 and FVC varied significantly between Indian genetic ancestries, being highest in Tibeto-Burmans and lowest in Dravidians. After statistical adjustments, FEV1 and FVC were positively correlated with waist-height-ratio, shoulder-height-ratio, normalized BMI, and blood hemoglobin. Lower FVC was associated with lower expiratory flows (PEF and FEF25-75), higher lung reactance (X5), higher airway resistance (R10 and R15), gastro-intestinal symptoms, and higher inflammation (IL-8 and IL-17). A sub-phenotype of thinness, higher inflammation (IFN-gamma, IL-17, TNF-alpha, IL-8) and lower FVC was identified on LPA for 35% of the sample.\\n\\nConclusionsSpirometric volumes in Indians are different between major racial subgroups but may also be abnormally low due to prevalent nutritional or environmental adversity. Care must be taken while establishing normative standards.\",\n \"Multi-task deep learning-based survival analysis on the prognosis of late AMD using the longitudinal data in AREDS\\nAge-related macular degeneration (AMD) is the leading cause of vision loss. Some patients experience vision loss over a delayed timeframe, others at a rapid pace. Physicians analyze time-of-visit fundus photographs to predict patient risk of developing late-AMD, the most severe form of AMD. Our study hypothesizes that 1) incorporating historical data improves predictive strength of developing late-AMD and 2) state-of-the-art deep-learning techniques extract more predictive image features than clinicians do. We incorporate longitudinal data from the Age-Related Eye Disease Studies and deep-learning extracted image features in survival settings to predict development of late-AMD. To extract image features, we used multi-task learning frameworks to train convolutional neural networks. Our findings show 1) incorporating longitudinal data improves prediction of late-AMD for clinical standard features, but only the current visit is informative when using complex features and 2) \\\"deep-features\\\" are more informative than clinician derived features. We make codes publicly available at https://github.com/bionlplab/AMD_prognosis_amia2021.\",\n \"Possibility of SARS-CoV-2 infection in metastatic microenvironment of cancer\\nAccording to a report from the World Health Organization, the mortality and severity rates among patients with cancer infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are significantly higher than those of individuals infected with SARS-CoV-2 without complications. Common and cancer-specific risk factors may be involved in the mortality and severity rates of coronavirus disease 2019 (COVID-19). Various factors have been determined to contribute to the aggravation of COVID-19 in patients with cancer. However, on the basis of current research, the factors involved in the aggravation of COVID-19 in patients with cancer have not been fully investigated. In the general course of treatment for patients with cancer, the detection of the formation of metastases in other organs is common. Therefore, the present study investigates the association between lung metastatic lesion formation and SARS-CoV-2 infectivity. On the basis of the results obtained, in the pulmonary micrometastatic niche of patients with ovarian cancer, alveolar epithelial stem-like cells adjacent to the ovarian cancer were observed. Moreover, it was revealed that angiotensin-converting enzyme 2, a host-side receptor for SARS-CoV-2, was expressed in alveolar epithelial stem-like cells adjacent to the ovarian cancer in the pulmonary micrometastatic niche. Furthermore, it was also observed that the SARS-CoV-2 spike glycoprotein receptor-binding domain binds to alveolar epithelial stem-like cells. In other words, it was suggested that patients with cancer and pulmonary micrometastases may be more susceptible to SARS-CoV-2. The prevention of de novo niche formation in metastatic disease may be a new strategy for the clinical treatment of COVID-19 for patients with cancer.\",\n \"Transdiagnostic connectome-based prediction of craving\\nCraving is a central construct in the study of motivation and human behavior and is also a clinical symptom of substance and non-substance-related addictive disorders. Thus, craving represents a target for transdiagnostic modeling. We applied connectome-based predictive modeling (CPM) to functional connectivity data in a large (N=274) transdiagnostic sample of individuals with and without substance-use-related conditions, to predict self-reported craving. CPM is a machine-learning approach used to identify neural signatures in functional connectivity data related to a specific phenotype. Functional connectomes were derived from three guided imagery conditions of personalized appetitive, stress, and neutral-relaxing experiences. Craving was rated before and after each imagery condition. CPM successfully predicted craving, thereby identifying a transdiagnostic craving network comprised primarily of the posterior cingulate cortex, hippocampus, visual cortex, and primary sensory areas. Findings suggest that craving may be associated with difficulties directing attention away from internal self-related processing, represented in the default mode network.\",\n \"Analysis of cell-specific peripheral blood biomarkers in severe allergic asthma identifies innate immune dysfunction\\nAsthma is a disease of complex origin and multiple pathologies. There are currently very few biomarkers of proven utility in its diagnosis, management or response to treatment. Recent studies have identified multiple asthma phenotypes following biofluid analysis; however, such findings may be driven by the well-characterised alterations in immune cell populations in asthma. We present a study designed to identify cell type-specific gene signatures of severe allergic asthma in peripheral blood samples. Using transcriptomic profiling of four magnetically purified peripheral blood cell types, we identify significant gene expression changes in monocytes and NK cells but not T lymphocytes in severe asthmatics. Pathway analysis indicates dysfunction of immune cell regulation and bacterial suppression in the NK cells. These gene expression changes may be useful on their own as prognostic peripheral blood cell markers of severe asthma, but also may indicate novel cell pathways for therapeutic intervention.\",\n \"Causes, Predictors, and Costs of Unplanned 30-Day Readmissions in Patients with Right Heart Failure.\\nOBJECTIVESThe aim of this study was to describe the frequency, causes, factors, and costs associated with right heart failure encounters.\\n\\nBACKGROUNDMultiple studies have looked into heart failure readmissions but there is no study to our knowledge specifically analyzing patients with right heart failure.\\n\\nMETHODSPatients with right heart failure diagnosis were identified using the 2017 Nationwide Readmission Database (NRD) and were evaluated for the rates, predictors, and costs of unplanned 30 days readmission. Weighted analysis was performed to obtain nationally representative data.\\n\\nRESULTSWe identified 7142 patients with right heart failure of whom 21% had an unplanned readmission within 30 days of the index discharge. Patients with history of Coronary artery bypass grafting (p=0.033; OR 2.359; 95% CI 1.071 - 5.197), Chronic kidney disease (p<0.001; OR 1.607; 95% CI 1.402 - 1.843), atrial fibrillation (p=0.014; OR 1.417; 95% CI 1.072-1.873) had high odds of unplanned 30 day readmissions while obesity (p<0.001; OR 0.686; 95% CI 0.594 - 0.792) had negative odds of such readmissions.\\n\\nCONCLUSIONSThirty-day unplanned readmissions remain a significant issue affecting over 1 in 5 patients with right heart failure. Early unplanned readmissions are associated with significant mortality and financial burden in these patients.\",\n \"Tumour volume distribution can yield information on tumour growth and tumour control\\nBackgroundIt is shown that tumour volume distributions, can yield information on two aspects of cancer research: tumour induction and tumour control.\\n\\nMaterials and methodsFrom the hypothesis that the intrinsic distribution of breast cancer volumes follows an exponential distribution, firstly the probability density function of tumour growth time was deduced via a mathematical transformation of the probability density functions of tumour volumes. In a second step, the distribution of tumour volumes was used to model the variation of the clonogenic cell number between patients in order to determine tumour control probabilities for radiotherapy patients.\\n\\nResultsDistribution of lag times, i.e. the time from the appearance of the first fully malignant cell until a clinicaly observable cancer, can be used to deduce the probability of tumour induction as a function of patient age. The integration of the volume variation with a Poisson-TCP model results in a logistic function which explains population-averaged survival data of radiotherapy patients.\\n\\nConclusionsThe inclusion of tumour volume distributions into the TCP formalism enables a direct link to be deduced between a cohort TCP model (logistic) and a TCP model for individual patients (Poisson). The TCP model can be applied to non-uniform tumour dose distributions.\",\n \"Patient and physician shared decision making behaviors in oncology: Evidence on adequate measurement properties of the iSHARE questionnaires\\nObjectivesWe have developed two questionnaires to assess the shared decision making (SDM) process in oncology; the iSHAREpatient and iSHAREphysician. In this study, we aimed to determine: scores, construct validity, test-retest agreement (iSHAREpatient), and inter-rater (iSHAREpatient-iSHAREphysician) agreement.\\n\\nMethodsPhysicians from seven Dutch hospitals recruited cancer patients, and completed the iSHAREphysician and SDM-Questionnaire-physician version. Their patients completed the: iSHAREpatient, 9-item SDM-Questionnaire, Decisional Conflict Scale, Combined Outcome Measure for Risk communication And treatment Decision making Effectiveness, and Perceived Efficacy in Patient-Physician Interactions. We formulated, respectively, one (iSHAREphysician) and 10 (iSHAREpatient) a priori hypotheses regarding correlations between the iSHARE questionnaires and questionnaires assessing related constructs. To assess test-retest agreement patients completed the iSHAREpatient again 1-2 weeks later.\\n\\nResultsIn total, 151 treatment decision making processes with unique patients were rated. Dimension and total iSHARE scores were high both in patients and physicians. The hypothesis on the iSHAREphysician and 9/10 hypotheses on the iSHAREpatient were confirmed. Test-retest and inter-rater agreement were >.60 for most items.\\n\\nConclusionsThe iSHARE questionnaires show high scores, have good construct validity, substantial test-retest agreement, and moderate inter-rater agreement.\\n\\nPractice implicationsResults from the iSHARE questionnaires can inform both physician- and patient-directed efforts to improve SDM in clinical practice.\",\n \"AnmO2l: An open-source pulse-dose oxygen conserving device for the COVID-19 crisis\\nThe surge of COVID-19 cases in India and around the world has resulted in acute oxygen shortage. Oxygen therapy through nasal cannula with flow rates of 1-6 L/min is an effective treatment for many COVID-19 patients in non-critical conditions and may help prevent disease progression. The same treatment is also used in post-acute care for recovering COVID-19 patients. Here we describe a simple, open source, and rapidly manufacturable oxygen conservation device for use with dual-port nasal cannula that can extend the life of current oxygen supply by almost two to three times, which we hope will help towards coping with the ongoing crisis.\",\n \"Using Whole Genome Sequencing to Characterize Clinically Significant Blood Groups Among Healthy Older Australians\\nThere have been no comprehensive studies of a full range of blood group polymorphisms within the Australian population. The problem is compounded by the absence of any databases carrying genomic information on chronically transfused patients and low frequency blood group antigens in Australia. Here, we use RBCeq, a web server-based blood group genotyping software, to identify unique blood group variants among Australians and compare the variation detected versus global data. Whole genome sequencing data was analysed from for 2796 healthy older Australians from the Medical Genome Reference Bank and compared with data from 1000G phase 3 (1KGP3) databases comprising 661 African, 347 American, 503 European, 504 East Asian, and 489 South Asian participants. There were 688 rare variants detected in this Australian sample population, including nine variants that had clinical associations. Notably, we identified 149 variants that were computationally predicted to be novel and deleterious. No clinically significant rare or novel variants were found associated with the genetically complex ABO blood group system. For the Rh blood group system, one novel and 16 rare variants were found. Our detailed blood group profiling results provide a starting point for the creation of an Australian blood group variant database.\\n\\nKey pointsO_LIWe identified unique blood group variants among the healthy older Australian population compared with global data using RBCeq software.\\nC_LIO_LIOur detailed blood group profiling result may be a starting point for the creation of an Australian blood group variant database.\\nC_LI\",\n \"Association of Egg Consumption, Metabolic Markers, and Risk of Cardiovascular Diseases: A Nested Case-control Study\\nObjectiveTo simultaneously explore the associations of self-reported egg consumption with plasma metabolic markers and these markers with CVD risk.\\n\\nMethodsTotally 4,778 participants (3,401 CVD cases subdivided into subtypes and 1,377 controls) aged 30-79 were selected from a nested case-control study based on the China Kadoorie Biobank. Targeted nuclear magnetic resonance was used to quantify 225 metabolites and derived traits in baseline plasma samples. Linear regression was conducted to assess associations between self-reported egg consumption and metabolic markers, which were further compared with associations between metabolic markers and CVD risk.\\n\\nResultsEgg consumption was associated with 24 out of 225 markers, including positive associations for apolipoprotein A1, acetate, mean HDL diameter, and lipid profiles of very large and large HDL, and inverse associations for total cholesterol and cholesterol esters in small VLDL. Among these 24 markers, 14 of them were associated with CVD risk. In general, the associations of metabolic markers with egg consumption and of metabolic markers with CVD risk showed opposite patterns.\\n\\nConclusionsIn the Chinese population, egg consumption is associated with several metabolic markers, which may partially explain the protective effect of egg consumption on CVD.\",\n \"Role of physiotherapy team in critically ill COVID-19 patients pronation: can a multidisciplinary management reduce the complications rate?\\nObjectivesDuring the pandemic, critically ill COVID-19 patients management presented an increased workload for Intensive Care Unit (ICU) nursing staff, particularly during pronation maneuvers, with high risk of complications. In this scenario, a support during pronation by the ICU Physiotherapy Team was introduced.\\n\\nResearch methodologyRetrospective analysis. Consecutive critically ill COVID-19 patients.\\n\\nSettingA COVID-19 Center in southern Switzerland, between March 16th and April 30th, 2020.\\n\\nMain Outcome MeasuresRates and characteristics of pronation-related complications.\\n\\nResultsForty-two patients on mechanical ventilation (MV) were treated; 296 standard prone/supine positioning were performed, with 3.52 cycles/patient. One (0.3%) major complication was observed, while fourteen (33.3%) patients developed minor complications, e.g. pressure injuries. The incidence of pressure sores was related to ICU length-of-stay (LOS) (p = 0.029) and MV days (p = 0.015), while their number (n = 27) further correlated with ICU LOS (p = 0.001) and MV days (p = 0.001). The propensity matching score analysis did not show any protective factor of pronation regarding pressure injuries (p = 0.448). No other significant correlation was found.\\n\\nConclusionThe specific pronation team determined a low rate of major complications in critically ill COVID19 patients. The high rate of minor complications appeared to be related to disease severity, rather than from pronation.\",\n \"Voice of the patient: Emergence of new motor and non-motor symptoms in early Parkinsons Disease?\\nObjectiveTo explore the utility of using patient reported emergence of new symptoms (ES) as an outcome measure during the early phase of the disease.\\n\\nMethodsWe analyzed data from MDS-UPDRS Part IB and Part II from the Safety, Tolerability, and Efficacy Assessment of Isradipine for PD (STEADY-PD3) study, with at least one annual follow-up over two years. We divided the sample into categories of follow-up visit (between 0 and 12-months, and 13 and 24-months) and the number of ES for each part of the scale between participants who started symptomatic treatment and those who did not (STx-yes/no). We assessed ES differences between participants STx in each follow-up visit using Mann-Whitney U test, and the Kaplan-Meier analyses.\\n\\nResultsOf 331 participants observed for months 0 to 12, 288 (87%) developed ES, and 182 (55%) started STx. For Part IB, the median number of ES did not significantly differ between the STx groups (Z=-0.86, p = 0.39), while for Part 2, the number of ES was significantly higher for the STx-yes group (Z=-2.38, p=0.02). Of 148 participants who continued to be observed for months 13 to 24, 114 (77%) developed ES, and 62 (42%) started STx. For Part IB, the median number of ES did not significantly differ between the STx groups (Z=-0.33, p = 0.74), while for Part 2, the number of ES was significantly higher for the STx-yes group (Z=-2.25, p=0.02).\\n\\nConclusionsAssessing ES among patient-reported experiences of daily living may provide a useful marker for tracking PD progression.\",\n \"Deep Learning based Intraretinal Layer Segmentation using Cascaded Compressed U-Net\\nAO_SCPLOWBSTRACTC_SCPLOWIntraretinal layer segmentation on macular optical coherence tomography (OCT) images generates non invasive biomarkers querying neuronal structures with near cellular resolution. While first deep learning methods have delivered promising results with high computing power demands, a reliable, power efficient and reproducible intraretinal layer segmentation is still an unmet need. We propose a cascaded two-stage network for intraretinal layer segmentation, with both networks being compressed versions of U-Net (CCU-INSEG). The first network is responsible for retinal tissue segmentation from OCT B-scans. The second network segments 8 intraretinal layers with high fidelity. By compressing U-Net, we achieve 392- and 26-time reductions in model size and parameters in the first and second network, respectively. Still, our method delivers almost similar accuracy compared to U-Net without additional constraints of computation and memory resources. At the post-processing stage, we introduce Laplacian-based outlier detection with layer surface hole filling by adaptive non-linear interpolation. We trained our method using 17,458 B-scans from patients with autoimmune optic neuropathies, i.e. multiple sclerosis, and healthy controls. Voxel-wise comparison against manual segmentation produces a mean absolute error of 2.3m, which is 2.5x better than the devices own segmentation. Voxel-wise comparison against external multicenter data leads to a mean absolute error of 2.6m for glaucoma data using the same gold standard segmentation approach, and 3.7m mean absolute error compared against an externally segmented reference data set. In 20 macular volume scans from patients with severe disease, 3.5% of B-scan segmentation results were rejected by an experienced grader, whereas this was the case in 41.4% of B-scans segmented with a graph-based reference method.\",\n \"A high-throughput microfluidic nano-immunoassay for detecting anti-SARS-CoV-2 antibodies in serum or ultra-low volume dried blood samples\\nNovel technologies are needed to facilitate large-scale detection and quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specific antibodies in human blood samples. Such technologies are essential to support seroprevalence studies, vaccine clinical trials, and to monitor quality and duration of immunity. We developed a microfluidic nano-immunnoassay for the detection of anti-SARS-CoV-2 IgG antibodies in 1024 samples per device. The method achieved a specificity of 100% and a sensitivity of 98% based on the analysis of 289 human serum samples. To eliminate the need for venipuncture, we developed low-cost, ultra-low volume whole blood sampling methods based on two commercial devices and repurposed a blood glucose test strip. The glucose test strip permits the collection, shipment, and analysis of 0.6 {micro}L whole blood easily obtainable from a simple fingerprick. The nano-immunoassay platform achieves high-throughput, high sensitivity and specificity, negligible reagent consumption, and a decentralized and simple approach to blood sample collection. We expect this technology to be immediately applicable to current and future SARS-CoV-2 related serological studies and to protein biomarker diagnostics in general.\",\n \"Association between comorbidities and death from COVID-19 in different age groups\\nBackgroundThis new COVID-19 pandemic challenges health systems around the world; therefore, it is extremely important to determine which patients with COVID-19 can evolve to more severe outcomes. Accordingly, we decided to assess the role that comorbidities play in death from COVID-19.\\n\\nMethodsTwo age groups (<60 and [≥] 60 years) were defined for analysis. Decision trees were made to identify which comorbidities had the highest fatality rate (FR). Multiple logistic regressions were performed to measure the association between comorbidities and death.\\n\\nResultsA significant difference was found between the FR of <60 group and [≥] 60 group. The most frequent comorbidity were cardiac diseases and diabetes. The combination of comorbidities with the highest FR was diabetes with kidney disease. Combinations of more than two comorbidities presented higher FR. The comorbidities had higher Odd ratios in the younger group than in the older group.\\n\\nConclusionsComorbidities seem to play a greater role in death from COVID-19 in the younger group, while in the> 60 group; age seems to be the most important factor. We assigned a score to the comorbidities and their combinations for both age groups to help the health personnel make decisions.\",\n \"Evaluating the effects of second-dose vaccine-delay policies in European countries: A simulation study based on data from Greece\\nThe results of a simulation-based evaluation of several policies for vaccine rollout are reported, particularly focusing on the effects of delaying the second dose of two-dose vaccines. In the presence of limited vaccine supply, the specific policy choice is a pressing issue for several countries worldwide, and the adopted course of action will affect the extension or easing of non-pharmaceutical interventions in the next months. We employ a suitably generalised, age-structure, stochastic SEIR (Susceptible [->] Exposed [->] Infectious [->] Removed) epidemic model that can accommodate quantitative descriptions of the major effects resulting from distinct vaccination strategies. The different rates of social contacts among distinct age-groups (as well as some other model parameters) are informed by a recent survey conducted in Greece, but the conclusions are much more widely applicable. The results are summarised and evaluated in terms of the total number of deaths and infections as well as life years lost. The optimal strategy is found to be one based on fully vaccinating the elderly/at risk as quickly as possible, while extending the time-interval between the two vaccine doses to 12 weeks for all individuals below 75 years old, in agreement with epidemic theory which suggests targeting a combination of susceptibility and infectivity. This policy, which is similar to the approaches adopted in the UK and in Canada, is found to be effective in reducing deaths and life years lost in the period while vaccination is still being carried out.\",\n \"High Brain-Derived Neurotrophic Factor (BDNF) and Negative Psychological Flexibility associate with Early Fatigue Syndrome in healthy females\\nBackgroundRecent studies showed that enhancing psychological flexibility could improve fatigue interference. Brain-Derived Neurotrophic Factor (BDNF), Heart Rate Variability (HRV), and Cortisol were proposed to involve biomarkers in psychological flexibility. Our study aims to explore the association of fatigue with psychological flexibility and related biomarkers.\\n\\nMethodA cross-sectional study gathered data from a baseline characteristic mindful volunteer. Each participant was self-evaluated with the questionnaire of fatigue and psychological flexibility. The participants were evaluated potential biomarkers related to psychological flexibility including HRV, serum cortisol, and BDNF within one week after responding to the questionnaire.\\n\\nResultsThe 47 healthy females including 22 nurses and 25 occupational therapy students, mean age 29.70 {+/-} 12.55 years. The prevalence of fatigue is 38.30%. The multivariate analysis showed the independent factors associated with fatigue including negative psychological flexibility (OR 1.31, p=0.03) and high BDNF (OR 1.33, p=0.05).\\n\\nConclusionOur study found that psychological flexibility and high BDNF was independent factors associate with fatigue. This result provide insight that intervention that increase either psychological flexibility may prevent fatigue symptoms. The high BDNF may reflex the adaptive response of fatigue person and may be potential biomarkers for detecting early fatigue conditions.\",\n \"Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study: Study Design\\nThe Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults at risk for coronavirus disease 2019 (COVID-19) comprising 14 established United States (US) prospective cohort studies. For decades, C4R cohorts have collected extensive data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R will link this pre-COVID phenotyping to information on SARS-CoV-2 infection and acute and post-acute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and broadly reflects the racial, ethnic, socioeconomic, and geographic diversity of the US. C4R is ascertaining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations, and high-quality events surveillance. Extensive pre-pandemic data minimize referral, survival, and recall bias. Data are being harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these will be pooled and shared widely to expedite collaboration and scientific findings. This unique resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including post-acute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term trajectories of health and aging.\",\n \"The role of the uncinate fasciculus in the risk-architecture of bipolar disorders: A meta-analysis\\nBackgroundBipolar disorder (BD) is a severe mental disorder, characterized by prominent mood swings and emotion regulation (ER) deficits. The uncinate fasciculus (UF), a white matter tract connecting the amygdala and the ventral prefrontal cortex, has been implicated in ER. Aberrancies in UF microstructure may be an endophenotype associated with increased risk for BD. However, findings in individuals with BD and at familial risk for BD (AR) have yielded inconsistent findings. This meta-analysis takes a region-of-interest approach to consolidate the available evidence and elucidate the role of the UF in the risk-architecture of BD.\\n\\nMethodsUsing web-based search engines, we identified diffusion tensor imaging studies focusing on the left and right UF and conducted meta-analyses comparing fractional anisotropy (FA) and radial diffusivity (RD) between BD or AR to healthy volunteers (HV).\\n\\nResultsWe included 32 studies (nBD=1186, nHV=2001; nAR=289, nHV=314). Compared to HV, individuals with BD showed lower FA in the right (p<.0001) and left UF (p=.010), and higher RD in the right UF (p=.009). We found no significant differences between AR and HV. In the right but not the left UF, AR individuals showed higher FA than BD (p=.043).\\n\\nConclusionComparable UF microstructure between AR and HV and higher FA in the right UF in AR compared to BD suggest that aberrancies in UF microstructure is not an endophenotype for BD. Longitudinal studies are needed to determine when UF abnormalities emerge in the context of BD.\",\n \"Preexisting diabetes and COVID-associated hyperglycaemia in patients with COVID-19 pneumonia\\nAO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSAimC_ST_ABSThe aim of the current study was to compare clinical characteristics, laboratory findings and major outcomes of patients hospitalized for COVID-19 pneumonia with COVID-associated hyperglycaemia or preexisting diabetes.\\n\\nMethodsA cohort of 176 adult patients with a diagnosis of pre-existing diabetes (n=112) or COVID-associated hyperglycaemia (n=55) was studied. Clinical outcomes and laboratory findings were analysed according to the presence of the two conditions. The time to viral clearance was assessed during the follow-up after hospital discharge.\\n\\nResultPatients with COVID-associated hyperglycaemia had lower BMI, significantly less comorbidities and higher levels of inflammatory markers and indicators of multi-organ injury than those with preexisting diabetes. No differences between preexisting diabetes and COVID-associated hyperglycaemia were evident for symptoms at admission, humoral response against SARS-CoV-2 or autoantibodies to glutamic acid decarboxylase or interferon alpha-4. COVID-associated hyperglycaemia was independently associated with the risk of adverse clinical outcome defined as ICU admission or death (HR 2.11, 95% CI 1.34-3.31; p=0.001), even after adjustment for age, sex and other selected variables associated with COVID-19 severity. Furthermore, we documented a negative association (HR 0.661, 95% CI 0.43-1.02; p=0.063) between COVID-associated hyperglycaemia and the time to swab negativization.\\n\\nConclusionsThe recognition of hyperglycaemia as a specific clinical entity associated with COVID-19 pneumonia is relevant for early and appropriate patient management and close monitoring for the progression of disease severity.\",\n \"Rapid Screening of COVID-19 Disease Directly from Clinical Nasopharyngeal Swabs using the MasSpec Pen Technology\\nThe outbreak of COVID-19 has created an unprecedent global crisis. While PCR is the gold standard method for detecting active SARS-CoV-2 infection, alternative high-throughput diagnostic tests are of significant value to meet universal testing demands. Here, we describe a new design of the MasSpec Pen technology integrated to electrospray ionization (ESI) for direct analysis of clinical swabs and investigate its use for COVID-19 screening. The redesigned MasSpec Pen system incorporates a disposable sampling device refined for uniform and efficient analysis of swab tips via liquid extraction directly coupled to a ESI source. Using this system, we analyzed nasopharyngeal swabs from 244 individuals including symptomatic COVID-19 positive, symptomatic negative, and asymptomatic negative individuals, enabling rapid detection of rich lipid profiles. Two statistical classifiers were generated based on the lipid information aquired. Classifier 1 was built to distinguish symptomatic PCR-positive from asymptomatic PCR-negative individuals, yielding cross-validation accuracy of 83.5%, sensitivity of 76.6%, and specificity of 86.6%, and validation set accuracy of 89.6%, sensitivity of 100%, and specificity of 85.3%. Classifier 2 was built to distinguish symptomatic PCR-positive patients from negative individuals including symptomatic PCR-negative patients with moderate to severe symptoms and asymptomatic individuals, yielding a cross-validation accuracy of 78.4% accuracy, specificity of 77.21%, and sensitivity of 81.8%. Collectively, this study suggests that the lipid profiles detected directly from nasopharyngeal swabs using MasSpec Pen-ESI MS allows fast (under a minute) screening of COVID-19 disease using minimal operating steps and no specialized reagents, thus representing a promising alternative high-throughput method for screening of COVID-19.\",\n \"How Timing of Stay-home Orders and Mobility Reductions Impacted First-Wave COVID-19 Deaths in US Counties\\nAs SARS-CoV-2 transmission continues to evolve, understanding how location-specific variations in non-pharmaceutical interventions and behaviors contributed to disease transmission during the initial epidemic wave will be key for future control strategies. We offer a rigorous statistical analysis of the relative effectiveness of the timing of both official stay-at-home orders and population mobility reductions during the initial stage of the US epidemic. We use a Bayesian hierarchical regression to fit county-level mortality data from the first case on Jan 21 2020 through Apr 20 2020 and quantify associations between the timing of stay-at-home orders and population mobility with epidemic control. We find that among 882 counties with an early local epidemic, a 10-day delay in the enactment of stay-at-home orders would have been associated with 14,700 additional deaths by Apr 20 (95% credible interval: 9,100, 21,500), whereas shifting orders 10 days earlier would have been associated with nearly 15,700 fewer lives lost (95% credible interval: 11,350, 18,950). Analogous estimates are available for reductions in mobility--which typically occurred before stay-at-home orders--and are also stratified by county urbanicity, showing significant heterogeneity. Results underscore the importance of timely policy and behavioral action for early-stage epidemic control.\",\n \"epiLiver a novel tumor specific, high throughput and cost-effective blood test for specific detection of liver cancer (HCC)\\nRobust cost effective and high-throughput tests for early detection of cancer in otherwise healthy people could potentially revolutionize public-health and the heavy personal and public burden of the morbidity and mortality from cancer. Several studies have delineated tumor specific DNA methylation profiles that could serve as biomarkers for early detection of Hepatocellular Carcinoma (HCC) as well as other cancers in liquid biopsies. Several published DNA methylation markers fail to distinguish HCC DNA from DNA from other tissues and other cancers that are potentially present in plasma. We describe a set of DNA methylation signatures in HCC that are \\\"categorically\\\" distinct from normal tissues and blood DNA methylation profiles. We develop a classifier combined of 4 CG sites that is sufficient to detect HCC in TCGA HCC data set at high accuracy. A single CG site at the F12 gene is sufficient to differentiate HCC samples from thousands of other blood samples, normal tissues and 31 tumors in the TCGA and Gene Expression Omnibus (GEO) data repository (n=11,704). A \\\"next generation sequencing\\\"-targeted-multiplexed high-throughput assay was developed, which was used to examine in a clinical study plasma samples from HCC, chronic hepatitis B (CHB) patients and healthy controls (n=398). The sensitivity for HCC detection was 84.5% at a specificity of 95% and AUC of 0.94. Applying this assay for routine follow up of people who are at high risk for developing HCC could have a significant impact on reducing the morbidity and mortality from HCC.\",\n \"Feasibility of Continuous Distal Body Temperature for Passive, Early Pregnancy Detection\\nThe majority of American women become aware of pregnancy ~3-7 weeks after conception, and all must seek testing to confirm their pregnant status. The delay between conception and awareness is often a time in which contraindicated behaviors take place. However, there is long standing evidence that passive, early pregnancy detection may be possible using body temperature. To address this possibility, we analyzed 30 individuals continuous distal body temperature (DBT) in the 180 days surrounding self-reported conception in comparison to self-reported pregnancy confirmation. Features of DBT nightly maxima changed rapidly following self-reported conception, reaching uniquely elevated values after a median of 5.5 {+/-} 3.5 days, whereas individuals reported a positive pregnancy test result at a median of 14.5 {+/-} 4.2 days. Together, we were able to generate a retrospective, hypothetical alert a median of 9 {+/-} 3.9 days prior to the date at which individuals received a positive pregnancy test. Continuous temperature-derived features can provide early, passive indication of pregnancy onset. We propose these features for testing and refinement in clinical settings, and for exploration in large, diverse cohorts. The development of pregnancy detection using DBT may reduce the delay from conception to awareness and increase the agency of pregnant individuals.\",\n \"Longitudinal changes in physical activity during and after the first national lockdown due to the COVID-19 pandemic in England\\nBackgroundRecent studies have shown reduced physical activity at early stages of the COVID-19 pandemic. However, there is a lack of investigation on longitudinal changes in physical activity beyond lockdowns and stay at home orders. Moreover, it is unclear if there is heterogeneity in physical activity growth trajectories. This study aimed to explore longitudinal patterns of physical activity and factors associated with them.\\n\\nMethodsData were from the UCL COVID -19 Social Study. The analytical sample consisted of 35,915 adults in England who were followed up for 22 weeks from 24th March to 23rd August 2020. Data were analysed using growth mixture models.\\n\\nFindingsOur analyses identified six classes of growth trajectories, including three stable classes showing little change over time (62.4% in total), two classes showing decreasing physical activity (28.6%), and one class showing increasing physical activity over time (9%). A range of factors were found to be associated the class membership of physical activity trajectories, such as age, gender, education, income, employment status, and health.\\n\\nInterpretationThere is substantial heterogeneity in longitudinal changes in physical activity during the COVID-19 pandemic. However, a substantial proportion of our sample showed persistent physical inactivity or decreasing physical activity. Given the well-established linked between physical activity and health, persistent or increased physical inactivity is likely to have both immediate and long-term implications for peoples physical and mental health, as well as general wellbeing. More efforts are needed to promote physical activity during the pandemic and beyond.\\n\\nFundingNuffield Foundation, UK Research and Innovation, Wellcome Trust\",\n \"Single cell sequencing reveals expanded cytotoxic CD4+ T cells and two states of peripheral helper T cells in synovial fluid of ACPA+ RA patients\\nRheumatoid arthritis is an autoimmune disease affecting the synovial joints where different subsets of CD4+ T cells are suspected to play a pathogenic role. So far, our understanding of the contribution of cytotoxic CD4+ T cells is incomplete, particularly in the context of the recently described peripheral helper T-cell subset (TPH). Here, using single cell sequencing and multi-parameter flow cytometry, we show that cytotoxic CD4+ T cells are enriched in synovial fluid of anti-citrullinated peptides antibody (ACPA)-positive RA patients. We identify two distinct TPH states differentially characterized by the expression of CXCL13 and PRDM1, respectively. Our data reveal that the adhesion G-Protein Coupled Receptor 56 (GPR56), a marker of circulating cytotoxic cells, delineates the synovial TPH CD4+ T-cell subset. At the site of inflammation, GPR56+CD4+ T cells expressed the tissue-resident memory markers LAG-3, CXCR6 and CD69. Further, TCR clonality analysis revealed that most expanded clones in SF are contained within the cytotoxic and the CXCL13+ TPH CD4+ T-cell populations. Finally, the detection of common TCRs between the two TPH and cytotoxic CD4+ T-cell clusters suggest a shared differentiation. Our study provides comprehensive immunoprofiling of the heterogenous T-cell subsets at the site of inflammation in ACPA+ RA and suggests GPR56 as a therapeutic target to modulate TPH cells and cytotoxic CD4+ T cell function.\",\n \"Amyloid-associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer\\nFor optimal design of anti-amyloid-{beta} (A{beta}) and anti-tau clinical trials, it is important to understand how A{beta} and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with PET and subsequent cognitive decline across the Alzheimers disease (AD) continuum. In early stages of AD, increased concentration of soluble CSF p-tau was the main driver of accumulation of insoluble tau aggregates across the brain, and mediated the effect of A{beta} on tau aggregation. Further, higher soluble p-tau concentrations were mainly related to faster accumulation of tau aggregates in the regions with strong functional connectivity to individual tau epicenters. In this early stage, higher soluble p-tau concentrations were associated with cognitive decline, which was mediated by faster increase of tau aggregates. In AD dementia, when A{beta} fibrils and soluble p-tau levels have plateaued, cognitive decline was driven by the accumulation rate of insoluble tau aggregates. Our data suggest that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD.\",\n \"Simulating the impact of different vaccination policies on the COVID-19 pandemic in New York City\\nPurposeTo analyze potential COVID-19 epidemic outcomes in New York City under different SARS-CoV-2 virus circulation scenarios and vaccine rollout policies from early Jan 2021 to end of June 2021.\\n\\nKey findingsIn anticipation of the potential arrival and dominance of the more infectious SARS-CoV-2 variant:\\n\\nO_LIMass-vaccination would be critical to mitigating epidemic severity (26-52% reduction in infections, hospitalizations, and deaths, compared to no vaccination, provided the new UK variant supplants currently circulating variants).\\nC_LIO_LIPrioritizing key risk groups for earlier vaccination would lead to greater reductions in hospitalizations and deaths than infections. Thus, in general this would be a good strategy.\\nC_LIO_LICurrent vaccination prioritization policy is suboptimal. To avert more hospitalizations and deaths, mass-vaccination of all individuals 65 years or older should be done as soon as possible. For groups listed in the same phase, 65+ year-olds should be given first priority ahead of others.\\nC_LIO_LIAvailable vaccine doses should be given to the next priority groups as soon as possible without awaiting hesitant up-stream groups.\\nC_LIO_LIWhile efficacy of vaccination off-protocol is unknown, provided immune response following a first vaccine dose persists, delaying the 2nd vaccine dose by [~]1 month (i.e. administer the two doses 8 weeks apart) can substantially reduce infections, hospitalizations, and deaths compared to the 3-week apart regimen. Across all scenarios tested here, delaying the 2nd vaccine dose leads to the largest reduction in severe epidemic outcomes (e.g. hospitalizations and deaths). Therefore, to protect as many people as possible, this strategy should be considered if rapid increases in infections, hospitalization or deaths and/or shortages in vaccines were to occur.\\nC_LI\",\n \"Social relationships and activities following elimination of SARS-CoV-2: a qualitative cross-sectional study\\nObjectivesTo investigate how successfully SARS-CoV-2 elimination strategies fulfil their promise of allowing a return to a normal social life, and to identify obstacles and challenges that may inhibit the realisation of this goal.\\n\\nDesignQualitative cross-sectional survey.\\n\\nSettingNew Zealand community cohort.\\n\\nParticipants1040 respondents entered the study (18-90 years, M = 48.18.11, SD = 15.52, 76% women). 966 completed the questions relevant to this article. Participants were recruited via online advertisement campaigns designed to maximise variation in the sample as far as practicably possible.\\n\\nMain outcome measuresThematic analysis of participants narratives.\\n\\nResultsA majority of participants reported that the elimination of SARS-CoV-2 had allowed their life to go back to being more or less the same as before the pandemic. A small number indicated the pandemic had inspired them to become more social following elimination. Nevertheless, a sizeable minority of respondents reported being less social, even many months after SARS-CoV-2 had been eliminated. This was often because of fears that the virus might be circulating undetected, or because the March-May 2020 lockdown had led to changes in relationships and personal habits that were not easily reversed. Becoming less social was associated with having an underlying health condition that heightened ones vulnerability to COVID-19 (p = 0.00005) and older age (p = 0.007).\\n\\nConclusionsElimination strategies can successfully allow the public to return to a pre-pandemic normal - or reinvent and improve their social lives should they wish. However, such outcomes are not inevitable. Re-establishing social connections after elimination can sometimes be a challenging process, with which people may need support. Plans for providing such support should be an integral part of elimination strategies.\",\n \"Effects of Diabetes and Blood Glucose on COVID-19 Mortality: A Retrospective Observational Study\\nOBJECTIVETo investigate the association of diabetes and blood glucose on mortality of patients with Coronavirus Disease 2019 (COVID-19).\\n\\nRESEARCH DESIGN AND METHODSThis was a retrospective observational study of all patients with COVID-19 admitted to Huo-Shen-Shan Hospital, Wuhan, China. The hospital was built only for treating COVID-19 and opened on February 5, 2020. The primary endpoint was all-cause mortality during hospitalization.\\n\\nRESULTSAmong 2877 hospitalized patients, 13.5% (387/2877) had a history of diabetes and 1.9% (56/2877) died in hospital. After adjustment for confounders, patients with diabetes had a 2-fold increase in the hazard of mortality as compared to patients without diabetes (adjusted HR 2.11, 95%CI: 1.16-3.83, P=0.014). The on-admission glucose (per mmol/L[≥]4mmol/L) was significantly associated with subsequent mortality on COVID-19 (adjusted HR 1.17, 95%CI: 1.10-1.24, P<0.001).\\n\\nCONCLUSIONSDiabetes and on-admission glucose (per mmol/L[≥]4mmol/L) are associated with increased mortality in patients with COVID-19. These data support that blood glucose should be properly controlled for possibly better survival outcome in patients with COVID-19.\",\n \"Functional implications of aging-related lncRNAs for predicting prognosis and immune status in glioma patients\\nGlioma, is the most prevalent intracranial tumor with high recurrence and mortality rate. Long noncoding RNAs (lncRNAs) play a critical role in the occurrence and progression of tumors as well as in aging regulation. Our study aimed to establish a new glioma prognosis model by integrating aging-related lncRNAs expression profiles and clinical parameters in glioma patients from the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) datasets. The Pearson correlation analysis (|R|> 0.6, P<0.001) was performed to explore the aging-related lncRNAs, and univariate cox tregresion and least absolute shrinkage and selection operator (LASSO) regression were used to screening prognostic signature in glioma patients. Based on the fifteen lncRNAs, we can divide glioma patients into three subtypes, and developed a prognostic model. Kaplan-Meier survival curve analysis showed that low-risk patients had longer survival time than high-risk group. Principal component analysis indicated that aging-related lncRNAs signature had a clear distinction between high- and low-risk groups. We also found that fifteen target lncRNAs were closely correlated with 119 genes by establishing a co-expression network. In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis displayed different function and pathways enrichment in high-and low-risk groups. The different missense mutations were observed in two groups, and the most frequent variant types were single nucleotide polymorphism (SNP). This study demonstrated that the novel aging-related lncRNAs signature had an important prognosis prediction and may contribute to individual treatment for glioma.\",\n \"Comparison of Phase Angle Using Bioelectrical Impedance Analysis According to Device Type and Examination Posture\\nBackgroundBioelectrical impedance analysis (BIA) is gaining popularity as a body composition assessment tool for patients. Although it has been studied and validated in different populations, age groups, and clinical settings, including critically ill patients, there are concerns about BIA reproducibility and reliability in different device types and postures. This study aimed to evaluate the reliability of BIA according to different devices, postures, and lead types.\\n\\nMethodsCross-sectional observational data of 74 healthy volunteers (32 women and 42 men) were collected. We used two types of devices, three types of postures (standing, sitting, and lying), and two lead types (clamp lead and adhesive lead) to measure the whole-body phase angle (phA) at a single frequency of 50 kHz. The measurements were validated using the intraclass correlation coefficient (ICC) and Bland-Altman plot analysis.\\n\\nResultsAll phA measurements recorded with two types of devices, three different postures, and two types of leads were equivalent to each other (mean ICC = 0.9932, 95% confidence interval (CI) 0.9905-0.0053). The average mean difference in phA was 0.31 (95% CI 0.16- 0.46). The largest phA value was measured using BWA with an adhesive-type lead in the lying position. There were no differences between standing and sitting positions.\\n\\nConclusionThis is the first study to show the consistency and reliability of BIA in measuring phA using different devices, lead types, and postures. This could provide the confidence that BIA can be used in various clinical settings.\",\n \"Validation of motor and functional scales for the evaluation of adult patients with 5q spinal muscular atrophy\\nObjectiveTo assess in adult spinal muscular atrophy (SMA) patients the construct validity and responsiveness of several outcome measures.\\n\\nMethodsPatients older than 15 years and followed-up at least for 6 months, between October 2015 and August 2020, with one motor function scale (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb module, RULM) in five referral centers were included. Bedside functional scales (Egen Klassification, EK2; Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, ALSFRS-R) were also collected when available. Correlations and regression models were performed to evaluate the construct validity. The monthly slopes of change were used to calculate their responsiveness.\\n\\nResultsThe study included 79 SMA patients, followed up for a mean of 16 months. All scales showed strong or very strong correlations with each other. A floor effect in motor function scales was found in weakest patients (HFMSE < 5 and RULM<10), and a ceiling effect in stronger patients (with HFMSE >55 and RULM > 35), when compared with other scales. ALSFRS-R (B=0.72) showed a strong discriminating ability between walkers, sitters, and non-sitters, and HFMSE (B=0.86) between walkers and sitters. The responsiveness was overall low, although in treated patients a moderate responsiveness was found for ALSFRS-R and HFMSE in walkers (0.69 and 0.61 respectively), and for EK2 in sitters (0.65) and non-sitters (0.60).\\n\\nConclusionsThis study shows the validity in SMA adult patients of commonly used scales. Overall, bedside functional scales showed some advantages over motor function scales, although all scales showed low responsiveness in untreated patients.\",\n \"HAVAs: Alzheimer s Disease Detection using Normative and Pathological Lifespan Models\\nIn this paper, we present an innovative MRI-based method for Alzheimers Disease (AD) detection and mild cognitive impairment (MCI) prognostic, using lifespan trajectories of brain structures. After a full screening of the most discriminant structures between AD and normal aging based on MRI volumetric analysis of 3032 subjects, we propose a novel Hippocampal-Amygdalo-Ventricular Alzheimer score (HAVAs) based on normative lifespan models and AD lifespan models. During a validation on three external datasets on 1039 subjects, our approach showed very accurate detection (AUC [≥] 94%) of patients with AD compared to control subjects and accurate discrimination (AUC=78%) between progressive MCI and stable MCI (during a 3 years follow-up). Compared to normative modelling and recent state-of-the-art deep learning methods, our method demonstrated better classification performance. Moreover, HAVAs simplicity makes it fully understandable and thus well-suited for clinical practice or future pharmaceutical trials.\",\n \"A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank\\nGenome-first approaches to analyzing rare variants can reveal new insights into human biology and disease. Because pathogenic variants are often rare, new discovery requires aggregating rare coding variants into gene burdens for sufficient power. However, a major challenge is deciding which variants to include in gene burden tests. Pathogenic variants in MYBPC3 and MYH7 are well-known causes of hypertrophic cardiomyopathy (HCM), and focusing on these positive control genes in a genome-first approach could help inform variant selection methods and gene burdening strategies for other genes and diseases. Integrating exome sequences with electronic health records among 41,759 participants in the Penn Medicine BioBank, we evaluated the performance of aggregating predicted loss-of-function (pLOF) and/or predicted deleterious missense (pDM) variants in MYBPC3 and MYH7 for gene burden phenome-wide association studies (PheWAS). The approach to grouping rare variants for these two genes produced very different results: pLOFs but not pDM variants in MYBPC3 were strongly associated with HCM, whereas the opposite was true for MYH7. Detailed review of clinical charts revealed that only 38.5% of patients with HCM diagnoses carrying an HCM-associated variant in MYBPC3 or MYH7 had a clinical genetic test result. Additionally, 26.7% of MYBPC3 pLOF carriers without HCM diagnoses had clear evidence of left atrial enlargement and/or septal/LV hypertrophy on echocardiography. Our study shows the importance of evaluating both pLOF and pDM variants for gene burden testing in future studies to uncover novel gene-disease relationships and identify new pathogenic loss-of-function variants across the human genome through genome-first analyses of healthcare-based populations.\",\n \"Distinct microRNA expression signatures of primary and secondary central nervous system lymphomas\\nCentral nervous system (CNS) lymphoma is a rare and aggressive non-Hodgkin lymphoma that might arise in the CNS (primary CNS lymphoma, PCNSL) or disseminates from a systemic lymphoma to the CNS (secondary CNS lymphoma, SCNSL). Dysregulated expression of microRNAs (miRNAs) is associated with various pathological processes and miRNA expression patterns may have diagnostic, prognostic and therapeutic implications. However, miRNA expression is understudied in CNS lymphomas. Here, we performed expression analysis of 798 miRNAs in 73 CNS lymphoma samples using the NanoString platform, followed by a detailed statistical analysis to identify potential novel biomarkers characterizing subgroups and to examine differences based on their primary and secondary nature, molecular subtype, mutational patterns and survival. We describe the general expression patterns of miRNAs across CNS lymphoma samples and identified 31 differentially expressed miRNAs between primary and secondary groups. Additionally, we identified 7 more miRNAs associated with a molecular subtype and 25 associated with mutation status. Using unsupervised clustering methods, we defined a small but distinct primary CNS lymphoma subgroup, with characteristically different expression patterns compared to the rest of the cases. Finally, we identified differentially regulated pathways in the above comparisons and assessed the utility of miRNA expression patterns in predicting survival. Our study identifies a novel CNS lymphoma subgroup defined by distinct miRNAs, proves the importance of specific miRNAs and pathways in their pathogenesis, and provides the basis for future research.\",\n \"Death, Demography and the Denominator: Age-Adjusted Influenza-18 Mortality in Ireland\\nUsing the Irish experience of the Spanish flu, we demonstrate that pandemic mortality statistics are sensitive to the demographic composition of a country. We build a population database for Irelands 32 counties with vital statistics on births, ageing, migration and deaths. We show how age-at-death statistics in 1918 and 1919 should be used to construct the age-adjusted mortality statistics necessary to make comparisons across time and space. We conclude that studies of the economic consequences of Influenza-18 and Covid-19 must better control for demographic factors if they are to yield useful policy-relevant results. For example, while Northern Ireland has a higher crude death rate in the current pandemic, it also has an older population; age-adjusted mortality paints a very different picture.\",\n \"Structural disconnectome mapping of cognitive function in post-stroke patients\\nSequalae following stroke represents a significant challenge in current rehabilitation. The location and size of focal lesions are only moderately predictive of the diverse cognitive outcome after stroke. One explanation building on recent work on brain networks proposes that the cognitive consequences of focal lesions are caused by damages to anatomically distributed brain networks supporting cognition rather than specific lesion locations. To investigate the association between post-stroke structural disconnectivity and cognitive performance, we estimated individual level whole-brain disconnectivity probability maps based on lesion maps from 102 stroke patients using normative data from healthy controls. Cognitive performance was assessed in the whole sample using Montreal Cognitive Assessment, and a more comprehensive computerized test protocol was performed on a subset (n=82). Multivariate analysis using Partial Least Squares on the disconnectome maps revealed that higher disconnectivity in right insular and frontal operculum, superior temporal gyrus and putamen was associated with poorer MoCA performance, indicating that lesions in regions connected with these brain regions are more likely to cause cognitive impairment. Furthermore, our results indicated that disconnectivity within these clusters was associated with poorer performance across multiple cognitive domains. These findings demonstrate that the extent and distribution of structural disconnectivity following stroke are sensitive to cognitive deficits and may provide important clinical information predicting post stroke cognitive sequalae.\",\n \"Molecular portrait of prostate tissue probed by MALDI Imaging Mass Spectrometry\\nBenign prostatic hyperplasia (BPH) is the most common condition in aging men, associated with lower urinary tract symptoms. BPH has been suggested to be a risk factor for certain urologic cancers, but the current evidence is inconsistent. The gold-standard method for the diagnosis of BPH is histopathology. Histopathology displays the cellular morphologies of tissues wherein characteristic changes pertaining specifically to BPH can be identified. However, the onset of BPH might be associated with minimal phenotypic changes in cellular morphologies in tissues that histopathology might not be able to detect successfully. Therefore, to understand the onset of a disease and its pathogenesis it is important to investigate the detailed molecular profiles associated with the disease that might help in the diagnosis and to understand the insights of the disease pathogenesis. Over the last decade, imaging mass spectrometry has been used to explore the spatial distribution and expression profiles of several molecules with their two-dimensional heterogeneity retained across the tissues. In the present study, using MALDI mass spectrometry based tissue imaging platform, we observed the expression of several proteins across human prostate tissue sections diagnosed with BPH. The proteins were identified and characterized using tissue proteomics approach. We could successfully identify the on-tissue distribution of ribonuclease T2, vinculin, isoform 2 of tropomyosin alpha-3 chain and mitochondrial citrate synthase proteins using this approach. Therefore, imaging mass spectrometry might be a potential tool to complement the findings of histopathology in diagnosis of BPH in human prostate tissues.\",\n \"Title: Health and Healthcare Variables Associated with Italy's Excess Mortality during the First Wave of the COVID-19 pandemic: An Ecological Study.\\nBackgroundHealthcare factors have strongly influenced the propagation of COVID-19. The present study aims to examine whether excess mortality during the first phase of the COVID-19 outbreak in Italy was associated with health, healthcare, demographic, and socioeconomic indicators measured at a provincial level.\\n\\nMethodsThe present ecological study concerns the raw number of deaths from Jan. 1 to Apr. 30, 2020 and the mean number of deaths in the same months of 2015 to 2019, per province. Information on socioeconomic factors and healthcare settings were extracted from the most recently updated databases on the ISTAT website. Two multilevel, multivariate models were constructed to test whether excess mortality was associated with the indicators across 107 provinces in Italy.\\n\\nResultsOn linear multilevel, multivariate analysis, AIDS mortality rate (p-value <0.05) correlates positively with excess mortality, while a higher density of General Practitioners (number of GPs per 1,000 population) is associated with lower excess mortality (p-value <0.05). After controlling for the diffusion of COVID-19 in each province, the significance of GP density increases (p-value <0.001) and the rate of hospitalization in long-term care wards is positively associated (p-value <0.05) with excess mortality.\\n\\nConclusionSome health and healthcare variables are strongly associated with excess mortality caused by COVID-19 in Italy and should be considered to implement mitigation policies and increase healthcare resilience.\",\n \"Transdiagnostic neurocognitive deficits in patients with type 2 diabetes mellitus, major depressive disorder, bipolar disorder, and schizophrenia: A 1-year follow-up study\\nBackgroundImpairments in neurocognition are critical factors in patients with major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ), and also in those with somatic diseases such as type 2 diabetes mellitus (T2DM). Intriguingly, these severe mental illnesses are associated with an increased co-occurrence of diabetes (direct comorbidity). This study sought to investigate the neurocognition and social functioning across T2DM, MDD, BD, and SZ using a transdiagnostic and longitudinal approach.\\n\\nMethodsA total of 165 subjects, including 30 with SZ, 42 with BD, 35 with MDD, 30 with T2DM, and 28 healthy controls (HC), were assessed twice at a 1-year interval using a comprehensive, integrated test battery on neuropsychological and social functioning.\\n\\nResultsCommon neurocognitive impairments in somatic and psychiatric disorders were identified, including deficits in short-term memory and cognitive reserve (p < 0.01; {eta}2p = 0.08-0.31). Social functioning impairments were observed in almost all the disorders (p < 0.0001; {eta}2p = 0.29-0.49). Transdiagnostic deficits remained stable across the 1-year follow-up (p < 0.001; {eta}2p = 0.13-0.43) and could accurately differentiate individuals with somatic and psychiatric disorders ({chi}2 = 48.0, p < 0.0001).\\n\\nConclusionsThis longitudinal study provides evidence of the overlap in neurocognition deficits across somatic and psychiatric diagnostic categories, such as T2DM, MDD, BD, and SZ, which have high comorbidity. This overlap may be a result of shared genetic and environmental etiological factors. The findings further lay forth promising avenues for research on transdiagnostic phenotypes of neurocognition in these disorders, in addition to their biological bases.\",\n \"Lack of latent tuberculosis screening in HIV patients and delay in Anti-Retroviral Therapy initiation in HIV-TB co-infection: A 11-year study in an intermediate TB-burden country\\nObjectivesTuberculosis (TB) is a common infection in HIV patients. Our study aims to determine the prevalence and characteristics of HIV-TB co-infected patients in Singapore, a high-income, intermediate TB-burden country.\\n\\nMethodsRetrospective data of 11-years was obtained from the National University Hospital (NUH), a quaternary care hospital and the National Centre for Infectious Diseases, the national HIV centre.\\n\\nResultsFrom December 2005 to December 2016, 48 out of 819 HIV patients and 272 out of 3,196 HIV patients who were managed in NUH and TTSH respectively, were diagnosed with TB. 89.1% (n=285) were males and 2 (0.6%) were screened for latent TB on HIV diagnosis. The median age at TB diagnosis was 47.3 years old (Interquartile range, IQR 41-57). Mean CD4 count at TB diagnosis was 125.0 {+/-} 153.9 cells/mm3. 124 (38.6%) patients had CD4 < 50 cells/mm3. 41.3% (n=132) of patients had HIV diagnosed at least 6 weeks before TB diagnosis, indicating an opportunity to initiate latent TB preventive therapy. 55.0% (n=176) had HIV and TB concomitantly diagnosed within 6 weeks whilst 2.25% (n=7) had TB diagnosed before HIV. Of those HIV-TB co-infected patients with CD4 [≤] 50 cells/mm3, 18 (14.2%) had anti-retroviral therapy (ART) started <2 weeks. TB-related mortality was 5.3% (n=17) and 3.75% (n=12) were lost to follow-up.\\n\\nConclusionThere is a lack of latent TB screening in HIV patients and a delay in initiation of ART in HIV-TB patients with low CD4 counts in our study. Clinical practices can be further improved for the benefit of outcomes in HIV-TB patients.\",\n \"Characterization of the gene expression profile in younger and older low-grade glioma patients\\nLow-grade gliomas (LGG) are the slowest growing type of brain cancer that often affects young adults. Of all LGG cases, older patients were associated with the poor prognosis compared to younger patients. However, the molecular mechanism underlying this association remains unclear. Here, we compared genes expression profiles between younger (age[≤]50) and older (age > 50) patients from The Cancer Genome Atlas (TCGA) and demonstrate the age-related gene expressions. Pathway and gene set enrichment analysis reveal that differentially expressed genes (DEGs) between tumors of older and younger patients have been involved in cancer-related biological procedures, such as, transcriptional misregulation in cancer, nucleotide synthesis, mTOR, and DNA damage repair signaling. We also demonstrated that older patients have higher expression of Mitosis Kinase Score (MKS) and Tumor Inflammation Signature (TIS) which reflects high cell proliferation and high immune cell activity; respectively. The comprehensive characterization of gene-expression profiles in younger versus older LGG may explain the age-related prognosis and facilitate the development of potential therapeutic biomarkers for LGG.\",\n \"Effective connectivity during faces processing in major depression: Distinguishing markers of pathology, risk, and resilience\\nBackgroundAberrant brain connectivity during emotional processing, especially within the fronto-limbic pathway, is one of the hallmarks of major depressive disorder (MDD). However, a lack of systematic approaches in previous studies made it difficult to determine whether a specific alteration in brain connectivity reflects a cause, correlate, or effect of the disorder. The current study aimed to investigate neural mechanisms that correspond to disease, risk and resilience in major depression during implicit processing of emotion cues.\\n\\nMethodsForty-eight patients with MDD, 49 first-degree relatives of patients with MDD and 103 healthy controls performed a face-matching task during functional magnetic resonance imaging. We used dynamic causal modelling to estimate task-dependent effective connectivity at the subject level. Parametric empirical Bayes was then performed to quantify group differences in effective connectivity.\\n\\nResultsDepressive pathology was associated with decreased effective connectivity from the left amygdala and left dorsolateral prefrontal cortex to the right fusiform gyrus, whereas familial risk for depression corresponded to decreased connectivity from the right orbitofrontal cortex to the left insula and from the left orbitofrontal cortex to the right fusiform gyrus. Resilience for depression was related to increased connectivity from the anterior cingulate cortex to the left dorsolateral prefrontal cortex.\\n\\nConclusionsOur results suggest that the depressive state alters top-down control of higher visual regions during the processing of emotional faces, whereas increased connectivity within the cognitive control network promotes resilience to depression.\",\n \"Early estimates of SARS-CoV-2 Omicron variant severity based on a matched cohort study, Ontario, Canada\\nWhile it is now evident that Omicron is rapidly replacing Delta, largely due to immune escape, it is less clear how the severity of Omicron compares to Delta. In Ontario, we sought to examine hospitalization and death associated with Omicron, as compared to cases infected with Delta. We conducted a matched cohort study, considering time to hospitalization or death as the outcome. Cases were matched on gender, age, vaccination status, health region and onset date. We identified 29,594 Omicron cases that met eligibility criteria, of which 11,622 could be matched with at least one Delta case (N=14,181). There were 59 (0.51%) hospitalizations and 3 (0.03%) deaths among matched Omicron cases, compared to 221 (1.6%) hospitalizations and 17 (0.12%) deaths among matched Delta cases. The risk of hospitalization or death was 65% lower (hazard ratio, HR=0.35, 95%CI: 0.26, 0.46) among Omicron cases compared to Delta cases, while risk of intensive care unit admission or death was 83% lower (HR=0.17, 95%CI: 0.08, 0.37). While severity is likely to be reduced, the absolute number of hospitalizations and impact on the healthcare system may nevertheless be significant due to the increased transmissibility of Omicron.\",\n \"BinomiRare: A carriers-only test for association of rare genetic variants with a binary outcome for mixed models and any case-control proportion\\nWhole genome and exome sequencing studies have become increasingly available and are being used to identify rare genetic variants associated with health and disease outcomes. Investigators routinely use mixed models to account for genetic relatedness or other clustering variables (e.g. family or household) when testing genetic associations. However, no existing tests of the association of a rare variant association with a binary outcome in the presence of correlated data controls the Type 1 error where there are (1) few carriers of the rare allele, (2) a small proportion of cases relative to controls, and (3) covariates to adjust for. Here, we address all three issues in developing the carriers-only test framework for testing rare variant association with a binary trait. In this framework, we estimate outcome probabilities under the null hypothesis, and then use them, within the carriers, to test variant associations. We extend the BinomiRare test, which was previously proposed for independent observations, and develop the Conway-Maxwell-Poisson (CMP) test, and study their properties in simulations. We show that the BinomiRare test always controls the type 1 error, while the CMP test sometimes does not. We then use the BinomiRare test to test the association of rare genetic variants in target genes with small vessel disease stroke, short sleep, and venous thromboembolism, in whole-genome sequence data from the Trans-Omics for Precision Medicine program.\",\n \"Behavioral Markers for Deficits in Speed of Processing in Cerebrovascular Disease\\nObjectiveTo assess overlap and uniqueness of established behavioral markers of speed of processing for different aspects of visual information within a cerebrovascular disease cohort, and to examine the link between these speed of processing markers and functional behavior, specifically walking.\\n\\nMethodsA cohort of 161 participants with cerebrovascular disease recruited to the Ontario Neurodegenerative Disease Research Initiative (ONDRI) were examined with three types of assessments: neuropsychology, saccadic eye movement and gait. Principal component analysis (PCA) and canonical correlation analysis (CCA) were performed on select variables from these assessments to reveal commonalities and discrepancies among the measures.\\n\\nResultsPCA analysis revealed different variable patterns between neuropsychology and saccade assessments, with the first component characterized primarily by neuropsychology, and the second and third components more influenced by the saccade assessments. CCA analysis did not reveal association between different types of assessments with the exception of a modest, but significant, positive association between speed of processing measures from the neuropsychological assessments and gait speed.\\n\\nDiscussionNeuropsychological tests and the pro-saccade task can be used for assessment of speed of processing for two major features of visual information, visual perception vs. spatial location. Despite a general lack of association between different types of assessments, combining gait speed as an important contributor to the models reinforces the idea of the link between speed of processing and complex function such as walking, and provides support for the importance of attending to the potential consequences of changes in speed of processing after neurologic injury.\",\n \"Effect of Digoxin on Interstage Outcomes following Stage I Palliation for Functionally Univentricular Hearts: A Systematic Review and Meta-Analysis\\nObjectivesThe goal of this systematic review and meta-analysis is to investigate the effects of digoxin on outcomes following stage I palliation for functionally univentricular hearts.\\n\\nData SourcesWe conducted electronic searches of PubMed, Ovid and Cochrane.\\n\\nStudy SelectionInclusion criteria included publication dates 1970-2018, children with functionally univentricular hearts between stage I and stage II palliation who received digoxin were compared to those who did not.\\n\\nData ExtractionWe identified 148 unique citations; 5 full-text articles were included in the final review. Data from 4 studies was pooled for meta-analysis.\\n\\nData SynthesisA total of 4 studies with 1,498 patients were included in the final analyses. Patient enrollment occurred between 2003 and 2013. A majority of patients were born full-term and approximately 25% were diagnosed with a syndrome. The most common cardiac diagnosis was hypoplastic left heart syndrome (70%). The most common initial surgical palliation was the Norwood procedure with a right ventricle to pulmonary artery conduit. The total amount of deaths was 121 (12 digoxin group versus 109 no digoxin group). The interstage mortality was reduced in the digoxin group [OR 0.25(95% CI 0.14 to 0.47)]. There was no statistically significant difference in the presence of arrhythmias or other complications.\\n\\nConclusionsThis systematic review and meta-analysis suggests that digoxin significantly decreases interstage period mortality with a concurrent significant decrease in weight for age. The odds of arrhythmia or other complications are not significantly different with digoxin based on current data.\",\n \"A brain structural connectivity biomarker for diagnosis of autism spectrum disorder in early childhood\\nObjectiveAutism spectrum disorder (ASD) is associated with altered brain development, but it is unclear which specific structural changes may serve as potential diagnostic markers. This study aimed to identify and model brain-wide differences in structural connectivity using MRI diffusion tensor imaging (DTI) in young ASD and typically developing (TD) children (3{middle dot}5-6 years old).\\n\\nMethodsNinety-three ASD and 26 TD children were included in a discovery dataset and 12 ASD and 9 TD children from different sites included as independent validation datasets. Brain-wide (294 regions) structural connectivity was measured using DTI (fractional anisotropy, FA) under sedation together with symptom severity and behavioral and cognitive development. A connection matrix was constructed for each child for comparisons between ASD and TD groups. Pattern classification was performed and the resulting model tested on two independent datasets.\\n\\nResultsThirty-three structural connections showed increased FA in ASD compared to TD children and associated with both symptom severity and general cognitive development. The majority (29/33) involved the frontal lobe and comprised five different networks with functional relevance to default mode, motor control, social recognition, language and reward. Overall, classification accuracy is very high in the discovery dataset 96.77%, and 91{middle dot}67% and 88{middle dot}89% in the two independent validation datasets.\\n\\nConclusionsIdentified structural connectivity differences primarily involving the frontal cortex can very accurately distinguish individual ASD from TD children and may therefore represent a robust early brain biomarker.\",\n \"Automation of plate inoculation and reading reduces process time in the clinical microbiology laboratory, compared to a manual workflow\\nWe evaluated the benefits of automation for clinical microbiology laboratory workflow and compared the time required for culture inoculation and plate reading between manual processes and BD Kiestra (but Kiestra) automation. Kiestra automation consists of different modules, each of which facilitate different tasks and work together from specimen inoculation to results reporting. We tracked the steps and measured the associated times-to-completion for both manual and automated workflows, including number of plate touches, hands-on-time (HOT), total technologist time (TTT), and walk-away time (WAT). Manual and automated processes both included 90 samples, and a total of 180 agar plates. There were three media quantity protocols used to mimic common laboratory samples: 1) 30 urine specimens on one biplate; 2) 30 urine specimens divided across two plates; and 3) 30 blood or wound specimens divided across three plates; all cultures incubated for a minimum of 18 hours prior to reading or imaging. Automation reduced HOT by 85% and overall plate touches by 88%. Automated inoculation (through implementation of the BD InoqulA module) resulted in a 100% reduction in plate touches and created 81.5-minutes of WAT. Automation of culture reading (through implementation of the BD ReadA incubation/plate imaging module and BD Synapsys Informatics) reduced HOT by 53%. Overall, laboratory automation resulted in shorter TTT and created WAT when compared to manual processes. Automation can facilitate increased processing capacity, more efficient use of the labor force, and reduced time to results in the clinical microbiology laboratory.\",\n \"Predicting COVID-19 Vaccine Efficacy from Neutralizing Antibody Levels\\nRecent studies using data accrued from global SARS-CoV-2 vaccination efforts have demonstrated that breakthrough infections are correlated with levels of neutralizing antibodies. The decrease in neutralizing antibody titers of vaccinated individuals over time, combined with the emergence of more infectious variants of concern has resulted in waning vaccine efficacy against infection and a rise in breakthrough infections. Here we use a combination of neutralizing antibody measurements determined by a high throughput surrogate viral neutralization test (sVNT) together with published data from vaccine clinical trials and comparative plaque reduction neutralization test (PRNT) between SARS-CoV-2 variants to develop a model for vaccine efficacy (VE) against symptomatic infection. Vaccine efficacy estimates using this model show good concordance with real world data from the US and Israel. Our work demonstrates that appropriately calibrated neutralizing antibody measurements determined by high throughput sVNT can be used to provide a semi-quantitative estimate of protection against infection. Given the highly variable antibody levels among the vaccinated population, this model may be of use in identification of individuals with an elevated risk of breakthrough infections.\",\n \"Similar Rates of AKI during the First Two Waves of COVID-19 in Northern Italy: a single-center study\\nIntroductionTwo waves of COVID-19 cases have overwhelmed most European countries during 2020. It is unclear if the incidence of acute kidney injury (AKI) has changed during the COVID-19 outbreaks. This study aims to evaluate the differences in incidence, risk factors and outcome of AKI in patients with SARS-CoV-2 infection during the first and second wave of COVID-19.\\n\\nMethodWe reviewed the health medical records of 792 consecutive patients with COVID-19 hospitalized at the University Hospital of Modena, Italy, from February 25 to December 14, 2020.\\n\\nResultsAKI was diagnosed in 122 (15.4%) patients. Incidence of AKI remained steady rate during wave-1 (15.9%) and wave-2 (14.7%) (P=0.89). AKI patients were older (P=<0.001) and had a more severe respiratory impairment (PO2/FO2) (P=[≤]0.001) than their non-AKI counterparts. AKI led to a longer hospital stay (P=0.001), complicated with a higher rate of ICU admission. COVID-19-related AKI was associate with 59.7% of deaths during wave-1 and 70.6% during wave-2. At the end of the period of observation, 24% (wave-1) and 46.7% (wave-2) of survivors were discharged with a not fully recovered kidney function. Risk factors for AKI in patients with COVID-19 were diuretics (HR=5.3; 95%CI, 1.2-23.3; P=0.025) and cardiovascular disease (HR, 2.23; 95%CI, 1.05-5.1; P=0.036).\\n\\nConclusionThe incidence of AKI (about 15%) remained unchanged during 2020, regardless of the trend of COVID-19. AKI occurred in patients with severe COVID-19 symptoms and was associated with a higher incidence of deaths than non-AKI patients. The risk factors of COVID-19-related AKI were diuretic therapy and cardiovascular disease.\",\n \"High-Throughput Clinical Trial Emulation with Real World Data and Machine Learning: A Case Study of Drug Repurposing for Alzheimer's Disease\\nClinical trial emulation, which is the process of mimicking targeted randomized controlled trials (RCT) with real-world data (RWD), has attracted growing attention and interest in recent years from the pharmaceutical industry. Different from RCTs which have stringent eligibility criteria for recruiting participants, RWD are more representative of real-world patients to whom the drugs will be prescribed. One technical challenge for trial emulation is how to conduct effective confounding control with complex RWD so that the treatment effects can be objectively derived. Recently many approaches, including deep learning algorithms, have been proposed for this goal, but there is still no systematic evaluation and practical guidance on them. In this paper, we emulate 430, 000 trials from two large-scale RWD warehouses, covering both electronic health records (EHR) and general claims, over 170 million patients spanning more than 10 years, aiming to identify new indications of approved drugs for Alzheimers disease (AD). We have investigated the behaviors of multiple different approaches including logistic regression and deep learning models, and propose a new model selection strategy that can significantly improve the performance of confounding balance of the participants in different arms of emulated trials. We demonstrate that regularized logistic regression-based propensity score (PS) model outperforms the deep learning-based PS model and others, which contradicts with our intuitions to a certain extent. Finally, we identified 8 drugs whose original indications are not AD (pantoprazole, gabapentin, acetaminophen, atorvastatin, albuterol, fluticasone, amoxicillin, and omeprazole), hold great potential of being beneficial to AD patients.\",\n \"One Shot Model For The Prediction of COVID-19 and Lesions Segmentation In Chest CT Scans Through The Affinity Among Lesion Mask Features\\nWe introduce a model that segments lesions and predicts COVID-19 from chest CT scans through the derivation of an affinity matrix between lesion masks. The novelty of the methodology is based on the computation of the affinity between the lesion masks features extracted from the image. First, a batch of vectorized lesion masks is constructed. Then, the model learns the parameters of the affinity matrix that captures the relationship between features in each vector. Finally, the affinity is expressed as a single vector of pre-defined length. Without any complicated data manipulation, class balancing tricks, and using only a fraction of the training data, we achieve a 91.74% COVID-19 sensitivity, 85.35% common pneumonia sensitivity, 97.26% true negative rate and 91.94% F1-score. Ablation studies show that the method can quickly generalize to new datasets. All source code, models and results are publicly available on https://github.com/AlexTS1980/COVID-Affinity-Model.\",\n \"Retinal fundus photographs capture hemoglobin loss after blood donation\\nRecently it was shown that blood hemoglobin concentration could be predicted from retinal fundus photographs by deep learning models. However, it is unclear whether the models were quantifying current blood hemoglobin level, or estimating based on subjects pretest probability of having anemia. Here, we conducted an observational study with 14 volunteers who donated blood at an on site blood drive held by the local blood center (ie, at which time approximately 10% of their blood was removed). When the deep learning model was applied to retinal fundus photographs taken before and after blood donation, it detected a decrease in blood hemoglobin concentration within each subject at 2-3 days after donation, suggesting that the model was quantifying subacute hemoglobin changes instead of predicting subjects risk. Additional randomized or controlled studies can further validate this finding.\",\n \"The common H202D variant in GDF-15 does not affect its bioactivity but can significantly interfere with measurement of its circulating levels\\nGenetic variants in proteins can interfere with measurement of their circulating concentrations. Given the growing biomedical importance of GDF-15, we wished to establish whether a common histidine to aspartate variant present in position 6 of the mature GDF-15 protein (H202D variant) interfered with its measurement by two commonly used immunoassays. We first examined the detectability of recombinant monomers, homodimers and heterodimers of GDF-15 by assays and/or reagents used in two widely used immunoassays (Roche Elecsys(R) GDF-15 and the R&D antibody combinations used in their Quantikine(R) and DuoSet(R) ELISAs). The Roche assay detected the H and D containing peptides similarly but the assays based on the R&D reagents consistently underreported concentrations of the D-containing variant peptide. Measurements of plasma concentrations of GDF-15 in genotyped human participants showed that the R&D reagents reported values in heterozygotes were [~]25% lower, and in homozygotes, 50% lower than the Roche assay. We finally studied the activation of the GDF-15 receptor, GFRAL-Ret, in a cell based assay and found that the activities of the HH and DD containing GDF-15 peptide were indistinguishable. These results have implications for the interpretation of genetic epidemiological studies which have used the R&D reagents to measure GDF-15, and for the emerging clinical use of GDF-15 as a diagnostic and prognostic biomarker. We provide correction equations, which may be of utility for the analysis of data generated with the R&D reagents where the genotype of the participants is known.\",\n \"Longitudinal changes in brain diffusion MRI indices during and after proton beam therapy in a child with pilocytic astrocytoma: a case report\\nBackgroundProton beam therapy (PBT) is an effective pediatric brain tumor treatment. However, resulting microstructural changes within and around irradiated tumors are unknown. We retrospectively applied Diffusion-Tensor-Imaging (DTI) and Free-Water-Imaging (FWI) on diffusion-weighted Magnetic Resonance Imaging (dMRI) data to monitor microstructural changes during-PBT and after 8 months, in a pilocytic astrocytoma (PA) and normal-appearing white matter (NAWM).\\n\\nMethodsWe evaluated conventional MRI and dMRI-derived indices from six MRI sessions in a child with a hypothalamic PA: at baseline (t0), during-PBT (t1-t4), and after 8 months (t5). Tumor voxels were classified as \\\"solid\\\" or \\\"fluid\\\" based on FWI.\\n\\nResultsWhile during PBT tumor volume remained stable, dMRI analyses identified two different response patterns: i) an increase in fluid content and diffusivity with anisotropy reductions in solid voxels at t1, followed by ii) smaller variations in fluid content but higher anisotropy in solid voxels at t2-t4. At follow-up (t5), tumor volume, its fluid content, and diffusivity in solid voxels increased. NAWM showed dose-dependent microstructural changes.\\n\\nConclusionsThe use of dMRI and FWI showed complex dynamic microstructural changes in the irradiated mass during PBT and at follow-up, opening new avenues in our understanding of radiation-induced pathophysiologic mechanisms in tumor and surrounding tissues.\",\n \"A claims-based score for the prediction of bleeding in a contemporary cohort of patients receiving oral anticoagulation for venous thromboembolism\\nBackgroundCurrent scores for bleeding risk assessment in patients with venous thromboembolism (VTE) undergoing oral anticoagulation (OAC) have limited predictive capacity. We developed and internally validated a bleeding prediction model using healthcare claims data.\\n\\nMethods and ResultsWe selected patients with incident VTE in the 2011-2017 MarketScan databases initiating OAC. Hospitalized bleeding events were identified using validated algorithms in the 180 days after VTE diagnosis. We evaluated demographic factors, comorbidities, and medication use prior to OAC initiation as potential predictors of bleeding using stepwise selection of variables in Cox models ran on 1000 bootstrap samples of the patient population. Variables included in >60% of all models were selected for the final analysis. We internally validated the model using bootstrapping and correcting for optimism. We included 165,434 VTE patients initiating OAC, of which 2,294 had a bleeding event. After undergoing the variable selection process, the final model included 20 terms (15 main effects and 5 interactions). The c-statistic for the final model was 0.68 (95% confidence interval [CI] 0.67-0.69). The internally validated c-statistic corrected for optimism was 0.68 (95%CI 0.67-0.69). For comparison, the c-statistic of the HAS-BLED score in this population was 0.62 (95%CI 0.61-0.63).\\n\\nConclusionWe have developed a novel model for bleeding prediction in VTE using large healthcare claims databases. Performance of the model was moderately good, highlighting the urgent need to identify better predictors of bleeding to inform treatment decisions.\",\n \"Rapid, High-Throughput, Cost Effective Whole Genome Sequencing of SARS-CoV-2 Using a Condensed One Hour Library Preparation of the Illumina DNA Prep Kit\\nThe ongoing COVID-19 pandemic necessitates cost-effective, high-throughput, and timely genomic sequencing of SARS-CoV-2 viruses for outbreak investigations, identifying variants of concern (VoC), characterizing vaccine breakthrough infections, and public health surveillance. Additionally, the enormous demand of genomic sequencing on supply chains and the resulting shortages of laboratory supplies necessitate the use of low-reagent and low-consumable methods. Here, we report an optimized library preparation method where the same protocol can be used in a STAT scenario, from sample to sequencer in as little as eight hours, and a high-throughput scenario, where one technologist can perform 576 library preparations over the course of one 8-hour shift. This new method uses Freed et al.s 1200 bp primer sets (Biol Methods Protoc 5:bpaa014, 2020, https://doi.org/10.1093/biomethods/bpaa014) and a modified and truncated Illumina DNA Prep workflow (Illumina, CA, USA). Compared to the original, application of this new method in hundreds of clinical specimens demonstrated equivalent results to the full-length DNA Prep workflow at 45% the cost, 15% of consumables required (such as pipet tips), 25% of manual hands-on time, and 15% of on-instrument time if performing on a liquid handler, with no compromise in sequence quality. Results suggest that this new method is a rapid, simple, cost-effective, and high-quality SARS-CoV-2 whole genome sequencing protocol.\",\n \"The fragility index in randomised controlled trials of interventions for aneurysmal subarachnoid haemorrhage: a systematic review\\nBackgroundFragility analysis supplements the p-value and risk of bias assessment in the interpretation of results of randomised controlled trials. In this systematic review we determine the fragility index (FI) and fragility quotient (FQ) of randomized trials in aneurysmal subarachnoid haemorrhage.\\n\\nMethodsThis is a systematic review registered with PROSPERO (ID: CRD42020173604). Randomised controlled trials in adults with aneurysmal subarachnoid haemorrhage were analysed if they reported a statistically significant primary outcome of mortality, function (e.g. modified Rankin Scale), vasospasm or delayed neurological deterioration.\\n\\nResultsWe identified 3809 records with 17 randomized trials selected for analysis. The median fragility index was 3 (inter-quartile range 0-5) and the median fragility quotient was 0.012 (IQR 0-0.034). Six of nineteen trial outcomes (31.6%) had an fragility index of 0. In seven trials (36.8%), the number of participants lost to follow-up was greater than or equal to the fragility index. Only 17.6% of trials are at low risk of bias.\\n\\nConclusionsRandomised controlled trial evidence supporting management of aneurysmal subarachnoid haemorrhage is weaker than indicated by conventional analysis using p-values alone. Increased use of fragility analysis by clinicians and researchers could improve the translation of evidence to practice.\",\n \"Effects of bariatric surgery on functional connectivity of the reward and default mode network: a pre-registered analysis\\nObesity imposes serious health risks and involves alterations in resting-state functional connectivity of brain networks involved in eating behavior. Bariatric surgery is an effective treatment, but its effects on functional connectivity are still under debate. In this pre-registered study, we aimed to determine the effects of bariatric surgery on major resting-state brain networks (reward and default mode network) in a longitudinal controlled design. 33 bariatric surgery patients and 15 obese waiting-list control patients (37 females; aged 44.15 {+/-} 11.86 SD years (range 21-68)) underwent magnetic resonance imaging at baseline, after 6 and 12 months. We conducted a pre-registered whole-brain time-by-group interaction analysis, and a time-by-group interaction analysis on within-network connectivity (https://osf.io/f8tpn/, https://osf.io/59bh7/). In exploratory analyses, we investigated the effects of weight loss and head motion. Bariatric surgery compared to waiting did not significantly affect functional connectivity (FWE-corrected p > 0.05), neither whole-brain nor within-network. In exploratory analyses, surgery-related BMI decrease (FWE-corrected p = 0.041) and higher average head motion (FWE-corrected p = 0.021) resulted in significantly stronger connectivity of the reward network with medial posterior frontal regions. This pre-registered well-controlled study did not support a strong effect of bariatric surgery, compared to waiting, on major resting-state brain networks after 6 months. Exploratory analyses indicated that head motion might have confounded the effects. Data pooling and more rigorous control of within-scanner head motion during data acquisition are needed to substantiate effects of bariatric surgery on brain organization.\",\n \"Polygenic basis and biomedical consequences of telomere length variation\\nTelomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence1. Here we characterize the genetic architecture of naturally-occurring variation in leucocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized participants in UK Biobank2. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 novel). Genetically-determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular, and inflammatory pathologies. Finally, we estimated that at age 40 years, people with >1-SD shorter compared to [≥]1-SD longer LTL than the population mean had 2.5 years lower life expectancy. Overall, we furnish novel insights into the genetic regulation of LTL, reveal LTLs wide-ranging influences on physiological traits, diseases, and longevity, and provide a powerful resource available to the global research community.\",\n \"Estimating the risk reduction of isolation on COVID-19 non-household transmission and severe/critical illness in non-immune individuals: September to November 2021\\nIn the fall 2021, immunity mandates/passports for COVID-19 started to be discussed and implemented globally. In addition to increasing vaccination levels, these interventions isolate non-immune individuals from various settings to reduce non-household transmission and severe/critical illness. This is based on the hypothesis that the non-immune are at high absolute risk of these outcomes. However, these absolute risks were not quantified in the literature such that the absolute risk reductions of isolation on these outcomes remain unknown. This study estimated these absolute risks from September to November 2021 prior to the emergence of Omicron (B.1.1.529) using known data on the risk of infection, transmission in non-household settings, and age-stratified severe/critical illness in non-immune individuals for the Delta (B.1.617.2) variant, focusing on the European Union, United Kingdom, United States, Canada, Australia, and Israel. This allowed us to quantify the absolute risk reductions of isolation on (1) non-household transmission from the non-immune and (2) severe/critical illness amongst the non-immune in these regions during this period. We observed that on any given day the absolute risk reductions of isolation were typically small for transmission in most types of non-household settings and severe/critical illness in most age-groups, especially those aged <40. During a wave or sustained higher infection risks, the risk reductions were modest only for transmission in intimate social gatherings and severe/critical illness in adults aged [≥]50-60. The limitations of this study and the implications for the expected benefits of isolating non-immune individuals on reducing these outcomes are discussed.\",\n \"Trends in clinical characteristics and associations of severe non-respiratory events related to SARS-CoV-2\\nBackgroundThe 2019 novel coronavirus (SARS-CoV-2) is reported to result in both respiratory and non-respiratory severe health outcomes, but quantitative assessment of the risk - while adjusting for underlying risk driven by comorbidities - is not yet established.\\n\\nMethodsA retrospective observational study using electronic health records of 9,344,021 individuals across the U.S. with at-least 1 year of clinical history and followed up throughout 2020.\\n\\nResults131,329 individuals were associated with SARS-CoV-2 infection by January 6, 2021 in three distinct surges. While the age and number of preexisting conditions had decreased throughout the pandemic, the characteristics of those who experienced severe health events did not.\\n\\nDuring the second surge, between June 7 and November 18, 2020, 425,988 individuals in the base cohort were admitted to emergency rooms or hospitals. Among them, 15,486 were detected with SAR-CoV-2 within few days of admission. Significant adjusted odds ratios were observed between SARS-CoV-2 infection and the following severe health events: respiratory (4.38, 95% confidence interval 4.16- 4.62), bacterial pneumonia (3.25, 2.76-3.83), sepsis (1.71, 1.53-1.91), renal (1.69, 1.57-1.83), hematologic/immune (1.32, 1.20-1.45), neurological (1.23, 1.09-1.38).\\n\\nConclusionsSARS-CoV-2 infection among hospitalized patients is associated with non-negligible increased risk of severe events including multiple non-respiratory ones. These associations, which complement recent studies, are persistent even after accounting for sources of selection and confounding bias, increasing the confidence they are not spurious.\",\n \"Seroresponse to third doses of SARS-CoV-2 vaccine among patients receiving maintenance dialysis\\nGiven the increased morbidity and mortality from COVID-19 among patients undergoing maintenance dialysis, we examined the seroresponse to an additional dose of SARS-CoV-2 mRNA vaccine, using a hypothesized protective anti-spike protein IgG antibody threshold of 7 based on prior work. Among 395 patients, 384 (97%) had seroresponse [≥]7 following administration of the third dose. Among those with suboptimal (peak <7) and minimal (peak <1) seroresponse to an initial mRNA vaccine regimen, the rate of seroresponse [≥]7 following a third dose was 97% (36 of 37) and 64% (14 of 22), respectively. Given ongoing high rates of COVID-19 and rapidly waning immunity after an initial vaccine series, we recommend a third mRNA vaccine dose be standard for all patients receiving maintenance dialysis.\",\n \"Bayesian approach to comparing the left ventricular volume in myocardial infarction and in normal cases\\nIntroductionPost-contrast delayed-enhancement MRI helps to show the extent of myocardial infarction (MI), as well as allowing the morphometric analysis of the heart structure, e.g., left ventricular volume (LVV). Here the author deployed Bayesian implementation of statistical inference to determine the difference between the LVV in MI cases and in normal controls.\\n\\nMethodsSixty-seven MI patients and thirty-three controls from the EMIDEC dataset challenge were used. These were acquired at the University Hospital of Dijon (France). A cardiologist with 10 years of experience in cardiology and MRI and a biophysicist with 20 years of experience of cardiovascular MRI supervised the acquisition and annotated the images. ITK-Snap was used to extract the LVV and Bayesian inference were used to investigate the data.\\n\\nResultsPatients with MI were younger than the controls (58.3 {+/-} 11.5 vs. 66.5 {+/-} 12.9 years; BF10 = 17.9). With age taken into consideration, the patients showed larger LVV relative to the controls (128.1 {+/-} 46.3 vs. 83.4 {+/-} 24.4 cm3; post-hoc BF10 = 12663.8).\\n\\nSummaryUsing Bayesian approach, we can conclude decisively that there is volumetric difference or remodeling in individuals with MI.\",\n \"Treatment of Early Hypertension among Persons Living with HIV in Haiti: protocol for a randomized controlled trial\\nBackgroundPeople living with HIV (PLWH) are at increased risk of cardiovascular disease (CVD) and death, with greater burdens of both HIV and CVD in lower-middle income countries. Treating prehypertension in PLWH may reduce progression to hypertension, CVD risk and potentially mortality. However, no trial has evaluated earlier blood pressure treatment for PLWH. We propose a randomized controlled trial to assess the feasibility, benefits, and risks of initiating antihypertensive treatment among PLWH with prehypertension, comparing prehypertension treatment to standard of care following current WHO guidelines.\\n\\nMethodsA total of 250 adults 18-65 years and living with HIV (PLWH) with viral suppression in the past 12 months, who have prehypertension will be randomized to prehypertension treatment versus standard of care. Prehypertension is defined as having a systolic blood pressure (SBP) 120-139 mmHg or diastolic blood pressure (DBP) 80-89 mmHg. In the prehypertension treatment arm, participants will initiate amlodipine 5 mg daily immediately. In the standard of care arm, participants will initiate amlodipine only if they develop hypertension defined as SBP [≥] 140 mmHg or DBP [≥] 90 mmHg. The primary outcome is the difference in mean change of SBP from enrollment to 12 months. Secondary outcomes include feasibility, acceptability, adverse effects, HIV viral suppression, and medication adherence. Qualitative in-depth interviews with providers and participants will explore attitudes about initiating amlodipine, satisfaction, perceived CVD risk, and implementation challenges.\\n\\nDiscussionPLWH have a higher CVD risk and may benefit from a lower BP threshold for initiation of antihypertensive treatment.\\n\\nTrial registrationClinicaltrials.gov registration number NCT04692467, registration date December 15, 2020, protocol ID 20-03021735.\",\n \"Building Prediction Models for 30-Day Readmissions Among ICU Patients Using Both Structured and Unstructured Data in Electronic Health Records\\nICU readmissions are associated with poor outcomes for patients and poor performance of hospitals. Patients who are readmitted have an increased risk of in-hospital deaths; hospitals with a higher readmission rate have a reduced profitability, due to an increase in cost and reduced payments from Medicare and Medicaid programs. Predicting a patients likelihood of being readmitted to the ICU can help reduce early discharges, the risk of in-hospital deaths, and help increase profitability. In this study, we built and evaluated multiple machine learning models to predict 30-day readmission rates of ICU patients in the MIMIC-III database. We used both the structured data including demographics, laboratory tests, comorbidities, and unstructured discharge summaries as the predictors and evaluated different combinations of features. The best performing model in this study Logistic Regression achieved an AUROC of 75.7%. This study shows the potential of leveraging machine learning and deep learning for predicting ICU readmissions.\",\n \"Development and Pilot Testing of a Five Item Traumatic Stress Screener for Use with Adolescents in Pediatric Primary Care\\nObjectivesTo develop and assess the psychometric properties of the Adolescent Primary Care Traumatic Stress Screen (APCTSS), a five-item yes/no screener for PTSD symptoms in adolescents, and the first developed for pediatric primary care.\\n\\nStudy DesignThe APCTSS was developed by combining and adapting the UCLA PTSD Reaction Index for DSM-5 with the adult Primary Care PTSD Screen for DSM-5. Adolescent medicine patients were universally approached during clinic visits. With a response rate of 83.6%, 178 patients aged 13-22 (M=18.4, SD=2.3), 64.4% female; 62.1% Black or African-American and 20.7% Hispanic/Latinx, were enrolled. Patients completed APCTSS, Patient Health Questionnaire for Adolescents (PHQ-A), and Child PTSD Symptom Scale for DSM-5 Interview (CPSS-5-I), and 61 completed the Traumatic Events Screening Inventory for Children (TESI-C).\\n\\nResults56.7% reported a criterion A trauma, 30.1% met criteria for PTSD, 7.4% met criteria for subsyndromal PTSD, and 19.0% for post-event impairing symptoms. Scores [≥] 2 on the APCTSS optimized sensitivity (.79; 95% CI=.66 to .89) and specificity (.68; 95% CI=.55 to .76) for PTSD, with an area under the curve (AUC) of .79. Sensitivity (.86; 95% CI=.65 to .90), specificity (.77; 95% CI=.60 to .90), and AUC (.86) were even stronger when the TESI-C was used to assess criterion A for PTSD diagnosis. Over half (56.0%) of patients who screened positive on the APCTSS were missed by the PHQ-A.\\n\\nConclusionsThe APCTSS shows promise as an internally consistent, valid, and effective tool for identifying adolescents at high risk of PTSD and traumatic stress.\",\n \"RESISTANCE CONFERRING MUTATIONS IN SARS-CoV-2 DELTA FOLLOWING SOTROVIMAB INFUSION\\nSeveral Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) neutralising monoclonal antibodies (mAbs) have received emergency use authorisation by regulatory agencies for treatment and prevention of Coronavirus Disease 2019 (COVID-19), including in patients at risk for progression to severe disease. Here we report the persistence of viable SARS-CoV-2 in patients treated with sotrovimab and the rapid development of spike gene mutations that have been shown to confer high level resistance to sotrovimab in vitro. We highlight the need for SARS-CoV-2 genomic surveillance in at risk individuals to inform stewardship of mAbs use and prevent potential treatment failures.\",\n \"Assessing the performance of a serological point-of-care test in measuring detectable antibodies against SARS-CoV-2\\nObjectiveTo investigate the performance of a rapid point-of-care antibody test, the BioMedomics COVID-19 IgM/IgG Rapid Test, in comparison with a high-quality, validated, laboratory-based platform, the Roche Elecsys Anti-SARS-CoV-2 assay.\\n\\nMethodsSerological testing was conducted on 708 individuals. Concordance metrics were estimated. Logistic regression was used to assess associations with seropositivity.\\n\\nResultsSARS-CoV-2 seroprevalence was 63.4% (449/708; 95% CI 59.8%-66.9%) using the BioMedomics assay and 71.9% (509/708; 95% CI 68.5%-75.1%) using the Elecsys assay. There were 62 discordant results between the two assays. One specimen was seropositive in the BioMedomics assay, but seronegative in the Elecsys assay, while 61 specimens were seropositive in the Elecsys assay, but seronegative in the BioMedomics assay. Positive, negative, and overall percent agreements between the two assays were 88.0% (95% CI 84.9%-90.6%), 99.5% (95% CI 97.2%-99.9%), and 91.2% (95% CI 88.9%-93.1%), respectively, with a Cohens kappa of 0.80 (95% CI 0.77-0.83), indicating excellent agreement. Excluding specimens with lower antibody titers, the agreement improved with positive, negative, and overall percent concordance of 91.2% (95% CI 88.2%-93.6%), 99.5% (95% CI 97.2%-99.9%), and 93.9% (95% CI 91.7%-95.5%), respectively, and a Cohens kappa of 0.87 (95% CI 0.84-0.89). Logistic regression confirmed better agreement with higher antibody titers.\\n\\nConclusionThe BioMedomics COVID-19 IgM/IgG Rapid Test demonstrated excellent performance in measuring detectable antibodies against SARS-CoV-2, supporting the utility of such rapid point-of-care serological testing to guide the public health responses and possible vaccine prioritization.\",\n \"A comprehensive analysis of outcomes between COVID-19 patients with an elevated serum lipase compared to those with pancreatitis.\\nBackground and AimsCOVID-19 patients may have asymptomatic hyperlipasemia without abdominal imaging findings or abdominal pain. In addition, primary and secondary pancreatitis have been described in COVID-19 patients. There is limited information on how the groups compare in outcomes. The aim is to compare outcomes among these groups.\\n\\nMethodsThis is a retrospective study from 12 hospitals within one healthcare system examining outcomes between hospitalized COVID-19 patients with a lipase <3x upper limit of normal (ULN), asymptomatic hyperlipasemia (>3x ULN), secondary pancreatitis (typical respiratory COVID-19 symptoms and found to have pancreatitis), and primary pancreatitis (presenting with pancreatitis).\\n\\nResultsOf 11,883 patients admitted with COVID-19, 1,560 patients were included: 1,155 COVID-19 patients with a normal serum lipase (control group), 270 with an elevated lipase <3x ULN, 46 patients with asymptomatic hyperlipasemia with a lipase 3xULN, 57 patients with secondary pancreatitis, and 32 patients with primary pancreatitis. On adjusted multivariate analysis, the elevated lipase <3x ULN and asymptomatic hyperlipasemia groups had worse outcomes. The mortality was OR1.6 (95% CI 1.2-2.2) and 1.1 (95% CI 0.5-2.3), respectively. The need for mechanical ventilation was OR 2.8 (95% CI 1.2-2.1) and 2.8 (95% CI 1.5-5.2), respectively. Longer length of stay was OR 1.5 (95%CI 1.1-2.0) and 3.16 (95%CI 1.5-6.5), respectively.\\n\\nConclusionCOVID-19 patients with an elevated lipase< 3x ULN and asymptomatic hyperlipasemia have generally worse outcomes than those with pancreatitis. This could be attributed to extrapancreatic causes (liver failure, renal failure, enteritis, etc), which may signify a more severe course of clinical disease.\",\n \"Tele-Rapid Response Team (Tele-RRT): Implementation and outcomes of Safety Network System. Before and after cohort study.\\nBackgroundRapid Response Teams were developed to provide interventions for deteriorating patients. Their activation depends on timely detection of deterioration. Automated calculation of warning signs may lead to early recognition, and improvement of RRT effectiveness.\\n\\nMethodThis was a \\\"Before\\\" and \\\"After\\\" study, in the \\\"Before\\\" period ward nurses activated RRT after manually recording vital signs and calculating warning scores. In the \\\"After\\\" period, vital signs and warning calculations were automatically relayed to RRT through a wireless monitoring network.\\n\\nResultsThe \\\"After\\\" group had significantly lower incidence and rates of cardiopulmonary resuscitation compared to the \\\"Before\\\" group (2.3 / 1000 inpatient days versus 3.8 / 1000 inpatient days respectively, p = 0.01), the \\\"Before\\\" group had a significantly higher hospital length of stay, and significantly fewer visits by the RRT. In multivariable logistic regression model, being in the \\\"After\\\" group decreases odds of CPR by 30% (OR = 0.7 [95% CI: 0.44 - 0.97]; p = 0.02). There was no difference between groups in unplanned ICU admission or readmission.\\n\\nConclusionAutomated activation of the RRT resulted in significant reduction of CPR events and rate, reduction of hospital length of stay, and increase in the number of visits by the RRT. There was no difference in unplanned ICU admission or readmission.\"\n]","isConversational":false},"cluster":{"kind":"number","value":9,"string":"9"}}},{"rowIdx":227,"cells":{"query":{"kind":"string","value":"Early prediction of renal graft function: Analysis of a multi-centre, multi-level data set\nIntroductionLong-term graft survival rates after renal transplantation are still moderate. We aimed to build an early predictor of an established long-term outcomes marker, the glomerular filtration rate (eGFR) one year post-transplant (eGFR-1y).\n\nMaterials and MethodsA large cohort of 376 patients was characterized for a multi-level bio-marker panel including gene expression, cytokines, metabolomics and antibody reactivity profiles. Almost one thousand samples from the pre-transplant and early post-transplant period were analysed. Machine learning-based predictors were built employing stacked generalization.\n\nResultsPre-transplant data led to a prediction achieving a Pearsons correlation coefficient of r=0.39 between measured and predicted eGFR-1y. Two weeks post-transplant, the correlation was improved to r=0.63, and at the third month, to r=0.76. eGFR values were remarkably stable throughout the first year post-transplant and were the best estimators of eGFR-1y already two weeks post-transplant. Several markers were associated with eGFR: The cytokine stem cell factor demonstrated a strong negative correlation; and a subset of 19 NMR bins of the urine metabolome data was shown to have potential applications in non-invasive eGFR monitoring. Importantly, we identified the expression of the genes TMEM176B and HMMR as potential prognostic markers for changes in the eGFR.\n\nDiscussionOur multi-centre, multi-level data set represents a milestone in the efforts to predict transplant outcome. While an acceptable predictive capacity was achieved, we are still very far from predicting changes in the eGFR precisely. Further studies employing further marker panels are needed in order to establish predictors of eGFR-1y for clinical application; herein, gene expression markers seem to hold the most promise."},"positive":{"kind":"list like","value":["COVID-19 in 823 Transplant patients: A Systematic Scoping Review\nBackgroundManagement of COVID-19 in transplant patients is a big challenge. Data on immunosuppression management, clinical picture, and outcomes are lacking.\n\nObjectivesTo summarize the current literature on COVID-19 in transplant patients especially the data regarding the immunosuppression protocols, clinical presentation, and outcomes.\n\nSearch strategyA systematic search of MEDLINE, EBSCO, CENTRAL, CINAHL, LitCovid, Web of Science, and Scopus electronic databases. The references of the relevant studies were also searched. The search was last updated on June 3, 2020.\n\nSelection CriteriaPrimary reports of solid organ transplant patients who developed COVID-19. An overlap of cases in different reports was checked.\n\nData collection and analysisA descriptive summary of immunosuppression therapy (before and after COVID-19), clinical presentation (symptoms, imaging, laboratory, and disease severity), management (oxygen therapy, antiviral, and antibacterial), major outcomes (Intensive care admission, invasive mechanical ventilation, acute kidney injury), and mortality.\n\nMain resultsWe identified 74 studies reporting 823 cases of solid organ transplantation with COVID-19. Among 372 patients, 114 (30.6%) were mild COVID-19, 101 (27.2%) moderate, and 157 (42.2%) severe or critical.\n\nMajor outcomes included intensive care unit admission, invasive ventilation, and acute kidney injury, which occurred in 121 (14.7%), 97 (11.8%), and 63 (7.7%) of patients, respectively. Mortality was reported in 160 (19.4%) patients. Missing individual data hindered making clinical correlations.\n\nConclusionCOVID-19 in solid organ transplant patients probably has a more disease severity, worse major outcomes (Intensive care admission, invasive ventilation, acute kidney injury), and higher mortality than in non-transplant patients.","Torque teno virus load predicts allograft rejection but not viral infection after kidney transplantation\nThe main challenge of immunosuppressive therapy after solid organ transplantation is to create a new immunological balance that prevents organ rejection and does not promote opportunistic infection. Torque teno virus (TTV) a ubiquitous and non-pathogenic single-stranded DNA virus has been proposed as a marker of functional immunity in immunocompromised patients. Here investigate whether TTV loads predict the risk of common viral infection and allograft rejection in kidney transplantation recipients.\n\nIn a retrospective cohort of 389 kidney transplantation recipients, individual TTV loads in were measured by qPCR in consecutive plasma samples during one year follow-up. The endpoints were allograft rejection, BK polyomavirus (BKPyV) viremia and cytomegalovirus (CMV) viremia. Repeated TTV measurements and rejection and infection survival data were analysed in a joint model.\n\nDuring follow-up, TTV DNA detection in the transplant recipients increased from 85 to 100%. The median viral load increased to 107 genome copies/ml within three months after transplantation. Rejection, BKPyV viremia and CMV viremia occurred in 23%, 27% and 17% of the patients, respectively. With every 10-fold TTV load-increase, the risk of rejection decreased considerably (HR: 0.74, CI 95%: 0.71-0.76), while the risk of BKPyV and CMV viremia remained the same (HR: 1.03, CI 95%: 1.03-1.04 and HR: 1.01, CI 95%: 1.01-1.01).\n\nIn conclusion, TTV load kinetics predict allograft rejection in kidney transplantation recipients, but not the BKPyV and CMV infection. The potential use of TTV load levels as a guide for optimal immunosuppressive drug dosage to prevent allograft rejection deserves further validation.","Weak anti-SARS-CoV-2 antibody response after the first injection of an mRNA COVID-19 vaccine in kidney transplant recipients\nData concerning the anti-SARS-CoV-2 antibody response after mRNA COVID-19 vaccine in kidney transplant recipients (KTRs) are currently lacking. Here, we sought to examine this issue by analyzing the serological response observed in 241 KTRs after a first vaccine injection. Our results indicate that KTRs have a weak anti-SARS-CoV-2 antibody response, ultimately resulting in a low seroconversion rate (26/241, 10.8%). This phenomenon likely stems from a high immunosuppression burden in this clinical population.","The effect of CYP3A4 genetic polymorphisms on the pharmacokinetics of calcineurin inhibitors in renal transplant recipients: a systematic review and meta-analysis protocol\nBackgroundCalcineurin inhibitors (CNIs) are metabolized by CYP3A4. Polymorphisms in the CYP3A4 gene alter the activity of CYP3A4 protein and therefore affect the CNIs concentrations. Results of studies that investigated the association between CYP3A4 polymorphisms and CNIs pharmacokinetics are controversial. Therefore, this systematic review and meta-analysis will evaluate the effect of CYP3A4 polymorphisms on the pharmacokinetics of CNIs in renal transplant recipients.\n\nMethodThis protocol is developed according to the PRISMA-P guideline and registered in PROSPERO (CRD42020145219). The MeSH/Emtree terms of CYP3A4 polymorphisms and CNIs pharmacokinetics in PECO-based question will be obtained from the comprehensive literature search on PubMed/MEDLINE, Scopus, Web of Science, Embase, CENTRAL, and ProQuest without any language limitation from 1 January 1998 to 31 March 2021. Google Scholar search engine, registries, conference papers, and key journals will also be searched. Screening, selection, quality assessment, and data extraction will be performed by two independent reviewers. Statistical heterogeneity will be calculated by the Q Cochrane test and I2 statistic. Publication bias and sensitivity analysis will be evaluated by appropriate tests.\n\nResults and conclusionAccording to the meta-analysis of the aggregated data from the relevant primary studies, the association between CYP3A4 polymorphisms and CNIs pharmacokinetics will be reported, which possibly help the pharmacogenetic-guided dosing approach.","Donor race has no role in predicting allograft and patient survival among kidney transplant recipients\nA heated debate in creatinine-based estimated glomerular filtration rate (eGFR) calculation is the inclusion of race alongside biological factors, such as age and gender. Similarly, the race variable was included in the calculation of the Kidney Donor Risk Index (KDRI) as deceased donor kidneys from black donors have historically been shown to be associated with lower allograft or patient survival. Given the current climate of uncertainty with the use of race in nephrology, we sought to answer the question of whether removing the donor race variable from the KDRI would alter its validity to assess allograft and patient survival. Our modeling and analysis showed that removing donor race from the original KDRI did not alter the overall model predictability of allograft failure or patient mortality. Clinical risk factors included in the KDRI have largely accounted for differential risk between black and other donors. Adding donor race into the KDRI only shifts how risk is attributed to these clinical risk factors, without yielding better prediction of outcomes than the model without race.","Impaired Humoral and Cellular Immunity after SARS-CoV2 BNT162b2 (Tozinameran) Prime-Boost Vaccination in Kidney Transplant Recipients\nNovel mRNA-based vaccines have been proven powerful tools to combat the global pandemic caused by SARS-CoV2 with BNT162b2 efficiently protecting individuals from COVID-19 across a broad age range. Still, it remains largely unknown how renal insufficiency and immunosuppressive medication affect development of vaccine induced immunity. We therefore comprehensively analyzed humoral and cellular responses in kidney transplant recipients after prime-boost vaccination with BNT162b2. As opposed to all healthy vaccinees and the majority of hemodialysis patients, only 4/39 and 1/39 transplanted individuals showed IgA and IgG seroconversion at day 8{+/-}1 after booster immunization with minor changes until day 23{+/-}5, respectively. Although most transplanted patients mounted spike-specific T helper cell responses, frequencies were significantly reduced compared to controls and dialysis patients, accompanied by a broad impairment in effector cytokine production, memory differentiation and activation-related signatures. Spike-specific CD8+ T cell responses were less abundant than their CD4+ counterparts in healthy controls and hemodialysis patients and almost undetectable in transplant patients. Signs of alloreactivity promoted by BNT162b2 were not documented within the observation period. In summary, our data strongly suggest revised vaccination approaches in immunosuppressed patients, including individual immune monitoring for protection of this vulnerable group at risk to develop severe COVID-19.","Donor genetic variants in interleukin-6 and interleukin-6 receptor associate with biopsy-proven rejection following kidney transplantation.\nRejection after kidney transplantation remains an important cause of allograft failure that markedly impacts morbidity. Cytokines are a major player in rejection, and we, therefore, explored the impact of interleukin-6 (IL6) and IL-6 receptor (IL6R) gene polymorphisms on the occurrence of rejection after renal transplantation. We performed an observational cohort study analyzing both donor and recipient DNA in 1,271 renal transplant-pairs from the University Medical Center Groningen in The Netherlands and associated single nucleotide polymorphisms (SNPs) with biopsy-proven rejection after kidney transplantation. The C-allele of the IL6R SNP (Asp358Ala; rs2228145 A>C, formerly rs8192284) in donor kidneys conferred a reduced risk of rejection following renal transplantation (HR 0.78 per C-allele; 95%-CI 0.67-0.90; P=0.001). On the other hand, the C-allele of the IL6 SNP (at position-174 in the promoter; rs1800795 G>C) in donor kidneys was associated with an increased risk of rejection for male organ donors (HR per C-allele 1.31; 95%-CI 1.08-1.58; P=0.0006), but not female organ donors (P=0.33). In contrast, neither the IL6 nor IL6R SNP in the recipient showed an association with renal transplant rejection. In conclusion, donor IL6 and IL6R genotypes but not recipient genotypes represent an independent prognostic marker for biopsy-proven renal allograft rejection.","Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes\nApolipoprotein L1 (APOL1) risk alleles in donor kidneys associate with graft loss but whether recipient risk allele expression impacts kidney transplant outcomes is unclear. To test whether recipient APOL1 allelic variants independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data of donors and recipients from two kidney transplant cohorts, Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation 1/17 (CTOT1/17). We estimated genetic ancestry (quantified as proportion of African ancestry or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we observed that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with increased risk of death-censored allograft loss (DCAL), independent of genetic ancestry (HR = 2.14; P = 0.006), and within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with increased risk of any T cell-mediated rejection (TCMR) event. Analysis of the CTOT cohort validated these associations. Ex vivo studies of peripheral blood mononuclear cells revealed unanticipated high APOL1 expression in activated CD4+/CD8+ T cells and natural killer cells. We detected enriched immune response gene pathways in G1/G2 allele carriers vs. non-carriers among patients on the kidney waitlist and healthy controls. Together our findings highlight a previously unrecognized contribution of recipient APOL1 risk alleles to renal allograft outcomes. This immunomodulatory role has broader implications for immune mediated injury to native kidneys.","Cellular immunity predominates over humoral immunity after the first dose of COVID-19 vaccines in solid organ transplant recipients\nKnowledge on the vaccine-induced cellular and humoral immunity and on immunogenicity of vector-based and mRNA vaccines in solid organ transplant recipients is limited. Therefore, SARS-CoV-2 specific T-cells and antibodies were analyzed in 40 transplant recipients and 70 age-matched controls after the first dose of vector-based or mRNA vaccines. Plasmablasts and SARS-CoV-2 specific CD4 and CD8 T-cells were quantified using flow-cytometry. Specific antibodies were analyzed by ELISA and neutralization assay. SARS-CoV-2 specific antibodies and T-cells were induced in both groups with significantly lower levels in patients. While antibodies were detected in 80% of controls and 5.3% of patients, specific CD4 and/or CD8 T-cells were more frequently found in both controls (84.3%) and patients (23.7%). The two vaccine types showed notable differences, as IgG and neutralizing activity were more pronounced after mRNA vaccination (p<0.0001 each), whereas CD4 and CD8 T-cell levels were higher after vector vaccination (p=0.009; p<0.0001). Plasmablast numbers were significantly higher in controls and correlated with SARS-CoV-2 specific IgG- and CD4 T-cell levels. In conclusion, assessment of antibodies is not sufficient to identify COVID-19-vaccine responders. Together with differences in immunogenicity among vaccines, this necessitates combined analysis of humoral and cellular immunity to reliably assess responders among immunocompetent and immunocompromised individuals.","T Cell Positive B Cell Negative Flow Cytometry Crossmatch (FCXM): Frequency, HLA-Locus Specificity, and Mechanisms Among 3073 Clinical FCXM Tests\nBackgroundA T cell positive and B cell negative (T+B-) flow cytometry crossmatch (FCXM) result remains a conundrum since HLA-class I antigens are expressed on both T and B cells. We investigated the frequency, HLA specificity of the antibodies and mechanisms for the T+B- FCXM result.\n\nMethodsWe analyzed 3073 clinical FCXM tests performed in an American Society of Histocompatibility and Immunogenetics accredited histocompatibility laboratory. The sera associated with the T+B- FCXM were also tested for donor HLA IgG antibodies using LABScreen single antigen assays.\n\nResultsAmong the 3073 FCXM tests, 1963 were T-B-, 811 were T-B+, 274 were T+B+, and 25 were T+B-. IgG antibodies directed at donor HLA-A, B, or Cw locus determined antigens (DSA) were identified in all 25 sera and the summed mean fluorescence intensity (MFI) of DSA ranged from 212 to 53,187. Correlational analyses identified a significant association between the summed MFI of class I DSA, and the median channel fluorescence (MCF) of T cells treated with the recipient serum (Spearman rank correlation, rs=0.34, P=0.05) but not with the MCF of B cells (rs=0.23, P=0.24). We identified that differential binding of anti-HLA antibodies to T cells and B cells and the B cell channel shift threshold used to classify a B cell FCXM are potential contributors to a T+B- FCXM result.\n\nConclusionsOur analysis of 3073 FCXM, in addition to demonstrating that HLA antibodies directed at HLA-A, B or Cw locus are associated with a T+B- result, identified mechanisms for the surprising T+B- FCXM result.","Phenotypic and functional characterisation of circulating cytomegalovirus-specific T cells in healthy virus carriers and lung transplant candidates\nThis manuscript has been withdrawn by the authors as it was submitted and made public without appropriate approval. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.","Early microbiome and metabolome signatures in pediatric patients undergoing allogeneic hematopoietic cell transplantation\nBackgroundThe contribution of the gastrointestinal tract microbiome to outcomes after allogeneic hematopoietic cell transplantation (HCT) is increasingly recognized. Investigations of larger pediatric cohorts aimed at defining the microbiome state and associated metabolic patterns pre-transplant are needed.\n\nMethodsWe sought to describe the pre-transplant stool microbiome in pediatric allogenic HCT patients at four centers. We performed shotgun metagenomic sequencing and untargeted metabolic profiling on pre-transplant stool samples. Samples were compared with normal age-matched controls and by clinical characteristics. We then explored associations between stool microbiome measurements and metabolite concentrations.\n\nResultsWe profiled stool samples from 88 pediatric allogeneic HCT patients, a median of 4 days before transplant. Pre-transplant stool samples differed from healthy controls based on indices of alpha diversity and in the proportional abundance of specific taxa and bacterial genes. Relative to stool from healthy patients, samples from HCT patients had decreased proportion of Bacteroides, Ruminococcaeae and genes involved in butyrate production, but were enriched for gammaproteobacterial species. No systematic differences in stool microbiome or metabolomic profiles by age, transplant indication or hospital were noted. Stool metabolites demonstrated strong correlations with microbiome composition.\n\nDiscussionStool samples from pediatric allogeneic HCT patients demonstrate substantial dysbiosis early in the transplant course. As microbiome disruptions associate with adverse transplant outcomes, pediatric-specific analyses examining longitudinal microbiome and metabolome change are imperative to identify causal associations and to inform rational design of interventions.","Deceased donor kidney degradomics indicates cytoskeletal proteolytic alterations impacting post-transplant function.\nBackgroundIn brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys that adversely impacts the quality of grafts. Here, we hypothesized that DBD kidneys may undergo proteolytic processes that renders grafts susceptible to post-transplant dysfunction.\n\nMaterial & MethodsUsing mass spectrometry and immunoblotting analyses, we profiled degradation patterns of cytoskeletal proteins in deceased (n=55) and living (n=10) donor kidneys.\n\nResultsWe found that in DBD kidneys, key podocyte cytoskeletal proteins had been proteolytically cleaved. Generated degradation profiles were not associated to donor related demographic and clinical factors but were associated to suboptimal post-transplant function. Strikingly, -actinin -4 and Talin-1 degradation profiles were not observed in circulatory-death or living-donor kidneys. As Talin-1 is a specific proteolytic target of Calpain-1, we investigated a potential trigger of Calpain activation and Talin-1 degradation using ex-vivo precision-cut human kidney slices and in-vitro immortalised human podocytes. Notably, we found that Transforming-Growth Factor-{beta} (TGF-{beta}) activated Calpain-1 and proteolytically cleaved Talin-1 to generate distinct peptide fragments. These peptide fragments were of similar size and matched the degradation patterns observed in DBD kidneys. Talin-1 degradation was prevented in vitro by Calpain-1 inhibition.\n\nConclusionsHere, we provide initial evidence that DBD kidneys are susceptible to cytoskeletal protein degradation that impacts posttransplant kidney function. Subsequent studies should aim to further investigate the link between brain death and activation of proteolytic pathways exploring new therapeutic opportunities.","A functional TGFB1 polymorphism in the donor associates with long-term graft survival after kidney transplantation.\nIntroductionImprovement of long-term outcomes in kidney transplantation remains one of the most pressing challenges, yet drug development is stagnating. Human genetics offers an opportunity for much-needed target validation in transplantation. Conflicting data exists about the effect of transforming growth factor-beta 1 (TGF-{beta}1) on kidney transplant survival, since TGF-{beta}1 has profibrotic and protective effects. We therefore the impact of a recently discovered functional TGBF1 polymorphism on long-term kidney graft survival.\n\nMethodsWe performed an observational cohort study analyzing recipient and donor DNA in 1,271 kidney transplant-pairs from the University Medical Center Groningen in The Netherlands and associated a low-producing TGBF1 polymorphism (rs1800472-C>T) with 5, 10, and 15-year death-censored kidney graft survival.\n\nResultsDonor genotype frequencies of s1800472 in TGBF1 differed significantly between patients with and without graft loss (P=0.042). Additionally, the low-producing TGBF1 polymorphism in the donor was associated with an increased risk of graft loss following kidney transplantation (HR 2.13 for the T-allele; 95%-CI 1.16-3.90; P=0.015). The incidence of graft loss within 15 years of follow-up 16.4% in the CC-genotype group and 28.9% in the CT-genotype group. After adjustment for transplant-related covariates, the association between the TGBF1 polymorphism in the donor and graft loss remained significant. In contrast, there was no association between the TGBF1 polymorphism in the recipient and graft loss.\n\nConclusionKidney allografts possessing a low-producing TGBF1 polymorphism have a higher risk of late graft loss. Our study adds to a growing body of evidence that TGF-{beta}1 is beneficial, rather than harmful, for kidney transplant survival.","Comparison of infected and vaccinated transplant recipients highlights the role of Tfh and neutralizing IgG in COVID-19 protection\nTransplant recipients, which receive therapeutic immunosuppression to prevent graft rejection, are characterized by high COVID-19-related mortality and defective response to vaccines. Having observed that previous infection by SARS-CoV-2 but not the standard \"2 doses\" scheme of vaccination, provided complete protection against COVID-19 to transplant recipients, we undertook this translational study to compare the cellular and humoral immune responses of these 2 groups of patients. Neutralizing anti-Receptor Binding Domain (RBD) IgG were identified as the critical immune effectors associated with protection. Generation of anti-RBD IgG was dependent upon spike-specific T follicular helper (Tfh) CD4+ T cells, which acted as limiting checkpoint. Tfh generation was impeded by high dose mycophenolate mofetil in non-responders to vaccine but not in infected patients, suggesting that increasing immunogenicity of vaccine could improve response rate to mRNA vaccine. This theory was validated in two independent prospective cohorts, in which administration of a 3rd dose of vaccine resulted in the generation of anti-RBD IgG in half of non-responders to 2 doses.\n\nOne sentence summaryThe generation of neutralizing IgG, which protects kidney transplant recipients from COVID-19, requires T follicular helper cells.","Tumor necrosis factor-α gene polymorphism is associated with short- and long-term kidney allograft outcomes.\nIntroductionKidney transplantation has excellent short-term results with current immunosuppression regimes, but long-term outcomes have barely improved. Hence, there is a need for new therapeutic options to increase long-term survival of kidney grafts. Drug development for transplantation has slowly plateaued, limiting progress while making drug repurposing an attractive alternative. We, therefore, investigated the impact of tumor necrosis factor-alpha (TNF-) gene (TNF) polymorphisms on kidney graft survival.\n\nMethodsWe performed a prospective cohort study to assess the association of TNF polymorphisms (rs1800629 G>A and rs3093662 A>G) with primary non-function (PNF) and death-censored kidney allograft survival in 1,271 kidney transplant pairs from the University Medical Center Groningen in The Netherlands.\n\nResultsThe G-allele of the TNF rs3093662 polymorphism in donor kidneys was associated with a higher risk of PNF (odds ratio: 2.05; 95%-CI: 1.06-3.97; P = 0.032). Furthermore, the G-allele of this TNF rs3093662 polymorphism in the donor was also associated with worse 5-year, 10-year, and 15-year death-censored kidney graft survival (P < 0.05). The cumulative incidence of graft loss was 15.9% in the reference AA-genotype group and 25.2% in the AG/GG-genotype group, respectively. In multivariable analysis, the association between the TNF rs3093662 polymorphism in the donor and 15-year death-censored kidney graft survival remained significant (hazard ratio: 1.51; 95%-CI: 1.05-2.19, P = 0.028).\n\nConclusionKidney allografts possessing a high-producing TNF polymorphism have a greater risk of immediate and late graft loss. Our study adds to a growing body of literature indicating the potential of TNF- blockade in improving kidney transplantation outcomes.","Predictive factors of response to 3rd dose of COVID-19 mRNA vaccine in kidney transplant recipients\nOnly a minority of kidney transplant recipients (KTRs) develop protective neutralizing titers of anti-receptor binding domain of spike protein (RBD) IgG after two doses of mRNA COVID-19 vaccine. Administration of a third dose of mRNA vaccine to KTRs with sub-optimal response increase anti-RBD IgG titers but with high inter-individual variability. Patients with the higher response rate to the third dose of vaccine can be identified by the presence of low anti-RBD IgG titers and spike-specific CD4+ T cells in their circulation 14 days after the second dose.","Antibody response to a fourth mRNA Covid-19 vaccine boost in weak responder kidney transplant recipients\nThe US FDA has recently authorized immunocompromised people to receive a third dose of mRNA Covid-19 vaccine following the two-doses regimen to further boost protection. Unfortunately, a non-negligible proportion of people treated with immunosuppressive drugs either do not respond or show only a weak response after a third boost and should, therefore, still be considered at risk of severe Covid-19. As of June 2021, we were granted the opportunity to offer a fourth vaccine dose to French solid organ transplant recipients who still showed a weak antibody response after the third dose. In this multicenter study, we demonstrate that that the protection conferred by a fourth dose is adequate for the majority of kidney transplant recipients.","Public perception of organ donation and transplantation policies in Southern Spain\nBackgroundThis research explores how public awareness and attitudes towards donation and transplantation policies may contribute to Spains success in cadaveric organ donation.\n\nMaterials and MethodsA representative sample of 813 people residing in Andalusia (Southern Spain) were surveyed by telephone or via Internet between October and December 2018.\n\nResultsMost participants trust Spains donation and transplantation system (93%) and wish to donate their organs after death (76%). Among donors, a majority have expressed their consent (59%), while few non-donors have expressed their refusal (14%). Only a minority is aware of the presumed consent system in force (28%) and feel sufficiently informed regarding the requirements needed to be an organ donor (16%). Participants mainly consider that relatives should represent the deceaseds preferences and be consulted when the deceaseds wishes are unknown, as is the case in Spain.\n\nConclusionsPublic trust in the transplant system may contribute to Spains high performance in organ donation. High levels of societal support towards organ donation and transplantation do not correspond in Spain with similar levels of public awareness of donation and transplantation policies.","Real-world Effectiveness of 2-dose SARS-CoV-2 Vaccination in Kidney Transplant Recipients\nThe humoral response to two doses of SARS-CoV-2 (Covid-19) vaccine among transplant recipients is inferior to immunocompetent individuals.1 Data on the real-world effectiveness of vaccination in kidney transplant recipients [KTRs] are lacking. We performed a cohort study to investigate the impact of vaccination on Covid-19 infection and outcomes in our kidney transplant program.","Perfusate metabolomics content and tubular transporters expression during kidney graft preservation by hypothermic machine perfusion\nBackgroundIschemia-related injury during the pre-implantation period impacts kidney graft outcome. Evaluating these lesions by a non-invasive approach before transplantation could help to understand the mechanisms of graft injury and identify potential biomarkers predictive of graft outcomes. This study aims to determine metabolomic content of graft perfusion fluids and its dependence on preservation time and to explore whether tubular transporters are possibly involved in the metabolomics variations observed.\n\nMethodsKidneys were stored on hypothermic perfusion machines. We evaluated the metabolomic profiles of perfusion fluids (n=35) using Liquid Chromatography coupled with tandem Mass Spectrometry and studied the transcriptional expression of tubular transporters on pre-implantation biopsies (n=26). We used univariate and multivariate analyses to assess the impact of perfusion time on these parameters and their relationship with graft outcome.\n\nResultsSeventy-two metabolites were found in preservation fluids at the end of perfusion, of which 40% were already present in the native conservation solution. We observed an increase of 23 metabolites with longer perfusion time and a decrease for 8. The predictive model for time-dependent variation of metabolomics content showed good performance (R2= 76%, Q2= 54%, accuracy= 41%, permutations test significant). Perfusion time had no effect on the mRNA expression of transporters. We found no correlation between metabolomics and transporters expression. Neither the metabolomics profile nor the transporters expression were predictive of graft outcome.\n\nConclusionOur results open the way for further studies, focusing on both intra- and extra-tissue metabolome, to investigate whether transporter alterations can explain the variations observed in pre-implantation period.","Identifying opportunities for improving the organ supply through race-stratified data\nOrgan procurement in the US has received attention from government officials and policymakers the last two years, culminating in CMS releasing an updated Final Rule related to organ donation this year. This regulatory change revises how organ procurement organizations (OPOs), the federal contractors tasked with managing deceased donation, are evaluated and certified/de-certified. We used 2019 data and the CMS methodology to calculate race-stratified donation data among racial/ethnic minorities across the 57 OPOs. We found that the variability in donation rates across the 57 OPOs are greater among minority populations than non-Hispanic white potential donors. Among Tier 3 OPOs, there are: a) some with low donation rates across all racial/ethnic groups; b) some with low donation rates among only certain groups, and c) some where donation rates are lowest among non-Hispanic white patients. Among low-performing OPOs, these race/ethnicity-stratified data show that under-performance in certain areas is not due to the population demographics, and identifies areas for targeted interventions to increase donation and avoid decertification","Ruxolitinib As a Salvage Therapy for Acute and Chronic Graft-versus-Host Disease in Children and Young Adults: a single institution experience.\nBackgroundRuxolitinib, a Janus kinase (JAK)-1/JAK-2 inhibitor that reduces T-cell activation and proliferation leading to a potent anti-inflammatory effect, was recently approved to treat steroid-refractory acute graft-versus-host disease (aGvHD) and is under study for chronic GvHD (cGvHD). However, there are few reports on its use in pediatric and young adult patients with GvHD.\n\nMethodsWe retrospectively report our single center experience with ruxolitinib in 15 patients aged 11-29 years: 5 patients with steroid refractory/steroid dependent aGvHD and 10 patients with cGvHD who had failed at least one systemic therapy.\n\nResultsIn the aGvHD group, ruxolitinib led to an overall response rate (ORR) of 40% at day 28 and 80% with longer follow-up (complete response, CR 60%), with a median of 21 days (5-74) to achieve a response. In the cGvHD group (9 evaluable patients), we observed an ORR of 67% and a CR of 22%, with a median of 78 days (35-180) to achieve a response. Adverse events included cytopenias, gastrointestinal symptoms, infections, and an allergic reaction attributable to ruxolitinib.\n\nConclusionsOverall, our results show that ruxolitinib is an effective salvage therapy for severe GvHD in pediatric and young adult patients. The toxicities noted warrant adequate antimicrobial prophylaxis and close monitoring of blood counts.","Targeting Versus Tailoring Educational Videos for Encouraging Deceased Organ Donor Registration in Black-Owned Barbershops\nIn the U.S., Black men have highest risk for requiring kidney transplants but are among those least likely to register for organ donation. Prior outreach used videos culturally targeted for Black communities, yet registration rates remain insufficient to meet demand. Therefore, we assessed whether generic versus videos culturally targeted or personally tailored based on prior organ donation beliefs differentially increase organ donor registration. In a randomized controlled trial, 1,353 participants in Black-owned barbershops viewed generic, targeted, or tailored videos about organ donation. Logistic regression models assessed relative impact of videos on: 1) immediate organ donor registration, 2) taking brochures, and 3) change in organ donation willingness stage of change from baseline. Randomization yielded approximately equal groups related to demographics and baseline willingness and beliefs. Neither targeted nor tailored videos differentially affected registration compared with the generic video, but participants in targeted and tailored groups were more likely to take brochures. Targeted (OR=1.74) and tailored (OR=1.57) videos were associated with incremental increases in organ donation willingness stage of change compared to the generic video. Distributing culturally targeted and individually tailored videos increased organ donor willingness stage of change among Black men in black-owned barbershops but was insufficient for encouraging registration.","A Pilot Randomized Controlled Trial of de novo Belatacept-Based Immunosuppression in Lung Transplantation\nThe development of donor-specific antibodies (DSA) after lung transplantation is common and results in adverse outcomes. In kidney transplantation, Belatacept has been associated with a lower incidence of DSA, but experience with Belatacept in lung transplantation is limited. We conducted a 2-center pilot randomized controlled trial of de novo immunosuppression with Belatacept after lung transplantation to assess the feasibility of conducting a pivotal trial. Twenty-seven participants were randomized to Control (Tacrolimus, Mycophenolate Mofetil, and prednisone, n = 14) or Belatacept-based immunosuppression (Tacrolimus, Belatacept, and prednisone until day 89 followed by Belatacept, Mycophenolate Mofetil, and prednisone, n = 13). All participants were treated with rabbit anti-thymocyte globulin for induction immunosuppression. We permanently stopped randomization and treatment with Belatacept after 3 participants in the Belatacept arm died compared to none in the Control arm. Subsequently, 2 additional participants in the Belatacept arm died for a total of 5 deaths compared to none in the Control arm (log rank p = 0.016). We did not detect a significant difference in DSA development, acute cellular rejection, or infection between the 2 groups. We conclude that this investigational regimen using Belatacept after lung transplantation is associated with significantly increased mortality.","A fourth dose of the mRNA-1273 SARS-CoV-2 vaccine improves serum neutralization against the delta variant in kidney transplant recipients\nIn immunocompetent subjects, the effectiveness of SARS-CoV-2 vaccines against the delta variant appears three- to five-fold lower than that observed against the alpha variant. Additionally, three doses of SARS-CoV-2 mRNA-based vaccines might be unable to elicit a sufficient immune response against any variant in immunocompromised kidney transplant recipients. This study describes the kinetics of the neutralizing antibody (NAbs) response against the delta strain before and after a fourth dose of a mRNA vaccine in 67 kidney transplant recipients who had experienced a weak antibody response after three doses. While only 16% of patients harbored NAbs against the delta strain prior to the fourth injection - this percentage raised to 66% afterwards. We also found that, after the fourth dose, the NAbs titer increased significantly (p=0.0001) from <7.5 (IQR : <7.5-15.1) to 47.1 (IQR <7.5-284.2). Collectively, our data indicate that a fourth dose of the mRNA-1273 vaccine in kidney transplant recipients with a weak antibody response after three previous doses improves serum neutralization against the delta variant.","Changing of therapeutic trends between the 1st and 2nd wave did not reduce COVID-19 related mortality of renal transplant recipients: a national registry study.\nSARS-CoV-2 pandemic evolved in two consecutive waves over 2020 (for France: 1st wave from March 1 to July 31; and 2nd wave from August 1 to December 31). Improvements in the management of COVID-19 led to a reduction of mortality rates in hospitalized patients during the second wave. Whether this progress also benefited to kidney transplant recipients (KTR), a population particularly vulnerable to severe COVID-19, remained unclear.\n\nIn France, 957 KTR were hospitalized for COVID-19 in 2020 and their data were prospectively collected in the French SOT COVID registry. The presentation, management, and outcomes of the 359 KTR diagnosed during the 1st wave were compared to those of the 598 of the 2nd wave. Baseline comorbidities were largely similar between KTR of the 2 waves. Maintenance immunosuppression was reduced in most patients but withdrawal of antimetabolite (73.7% vs 58.4%, p<0.001) or CNI (32.1% vs 16.6%, p<0.001) was less frequent during the 2nd wave. Hydroxychloroquine and azithromycin that were commonly used during the 1st wave (21.7% and 30.9%, respectively) were almost abandoned during the 2nd. In contrast, the use of high dose corticosteroids doubled (19.5% vs. 41.6%, p<0.001). Despite these changing trends in COVID-19 management, 60-day mortality was not statistically different between the 2 waves (25.3% vs. 23.9%; Log Rank, p=0.48).\n\nWe conclude that changing of therapeutic trends during 2020 did not reduce COVID-19 related mortality in KTR. Our data indirectly support the importance of vaccination and monoclonal neutralizing anti-SARS-CoV-2 antibodies to protect KTR from severe COVID-19.","Humoral immune responses against SARS-CoV-2 variants including omicron in solid organ transplant recipients after three doses of a COVID-19 mRNA vaccine\nBackgroundSolid organ transplant recipients (SOTR), who typically receive post-transplant immunosuppression, show increased COVID-19-related mortality. It is unclear whether an additional dose of COVID-19 vaccines in SOTR can overcome the reduced immune responsiveness against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants.\n\nMethodsWe performed a prospective cohort study of 53 SOTR receiving SARS-CoV-2 vaccination into a prospective cohort study performing detailed immunoprofiling of humoral immune responses against SARS-CoV-2 and its variants.\n\nResultsPrior to the additional vaccine dose, 60.3% of SOTR showed no measurable neutralization and only 18.9% demonstrated neutralizing activity of >90% following two vaccine doses. More intensive immunosuppression, antimetabolites in particular, negatively impacted antiviral immunity. While absolute IgG levels were lower in SOTR than controls, antibody titers against microbial recall antigens were in fact higher. In contrast, SOTR showed reduced vaccine-induced IgG/IgA antibody titers against SARS-CoV-2 and its delta variants. Vaccinated SOTR showed a markedly fewer linear B cell epitopes, indicating reduced B cell diversity. Importantly, a third vaccine dose led to an increase in anti-SARS-CoV-2 antibody titers and neutralizing activity across alpha, beta and delta variants. However, we observed a significant decrease in anti-spike antibody titers with the omicron variant.\n\nConclusionsOnly a small subgroup of SOTR generated functionally relevant antibodies after completing the initial vaccine series based on dysfunctional priming of immune responses against novel antigens. An additional dose of the vaccine results in dramatically improved antibody responses against all SARS-CoV-2 variants except omicron.","Human Leukocyte Antigen Homozygosity Contributes to Sensitization in Kidney Transplant Candidates\nBackgroundHomozygosity for human leukocyte antigens (HLA) has been associated with adverse outcomes after viral infection as well as pregnancy-induced HLA sensitization. We sought to assess the relationship between HLA locus homozygosity and the level of HLA antibody sensitization.\n\nMethodsWe measured sensitization using the calculated panel reactive antibody (CPRA) value for a large cohort of 147,461 patients added to the US OPTN/UNOS kidney transplant waitlist between December 2014 and December 2019. We used multinomial logistic modeling to compare 62,510 sensitized patients to 84,955 unsensitized controls.\n\nResultsWe found that the number of homozygous HLA loci was strongly associated with the level of sensitization. Within highly- or extremely-sensitized candidates, women displayed a higher relative abundance of HLA homozygosity at multiple HLA loci as compared to men, with attenuation of this effect in Black candidates. In multinomial logistic modeling, the number of homozygous HLA loci was an independent predictor of sensitization and interacted with female sex but not with other factors associated with sensitization.\n\nConclusionsThis study shows that HLA homozygosity is an innate genetic factor that contributes to HLA sensitization, and enhances the effect of pregnancy-related sensitization.","Trends in underlying causes of death in solid organ transplant recipients between 2010 and 2020: Using the CLASS method for determining specific causes of death\nMonitoring specific underlying causes of death in solid organ transplant (SOT) recipients is important in order to identify emerging trends and health challenges.\n\nThis retrospective cohort study includes all SOT recipients transplanted at Rigshospitalet between January 1st, 2010 and December 31st, 2019. The underlying cause of death was determined using the newly developed Classification of Death Causes after Transplantation (CLASS) method. Cox regression analyses assessed risk factors for all-cause and cause-specific mortality.\n\nOf the 1774 SOT recipients included, 299 patients died during a total of 7511 person-years of follow-up (PYFU) with cancer (N=57, 19%), graft rejection (N=55, 18%) and infections (N=52, 17%) being the most frequent causes of death.\n\nWe observed a lower risk of all-cause death with increasing transplant year (HR 0.91, 95% CI 0.86-0.96 per 1-year increase), alongside death from graft rejection (HR 0.84 per year, 95% CI 0.74-0.95) and death from infections (HR 0.87 per year, 95% CI 0.77-0.98).\n\nFurther, there was a trend towards lower cumulative incidence of death from cardiovascular disease, graft failure and cancer in more recent years, while death from other organ specific and non-organ specific causes did not decrease.\n\nAll-cause mortality among SOT recipients has decreased over the past decade, mainly due to a decrease in graft rejection- and infection-related deaths. Conversely, causes from a broad range of diseases have remained unchanged, suggesting that cause of death among SOT recipients is increasingly diverse and warrants a multidisciplinary effort and attention in the future.","Prior SARS-CoV2 infection in vaccinated solid organ transplant recipients induces potent neutralization responses against variants, including Omicron\nFactors affecting functional antibody responses in solid organ transplant recipients (SOTRs) to current SARS-CoV2 vaccines are not well understood. Here, we measured vaccine-induced neutralizing activities against the D614G-CoV2 baseline virus and eight variants, including Omicron, in a panel of CoV2 infected- (n=13) and uninfected- (n=63) vaccinated kidney and heart transplant recipients. In the CoV2 uninfected-vaccinated subset, only 19% and 35% of two and three-dose vaccinated recipients respectively possessed minimally protective neutralizing plasma antibody titers (IC50>1:50) against D614G. In contrast, all of the CoV2 infected-vaccinated SOTRs who received two vaccine doses possessed titers exceeding minimal protection; 12/13 exhibiting strong protection (IC50>1:600) against D614G with minimal increases provided by a third dose. Omicron was the most resistant variant: only 10% of CoV2 uninfected-vaccinated SOTRs reached the minimally protective neutralization titer, while 76% of CoV2 infected-vaccinated SOTRs exceeded this value. These results indicate that prior infection and vaccination can induce highly protective antibody responses in many SOTRs, and identify important factors (shorter time since transplantation, prednisone administration, and African American ethnicity) that limit these responses. Overall, these results suggest factors to consider in establishing optimum COVID-19 vaccination strategies in these cohorts."],"string":"[\n \"COVID-19 in 823 Transplant patients: A Systematic Scoping Review\\nBackgroundManagement of COVID-19 in transplant patients is a big challenge. Data on immunosuppression management, clinical picture, and outcomes are lacking.\\n\\nObjectivesTo summarize the current literature on COVID-19 in transplant patients especially the data regarding the immunosuppression protocols, clinical presentation, and outcomes.\\n\\nSearch strategyA systematic search of MEDLINE, EBSCO, CENTRAL, CINAHL, LitCovid, Web of Science, and Scopus electronic databases. The references of the relevant studies were also searched. The search was last updated on June 3, 2020.\\n\\nSelection CriteriaPrimary reports of solid organ transplant patients who developed COVID-19. An overlap of cases in different reports was checked.\\n\\nData collection and analysisA descriptive summary of immunosuppression therapy (before and after COVID-19), clinical presentation (symptoms, imaging, laboratory, and disease severity), management (oxygen therapy, antiviral, and antibacterial), major outcomes (Intensive care admission, invasive mechanical ventilation, acute kidney injury), and mortality.\\n\\nMain resultsWe identified 74 studies reporting 823 cases of solid organ transplantation with COVID-19. Among 372 patients, 114 (30.6%) were mild COVID-19, 101 (27.2%) moderate, and 157 (42.2%) severe or critical.\\n\\nMajor outcomes included intensive care unit admission, invasive ventilation, and acute kidney injury, which occurred in 121 (14.7%), 97 (11.8%), and 63 (7.7%) of patients, respectively. Mortality was reported in 160 (19.4%) patients. Missing individual data hindered making clinical correlations.\\n\\nConclusionCOVID-19 in solid organ transplant patients probably has a more disease severity, worse major outcomes (Intensive care admission, invasive ventilation, acute kidney injury), and higher mortality than in non-transplant patients.\",\n \"Torque teno virus load predicts allograft rejection but not viral infection after kidney transplantation\\nThe main challenge of immunosuppressive therapy after solid organ transplantation is to create a new immunological balance that prevents organ rejection and does not promote opportunistic infection. Torque teno virus (TTV) a ubiquitous and non-pathogenic single-stranded DNA virus has been proposed as a marker of functional immunity in immunocompromised patients. Here investigate whether TTV loads predict the risk of common viral infection and allograft rejection in kidney transplantation recipients.\\n\\nIn a retrospective cohort of 389 kidney transplantation recipients, individual TTV loads in were measured by qPCR in consecutive plasma samples during one year follow-up. The endpoints were allograft rejection, BK polyomavirus (BKPyV) viremia and cytomegalovirus (CMV) viremia. Repeated TTV measurements and rejection and infection survival data were analysed in a joint model.\\n\\nDuring follow-up, TTV DNA detection in the transplant recipients increased from 85 to 100%. The median viral load increased to 107 genome copies/ml within three months after transplantation. Rejection, BKPyV viremia and CMV viremia occurred in 23%, 27% and 17% of the patients, respectively. With every 10-fold TTV load-increase, the risk of rejection decreased considerably (HR: 0.74, CI 95%: 0.71-0.76), while the risk of BKPyV and CMV viremia remained the same (HR: 1.03, CI 95%: 1.03-1.04 and HR: 1.01, CI 95%: 1.01-1.01).\\n\\nIn conclusion, TTV load kinetics predict allograft rejection in kidney transplantation recipients, but not the BKPyV and CMV infection. The potential use of TTV load levels as a guide for optimal immunosuppressive drug dosage to prevent allograft rejection deserves further validation.\",\n \"Weak anti-SARS-CoV-2 antibody response after the first injection of an mRNA COVID-19 vaccine in kidney transplant recipients\\nData concerning the anti-SARS-CoV-2 antibody response after mRNA COVID-19 vaccine in kidney transplant recipients (KTRs) are currently lacking. Here, we sought to examine this issue by analyzing the serological response observed in 241 KTRs after a first vaccine injection. Our results indicate that KTRs have a weak anti-SARS-CoV-2 antibody response, ultimately resulting in a low seroconversion rate (26/241, 10.8%). This phenomenon likely stems from a high immunosuppression burden in this clinical population.\",\n \"The effect of CYP3A4 genetic polymorphisms on the pharmacokinetics of calcineurin inhibitors in renal transplant recipients: a systematic review and meta-analysis protocol\\nBackgroundCalcineurin inhibitors (CNIs) are metabolized by CYP3A4. Polymorphisms in the CYP3A4 gene alter the activity of CYP3A4 protein and therefore affect the CNIs concentrations. Results of studies that investigated the association between CYP3A4 polymorphisms and CNIs pharmacokinetics are controversial. Therefore, this systematic review and meta-analysis will evaluate the effect of CYP3A4 polymorphisms on the pharmacokinetics of CNIs in renal transplant recipients.\\n\\nMethodThis protocol is developed according to the PRISMA-P guideline and registered in PROSPERO (CRD42020145219). The MeSH/Emtree terms of CYP3A4 polymorphisms and CNIs pharmacokinetics in PECO-based question will be obtained from the comprehensive literature search on PubMed/MEDLINE, Scopus, Web of Science, Embase, CENTRAL, and ProQuest without any language limitation from 1 January 1998 to 31 March 2021. Google Scholar search engine, registries, conference papers, and key journals will also be searched. Screening, selection, quality assessment, and data extraction will be performed by two independent reviewers. Statistical heterogeneity will be calculated by the Q Cochrane test and I2 statistic. Publication bias and sensitivity analysis will be evaluated by appropriate tests.\\n\\nResults and conclusionAccording to the meta-analysis of the aggregated data from the relevant primary studies, the association between CYP3A4 polymorphisms and CNIs pharmacokinetics will be reported, which possibly help the pharmacogenetic-guided dosing approach.\",\n \"Donor race has no role in predicting allograft and patient survival among kidney transplant recipients\\nA heated debate in creatinine-based estimated glomerular filtration rate (eGFR) calculation is the inclusion of race alongside biological factors, such as age and gender. Similarly, the race variable was included in the calculation of the Kidney Donor Risk Index (KDRI) as deceased donor kidneys from black donors have historically been shown to be associated with lower allograft or patient survival. Given the current climate of uncertainty with the use of race in nephrology, we sought to answer the question of whether removing the donor race variable from the KDRI would alter its validity to assess allograft and patient survival. Our modeling and analysis showed that removing donor race from the original KDRI did not alter the overall model predictability of allograft failure or patient mortality. Clinical risk factors included in the KDRI have largely accounted for differential risk between black and other donors. Adding donor race into the KDRI only shifts how risk is attributed to these clinical risk factors, without yielding better prediction of outcomes than the model without race.\",\n \"Impaired Humoral and Cellular Immunity after SARS-CoV2 BNT162b2 (Tozinameran) Prime-Boost Vaccination in Kidney Transplant Recipients\\nNovel mRNA-based vaccines have been proven powerful tools to combat the global pandemic caused by SARS-CoV2 with BNT162b2 efficiently protecting individuals from COVID-19 across a broad age range. Still, it remains largely unknown how renal insufficiency and immunosuppressive medication affect development of vaccine induced immunity. We therefore comprehensively analyzed humoral and cellular responses in kidney transplant recipients after prime-boost vaccination with BNT162b2. As opposed to all healthy vaccinees and the majority of hemodialysis patients, only 4/39 and 1/39 transplanted individuals showed IgA and IgG seroconversion at day 8{+/-}1 after booster immunization with minor changes until day 23{+/-}5, respectively. Although most transplanted patients mounted spike-specific T helper cell responses, frequencies were significantly reduced compared to controls and dialysis patients, accompanied by a broad impairment in effector cytokine production, memory differentiation and activation-related signatures. Spike-specific CD8+ T cell responses were less abundant than their CD4+ counterparts in healthy controls and hemodialysis patients and almost undetectable in transplant patients. Signs of alloreactivity promoted by BNT162b2 were not documented within the observation period. In summary, our data strongly suggest revised vaccination approaches in immunosuppressed patients, including individual immune monitoring for protection of this vulnerable group at risk to develop severe COVID-19.\",\n \"Donor genetic variants in interleukin-6 and interleukin-6 receptor associate with biopsy-proven rejection following kidney transplantation.\\nRejection after kidney transplantation remains an important cause of allograft failure that markedly impacts morbidity. Cytokines are a major player in rejection, and we, therefore, explored the impact of interleukin-6 (IL6) and IL-6 receptor (IL6R) gene polymorphisms on the occurrence of rejection after renal transplantation. We performed an observational cohort study analyzing both donor and recipient DNA in 1,271 renal transplant-pairs from the University Medical Center Groningen in The Netherlands and associated single nucleotide polymorphisms (SNPs) with biopsy-proven rejection after kidney transplantation. The C-allele of the IL6R SNP (Asp358Ala; rs2228145 A>C, formerly rs8192284) in donor kidneys conferred a reduced risk of rejection following renal transplantation (HR 0.78 per C-allele; 95%-CI 0.67-0.90; P=0.001). On the other hand, the C-allele of the IL6 SNP (at position-174 in the promoter; rs1800795 G>C) in donor kidneys was associated with an increased risk of rejection for male organ donors (HR per C-allele 1.31; 95%-CI 1.08-1.58; P=0.0006), but not female organ donors (P=0.33). In contrast, neither the IL6 nor IL6R SNP in the recipient showed an association with renal transplant rejection. In conclusion, donor IL6 and IL6R genotypes but not recipient genotypes represent an independent prognostic marker for biopsy-proven renal allograft rejection.\",\n \"Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes\\nApolipoprotein L1 (APOL1) risk alleles in donor kidneys associate with graft loss but whether recipient risk allele expression impacts kidney transplant outcomes is unclear. To test whether recipient APOL1 allelic variants independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data of donors and recipients from two kidney transplant cohorts, Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation 1/17 (CTOT1/17). We estimated genetic ancestry (quantified as proportion of African ancestry or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we observed that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with increased risk of death-censored allograft loss (DCAL), independent of genetic ancestry (HR = 2.14; P = 0.006), and within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with increased risk of any T cell-mediated rejection (TCMR) event. Analysis of the CTOT cohort validated these associations. Ex vivo studies of peripheral blood mononuclear cells revealed unanticipated high APOL1 expression in activated CD4+/CD8+ T cells and natural killer cells. We detected enriched immune response gene pathways in G1/G2 allele carriers vs. non-carriers among patients on the kidney waitlist and healthy controls. Together our findings highlight a previously unrecognized contribution of recipient APOL1 risk alleles to renal allograft outcomes. This immunomodulatory role has broader implications for immune mediated injury to native kidneys.\",\n \"Cellular immunity predominates over humoral immunity after the first dose of COVID-19 vaccines in solid organ transplant recipients\\nKnowledge on the vaccine-induced cellular and humoral immunity and on immunogenicity of vector-based and mRNA vaccines in solid organ transplant recipients is limited. Therefore, SARS-CoV-2 specific T-cells and antibodies were analyzed in 40 transplant recipients and 70 age-matched controls after the first dose of vector-based or mRNA vaccines. Plasmablasts and SARS-CoV-2 specific CD4 and CD8 T-cells were quantified using flow-cytometry. Specific antibodies were analyzed by ELISA and neutralization assay. SARS-CoV-2 specific antibodies and T-cells were induced in both groups with significantly lower levels in patients. While antibodies were detected in 80% of controls and 5.3% of patients, specific CD4 and/or CD8 T-cells were more frequently found in both controls (84.3%) and patients (23.7%). The two vaccine types showed notable differences, as IgG and neutralizing activity were more pronounced after mRNA vaccination (p<0.0001 each), whereas CD4 and CD8 T-cell levels were higher after vector vaccination (p=0.009; p<0.0001). Plasmablast numbers were significantly higher in controls and correlated with SARS-CoV-2 specific IgG- and CD4 T-cell levels. In conclusion, assessment of antibodies is not sufficient to identify COVID-19-vaccine responders. Together with differences in immunogenicity among vaccines, this necessitates combined analysis of humoral and cellular immunity to reliably assess responders among immunocompetent and immunocompromised individuals.\",\n \"T Cell Positive B Cell Negative Flow Cytometry Crossmatch (FCXM): Frequency, HLA-Locus Specificity, and Mechanisms Among 3073 Clinical FCXM Tests\\nBackgroundA T cell positive and B cell negative (T+B-) flow cytometry crossmatch (FCXM) result remains a conundrum since HLA-class I antigens are expressed on both T and B cells. We investigated the frequency, HLA specificity of the antibodies and mechanisms for the T+B- FCXM result.\\n\\nMethodsWe analyzed 3073 clinical FCXM tests performed in an American Society of Histocompatibility and Immunogenetics accredited histocompatibility laboratory. The sera associated with the T+B- FCXM were also tested for donor HLA IgG antibodies using LABScreen single antigen assays.\\n\\nResultsAmong the 3073 FCXM tests, 1963 were T-B-, 811 were T-B+, 274 were T+B+, and 25 were T+B-. IgG antibodies directed at donor HLA-A, B, or Cw locus determined antigens (DSA) were identified in all 25 sera and the summed mean fluorescence intensity (MFI) of DSA ranged from 212 to 53,187. Correlational analyses identified a significant association between the summed MFI of class I DSA, and the median channel fluorescence (MCF) of T cells treated with the recipient serum (Spearman rank correlation, rs=0.34, P=0.05) but not with the MCF of B cells (rs=0.23, P=0.24). We identified that differential binding of anti-HLA antibodies to T cells and B cells and the B cell channel shift threshold used to classify a B cell FCXM are potential contributors to a T+B- FCXM result.\\n\\nConclusionsOur analysis of 3073 FCXM, in addition to demonstrating that HLA antibodies directed at HLA-A, B or Cw locus are associated with a T+B- result, identified mechanisms for the surprising T+B- FCXM result.\",\n \"Phenotypic and functional characterisation of circulating cytomegalovirus-specific T cells in healthy virus carriers and lung transplant candidates\\nThis manuscript has been withdrawn by the authors as it was submitted and made public without appropriate approval. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.\",\n \"Early microbiome and metabolome signatures in pediatric patients undergoing allogeneic hematopoietic cell transplantation\\nBackgroundThe contribution of the gastrointestinal tract microbiome to outcomes after allogeneic hematopoietic cell transplantation (HCT) is increasingly recognized. Investigations of larger pediatric cohorts aimed at defining the microbiome state and associated metabolic patterns pre-transplant are needed.\\n\\nMethodsWe sought to describe the pre-transplant stool microbiome in pediatric allogenic HCT patients at four centers. We performed shotgun metagenomic sequencing and untargeted metabolic profiling on pre-transplant stool samples. Samples were compared with normal age-matched controls and by clinical characteristics. We then explored associations between stool microbiome measurements and metabolite concentrations.\\n\\nResultsWe profiled stool samples from 88 pediatric allogeneic HCT patients, a median of 4 days before transplant. Pre-transplant stool samples differed from healthy controls based on indices of alpha diversity and in the proportional abundance of specific taxa and bacterial genes. Relative to stool from healthy patients, samples from HCT patients had decreased proportion of Bacteroides, Ruminococcaeae and genes involved in butyrate production, but were enriched for gammaproteobacterial species. No systematic differences in stool microbiome or metabolomic profiles by age, transplant indication or hospital were noted. Stool metabolites demonstrated strong correlations with microbiome composition.\\n\\nDiscussionStool samples from pediatric allogeneic HCT patients demonstrate substantial dysbiosis early in the transplant course. As microbiome disruptions associate with adverse transplant outcomes, pediatric-specific analyses examining longitudinal microbiome and metabolome change are imperative to identify causal associations and to inform rational design of interventions.\",\n \"Deceased donor kidney degradomics indicates cytoskeletal proteolytic alterations impacting post-transplant function.\\nBackgroundIn brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys that adversely impacts the quality of grafts. Here, we hypothesized that DBD kidneys may undergo proteolytic processes that renders grafts susceptible to post-transplant dysfunction.\\n\\nMaterial & MethodsUsing mass spectrometry and immunoblotting analyses, we profiled degradation patterns of cytoskeletal proteins in deceased (n=55) and living (n=10) donor kidneys.\\n\\nResultsWe found that in DBD kidneys, key podocyte cytoskeletal proteins had been proteolytically cleaved. Generated degradation profiles were not associated to donor related demographic and clinical factors but were associated to suboptimal post-transplant function. Strikingly, -actinin -4 and Talin-1 degradation profiles were not observed in circulatory-death or living-donor kidneys. As Talin-1 is a specific proteolytic target of Calpain-1, we investigated a potential trigger of Calpain activation and Talin-1 degradation using ex-vivo precision-cut human kidney slices and in-vitro immortalised human podocytes. Notably, we found that Transforming-Growth Factor-{beta} (TGF-{beta}) activated Calpain-1 and proteolytically cleaved Talin-1 to generate distinct peptide fragments. These peptide fragments were of similar size and matched the degradation patterns observed in DBD kidneys. Talin-1 degradation was prevented in vitro by Calpain-1 inhibition.\\n\\nConclusionsHere, we provide initial evidence that DBD kidneys are susceptible to cytoskeletal protein degradation that impacts posttransplant kidney function. Subsequent studies should aim to further investigate the link between brain death and activation of proteolytic pathways exploring new therapeutic opportunities.\",\n \"A functional TGFB1 polymorphism in the donor associates with long-term graft survival after kidney transplantation.\\nIntroductionImprovement of long-term outcomes in kidney transplantation remains one of the most pressing challenges, yet drug development is stagnating. Human genetics offers an opportunity for much-needed target validation in transplantation. Conflicting data exists about the effect of transforming growth factor-beta 1 (TGF-{beta}1) on kidney transplant survival, since TGF-{beta}1 has profibrotic and protective effects. We therefore the impact of a recently discovered functional TGBF1 polymorphism on long-term kidney graft survival.\\n\\nMethodsWe performed an observational cohort study analyzing recipient and donor DNA in 1,271 kidney transplant-pairs from the University Medical Center Groningen in The Netherlands and associated a low-producing TGBF1 polymorphism (rs1800472-C>T) with 5, 10, and 15-year death-censored kidney graft survival.\\n\\nResultsDonor genotype frequencies of s1800472 in TGBF1 differed significantly between patients with and without graft loss (P=0.042). Additionally, the low-producing TGBF1 polymorphism in the donor was associated with an increased risk of graft loss following kidney transplantation (HR 2.13 for the T-allele; 95%-CI 1.16-3.90; P=0.015). The incidence of graft loss within 15 years of follow-up 16.4% in the CC-genotype group and 28.9% in the CT-genotype group. After adjustment for transplant-related covariates, the association between the TGBF1 polymorphism in the donor and graft loss remained significant. In contrast, there was no association between the TGBF1 polymorphism in the recipient and graft loss.\\n\\nConclusionKidney allografts possessing a low-producing TGBF1 polymorphism have a higher risk of late graft loss. Our study adds to a growing body of evidence that TGF-{beta}1 is beneficial, rather than harmful, for kidney transplant survival.\",\n \"Comparison of infected and vaccinated transplant recipients highlights the role of Tfh and neutralizing IgG in COVID-19 protection\\nTransplant recipients, which receive therapeutic immunosuppression to prevent graft rejection, are characterized by high COVID-19-related mortality and defective response to vaccines. Having observed that previous infection by SARS-CoV-2 but not the standard \\\"2 doses\\\" scheme of vaccination, provided complete protection against COVID-19 to transplant recipients, we undertook this translational study to compare the cellular and humoral immune responses of these 2 groups of patients. Neutralizing anti-Receptor Binding Domain (RBD) IgG were identified as the critical immune effectors associated with protection. Generation of anti-RBD IgG was dependent upon spike-specific T follicular helper (Tfh) CD4+ T cells, which acted as limiting checkpoint. Tfh generation was impeded by high dose mycophenolate mofetil in non-responders to vaccine but not in infected patients, suggesting that increasing immunogenicity of vaccine could improve response rate to mRNA vaccine. This theory was validated in two independent prospective cohorts, in which administration of a 3rd dose of vaccine resulted in the generation of anti-RBD IgG in half of non-responders to 2 doses.\\n\\nOne sentence summaryThe generation of neutralizing IgG, which protects kidney transplant recipients from COVID-19, requires T follicular helper cells.\",\n \"Tumor necrosis factor-α gene polymorphism is associated with short- and long-term kidney allograft outcomes.\\nIntroductionKidney transplantation has excellent short-term results with current immunosuppression regimes, but long-term outcomes have barely improved. Hence, there is a need for new therapeutic options to increase long-term survival of kidney grafts. Drug development for transplantation has slowly plateaued, limiting progress while making drug repurposing an attractive alternative. We, therefore, investigated the impact of tumor necrosis factor-alpha (TNF-) gene (TNF) polymorphisms on kidney graft survival.\\n\\nMethodsWe performed a prospective cohort study to assess the association of TNF polymorphisms (rs1800629 G>A and rs3093662 A>G) with primary non-function (PNF) and death-censored kidney allograft survival in 1,271 kidney transplant pairs from the University Medical Center Groningen in The Netherlands.\\n\\nResultsThe G-allele of the TNF rs3093662 polymorphism in donor kidneys was associated with a higher risk of PNF (odds ratio: 2.05; 95%-CI: 1.06-3.97; P = 0.032). Furthermore, the G-allele of this TNF rs3093662 polymorphism in the donor was also associated with worse 5-year, 10-year, and 15-year death-censored kidney graft survival (P < 0.05). The cumulative incidence of graft loss was 15.9% in the reference AA-genotype group and 25.2% in the AG/GG-genotype group, respectively. In multivariable analysis, the association between the TNF rs3093662 polymorphism in the donor and 15-year death-censored kidney graft survival remained significant (hazard ratio: 1.51; 95%-CI: 1.05-2.19, P = 0.028).\\n\\nConclusionKidney allografts possessing a high-producing TNF polymorphism have a greater risk of immediate and late graft loss. Our study adds to a growing body of literature indicating the potential of TNF- blockade in improving kidney transplantation outcomes.\",\n \"Predictive factors of response to 3rd dose of COVID-19 mRNA vaccine in kidney transplant recipients\\nOnly a minority of kidney transplant recipients (KTRs) develop protective neutralizing titers of anti-receptor binding domain of spike protein (RBD) IgG after two doses of mRNA COVID-19 vaccine. Administration of a third dose of mRNA vaccine to KTRs with sub-optimal response increase anti-RBD IgG titers but with high inter-individual variability. Patients with the higher response rate to the third dose of vaccine can be identified by the presence of low anti-RBD IgG titers and spike-specific CD4+ T cells in their circulation 14 days after the second dose.\",\n \"Antibody response to a fourth mRNA Covid-19 vaccine boost in weak responder kidney transplant recipients\\nThe US FDA has recently authorized immunocompromised people to receive a third dose of mRNA Covid-19 vaccine following the two-doses regimen to further boost protection. Unfortunately, a non-negligible proportion of people treated with immunosuppressive drugs either do not respond or show only a weak response after a third boost and should, therefore, still be considered at risk of severe Covid-19. As of June 2021, we were granted the opportunity to offer a fourth vaccine dose to French solid organ transplant recipients who still showed a weak antibody response after the third dose. In this multicenter study, we demonstrate that that the protection conferred by a fourth dose is adequate for the majority of kidney transplant recipients.\",\n \"Public perception of organ donation and transplantation policies in Southern Spain\\nBackgroundThis research explores how public awareness and attitudes towards donation and transplantation policies may contribute to Spains success in cadaveric organ donation.\\n\\nMaterials and MethodsA representative sample of 813 people residing in Andalusia (Southern Spain) were surveyed by telephone or via Internet between October and December 2018.\\n\\nResultsMost participants trust Spains donation and transplantation system (93%) and wish to donate their organs after death (76%). Among donors, a majority have expressed their consent (59%), while few non-donors have expressed their refusal (14%). Only a minority is aware of the presumed consent system in force (28%) and feel sufficiently informed regarding the requirements needed to be an organ donor (16%). Participants mainly consider that relatives should represent the deceaseds preferences and be consulted when the deceaseds wishes are unknown, as is the case in Spain.\\n\\nConclusionsPublic trust in the transplant system may contribute to Spains high performance in organ donation. High levels of societal support towards organ donation and transplantation do not correspond in Spain with similar levels of public awareness of donation and transplantation policies.\",\n \"Real-world Effectiveness of 2-dose SARS-CoV-2 Vaccination in Kidney Transplant Recipients\\nThe humoral response to two doses of SARS-CoV-2 (Covid-19) vaccine among transplant recipients is inferior to immunocompetent individuals.1 Data on the real-world effectiveness of vaccination in kidney transplant recipients [KTRs] are lacking. We performed a cohort study to investigate the impact of vaccination on Covid-19 infection and outcomes in our kidney transplant program.\",\n \"Perfusate metabolomics content and tubular transporters expression during kidney graft preservation by hypothermic machine perfusion\\nBackgroundIschemia-related injury during the pre-implantation period impacts kidney graft outcome. Evaluating these lesions by a non-invasive approach before transplantation could help to understand the mechanisms of graft injury and identify potential biomarkers predictive of graft outcomes. This study aims to determine metabolomic content of graft perfusion fluids and its dependence on preservation time and to explore whether tubular transporters are possibly involved in the metabolomics variations observed.\\n\\nMethodsKidneys were stored on hypothermic perfusion machines. We evaluated the metabolomic profiles of perfusion fluids (n=35) using Liquid Chromatography coupled with tandem Mass Spectrometry and studied the transcriptional expression of tubular transporters on pre-implantation biopsies (n=26). We used univariate and multivariate analyses to assess the impact of perfusion time on these parameters and their relationship with graft outcome.\\n\\nResultsSeventy-two metabolites were found in preservation fluids at the end of perfusion, of which 40% were already present in the native conservation solution. We observed an increase of 23 metabolites with longer perfusion time and a decrease for 8. The predictive model for time-dependent variation of metabolomics content showed good performance (R2= 76%, Q2= 54%, accuracy= 41%, permutations test significant). Perfusion time had no effect on the mRNA expression of transporters. We found no correlation between metabolomics and transporters expression. Neither the metabolomics profile nor the transporters expression were predictive of graft outcome.\\n\\nConclusionOur results open the way for further studies, focusing on both intra- and extra-tissue metabolome, to investigate whether transporter alterations can explain the variations observed in pre-implantation period.\",\n \"Identifying opportunities for improving the organ supply through race-stratified data\\nOrgan procurement in the US has received attention from government officials and policymakers the last two years, culminating in CMS releasing an updated Final Rule related to organ donation this year. This regulatory change revises how organ procurement organizations (OPOs), the federal contractors tasked with managing deceased donation, are evaluated and certified/de-certified. We used 2019 data and the CMS methodology to calculate race-stratified donation data among racial/ethnic minorities across the 57 OPOs. We found that the variability in donation rates across the 57 OPOs are greater among minority populations than non-Hispanic white potential donors. Among Tier 3 OPOs, there are: a) some with low donation rates across all racial/ethnic groups; b) some with low donation rates among only certain groups, and c) some where donation rates are lowest among non-Hispanic white patients. Among low-performing OPOs, these race/ethnicity-stratified data show that under-performance in certain areas is not due to the population demographics, and identifies areas for targeted interventions to increase donation and avoid decertification\",\n \"Ruxolitinib As a Salvage Therapy for Acute and Chronic Graft-versus-Host Disease in Children and Young Adults: a single institution experience.\\nBackgroundRuxolitinib, a Janus kinase (JAK)-1/JAK-2 inhibitor that reduces T-cell activation and proliferation leading to a potent anti-inflammatory effect, was recently approved to treat steroid-refractory acute graft-versus-host disease (aGvHD) and is under study for chronic GvHD (cGvHD). However, there are few reports on its use in pediatric and young adult patients with GvHD.\\n\\nMethodsWe retrospectively report our single center experience with ruxolitinib in 15 patients aged 11-29 years: 5 patients with steroid refractory/steroid dependent aGvHD and 10 patients with cGvHD who had failed at least one systemic therapy.\\n\\nResultsIn the aGvHD group, ruxolitinib led to an overall response rate (ORR) of 40% at day 28 and 80% with longer follow-up (complete response, CR 60%), with a median of 21 days (5-74) to achieve a response. In the cGvHD group (9 evaluable patients), we observed an ORR of 67% and a CR of 22%, with a median of 78 days (35-180) to achieve a response. Adverse events included cytopenias, gastrointestinal symptoms, infections, and an allergic reaction attributable to ruxolitinib.\\n\\nConclusionsOverall, our results show that ruxolitinib is an effective salvage therapy for severe GvHD in pediatric and young adult patients. The toxicities noted warrant adequate antimicrobial prophylaxis and close monitoring of blood counts.\",\n \"Targeting Versus Tailoring Educational Videos for Encouraging Deceased Organ Donor Registration in Black-Owned Barbershops\\nIn the U.S., Black men have highest risk for requiring kidney transplants but are among those least likely to register for organ donation. Prior outreach used videos culturally targeted for Black communities, yet registration rates remain insufficient to meet demand. Therefore, we assessed whether generic versus videos culturally targeted or personally tailored based on prior organ donation beliefs differentially increase organ donor registration. In a randomized controlled trial, 1,353 participants in Black-owned barbershops viewed generic, targeted, or tailored videos about organ donation. Logistic regression models assessed relative impact of videos on: 1) immediate organ donor registration, 2) taking brochures, and 3) change in organ donation willingness stage of change from baseline. Randomization yielded approximately equal groups related to demographics and baseline willingness and beliefs. Neither targeted nor tailored videos differentially affected registration compared with the generic video, but participants in targeted and tailored groups were more likely to take brochures. Targeted (OR=1.74) and tailored (OR=1.57) videos were associated with incremental increases in organ donation willingness stage of change compared to the generic video. Distributing culturally targeted and individually tailored videos increased organ donor willingness stage of change among Black men in black-owned barbershops but was insufficient for encouraging registration.\",\n \"A Pilot Randomized Controlled Trial of de novo Belatacept-Based Immunosuppression in Lung Transplantation\\nThe development of donor-specific antibodies (DSA) after lung transplantation is common and results in adverse outcomes. In kidney transplantation, Belatacept has been associated with a lower incidence of DSA, but experience with Belatacept in lung transplantation is limited. We conducted a 2-center pilot randomized controlled trial of de novo immunosuppression with Belatacept after lung transplantation to assess the feasibility of conducting a pivotal trial. Twenty-seven participants were randomized to Control (Tacrolimus, Mycophenolate Mofetil, and prednisone, n = 14) or Belatacept-based immunosuppression (Tacrolimus, Belatacept, and prednisone until day 89 followed by Belatacept, Mycophenolate Mofetil, and prednisone, n = 13). All participants were treated with rabbit anti-thymocyte globulin for induction immunosuppression. We permanently stopped randomization and treatment with Belatacept after 3 participants in the Belatacept arm died compared to none in the Control arm. Subsequently, 2 additional participants in the Belatacept arm died for a total of 5 deaths compared to none in the Control arm (log rank p = 0.016). We did not detect a significant difference in DSA development, acute cellular rejection, or infection between the 2 groups. We conclude that this investigational regimen using Belatacept after lung transplantation is associated with significantly increased mortality.\",\n \"A fourth dose of the mRNA-1273 SARS-CoV-2 vaccine improves serum neutralization against the delta variant in kidney transplant recipients\\nIn immunocompetent subjects, the effectiveness of SARS-CoV-2 vaccines against the delta variant appears three- to five-fold lower than that observed against the alpha variant. Additionally, three doses of SARS-CoV-2 mRNA-based vaccines might be unable to elicit a sufficient immune response against any variant in immunocompromised kidney transplant recipients. This study describes the kinetics of the neutralizing antibody (NAbs) response against the delta strain before and after a fourth dose of a mRNA vaccine in 67 kidney transplant recipients who had experienced a weak antibody response after three doses. While only 16% of patients harbored NAbs against the delta strain prior to the fourth injection - this percentage raised to 66% afterwards. We also found that, after the fourth dose, the NAbs titer increased significantly (p=0.0001) from <7.5 (IQR : <7.5-15.1) to 47.1 (IQR <7.5-284.2). Collectively, our data indicate that a fourth dose of the mRNA-1273 vaccine in kidney transplant recipients with a weak antibody response after three previous doses improves serum neutralization against the delta variant.\",\n \"Changing of therapeutic trends between the 1st and 2nd wave did not reduce COVID-19 related mortality of renal transplant recipients: a national registry study.\\nSARS-CoV-2 pandemic evolved in two consecutive waves over 2020 (for France: 1st wave from March 1 to July 31; and 2nd wave from August 1 to December 31). Improvements in the management of COVID-19 led to a reduction of mortality rates in hospitalized patients during the second wave. Whether this progress also benefited to kidney transplant recipients (KTR), a population particularly vulnerable to severe COVID-19, remained unclear.\\n\\nIn France, 957 KTR were hospitalized for COVID-19 in 2020 and their data were prospectively collected in the French SOT COVID registry. The presentation, management, and outcomes of the 359 KTR diagnosed during the 1st wave were compared to those of the 598 of the 2nd wave. Baseline comorbidities were largely similar between KTR of the 2 waves. Maintenance immunosuppression was reduced in most patients but withdrawal of antimetabolite (73.7% vs 58.4%, p<0.001) or CNI (32.1% vs 16.6%, p<0.001) was less frequent during the 2nd wave. Hydroxychloroquine and azithromycin that were commonly used during the 1st wave (21.7% and 30.9%, respectively) were almost abandoned during the 2nd. In contrast, the use of high dose corticosteroids doubled (19.5% vs. 41.6%, p<0.001). Despite these changing trends in COVID-19 management, 60-day mortality was not statistically different between the 2 waves (25.3% vs. 23.9%; Log Rank, p=0.48).\\n\\nWe conclude that changing of therapeutic trends during 2020 did not reduce COVID-19 related mortality in KTR. Our data indirectly support the importance of vaccination and monoclonal neutralizing anti-SARS-CoV-2 antibodies to protect KTR from severe COVID-19.\",\n \"Humoral immune responses against SARS-CoV-2 variants including omicron in solid organ transplant recipients after three doses of a COVID-19 mRNA vaccine\\nBackgroundSolid organ transplant recipients (SOTR), who typically receive post-transplant immunosuppression, show increased COVID-19-related mortality. It is unclear whether an additional dose of COVID-19 vaccines in SOTR can overcome the reduced immune responsiveness against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants.\\n\\nMethodsWe performed a prospective cohort study of 53 SOTR receiving SARS-CoV-2 vaccination into a prospective cohort study performing detailed immunoprofiling of humoral immune responses against SARS-CoV-2 and its variants.\\n\\nResultsPrior to the additional vaccine dose, 60.3% of SOTR showed no measurable neutralization and only 18.9% demonstrated neutralizing activity of >90% following two vaccine doses. More intensive immunosuppression, antimetabolites in particular, negatively impacted antiviral immunity. While absolute IgG levels were lower in SOTR than controls, antibody titers against microbial recall antigens were in fact higher. In contrast, SOTR showed reduced vaccine-induced IgG/IgA antibody titers against SARS-CoV-2 and its delta variants. Vaccinated SOTR showed a markedly fewer linear B cell epitopes, indicating reduced B cell diversity. Importantly, a third vaccine dose led to an increase in anti-SARS-CoV-2 antibody titers and neutralizing activity across alpha, beta and delta variants. However, we observed a significant decrease in anti-spike antibody titers with the omicron variant.\\n\\nConclusionsOnly a small subgroup of SOTR generated functionally relevant antibodies after completing the initial vaccine series based on dysfunctional priming of immune responses against novel antigens. An additional dose of the vaccine results in dramatically improved antibody responses against all SARS-CoV-2 variants except omicron.\",\n \"Human Leukocyte Antigen Homozygosity Contributes to Sensitization in Kidney Transplant Candidates\\nBackgroundHomozygosity for human leukocyte antigens (HLA) has been associated with adverse outcomes after viral infection as well as pregnancy-induced HLA sensitization. We sought to assess the relationship between HLA locus homozygosity and the level of HLA antibody sensitization.\\n\\nMethodsWe measured sensitization using the calculated panel reactive antibody (CPRA) value for a large cohort of 147,461 patients added to the US OPTN/UNOS kidney transplant waitlist between December 2014 and December 2019. We used multinomial logistic modeling to compare 62,510 sensitized patients to 84,955 unsensitized controls.\\n\\nResultsWe found that the number of homozygous HLA loci was strongly associated with the level of sensitization. Within highly- or extremely-sensitized candidates, women displayed a higher relative abundance of HLA homozygosity at multiple HLA loci as compared to men, with attenuation of this effect in Black candidates. In multinomial logistic modeling, the number of homozygous HLA loci was an independent predictor of sensitization and interacted with female sex but not with other factors associated with sensitization.\\n\\nConclusionsThis study shows that HLA homozygosity is an innate genetic factor that contributes to HLA sensitization, and enhances the effect of pregnancy-related sensitization.\",\n \"Trends in underlying causes of death in solid organ transplant recipients between 2010 and 2020: Using the CLASS method for determining specific causes of death\\nMonitoring specific underlying causes of death in solid organ transplant (SOT) recipients is important in order to identify emerging trends and health challenges.\\n\\nThis retrospective cohort study includes all SOT recipients transplanted at Rigshospitalet between January 1st, 2010 and December 31st, 2019. The underlying cause of death was determined using the newly developed Classification of Death Causes after Transplantation (CLASS) method. Cox regression analyses assessed risk factors for all-cause and cause-specific mortality.\\n\\nOf the 1774 SOT recipients included, 299 patients died during a total of 7511 person-years of follow-up (PYFU) with cancer (N=57, 19%), graft rejection (N=55, 18%) and infections (N=52, 17%) being the most frequent causes of death.\\n\\nWe observed a lower risk of all-cause death with increasing transplant year (HR 0.91, 95% CI 0.86-0.96 per 1-year increase), alongside death from graft rejection (HR 0.84 per year, 95% CI 0.74-0.95) and death from infections (HR 0.87 per year, 95% CI 0.77-0.98).\\n\\nFurther, there was a trend towards lower cumulative incidence of death from cardiovascular disease, graft failure and cancer in more recent years, while death from other organ specific and non-organ specific causes did not decrease.\\n\\nAll-cause mortality among SOT recipients has decreased over the past decade, mainly due to a decrease in graft rejection- and infection-related deaths. Conversely, causes from a broad range of diseases have remained unchanged, suggesting that cause of death among SOT recipients is increasingly diverse and warrants a multidisciplinary effort and attention in the future.\",\n \"Prior SARS-CoV2 infection in vaccinated solid organ transplant recipients induces potent neutralization responses against variants, including Omicron\\nFactors affecting functional antibody responses in solid organ transplant recipients (SOTRs) to current SARS-CoV2 vaccines are not well understood. Here, we measured vaccine-induced neutralizing activities against the D614G-CoV2 baseline virus and eight variants, including Omicron, in a panel of CoV2 infected- (n=13) and uninfected- (n=63) vaccinated kidney and heart transplant recipients. In the CoV2 uninfected-vaccinated subset, only 19% and 35% of two and three-dose vaccinated recipients respectively possessed minimally protective neutralizing plasma antibody titers (IC50>1:50) against D614G. In contrast, all of the CoV2 infected-vaccinated SOTRs who received two vaccine doses possessed titers exceeding minimal protection; 12/13 exhibiting strong protection (IC50>1:600) against D614G with minimal increases provided by a third dose. Omicron was the most resistant variant: only 10% of CoV2 uninfected-vaccinated SOTRs reached the minimally protective neutralization titer, while 76% of CoV2 infected-vaccinated SOTRs exceeded this value. These results indicate that prior infection and vaccination can induce highly protective antibody responses in many SOTRs, and identify important factors (shorter time since transplantation, prednisone administration, and African American ethnicity) that limit these responses. Overall, these results suggest factors to consider in establishing optimum COVID-19 vaccination strategies in these cohorts.\"\n]","isConversational":false},"negative":{"kind":"list like","value":["Multi-trait genome-wide association study identifies new loci associated with sleep apnoea risk\nBackgroundSleep apnoea is a disorder characterised by periods of halted breathing during sleep. Despite its association with severe health conditions such as cardiovascular disease, liver problems and metabolic syndrome, the aetiology of sleep apnoea remain understudied, and previous genetic analyses have not identified many robustly associated genetic risk variants.\n\nMethodsWe performed a genome-wide association study (GWAS) meta-analysis of sleep apnoea across five cohorts (NTotal=523,366) and multi-trait analysis of GWAS (MTAG) to boost statistical power, leveraging the high genetic correlation between sleep apnoea and snoring. GWAS and MTAG results were adjusted to control for the effects of body mass index (BMI) using the multi-trait-based conditional & joint analysis (mtCOJO) method. Lead hit replication was conducted in an independent sample GWAS from 23andMe, Inc. that included BMI as a covariate (NTotal=1,477,352; Ncases=175,522). Lastly, we explored genetic correlations with other complex traits and performed a phenome-wide screen for causally associated phenotypes using the latent causal variable method.\n\nResultsOur MTAG with snoring uncovered a total of 49 independent significant sleep apnoea loci; adjusting for BMI showed that approximately half of those loci act via their effects on BMI/obesity. Twenty-nine variants replicated in the 23andMe cohort. Several complex traits, including multisite chronic pain, diabetes, eye disorders, high blood pressure, osteoarthritis, chronic obstructive pulmonary disease, and BMI-related traits were genetically correlated with sleep apnoea.\n\nConclusionsOur study identifies multiple robust genetic markers for sleep apnoea, increasing our understanding of the aetiology of this condition and its relationship with other complex traits.","LRRK2 coding variants and the risk of Parkinson's disease\nBackgroundThe leucine-rich repeat kinase 2 (LRRK2) gene harbors both rare highly damaging missense variants (e.g. p.G2019S) and common non-coding variants (e.g. rs76904798) with lower effect sizes that are associated with Parkinsons disease risk.\n\nObjectivesThis study aimed to investigate in a large meta-analysis whether the LRRK2 GWAS signal represented by rs76904798 is independently associated with Parkinsons disease risk from LRRK2 coding variation, and whether complex linkage disequilibrium structures with p.G2019S and the 5 non-coding haplotype account for the association of LRRK2 coding variants.\n\nMethodsWe performed a meta-analysis using imputed genotypes from 17,838 cases, 13,404 proxy-cases and 173,639 healthy controls of European ancestry. We excluded carriers of p.G2019S and/or rs76904798 to clarify the role of LRRK2 coding variation in mediating disease risk, and excluded carriers of relatively rare LRRK2 coding variants to assess the independence of rs76904798. We also investigated the co-inheritance of LRRK2 coding variants with p.G2019S, rs76904798 and p.N2081D.\n\nResultsLRRK2 rs76904798 remained significantly associated with Parkinsons disease after excluding carriers of relatively rare LRRK2 coding variants. LRRK2 p.R1514Q and p.N2081D were frequently co-inherited with rs76904798 and the allele distribution of p.S1647T significantly changed among cases after removing rs76904798 carriers.\n\nConclusionsThese data suggest that the LRRK2 coding variants previously linked to Parkinsons disease (p.N551K, p.R1398H, p.M1646T and p.N2081D) do not drive the 5 non-coding GWAS signal. These data, however, do not preclude the independent association of the haplotype p.N551K-p.R1398H and p.M1646T with altered disease risk.","Clinicopathological and Imaging Features of Primary Biliary Cholangitis\nAbstract/KeywordsO_ST_ABSBackground and AimsC_ST_ABSPrimary biliary cholangitis (PBC) is a chronic inflammatory autoimmune disease of the biliary epithelial cells, causing slow progression of cholestasis and fibrosis. The aim of the study is to summarize the imaging features of PBC and examine the correlation between its clinicopathological and radiologic features, elucidating the specific clinicopathological and radiologic differences between male and female PBC patients, as well as between AMA-positive and AMA-negative PBC patients.\n\nMethodsDemographic, laboratory, radiologic and survival data were collected retrospectively for patients diagnosed and treated for PBC at the Mount Sinai Health System between 2016 and 2020 with at least one ultrasound, CT, or MRI of abdomen available for assessment. Biochemical and radiologic data were compared between male v.s. female groups, and AMA-positive v.s. AMA-negative group.\n\nResultsA total of 273 patients diagnosed with PBC were included. Non-specific hepatic parenchymal disease, cirrhosis, cholelithiasis, splenomegaly, lymphadenopathy, benign liver masses/cysts were the most common features on abdominal images. 24% of PBC patients had biliary tree abnormalities on MRI. LAD was reported in 38-47% of PBC patients. There was no significant difference in age, race, or ethnicity between the sexes of patients with PBC, however imaging characteristics of portal hypertension were more frequently seen in men. AMA-negative PBC patients had similar distributions of age, race/ethnicity and survival to AMA-positive PBC patients.\n\nConclusionOur study summarized the clinicopathological and imaging features of PBC and distinct subgroups. This would assist in the diagnosis of PBC and avoid over-testing in real-world practice.","Disease-modifying therapies for T1 hypointense lesions (Black Holes) volume in patients with multiple sclerosis: Protocol for a systematic review and meta-analysis\nRationaleA major part of diagnosis and follow-up in patients with multiple sclerosis is based on MRI evaluations. As T1-hypointense lesions represent neural destruction or axonal loss and anticipate irreversible disability in the patients, evaluation of the effects of Disease-modifying therapies (DMTs) on the volume of black holes seems necessary.\n\nObjectivesTo evaluate the effects of FDA approved disease-modifying therapies (DMTs) on T1 hypointense lesions (Black Holes) volume in patients with multiple sclerosis (MS)\n\nData sourcesWe will search MEDLINE (through Ovid), Embase, and CENTRAL. We wont consider any timeframe, language, or geographical restrictions.\n\nMethodsWe will include only randomized controlled trials (RCTs) that have evaluated the effects of DMTs on black holes mean volume in adult patients diagnosed with any phenotype of multiple sclerosis (MS) in comparison to the placebo, routine care, or no treatment regimen. We will assess the risk of bias in the primary studies using the Revised Cochrane risk-of-bias tool for randomized trials (RoB2). Data will be synthesized based on the random-effects model and results will be plotted on a forest plot. Heterogeneity will be assessed using I2 statistics. If feasible, we will also perform subgroup analyses for each DMT.\n\nFundingThis study is not funded.\n\nRegistrationPROSPERO submission ID: 262883.","The Immunogenetic Basis of Idiopathic Bone Marrow Failure Syndromes: A Paradox of Similarity and Self-Presentation\nIdiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure disorder initiated by a human leukocyte antigen (HLA)-restricted T-cell response to unknown antigens. Immunogenetic patterns associated with self-antigenic presentation remain unclear. Herein we analyzed the molecular landscape of HLA complexes and T-cell receptor (TCR) repertoires of a large cohort of IAA patients and controls. We show that antigen binding sites of class II HLA molecules in IAA are characterized by a high level of structural homology, only partially explained by specific risk allele profiles, implying reduced binding capabilities compared to controls. Few amino acids within the synapsis HLA-DRB1-antigen-TCR, are identified as strongly associated with IAA phenotype. Those structural patterns may affect TCR repertoires, promoting immunological cross-reactivity and autoimmunity. These findings inform on the immunogenetic risk associated with IAA and on general pathophysiological mechanisms potentially involved in autoimmunity.\n\nKey pointsO_LIClass II human leukocyte antigen (HLA) loci in idiopathic bone marrow failure (BMF) syndromes are characterized by low functional divergence and decreased peptide binding capabilities, only partially explained by enrichment in risk alleles.\nC_LIO_LIA superstructure at the interface with the peptide binding site of DRB1 locus, potentially involved in the presentation of self-antigenic specificities, can be identified in BMF patients.\nC_LIO_LIThis immunogenetic pattern may contribute to decrease T-cell receptor repertoire diversity, expand autoreactive T-cell clones and increase autoimmune propensity in BMF.\nC_LI","Characteristics of Patients Referred to a Cardiovascular Disease Clinic for Post-Acute Sequelae of SARS-CoV-2 Infection\nThere is limited literature on the cardiovascular manifestations of post-acute sequelae of SARS-CoV-2 infection (PASC). We aimed to describe the characteristics, diagnostic evaluations, and cardiac diagnoses in patients referred to a cardiovascular disease clinic designed for patients with PASC from May 2020 to September 2021. Of 126 patients, average age was 46 years (range 19-81 years), 43 (34%) were male. Patients presented on average five months after COVID-19 diagnosis. 30 (24%) patients were hospitalized for acute COVID-19. Severity of acute COVID-19 was mild in 37%, moderate in 41%, severe in 11%, and critical in 9%. Patients were also followed for PASC by pulmonology (53%), neurology (33%), otolaryngology (11%), and rheumatology (7%). Forty-three patients (34%) did not have significant comorbidities. The most common symptoms were dyspnea (52%), chest pain/pressure (48%), palpitations (44%), and fatigue (42%), commonly associated with exertion or exercise intolerance. The following cardiovascular diagnoses were identified: nonischemic cardiomyopathy (5%); new ischemia (3%); coronary vasospasm (2%); new atrial fibrillation (2%), new supraventricular tachycardia (2%); myocardial involvement (15%) by cardiac MRI, characterized by late gadolinium enhancement (LGE; 60%) or inflammation (48%). The remaining 97 patients (77%) exhibited common symptoms of fatigue, dyspnea on exertion, tachycardia, or chest pain, which we termed \"cardiovascular PASC syndrome.\" Three of these people met criteria for postural orthostatic tachycardia syndrome. Lower severity of acute COVID-19 was a significant predictor of cardiovascular PASC syndrome. In this cohort of patients referred to cardiology for PASC, 23% had a new diagnosis, but most displayed a pattern of symptoms associated with exercise intolerance.","Easy-BILAG: a new tool for simplified recording of SLE disease activity using BILAG-2004 index.\nObjectiveBILAG-2004 index is a comprehensive disease activity instrument for SLE but administrative burden and frequency of errors limits its use in routine practice. We aimed to develop a tool for more accurate, time-efficient scoring of BILAG-2004 index with full fidelity to the existing instrument.\n\nMethodsFrequency of BILAG-2004 items was collated from a BILAG-biologics registry (BILAG-BR) dataset. Easy-BILAG prototypes were drafted to address known issues affecting speed and accuracy. After expert-verification, accuracy and usability of the finalised Easy-BILAG was validated against standard format BILAG-2004 index in a workbook exercise of 10 case vignettes. 33 professionals with a range of expertise from 14 UK centres completed the validation exercise.\n\nResultsEasy-BILAG incorporates all items present in [≥]5% BILAG-BR records, plus full constitutional and renal domains into a rapid single-page assessment. An embedded glossary and colour-coding assists scoring each domain. A second page captures rarer manifestations when needed. In the validation exercise, Easy-BILAG yielded higher median scoring accuracy (96.7%) than standard BILAG-2004 documentation (87.8%, p=0.001), with better inter-rater agreement. Easy-BILAG was completed faster (59.5min) than the standard format (80.0min, p=0.04) for 10 cases. An advantage in accuracy was observed with Easy-BILAG use among general hospital rheumatologists (91.3 vs 75.0, p=0.02), leading to equivalent accuracy as tertiary centre rheumatologists. Clinicians rated Easy-BILAG as intuitive, convenient, and well adapted for routine practice.\n\nConclusionEasy-BILAG facilitates more rapid and accurate scoring of BILAG-2004 across all clinical settings which could improve patient care and biologics prescribing. Easy-BILAG should be adopted wherever BILAG-2004 assessment is required.","Vitamin D receptor polymorphisms in overweight/obese chronic kidney disease patients undergoing hemodialysis\nBackgroundMany studies were carried out to investigate the relationship between single nucleotide polymorphisms (SNPs) in vitamin D receptor (VDR) gene with obesity. However, little is known about the role of VDR gene polymorphism with obesity in hemodialysis (HD) patients. Therefore, we aimed to investigate VDR gene TaqI, ApaI and FokI SNPs in overweight/obese HD patients.\n\nMethodsSeventy one normal weight and 68 overweight/obese HD patients were included in study. PCR-RFLP method was used for genotyping. Demographic and laboratory data obtained from medical records of patients.\n\nResultsFor all three SNPs, no significant association was found between normal and overweight/obese patients (P>0.05). Lower HDL concentrations and higher levels of triglyceride (TG) and glucose were detected in the obese/overweight patients compared to normal weight (p<0.001 for HDL, and TG and p=0.023 for glucose). In obese/overweight patients, subjects with CC genotype of TaqI showed higher PTH level (717.1{+/-}616.4 pg/ml) than those TC genotype (342.7{+/-}360.8 pg/ml) and TT genotype (310.2{+/-}323.4 pg/ml) (p=0.028); higher TG level was found in patients with CC genotype of ApaI (627.3{+/-}653.0 mg/dl) compared to AA (223.3{+/-}156.6) and AC genotypes (193.1{+/-}85.4) (p<0.001). Obese/overweight patients carrying FokI TT genotype had higher glucose concentration compared to those carrying CC and CT genotypes (CC=183.4{+/-}128.4 mg/dl; TT=151.9{+/-}66.1 mg/dl; CT=107.6{+/-}41.9 mg/dl, p=0.008).\n\nConclusionsOur study suggest that VDR TaqI, ApaI and FokI polymorphisms are not associated with obesity in HD patients. However, they might be increase the risk of secondary hyperparathyroidism, dyslipidemia, and hyperglycemia, which are among the most common obesity related comorbidities of chronic kidney disease.","Heterogeneity in statin responses explained by variation in the human gut microbiome\nStatins remain one of the most prescribed medications worldwide. While effective in decreasing atherosclerotic cardiovascular disease risk, statin use is associated with several side effects for a subset of patients, including disrupted metabolic control and increased risk of type II diabetes. We investigated the potential role of the gut microbiome in modifying patient response to statin therapy. In a cohort of >1840 individuals, we find that the hydrolyzed substrate for 3-hydroxy-3-methylglutarate-CoA (HMG-CoA) reductase, HMG, may serve as a reliable marker for statin on-target effects. Through exploring gut microbiome associations between blood-derived measures of statin effectiveness and metabolic health parameters among statin users and non-users, we find that heterogeneity in statin response is associated with variation in the gut microbiome. A Bacteroides rich, -diversity depleted, microbiome composition corresponds to the strongest statin on-target response, but also greatest disruption to glucose homeostasis, indicating lower treatment doses and/or complementary therapies may be beneficial in those individuals. Our findings suggest a potential path towards personalizing statin treatment through gut microbiome monitoring.","Minimal observed impact of HLA genotype on hospitalization and severity of SARS-CoV-2 infection\nHLA is a critical component of the viral antigen presentation pathway. We investigated the relationship between severity of SARS-CoV-2 disease and HLA type in 3,235 individuals with confirmed SARS-CoV-2 infection. We found only the DPB1 locus to be associated with the binary outcome of whether an individual developed any COVID-19 symptoms. The number of peptides predicted to bind to an HLA allele had no significant relationship with disease severity both when stratifying individuals by ancestry or age and in a pooled analysis. Age, BMI, asthma status, and autoimmune disorder status were predictive of severity across multiple age and individual ancestry stratificiations. Overall, at the population level, we found HLA type is significantly less predictive of COVID-19 disease severity than certain demographic factors and clinical comorbidities.","Clinical Validation of Saliency Maps for Understanding Deep Neural Networks in Ophthalmology\nDeep neural networks (DNNs) have achieved physician-level accuracy on many imaging-based medical diagnostic tasks, for example classification of retinal images in ophthalmology. However, their decision mechanisms are often considered impenetrable leading to a lack of trust by clinicians and patients. To alle-viate this issue, a range of explanation methods have been proposed to expose the inner workings of DNNs leading to their decisions. For imaging-based tasks, this is often achieved via saliency maps. The quality of these maps are typically evaluated via perturbation analysis without experts involved. To facilitate the adoption and success of such automated systems, however, it is crucial to validate saliency maps against clinicians. In this study, we used three different network architectures and developed ensembles of DNNs to detect diabetic retinopathy and neovascular age-related macular degeneration from retinal fundus images and optical coherence tomography scans, respectively. We used a variety of explanation methods and obtained a comprehensive set of saliency maps for explaining the ensemble-based diagnostic decisions. Then, we systematically validated saliency maps against clinicians through two main analyses -- a direct comparison of saliency maps with the expert annotations of disease-specific pathologies and perturbation analyses using also expert annotations as saliency maps. We found the choice of DNN architecture and explanation method to significantly influence the quality of saliency maps. Guided Backprop showed consistently good performance across disease scenarios and DNN architectures, suggesting that it provides a suitable starting point for explaining the decisions of DNNs on retinal images.","High throughput SARS-CoV-2 variant analysis using molecular barcodes coupled with Next Generation Sequencing\nThe identification of SARS-CoV-2 variants across the globe and their implications on the outspread of the pandemic, infection potential and resistance to vaccination, requires modification of the current diagnostic methods to map out viral mutations rapidly and reliably. Here, we demonstrate that integrating DNA barcoding technology, sample pooling and Next Generation Sequencing (NGS) provide an applicable solution for large-population viral screening combined with specific variant analysis.\n\nOur solution allows high throughput testing by barcoding each sample, followed by pooling of test samples using a multi-step procedure. First, patient-specific barcodes are added to the primers used in a one-step RT-PCR reaction, amplifying three different viral genes and one human housekeeping gene (as internal control). Then, samples are pooled, purified and finally, the generated sequences are read using an Illumina NGS system to identify the positive samples with a sensitivity of 82.5% and a specificity of 97.3%. Using this solution, we were able to identify six known and one unknown SARS-CoV-2 variants in a screen of 960 samples out of which 258 (27%) were positive for the virus.\n\nThus, our diagnostic solution integrates the benefits of large population and epidemiological screening together with sensitive and specific identification of positive samples including variant analysis at a single nucleotide resolution.","Systematic Review and Scientific Rating of Commercial Apps Available in India for Diabetes Prevention\nBACKGROUNDScientific evidence for digital health applications (apps) which claim to help in the prevention and management of Type 2 diabetes (T2D) is limited.\n\nOBJECTIVESWe aimed to evaluate the quality of currently available health apps for prevention of T2D amongst Asian Indians.\n\nMETHODSUsing the keywords, diabetes prevention, healthy lifestyle and fitness, a total of 1486 apps available in India via Google Play were assessed for eligibility by two independent reviewers. After initial screening using specific inclusion and exclusion criteria, 50 apps underwent a pre-specified rating based on user reviews, number of downloads and app size. Sixteen apps that scored [≥] 9 were shortlisted for further review using the Mobile App Rating Scale (MARS). MARS contains 2 main categories: Category I (Application Quality) and Category II (Application Subjective Quality). The mean MARS scores were used to identify the top ranked apps.\n\nRESULTSThe mean score for Category I of MARS rating was highest for Google Fit: Health and Activity Tracking (4.55/5). This was followed by Healthifyme - Diet Plan, Health and Weight Loss (4.45/5). For Category II of MARS, Diabetes M, Google Fit: Health and Activity Tracking and Calorie Counter- My fitness pal, Healthifyme - Diet plan, Health and Weight Loss all scored equally well. On comparing the advantages and disadvantages of each of these applications, Google Fit: Health and Activity Tracking and Healthifyme - Diet plan, Health and Weight Loss again ranked the best.\n\nCONCLUSIONSOur review identifies two commercially available apps Google Fit: Health and Activity Tracking and Healthifyme - Diet plan, Health and Weight Loss as being user friendly and good quality. Although encouraging, further research is needed to evaluate the efficacy of these apps for prevention of diabetes.","Combination therapy of infliximab and thiopurines, but not monotherapy with infliximab or vedolizumab, is associated with attenuated IgA and neutralisation responses to SARS-CoV-2 in inflammatory bowel disease.\nThere is substantial interest regarding the perceived risk that immunomodulator and biologic therapy could have on COVID-19 disease severity among patients with inflammatory bowel disease (IBD) and clinicians. In this study, we show that infliximab/thiopurine combination therapy is associated with significantly lower IgA, a range of lower IgG responses as well as impaired neutralising antibody responses, compared to responses observed in healthy individuals. We also demonstrate that whilst IgG responses were significantly reduced in individuals with IBD treated with infliximab or vedolizumab monotherapy compared to healthy controls, there was no significant reduction in IgA and neutralising antibody responses. As neutralising antibody responses correlate with protection, this observation may provide the mechanistic explanation for the observation reported by the SECURE-IBD study that individuals on infliximab/thiopurine combination therapy were at greater risk of severe COVID-19 outcomes than patients on monotherapy.","High proportion of genome-wide homology and increased basal pvcrt levels in Plasmodium vivax late recurrences: a chloroquine therapeutic efficacy study\nChloroquine (CQ) is the first-line treatment for Plasmodium vivax malaria in most endemic countries. Monitoring P.vivax CQ resistance (CQR) is critical but remains challenged by the difficulty to distinguish real treatment failure from reinfection or liver relapse. Therapeutic efficacy of CQ against uncomplicated P.vivax malaria was evaluated in Gia Lai province, Vietnam. Sixty-seven patients were enrolled and followed-up for 42 days using microscopy and (RT)qPCR. Adequate clinical and parasitological response (ACPR) was 100% (66/66) on Day 28, but 75.4% (49/65) on Day 42. Eighteen recurrences (27.7%) were detected with a median time-to-recurrence of 42 days (IQR 35, 42) and blood CQ concentration <100ng/ml. Parasite genotyping by microsatellites, SNP-barcoding and whole-genome sequencing (WGS) identified a majority of homologous recurrences, with 80% (8/10) showing >98% identity-by-descent to paired Day 0 samples. Primary infections leading to recurrence occurred in younger individuals (median age for ACPR=25 years [IQR 20, 28]; recurrences=18 [16, 21]; p=0.002), had a longer parasite clearance time (PCT for ACPR=47.5h [IQR 36.2, 59.8]; recurrences=54.2h [48.4, 62.0]; p=0.035) and higher pvcrt gene expression (median relative expression ratio for ACPR=0.09 [IQR 0.05, 0.22]; recurrences=0.20 [0.15, 0.56]; p=0.002), but there was no difference in ex vivo CQ sensitivity. This study shows that CQ remained largely efficacious to treat P.vivax in Gia Lai, i.e. recurrences occurred late (>Day 28) and in the presence of low blood CQ concentrations. However, the combination of WGS and gene expression analysis (pvcrt) with clinical data (PCT) allowed to identify potential emergence of low-grade CQR that should be closely monitored.","Association between SARS-Cov-2 infection during pregnancy and adverse pregnancy outcomes: a re-analysis of data from Wei et al. (2021).\nBackgroundWei et al. have published a meta-analysis (MA) which aimed to \"evaluate the association between SARS-CoV-2 infection during pregnancy and adverse pregnancy outcomes\".\n\nUsing classical random-effects model, they found that SARS-CoV-2 infection was associated with preeclampsia, preterm birth and stillbirth.\n\nPerforming MA with low event rates or with few studies may be challenging as MA relies on several within and between study distributional assumptions.\n\nMethodsto assess the robustness of the results provided by Wei et al., we performed a sensitivity analysis using several frequentist and Bayesian meta-analysis methods. We also estimated fragility indexes.\n\nResultsFor eclampsia (patients with Covid-19 vs without), the confidence intervals of most frequentist models contain 1. All beta-binomial models (Bayesian) lead to credible intervals containing 1. The prediction interval, based on DL method ranges from 0.75 to 2.38. The fragility index is 2 for the DL method.\n\nFor preterm, the confidence (credible) intervals exclude 1. The prediction interval is broad, ranging from 0.84 to 20.61. The fragility index ranges from 27 to 10.\n\nFor stillbirth, the confidence intervals of most frequentist models contain 1. Six Bayesian MA models lead to credible intervals containing 1.The prediction interval ranges from 0.52 to 8.49. The fragility index is 3.\n\nInterpretationGiven the available data and the results of our broad sensitivity analysis, we can only suggest that SARS-CoV-2 infection during pregnancy is associated to preterm, and may be associated to preeclampsia. For stillbirth, more data are needed as none of the Bayesian analyses are conclusive.","Obesity and accelerated epigenetic aging in a high-risk cohort of children\nBackgroundNew insights into mechanisms linking obesity to poor health outcomes suggest a role for cellular aging pathways, casting obesity as a disease of accelerated biological aging. Although obesity has been linked to accelerated epigenetic aging in middle-aged adults, the impact during childhood remains unclear. We tested the association between body mass index (BMI) and accelerated epigenetic aging in a cohort of high-risk children. Participants were children (N=273, aged 8 to 14 years, 82% investigated for maltreatment) recruited to the Child Health Study, an ongoing prospective study of youth investigated for maltreatment and a comparison youth. BMI was measured as a continuous variable. Accelerated epigenetic aging of blood leukocytes was defined as the age-adjusted residuals of several established epigenetic aging clocks (Horvath, Hannum, GrimAge, PhenoAge) along with a newer algorithm, the DunedinPoAm, developed to quantify the pace-of-aging. Hypotheses were tested with generalized linear models.\n\nResultsHigher BMI was significantly correlated with older chronological age, maltreatment status, household income, blood cell counts, and three of the accelerated epigenetic aging measures: GrimAge (r=0.29, P<.0001), PhenoAge (r=0.25, P<.0001), and DunedinPoAm (r=0.37, P<.0001). In fully adjusted models, GrimAge (b=.06; P=.007) and DunedinPoAm (b=.0017; P<.0001) remained significantly associated with higher BMI. Maltreatment-status was not independently associated with accelerated epigenetic aging after accounting for other factors.\n\nConclusionIn a high-risk cohort of children, higher BMI predicted epigenetic aging as assessed by two epigenetic aging clocks. These results suggest the association between obesity and accelerated epigenetic aging begins in early life, with implications for future morbidity and mortality risk.","ATLAS: An automated association test using probabilistically linked health records with application to genetic studies\nObjectiveLarge amounts of health data are becoming available for biomedical research. Synthesizing information across databases with no gold standard mappings between records may provide a more complete picture of patient health and enable novel research studies. To do so, researchers may probabilistically link databases and conduct inference using the linked data. However, previous inference methods for linked data are constrained to specific linkage settings and exhibit low power. Here, we present ATLAS, an automated, flexible, and robust association testing algorithm for probabilistically linked data.\n\nMaterials and MethodsMissing variables are imputed at various thresholds using a weighted average method that propagates uncertainty from the linkage process. Next, an estimated effect size is obtained using a generalized linear model. ATLAS then conducts the threshold combination test by optimally combining p-values obtained from data imputed at varying thresholds using Fishers method and perturbation resampling.\n\nResultsIn simulations, ATLAS controls for type I error and exhibits high power compared to previous methods. In a real-world application study, incorporation of linked data-enabled analyses using ATLAS yielded two additional signifigant associations between rheumatoid arthritis genetic risk score and biomarkers.\n\nDiscussionThe ATLAS weighted average imputation weathers false matches and increases contribution of true matches to mitigate linkage error induced bias. ATLAS threshold combination test avoids arbitrarily choosing a threshold to rule a match, thus automating linked data-enabled analyses and preserving power.\n\nConclusionATLAS promises to enable novel and powerful research studies using linked data to capitalize on all available data sources.","Estimating Cuff-less Continuous Blood Pressure from Fingertip Photoplethysmogram Signals with Deep Neural Network Model\nObjectiveBlood pressure (BP) is an important physiological index reflecting cardiovascular function. Continuous blood pressure monitoring helps to reduce the prevalence and mortality of cardiovascular diseases. In this study, we aim to estimate systolic blood pressure (SBP) and diastolic blood pressure (DBP) values continuously based on fingertip photoplethysmogram (PPG) waveforms using deep neural network models.\n\nMethodsTwo models were proposed and both models consisted of three stages. The only difference between them was the method of extracting features from PPG signals in the first stage. Model 1 adopted Bidirectional Long Short-Term Memory (BiLSTM), while the other used convolutional neural network. Then, the residual connection was applied to multiple stacked LSTM layers in the second stage, following by the third stage with two fully connected layers.\n\nResultsOur proposed models outperformed other methods based on similar dataset or framework, while in our proposed models, the model 2 was superior to model 1. It satisfied the standard of Association for the Advancement of the Medical Instrumentation (AAMI) and obtained grade A for SBP and DBP estimation according to the British Hypertension Society (BHS) standard. The mean error (ME) and standard deviation (STD) for SBP and DBP estimations were 0.21 {+/-} 6.40 mmHg and 0.19 {+/-}4.71 mmHg, respectively.\n\nConclusionOur proposed models could extract important features of fingertip PPG waveforms automatically and realize cuff-less continuous BP monitoring, which can be helpful in the identification and early treatment of abnormal blood pressure, thus may reduce the occurrence of cardiovascular malignant events.","Genetic Contributions to Early and Late Onset Ischemic Stroke\nObjectiveTo determine the contribution of common genetic variants to risk of early onset ischemic stroke (IS).\n\nMethodsWe performed a meta-analysis of genome-wide association studies of early onset IS, ages 18-59, using individual level data or summary statistics in 16,927 cases and 576,353 non-stroke controls from 48 different studies across North America, Europe, and Asia. We further compared effect sizes at our most genome-wide significant loci between early and late onset IS and compared polygenic risk scores for venous thromboembolism between early versus later onset IS.\n\nResultsWe observed an association between early onset IS and ABO, a known stroke locus. The effect size of the peak ABO SNP, rs8176685, was significantly larger in early compared to late onset IS (OR 1.17 (95% C.I.: 1.11-1.22) vs 1.05 (0.99-1.12); p for interaction = 0.008). Analysis of genetically determined ABO blood groups revealed that early onset IS cases were more likely to have blood group A and less likely to have blood group O compared to both non-stroke controls and to late onset IS cases. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with early, compared to late, onset IS (p=0.008).\n\nConclusionThe ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with early onset IS, compared with late onset IS, supporting a stronger role of prothrombotic factors in early onset IS.","Associations between indicators of socioeconomic position and DNA methylation: A systematic review\nSocioeconomic position (SEP) is a major determinant of health across the life course. Yet, little is known about the biological mechanisms explaining this relationship. One possible explanation is through an epigenetic process called DNA methylation (DNAm), wherein the socioeconomic environment causes no alteration in the DNA sequence but modifies gene activity, gene expression, and therefore long-term health. To understand the evidence supporting a potential SEP-DNAm link, we performed a systematic review of published empirical findings on the association between SEP (from prenatal development to adulthood) and DNAm measured across the life course, with an eye toward evaluating how the timing, duration, and type of SEP exposure influenced DNAm. Across the 37 studies we identified, there was some evidence for the effect of SEP timing and duration on DNAm, with early-life SEP and persistently low SEP being particularly strong indicators of DNAm. Different indicators of SEP also had some unique associations with DNAm profiles, suggesting that SEP is not a singular concept, but rather that different aspects of the socioeconomic environment can shift DNAm patterns through distinct pathways. These differences with respect to SEP timing, duration, and type were notable because they were detected even among heterogenous study designs. Overall, findings from this review underscore the importance of analyzing SEP timing, duration, and type, given the complex relationship between SEP and DNAm across the lifespan. To guide future research, we highlight current limitations in the literature and propose recommendations for overcoming some of these challenges.","Casirivimab and imdevimab for the treatment of hospitalized patients with COVID-19\nBackgroundHospitalized patients with COVID-19 experience high mortality rates, ranging from 10% to 30%. Combined casirivimab and imdevimab (CAS+IMD) is authorized for use in outpatients with COVID-19 and in post-exposure prophylaxis. The UK-based platform RECOVERY study reported improved survival in hospitalized seronegative patients treated with CAS+IMD; however, in most of the world, anti-spike monoclonal antibody therapy is currently not approved for hospitalized patients.\n\nMethodsIn this phase I/II/III double-blind placebo-controlled trial, patients hospitalized with COVID-19 were randomized (1:1:1) to 2.4 g or 8.0 g of CAS+IMD or placebo, and characterized at baseline for viral load and SARS-CoV-2 endogenous immune response.\n\nResults1336 patients on low-flow or no supplemental oxygen were treated. The primary endpoint was met: in seronegative patients, the least squares mean difference (CAS+IMD vs placebo) for time-weighted average change from baseline viral load was -0.28 log10 copies/mL (95% confidence interval [CI] -0.51 to -0.05; P = .0172). The primary clinical analysis of death or mechanical ventilation from day 6 to 29 in patients with high viral load had a strong positive trend but did not reach significance. CAS+IMD numerically reduced all-cause mortality in seronegative patients through day 29 (relative risk reduction, 55.6%; 95% CI 24.2-74.0; nominal P = .0032). No safety concerns were noted.\n\nConclusionsIn hospitalized patients with COVID-19 on low-flow or no oxygen, CAS+IMD treatment reduced viral load and the risk of death or mechanical ventilation as well as all-cause mortality in the overall population, with the benefit driven by seronegative patients and no harm observed in seropositive patients.","Similar Rates of AKI during the First Two Waves of COVID-19 in Northern Italy: a single-center study\nIntroductionTwo waves of COVID-19 cases have overwhelmed most European countries during 2020. It is unclear if the incidence of acute kidney injury (AKI) has changed during the COVID-19 outbreaks. This study aims to evaluate the differences in incidence, risk factors and outcome of AKI in patients with SARS-CoV-2 infection during the first and second wave of COVID-19.\n\nMethodWe reviewed the health medical records of 792 consecutive patients with COVID-19 hospitalized at the University Hospital of Modena, Italy, from February 25 to December 14, 2020.\n\nResultsAKI was diagnosed in 122 (15.4%) patients. Incidence of AKI remained steady rate during wave-1 (15.9%) and wave-2 (14.7%) (P=0.89). AKI patients were older (P=<0.001) and had a more severe respiratory impairment (PO2/FO2) (P=[≤]0.001) than their non-AKI counterparts. AKI led to a longer hospital stay (P=0.001), complicated with a higher rate of ICU admission. COVID-19-related AKI was associate with 59.7% of deaths during wave-1 and 70.6% during wave-2. At the end of the period of observation, 24% (wave-1) and 46.7% (wave-2) of survivors were discharged with a not fully recovered kidney function. Risk factors for AKI in patients with COVID-19 were diuretics (HR=5.3; 95%CI, 1.2-23.3; P=0.025) and cardiovascular disease (HR, 2.23; 95%CI, 1.05-5.1; P=0.036).\n\nConclusionThe incidence of AKI (about 15%) remained unchanged during 2020, regardless of the trend of COVID-19. AKI occurred in patients with severe COVID-19 symptoms and was associated with a higher incidence of deaths than non-AKI patients. The risk factors of COVID-19-related AKI were diuretic therapy and cardiovascular disease.","A comparison of denoising methods in dynamic MRS using pseudo-synthetic data\nPurposeMR spectroscopy of dynamic systems is limited by low signal to noise. Denoising along a series of acquired spectra exploits their temporal correlation to improve the quality of individual spectra, and reduce errors in fitting metabolite peaks. In this study we compare the performance of several denoising methods.\n\nMethodsSix different denoising methods were considered: SIFT (Spectral Improvement by Fourier Thresholding), HSVD (Hankel Singular Value Decomposition), spline, wavelet, sliding window and sliding Gaussian. Pseudo-synthetic data was constructed to mimic 31Phosphorus spectra from exercising muscle. For each method the optimal tuning parameters were determined for SNRs of 2, 5, 10 and 20 using a Monte Carlo approach. Denoised data from each method was then fitted using the AMARES algorithm and the results compared to the pseudo-synthetic ground truth.\n\nResultsAll six methods produced improvements in both fitting accuracy and agreement with the ground truth, compared to unprocessed noisy data. The least effective methods, SIFT and HSVD, achieved around 10-20% reduction in RMS error, while the most effective, Spline, reduced RMS error by 70%. The improvement from denoising was typically greater for lower SNR data.\n\nConclusionsIndirect time domain denoising of dynamic MR spectroscopy data can substantially improve subsequent metabolite fitting. Spline-based denoising was found to be the most flexible and effective technique.","Cytogenetic & Molecular analysis in Premature Ovarian Failure\nIntroductionPremature Ovarian Failure (POF) being a heterogeneous genetic disease involves the interaction of multiple genetic defects and environmental factors and has been associated with several chromosomal abnormalities, single gene mutations, and genetic polymorphisms. BMP15 is a member of the transforming growth factor {beta} (TGF-{beta}) family. BMP15 gene product (protein) have 3 domians, mature domain (c-terminal region) of BMP15 binds to receptors located on granulosa cell surface to participate in key steps regarding ovarian function, such as granulosa cell proliferation and follicle maturation, ovulation rate modulation, oocyte competence determination and regulating granulosa cell sensitivity to FSH. Single nucleotide polymorphisms (SNPs) of the BMP-15 gene are associated with POF.\n\nMaterials & Methods30 POF patients and 30 healthy age matched controls were recruited for cytogenetic and molecular analysis. 10 ml whole blood was collected for karyotyping and PCR and PCR was performed for known SNPs of BMP-15 gene (-9C>G, 538G>A, 788insTCT and 852C>T) respectively. Amplified PCR products were sequenced commercially.\n\nObservation/ResultThirty cases (mean age 30 years) and thirty healthy controls (mean age 23 years) were recruited for the study. On cytogenetic analysis 2 cases had a 45, XO chromosomal complement. One case was heterozygous for the SNP (-9C>G) and one control was homozygous for the same SNP.\n\nDiscussionThe prevalence of this SNP was about 10.7% in cases & 3.3% in healthy controls. This polymorphism in promoter region may cause altered expression of the gene and results in POF.","Next-generation Serology by Mass Spectrometry: Readout of the SARS-CoV-2 Antibody Repertoire\nMethods of antibody detection are used to assess exposure or immunity to a pathogen. Here, we present Ig-MS, a novel serological readout that captures the immunoglobulin (Ig) repertoire at molecular resolution, including entire variable regions in Ig light and heavy chains. Ig-MS uses recent advances in protein mass spectrometry (MS) for multi-parametric readout of antibodies, with new metrics like Ion Titer (IT) and Degree of Clonality (DoC) capturing the heterogeneity and relative abundance of individual clones without sequencing of B cells. We apply Ig-MS to plasma from subjects with severe & mild COVID-19, using the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 as the bait for antibody capture. Importantly, we report a new data type for human serology, with compatibility to any recombinant antigen to gauge our immune responses to vaccination, pathogens, or autoimmune disorders.","Post discharge persistent symptoms after COVID-19 in rheumatic and musculoskeletal diseases\nOBJECTIVESTo describe persistent symptoms and consequences in Rheumatic and Musculoskeletal diseases (RMD) discharged from the hospital after Covid-19; to assess the roll of autoimmune rheumatic diseases (ARD) compared to and non-autoimmune rheumatic and musculoskeletal diseases (NARD) on persistent symptoms and consequences.\n\nMETHODSWe performed a cross-sectional observational study. RMD attended at a rheumatology outpatient clinic in Madrid with Covid-19 that required hospital admission were included. The main outcomes were persistence of symptoms and health consequences related to Covid19 after discharge. Independent variable was RMD group (ARD and NARD) and covariates were sociodemographic, clinical, and treatments. We ran a multivariable logistic regression model to assess the risk by RMD group on main outcomes.\n\nRESULTSWe included 105 patients and 51.5% had ARD. 68.57% reported at least one persistent symptom. The most frequent were dyspnea, fatigue, and chest pain. 31 patients had consequences. Lung damage was found in 11.4% of the patients, 18% had blood test abnormalities (10% lymphopenia), two died, one developed central retinal vein occlusion and one patient developed optic neuritis. 11 patients required readmission due to Covid-19 problems (16.7% ARD vs 3.9% NARD; p=0.053). No statistically significant differences by RMD groups were found in the final models.\n\nCONCLUSIONMany RMD patients have persistent symptoms, similar to other populations. This study also highlights that lung damage is the most frequent consequence. ARD compared to NARD does not seem to differ in terms of persistent symptoms or consequences, although ARD might have a greater number of readmissions due to Covid-19.","Machine Learning and Radiomics for Osteoporosis Risk Prediction Using X-ray Imaging\nOsteoporosis is a significant health and economic issue, as it predisposes patients to a higher risk of bone fracture. Measuring bone mineral density has been shown to be an accurate way to assess the risk for osteoporosis. The most common way for bone density testing is a dual-energy X-ray absorptiometry (DEXA) scan, which may be recommended for patients with increased risk of osteoporosis. Radiograph imaging is widely available in clinical settings and acquired for many reasons, such as trauma or pain. The goal of this project is to extract radiomics information from pelvic X-rays (both the hip and femoral neck regions) to assess the risk of osteoporosis (triaging patients into \"normal\" vs. \"at-risk\", or \"low risk\" vs. \"high risk\" categories). The motivation here is not to replace the DEXA scan but to proactively identify patients at risk for osteoporosis and appropriately refer them to management options. We apply machine learning-based radiomics techniques on a study cohort of 565 patients. Our preliminary results show that a correlation between the radiomics features extracted from pelvic X-rays and the level of osteoporosis risk derived from the DEXA test results.","Topographic volume-standardization atlas of the human brain\nObjectiveSpecific anatomical patterns are seen in various diseases affecting the brain. Clinical studies on the topography of pathologies are often limited by the absence of a normalization of the prevalence of pathologies to the relative volume of the affected anatomical structures. A comprehensive reference on the relative volumes of clinically relevant anatomical structures serving for such a normalization, is currently lacking.\n\nMethodsThe analyses are based on anatomical high-resolution three-dimensional T1-weighted magnetic resonance imaging data of 30 healthy Caucasian volunteers, including 14 females (mean age 37.79 years, SD 13.04) and 16 males (mean age 38.31 years, SD 16.91). Semi-automated anatomical segmentation was used, guided by a neuroanatomical parcellation algorithm differentiating 96 structures. Relative volumes were derived by normalizing parenchymal structures to the total individual encephalic volume and ventricular segments to the total individual ventricular volume.\n\nResultsThe present investigation provides the absolute and relative volumes of 96 anatomical parcellation units of the human encephalon. A larger absolute volume in males than in females is found for almost all parcellation units. While parenchymal structures display a trend towards decreasing volumes with increasing age, a significant inverse effect is seen with the ventricular system. The variances in volumes as well as the effects of gender and age are given for each structure before and after normalization.\n\nConclusionThe provided atlas constitutes an anatomically detailed and comprehensive analysis of the absolute and relative volumes of the human encephalic structures using a clinically oriented parcellation algorithm. It is intended to serve as a reference for volume-standardization in clinical studies on the topographic prevalence of pathologies.","Genome-wide Association Study of Pulmonary Function in Europeans and Africans from the UK Biobank Identifies Distinct Variants\nPulmonary function is an indicator of well-being, and pulmonary pathologies are the third major cause of death worldwide. FEV1, FVC, and PEF are quantitively used to assess pulmonary function. We conducted a genome-wide association analysis of pulmonary function in 383,471 individuals of European and 5,978 African descent represented in the UK Biobank. Here, we report 817 variants in Europeans and 3 in Africans associated (p-values < 5 x 10-8) with three pulmonary function parameters; FEV1, FVC and PEF. In addition to 377 variants in Europeans previously reported to be associated with phenotypes related to pulmonary function, we identified 330 novel loci, including an ISX intergenic variant rs369476290 on chromosome 22 in Africans and a KDM2A intron variant rs12790261 on chromosome 11 in Europeans. Remarkably, we find no shared variants among Africans and Europeans. Enrichment analyses of variants separately for each ancestry background revealed significant enrichment for terms related to pulmonary phenotypes in Europeans but not Africans. Further analysis of studies of pulmonary phenotypes revealed individuals of European background are disproportionally overrepresented in datasets compared to Africans, with the gap widening over the past five years. Our findings offer a better understanding of the different variants that modify pulmonary function in Africans and Europeans, a significant finding for future GWAS studies and medicine.","NeuroEPO improves cognition in Parkinson's disease. Preliminary report.\nBackgroundCognitive impairment is a feature of Parkinsons Disease (PD) from the early stages, but currently, no treatment for cognitive deficits in PD is available. Erythropoietin (EPO) has been studied for its potential neuroprotective properties in neurologic disorders with a beneficial action on cognition.\n\nObjectiveTo evaluate if NeuroEPO, a new formulation of EPO with low content of sialic acid, improves the cognitive function in PD patients.\n\nMethodsA double-blind, randomized, placebo-controlled physician lead trial was conducted. The sample was composed of 26 PD patients (HY stages I-II), where 15 received intranasal NeuroEPO for 5 weeks, and another age and gender-matched 11 patients were randomly assigned to the Placebo. All the samples received 9 months of intensive NeuroEPO treatment during a post-trial. The cognitive functions were assessed using a comprehensive neuropsychological battery before, one week, and 6 months after the first intervention and one week after a 9months post-trial. The effects of NeuroEPO were evaluated using a multivariate linear mixed-effects model using a latent variable for cognition instead of the raw neuropsychological scores.\n\nResultsA significant and direct effect of the Dose of NeuroEPO (p=0.00003) was found on cognitive performance with a strong positive influence of educational level (p=0.0032) and negative impact of age (p=0.0063).\n\nConclusionsThese preliminary results showed a positive effect of NeuroEPO on cognition in PD patients with better benefit for younger and higher educated patients.","Physical activity, sedentary behaviour, and sleep on Twitter: A labelled dataset for public health research\nAdvances in automated data processing, together with the unprecedented growth in user-generated social media (SM) content, have made public health surveillance (PHS) one of the long-lasting SM applications. However, the existing PHS systems feeding on SM data have not been widely deployed in national surveillance systems, which appears to stem from the lack of practitioners trust in SM data. More robust datasets over which machine learning (ML) models can be trained/tested reliably is a significant step toward overcoming this hurdle. The health implications of physical activity, sedentary behaviour, and sleep (PASS) are widely studied through traditional data sources, which are often out-of-date, costly to collect, and thus limited in quantity and coverage. We present LPHEADA, a multicountry and fully Labelled digital Public HEAlth DAtaset of tweets originated in Australia/Canada/United Kingdom/United States between November 2018-June 2020. LPHEADA contains 366,405 labels for 122,135 PASS-related tweets and provides details about the place/time/demographics associated with each tweet. LPHEADA is publicly available and can be utilized to develop (un)supervised ML models for digital PASS surveillance.","Comparative immunogenicity and effectiveness of mRNA-1273, BNT162b2 and Ad26.COV2.S COVID-19 vaccines\nBackgroundUnderstanding immunogenicity and effectiveness of SARS-CoV-2 vaccines is critical to guide rational use.\n\nMethodsWe compared the immunogenicity of mRNA-1273, BNT-162b2 or Ad26.COV2.S in ambulatory adults in Massachusetts, USA. To correlate immunogenicity with effectiveness of the three vaccines, we performed an inverse-variance meta-analysis of population level effectiveness from public health reports in >40 million individuals.\n\nResultsA single dose of either mRNA vaccine yielded comparable antibody and neutralization titers to convalescent individuals. Ad26.COV2.S yielded lower antibody concentrations and frequently negative neutralization titers. Bulk and cytotoxic T-cell responses were higher in mRNA1273 and BNT162b2 than Ad26.COV2.S recipients, and <50% of vaccinees demonstrate CD8+ T-cell responses to spike peptides. Antibody concentrations and neutralization titers increased comparably after the first dose of either vaccine, and further in recipients of a second dose. Prior infection was associated with high antibody concentrations and neutralization even after a single dose and regardless of vaccine. Neutralization of beta, gamma and delta strains were poorer regardless of vaccine. Relative to mRNA1273, the effectiveness of BNT162b2 was lower against infection and hospitalization; and Ad26COV2.S was lower against infection, hospitalization and death.\n\nConclusionsVariation in the immunogenicity correlates with variable effectiveness of the three FDA EUA vaccines deployed in the USA.","In Vivo Cortical Microstructure - A Proxy for Tauopathy & Cognitive Impairment\nAggregation of hyperphosphorylated tau protein is currently one of the most reliable indicators of Alzheimers pathology and cognitive impairment in older adults. However, it would be useful to have a non-invasive, accessible proxy measure that does not rely on Positron Emission Tomography (PET). We used data from multi-shell diffusion-weighted imaging (DWI) to assess indices from the Neurite Orientation Dispersion and Density Imaging (NODDI) model to determine possible proxies for tau and relationship with cognitive impairment. After controlling for age, sex, and the time difference between the scan acquisitions (DWI vs. PET), we used multiple factor analysis (MFA) to assess the fit between NODDI indices (orientation dispersion [ODI], neurite density [NDI], and free-water [fISO]), cortical thickness, and tau binding (via PET). We used data from 80 participants from the ADNI-3 sample who had a multi-shell DWI and an [18F]AV-1451 (tau) PET scan. Of these 80, 49 individuals were considered cognitively normal older adults (age ~74 years), 26 individuals had a diagnosis of mild cognitive impairment (age ~75 years), and five individuals had Alzheimers dementia (age ~78 years). fISO and tau shared a large amount of spatial overlap, and both strongly correlated with the first MFA dimension. Macrostructural features (such as cortical thickness and subcortical volume) introduced in a follow-up analysis were less related to this first MFA dimension than fISO and eight percent less than tau. Subsequent mediation analyses demonstrated that fISO mediated the relationship between cortical thickness and tau, explaining all of the variance. Microstructural features derived from advanced DWI acquisitions such as fISO may be useful proxies for tau. Cortical fISO, rather than cortical thickness, may represent the impact of tau on the brain (and, by extension, cognition).","Context Matters! Depression following childbirth or a chronic disease diagnosis shows specific risk factor profiles.\nProgress towards understanding the etiology of major depression (MD) is compromised by its clinical heterogeneity. The variety of contexts underlying the development of a major depressive episode may contribute to such heterogeneity. Here, we aimed to compare risk factor profiles of three subgroups of MD according to episode context.\n\nUsing self-report questionnaires and administrative records from the UK Biobank, we characterised three contextual subgroups of MD: postpartum depression (3,581 cases), depression following diagnosis of a chronic disease (409 cases) and a more typical (named heterogeneous) MD phenotype excluding the two prior contexts (34,699 cases). Controls with the same exposure were also defined. We tested each subgroup for association with MD polygenic risk scores (PRS) and other risk factors previously associated with MD (bipolar disorder PRS, neuroticism, reported trauma in childhood and adulthood, socioeconomic status, family history of depression, education).\n\nMD polygenic risk scores were associated with all subgroups, however, postpartum depression cases had higher PRS than heterogeneous MD cases (OR = 1.06, 95% CI: 1.02 - 1.10). Relative to heterogeneous depression, postpartum depression was more weakly associated with adulthood trauma and neuroticism. Relative to heterogeneous depression, depression following diagnosis of a chronic disease did not have higher MD polygenic risk scores but had weaker associations with neuroticism and reported trauma in adulthood and childhood.\n\nThe observed differences in risk factor profiles according to the context of a major depressive episode help provide insight into the heterogeneity of depression. Future studies dissecting such heterogeneity could help reveal more refined etiological insights.","Deep Learning in Opthalmology: Iris Melanocytic Tumor Intelligent Diagnosis\nRecently, Convolutional neural networks (CNN) have shown a growth due to their ability of learning different level image representations that helps in image classification in different fields. These networks have been trained on millions of images, so they gained a powerful ability of extracting the rightful features from input images, which results in accurate classification. In this research, we investigate the effects of transfer learning based convolutional neural networks for the iris tumor malignancy identification as it is notoriously hard to distinguish an iris nevus from an iris tumor. Features are transferred from a CNN trained on a source task, i.e. ImageNet, to a target task, i.e. iris tumor datasets. We transfer features learned from AlexNet and VGG-16 that are trained on ImageNet, to classify three different iris images types which are: iris nevus unaffected, iris cysts, and iris melanocytic tumors. The employed pre-trained models are modified by replacing their feedforward neural network classifier, Softmax, by a support vector machine (SVM) that is expected to slightly boost their performance (AlexNet-SVM and VGG16-SVM). All employed models are trained (fine-tuned) on a 60% of the available large dataset of iris images in order to investigate their power of generalization when trained using large amount of data. The networks are also tested on 40% of the data. The best performance was achieved by the VGG16-SVM which scored a high accuracy of 96.27% and strong features extraction capability as compared to the other models. Experimentally, it was seen that adding SVM contributed in improving the network performance compared to original models which use a feedforward neural network classifier.","Structured Understanding of Assessment and Plans in Clinical Documentation\nPhysicians record their detailed thought-processes about diagnoses and treatments as unstructured text in a section of a clinical note called the assessment and plan. This information is more clinically rich than structured billing codes assigned for an encounter but harder to reliably extract given the complexity of clinical language and documentation habits. We describe and release a dataset containing annotations of 579 admission and progress notes from the publicly available and de-identified MIMIC-III ICU dataset with over 30,000 labels identifying active problems, their assessment, and the category of associated action items (e.g. medication, lab test). We also propose deep-learning based models that approach human performance, with a F1 score of 0.88. We found that by employing weak supervision and domain specific data-augmentation, we could improve generalization across departments and reduce the number of human labeled notes without sacrificing performance.","Post-acute sequelae of COVID-19 in a non-hospitalized cohort: results from the Arizona CoVHORT\nClinical presentation, outcomes, and duration of COVID-19 has ranged dramatically. While some individuals recover quickly, others suffer from persistent symptoms, collectively known as post-acute sequelae of SAR-CoV-2 (PASC). Most PASC research has focused on hospitalized COVID-19 patients with moderate to severe disease. We used data from a diverse population-based cohort of Arizonans to estimate prevalence of various symptoms of PASC, defined as experiencing at least one symptom 30 days or longer. There were 303 non-hospitalized individuals with a positive lab-confirmed COVID-19 test who were followed for a median of 61 days (range 30-250). COVID-19 positive participants were mostly female (70%), non-Hispanic white (68%), and on average 44 years old. Prevalence of PASC at 30 days post-infection was 68.7% (95%CI 63.4, 73.9). The most common symptoms were fatigue (37.5%), shortness-of-breath (37.5%), brain fog (30.8%), and stress (30.8%). The median number of symptoms was 3 (range 1-20). Amongst 157 participants with longer follow-up ([≥]60 days), PASC prevalence was 77.1%.","A large, curated, open-source stroke neuroimaging dataset to improve lesion segmentation algorithms\nAccurate lesion segmentation is critical in stroke rehabilitation research for the quantification of lesion burden and accurate image processing. Current automated lesion segmentation methods for T1-weighted (T1w) MRIs, commonly used in rehabilitation research, lack accuracy and reliability. Manual segmentation remains the gold standard, but it is time-consuming, subjective, and requires significant neuroanatomical expertise. We previously released a large, open-source dataset of stroke T1w MRIs and manually segmented lesion masks (ATLAS v1.2, N=304) to encourage the development of better algorithms. However, many methods developed with ATLAS v1.2 report low accuracy, are not publicly accessible or are improperly validated, limiting their utility to the field. Here we present ATLAS v2.0 (N=955), a larger dataset of T1w stroke MRIs and manually segmented lesion masks that includes both training (public) and test (hidden) data. Algorithm development using this larger sample should lead to more robust solutions, and the hidden test data allows for unbiased performance evaluation via segmentation challenges. We anticipate that ATLAS v2.0 will lead to improved algorithms, facilitating large-scale stroke rehabilitation research.","Multi-state network meta-analysis of cause-specific survival data\nMultiple randomized controlled trials, each comparing a subset of competing interventions, can be synthesized by means of a network meta-analysis to estimate relative treatment effects between all interventions in the evidence base. Often there is an interest in estimating the relative treatment effects regarding time-to-event outcomes. Cancer treatment effectiveness is frequently quantified by analyzing overall survival (OS) and progression-free survival (PFS). In this paper we introduce a method for the joint network meta-analysis of PFS and OS that is based on a time-inhomogeneous tri-state (stable, progression, and death) Markov model where time-varying transition rates and relative treatment effects are modeled with known parametric survival functions or fractional polynomials. The data needed to run these analyses can be extracted directly from published survival curves. We demonstrate use by applying the methodology to a network of trials for the treatment of non-small-cell lung cancer. The proposed approach allows the joint synthesis of OS and PFS, relaxes the proportional hazards assumption, extends to a network of more than two treatments, and simplifies the parameterization of decision and cost-effectiveness analyses.","Efficacy of vasopressin, steroid, and epinephrine protocol for in-hospital cardiac arrest resuscitation: A systematic review and meta-analysis of randomized controlled trials with trial sequential analysis\nAimTo assess the effect of vasopressin, steroid and epinephrine (VSE) combination therapy on return of spontaneous circulation (ROSC) after in-hospital cardiac arrest (IHCA), and test the conclusiveness of evidence using trial sequential analysis (TSA).\n\nMethodsThe systematic search included PubMed, EMBASE, Scopus, and Cochrane Central Register of Controlled Trials. Randomized controlled trials that included adult patients with in-hospital cardiac arrest, with at least one group receiving combined vasopressin, epinephrine and steroid therapy were selected. Data was extracted independently by two reviewers. The main outcome of interest was ROSC. Other outcomes included survival to hospital discharge with good neurological outcomes and survival to 30 and 90 days with good neurological outcomes.\n\nResultsWe included a total of three randomized controlled trials (n=869 patients). Results showed that Vasopressin, steroid and epinephrine combination therapy increased return of spontaneous circulation (risk ratio, 1.32; 95% CI, 1.18-1.47) as compared to placebo. Trial sequential analysis demonstrated that the existing evidence is conclusive. This was also validated by the alpha-spending adjusted relative risk (1.32 [1.16, 1.49], p<0.0001). Other outcomes could not be meta-analysed due to differences in timeframe in the included studies.\n\nConclusionsVSE combination therapy administered in cardiopulmonary resuscitation led to improved rates of return of spontaneous circulation. Future trials of vasopressin, steroid and epinephrine combination therapy should evaluate survival to hospital discharge, neurological function and long-term survival.","Identification of B.1.346 lineage of SARS-CoV-2 in Japan: Genomic evidence of re-entry of Clade 20C\nObjectivesWhole SARS-CoV-2 genome sequencing from COVID-19 patients is useful for infection control and regional trends evaluation. We report a lineage data collected from hospitals in the Kanto region of Japan.\n\nMethodsWe performed whole genome sequencing in specimens of 198 COVID-19 patients at 13 collaborating hospitals in the Kanto region. Phylogenetic analysis and fingerprinting of the nucleotide substitutions underwent to differentiate and classify the viral lineages.\n\nResultsMore than 90% of the strains belonged to Clade 20B and two lineages (B.1.1.284 and B.1.1.214) have been detected predominantly in the Kanto region. However, one sample from a COVID-19 patient in November 2020, belonged to the B.1.346 lineage of Clade 20C, which has been prevalent in western United States. The patient had no history of overseas travel and no contact with anyone who had travelled abroad, suggesting that this strain appeared likely to have been imported from western United States, across the strict quarantine barrier.\n\nConclusionB.1.1.284 and B.1.1.214 have been identified predominantly in the Kanto region and B.1.346 of clade 20C in one patient was probably imported from western United States. These results illustrate that a decentralized network of hospitals can be significantly advantageous for monitoring regional molecular epidemiologic trends.\n\nHighlights{middle dot} Whole SARS-CoV-2 genome sequencing is useful for infection control\n{middle dot} B.1.1.284 and B.1.1.214 have been identified predominantly in the Kanto region\n{middle dot} B.1.346 of Clade 20C was detected in one COVID-19 patient in November\n{middle dot} Molecular genomic data sharing provides benefits to public health against COVID-19","Mutant IDH Inhibitors Induce Lineage Differentiation in IDH-mutant Oligodendroglioma\nRecent data showed promising signs of objective tumor responses in subsets of patients with low grade glioma treated with inhibitors of mutant IDH (IDHi) (1). However, the molecular and cellular underpinnings of such responses are not known. Here, we profiled 6,039 transcriptomes by single-cell or single-nucleus RNA-sequencing isolated from three IDH-mutant oligodendroglioma patients with clinical response to IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation and our dataset includes a matched pre- and on-treatment sample pair. We integrate our findings with analysis of 8,241 transcriptomes from seven untreated samples, 134 bulk samples from the TCGA and experimental models.(2,3) We find that IDHi treatment induces a robust differentiation towards glial lineages, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Our study provides the first evidence in patients of the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas.","Evaluating Digital Device Technology in Alzheimer's Disease via Artificial Intelligence\nThe use of digital technologies may help to diagnose Alzheimers Disease (AD) at the pre-symptomatic stage. However, before implementation into clinical practice, digital measures (DMs) need to be evaluated for their diagnostic benefit compared to established questionnaire-based assessments, such as the Mini-Mental State Examination (MMSE) for cognition and Functional Activity Questionnaire (FAQ) for daily functioning. Moreover, the quantitative and qualitative relationship of DMs to these well understood scores needs to be clarified to aid interpretation. In this work we analyzed data from 148 subjects, 58 cognitively normal and 90 at different stages of the disease, which had performed a smartphone based virtual reality game to assess cognitive function. In addition, we used clinical data from Alzheimers Disease Neuroimaging Initiative (ADNI). We employed an Artificial Intelligence (AI) based approach to elucidate the relationship of DMs to questionnaire-based cognition and functional activity scores. In addition, we used Machine Learning (ML) and statistical methods to assess the diagnostic benefit of DMs compared to questionnaire-based scores. We found non-trivial relationships between DMs, MMSE, and FAQ which can be visualized as a complex network. DMs, in particular those reflecting scores of individual tasks in the virtual reality game, showed a better ability to discriminate between different stages of the disease than questionnaire-based methods. Our results indicate that DMs have the potential to act as a crucial measure in the early diagnosis and staging of AD.","The Impact of Early Life Stress on the Genetic Influence on Brain and Cognitive Development in Children\nEarly life stress (ELS), such as abuse, neglect, and maltreatment, is a well-known risk factor for mental illness. However, it is unclear how ELS affects the brain and cognitive development. Identifying specific relationships of ELS with the genetic and brain-related underpinnings of cognitive development may reveal biological mechanisms responsible for the negative impact of ELS and those that lead to individual differences in sensitivity (or resilience) to ELS. In this study, to investigate the interlinked processes of cognitive development, we analyzed the multimodal data of DNA genotypes, brain imaging (MRI), and neuropsychological assessment (NIH Toolbox) outcomes of 4,276 children (ages 9 to 10 years, European ancestry) from the Adolescent Brain Cognitive Development (ABCD) study. We estimated the genetic influence on cognitive capacity using genome-wide polygenic scores (GPSs). Our regression and mediation analyses revealed significant causal relationships for the gene-brain-cognition pathway: Brain structural development significantly mediated the genetic influence on cognitive development (partial mediation effect = 0.016, PFWE<0.001). Interestingly, within the triangular relationship, we found a significant moderation effect of abuse only on the gene-to-brain pathway (Index of Moderated Mediation = -0.007; 95% CI= -0.012 [~] -0.002; PFWE<0.05). These findings indicate the negative modulatory effects of ELS on the genetic influence on brain structural development that lead to disadvantageous neurocognitive development in prepubertal children.","SARS-COV-2 INFECTION IN PRIMARY CARE: A SINGLE-CENTERED, RETROSPECTIVE, OBSERVATIONAL STUDY\nPurposeto describe the clinical characteristics of patients with confirmed SARS-CoV-2 infection in primary care and to analyze the predictive role of different risk factors on prognosis, especially living conditions.\n\nMethodsRetrospective longitudinal observational retrospective study by reviewing medical records from a primary care center since March 1 to April 30, 2020. Case definition of confirmed SARS-CoV-2 infection, sociodemographic data, clinical characteristics, comorbidity and living conditions were collected. The statistical analysis consisted in description of the sample, comparison of prognosis groups and analysis of prognostic factors.\n\nResultsA sample of 70 patients with confirmed SARS-CoV-2 infection was obtained, with comorbidity mainly related to arterial hypertension, overweight/obesity, hypercholesterolemia, diabetes and chronic pulmonary pathology. Pneumonia was present in 66%. Exitus occurred in 14% of the sample. Factors associated with mortality were advanced age (84 vs 55; p<0.0001), arterial hypertension (78% vs 41%; p=0.040), asthma-COPD (56% vs 13%; p=0.008) and atrial fibrillation (56% vs 5%; p=0.001).\n\nConclusionsThe study reflects the clinical practice of a primary care center. This kind of studies are essential to strengthen and reorganize the Health System and to try to anticipate the medium- to long-term consequences of COVID-19 on global health.","Metabologenomic approach reveals intestinal environmental features associated with barley-induced glucose tolerance improvements in Japanese cohort: a randomized controlled trial\nConsumption of barley has been known to exert beneficial effects on metabolic disorders; however, it has also been reported that there are inter-individual differences in these responses. Recent evidence has suggested that these individual differences are mediated by the gut microbiota. Therefore, in the present study, we aimed to understand the relationship between the intestinal environment, including gut microbiota, and metabolic disorders. A randomized controlled trial in Japanese subjects with 4-week consumption of barley or control food was conducted. In this study, we analyzed the intestinal environment, including microbiota and their metabolites, and blood parameters were assessed collectively. We found that microbial genera Blautia and Agathobacter belonging to Lachnospiraceae, and fecal metabolites such as azelate were increased 1.31-fold, 1.84-fold, and 1.48-fold after barley consumption, respectively. Furthermore, the subjects whose glucose tolerance were slightly impaired showed improvement in their glucose tolerance index following the barley consumption. Additionally, the analysis showed that the increase in the abundance of the Anaerostipes was correlated with the improvement in the glucose tolerance index. Our findings indicate that the effects of barley consumption for glucose tolerance are partly defined by the intestinal environment of consumers, providing a quantitative measurement of the dietary effect based on the intestinal environment.","Health service research definition builder: An R Shiny application for exploring diagnosis codes associated with services reported in routinely collected health data\nMany administrative health data-based studies define patient cohorts using procedure and diagnosis codes. The impact these criteria have on a studys final cohort is not always transparent to co-investigators or other audiences if access to the research data is restricted. We developed a SAS and R Shiny interactive research support tool which generates and displays the diagnosis code summaries associated with a selected medical service or procedure. This allows non-analyst users to interrogate claims data and groupings of reported diagnosis codes. The SAS program uses a tree classifier to find associated diagnosis codes with the service claims compared against a matched, random sample of claims without the service. Claims are grouped based on the overlap of these associated diagnosis codes. The Health Services Research (HSR) Definition Builder Shiny application uses this input to create interactive table and graphics, which updates estimated claim counts of the selected service as users select inclusion and exclusion criteria. This tool can help researchers develop preliminary and shareable definitions for cohorts for administrative health data research. It allows an additional validation step of examining frequency of all diagnosis codes associated with a service, reducing the risk of incorrect included or omitted codes from the final definition. In our results, we explore use of the application on three example services in 2016 US Medicare claims for patients aged over 65: knee arthroscopy, spinal fusion procedures and urinalysis. Readers can access the application at https://kelsey209.shinyapps.io/hsrdefbuilder/ and the code at https://github.com/kelsey209/hsrdefbuilder.","The Triangulation WIthin A STudy (TWIST) framework for causal inference within Pharmacogenetic research\nIn this paper we review the methodological underpinnings of the general pharmacogenetic approach for uncovering genetically-driven treatment effect heterogeneity. This typically utilises only individuals who are treated and relies on fairly strong baseline assumptions to estimate what we term the genetically moderated treatment effect (GMTE). When these assumptions are seriously violated, we show that a robust but less efficient estimate of the GMTE that incorporates information on the population of untreated individuals can instead be used. In cases of partial violation, we clarify when Mendelian randomization and a modified confounder adjustment method can also yield consistent estimates for the GMTE. A decision framework is then described to decide when a particular estimation strategy is most appropriate and how specific estimators can be combined to further improve efficiency. Triangulation of evidence from different data sources, each with their inherent biases and limitations, is becoming a well established principle for strengthening causal analysis. We call our framework Triangulation WIthin a STudy (TWIST) in order to emphasise that an analysis in this spirit is also possible within a single data set, using causal estimates that are approximately uncorrelated, but reliant on different sets of assumptions. We illustrate these approaches by re-analysing primary-care-linked UK Biobank data relating to CYP2C19 genetic variants, Clopidogrel use and stroke risk, and data relating to APOE genetic variants, statin use and Coronary Artery Disease.","Hi-C detects genomic structural variants in peripheral blood of pediatric leukemia patients\nB-cell acute lymphoblastic leukemia (B-ALL) is often driven by chromosome translocations that result in recurrent and well-studied gene fusions. Currently, fluorescent in-situ hybridization probes are employed to detect candidate translocations in bone marrow samples from B-ALL patients. Recently Hi-C, a sequencing-based technique originally designed to reconstruct the three-dimensional architecture of the nuclear genome, was shown to effectively recognize structural variants. Here, we demonstrate that Hi-C can be used as a genome-wide assay to detect translocations and other structural variants of potential clinical interest. Structural variants were identified in both bone marrow and peripheral blood samples, including an ETV6-RUNX1 translocation present in one pediatric B-ALL patient. Our report provides proof-of-principle that Hi-C could be an effective strategy to globally detect driver structural variants in B-ALL peripheral blood specimens, reducing the need for invasive bone marrow biopsies and candidate-based clinical tests.","Multi-organ complement deposition in COVID-19 patients\nBackgroundIncreased levels of circulating complement activation products have been reported in COVID-19 patients, but only limited information is available on complement involvement at tissue level. The mechanisms and pathways of local complement activation remain unclear.\n\nMethodsWe performed immunofluorescence analyses of autopsy specimens of lungs, kidney and liver from nine COVID-19 patients who died of acute respiratory failure. Snap-frozen samples embedded in OCT were stained with antibodies against complement components and activation products, IgG and spike protein of SARS-CoV-2.\n\nFindingsLung deposits of C1q, C4, C3 and C5b-9 were localized in the capillaries of the interalveolar septa and on alveolar cells. IgG displayed a similar even distribution, suggesting classical pathway activation. The spike protein is a potential target of IgG, but its uneven distribution suggests that other viral and tissue molecules may be targeted by IgG. Factor B deposits were also seen in COVID-19 lungs and are consistent with activation of the alternative pathway, whereas MBL and MASP-2 were hardly detectable. Analysis of kidney and liver specimens mirrored findings observed in the lung. Complement deposits were seen on tubules and vessels of the kidney with only mild C5b-9 staining in glomeruli, and on hepatic artery and portal vein of the liver.\n\nInterpretationComplement deposits in different organs of deceased COVID-19 patients caused by activation of the classical and alternative pathways support the multi-organ nature of the disease.\n\nFundingGrants from the Italian Ministry of Health (COVID-2020-12371808) to PLM and National Institutes of Health HL150146 to NP are gratefully acknowledged.","Integrating de novo and inherited variants in over 42,607 autism cases identifies mutations in new moderate risk genes\nDespite the known heritable nature of autism spectrum disorder (ASD), studies have primarily identified risk genes with de novo variants (DNVs). To capture the full spectrum of ASD genetic risk, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases recruited online by SPARK. In the first stage, we analyzed 19,843 cases with one or both biological parents and found that known ASD or neurodevelopmental disorder (NDD) risk genes explain nearly 70% of the genetic burden conferred by DNVs. In contrast, less than 20% of genetic risk conferred by rare inherited loss-of-function (LoF) variants are explained by known ASD/NDD genes. We selected 404 genes based on the first stage of analysis and performed a meta-analysis with an additional 22,764 cases and 236,000 population controls. We identified 60 genes with exome-wide significance (p < 2.5e-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1, and HNRNPUL2). The association of NAV3 with ASD risk is entirely driven by rare inherited LoFs variants, with an average relative risk of 4, consistent with moderate effect. ASD individuals with LoF variants in the four moderate risk genes (NAV3, ITSN1, SCAF1, and HNRNPUL2, n = 95) have less cognitive impairment compared to 129 ASD individuals with LoF variants in well-established, highly penetrant ASD risk genes (CHD8, SCN2A, ADNP, FOXP1, SHANK3) (59% vs. 88%, p= 1.9e-06). These findings will guide future gene discovery efforts and suggest that much larger numbers of ASD cases and controls are needed to identify additional genes that confer moderate risk of ASD through rare, inherited variants.","Characteristics of Patients with Hematologic Malignancies Without Seroconversion Post-COVID19 Third Vaccine Dosing\nPatients with hematologic malignancies (HM) are at greater risk of severe morbidity and mortality caused by COVID19 and show a lower response to a two-dose COVID19 mRNA vaccine series. The primary objective of this retrospective cohort study is to explore the characteristics of the subset of patients with HM who had little to no change in SARS-CoV-2 spike antibody titer levels after a 3rd vaccine dose (3V) (-/-). As a secondary objective, we seek to compare the cohorts of patients who did and did not seroconvert post-3V to get a better understanding of the demographics and potential drivers of serostatus. A total of 625 patients with HM had two titer results at least 21 days apart pre- and post- the 3V dose. Among the participants who were seronegative prior to 3V (268), 149 (55.6%) seroconverted after the 3V dose and 119 (44.4%) did not. HM diagnosis was significantly associated with seroconversion status (P = .0003) with patients non-Hodgkin lymphoma 6 times the odds of not seroconverting compared to multiple myeloma patients (P = .0010). Among the cohort of patients who remained seronegative post-3V, 107 (90.0%) patients showed no reaction to 3V as indicated by pre- and post- 3V index values. This study focuses on an important subset of patients with HM who are not seroconverting after the COVID mRNA 3V, providing much needed data for clinicians to target and counsel this subset of patients.","Virtual Trials: Causally-validated treatment effects efficiently learned from an observational cancer registry\nRandomized controlled trials (RCTs) offer a clear causal interpretation of treatment effects, but are inefficient in terms of information gain per patient. Moreover, because they are intended to test cohort-level effects, RCTs rarely provide information to support precision medicine, which strives to choose the best treatment for an individual patient. If causal information could be efficiently extracted from widely available real-world data, the rapidity of treatment validation could be increased, and its costs reduced. Moreover, inferences could be made across larger, more diverse patient populations. We created a \"virtual trial\" by fitting a multilevel Bayesian survival model to treatment and outcome records self-reported by 451 brain cancer patients. The model recovers group-level treatment effects comparable to RCTs representing over 3200 patients. The model additionally discovers the feature-treatment interactions needed to make individual-level predictions for precision medicine. By learning from heterogeneous real-world data, virtual trials can generate more causal estimates with fewer patients than RCTs, and they can do so without artificially limiting the patient population. This demonstrates the value of virtual trials as a complement to large randomized controlled trials, especially in highly heterogeneous or rare diseases.","Epigenetic impairment and blunted transcriptional response to Mycobacterium tuberculosis of alveolar macrophages from persons living with HIV\nPersons living with HIV (PLWH) are at increased risk of tuberculosis (TB). HIV-associated TB is often the result of recent infection with Mycobacterium tuberculosis (Mtb) followed by rapid progression to disease. Alveolar macrophages (AM) are the first cells of the innate immune system that engage Mtb, but how HIV and antiretroviral therapy (ART) impact on the anti-mycobacterial response of AM is not known. To investigate the impact of HIV and ART on the transcriptomic and epigenetic response of AM to Mtb, we obtained AM by bronchoalveolar lavage from 20 PLWH receiving ART, 16 control subjects who were HIV-free (HC), and 14 subjects who received ART as pre-exposure prophylaxis (PrEP) to prevent HIV infection.\n\nFollowing in-vitro challenge with Mtb, AM from each group displayed overlapping but distinct profiles of significantly up- and down-regulated genes in response to Mtb. Compared to HC subjects, AM isolated from PLWH and PrEP subjects presented a substantially weaker transcriptional response. Further investigation of chromatin structure revealed that AM from control subjects challenged with Mtb responded with pronounced accessibility changes in over ten thousand regions. In stark contrast, AM obtained from PLWH and PrEP subjects displayed no significant changes in their chromatin state in response to Mtb. Collectively, these results revealed a previously unknown adverse effect of ART on the epigenetic landscape and transcriptional responsiveness of AM.","Response of human liver tissue to innate immune stimuli\nPrecision-cut human liver slice cultures (PCLS) has become an important alternative immunological platform in preclinical testing. To further evaluate the capacity of PCLS, we investigated the innate immune response to TLR3 agonist (poly-I:C) and TLR4 agonist (LPS) with the normal and pathological liver tissue. Pathological liver tissue was obtained from patients with active chronic HCV infection, and patients with former chronic HCV infection cured by recent Direct-Acting Antiviral (DAA) drug therapy. We found that hepatic innate immunity was not suppressed but enhanced in the HCV-infected tissue, compared with the healthy controls. Furthermore, despite recent HCV elimination, DAA-cured liver tissue manifested ongoing abnormalities in liver immunity. Sustained abnormal immune gene expression in DAA-cured samples were identified from direct ex vivo measurements and with TLR3 and TLR4 stimulation assays. Those genes that were up-regulated in chronic HCV-infected liver tissue were enriched in expression in the liver non-parenchymal cell compartment. These results demonstrated the utility of PCLS in studying the liver pathology and innate immunity.","The relationship between wild-type transthyretin amyloid load and ligamentum flavum thickness in lumbar stenosis patients\nBackgroundOne key contributor to lumbar stenosis is thickening of the ligamentum flavum (LF), a process still poorly understood. Wild-type transthyretin amyloid (ATTRwt) has been found in the LF of patients undergoing decompression surgery, suggesting that amyloid may play a role. However, it is unclear whether within patients harboring ATTRwt, the amount of amyloid is associated with LF thickness.\n\nMethodsFrom an initial cohort of 324 consecutive lumbar stenosis patients whose LF specimens from decompression surgery were sent for analysis (2018-2019), 33 patients met the following criteria: (1) Congo red-positive amyloid in the LF; (2) ATTRwt by mass spectrometry-based proteomics; and (3) an available preoperative MRI. Histological specimens were digitized, and amyloid load quantified through Trainable Weka Segmentation (TWS) machine learning. LF thicknesses were manually measured on axial T2-weighted preoperative MRI scans at each lumbar level, L1-S1. The sum of thicknesses at every lumbar LF level (L1-S1) equals \"lumbar LF burden.\"\n\nResultsPatients had a mean age of 72.7 years (range 59-87), were mostly male (61%) and white (82%); and predominantly had surgery at L4-L5 levels (73%). Amyloid load was positively correlated with LF thickness (R=0.345, p=0.0492) at the levels of surgical decompression. Furthermore, amyloid load was positively correlated with lumbar LF burden (R=0.383, p=0.0279).\n\nConclusionsAmyloid load is positively correlated with LF thickness and lumbar LF burden across all lumbar levels, in a dose-dependent manner. Further studies are needed to validate these findings, uncover the underlying pathophysiology, and pave the way towards using therapies that slow LF thickening.","Psychological, endocrine and polygenic predictors of emotional well-being during the COVID-19 pandemic\nStress is an established risk factor for somatic and mental disorders. The COVID-19 pandemic and the related countermeasures severely affect the lives of families. Prenatal stress, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and genetic factors might impact the well-being of individuals.\n\nThe present work is part of an ongoing birth cohort study and aims to investigate maternal perceived stress, early childhood HPA axis activity and polygenic risk scores (PRSs) as predictors of emotional well-being during the COVID-19 pandemic. All participants are part of the ongoing birth cohort study POSEIDON. Emotional well-being of children (n = 259) and mothers (n = 211) was assessed during the COVID-19 pandemic using the CRISIS questionnaire. Furthermore, associations between previously assessed maternal perceived stress (Perceived Stress Scale), childrens salivary and morning urine cortisol measures at 45 months, PRSs for depression, schizophrenia, loneliness and current emotional well-being were investigated.\n\nA positive association between the childs and the mothers emotional well-being was found. A worse emotional well-being was observed in both children and mothers during the pandemic compared to before. Childrens emotional well-being improved over the course of the pandemic, while mothers well-being worsened. Maternal perceived stress, salivary and morning urine cortisol and PRSs were not significantly associated with the assessed emotional wellbeing.\n\nThe present study confirms that emotional well-being of children and mothers is negatively affected by the COVID-19 pandemic, with differences in development over time. Future studies should examine which mechanisms contribute to stress-related associations and at which age they can be identified.","Pausing methotrexate improves immunogenicity of COVID-19 vaccination in patients with rheumatic diseases\nObjectiveTo study the effect of methotrexate (MTX) and its discontinuation on the humoral immune response after COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD).\n\nMethodsNeutralising SARS-CoV-2 antibodies were measured after second vaccination in 64 rheumatic patients on methotrexate therapy, 31 of whom temporarily paused medication without a fixed regimen. The control group consisted of 21 AIRD patients without immunosuppressive medication.\n\nResultsMTX patients showed a significantly lower median antibody response compared to AIRD patients without immunosuppressive therapy (p< 0.001). Young age (<60 years) and MTX-hold after vaccination were found to be the main factors influencing antibody response after vaccination, while BMI or MTX dose demonstrated no effect. For patients taking MTX, age correlated negatively with immune response (r=-0.49; p<0.001) and all patients with antibody levels (14 %) below the cut-off were older than 60 years. Patients who held MTX during at least one vaccination showed significantly higher median neutralising antibody levels after second vaccination, compared to patients who continued MTX therapy during both vaccinations (68.82 %, 92.73 %, p=<0.001). This effect was particularly pronounced in patients older than 60 years (p=0.0016). The impact of the time period after vaccination was greater than of the time before vaccination with the critical cut-off being 10 days.\n\nConclusionMTX reduces the immunogenicity of SARS-CoV-2 vaccination in an age-dependent manner. Our data further suggest that holding MTX for at least 10 days after vaccination significantly improves the antibody response in patients over 60 years of age.","Prenatal alcohol consumption and child IQ and cognition: a Mendelian randomization study\nBackgroundPrevious studies using Mendelian randomization have found that fetal alcohol exposure may be associated with lower IQ and test scores in childhood.\n\nObjectivesWe aim to replicate and extend these findings in Generation R Study, a birth cohort based in Rotterdam, the Netherlands.\n\nMethodsWe used data from Generation R which recruited pregnant women between 2002 and 2006. Alcohol use was assessed via questionnaire during each trimester. IQ was measured in the children between ages 5 and 8 using the Snijders-Oomen Non-Verbal Intelligence Test. Scores from a national standardized test administered around age 12 were used as a measure of cognition. We estimated the associations between ten genetic variants in the mothers previously found to be related to alcohol consumption and metabolism and each of the outcomes. In the children, we also estimated the association between the same genetic variants as well as two polygenic scores for alcohol consumption and the outcomes.\n\nResultsMaternal genetic variants were not found to be related to either outcome but wide confidence intervals did not preclude important effects. A few genetic variants in the children were suggestive of a decrease in IQ. Likewise, one genetic variant and the genetic score had estimates and confidence intervals consistent with increases in standardized test scores.\n\nConclusionsOur results provide slight support for associations between genetic variants in children related to maternal prenatal alcohol consumption and IQ and cognition outcomes. These findings are in line with two previous studies on this topic.","Polygenic effect on accelerated tau pathology accumulation in Alzheimer's disease: Implications for patient selection in clinical trials\nProgression of fibrillar tau is a key driver of dementia symptoms in Alzheimers disease (AD), but predictors of the rate of tau accumulation at patient-level are missing. Here we combined the to-date largest number of genetic risk variants of AD (n=85 lead SNPs) from recent GWAS to generate a polygenic score (PGS) predicting the rate of change in fibrillar tau. We found that a higher PGS was associated with higher rates of PET-assessed fibrillar-tau accumulation over a mean of 1.8 yrs (range = 0.6 - 4 yrs). This, in turn, mediated effects of the PGS on faster rates of cognitive decline. Sensitivity analysis showed that the effects were similar for men and women but pronounced in individuals with elevated levels of beta-amyloid and strongest for lead SNPs expressed in microglia. Together, our results demonstrate that the PGS predicts tau progression in Alzheimers disease, which could afford sample size savings by up to 34% when used alone and up to 61% when combined with APOE {varepsilon}4 genotype in clinical trials targeting tau pathology.","Age and Sex Differences in the Genetics of Cardiomyopathy\nAimsCardiomyopathy is a clinically and genetically heterogeneous disorder with age and sex-related differences in severity and outcomes. The aim of our study was to identify age and sex-related differences in the genetic architecture of cardiomyopathy.\n\nMethods and ResultsWe analyzed whole genome sequence data from 471 pediatric and 926 adult cardiomyopathy patients from our Heart Centre Biobank and from the Genomics England cohort. Overall yield of rare deleterious coding variants was higher in pediatric compared to adult onset cardiomyopathy, but not different by sex. MYH7, TNNT2, MYL3, and VCL variants were more frequent in pediatric patients; TTN and OBSCN variants were more frequent in adult patients, with MYH7 (Odds ratio 3.6; CI 2.1-6.3) and OBSCN (Odds ratio 5.5, CI 2.0-21.4) remaining significant after adjusting for multiple testing. Variants in early-onset cardiomyopathy clustered in highly constrained coding regions compared to those in adult patients (p=3.9x10-3). There were also differences between pediatric and adult patients in variant location within MYH7 and TTN genes. When analyzed by sex, variants in female compared to male patients were in more highly constrained coding regions (p=0.002).\n\nConclusionOur findings highlight under-appreciated genetic differences in early versus late onset cardiomyopathy. Variants in childhood cardiomyopathy and in female patients were in highly constrained coding regions of the genome suggesting greater deleterious effects and strong purifying selection in the general population. Knowledge of the affected gene, variant location within the gene, and variant constraint scores may be useful in predicting early versus late onset cardiomyopathy.","OCT2Hist: Non-Invasive Virtual Biopsy Using Optical Coherence Tomography\nHistological haematoxylin and eosin-stained (H&E) tissue sections are used as the gold standard for pathologic detection of cancer, tumour margin detection, and disease diagnosis1. Producing H&E sections, however, is invasive and time-consuming. Non-invasive optical imaging modalities, such as optical coherence tomography (OCT), permit label-free, micron-scale 3D imaging of biological tissue microstructure with significant depth (up to 1mm) and large fields-of-view2, but are difficult to interpret and correlate with clinical ground truth without specialized training3. Here we introduce the concept of a virtual biopsy, using generative neural networks to synthesize virtual H&E sections from OCT images. To do so we have developed a novel technique, \"optical barcoding\", which has allowed us to repeatedly extract the 2D OCT slice from a 3D OCT volume that corresponds to a given H&E tissue section, with very high alignment precision down to 25 microns. Using 1,005 prospectively collected human skin sections from Mohs surgery operations of 71 patients, we constructed the largest dataset of H&E images and their corresponding precisely aligned OCT images, and trained a conditional generative adversarial network4 on these image pairs. Our results demonstrate the ability to use OCT images to generate high-fidelity virtual H&E sections and entire 3D H&E volumes. Applying this trained neural network to in vivo OCT images should enable physicians to readily incorporate OCT imaging into their clinical practice, reducing the number of unnecessary biopsy procedures.","Impact of inspiratory vs expiratory incentive spirometry on obstructive, restrictive, and mixed ventilatory impairments: Study protocol. Effect of incentive spirometry on respiratory impairments.\nBackgroundRespiratory impairments are adjusted reduction in pulmonary function that manifests with adverse effects on an individuals state of health. The basis for identifying these impairments requires differentiation between normal and abnormal ventilatory capacity to avoid inaccurate and potentially harmful drug prescriptions and a mismatch of diagnoses. Incentive Spirometry (IS) is a technique designed to help patients achieve a pre-set volume of airflow; the volume is determined from predicted values or baseline measurements.\n\nMethodsFifty-four (54) patients with Obstructive, Restrictive, or Mixed type of respiratory impairments attending the respiratory clinic of Lagos State University Teaching Hospital, Ikeja (LASUTH) will be assessed for eligibility for the study. The study design will be a double-blind, randomized control trial with six intervention groups and three placebo control groups.\n\nThe studys independent variable will be an Inspiratory Incentive Spirometry (IIS) and Expiratory Incentive Spirometry (EIS), while Obstructive, Restrictive, and Mixed respiratory impairments will serve as the dependent variable for the study. Baseline Pulmonary Function Test (PFT) will be assessed on entry into the study, and after every procedure, six minutes walk (6MWT) test and CAT assessment test will be assessed at every two (2) weeks interval of the study. Data will be analyzed using descriptive and inferential statistics of repeated ANOVA; P<0.05.\n\nDiscussionThe study outcome will determine the relationship between inspiratory and expiratory incentive spirometry on respiratory impairments and deduce the best fit device for the respective impairment.\n\nTrial Registrationwww.pactr.org: PACTR202005904039357","Adaptive, Unlabeled and Real-time Approximate-Learning Platform (AURA) for Personalized Epileptic Seizure Forecasting\nA high performance event detection system is all you need for some predictive studies. Here, we present AURA: an Adaptive forecasting model trained with Unlabeled, Real-time data using internally generated Approximate labels on-the-fly. By harnessing the correlated nature of time-series data, a pair of detection and prediction models are coupled together such that the detection model generates labels automatically, which are then used to train the prediction model. AURA relies on several simple principles and assumptions: (i) the performance of an event prediction/forecasting model in the target application remains below the performance of an event detection model, (ii) detected events are treated as weak labels and deemed reliable enough for online training of a predictive model, and (iii) system performance and/or system responsive feedback characteristics can be tuned for a subject-under-test. For example, in medical patient monitoring, this enables personalizing forecasting models. Seizure prediction is identified as an ideal test case of AURA, as pre-ictal brainwaves are patient-specific and tailoring models to individual patients can significantly improve forecasting performance. AURA is used to generate an individual forecasting model for 10 patients, showing an average relative improvement in sensitivity by 14.30% and reduction in false alarms by 19.61%. This paper presents a proof-of-concept for the feasibility of online transfer-learning on a stream of time-series neurophysiological data that pave the way towards a low-power neuromorphic neuromodulation system.","The common H202D variant in GDF-15 does not affect its bioactivity but can significantly interfere with measurement of its circulating levels\nGenetic variants in proteins can interfere with measurement of their circulating concentrations. Given the growing biomedical importance of GDF-15, we wished to establish whether a common histidine to aspartate variant present in position 6 of the mature GDF-15 protein (H202D variant) interfered with its measurement by two commonly used immunoassays. We first examined the detectability of recombinant monomers, homodimers and heterodimers of GDF-15 by assays and/or reagents used in two widely used immunoassays (Roche Elecsys(R) GDF-15 and the R&D antibody combinations used in their Quantikine(R) and DuoSet(R) ELISAs). The Roche assay detected the H and D containing peptides similarly but the assays based on the R&D reagents consistently underreported concentrations of the D-containing variant peptide. Measurements of plasma concentrations of GDF-15 in genotyped human participants showed that the R&D reagents reported values in heterozygotes were [~]25% lower, and in homozygotes, 50% lower than the Roche assay. We finally studied the activation of the GDF-15 receptor, GFRAL-Ret, in a cell based assay and found that the activities of the HH and DD containing GDF-15 peptide were indistinguishable. These results have implications for the interpretation of genetic epidemiological studies which have used the R&D reagents to measure GDF-15, and for the emerging clinical use of GDF-15 as a diagnostic and prognostic biomarker. We provide correction equations, which may be of utility for the analysis of data generated with the R&D reagents where the genotype of the participants is known.","Quantitative Digitography Solves the Remote Measurement Problem in Parkinson's disease\nBackgroundAssessment of motor signs in Parkinsons disease (PD) has required an in-person examination. However, 50% of people with PD do not have access to a neurologist. Wearable sensors can provide remote measures of some motor signs but require continuous data acquisition for several days. A major unmet need is reliable metrics of all cardinal motor signs, including rigidity, from a simple short active task that can be performed remotely or in the clinic.\n\nObjectiveInvestigate whether thirty seconds of repetitive alternating finger tapping (RAFT) on a portable quantitative digitography (QDG) device, which measures amplitude and timing, produces reliable metrics of all cardinal motor signs in PD\n\nMethodsNinety-six individuals with PD and forty-two healthy controls performed a thirty-second QDG-RAFT task and clinical motor assessment. Eighteen individuals were followed longitudinally with repeated assessments for an average of three years and up to six years.\n\nResultsQDG-RAFT metrics differentiated individuals with PD from controls and provided validated metrics for total motor disability (MDS-UPDRS III) and for rigidity, bradykinesia, tremor, gait impairment and freezing of gait (FOG). Additionally, QDG-RAFT tracked disease progression over several years off therapy, and differentiated akinetic rigid from tremor dominant phenotypes, as well as people with from those without FOG.\n\nConclusionsQDG is a reliable technology, which will improve access to care, allows complex remote disease management, and accurate monitoring of disease progression over time in PD. QDG-RAFT also provides the comprehensive PD motor metrics needed for therapeutic trials.","Reproducible in vivo detection of locus coeruleus pathology in Parkinson's disease\nBackgroundPatients with Parkinsons disease undergo a loss of melanized neurons in substantia nigra pars compacta and locus coeruleus. There are very few in vivo studies of locus coeruleus pathology in Parkinsons disease with magnetic resonance imaging. Existing studies have used varying methodologies, and reproducibility has not been established for any approach.\n\nObjectivesWe used neuromelanin-sensitive magnetic resonance imaging to examine the reproducibility of locus coeruleus and substantia nigra pars compacta degeneration in discovery and validation cohorts.\n\nMethodsTwo cohorts, discovery and validation, recruited from the Emory Movement Disorders Clinic were scanned on two different magnetic resonance imaging scanners. In cohort 1, imaging data from 19 controls and 22 Parkinsons disease patients were acquired with a Siemens Trio 3 Tesla scanner using a 2D gradient echo sequence with magnetization transfer preparation pulse. Cohort 2 consisted of 33 controls and 39 Parkinsons disease patients were scanned on a Siemens Prisma 3 Tesla scanner with a similar imaging protocol. Nigral and locus coeruleus volumes were segmented in both cohorts.\n\nResultsNigral volume (Cohort 1: p=0.0148; Cohort 2: p=0.0011) and locus coeruleus volume (Cohort 1: p=0.0412; Cohort 2: p=0.0056) were significantly reduced in the Parkinsons disease group as compared to controls in both cohorts.\n\nInterpretationSubstantia nigra pars compacta volume and locus coeruleus volume were significantly reduced in Parkinsons disease compared to controls in both cohorts. This imaging approach robustly detects Parkinsons disease effects on these structures suggesting its use as a potential diagnostic biomarker of Parkinsons disease.","Surveillance of potential pathogens and antibiotic resistance in wastewater and surface water from Boston, USA and Vellore, India using long-read metagenomic sequencing\nEnvironmental sampling (wastewater) could be an efficient surveillance strategy to capture global emerging trends in the spread of antibiotic resistance. Long-read DNA sequencing can resolve the genetic context of antibiotic resistance genes (ARGs) and is a promising tool for non-culture-based monitoring of antibiotic-resistant pathogens and ARGs in environmental samples, but has not been rigorously validated against conventional methods. We tested long-read sequencing using the portable Nanopore MinION for surveying pathogens, ARGs, and antibiotic-resistant pathogens in municipal wastewater, hospital wastewater, and surface water collected from Boston, USA and Vellore, India. We compared detection of enteric pathogens by assembly of long reads, with and without short-read polishing, and unassembled raw long reads for ARGs to multiplex real-time PCR. Using real-time PCR as a benchmark, long-read metagenomics was 49% sensitive and 75% specific at pathogen detection in assembled contigs, and 16% sensitive and 100% specific at detecting 28 clinically relevant resistance genes in raw long reads. Short-read polishing did not substantially improve pathogen identification or impact ARG identification in the assembled contigs, demonstrating that short-read polishing is not required, which greatly reduces costs. The high specificity of ARG detection supports portable long-read sequencing as a valuable tool to profile ARGs and antibiotic-resistant pathogens for environmental surveillance programs.","Distinctive modularity and resilience of structural covariance network in first-episode antipsychotic-naive psychoses\nObjectiveDivergent findings in structural brain alterations in psychoses suggest that often-observed regions may exist within a network of susceptible regions. We built structural covariance networks (SCN) of volumes, cortical thickness, and surface area using the Human Connectome Project atlas-based parcellation of 358 regions on structural MRI data from 79 first-episode antipsychotic-naive psychosis patients (FEAP) and 68 controls.\n\nMethodsUsing graph theoretic methods, we obtained representative graph metrics of integration, segregation, resilience, centrality, importance, community structure, and hub distribution for all 3-morphometric features. We compared networks for resilience by simulated removal (\"attacks\") of nodes and hubs, and simulated replacement of correlations among nodes in FEAP with that of controls using DeltaCon metric.\n\nResultsVolume and thickness SCNs of FEAP showed differences in many graph metrics in opposite directions compared to controls but not surface area SCN. Network resilience did not show differences in the replacement simulation and hub \"attacks, but betweenness centrality-based node \"attacks\" showed FEAP network disintegrating with relatively fewer node removals with preserved global efficiency compared to controls. In FEAP, communities consisted of regions from different lobes and hubs were more distributed than in controls.\n\nConclusionsOur findings suggest decreased heterogeneity and less differentiated community structure of FEAP network that may not be attributed to illness chronicity and medications. Contribution of cortical thickness but not surface area suggests that disease/developmental processes may preferentially affect cortical thickness. Near-similar resilience of FEAP and control networks may shield controls from developing illness but may prevent fuller long-term recovery in FEAP.","Alpha globin gene copy number and hypertension risk among Black Americans\nBACKGROUNDAlpha globin is expressed in the endothelial cells of human resistance arteries where it binds to endothelial nitric oxide synthase and limits release of the vasodilator nitric oxide. Genomic deletion of the alpha globin gene (HBA) is common among Black Americans and could lead to increased endothelial nitric oxide signaling and reduced risk of hypertension.\n\nMETHODSCommunity-dwelling US adults aged 45 years or older were enrolled and examined from 2003 to 2007, followed by telephone every 6 months, and reexamined from 2013 to 2016. At both visits, trained personnel performed standardized, in-home blood pressure measurements and pill bottle review. Prevalent hypertension was defined as systolic blood pressure [≥] 140mmHg or diastolic blood pressure [≥] 90mmHg or anti-hypertensive medication use. Droplet digital PCR was used to determine HBA copy number. The associations of HBA copy number with prevalent hypertension, resistant hypertension, and incident hypertension were estimated using multivariable regression.\n\nRESULTSAmong 9,684 Black participants, 7,439 (77%) had hypertension at baseline and 1,044 of those had treatment-resistant hypertension. 1,000 participants were not hypertensive at baseline and participated in a follow up visit; 517 (52%) developed hypertension over median 9.2 years follow-up. Increased HBA copy number was not associated with prevalent hypertension (PR=1.00; 95%CI 0.98,1.02), resistant hypertension (PR=0.95; 95%CI 0.86,1.05), or incident hypertension (RR=0.96; 95%CI 0.86,1.07).\n\nCONCLUSIONSThere were no associations between increased HBA copy number and risk of hypertension. These findings suggest that genetic variation in alpha globin gene expression does not modify the risk of hypertension among Black American adults.","AugmentA: Patient-specific Augmented Atrial model Generation Tool\nDigital twins of patients hearts are a promising tool to assess arrhythmia vulnerability and to personalize therapy. However, the process of building personalized computational models can be challenging and requires a high level of human interaction. A pipeline to standardize the generation of a patients atrial digital twin from clinical data is therefore desirable. We propose a patient-specific Augmented Atria generation pipeline (AugmentA) as a highly automated framework which, starting from clinical geometrical data, provides ready-to-use atrial personalized computational models. AugmentA consists firstly of a preprocessing step applied to the input geometry. Secondly, the atrial orifices are identified and labelled using only one reference point per atrium. If the user chooses to fit a statistical shape model (SSM) to the input geometry, it is first rigidly aligned with the given mean shape before a nonrigid fitting procedure is applied. AugmentA automatically generates the fiber orientation and finds local conduction velocities by minimizing the error between the simulated and clinical local activation time (LAT) map. The pipeline was tested on a cohort of 29 patients on both segmented magnetic resonance images (MRI) and electroanatomical maps of the left atrium. Moreover, the pipeline was applied to a bi-atrial volumetric mesh derived from MRI. The pipeline robustly integrated fiber orientation and anatomical region annotations in 38.4{+/-}5.7 s. The error between insilico and clinical LAT maps was on average 12.7 ms. In conclusion, AugmentA offers an automated and comprehensive pipeline delivering atrial digital twins from clinical data in procedural time.","Pediatric Nemaline Myopathy: A systematic review using individual patient data\nContextNemaline myopathy (NM) is a skeletal muscle disease that affects 1 in 50,000 live births.\n\nObjectiveDevelop a narrative synthesis of the findings of a systematic review of the latest case descriptions of patients with nemaline myopathy.\n\nData SourcesA systematic search of MEDLINE, Embase, CINAHL, Web of Science, and Scopus was performed using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines using the keywords pediatric, child, nemaline myopathy, nemaline rod, rod myopathy.\n\nStudy SelectionCase studies focused on pediatric NM and published in English between January 1, 2010 and December 31, 2020 in order to represent the most recent findings.\n\nData ExtractionInformation was collected about the age of first signs, earliest presenting neuromuscular signs and symptoms, systems affected, progression, death, pathological description, and genetic changes.\n\nResultsOf a total of 385 records, 55 case reports or series were reviewed, covering 101 pediatric patients from 23 countries. We review varying presentations in children ranging in severity despite being caused by the same mutation, in addition to current and future clinical considerations relevant to the care of patients with nemaline myopathy.\n\nLimitationsThe results are limited by findings shared in the literature, which varied in their detail and sometimes lacked histological or genetic results. Trends and correlations may be altered by information available.\n\nConclusionsThis review synthesizes genetic, histopathologic, and disease presentation findings from pediatric nemaline myopathy case reports. These data strengthen our understanding of the wide spectrum of disease seen in nemaline myopathy. Future studies are needed to identify the underlying molecular mechanism of pathology, to improve diagnostics, and to develop better methods to improve quality of life for these patients.","Clinical improvement of DM1 patients reflected by reversal of disease-induced gene expression in blood\nMyotonic dystrophy type 1 (DM1) is an incurable multisystem disease caused by a CTG-repeat expansion in the DM1 protein kinase (DMPK) gene. The OPTIMISTIC clinical trial demonstrated positive and heterogenous effects of cognitive behavioral therapy (CBT) on the capacity for activity and social participations in DM1 patients. Here, we performed mRNA sequencing of full blood for 27 patients of the OPTIMISTIC cohort before and after the CBT intervention. We identified 608 genes for which their expression was significantly associated with the disease causing CTG-repeat expansion, as well as 1176 genes significantly associated with the average clinical response towards the intervention. Remarkably, all 97 genes significantly associated with both returned to more normal levels in patients who benefited most from CBT. This trend was consistent with the difference observed between DM1 patients and controls in an earlier study of blood mRNA expression levels, singling these genes out as candidate biomarkers for therapy response. Together these results highlight the ability to find disease relevant information in full blood of DM1 patients, opening new avenues to monitor therapy effects.","SARS-CoV-2 evolution and immune escape in immunocompromised patients treated with exogenous antibodies\nBackgroundSARS-CoV-2 mutations conferring escape from neutralizing antibodies can arise in immunocompromised patients with prolonged infection, but the conditions that facilitate immune escape are still not fully understood.\n\nMethodsWe characterized endogenous immune responses, within-host SARS-CoV-2 evolution, and autologous neutralization of the viral variants that arose in five immunocompromised patients with prolonged infection and B cell deficiencies.\n\nResultsIn two patients treated with the monoclonal antibody bamlanivimab, viral resistance to autologous serum arose early and persisted for several months, accompanied by ongoing evolution in the spike protein. These patients exhibited deficiencies in both T and B cell arms, and one patient succumbed to disease. In contrast, we did not observe spike mutations in immunologically important regions in patients who did not receive exogenous antibodies or who received convalescent plasma and had intact T cell responses to SARS-CoV-2.\n\nConclusionsOur results underscore the potential importance of multiple factors - the absence of an effective endogenous immune response, persistent virus replication, and selective pressure such as single-agent bamlanivimab - in promoting the emergence of SARS-CoV-2 mutations associated with immune evasion. These findings highlight the need for larger clinical studies in immunocompromised populations to better understand the ramifications of different therapies. Our results also confirm that patients with B cell deficiencies can elicit effector T cells and may suggest an important role for T cells in controlling infection, which is relevant to vaccines and therapeutics.","Wastewater monitoring outperforms case numbers as a tool to track COVID-19 incidence dynamics when test positivity rates are high\nWastewater-based epidemiology (WBE) has been shown to coincide with, or anticipate, confirmed COVID-19 case numbers. During periods with high test positivity rates, however, case numbers may be underreported, whereas wastewater does not suffer from this limitation. Here we investigated how the dynamics of new COVID-19 infections estimated based on wastewater monitoring or confirmed cases compare to true COVID-19 incidence dynamics. We focused on the first pandemic wave in Switzerland (February to April, 2020), when test positivity ranged up to 26%. SARS-CoV-2 RNA loads were determined 2-4 times per week in three Swiss wastewater treatment plants (Lugano, Lausanne and Zurich). Wastewater and case data were combined with a shedding load distribution and an infection-to-case confirmation delay distribution, respectively, to estimate incidence dynamics. Finally, the estimates were compared to reference incidence dynamics determined by a validated compartmental model. Incidence dynamics estimated based on wastewater data were found to better track the timing and shape of the reference infection peak compared to estimates based on confirmed cases. In contrast, case confirmations provided a better estimate of the subsequent decline in infections. Under a regime of high-test positivity rates, WBE thus provides critical information that is complementary to clinical data to monitor the pandemic trajectory.","Optimal symptom combinations to aid COVID-19 case identification: analysis from a community-based, prospective, observational cohort\nObjectivesDiagnostic work-up following any COVID-19 associated symptom will lead to extensive testing, potentially overwhelming laboratory capacity whilst primarily yielding negative results. We aimed to identify optimal symptom combinations to capture most cases using fewer tests with implications for COVID-19 vaccine developers across different resource settings and public health.\n\nMethodsUK and US users of the COVID-19 Symptom Study app who reported new-onset symptoms and an RT-PCR test within seven days of symptom onset were included. Sensitivity, specificity, and number of RT-PCR tests needed to identify one case (test per case [TPC]) were calculated for different symptom combinations. A multi-objective evolutionary algorithm was applied to generate combinations with optimal trade-offs between sensitivity and specificity.\n\nFindingsUK and US cohorts included 122,305 (1,202 positives) and 3,162 (79 positive) individuals. Within three days of symptom onset, the COVID-19 specific symptom combination (cough, dyspnoea, fever, anosmia/ageusia) identified 69% of cases requiring 47 TPC. The combination with highest sensitivity (fatigue, anosmia/ageusia, cough, diarrhoea, headache, sore throat) identified 96% cases requiring 96 TPC.\n\nInterpretationWe confirmed the significance of COVID-19 specific symptoms for triggering RT-PCR and identified additional symptom combinations with optimal trade-offs between sensitivity and specificity that maximize case capture given different resource settings.\n\nHighlightsO_LIWidely recommended symptoms identified only [~]70% COVID-19 cases\nC_LIO_LIAdditional symptoms increased case finding to > 90% but tests needed doubled\nC_LIO_LIOptimal symptom combinations maximise case capture considering available resources\nC_LIO_LIImplications for COVID-19 vaccine efficacy trials and wider public health\nC_LI","Survival rate of positive peritoneal cytology in endometrial cancer; a systematic review and meta-analysis\nBackgroundThe impact of positive peritoneal cytology on survival rate of endometrial cancer patients in different stages and histopathology is still controversial. We performed a systematic review and meta-analysis to investigate the influence of positive peritoneal cytology (PPC) on survival rate of patients with endometrial carcinoma.\n\nMethodsA systematic literature search of PubMed, Embase, Scopus, and Cochrane databases was conducted up to November 24, 2020. The quality of included studies was evaluated by Quality in prognosis study (QUIPS) tool.\n\nResultsInitially, 3014 articles were found, of which 65 met the inclusion criteria for qualitative analysis and 27 studies on 75897 patients with endometrial cancer were included in the meta-analysis. PPC was associated with a lower overall survival in endometrial cancer (HR= 2.102; 95% CI:1.629-2.711; P< 0.001). The findings also identified PPC as an independent prognostic factor for both disease-free survival (HR= 3.052; 95% CI: 2.348-2967; P< 0.001) and cancer specific survival (HR= 3.461; 95% CI: 2.280-5.254; P< 0.001). In addition, we meta-analyzed the studies in 21 subgroups based on staging and histopathology of the endometrial cancer which all identified PPC as a non-prognostic factor for cancer of endometrium.\n\nConclusionPPC is an independent prognostic factor for endometrial cancer survival rate in all staging and histopathologic subgroups.","IL-13 is a driver of COVID-19 severity\nImmune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here we report that elevated interleukin-13 (IL-13) was associated with the need for mechanical ventilation in two independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab had less severe disease. In SARS-CoV-2 infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, in the lung, hyaluronan synthase 1 (Has1) was the most downregulated gene and hyaluronan accumulation was decreased. Blockade of the hyaluronan receptor, CD44, reduced mortality in infected mice, supporting the importance of hyaluronan as a pathogenic mediator, and indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and hyaluronan has important implications for therapy of COVID-19 and potentially other pulmonary diseases.\n\nSummaryL-13 levels are elevated in patients with severe COVID-19. In a mouse model of disease, IL-13 neutralization results in reduced disease and lung hyaluronan deposition. Similarly, blockade of hyaluronans receptor, CD44, reduces disease, highlighting a novel mechanism for IL-13-mediated pathology.","Cardiovascular Complications of Modern Multiple Myeloma Therapy: Analysis of FDA Adverse Event Reporting System\nPurposeMultiple myeloma accounts for over 15% of hematological malignancies. In attempt to tackle this malady, the FDA approved four drugs in 2015 which has propagated further development of new anti-multiple myeloma since. However, the health safety of these new agents is still ill-defined. The aim of this study is to delineate the cardiovascular adverse events of these drugs.\n\nMethodsWe searched the cardiac adverse events of the newly approved FDA drugs since 2015 using the U.S. Food and Drug Administration Adverse Events Reporting System database (FAERS). We calculated the reporting odds ratio (ROR) with 95% confidence for four drugs that have the highest incidence of cardiovascular adverse events.\n\nResultsAmong the medications that have approved for MM Between 2015-2020, four novel drugs showed the highest incidence of cardiotoxicity. ROR (95% CI) for atrial fibrillation due to elotuzumab, Ixazomib, daratumumab, and panobinostat compared to other FAERS drugs was 5.8 (4.4-7.7), 1.93 (1.5-2.3), 4.8 (4.2-5.6), and 5.7 (4.1-8.1), respectively. The ROR (95% CI) for cardiac failure was 8.2 (6.4-10.5), 4.7 (4.1-5.4), 5.8 (4.9-6.7), and 5.6 (3.8-8.1) and ROR (95% CI) for coronary disease was 2.7 (1.9-3.9), 2.7 (2.3-3.2), 2,3 (1.9-2.8), and 4.6 (3.2-6.6) due to elotuzumab, Ixazomib, daratumumab, and panobinostat versus all other drugs in FAERS.\n\nConclusionsThe newly approved multiple myeloma therapy (elotuzumab, Ixazomib, daratumumab, panobinostat) are significantly associated with cardiotoxicity. These results highlight the importance of considering the cardiac history of patients with multiple myeloma when utilizing these novel agents.","Rapid, Near Point-of-Care Assay for HLA-B*57:01 Genotype Associated with Severe Hypersensitivity Reaction to Abacavir\nObjectiveThe nucleoside reverse transcriptase inhibitor abacavir is commonly used to treat young children with HIV infection. Abacavir can trigger a severe hypersensitivity reaction in people who are homozygous or heterozygous for HLA-B*57:01. Testing for HLA-B*57:01 prior to abacavir initiation is standard-of-care in high-resource settings, but current tests are too costly for resource-limited settings. To address this gap, we developed an inexpensive, simple-to-use rapid assay to detect HLA-B*57:01.\n\nMethodsWe designed and optimized a multiplexed PCR to amplify HLA-B*57 subtypes and the human beta-globin gene. Subsequently, probes annealed to the amplicon and were ligated when specific for the HLA-B*57:01 allele. Ligated products were detected by immunocapture in a lateral flow strip. Cell lines with known HLA genotypes were used to optimize the assay. The assay was then evaluated by comparing the genotype of clinical specimens (n=60) enriched for individuals with HLA-B*57:01 by the new assay to that from sequencing.\n\nResultsThe optimized multiplex PCR for B*57 and beta-globin resulted in a 40-minute, 35-cycle amplification, followed by a 20-minute ligation reaction and 15-minute detection step. Evaluation of the HLA-B*57:01 oligonucleotide ligation assay using clinical specimens had a sensitivity of 100% (n=27/27 typed as B*57:01) and specificity of 100% (n=33/33 typed as non-B*57:01) by visual interpretation of lateral flow strips.\n\nConclusionsThis rapid and economical assay can accurately detect the presence of HLA-B*57:01 in clinical specimens. Use of this assay could expand access to HLA-B*57:01 genotyping and facilitate safe same-day initiation of abacavir-based treatment.","Genetic variants associated with cross-disorder and disorder-specific risk for psychiatric disorders are enriched at epigenetically active sites in peripheral lymphoid cells\nMultiple psychiatric disorders have been associated with abnormalities in both the innate and adaptive immune systems. The role of these abnormalities in pathogenesis, and whether they are driven by psychiatric risk variants, remains unclear. We tested for enrichment of GWAS variants associated with multiple psychiatric disorders (cross-disorder or trans-diagnostic risk), or 5 specific disorders (cis-diagnostic risk), in regulatory elements in immune cells. We used three independent epigenetic datasets representing multiple organ systems and immune cell subsets. Trans-diagnostic and cis-diagnostic risk variants (for schizophrenia and depression) were enriched at epigenetically active sites in brain tissues and in lymphoid cells (T, B and NK cells), especially stimulated CD4+ T cells. There was no evidence for enrichment of either trans-risk or cis-risk variants for schizophrenia or depression in myeloid cells. This suggests a model where stimuli (e.g. infection) activate T cells to unmask the effects of psychiatric risk variants, contributing to the pathogenesis of mental health disorders.","Revisiting the diagnostic criteria for emergence from the minimally conscious state: An empirical investigation\nObjectiveTo determine whether consistent command-following (CCF) should be added to the diagnostic criteria for emergence from the minimally conscious state (MCS)\n\nDesignRetrospective cohort study\n\nSettingInpatient rehabilitation hospital\n\nParticipantsPatients with severe acquired brain injury and disorders of consciousness (DoC) admitted to a specialized rehabilitation program\n\nMain Outcome MeasureDifference between time to recovery of CCF and time to recovery of functional object use [FOU] or functional communication [FC] (the two existing criteria for emergence from MCS) as measured by the Coma Recovery Scale - Revised [CRS-R]).\n\nResultsOf 214 patients (median [interquartile range] age: 53 [34, 66] years, male: 134 (62.6%), traumatic etiology: 115 (53.7%), admission CRS-R total score: 10 [7, 13]) admitted to rehabilitation without CCF, FO, or FC, 162 (75.7%) recovered CCF and FOU or FC during the eight-week observation period. On average, recovery of CCF, FOU, and FC was observed within one day of one another, approximately 46 [38.25, 58] days post-injury. One hundred and sixteen patients (71.6%) recovered FOU or FC prior to or at the same time as CCF.\n\nConclusionsIn patients recovering from DoC, CCF reemerges around the same time as FOU and FC. This finding likely reflects the shared dependency of these behaviors on cognitive procecess (e.g., language comprehension, attention, motor control) that are essential for effective interpersonal interaction and social participation. Our results support the addition of CCF to the existing diagnostic criteria for emergence from MCS.","Correlation between faecal microbial taxa and ulcerative colitis in different phases of disease activity in a north Indian cohort\nBackground and AimsA link between gut microbiota and Ulcerative colitis (UC) has been established in several studies. However, only a few studies have examined specific changes in microbiota associated with different phases of disease activity in UC. In this study, we attempted to identify differentially abundant taxa between (i) UC patients and healthy controls and (ii) different phases of disease activity, in a genetically distinct north Indian (NI) population.\n\nMethods16S rRNA (V3-V4) sequencing of 105 patients with UC [newly diagnosed (n=14); patients in remission (n=36) and active disease (relapse, n=55)]; and 36 healthy controls was performed and analysed.\n\nResultsLower gut microbial diversity; enrichment of lactate-producing bacteria namely Streptococcus, Bifidobacterium and Lactobacillus; and depletion of butyrate-producing bacteria (e.g., Lachnospiraceae and Ruminococcaceae), were observed among UC patients. Subgroup analysis revealed differential abundance of Escherichia-Shigella, Streptococcus, Enterococcus and Faecalibacterium in newly diagnosed UC patients. No discrete microbial features were observed between patients in remission and those with active disease. Co-occurrence network analysis revealed a mutualistic association between opportunistic pathogens and Bifidobacterium and Lactobacillus and antagonistic relationship with butyrate-producers.\n\nConclusionThis first faecal microbiome study among NI UC cohort elucidated dysanaerobiosis; loss of short chain fatty acid producers and enrichment of inflammation associated microbes; population specific differential microbial genera; and a potential microbial signature for early dysbiosis.","IL-1 and IL-6 inhibitor hypersensitivity link to common HLA-DRB1*15 alleles\nIn Saper et al (2019), we described systemic JIA patients who developed a high-fatality diffuse lung disease (DLD) while on IL-1 or IL-6 inhibitors. We observed severe delayed drug hypersensitivity reactions (DHR) in a significant subset. Because alleles of the human leukocyte antigen (HLA) loci can mediate DHR, we investigated HLA genotype association with these DHR. We typed subjects treated with these inhibitors: 34 sJIA/DHR/DLD, 11 sJIA/DHR without DLD, 18 drug-tolerant sJIA, and 19 Kawasaki disease (KD) patients in an anti-IL-1(anakinra) trial. We also accessed genotypes from a large sJIA case/control cohort.\n\nWe first compared White subjects with sJIA/DHR to 550 ancestry-matched sJIA subjects. We found striking enrichments of HLA-DRB1*15:01, HLA-DQA1*01:02, and DQB1*06:02, alleles in near-complete linkage (White individuals). HLA-DRB 1*15:01 (as haplotype proxy) was increased in White sJIA subjects with DHR/DLD versus sJIA drug-tolerant controls and was observed upon inclusion of sJIA+DHR-only and KD+DHR White subjects. In our entire cohort regardless of ancestry, 75% carried HLA-DRB 1*15:01 or the structurally related DRB1*15:03 and DRB1*15:06, which were absent among drug-tolerant subjects (p=5 x 10-13; Odds Ratio lower bound=20.11).\n\nPatients who harbor HLA-DRB1*15 alleles are at high risk of developing DHR to anti-IL-1/IL-6. Our data also suggest DHR maybe a trigger/enhancer of DLD in sJIA patients and support performing prospective HLA screening in sJIA, its adult-onset counterpart, and other inflammatory conditions where these drugs are used, such as KD.","SplitStrains, a tool to identify and separate mixed Mycobacterium tuberculosis infections from WGS data\nThe occurrence of multiple strains of a bacterial pathogen such as M. tuberculosis or C. difficile within a single human host, referred to as a mixed infection, has important implications for both healthcare and public health. However, methods for detecting it, and especially determining the proportion and identities of the underlying strains, from WGS (whole-genome sequencing) data, have been limited.\n\nIn this paper we introduce SplitStrains, a novel method for addressing these challenges. Grounded in a rigorous statistical model, SplitStrains not only demonstrates superior performance in proportion estimation to other existing methods on both simulated as well as real M. tuberculosis data, but also successfully determines the identity of the underlying strains.\n\nWe conclude that SplitStrains is a powerful addition to the existing toolkit of analytical methods for data coming from bacterial pathogens, and holds the promise of enabling previously inaccessible conclusions to be drawn in the realm of public health microbiology.\n\nAuthor summaryWhen multiple strains of a pathogenic organism are present in a patient, it may be necessary to not only detect this, but also to identify the individual strains. However, this problem has not yet been solved for bacterial pathogens processed via whole-genome sequencing. In this paper, we propose the SplitStrains algorithm for detecting multiple strains in a sample, identifying their proportions, and inferring their sequences, in the case of Mycobacterium tuberculosis. We test it on both simulated and real data, with encouraging results. We believe that our work opens new horizons in public health microbiology by allowing a more precise detection, identification and quantification of multiple infecting strains within a sample.","Novel Application of a Multistate Model to Evaluate the Opioid Use Disorder Care Cascade: A Retrospective Cohort Study\nBackgroundEvaluating the opioid use disorder (OUD) care cascade can improve OUD treatment retention and care.\n\nObjectivesTo identify risk and protective factors for retention among patients in OUD treatment.\n\nMethodsWe conducted a retrospective cohort study among patients diagnosed with OUD using data from the Rhode Island (RI) All-Payer Claims Database from 2011 to 2019. Patients who initiated treatment (Stage 2) were classified into sub-stages of retention (Stage 3) corresponding to multistate modeling states capturing early retention (sub-stage 1), short and long-term retention (sub-stage 2), and short and long-term disengagement (sub-stage 3). The association of baseline characteristics with state transitions were evaluated.\n\nResultsA cohort of 6,939 RI residents diagnosed with OUD included 41% aged 40 to 60 years, 57.6% male, and 70.8% Medicaid beneficiaries. In sub-stage 1, cannabis (Relative risk ratios (RRR) = 1.16; 95% confidence interval (CI) = 1.04,1.29) and cocaine use disorders (RRR=1.15; 95% CI=1.05,1.25) increased early disengagement risk after engagement. Medicaid beneficiaries were less likely to experience early disengagement (RRR=0.81; 95% CI =0.76,0.87). In sub-stage 2, alcohol (RRR=1.29; 95% CI=1.13,1.47) or cocaine use disorders (RRR=1.18; 95% CI=1.01,1.40) increased risk of disengagement among patients in the retention states. In sub-stage 3, tobacco (RRR=1.10; 95% CI=1.01,1.21) and alcohol (RRR=1.14; 95% CI=1.03,1.27) use disorders were associated with re-engagement from disengaged states.\n\nConclusionThe multistate model applied to a cohort of patients initiating medication for OUD led to the identification of factors associated with treatment engagement and retention. These results may guide strategies to sustain treatment among OUD patients.","Linking common and rare disease genetics through gene regulatory networks\nGenetic variants identified through genome-wide association studies (GWAS) are typically non-coding and exert small regulatory effects on downstream genes, but which downstream genes are ultimately impacted and how they confer risk remains mostly unclear. Conversely, variants that cause rare Mendelian diseases are often coding and have a more direct impact on disease development. We demonstrate that common and rare genetic diseases can be linked by studying the gene regulatory networks impacted by common disease-associated variants. We implemented this in the Downstreamer method and applied it to 44 GWAS traits and find that predicted downstream \"key genes\" are enriched with Mendelian disease genes, e.g. key genes for height are enriched for genes that cause skeletal abnormalities and Ehlers-Danlos syndromes. We find that 82% of these key genes are located outside of GWAS loci, suggesting that they result from complex trans regulation rather than being impacted by disease-associated variants in cis. Finally, we discuss the challenges in reconstructing gene regulatory networks and provide a roadmap to improve identification of these highly connected genes for common traits and diseases.","Association between Systemic Lupus Erythematosus and Coronary Heart Disease: a retrospective case-control analysis and Mendelian Randomization Study\nObjectivesTo appraise the causal effect of systemic lupus erythematosus (SLE) for risk of Coronary heart disease (CHD).\n\nMethodsWe selected single nucleotide polymorphisms (SNPs) associated with SLE as instrumental variables (IVs) from three independent genome-wide association studies (GWAS), the three largest to date for SLE of European ancestry. Then we conducted two-sample Mendelian randomization (2SMR) analyses to estimate the effects of IVs on the odds of CHD and traditional coronary risk factors (including high LDL cholesterol levels, low HDL cholesterol levels, Apolipoprotein A-I, Apolipoprotein B, diabetes mellitus, and hypertension). Additionally, we searched for common risk loci between SLE and premature coronary atherosclerosis. Furthermore, we retrospectively reviewed the lipid profile of treatment-naive SLE patients and age-matched healthy controls.\n\nResultsGenetically predicted SLE did not increase the odds of CHD. Nevertheless, we found mild causal relationships between SLE and decreased HDL cholesterol levels, and between SLE and decreased apolipoprotein A-I. There was one common risk locus (rs597808) between SLE and premature coronary atherosclerosis at a genome-wide significance level (P<5 x 10-8). Retrospective analysis showed decreased HDL-cholesterol (0.98{+/-}0.516mmol/L vs. 1.46{+/-}0.307mmol/L in female, 0.76{+/-}0.199mmol/L vs. 1.19{+/-}0.257mmol/L in male; both P<0.001) and apolipoprotein A-I (1.06{+/-}0.314g/L vs. 1.37{+/-}0.205g/L in female, 0.87{+/-}0.174g/L vs. 1.24{+/-}0.200g/L in male; both P<0.001) in naive SLE patients.\n\nConclusionSLE may accelerate coronary atherosclerosis in young patients by reducing HDL cholesterol and apolipoprotein A-I intrinsically, but it seems not to play a predominant role in CHD development in old patients.","Genetic links in angioimmunoblastic T-cell lymphoma (AITL), clonal hematopoiesis and concomitant hematologic malignancies provide insights into the cell of origin, etiology and biomarker discovery for AITL\nWe generated and compared the mutation profiles through targeted sequencing of the primary tumors and matched bone marrow/peripheral blood samples in 25 patients with angioimmunoblastic T-cell lymphoma (AITL) and 2 with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Our results provided strong evidence that AITL/PTCL-NOS, clonal hematopoiesis (CH) as well as other concomitant myeloid and even B-cell hematologic neoplasms (CHN), frequently arose from common mutated hematopoietic stem cell clones. Aberrant AID/APOBEC activity-associated substitutions and tobacco smoking-associated substitutions were enriched in the early CH-associated mutations and late non-CH associated mutations during AITL/PTCL-NOS development, respectively. Moreover, survival analysis showed that the presence of CH harboring [≥] 2 pathogenic TET2 variants with [≥] 15% of allele burden conferred higher risk for CHN (P = 0.0034, hazard ratio = 10.81). These findings provide insights into the cell origin and etiology of AITL, and provide a novel stratification biomarker for CHN risk in AITL/PTCL-NOS patients.","Pharmacokinetics/pharmacodynamics by Race: Analysis of a Peginterferon Beta-1a Phase I Study\nBackgroundBlack/African-American participants are underrepresented in clinical trials but can experience a greater burden of disease, such as multiple sclerosis, than other racial groups in the United States. A phase 1, open-label, 2-period crossover study that demonstrated bioequivalence of subcutaneous (SC) and intramuscular (IM) injection of peginterferon beta-1a in healthy volunteers enrolled a similar proportion of Black/African-American and White participants, enabling a subgroup analysis comparing these groups.\n\nMethodsPeginterferon beta-1a 125 g was administered by SC or IM (1:1) injection, followed by a 28-day washout period before a second injection using the alternate method. Primary endpoints were maximum observed concentration (Cmax) and area under the concentration-time curve from Hour 0 to infinity (AUCinf). Secondary endpoints included safety, tolerability, and additional pharmacokinetic and pharmacodynamic parameters.\n\nFindingsThis analysis included 70 (51.5%) Black and 59 (43.3%) White participants. Black participants exhibited a 29.8% higher geometric mean Cmax of peginterferon beta-1a than White participants following SC administration and demonstrated similar values following IM administration. Black participants displayed 31.0% versus 11.8% higher geometric mean AUCinf values than White participants with SC versus IM administration. Neopterin dynamics and safety signals were similar between groups, with numerically fewer adverse events reported among Black participants.\n\nConclusionsNo clinically meaningful differences were identified between Black and White participants in pharmacokinetics/pharmacodynamics or safety related to peginterferon beta-1a administration, indicating that no change in dosing regimen is warranted for Black patients with MS.\n\nFundingFunding for medical writing support was provided by Biogen Inc. (Cambridge, MA, USA).","Increasing test specificity without impairing sensitivity - lessons learned from SARS-CoV-2 serology\nBackgroundSerological tests are widely used in various medical disciplines for diagnostic and monitoring purposes. Unfortunately, the sensitivity and specificity of test systems is often poor, leaving room for false positive and false negative results. However, conventional methods used to increase specificity decrease sensitivity and vice versa. Using SARS-CoV-2 serology as an example, we propose here a novel testing strategy: the \"Sensitivity Improved Two-Test\" or \" SIT2\" algorithm.\n\nMethodsSIT2 involves confirmatory re-testing of samples with results falling in a predefined retesting-zone of an initial screening test, with adjusted cut-offs to increase sensitivity. We verified and compared the performance of SIT2 to single tests and orthogonal testing (OTA) in an Austrian cohort (1,117 negative, 64 post-COVID positive samples) and validated the algorithm in an independent British cohort (976 negatives, 536 positives).\n\nResultsThe specificity of SIT2 was superior to single tests and non-inferior to OTA. The sensitivity was maintained or even improved using SIT2 when compared to single tests or OTA. SIT2 allowed correct identification of infected individuals even when a live virus neutralization assay could not detect antibodies. Compared to single testing or OTA, SIT2 significantly reduced total test errors to 0.46% (0.24-0.65) or 1.60% (0.94-2.38) at both 5% or 20% seroprevalence.\n\nConclusionFor SARS-CoV-2 serology, SIT2 proved to be the best diagnostic choice at both 5% and 20% seroprevalence in all tested scenarios. It is an easy to apply algorithm and can potentially be helpful for the serology of other infectious diseases.","Raman spectroscopy on blood serum probes of patients with end-stage liver disease\nRaman spectroscopy has shown to be a promising method for the examination of biomedical samples. However, until now, its efficacy has not been established in clinical diagnostics. In this study, Raman spectroscopys potential application in medical laboratories is evaluated for a large variety (38) of biomarkers. Given 234 serum samples from a cohort of patients with different stages of liver disease, we performed Raman spectroscopy at 780nm excitation wavelength. The Raman spectra were analyzed in combination with the results of routine diagnostics using specifically developed complex mathematical algorithms, including fluorescence filtering, frequency subset selection and several overfitting circumventing strategies, such as independent validation. With the results of this cohort, which were validated in 328 independent samples, a significant proof-of-concept study was completed. This study highlights the need to prevent overfitting and to use independent data for validation. The results reveal that Raman spectroscopy has high potential for use in medical laboratory diagnostics to simultaneously quantify multiple biomarkers.","Autoantibodies Detected in MIS-C Patients due to Administration of Intravenous Immunoglobulin\nThe autoantibody profile associated with known autoimmune diseases in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that adults with COVID-19 had a moderate prevalence of autoantibodies against the lung antigen KCNRG, and SLE-associated Smith autoantigen. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute insulin-dependent diabetes. While autoantibodies associated with SLE/Sjogrens syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring in vivo decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Together these findings demonstrate that administration of high-dose IVIG is responsible for the detection of several autoantibodies in MIS-C and KD. Further studies are needed to investigate autoantibody production in MIS-C patients, independently from IVIG administration.","Plasma biomarkers associated with survival and thrombosis in hospitalized COVID-19 patients\nSevere coronavirus disease-19 (COVID-19) has been associated with fibrin-mediated hypercoagulability and thromboembolic complications. To evaluate potential biomarkers of coagulopathy and disease severity in COVID-19, we measured plasma levels of eight biomarkers potentially associated with coagulation, fibrinolysis, and platelet function in 43 controls and 63 COVID-19 patients, including 47 patients admitted to the intensive care unit (ICU) and 16 non-ICU patients. COVID-19 patients showed significantly elevated levels of fibrinogen, tissue plasminogen activator (t-PA), and its inhibitor plasminogen activation inhibitor 1 (PAI-1), as well as ST2 (the receptor for interleukin 33) and von Willebrand factor (vWF) compared to the control group. We found that higher levels of t-PA, ST2, and vWF at the time of admission were associated with lower survival rates, and that thrombotic events were more frequent in patients with initial higher levels of vWF. These results support a predictive role of specific biomarkers such as t-PA and vWF in the pathophysiology of COVID-19. The data provide support for the case that hypercoagulability in COVID-19 is fibrin-mediated, but also highlights the important role that vWF may play in the genesis of thromboses in the pathophysiology of COVID-19. Interventions designed to enhance fibrinolysis and reduce platelet aggregation might prove to be useful adjuncts in the treatment of coagulopathy in a subset of COVID-19 patients.","Analysis of MRI-derived spleen iron in the UK Biobank identifies genetic variation linked to iron homeostasis and erythrocyte morphology\nAging, and the pathogenesis of many common diseases, involves iron homeostasis. A key role in iron homeostasis is played by the spleen, which is the largest filter of the blood and performs iron reuptake from old or damaged erythrocytes. Despite this important role, spleen iron content has not been measured previously in a large, population-based cohort. In this study, we quantify spleen iron in 41,764 participants of the UK Biobank using magnetic resonance imaging (MRI). We find that epidemiologic and environmental factors such as increased age, higher red meat consumption and lower alcohol intake correlate with higher spleen iron. Through genome-wide association study, we identify genetic associations between spleen iron and common variation at seven loci, including in two hereditary spherocytosis (HS) genes, ANK1 and SPTA1. HS-causing mutations in these genes are associated with lower reticulocyte volume and increased reticulocyte percentage, while our common alleles are associated with increased expression of ANK1 and SPTA1 in blood and with larger reticulocyte volume and reduced reticulocyte percentage. As genetic modifiers, these common alleles may explain mild spherocytosis phenotypes observed in some HS allele carriers. Further, we identify an association between spleen iron and MS4A7, which colocalizes with a quantitative trait locus for MS4A7 alternative splicing in whole blood, and with monocyte count and fraction. Through quantification of spleen iron in a large human cohort, we extend our understanding of epidemiological and genetic factors associated with iron recycling and erythrocyte morphology.","COVID-19 mortality risk correlates inversely with vitamin D3 status, and a mortality rate close to zero could theoretically be achieved at 50 ng/ml 25(OH)D3: Results of a systematic review and meta-analysis\nBackgroundMuch research shows that blood calcidiol (25(OH)D3) levels correlate strongly with SARS-CoV-2 infection severity. There is open discussion regarding whether low D3 is caused by the infection or if deficiency negatively affects immune defense. The aim of this study was to collect further evidence on this topic.\n\nMethodsSystematic literature search was performed to identify retrospective cohort as well as clinical studies on COVID-19 mortality rates versus D3 blood levels. Mortality rates from clinical studies were corrected for age, sex and diabetes. Data were analyzed using correlation and linear regression.\n\nResultsOne population study and seven clinical studies were identified, which reported D3 blood levels pre-infection or on the day of hospital admission. They independently showed a negative Pearson correlation of D3 levels and mortality risk (r(17)=-.4154, p=.0770/r(13)=-.4886, p=.0646). For the combined data, median (IQR) D3 levels were 23.2 ng/ml (17.4 - 26.8), and a significant Pearson correlation was observed (r(32)=-.3989, p=.0194). Regression suggested a theoretical point of zero mortality at approximately 50 ng/ml D3.\n\nConclusionsThe two datasets provide strong evidence that low D3 is a predictor rather than a side effect of the infection. Despite ongoing vaccinations, we recommend raising serum 25(OH)D levels to above 50 ng/ml to prevent or mitigate new outbreaks due to escape mutations or decreasing antibody activity.\n\nTrial registrationNot applicable.","Structural and diffusion weighted brain imaging biomarkers for ADHD and its symptomology in very young (4-7-year-old) children\nThe current study aimed to identify the key neurobiology of Attention-Deficit/Hyperactivity Disorder (ADHD), as it relates to ADHD diagnostic category and symptoms of hyperactive/impulsive behavior and inattention. To do so, we adapted a predictive modeling approach to identify the key structural and diffusion weighted brain imaging measures, and their relative standing with respect to teacher ratings of executive function - EF (measured by the Metacognition Index of the Behavior Rating Inventory of Executive Function- BRIEF), negativity and emotion regulation - ER (measured by the Emotion Regulation Checklist, ERC), in a critical young age range (ages 4 to 7, mean age 5.52 years, 82.2% Hispanic/Latino), where initial contact with educators and clinicians typically take place. Teacher ratings of EF and ER were predictive of both ADHD diagnostic category and symptoms of hyperactive/impulsive behavior and inattention. Among the neural measures evaluated, the current study identified the critical importance of the largely understudied diffusion weighted imaging measures for the underlying neurobiology of ADHD and its associated symptomology. Specifically, our analyses implicated the inferior frontal gyrus, the pericallosal sulcus, and the caudate as critical predictors of ADHD diagnostic category and its associated symptomology, above and beyond teacher ratings of EF and ER. Collectively, the current set of findings have implications for theories of ADHD, the relative utility of neurobiological measures with respect to teacher ratings of EF and ER, and the developmental trajectory of its underlying neurobiology.","Non-invasively measured brain activity and radiological progression in diffuse glioma\nNon-invasively measured brain activity is related to progression-free survival in glioma patients, suggesting its potential as a marker of glioma progression. We therefore assessed the relationship between brain activity and increasing tumor volumes on routine clinical magnetic resonance imaging (MRI) in glioma patients. Postoperative magnetoencephalography (MEG) was recorded in 45 diffuse glioma patients. Brain activity was estimated using three measures (absolute broadband power, offset and slope) calculated at three spatial levels: global average, averaged across the peritumoral areas, and averaged across the homologues of these peritumoral areas in the contralateral hemisphere. Tumors were segmented on MRI. Changes in tumor volume between the two scans surrounding the MEG were calculated and correlated with brain activity. Brain activity was compared between patient groups classified into having increasing or stable tumor volume. Results show that brain activity was significantly increased in the tumor hemisphere in general, and in peritumoral regions specifically. However, none of the measures and spatial levels of brain activity correlated with changes in tumor volume, nor did they differ between patients with increasing versus stable tumor volumes. Longitudinal studies in more homogeneous subgroups of glioma patients are necessary to further explore the clinical potential of non-invasively measured brain activity.","Clinical Outcome of Neurological patients with COVID-19: the impact of Healthcare organization improvement between waves.\nObjectiveThe aim of this study is to evaluate the differences of clinical presentations and the impact of healthcare organization on outcomes of neurological COVID-19 patients admitted during the first and second pandemic waves.\n\nMethodsIn this single center cohort study, we included all patients with SARS-CoV-2 infection admitted to a Neuro-COVID Unit. Demographic, clinical and laboratory data were compared between patients admitted during the first and second waves of COVID-19 pandemic.\n\nResults223 patients were included, of whom 112 and 111 hospitalized during the first and second pandemic waves, respectively. Patients admitted during the second wave were younger and exhibited pulmonary COVID-19 severity, resulting in less oxygen support (n=41, 36.9% vs n=79, 70.5%, p<0.001) and lower mortality rates (14.4% vs 31.3%, p=0.004). The different healthcare strategies and early steroid treatment emerged as significant predictors of mortality independently from age, premorbid conditions and COVID-19 severity in cox regression analyses.\n\nConclusionsDifferences in healthcare strategies during the second phase of COVID-19 pandemic probably explain the differences in clinical outcomes independently of disease severity, underlying the importance of standardized early management of neurological patients with SARS-CoV-2 infection.","Validity of the Web-based, Self-directed, NeuroCognitive Performance Test in MCI\nDigital cognitive tests offer several potential advantages over established paper-pencil tests but have not yet been fully evaluated for the clinical evaluation of mild cognitive impairment. The NeuroCognitive Performance Test (NCPT) is a web-based, self-directed, modular battery intended for repeated assessments of multiple cognitive domains. Using a sample of 101 MCI subjects, we report in this study that the NCPT composite is significantly correlated with both a composite measure of established tests (r=0.77, p<0.0001) as well as with the ADAS-Cog (r=0.55, p<0.0001). Both test batteries had a similar factor structure that included a large \"g\" component with a high eigenvalue. Further, both the NCPT and established tests significantly (p< 0.01) predicted the UPSA and FAQ, measures of daily functioning. Despite limitations such as a relatively small sample, absence of control group and cross-sectional nature, these findings are consistent with the growing literature on the promise of self-directed, web-based cognitive assessments for MCI.","Automation of plate inoculation and reading reduces process time in the clinical microbiology laboratory, compared to a manual workflow\nWe evaluated the benefits of automation for clinical microbiology laboratory workflow and compared the time required for culture inoculation and plate reading between manual processes and BD Kiestra (but Kiestra) automation. Kiestra automation consists of different modules, each of which facilitate different tasks and work together from specimen inoculation to results reporting. We tracked the steps and measured the associated times-to-completion for both manual and automated workflows, including number of plate touches, hands-on-time (HOT), total technologist time (TTT), and walk-away time (WAT). Manual and automated processes both included 90 samples, and a total of 180 agar plates. There were three media quantity protocols used to mimic common laboratory samples: 1) 30 urine specimens on one biplate; 2) 30 urine specimens divided across two plates; and 3) 30 blood or wound specimens divided across three plates; all cultures incubated for a minimum of 18 hours prior to reading or imaging. Automation reduced HOT by 85% and overall plate touches by 88%. Automated inoculation (through implementation of the BD InoqulA module) resulted in a 100% reduction in plate touches and created 81.5-minutes of WAT. Automation of culture reading (through implementation of the BD ReadA incubation/plate imaging module and BD Synapsys Informatics) reduced HOT by 53%. Overall, laboratory automation resulted in shorter TTT and created WAT when compared to manual processes. Automation can facilitate increased processing capacity, more efficient use of the labor force, and reduced time to results in the clinical microbiology laboratory.","Herpesvirus Reactivations in Critically-Ill COVID-19 Patients with Autoantibodies Neutralizing Type I Interferons\nAutoantibodies neutralizing the antiviral action of type I interferons (IFNs) have been associated with pre-disposition to severe COVID-19. Here, we screened for such autoantibodies in 103 critically-ill COVID-19 patients in a tertiary intensive care unit in Switzerland. Eleven patients (10.7%), but no healthy donors, had neutralizing anti-IFN or anti-IFN/anti-IFN{omega} IgG in plasma/serum, but anti-IFN IgM or IgA was rare. One patient had non-neutralizing anti-IFN IgG. Strikingly, all patients with plasma anti-IFN IgG also had anti-IFN IgG in tracheobronchial secretions, identifying these autoantibodies at anatomical sites relevant for SARS-CoV-2 infection. Longitudinal analyses revealed patient heterogeneity in terms of increasing, decreasing, or stable anti-IFN IgG levels throughout the length of hospitalization. Notably, presence of anti-IFN autoantibodies in this critically-ill COVID-19 cohort appeared to predict herpesvirus (herpes simplex viruses types 1 and 2, HSV-1/-2; and/or cytomegalovirus, CMV) reactivations, which are linked to worse clinical outcomes. Indeed, all seven tested COVID-19 patients with anti-IFN IgG in our cohort (100%) suffered from one or more herpesvirus reactivations, and analysis revealed that these patients were substantially more likely to experience CMV reactivation than COVID-19 patients without anti-IFN autoantibodies, even when adjusting for systemic steroid treatment (odds ratio 7.28, 95%-CI 1.14-46.31, p=0.036). As the IFN system deficiency caused by neutralizing anti-IFN autoantibodies likely directly and indirectly exacerbates herpesvirus reactivations in critically-ill patients, early diagnosis of anti-IFN IgG could be rapidly used to inform risk-group stratification and treatment options.","Transdiagnostic connectome-based prediction of craving\nCraving is a central construct in the study of motivation and human behavior and is also a clinical symptom of substance and non-substance-related addictive disorders. Thus, craving represents a target for transdiagnostic modeling. We applied connectome-based predictive modeling (CPM) to functional connectivity data in a large (N=274) transdiagnostic sample of individuals with and without substance-use-related conditions, to predict self-reported craving. CPM is a machine-learning approach used to identify neural signatures in functional connectivity data related to a specific phenotype. Functional connectomes were derived from three guided imagery conditions of personalized appetitive, stress, and neutral-relaxing experiences. Craving was rated before and after each imagery condition. CPM successfully predicted craving, thereby identifying a transdiagnostic craving network comprised primarily of the posterior cingulate cortex, hippocampus, visual cortex, and primary sensory areas. Findings suggest that craving may be associated with difficulties directing attention away from internal self-related processing, represented in the default mode network.","A multiplexed Cas13-based assay with point-of-care attributes for simultaneous COVID-19 diagnosis and variant surveillance\nPoint-of-care (POC) nucleic acid detection technologies are poised to aid gold-standard technologies in controlling the COVID-19 pandemic, yet shortcomings in the capability to perform critically needed complex detection--such as multiplexed detection for viral variant surveillance--may limit their widespread adoption. Herein, we developed a robust multiplexed CRISPR-based detection using LwaCas13a and PsmCas13b to simultaneously diagnose SARS-CoV-2 infection and pinpoint the causative SARS-CoV-2 variant of concern (VOC)-- including globally dominant VOCs Delta (B.1.617.2) and Omicron (B.1.1.529)--all while maintaining high levels of accuracy upon the detection of multiple SARS-CoV-2 gene targets. The platform has several attributes suitable for POC use: premixed, freeze-dried reagents for easy use and storage; convenient direct-to-eye or smartphone-based readouts; and a one-pot variant of the multiplexed detection. To reduce reliance on proprietary reagents and enable sustainable use of such a technology in low- and middle-income countries, we locally produced and formulated our own recombinase polymerase amplification reaction and demonstrated its equivalent efficiency to commercial counterparts. Our tool--CRISPR-based detection for simultaneous COVID-19 diagnosis and variant surveillance which can be locally manufactured--may enable sustainable use of CRISPR diagnostics technologies for COVID- 19 and other diseases in POC settings.","An overview of the National COVID-19 Chest Imaging Database: data quality and cohort analysis\nThe National COVID-19 Chest Imaging Database (NCCID) is a centralised database containing chest X-rays, chest Computed Tomography (CT) scans and cardiac Magnetic Resonance Images (MRI) from patients across the UK, jointly established by NHSX, the British Society of Thoracic Imaging (BSTI), Royal Surrey NHS Foundation Trust (RSNFT) and Faculty. The objective of the initiative is to support a better understanding of the coronavirus SARS-CoV-2 disease (COVID-19) and development of machine learning (ML) technologies that will improve care for patients hospitalised with a severe COVID-19 infection. The NCCID is now accumulating data from 20 NHS Trusts and Health Boards across England and Wales, with a total contribution of approximately 25,000 imaging studies in the training set (at time of writing) and is actively being used as a research tool by several organisations. This paper introduces the training dataset, including a snapshot analysis performed by NHSX covering: the completeness of clinical data, the availability of image data for the various use-cases (diagnosis, prognosis and longitudinal risk) and potential model confounders within the imaging data. The aim is to inform both existing and potential data users of the NCCIDs suitability for developing diagnostic/prognostic models. In addition, a cohort analysis was performed to measure the representativeness of the NCCID to the wider COVID-19 affected population. Three major aspects were included: geographic, demographic and temporal coverage, revealing good alignment in some categories, e.g., sex and identifying areas for improvements to data collection methods, particularly with respect to geographic coverage. All analyses and discussions are focused on the implications for building ML tools that will generalise well to the clinical use cases.","Automation improves repeatability of retinal oximetry measurements\nPurposeRetinal oximetry is a technique based on spectrophotometry where images are analyzed with software capable of calculating vessel oxygen saturation and vessel diameter. In this study, the effect of automation of measurements of retinal vessel oxygen saturation and vessel diameter is explored.\n\nMethodsUntil now, operators have had to choose each vessel segment to be measured explicitly. A new, automatic version of the software automatically selects the vessels once the operator defines a measurement area.\n\nFive operators analyzed image pairs from the right eye of 23 healthy subjects with semiautomated retinal oximetry analysis software, Oxymap Analyzer (v2.5.1), and an automated version (v3.0). Inter- and intra-operator variability was investigated using the intraclass correlation coefficient (ICC) between oxygen saturation measurements of vessel segments in the same area of the retina.\n\nResultsFor manual saturation measurements, the inter-rater ICC was 0.80 for arterioles and venules. For automated saturation measurements, the inter-rater ICC was 0.97 for arterioles and 0.96 for venules. For manual diameter measurements, the inter-rater ICC was 0.71 for arterioles and venules. For automated diameter measurements the inter-rater ICC was 0.97 for arterioles and 0.95 for venules. The inter-rater ICCs were different (p < 0.01) between the semiautomated and automated version in all instances.\n\nConclusionAutomated measurements of retinal oximetry values are more repeatable compared to measurements where vessels are selected manually.","Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder\nABBSTRACTDYRK1A-related intellectual disability (ID) is among the most frequent monogenic form of ID. We refined the description of this disorder by reporting clinical and molecular data of forty individuals with ID harboring DYRK1A variants. We developed a combination of tools to interpret missense variants, which remains a major challenge in human genetics: i) a specific DYRK1A clinical score, ii) amino acid conservation data generated from one hundred of DYRK1A sequences across different taxa, iii) in vitro overexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins, and iv) a specific blood DNA methylation signature. This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, yet reported as pathogenic, and showed it does not cause obvious phenotype in mice, emphasizing the need to take care when interpreting variants, even those occurring de novo.","A novel syndrome caused by the constitutional gain-of-function variant p.Glu1099Lys in NSD2\nPurposeNSD2 dimethylates histone H3 at lysine 36 (H3K36me2) and is located in the Wolf-Hirschhorn syndrome (WHS) region. Recent descriptions delineated loss-of-function (LoF) variants in NSD2 with a distinct disorder. The oncogenic missense variant p.Glu1099Lys occures somatically in leukemia and has a gain-of-function (GoF) effect.\n\nMethodsWe describe two unrelated individuals carrying c.3295G>A, p.Glu1099Lys as heterozygous de novo germline variants identified by exome sequencing of blood DNA and subsequently confirmed in two ectodermal tissues. We use omics data from the Cancer Cell Line Encyclopedia to analyze the GoF effect.\n\nResultsClinically these individuals are characterized by intellectual disability, coarse/ square facial gestalt, abnormalities of the hands and organomegaly. We confirmed increased K36me2 methylation in lines with either NSD2 GoF variants or duplications. Cells with GoF variants showed increased DNA promoter methylation and dysregulated RNA expression, influencing cellular modules involved in white blood cell activation, cell growth and organ development.\n\nConclusionNSD2 GoF caused by the missense variant p.Glu1099Lys leads to a novel syndromic phenotype distinct from both the previously described LoF phenotypes. Other variants causing NSD2 hyperactivation or overexpression may cause a similar phenotype. This syndrome should be distinguished from the recently named Rauch-Steindl syndrome caused by NSD2 haploinsufficiency.","Patient and physician shared decision making behaviors in oncology: Evidence on adequate measurement properties of the iSHARE questionnaires\nObjectivesWe have developed two questionnaires to assess the shared decision making (SDM) process in oncology; the iSHAREpatient and iSHAREphysician. In this study, we aimed to determine: scores, construct validity, test-retest agreement (iSHAREpatient), and inter-rater (iSHAREpatient-iSHAREphysician) agreement.\n\nMethodsPhysicians from seven Dutch hospitals recruited cancer patients, and completed the iSHAREphysician and SDM-Questionnaire-physician version. Their patients completed the: iSHAREpatient, 9-item SDM-Questionnaire, Decisional Conflict Scale, Combined Outcome Measure for Risk communication And treatment Decision making Effectiveness, and Perceived Efficacy in Patient-Physician Interactions. We formulated, respectively, one (iSHAREphysician) and 10 (iSHAREpatient) a priori hypotheses regarding correlations between the iSHARE questionnaires and questionnaires assessing related constructs. To assess test-retest agreement patients completed the iSHAREpatient again 1-2 weeks later.\n\nResultsIn total, 151 treatment decision making processes with unique patients were rated. Dimension and total iSHARE scores were high both in patients and physicians. The hypothesis on the iSHAREphysician and 9/10 hypotheses on the iSHAREpatient were confirmed. Test-retest and inter-rater agreement were >.60 for most items.\n\nConclusionsThe iSHARE questionnaires show high scores, have good construct validity, substantial test-retest agreement, and moderate inter-rater agreement.\n\nPractice implicationsResults from the iSHARE questionnaires can inform both physician- and patient-directed efforts to improve SDM in clinical practice.","Daily tenofovir disoproxil fumarate/emtricitabine and hydroxychloroquine for pre-exposure prophylaxis of COVID-19: a double-blind placebo controlled randomized trial in healthcare workers\nObjectiveTo assess the effect of hydroxychloroquine (HCQ), Tenofovir disoproxil fumarate/Emtricitabine (TDF/FTC), and their combination as pre-exposure prophylaxis on the risk of symptomatic COVID-19.\n\nMethodsEPICOS is a double-blind, placebo-controlled randomized trial conducted in 51 hospitals in Spain, Bolivia, and Venezuela. Healthcare workers with negative SARS-CoV-2 IgM/IgG test were randomly assigned to: daily TDF/FTC plus HCQ for 12 weeks, TDF/FTC plus HCQ placebo, HCQ plus TDF/FTC placebo and TDF/FTC placebo plus HCQ placebo. The primary outcome was laboratory-confirmed, symptomatic COVID-19. We also studied any (symptomatic or asymptomatic) COVID-19 infection. We compared group-specific 14-week risks via differences and ratios with 95% confidence intervals (CI).\n\nResultsOf 1002 individuals screened, 926 (92.4%) were eligible; 64.2% recruited in Spain, 22.3% in Bolivia, and 13.6% in Venezuela. Median age was 38 years (range 18 - 68), 62.5% were female, 62.3% worked at inpatient care, and comorbidities were rare. Compared with the placebo group, 14-week risk ratios (95% CI) of symptomatic COVID-19 were 0.39 (0.00, 1.98) for TDF+HCQ, 0.34 (0.00, 2.06) for TDF, and 0.49 (0.00, 2.29) for HCQ. Corresponding risk ratios of any COVID-19 were 0.51 (0.21, 1.00) for TDF+HCQ, 0.81 (0.44, 1.49) for TDF, and 0.73 (0.41, 1.38) for HCQ. Adverse events were generally mild.\n\nConclusionA beneficial effect of TDF/FTC and HCQ, alone or in combination, as pre-exposure prophylaxis for COVID-19 cannot be ruled out but effect estimates are imprecise because the target sample size was not met. These findings support launching randomized trials of TDF/FTC for the early treatment of COVID-19.","Persistence of functional memory B cells recognizing SARS-CoV-2 variants despite loss of specific IgG\nWhile some COVID-19 patients maintain SARS-CoV-2-specific serum IgGs for more than 6 months post-infection, others, especially mild cases, eventually lose IgG levels. We aimed to assess the persistence of SARS-CoV-2-specific B cells in patients who have lost specific IgGs and analyzed the reactivity of the immunoglobulins produced by these B cells. Circulating IgG memory B cells specific for SARS-CoV-2 were detected in all 16 patients 1-8 months post-infection, and 11 participants had specific IgA B cells. Four patients lost specific serum IgG after 5-8 months but had SARS-CoV-2-specific-B-cell levels comparable to those of seropositive donors. Immunoglobulins produced after in vitro differentiation blocked receptor-binding domain (RBD) binding to the cellular receptor ACE-2, indicating neutralizing activity. Memory-B-cell-derived IgGs recognized the RBD of B.1.1.7 similarly to the wild-type, while reactivity to B.1.351 and P.1. decreased by 30% and 50%, respectively. Memory-B-cell differentiation into antibody-producing cells is a more sensitive method for detecting previous infection than measuring serum antibodies. Circulating SARS-CoV-2 IgG memory B cells persist, even in the absence of specific serum IgG; produce neutralizing antibodies; and show differential cross-reactivity to emerging variants of concern. These features of SARS-CoV-2-specific memory B cells will help to understand and promote long-term protection.","Weakly supervised and transfer learning for adenocarcinoma classification in transurethral resection of the prostate whole slide images\nThe transurethral resection of the prostate (TUR-P) is generally considered an option for benign prostatic diseases especially nodular hyperplasia patients who have moderate to severe urinary problems that have not responded to medication. Importantly, incidental prostate cancer are diagnosed at the time of TUR-P for benign prostatic disease. Since diagnosing a large number of cases containing TUR-P specimens which are characterized by a very large volume of tissue fragments by pathologists using a conventional microscope is time-consuming and limited in terms of human resources. Thus, it is necessary to develop new techniques which can rapidly and accurately screen large numbers of TUR-P specimens. Computational pathology applications which can assist pathologists in detecting prostate adenocarcinoma from TUR-P whole slide images (WSIs) would be of great benefit for routine histopathological workflow. In this study, we trained deep learning models to classify TUR-P WSIs into prostate adenocarcinoma and benign (non-neoplastic) lesions using transfer and weakly supervised learning. We evaluated the models on TUR-P, needle biopsy, and The Cancer Genome Atlas (TCGA) public dataset test sets, achieving an ROC-AUC up to 0.984 in TUR-P test sets for adenocarcinoma. The results demonstrate the high promising potential of deployment in a practical TUR-P histopathological diagnostic workflow system.","Sensitivity of rapid antigen testing and RT-PCR performed on nasopharyngeal swabs versus saliva samples in COVID-19 hospitalized patients: results of a prospective comparative trial (RESTART).\nObjectivesSaliva sampling could serve as an alternative non-invasive sample for SARS-CoV-2 diagnosis while rapid antigen testing (RAT) might help to mitigate the shortage of reagents sporadically encountered with RT-PCR. Thus, in the RESTART study we compared antigen and RT-PCR testing methods on nasopharyngeal (NP) swabs and salivary samples.\n\nMethodsWe conducted a prospective observational study among COVID-19 hospitalized patients between 10th December 2020 and 1st February 2021. Paired saliva and NP samples were investigated by RT-PCR (Cobas 6800, Roche-Switzerland) and by two rapid antigen tests: One Step Immunoassay Exdia(R) COVID-19 Ag (Precision Biosensor, Korea) and Standard Q(R) COVID-19 Rapid Antigen Test (Roche-Switzerland).\n\nResultsA total of 58 paired NP-saliva specimens were collected. Thirty-two of 58 (55%) patients were hospitalized in the intensive care unit and the median duration of symptoms was 11 days (IQR 5-19). NP and salivary RT-PCR exhibited sensitivity of 98% and 69% respectively whereas the specificity of these RT-PCRs assays were of 100%. NP RAT exhibited much lower diagnostic performances with sensitivities of 35% and 41% for the Standard Q(R) and Exdia(R) assays respectively, when a wet-swab approach was used (i.e. when the swab was diluted in the viral transport medium (VTM) before testing). The sensitivity of the dry-swab approach was slightly better (47%). These antigen tests exhibited very low sensitivity (4 and 8%) when applied to salivary swabs.\n\nConclusionsNasopharyngeal RT-PCR is the most accurate test for COVID-19 diagnosis in hospitalized patients. RT-PCR on salivary samples may be used when nasopharyngeal swabs are contraindicated. RAT are not appropriate for hospitalized patients.","Interaction studies of risk proteins in human induced neurons reveal convergent biology and novel mechanisms underlying autism spectrum disorders\nSequencing studies of autism spectrum disorders (ASDs) have identified numerous risk genes with enriched expression in the human brain, but it is still unclear how these genes converge into cell type-specific networks and how their encoded proteins mechanistically contribute to ASDs. To address this question, we performed brain cell type-specific interaction proteomics to build a protein-protein interaction network for 13 ASD risk genes in human excitatory neurons derived from iPS cells. The network contains many (>90%) reproducible interactions not reported in the literature and is enriched for transcriptionally perturbed genes observed in layer 2/3 cortical neurons of ASD patients, indicating that it can be explored for ASD-relevant biological discovery. We leveraged the network dataset to show that the brain-specific isoform of ANK2 is important for its interactions with synaptic proteins and characterized a PTEN-AKAP8L interaction that influences neuronal growth through the mTOR pathway. The IGF2BP1-3 complex emerges as a point of convergence in the network, and we showed that this complex is involved in a transcriptional circuit concentrating both common and rare variant risk of ASDs. Finally, we found the network itself enriched for ASD rare variant risk, indicating that it can complement genetic datasets for prioritizing additional risk genes. Our findings establish brain cell type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in ASDs and illustrate how both individual and convergent interactions lead to biological insights into the disease.","Recovery Time and Its Predictors among Women Admitted with Obstetric Fistula in Jimma University Medical Center Southwest, Ethiopia: A Retrospective Cohort Study\nBackgroundObstetric fistula is one of the most shocking medical disabilities that women face as a result of problems caused by a lack of surgical intervention.\n\nMethodsFrom January 2011 to February 2017, a retrospective analysis was undertaken on obstetric fistula participants who received undergone surgical repair at the Jimma University Medical Center.\n\nResults81.4% of fistula patients were reported to have recovered. The results of lognormal inverse-Gaussian frailty model revealed that weight [≥]50kg ([FE]= 0.86, 95% CI: 0.747, 0.99), divorced ([FE]=1.2, 95% CI: 1.028, 1.413), urban residence ([FE]= 1.56, 95% CI: 01.046, 2.317), urine incontinence >3 months ([FE]=1.2, 95% CI: 1.056, 1.371), no antenatal care ([FE]=1.189, 95% CI:1.023, 1.382), duration of labor <2days ([FE]= 0.86, 95% CI: 0.758, 0.986), health center delivery ([FE]= 0.76, 95% CI: 0.576, 0.989), vaginal delivery ([FE]= 1.5, 95% CI: 1.125, 1.996), and partially damaged urethra ([FE]=1.59, 95% CI: 1.168, 2.166) and recto-vaginal fistula([FE]= 0.735, 95%CI: 0.6045, 0.894) were associated with the recovery time.\n\nConclusionPatients with a weight < 50 kg, delivery at a health center, labor lasting <2 days, urinary incontinence lasting <3 months, antenatal care follow-up, cesarean section delivery, urethra status not damaged, and recto-vaginal fistula had a faster recovery period.","Regional medical inter-institutional cooperation in medical provider network constructed using patient claims data from Japan\nThe aging world population requires a sustainable and high-quality healthcare system. To examine the efficiency of medical cooperation, medical provider and physician networks were constructed using patient claims data. Previous studies have shown that these networks contain information on medical cooperation. However, the usage patterns of multiple medical providers in a series of medical services have not been considered. In addition, these studies used only general network features to represent medical cooperation, but their expressive ability was low. To overcome these limitations, we analyzed the medical provider network to examine its overall contribution to the quality of healthcare provided by cooperation between medical providers in a series of medical services. This study focused on: i) the method of feature extraction from the network, ii) incorporation of the usage pattern of medical providers, and iii) expressive ability of the statistical model. Femoral neck fractures were selected as the target disease. To build the medical provider networks, we analyzed the patient claims data from a single prefecture in Japan between January 1, 2014 and December 31, 2019. We considered four types of models: a model using node strength and linear regression to a model using feature representation by node2vec and regression tree ensemble, which is a machine learning method. The results showed that a stronger medical provider reduces the duration of hospital stay. The overall contribution of the medical cooperation to the duration of hospital stay extracted from the medical provider network using node2vec is approximately 20%, which is approximately 20 times higher than the model using strength.","Common Data Elements, Scalable Data Management Infrastructure and Analytics Workflows for Large-scale Neuroimaging Studies\n1.Neuroscience studies require considerable bioinformatic support and expertise. Numerous high-dimensional and multimodal datasets must be preprocessed and integrated to create robust and reproducible analysis pipelines. We describe a common data elements and scalable data management infrastructure that allows multiple analytics workflows to facilitate preprocessing, analysis and sharing of large-scale multi-level data. The process uses the Brain Imaging Data Structure (BIDS) format and supports MRI, fMRI, EEG, clinical and laboratory data. The infrastructure provides support for other datasets such as Fitbit and flexibility for developers to customize the integration of new types of data. Exemplar results from 200+ participants and 11 different pipelines demonstrate the utility of the infrastructure.","Point-of-Care Ultrasound (POCUS) Predicts Clinical Outcomes in Patients with COVID-19.\nIntroductionPoint-of-care ultrasound (POCUS) may detect the cardiopulmonary manifestations of COVID-19 and expediently predict patient outcomes.\n\nMethodsWe conducted a prospective cohort study at four medical centers from 3/2020-1/2021 to evaluate POCUS findings and clinical outcomes with COVID-19. Our inclusion criteria included adult patients hospitalized for COVID-19 who received cardiac or lung POCUS with a 12-zone protocol. Images were interpreted by two reviewers blinded to clinical outcomes. Our primary outcome was ICU admission incidence. Secondary outcomes included intubation and supplemental oxygen usage.\n\nResultsN=160 patients (N=201 scans) were included. Scans were collected a median 23 hours (IQR:7-80) from emergency department triage. Triage POCUS findings associated with ICU admission included B-lines (OR 4.41 [95% CI:1.71-14.30]; p<0.01) or consolidation (OR 2.49 [95% CI:1.35-4.86]; p<0.01). B-lines were associated with intubation (OR 3.10 [95% CI:1.15-10.27]; p=0.02) and supplemental oxygen usage (OR 3.74 [95% CI:1.63-8.63; p<0.01).\n\nConsolidations present on triage were associated with the need for oxygen at discharge (OR 2.16 [95% CI: 1.01-4.70]; p=0.047). A normal lung triage scan was protective for ICU admission (OR 0.28 [95% CI:0.09-0.75; p<0.01) or need for supplemental oxygen during the hospitalization (OR 0.26 [95% CI:0.11-0.61]; p<0.01). Triage cardiac POCUS scans were not associated with any outcomes.\n\nDiscussionLung POCUS findings detected early in the hospitalization may provide expedient risk stratification for important COVID-19 clinical outcomes, including ICU admission, intubation, or need for oxygen on discharge. A normal admission scan appears protective against adverse outcomes, which may aid in triage decisions of patients.","Using brain cell-type-specific protein interactomes to interpret genetic data in schizophrenia\nGenetics have nominated many schizophrenia risk genes that lack functional interpretation. To empower such interpretation, we executed interaction proteomics for six risk genes in human induced neurons and found the resulting protein network to be enriched for common variant risk of schizophrenia in Europeans and East Asians. The network is down-regulated in layer 5/6 cortical neurons of patients and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and also contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in patients with schizophrenia and bipolar disease. Our findings establish brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and psychiatric diseases.\n\nOne Sentence SummaryNeuronal protein interactomes is an organizing framework for integrating genetic and transcriptomic data in schizophrenia."],"string":"[\n \"Multi-trait genome-wide association study identifies new loci associated with sleep apnoea risk\\nBackgroundSleep apnoea is a disorder characterised by periods of halted breathing during sleep. Despite its association with severe health conditions such as cardiovascular disease, liver problems and metabolic syndrome, the aetiology of sleep apnoea remain understudied, and previous genetic analyses have not identified many robustly associated genetic risk variants.\\n\\nMethodsWe performed a genome-wide association study (GWAS) meta-analysis of sleep apnoea across five cohorts (NTotal=523,366) and multi-trait analysis of GWAS (MTAG) to boost statistical power, leveraging the high genetic correlation between sleep apnoea and snoring. GWAS and MTAG results were adjusted to control for the effects of body mass index (BMI) using the multi-trait-based conditional & joint analysis (mtCOJO) method. Lead hit replication was conducted in an independent sample GWAS from 23andMe, Inc. that included BMI as a covariate (NTotal=1,477,352; Ncases=175,522). Lastly, we explored genetic correlations with other complex traits and performed a phenome-wide screen for causally associated phenotypes using the latent causal variable method.\\n\\nResultsOur MTAG with snoring uncovered a total of 49 independent significant sleep apnoea loci; adjusting for BMI showed that approximately half of those loci act via their effects on BMI/obesity. Twenty-nine variants replicated in the 23andMe cohort. Several complex traits, including multisite chronic pain, diabetes, eye disorders, high blood pressure, osteoarthritis, chronic obstructive pulmonary disease, and BMI-related traits were genetically correlated with sleep apnoea.\\n\\nConclusionsOur study identifies multiple robust genetic markers for sleep apnoea, increasing our understanding of the aetiology of this condition and its relationship with other complex traits.\",\n \"LRRK2 coding variants and the risk of Parkinson's disease\\nBackgroundThe leucine-rich repeat kinase 2 (LRRK2) gene harbors both rare highly damaging missense variants (e.g. p.G2019S) and common non-coding variants (e.g. rs76904798) with lower effect sizes that are associated with Parkinsons disease risk.\\n\\nObjectivesThis study aimed to investigate in a large meta-analysis whether the LRRK2 GWAS signal represented by rs76904798 is independently associated with Parkinsons disease risk from LRRK2 coding variation, and whether complex linkage disequilibrium structures with p.G2019S and the 5 non-coding haplotype account for the association of LRRK2 coding variants.\\n\\nMethodsWe performed a meta-analysis using imputed genotypes from 17,838 cases, 13,404 proxy-cases and 173,639 healthy controls of European ancestry. We excluded carriers of p.G2019S and/or rs76904798 to clarify the role of LRRK2 coding variation in mediating disease risk, and excluded carriers of relatively rare LRRK2 coding variants to assess the independence of rs76904798. We also investigated the co-inheritance of LRRK2 coding variants with p.G2019S, rs76904798 and p.N2081D.\\n\\nResultsLRRK2 rs76904798 remained significantly associated with Parkinsons disease after excluding carriers of relatively rare LRRK2 coding variants. LRRK2 p.R1514Q and p.N2081D were frequently co-inherited with rs76904798 and the allele distribution of p.S1647T significantly changed among cases after removing rs76904798 carriers.\\n\\nConclusionsThese data suggest that the LRRK2 coding variants previously linked to Parkinsons disease (p.N551K, p.R1398H, p.M1646T and p.N2081D) do not drive the 5 non-coding GWAS signal. These data, however, do not preclude the independent association of the haplotype p.N551K-p.R1398H and p.M1646T with altered disease risk.\",\n \"Clinicopathological and Imaging Features of Primary Biliary Cholangitis\\nAbstract/KeywordsO_ST_ABSBackground and AimsC_ST_ABSPrimary biliary cholangitis (PBC) is a chronic inflammatory autoimmune disease of the biliary epithelial cells, causing slow progression of cholestasis and fibrosis. The aim of the study is to summarize the imaging features of PBC and examine the correlation between its clinicopathological and radiologic features, elucidating the specific clinicopathological and radiologic differences between male and female PBC patients, as well as between AMA-positive and AMA-negative PBC patients.\\n\\nMethodsDemographic, laboratory, radiologic and survival data were collected retrospectively for patients diagnosed and treated for PBC at the Mount Sinai Health System between 2016 and 2020 with at least one ultrasound, CT, or MRI of abdomen available for assessment. Biochemical and radiologic data were compared between male v.s. female groups, and AMA-positive v.s. AMA-negative group.\\n\\nResultsA total of 273 patients diagnosed with PBC were included. Non-specific hepatic parenchymal disease, cirrhosis, cholelithiasis, splenomegaly, lymphadenopathy, benign liver masses/cysts were the most common features on abdominal images. 24% of PBC patients had biliary tree abnormalities on MRI. LAD was reported in 38-47% of PBC patients. There was no significant difference in age, race, or ethnicity between the sexes of patients with PBC, however imaging characteristics of portal hypertension were more frequently seen in men. AMA-negative PBC patients had similar distributions of age, race/ethnicity and survival to AMA-positive PBC patients.\\n\\nConclusionOur study summarized the clinicopathological and imaging features of PBC and distinct subgroups. This would assist in the diagnosis of PBC and avoid over-testing in real-world practice.\",\n \"Disease-modifying therapies for T1 hypointense lesions (Black Holes) volume in patients with multiple sclerosis: Protocol for a systematic review and meta-analysis\\nRationaleA major part of diagnosis and follow-up in patients with multiple sclerosis is based on MRI evaluations. As T1-hypointense lesions represent neural destruction or axonal loss and anticipate irreversible disability in the patients, evaluation of the effects of Disease-modifying therapies (DMTs) on the volume of black holes seems necessary.\\n\\nObjectivesTo evaluate the effects of FDA approved disease-modifying therapies (DMTs) on T1 hypointense lesions (Black Holes) volume in patients with multiple sclerosis (MS)\\n\\nData sourcesWe will search MEDLINE (through Ovid), Embase, and CENTRAL. We wont consider any timeframe, language, or geographical restrictions.\\n\\nMethodsWe will include only randomized controlled trials (RCTs) that have evaluated the effects of DMTs on black holes mean volume in adult patients diagnosed with any phenotype of multiple sclerosis (MS) in comparison to the placebo, routine care, or no treatment regimen. We will assess the risk of bias in the primary studies using the Revised Cochrane risk-of-bias tool for randomized trials (RoB2). Data will be synthesized based on the random-effects model and results will be plotted on a forest plot. Heterogeneity will be assessed using I2 statistics. If feasible, we will also perform subgroup analyses for each DMT.\\n\\nFundingThis study is not funded.\\n\\nRegistrationPROSPERO submission ID: 262883.\",\n \"The Immunogenetic Basis of Idiopathic Bone Marrow Failure Syndromes: A Paradox of Similarity and Self-Presentation\\nIdiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure disorder initiated by a human leukocyte antigen (HLA)-restricted T-cell response to unknown antigens. Immunogenetic patterns associated with self-antigenic presentation remain unclear. Herein we analyzed the molecular landscape of HLA complexes and T-cell receptor (TCR) repertoires of a large cohort of IAA patients and controls. We show that antigen binding sites of class II HLA molecules in IAA are characterized by a high level of structural homology, only partially explained by specific risk allele profiles, implying reduced binding capabilities compared to controls. Few amino acids within the synapsis HLA-DRB1-antigen-TCR, are identified as strongly associated with IAA phenotype. Those structural patterns may affect TCR repertoires, promoting immunological cross-reactivity and autoimmunity. These findings inform on the immunogenetic risk associated with IAA and on general pathophysiological mechanisms potentially involved in autoimmunity.\\n\\nKey pointsO_LIClass II human leukocyte antigen (HLA) loci in idiopathic bone marrow failure (BMF) syndromes are characterized by low functional divergence and decreased peptide binding capabilities, only partially explained by enrichment in risk alleles.\\nC_LIO_LIA superstructure at the interface with the peptide binding site of DRB1 locus, potentially involved in the presentation of self-antigenic specificities, can be identified in BMF patients.\\nC_LIO_LIThis immunogenetic pattern may contribute to decrease T-cell receptor repertoire diversity, expand autoreactive T-cell clones and increase autoimmune propensity in BMF.\\nC_LI\",\n \"Characteristics of Patients Referred to a Cardiovascular Disease Clinic for Post-Acute Sequelae of SARS-CoV-2 Infection\\nThere is limited literature on the cardiovascular manifestations of post-acute sequelae of SARS-CoV-2 infection (PASC). We aimed to describe the characteristics, diagnostic evaluations, and cardiac diagnoses in patients referred to a cardiovascular disease clinic designed for patients with PASC from May 2020 to September 2021. Of 126 patients, average age was 46 years (range 19-81 years), 43 (34%) were male. Patients presented on average five months after COVID-19 diagnosis. 30 (24%) patients were hospitalized for acute COVID-19. Severity of acute COVID-19 was mild in 37%, moderate in 41%, severe in 11%, and critical in 9%. Patients were also followed for PASC by pulmonology (53%), neurology (33%), otolaryngology (11%), and rheumatology (7%). Forty-three patients (34%) did not have significant comorbidities. The most common symptoms were dyspnea (52%), chest pain/pressure (48%), palpitations (44%), and fatigue (42%), commonly associated with exertion or exercise intolerance. The following cardiovascular diagnoses were identified: nonischemic cardiomyopathy (5%); new ischemia (3%); coronary vasospasm (2%); new atrial fibrillation (2%), new supraventricular tachycardia (2%); myocardial involvement (15%) by cardiac MRI, characterized by late gadolinium enhancement (LGE; 60%) or inflammation (48%). The remaining 97 patients (77%) exhibited common symptoms of fatigue, dyspnea on exertion, tachycardia, or chest pain, which we termed \\\"cardiovascular PASC syndrome.\\\" Three of these people met criteria for postural orthostatic tachycardia syndrome. Lower severity of acute COVID-19 was a significant predictor of cardiovascular PASC syndrome. In this cohort of patients referred to cardiology for PASC, 23% had a new diagnosis, but most displayed a pattern of symptoms associated with exercise intolerance.\",\n \"Easy-BILAG: a new tool for simplified recording of SLE disease activity using BILAG-2004 index.\\nObjectiveBILAG-2004 index is a comprehensive disease activity instrument for SLE but administrative burden and frequency of errors limits its use in routine practice. We aimed to develop a tool for more accurate, time-efficient scoring of BILAG-2004 index with full fidelity to the existing instrument.\\n\\nMethodsFrequency of BILAG-2004 items was collated from a BILAG-biologics registry (BILAG-BR) dataset. Easy-BILAG prototypes were drafted to address known issues affecting speed and accuracy. After expert-verification, accuracy and usability of the finalised Easy-BILAG was validated against standard format BILAG-2004 index in a workbook exercise of 10 case vignettes. 33 professionals with a range of expertise from 14 UK centres completed the validation exercise.\\n\\nResultsEasy-BILAG incorporates all items present in [≥]5% BILAG-BR records, plus full constitutional and renal domains into a rapid single-page assessment. An embedded glossary and colour-coding assists scoring each domain. A second page captures rarer manifestations when needed. In the validation exercise, Easy-BILAG yielded higher median scoring accuracy (96.7%) than standard BILAG-2004 documentation (87.8%, p=0.001), with better inter-rater agreement. Easy-BILAG was completed faster (59.5min) than the standard format (80.0min, p=0.04) for 10 cases. An advantage in accuracy was observed with Easy-BILAG use among general hospital rheumatologists (91.3 vs 75.0, p=0.02), leading to equivalent accuracy as tertiary centre rheumatologists. Clinicians rated Easy-BILAG as intuitive, convenient, and well adapted for routine practice.\\n\\nConclusionEasy-BILAG facilitates more rapid and accurate scoring of BILAG-2004 across all clinical settings which could improve patient care and biologics prescribing. Easy-BILAG should be adopted wherever BILAG-2004 assessment is required.\",\n \"Vitamin D receptor polymorphisms in overweight/obese chronic kidney disease patients undergoing hemodialysis\\nBackgroundMany studies were carried out to investigate the relationship between single nucleotide polymorphisms (SNPs) in vitamin D receptor (VDR) gene with obesity. However, little is known about the role of VDR gene polymorphism with obesity in hemodialysis (HD) patients. Therefore, we aimed to investigate VDR gene TaqI, ApaI and FokI SNPs in overweight/obese HD patients.\\n\\nMethodsSeventy one normal weight and 68 overweight/obese HD patients were included in study. PCR-RFLP method was used for genotyping. Demographic and laboratory data obtained from medical records of patients.\\n\\nResultsFor all three SNPs, no significant association was found between normal and overweight/obese patients (P>0.05). Lower HDL concentrations and higher levels of triglyceride (TG) and glucose were detected in the obese/overweight patients compared to normal weight (p<0.001 for HDL, and TG and p=0.023 for glucose). In obese/overweight patients, subjects with CC genotype of TaqI showed higher PTH level (717.1{+/-}616.4 pg/ml) than those TC genotype (342.7{+/-}360.8 pg/ml) and TT genotype (310.2{+/-}323.4 pg/ml) (p=0.028); higher TG level was found in patients with CC genotype of ApaI (627.3{+/-}653.0 mg/dl) compared to AA (223.3{+/-}156.6) and AC genotypes (193.1{+/-}85.4) (p<0.001). Obese/overweight patients carrying FokI TT genotype had higher glucose concentration compared to those carrying CC and CT genotypes (CC=183.4{+/-}128.4 mg/dl; TT=151.9{+/-}66.1 mg/dl; CT=107.6{+/-}41.9 mg/dl, p=0.008).\\n\\nConclusionsOur study suggest that VDR TaqI, ApaI and FokI polymorphisms are not associated with obesity in HD patients. However, they might be increase the risk of secondary hyperparathyroidism, dyslipidemia, and hyperglycemia, which are among the most common obesity related comorbidities of chronic kidney disease.\",\n \"Heterogeneity in statin responses explained by variation in the human gut microbiome\\nStatins remain one of the most prescribed medications worldwide. While effective in decreasing atherosclerotic cardiovascular disease risk, statin use is associated with several side effects for a subset of patients, including disrupted metabolic control and increased risk of type II diabetes. We investigated the potential role of the gut microbiome in modifying patient response to statin therapy. In a cohort of >1840 individuals, we find that the hydrolyzed substrate for 3-hydroxy-3-methylglutarate-CoA (HMG-CoA) reductase, HMG, may serve as a reliable marker for statin on-target effects. Through exploring gut microbiome associations between blood-derived measures of statin effectiveness and metabolic health parameters among statin users and non-users, we find that heterogeneity in statin response is associated with variation in the gut microbiome. A Bacteroides rich, -diversity depleted, microbiome composition corresponds to the strongest statin on-target response, but also greatest disruption to glucose homeostasis, indicating lower treatment doses and/or complementary therapies may be beneficial in those individuals. Our findings suggest a potential path towards personalizing statin treatment through gut microbiome monitoring.\",\n \"Minimal observed impact of HLA genotype on hospitalization and severity of SARS-CoV-2 infection\\nHLA is a critical component of the viral antigen presentation pathway. We investigated the relationship between severity of SARS-CoV-2 disease and HLA type in 3,235 individuals with confirmed SARS-CoV-2 infection. We found only the DPB1 locus to be associated with the binary outcome of whether an individual developed any COVID-19 symptoms. The number of peptides predicted to bind to an HLA allele had no significant relationship with disease severity both when stratifying individuals by ancestry or age and in a pooled analysis. Age, BMI, asthma status, and autoimmune disorder status were predictive of severity across multiple age and individual ancestry stratificiations. Overall, at the population level, we found HLA type is significantly less predictive of COVID-19 disease severity than certain demographic factors and clinical comorbidities.\",\n \"Clinical Validation of Saliency Maps for Understanding Deep Neural Networks in Ophthalmology\\nDeep neural networks (DNNs) have achieved physician-level accuracy on many imaging-based medical diagnostic tasks, for example classification of retinal images in ophthalmology. However, their decision mechanisms are often considered impenetrable leading to a lack of trust by clinicians and patients. To alle-viate this issue, a range of explanation methods have been proposed to expose the inner workings of DNNs leading to their decisions. For imaging-based tasks, this is often achieved via saliency maps. The quality of these maps are typically evaluated via perturbation analysis without experts involved. To facilitate the adoption and success of such automated systems, however, it is crucial to validate saliency maps against clinicians. In this study, we used three different network architectures and developed ensembles of DNNs to detect diabetic retinopathy and neovascular age-related macular degeneration from retinal fundus images and optical coherence tomography scans, respectively. We used a variety of explanation methods and obtained a comprehensive set of saliency maps for explaining the ensemble-based diagnostic decisions. Then, we systematically validated saliency maps against clinicians through two main analyses -- a direct comparison of saliency maps with the expert annotations of disease-specific pathologies and perturbation analyses using also expert annotations as saliency maps. We found the choice of DNN architecture and explanation method to significantly influence the quality of saliency maps. Guided Backprop showed consistently good performance across disease scenarios and DNN architectures, suggesting that it provides a suitable starting point for explaining the decisions of DNNs on retinal images.\",\n \"High throughput SARS-CoV-2 variant analysis using molecular barcodes coupled with Next Generation Sequencing\\nThe identification of SARS-CoV-2 variants across the globe and their implications on the outspread of the pandemic, infection potential and resistance to vaccination, requires modification of the current diagnostic methods to map out viral mutations rapidly and reliably. Here, we demonstrate that integrating DNA barcoding technology, sample pooling and Next Generation Sequencing (NGS) provide an applicable solution for large-population viral screening combined with specific variant analysis.\\n\\nOur solution allows high throughput testing by barcoding each sample, followed by pooling of test samples using a multi-step procedure. First, patient-specific barcodes are added to the primers used in a one-step RT-PCR reaction, amplifying three different viral genes and one human housekeeping gene (as internal control). Then, samples are pooled, purified and finally, the generated sequences are read using an Illumina NGS system to identify the positive samples with a sensitivity of 82.5% and a specificity of 97.3%. Using this solution, we were able to identify six known and one unknown SARS-CoV-2 variants in a screen of 960 samples out of which 258 (27%) were positive for the virus.\\n\\nThus, our diagnostic solution integrates the benefits of large population and epidemiological screening together with sensitive and specific identification of positive samples including variant analysis at a single nucleotide resolution.\",\n \"Systematic Review and Scientific Rating of Commercial Apps Available in India for Diabetes Prevention\\nBACKGROUNDScientific evidence for digital health applications (apps) which claim to help in the prevention and management of Type 2 diabetes (T2D) is limited.\\n\\nOBJECTIVESWe aimed to evaluate the quality of currently available health apps for prevention of T2D amongst Asian Indians.\\n\\nMETHODSUsing the keywords, diabetes prevention, healthy lifestyle and fitness, a total of 1486 apps available in India via Google Play were assessed for eligibility by two independent reviewers. After initial screening using specific inclusion and exclusion criteria, 50 apps underwent a pre-specified rating based on user reviews, number of downloads and app size. Sixteen apps that scored [≥] 9 were shortlisted for further review using the Mobile App Rating Scale (MARS). MARS contains 2 main categories: Category I (Application Quality) and Category II (Application Subjective Quality). The mean MARS scores were used to identify the top ranked apps.\\n\\nRESULTSThe mean score for Category I of MARS rating was highest for Google Fit: Health and Activity Tracking (4.55/5). This was followed by Healthifyme - Diet Plan, Health and Weight Loss (4.45/5). For Category II of MARS, Diabetes M, Google Fit: Health and Activity Tracking and Calorie Counter- My fitness pal, Healthifyme - Diet plan, Health and Weight Loss all scored equally well. On comparing the advantages and disadvantages of each of these applications, Google Fit: Health and Activity Tracking and Healthifyme - Diet plan, Health and Weight Loss again ranked the best.\\n\\nCONCLUSIONSOur review identifies two commercially available apps Google Fit: Health and Activity Tracking and Healthifyme - Diet plan, Health and Weight Loss as being user friendly and good quality. Although encouraging, further research is needed to evaluate the efficacy of these apps for prevention of diabetes.\",\n \"Combination therapy of infliximab and thiopurines, but not monotherapy with infliximab or vedolizumab, is associated with attenuated IgA and neutralisation responses to SARS-CoV-2 in inflammatory bowel disease.\\nThere is substantial interest regarding the perceived risk that immunomodulator and biologic therapy could have on COVID-19 disease severity among patients with inflammatory bowel disease (IBD) and clinicians. In this study, we show that infliximab/thiopurine combination therapy is associated with significantly lower IgA, a range of lower IgG responses as well as impaired neutralising antibody responses, compared to responses observed in healthy individuals. We also demonstrate that whilst IgG responses were significantly reduced in individuals with IBD treated with infliximab or vedolizumab monotherapy compared to healthy controls, there was no significant reduction in IgA and neutralising antibody responses. As neutralising antibody responses correlate with protection, this observation may provide the mechanistic explanation for the observation reported by the SECURE-IBD study that individuals on infliximab/thiopurine combination therapy were at greater risk of severe COVID-19 outcomes than patients on monotherapy.\",\n \"High proportion of genome-wide homology and increased basal pvcrt levels in Plasmodium vivax late recurrences: a chloroquine therapeutic efficacy study\\nChloroquine (CQ) is the first-line treatment for Plasmodium vivax malaria in most endemic countries. Monitoring P.vivax CQ resistance (CQR) is critical but remains challenged by the difficulty to distinguish real treatment failure from reinfection or liver relapse. Therapeutic efficacy of CQ against uncomplicated P.vivax malaria was evaluated in Gia Lai province, Vietnam. Sixty-seven patients were enrolled and followed-up for 42 days using microscopy and (RT)qPCR. Adequate clinical and parasitological response (ACPR) was 100% (66/66) on Day 28, but 75.4% (49/65) on Day 42. Eighteen recurrences (27.7%) were detected with a median time-to-recurrence of 42 days (IQR 35, 42) and blood CQ concentration <100ng/ml. Parasite genotyping by microsatellites, SNP-barcoding and whole-genome sequencing (WGS) identified a majority of homologous recurrences, with 80% (8/10) showing >98% identity-by-descent to paired Day 0 samples. Primary infections leading to recurrence occurred in younger individuals (median age for ACPR=25 years [IQR 20, 28]; recurrences=18 [16, 21]; p=0.002), had a longer parasite clearance time (PCT for ACPR=47.5h [IQR 36.2, 59.8]; recurrences=54.2h [48.4, 62.0]; p=0.035) and higher pvcrt gene expression (median relative expression ratio for ACPR=0.09 [IQR 0.05, 0.22]; recurrences=0.20 [0.15, 0.56]; p=0.002), but there was no difference in ex vivo CQ sensitivity. This study shows that CQ remained largely efficacious to treat P.vivax in Gia Lai, i.e. recurrences occurred late (>Day 28) and in the presence of low blood CQ concentrations. However, the combination of WGS and gene expression analysis (pvcrt) with clinical data (PCT) allowed to identify potential emergence of low-grade CQR that should be closely monitored.\",\n \"Association between SARS-Cov-2 infection during pregnancy and adverse pregnancy outcomes: a re-analysis of data from Wei et al. (2021).\\nBackgroundWei et al. have published a meta-analysis (MA) which aimed to \\\"evaluate the association between SARS-CoV-2 infection during pregnancy and adverse pregnancy outcomes\\\".\\n\\nUsing classical random-effects model, they found that SARS-CoV-2 infection was associated with preeclampsia, preterm birth and stillbirth.\\n\\nPerforming MA with low event rates or with few studies may be challenging as MA relies on several within and between study distributional assumptions.\\n\\nMethodsto assess the robustness of the results provided by Wei et al., we performed a sensitivity analysis using several frequentist and Bayesian meta-analysis methods. We also estimated fragility indexes.\\n\\nResultsFor eclampsia (patients with Covid-19 vs without), the confidence intervals of most frequentist models contain 1. All beta-binomial models (Bayesian) lead to credible intervals containing 1. The prediction interval, based on DL method ranges from 0.75 to 2.38. The fragility index is 2 for the DL method.\\n\\nFor preterm, the confidence (credible) intervals exclude 1. The prediction interval is broad, ranging from 0.84 to 20.61. The fragility index ranges from 27 to 10.\\n\\nFor stillbirth, the confidence intervals of most frequentist models contain 1. Six Bayesian MA models lead to credible intervals containing 1.The prediction interval ranges from 0.52 to 8.49. The fragility index is 3.\\n\\nInterpretationGiven the available data and the results of our broad sensitivity analysis, we can only suggest that SARS-CoV-2 infection during pregnancy is associated to preterm, and may be associated to preeclampsia. For stillbirth, more data are needed as none of the Bayesian analyses are conclusive.\",\n \"Obesity and accelerated epigenetic aging in a high-risk cohort of children\\nBackgroundNew insights into mechanisms linking obesity to poor health outcomes suggest a role for cellular aging pathways, casting obesity as a disease of accelerated biological aging. Although obesity has been linked to accelerated epigenetic aging in middle-aged adults, the impact during childhood remains unclear. We tested the association between body mass index (BMI) and accelerated epigenetic aging in a cohort of high-risk children. Participants were children (N=273, aged 8 to 14 years, 82% investigated for maltreatment) recruited to the Child Health Study, an ongoing prospective study of youth investigated for maltreatment and a comparison youth. BMI was measured as a continuous variable. Accelerated epigenetic aging of blood leukocytes was defined as the age-adjusted residuals of several established epigenetic aging clocks (Horvath, Hannum, GrimAge, PhenoAge) along with a newer algorithm, the DunedinPoAm, developed to quantify the pace-of-aging. Hypotheses were tested with generalized linear models.\\n\\nResultsHigher BMI was significantly correlated with older chronological age, maltreatment status, household income, blood cell counts, and three of the accelerated epigenetic aging measures: GrimAge (r=0.29, P<.0001), PhenoAge (r=0.25, P<.0001), and DunedinPoAm (r=0.37, P<.0001). In fully adjusted models, GrimAge (b=.06; P=.007) and DunedinPoAm (b=.0017; P<.0001) remained significantly associated with higher BMI. Maltreatment-status was not independently associated with accelerated epigenetic aging after accounting for other factors.\\n\\nConclusionIn a high-risk cohort of children, higher BMI predicted epigenetic aging as assessed by two epigenetic aging clocks. These results suggest the association between obesity and accelerated epigenetic aging begins in early life, with implications for future morbidity and mortality risk.\",\n \"ATLAS: An automated association test using probabilistically linked health records with application to genetic studies\\nObjectiveLarge amounts of health data are becoming available for biomedical research. Synthesizing information across databases with no gold standard mappings between records may provide a more complete picture of patient health and enable novel research studies. To do so, researchers may probabilistically link databases and conduct inference using the linked data. However, previous inference methods for linked data are constrained to specific linkage settings and exhibit low power. Here, we present ATLAS, an automated, flexible, and robust association testing algorithm for probabilistically linked data.\\n\\nMaterials and MethodsMissing variables are imputed at various thresholds using a weighted average method that propagates uncertainty from the linkage process. Next, an estimated effect size is obtained using a generalized linear model. ATLAS then conducts the threshold combination test by optimally combining p-values obtained from data imputed at varying thresholds using Fishers method and perturbation resampling.\\n\\nResultsIn simulations, ATLAS controls for type I error and exhibits high power compared to previous methods. In a real-world application study, incorporation of linked data-enabled analyses using ATLAS yielded two additional signifigant associations between rheumatoid arthritis genetic risk score and biomarkers.\\n\\nDiscussionThe ATLAS weighted average imputation weathers false matches and increases contribution of true matches to mitigate linkage error induced bias. ATLAS threshold combination test avoids arbitrarily choosing a threshold to rule a match, thus automating linked data-enabled analyses and preserving power.\\n\\nConclusionATLAS promises to enable novel and powerful research studies using linked data to capitalize on all available data sources.\",\n \"Estimating Cuff-less Continuous Blood Pressure from Fingertip Photoplethysmogram Signals with Deep Neural Network Model\\nObjectiveBlood pressure (BP) is an important physiological index reflecting cardiovascular function. Continuous blood pressure monitoring helps to reduce the prevalence and mortality of cardiovascular diseases. In this study, we aim to estimate systolic blood pressure (SBP) and diastolic blood pressure (DBP) values continuously based on fingertip photoplethysmogram (PPG) waveforms using deep neural network models.\\n\\nMethodsTwo models were proposed and both models consisted of three stages. The only difference between them was the method of extracting features from PPG signals in the first stage. Model 1 adopted Bidirectional Long Short-Term Memory (BiLSTM), while the other used convolutional neural network. Then, the residual connection was applied to multiple stacked LSTM layers in the second stage, following by the third stage with two fully connected layers.\\n\\nResultsOur proposed models outperformed other methods based on similar dataset or framework, while in our proposed models, the model 2 was superior to model 1. It satisfied the standard of Association for the Advancement of the Medical Instrumentation (AAMI) and obtained grade A for SBP and DBP estimation according to the British Hypertension Society (BHS) standard. The mean error (ME) and standard deviation (STD) for SBP and DBP estimations were 0.21 {+/-} 6.40 mmHg and 0.19 {+/-}4.71 mmHg, respectively.\\n\\nConclusionOur proposed models could extract important features of fingertip PPG waveforms automatically and realize cuff-less continuous BP monitoring, which can be helpful in the identification and early treatment of abnormal blood pressure, thus may reduce the occurrence of cardiovascular malignant events.\",\n \"Genetic Contributions to Early and Late Onset Ischemic Stroke\\nObjectiveTo determine the contribution of common genetic variants to risk of early onset ischemic stroke (IS).\\n\\nMethodsWe performed a meta-analysis of genome-wide association studies of early onset IS, ages 18-59, using individual level data or summary statistics in 16,927 cases and 576,353 non-stroke controls from 48 different studies across North America, Europe, and Asia. We further compared effect sizes at our most genome-wide significant loci between early and late onset IS and compared polygenic risk scores for venous thromboembolism between early versus later onset IS.\\n\\nResultsWe observed an association between early onset IS and ABO, a known stroke locus. The effect size of the peak ABO SNP, rs8176685, was significantly larger in early compared to late onset IS (OR 1.17 (95% C.I.: 1.11-1.22) vs 1.05 (0.99-1.12); p for interaction = 0.008). Analysis of genetically determined ABO blood groups revealed that early onset IS cases were more likely to have blood group A and less likely to have blood group O compared to both non-stroke controls and to late onset IS cases. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with early, compared to late, onset IS (p=0.008).\\n\\nConclusionThe ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with early onset IS, compared with late onset IS, supporting a stronger role of prothrombotic factors in early onset IS.\",\n \"Associations between indicators of socioeconomic position and DNA methylation: A systematic review\\nSocioeconomic position (SEP) is a major determinant of health across the life course. Yet, little is known about the biological mechanisms explaining this relationship. One possible explanation is through an epigenetic process called DNA methylation (DNAm), wherein the socioeconomic environment causes no alteration in the DNA sequence but modifies gene activity, gene expression, and therefore long-term health. To understand the evidence supporting a potential SEP-DNAm link, we performed a systematic review of published empirical findings on the association between SEP (from prenatal development to adulthood) and DNAm measured across the life course, with an eye toward evaluating how the timing, duration, and type of SEP exposure influenced DNAm. Across the 37 studies we identified, there was some evidence for the effect of SEP timing and duration on DNAm, with early-life SEP and persistently low SEP being particularly strong indicators of DNAm. Different indicators of SEP also had some unique associations with DNAm profiles, suggesting that SEP is not a singular concept, but rather that different aspects of the socioeconomic environment can shift DNAm patterns through distinct pathways. These differences with respect to SEP timing, duration, and type were notable because they were detected even among heterogenous study designs. Overall, findings from this review underscore the importance of analyzing SEP timing, duration, and type, given the complex relationship between SEP and DNAm across the lifespan. To guide future research, we highlight current limitations in the literature and propose recommendations for overcoming some of these challenges.\",\n \"Casirivimab and imdevimab for the treatment of hospitalized patients with COVID-19\\nBackgroundHospitalized patients with COVID-19 experience high mortality rates, ranging from 10% to 30%. Combined casirivimab and imdevimab (CAS+IMD) is authorized for use in outpatients with COVID-19 and in post-exposure prophylaxis. The UK-based platform RECOVERY study reported improved survival in hospitalized seronegative patients treated with CAS+IMD; however, in most of the world, anti-spike monoclonal antibody therapy is currently not approved for hospitalized patients.\\n\\nMethodsIn this phase I/II/III double-blind placebo-controlled trial, patients hospitalized with COVID-19 were randomized (1:1:1) to 2.4 g or 8.0 g of CAS+IMD or placebo, and characterized at baseline for viral load and SARS-CoV-2 endogenous immune response.\\n\\nResults1336 patients on low-flow or no supplemental oxygen were treated. The primary endpoint was met: in seronegative patients, the least squares mean difference (CAS+IMD vs placebo) for time-weighted average change from baseline viral load was -0.28 log10 copies/mL (95% confidence interval [CI] -0.51 to -0.05; P = .0172). The primary clinical analysis of death or mechanical ventilation from day 6 to 29 in patients with high viral load had a strong positive trend but did not reach significance. CAS+IMD numerically reduced all-cause mortality in seronegative patients through day 29 (relative risk reduction, 55.6%; 95% CI 24.2-74.0; nominal P = .0032). No safety concerns were noted.\\n\\nConclusionsIn hospitalized patients with COVID-19 on low-flow or no oxygen, CAS+IMD treatment reduced viral load and the risk of death or mechanical ventilation as well as all-cause mortality in the overall population, with the benefit driven by seronegative patients and no harm observed in seropositive patients.\",\n \"Similar Rates of AKI during the First Two Waves of COVID-19 in Northern Italy: a single-center study\\nIntroductionTwo waves of COVID-19 cases have overwhelmed most European countries during 2020. It is unclear if the incidence of acute kidney injury (AKI) has changed during the COVID-19 outbreaks. This study aims to evaluate the differences in incidence, risk factors and outcome of AKI in patients with SARS-CoV-2 infection during the first and second wave of COVID-19.\\n\\nMethodWe reviewed the health medical records of 792 consecutive patients with COVID-19 hospitalized at the University Hospital of Modena, Italy, from February 25 to December 14, 2020.\\n\\nResultsAKI was diagnosed in 122 (15.4%) patients. Incidence of AKI remained steady rate during wave-1 (15.9%) and wave-2 (14.7%) (P=0.89). AKI patients were older (P=<0.001) and had a more severe respiratory impairment (PO2/FO2) (P=[≤]0.001) than their non-AKI counterparts. AKI led to a longer hospital stay (P=0.001), complicated with a higher rate of ICU admission. COVID-19-related AKI was associate with 59.7% of deaths during wave-1 and 70.6% during wave-2. At the end of the period of observation, 24% (wave-1) and 46.7% (wave-2) of survivors were discharged with a not fully recovered kidney function. Risk factors for AKI in patients with COVID-19 were diuretics (HR=5.3; 95%CI, 1.2-23.3; P=0.025) and cardiovascular disease (HR, 2.23; 95%CI, 1.05-5.1; P=0.036).\\n\\nConclusionThe incidence of AKI (about 15%) remained unchanged during 2020, regardless of the trend of COVID-19. AKI occurred in patients with severe COVID-19 symptoms and was associated with a higher incidence of deaths than non-AKI patients. The risk factors of COVID-19-related AKI were diuretic therapy and cardiovascular disease.\",\n \"A comparison of denoising methods in dynamic MRS using pseudo-synthetic data\\nPurposeMR spectroscopy of dynamic systems is limited by low signal to noise. Denoising along a series of acquired spectra exploits their temporal correlation to improve the quality of individual spectra, and reduce errors in fitting metabolite peaks. In this study we compare the performance of several denoising methods.\\n\\nMethodsSix different denoising methods were considered: SIFT (Spectral Improvement by Fourier Thresholding), HSVD (Hankel Singular Value Decomposition), spline, wavelet, sliding window and sliding Gaussian. Pseudo-synthetic data was constructed to mimic 31Phosphorus spectra from exercising muscle. For each method the optimal tuning parameters were determined for SNRs of 2, 5, 10 and 20 using a Monte Carlo approach. Denoised data from each method was then fitted using the AMARES algorithm and the results compared to the pseudo-synthetic ground truth.\\n\\nResultsAll six methods produced improvements in both fitting accuracy and agreement with the ground truth, compared to unprocessed noisy data. The least effective methods, SIFT and HSVD, achieved around 10-20% reduction in RMS error, while the most effective, Spline, reduced RMS error by 70%. The improvement from denoising was typically greater for lower SNR data.\\n\\nConclusionsIndirect time domain denoising of dynamic MR spectroscopy data can substantially improve subsequent metabolite fitting. Spline-based denoising was found to be the most flexible and effective technique.\",\n \"Cytogenetic & Molecular analysis in Premature Ovarian Failure\\nIntroductionPremature Ovarian Failure (POF) being a heterogeneous genetic disease involves the interaction of multiple genetic defects and environmental factors and has been associated with several chromosomal abnormalities, single gene mutations, and genetic polymorphisms. BMP15 is a member of the transforming growth factor {beta} (TGF-{beta}) family. BMP15 gene product (protein) have 3 domians, mature domain (c-terminal region) of BMP15 binds to receptors located on granulosa cell surface to participate in key steps regarding ovarian function, such as granulosa cell proliferation and follicle maturation, ovulation rate modulation, oocyte competence determination and regulating granulosa cell sensitivity to FSH. Single nucleotide polymorphisms (SNPs) of the BMP-15 gene are associated with POF.\\n\\nMaterials & Methods30 POF patients and 30 healthy age matched controls were recruited for cytogenetic and molecular analysis. 10 ml whole blood was collected for karyotyping and PCR and PCR was performed for known SNPs of BMP-15 gene (-9C>G, 538G>A, 788insTCT and 852C>T) respectively. Amplified PCR products were sequenced commercially.\\n\\nObservation/ResultThirty cases (mean age 30 years) and thirty healthy controls (mean age 23 years) were recruited for the study. On cytogenetic analysis 2 cases had a 45, XO chromosomal complement. One case was heterozygous for the SNP (-9C>G) and one control was homozygous for the same SNP.\\n\\nDiscussionThe prevalence of this SNP was about 10.7% in cases & 3.3% in healthy controls. This polymorphism in promoter region may cause altered expression of the gene and results in POF.\",\n \"Next-generation Serology by Mass Spectrometry: Readout of the SARS-CoV-2 Antibody Repertoire\\nMethods of antibody detection are used to assess exposure or immunity to a pathogen. Here, we present Ig-MS, a novel serological readout that captures the immunoglobulin (Ig) repertoire at molecular resolution, including entire variable regions in Ig light and heavy chains. Ig-MS uses recent advances in protein mass spectrometry (MS) for multi-parametric readout of antibodies, with new metrics like Ion Titer (IT) and Degree of Clonality (DoC) capturing the heterogeneity and relative abundance of individual clones without sequencing of B cells. We apply Ig-MS to plasma from subjects with severe & mild COVID-19, using the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 as the bait for antibody capture. Importantly, we report a new data type for human serology, with compatibility to any recombinant antigen to gauge our immune responses to vaccination, pathogens, or autoimmune disorders.\",\n \"Post discharge persistent symptoms after COVID-19 in rheumatic and musculoskeletal diseases\\nOBJECTIVESTo describe persistent symptoms and consequences in Rheumatic and Musculoskeletal diseases (RMD) discharged from the hospital after Covid-19; to assess the roll of autoimmune rheumatic diseases (ARD) compared to and non-autoimmune rheumatic and musculoskeletal diseases (NARD) on persistent symptoms and consequences.\\n\\nMETHODSWe performed a cross-sectional observational study. RMD attended at a rheumatology outpatient clinic in Madrid with Covid-19 that required hospital admission were included. The main outcomes were persistence of symptoms and health consequences related to Covid19 after discharge. Independent variable was RMD group (ARD and NARD) and covariates were sociodemographic, clinical, and treatments. We ran a multivariable logistic regression model to assess the risk by RMD group on main outcomes.\\n\\nRESULTSWe included 105 patients and 51.5% had ARD. 68.57% reported at least one persistent symptom. The most frequent were dyspnea, fatigue, and chest pain. 31 patients had consequences. Lung damage was found in 11.4% of the patients, 18% had blood test abnormalities (10% lymphopenia), two died, one developed central retinal vein occlusion and one patient developed optic neuritis. 11 patients required readmission due to Covid-19 problems (16.7% ARD vs 3.9% NARD; p=0.053). No statistically significant differences by RMD groups were found in the final models.\\n\\nCONCLUSIONMany RMD patients have persistent symptoms, similar to other populations. This study also highlights that lung damage is the most frequent consequence. ARD compared to NARD does not seem to differ in terms of persistent symptoms or consequences, although ARD might have a greater number of readmissions due to Covid-19.\",\n \"Machine Learning and Radiomics for Osteoporosis Risk Prediction Using X-ray Imaging\\nOsteoporosis is a significant health and economic issue, as it predisposes patients to a higher risk of bone fracture. Measuring bone mineral density has been shown to be an accurate way to assess the risk for osteoporosis. The most common way for bone density testing is a dual-energy X-ray absorptiometry (DEXA) scan, which may be recommended for patients with increased risk of osteoporosis. Radiograph imaging is widely available in clinical settings and acquired for many reasons, such as trauma or pain. The goal of this project is to extract radiomics information from pelvic X-rays (both the hip and femoral neck regions) to assess the risk of osteoporosis (triaging patients into \\\"normal\\\" vs. \\\"at-risk\\\", or \\\"low risk\\\" vs. \\\"high risk\\\" categories). The motivation here is not to replace the DEXA scan but to proactively identify patients at risk for osteoporosis and appropriately refer them to management options. We apply machine learning-based radiomics techniques on a study cohort of 565 patients. Our preliminary results show that a correlation between the radiomics features extracted from pelvic X-rays and the level of osteoporosis risk derived from the DEXA test results.\",\n \"Topographic volume-standardization atlas of the human brain\\nObjectiveSpecific anatomical patterns are seen in various diseases affecting the brain. Clinical studies on the topography of pathologies are often limited by the absence of a normalization of the prevalence of pathologies to the relative volume of the affected anatomical structures. A comprehensive reference on the relative volumes of clinically relevant anatomical structures serving for such a normalization, is currently lacking.\\n\\nMethodsThe analyses are based on anatomical high-resolution three-dimensional T1-weighted magnetic resonance imaging data of 30 healthy Caucasian volunteers, including 14 females (mean age 37.79 years, SD 13.04) and 16 males (mean age 38.31 years, SD 16.91). Semi-automated anatomical segmentation was used, guided by a neuroanatomical parcellation algorithm differentiating 96 structures. Relative volumes were derived by normalizing parenchymal structures to the total individual encephalic volume and ventricular segments to the total individual ventricular volume.\\n\\nResultsThe present investigation provides the absolute and relative volumes of 96 anatomical parcellation units of the human encephalon. A larger absolute volume in males than in females is found for almost all parcellation units. While parenchymal structures display a trend towards decreasing volumes with increasing age, a significant inverse effect is seen with the ventricular system. The variances in volumes as well as the effects of gender and age are given for each structure before and after normalization.\\n\\nConclusionThe provided atlas constitutes an anatomically detailed and comprehensive analysis of the absolute and relative volumes of the human encephalic structures using a clinically oriented parcellation algorithm. It is intended to serve as a reference for volume-standardization in clinical studies on the topographic prevalence of pathologies.\",\n \"Genome-wide Association Study of Pulmonary Function in Europeans and Africans from the UK Biobank Identifies Distinct Variants\\nPulmonary function is an indicator of well-being, and pulmonary pathologies are the third major cause of death worldwide. FEV1, FVC, and PEF are quantitively used to assess pulmonary function. We conducted a genome-wide association analysis of pulmonary function in 383,471 individuals of European and 5,978 African descent represented in the UK Biobank. Here, we report 817 variants in Europeans and 3 in Africans associated (p-values < 5 x 10-8) with three pulmonary function parameters; FEV1, FVC and PEF. In addition to 377 variants in Europeans previously reported to be associated with phenotypes related to pulmonary function, we identified 330 novel loci, including an ISX intergenic variant rs369476290 on chromosome 22 in Africans and a KDM2A intron variant rs12790261 on chromosome 11 in Europeans. Remarkably, we find no shared variants among Africans and Europeans. Enrichment analyses of variants separately for each ancestry background revealed significant enrichment for terms related to pulmonary phenotypes in Europeans but not Africans. Further analysis of studies of pulmonary phenotypes revealed individuals of European background are disproportionally overrepresented in datasets compared to Africans, with the gap widening over the past five years. Our findings offer a better understanding of the different variants that modify pulmonary function in Africans and Europeans, a significant finding for future GWAS studies and medicine.\",\n \"NeuroEPO improves cognition in Parkinson's disease. Preliminary report.\\nBackgroundCognitive impairment is a feature of Parkinsons Disease (PD) from the early stages, but currently, no treatment for cognitive deficits in PD is available. Erythropoietin (EPO) has been studied for its potential neuroprotective properties in neurologic disorders with a beneficial action on cognition.\\n\\nObjectiveTo evaluate if NeuroEPO, a new formulation of EPO with low content of sialic acid, improves the cognitive function in PD patients.\\n\\nMethodsA double-blind, randomized, placebo-controlled physician lead trial was conducted. The sample was composed of 26 PD patients (HY stages I-II), where 15 received intranasal NeuroEPO for 5 weeks, and another age and gender-matched 11 patients were randomly assigned to the Placebo. All the samples received 9 months of intensive NeuroEPO treatment during a post-trial. The cognitive functions were assessed using a comprehensive neuropsychological battery before, one week, and 6 months after the first intervention and one week after a 9months post-trial. The effects of NeuroEPO were evaluated using a multivariate linear mixed-effects model using a latent variable for cognition instead of the raw neuropsychological scores.\\n\\nResultsA significant and direct effect of the Dose of NeuroEPO (p=0.00003) was found on cognitive performance with a strong positive influence of educational level (p=0.0032) and negative impact of age (p=0.0063).\\n\\nConclusionsThese preliminary results showed a positive effect of NeuroEPO on cognition in PD patients with better benefit for younger and higher educated patients.\",\n \"Physical activity, sedentary behaviour, and sleep on Twitter: A labelled dataset for public health research\\nAdvances in automated data processing, together with the unprecedented growth in user-generated social media (SM) content, have made public health surveillance (PHS) one of the long-lasting SM applications. However, the existing PHS systems feeding on SM data have not been widely deployed in national surveillance systems, which appears to stem from the lack of practitioners trust in SM data. More robust datasets over which machine learning (ML) models can be trained/tested reliably is a significant step toward overcoming this hurdle. The health implications of physical activity, sedentary behaviour, and sleep (PASS) are widely studied through traditional data sources, which are often out-of-date, costly to collect, and thus limited in quantity and coverage. We present LPHEADA, a multicountry and fully Labelled digital Public HEAlth DAtaset of tweets originated in Australia/Canada/United Kingdom/United States between November 2018-June 2020. LPHEADA contains 366,405 labels for 122,135 PASS-related tweets and provides details about the place/time/demographics associated with each tweet. LPHEADA is publicly available and can be utilized to develop (un)supervised ML models for digital PASS surveillance.\",\n \"Comparative immunogenicity and effectiveness of mRNA-1273, BNT162b2 and Ad26.COV2.S COVID-19 vaccines\\nBackgroundUnderstanding immunogenicity and effectiveness of SARS-CoV-2 vaccines is critical to guide rational use.\\n\\nMethodsWe compared the immunogenicity of mRNA-1273, BNT-162b2 or Ad26.COV2.S in ambulatory adults in Massachusetts, USA. To correlate immunogenicity with effectiveness of the three vaccines, we performed an inverse-variance meta-analysis of population level effectiveness from public health reports in >40 million individuals.\\n\\nResultsA single dose of either mRNA vaccine yielded comparable antibody and neutralization titers to convalescent individuals. Ad26.COV2.S yielded lower antibody concentrations and frequently negative neutralization titers. Bulk and cytotoxic T-cell responses were higher in mRNA1273 and BNT162b2 than Ad26.COV2.S recipients, and <50% of vaccinees demonstrate CD8+ T-cell responses to spike peptides. Antibody concentrations and neutralization titers increased comparably after the first dose of either vaccine, and further in recipients of a second dose. Prior infection was associated with high antibody concentrations and neutralization even after a single dose and regardless of vaccine. Neutralization of beta, gamma and delta strains were poorer regardless of vaccine. Relative to mRNA1273, the effectiveness of BNT162b2 was lower against infection and hospitalization; and Ad26COV2.S was lower against infection, hospitalization and death.\\n\\nConclusionsVariation in the immunogenicity correlates with variable effectiveness of the three FDA EUA vaccines deployed in the USA.\",\n \"In Vivo Cortical Microstructure - A Proxy for Tauopathy & Cognitive Impairment\\nAggregation of hyperphosphorylated tau protein is currently one of the most reliable indicators of Alzheimers pathology and cognitive impairment in older adults. However, it would be useful to have a non-invasive, accessible proxy measure that does not rely on Positron Emission Tomography (PET). We used data from multi-shell diffusion-weighted imaging (DWI) to assess indices from the Neurite Orientation Dispersion and Density Imaging (NODDI) model to determine possible proxies for tau and relationship with cognitive impairment. After controlling for age, sex, and the time difference between the scan acquisitions (DWI vs. PET), we used multiple factor analysis (MFA) to assess the fit between NODDI indices (orientation dispersion [ODI], neurite density [NDI], and free-water [fISO]), cortical thickness, and tau binding (via PET). We used data from 80 participants from the ADNI-3 sample who had a multi-shell DWI and an [18F]AV-1451 (tau) PET scan. Of these 80, 49 individuals were considered cognitively normal older adults (age ~74 years), 26 individuals had a diagnosis of mild cognitive impairment (age ~75 years), and five individuals had Alzheimers dementia (age ~78 years). fISO and tau shared a large amount of spatial overlap, and both strongly correlated with the first MFA dimension. Macrostructural features (such as cortical thickness and subcortical volume) introduced in a follow-up analysis were less related to this first MFA dimension than fISO and eight percent less than tau. Subsequent mediation analyses demonstrated that fISO mediated the relationship between cortical thickness and tau, explaining all of the variance. Microstructural features derived from advanced DWI acquisitions such as fISO may be useful proxies for tau. Cortical fISO, rather than cortical thickness, may represent the impact of tau on the brain (and, by extension, cognition).\",\n \"Context Matters! Depression following childbirth or a chronic disease diagnosis shows specific risk factor profiles.\\nProgress towards understanding the etiology of major depression (MD) is compromised by its clinical heterogeneity. The variety of contexts underlying the development of a major depressive episode may contribute to such heterogeneity. Here, we aimed to compare risk factor profiles of three subgroups of MD according to episode context.\\n\\nUsing self-report questionnaires and administrative records from the UK Biobank, we characterised three contextual subgroups of MD: postpartum depression (3,581 cases), depression following diagnosis of a chronic disease (409 cases) and a more typical (named heterogeneous) MD phenotype excluding the two prior contexts (34,699 cases). Controls with the same exposure were also defined. We tested each subgroup for association with MD polygenic risk scores (PRS) and other risk factors previously associated with MD (bipolar disorder PRS, neuroticism, reported trauma in childhood and adulthood, socioeconomic status, family history of depression, education).\\n\\nMD polygenic risk scores were associated with all subgroups, however, postpartum depression cases had higher PRS than heterogeneous MD cases (OR = 1.06, 95% CI: 1.02 - 1.10). Relative to heterogeneous depression, postpartum depression was more weakly associated with adulthood trauma and neuroticism. Relative to heterogeneous depression, depression following diagnosis of a chronic disease did not have higher MD polygenic risk scores but had weaker associations with neuroticism and reported trauma in adulthood and childhood.\\n\\nThe observed differences in risk factor profiles according to the context of a major depressive episode help provide insight into the heterogeneity of depression. Future studies dissecting such heterogeneity could help reveal more refined etiological insights.\",\n \"Deep Learning in Opthalmology: Iris Melanocytic Tumor Intelligent Diagnosis\\nRecently, Convolutional neural networks (CNN) have shown a growth due to their ability of learning different level image representations that helps in image classification in different fields. These networks have been trained on millions of images, so they gained a powerful ability of extracting the rightful features from input images, which results in accurate classification. In this research, we investigate the effects of transfer learning based convolutional neural networks for the iris tumor malignancy identification as it is notoriously hard to distinguish an iris nevus from an iris tumor. Features are transferred from a CNN trained on a source task, i.e. ImageNet, to a target task, i.e. iris tumor datasets. We transfer features learned from AlexNet and VGG-16 that are trained on ImageNet, to classify three different iris images types which are: iris nevus unaffected, iris cysts, and iris melanocytic tumors. The employed pre-trained models are modified by replacing their feedforward neural network classifier, Softmax, by a support vector machine (SVM) that is expected to slightly boost their performance (AlexNet-SVM and VGG16-SVM). All employed models are trained (fine-tuned) on a 60% of the available large dataset of iris images in order to investigate their power of generalization when trained using large amount of data. The networks are also tested on 40% of the data. The best performance was achieved by the VGG16-SVM which scored a high accuracy of 96.27% and strong features extraction capability as compared to the other models. Experimentally, it was seen that adding SVM contributed in improving the network performance compared to original models which use a feedforward neural network classifier.\",\n \"Structured Understanding of Assessment and Plans in Clinical Documentation\\nPhysicians record their detailed thought-processes about diagnoses and treatments as unstructured text in a section of a clinical note called the assessment and plan. This information is more clinically rich than structured billing codes assigned for an encounter but harder to reliably extract given the complexity of clinical language and documentation habits. We describe and release a dataset containing annotations of 579 admission and progress notes from the publicly available and de-identified MIMIC-III ICU dataset with over 30,000 labels identifying active problems, their assessment, and the category of associated action items (e.g. medication, lab test). We also propose deep-learning based models that approach human performance, with a F1 score of 0.88. We found that by employing weak supervision and domain specific data-augmentation, we could improve generalization across departments and reduce the number of human labeled notes without sacrificing performance.\",\n \"Post-acute sequelae of COVID-19 in a non-hospitalized cohort: results from the Arizona CoVHORT\\nClinical presentation, outcomes, and duration of COVID-19 has ranged dramatically. While some individuals recover quickly, others suffer from persistent symptoms, collectively known as post-acute sequelae of SAR-CoV-2 (PASC). Most PASC research has focused on hospitalized COVID-19 patients with moderate to severe disease. We used data from a diverse population-based cohort of Arizonans to estimate prevalence of various symptoms of PASC, defined as experiencing at least one symptom 30 days or longer. There were 303 non-hospitalized individuals with a positive lab-confirmed COVID-19 test who were followed for a median of 61 days (range 30-250). COVID-19 positive participants were mostly female (70%), non-Hispanic white (68%), and on average 44 years old. Prevalence of PASC at 30 days post-infection was 68.7% (95%CI 63.4, 73.9). The most common symptoms were fatigue (37.5%), shortness-of-breath (37.5%), brain fog (30.8%), and stress (30.8%). The median number of symptoms was 3 (range 1-20). Amongst 157 participants with longer follow-up ([≥]60 days), PASC prevalence was 77.1%.\",\n \"A large, curated, open-source stroke neuroimaging dataset to improve lesion segmentation algorithms\\nAccurate lesion segmentation is critical in stroke rehabilitation research for the quantification of lesion burden and accurate image processing. Current automated lesion segmentation methods for T1-weighted (T1w) MRIs, commonly used in rehabilitation research, lack accuracy and reliability. Manual segmentation remains the gold standard, but it is time-consuming, subjective, and requires significant neuroanatomical expertise. We previously released a large, open-source dataset of stroke T1w MRIs and manually segmented lesion masks (ATLAS v1.2, N=304) to encourage the development of better algorithms. However, many methods developed with ATLAS v1.2 report low accuracy, are not publicly accessible or are improperly validated, limiting their utility to the field. Here we present ATLAS v2.0 (N=955), a larger dataset of T1w stroke MRIs and manually segmented lesion masks that includes both training (public) and test (hidden) data. Algorithm development using this larger sample should lead to more robust solutions, and the hidden test data allows for unbiased performance evaluation via segmentation challenges. We anticipate that ATLAS v2.0 will lead to improved algorithms, facilitating large-scale stroke rehabilitation research.\",\n \"Multi-state network meta-analysis of cause-specific survival data\\nMultiple randomized controlled trials, each comparing a subset of competing interventions, can be synthesized by means of a network meta-analysis to estimate relative treatment effects between all interventions in the evidence base. Often there is an interest in estimating the relative treatment effects regarding time-to-event outcomes. Cancer treatment effectiveness is frequently quantified by analyzing overall survival (OS) and progression-free survival (PFS). In this paper we introduce a method for the joint network meta-analysis of PFS and OS that is based on a time-inhomogeneous tri-state (stable, progression, and death) Markov model where time-varying transition rates and relative treatment effects are modeled with known parametric survival functions or fractional polynomials. The data needed to run these analyses can be extracted directly from published survival curves. We demonstrate use by applying the methodology to a network of trials for the treatment of non-small-cell lung cancer. The proposed approach allows the joint synthesis of OS and PFS, relaxes the proportional hazards assumption, extends to a network of more than two treatments, and simplifies the parameterization of decision and cost-effectiveness analyses.\",\n \"Efficacy of vasopressin, steroid, and epinephrine protocol for in-hospital cardiac arrest resuscitation: A systematic review and meta-analysis of randomized controlled trials with trial sequential analysis\\nAimTo assess the effect of vasopressin, steroid and epinephrine (VSE) combination therapy on return of spontaneous circulation (ROSC) after in-hospital cardiac arrest (IHCA), and test the conclusiveness of evidence using trial sequential analysis (TSA).\\n\\nMethodsThe systematic search included PubMed, EMBASE, Scopus, and Cochrane Central Register of Controlled Trials. Randomized controlled trials that included adult patients with in-hospital cardiac arrest, with at least one group receiving combined vasopressin, epinephrine and steroid therapy were selected. Data was extracted independently by two reviewers. The main outcome of interest was ROSC. Other outcomes included survival to hospital discharge with good neurological outcomes and survival to 30 and 90 days with good neurological outcomes.\\n\\nResultsWe included a total of three randomized controlled trials (n=869 patients). Results showed that Vasopressin, steroid and epinephrine combination therapy increased return of spontaneous circulation (risk ratio, 1.32; 95% CI, 1.18-1.47) as compared to placebo. Trial sequential analysis demonstrated that the existing evidence is conclusive. This was also validated by the alpha-spending adjusted relative risk (1.32 [1.16, 1.49], p<0.0001). Other outcomes could not be meta-analysed due to differences in timeframe in the included studies.\\n\\nConclusionsVSE combination therapy administered in cardiopulmonary resuscitation led to improved rates of return of spontaneous circulation. Future trials of vasopressin, steroid and epinephrine combination therapy should evaluate survival to hospital discharge, neurological function and long-term survival.\",\n \"Identification of B.1.346 lineage of SARS-CoV-2 in Japan: Genomic evidence of re-entry of Clade 20C\\nObjectivesWhole SARS-CoV-2 genome sequencing from COVID-19 patients is useful for infection control and regional trends evaluation. We report a lineage data collected from hospitals in the Kanto region of Japan.\\n\\nMethodsWe performed whole genome sequencing in specimens of 198 COVID-19 patients at 13 collaborating hospitals in the Kanto region. Phylogenetic analysis and fingerprinting of the nucleotide substitutions underwent to differentiate and classify the viral lineages.\\n\\nResultsMore than 90% of the strains belonged to Clade 20B and two lineages (B.1.1.284 and B.1.1.214) have been detected predominantly in the Kanto region. However, one sample from a COVID-19 patient in November 2020, belonged to the B.1.346 lineage of Clade 20C, which has been prevalent in western United States. The patient had no history of overseas travel and no contact with anyone who had travelled abroad, suggesting that this strain appeared likely to have been imported from western United States, across the strict quarantine barrier.\\n\\nConclusionB.1.1.284 and B.1.1.214 have been identified predominantly in the Kanto region and B.1.346 of clade 20C in one patient was probably imported from western United States. These results illustrate that a decentralized network of hospitals can be significantly advantageous for monitoring regional molecular epidemiologic trends.\\n\\nHighlights{middle dot} Whole SARS-CoV-2 genome sequencing is useful for infection control\\n{middle dot} B.1.1.284 and B.1.1.214 have been identified predominantly in the Kanto region\\n{middle dot} B.1.346 of Clade 20C was detected in one COVID-19 patient in November\\n{middle dot} Molecular genomic data sharing provides benefits to public health against COVID-19\",\n \"Mutant IDH Inhibitors Induce Lineage Differentiation in IDH-mutant Oligodendroglioma\\nRecent data showed promising signs of objective tumor responses in subsets of patients with low grade glioma treated with inhibitors of mutant IDH (IDHi) (1). However, the molecular and cellular underpinnings of such responses are not known. Here, we profiled 6,039 transcriptomes by single-cell or single-nucleus RNA-sequencing isolated from three IDH-mutant oligodendroglioma patients with clinical response to IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation and our dataset includes a matched pre- and on-treatment sample pair. We integrate our findings with analysis of 8,241 transcriptomes from seven untreated samples, 134 bulk samples from the TCGA and experimental models.(2,3) We find that IDHi treatment induces a robust differentiation towards glial lineages, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Our study provides the first evidence in patients of the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas.\",\n \"Evaluating Digital Device Technology in Alzheimer's Disease via Artificial Intelligence\\nThe use of digital technologies may help to diagnose Alzheimers Disease (AD) at the pre-symptomatic stage. However, before implementation into clinical practice, digital measures (DMs) need to be evaluated for their diagnostic benefit compared to established questionnaire-based assessments, such as the Mini-Mental State Examination (MMSE) for cognition and Functional Activity Questionnaire (FAQ) for daily functioning. Moreover, the quantitative and qualitative relationship of DMs to these well understood scores needs to be clarified to aid interpretation. In this work we analyzed data from 148 subjects, 58 cognitively normal and 90 at different stages of the disease, which had performed a smartphone based virtual reality game to assess cognitive function. In addition, we used clinical data from Alzheimers Disease Neuroimaging Initiative (ADNI). We employed an Artificial Intelligence (AI) based approach to elucidate the relationship of DMs to questionnaire-based cognition and functional activity scores. In addition, we used Machine Learning (ML) and statistical methods to assess the diagnostic benefit of DMs compared to questionnaire-based scores. We found non-trivial relationships between DMs, MMSE, and FAQ which can be visualized as a complex network. DMs, in particular those reflecting scores of individual tasks in the virtual reality game, showed a better ability to discriminate between different stages of the disease than questionnaire-based methods. Our results indicate that DMs have the potential to act as a crucial measure in the early diagnosis and staging of AD.\",\n \"The Impact of Early Life Stress on the Genetic Influence on Brain and Cognitive Development in Children\\nEarly life stress (ELS), such as abuse, neglect, and maltreatment, is a well-known risk factor for mental illness. However, it is unclear how ELS affects the brain and cognitive development. Identifying specific relationships of ELS with the genetic and brain-related underpinnings of cognitive development may reveal biological mechanisms responsible for the negative impact of ELS and those that lead to individual differences in sensitivity (or resilience) to ELS. In this study, to investigate the interlinked processes of cognitive development, we analyzed the multimodal data of DNA genotypes, brain imaging (MRI), and neuropsychological assessment (NIH Toolbox) outcomes of 4,276 children (ages 9 to 10 years, European ancestry) from the Adolescent Brain Cognitive Development (ABCD) study. We estimated the genetic influence on cognitive capacity using genome-wide polygenic scores (GPSs). Our regression and mediation analyses revealed significant causal relationships for the gene-brain-cognition pathway: Brain structural development significantly mediated the genetic influence on cognitive development (partial mediation effect = 0.016, PFWE<0.001). Interestingly, within the triangular relationship, we found a significant moderation effect of abuse only on the gene-to-brain pathway (Index of Moderated Mediation = -0.007; 95% CI= -0.012 [~] -0.002; PFWE<0.05). These findings indicate the negative modulatory effects of ELS on the genetic influence on brain structural development that lead to disadvantageous neurocognitive development in prepubertal children.\",\n \"SARS-COV-2 INFECTION IN PRIMARY CARE: A SINGLE-CENTERED, RETROSPECTIVE, OBSERVATIONAL STUDY\\nPurposeto describe the clinical characteristics of patients with confirmed SARS-CoV-2 infection in primary care and to analyze the predictive role of different risk factors on prognosis, especially living conditions.\\n\\nMethodsRetrospective longitudinal observational retrospective study by reviewing medical records from a primary care center since March 1 to April 30, 2020. Case definition of confirmed SARS-CoV-2 infection, sociodemographic data, clinical characteristics, comorbidity and living conditions were collected. The statistical analysis consisted in description of the sample, comparison of prognosis groups and analysis of prognostic factors.\\n\\nResultsA sample of 70 patients with confirmed SARS-CoV-2 infection was obtained, with comorbidity mainly related to arterial hypertension, overweight/obesity, hypercholesterolemia, diabetes and chronic pulmonary pathology. Pneumonia was present in 66%. Exitus occurred in 14% of the sample. Factors associated with mortality were advanced age (84 vs 55; p<0.0001), arterial hypertension (78% vs 41%; p=0.040), asthma-COPD (56% vs 13%; p=0.008) and atrial fibrillation (56% vs 5%; p=0.001).\\n\\nConclusionsThe study reflects the clinical practice of a primary care center. This kind of studies are essential to strengthen and reorganize the Health System and to try to anticipate the medium- to long-term consequences of COVID-19 on global health.\",\n \"Metabologenomic approach reveals intestinal environmental features associated with barley-induced glucose tolerance improvements in Japanese cohort: a randomized controlled trial\\nConsumption of barley has been known to exert beneficial effects on metabolic disorders; however, it has also been reported that there are inter-individual differences in these responses. Recent evidence has suggested that these individual differences are mediated by the gut microbiota. Therefore, in the present study, we aimed to understand the relationship between the intestinal environment, including gut microbiota, and metabolic disorders. A randomized controlled trial in Japanese subjects with 4-week consumption of barley or control food was conducted. In this study, we analyzed the intestinal environment, including microbiota and their metabolites, and blood parameters were assessed collectively. We found that microbial genera Blautia and Agathobacter belonging to Lachnospiraceae, and fecal metabolites such as azelate were increased 1.31-fold, 1.84-fold, and 1.48-fold after barley consumption, respectively. Furthermore, the subjects whose glucose tolerance were slightly impaired showed improvement in their glucose tolerance index following the barley consumption. Additionally, the analysis showed that the increase in the abundance of the Anaerostipes was correlated with the improvement in the glucose tolerance index. Our findings indicate that the effects of barley consumption for glucose tolerance are partly defined by the intestinal environment of consumers, providing a quantitative measurement of the dietary effect based on the intestinal environment.\",\n \"Health service research definition builder: An R Shiny application for exploring diagnosis codes associated with services reported in routinely collected health data\\nMany administrative health data-based studies define patient cohorts using procedure and diagnosis codes. The impact these criteria have on a studys final cohort is not always transparent to co-investigators or other audiences if access to the research data is restricted. We developed a SAS and R Shiny interactive research support tool which generates and displays the diagnosis code summaries associated with a selected medical service or procedure. This allows non-analyst users to interrogate claims data and groupings of reported diagnosis codes. The SAS program uses a tree classifier to find associated diagnosis codes with the service claims compared against a matched, random sample of claims without the service. Claims are grouped based on the overlap of these associated diagnosis codes. The Health Services Research (HSR) Definition Builder Shiny application uses this input to create interactive table and graphics, which updates estimated claim counts of the selected service as users select inclusion and exclusion criteria. This tool can help researchers develop preliminary and shareable definitions for cohorts for administrative health data research. It allows an additional validation step of examining frequency of all diagnosis codes associated with a service, reducing the risk of incorrect included or omitted codes from the final definition. In our results, we explore use of the application on three example services in 2016 US Medicare claims for patients aged over 65: knee arthroscopy, spinal fusion procedures and urinalysis. Readers can access the application at https://kelsey209.shinyapps.io/hsrdefbuilder/ and the code at https://github.com/kelsey209/hsrdefbuilder.\",\n \"The Triangulation WIthin A STudy (TWIST) framework for causal inference within Pharmacogenetic research\\nIn this paper we review the methodological underpinnings of the general pharmacogenetic approach for uncovering genetically-driven treatment effect heterogeneity. This typically utilises only individuals who are treated and relies on fairly strong baseline assumptions to estimate what we term the genetically moderated treatment effect (GMTE). When these assumptions are seriously violated, we show that a robust but less efficient estimate of the GMTE that incorporates information on the population of untreated individuals can instead be used. In cases of partial violation, we clarify when Mendelian randomization and a modified confounder adjustment method can also yield consistent estimates for the GMTE. A decision framework is then described to decide when a particular estimation strategy is most appropriate and how specific estimators can be combined to further improve efficiency. Triangulation of evidence from different data sources, each with their inherent biases and limitations, is becoming a well established principle for strengthening causal analysis. We call our framework Triangulation WIthin a STudy (TWIST) in order to emphasise that an analysis in this spirit is also possible within a single data set, using causal estimates that are approximately uncorrelated, but reliant on different sets of assumptions. We illustrate these approaches by re-analysing primary-care-linked UK Biobank data relating to CYP2C19 genetic variants, Clopidogrel use and stroke risk, and data relating to APOE genetic variants, statin use and Coronary Artery Disease.\",\n \"Hi-C detects genomic structural variants in peripheral blood of pediatric leukemia patients\\nB-cell acute lymphoblastic leukemia (B-ALL) is often driven by chromosome translocations that result in recurrent and well-studied gene fusions. Currently, fluorescent in-situ hybridization probes are employed to detect candidate translocations in bone marrow samples from B-ALL patients. Recently Hi-C, a sequencing-based technique originally designed to reconstruct the three-dimensional architecture of the nuclear genome, was shown to effectively recognize structural variants. Here, we demonstrate that Hi-C can be used as a genome-wide assay to detect translocations and other structural variants of potential clinical interest. Structural variants were identified in both bone marrow and peripheral blood samples, including an ETV6-RUNX1 translocation present in one pediatric B-ALL patient. Our report provides proof-of-principle that Hi-C could be an effective strategy to globally detect driver structural variants in B-ALL peripheral blood specimens, reducing the need for invasive bone marrow biopsies and candidate-based clinical tests.\",\n \"Multi-organ complement deposition in COVID-19 patients\\nBackgroundIncreased levels of circulating complement activation products have been reported in COVID-19 patients, but only limited information is available on complement involvement at tissue level. The mechanisms and pathways of local complement activation remain unclear.\\n\\nMethodsWe performed immunofluorescence analyses of autopsy specimens of lungs, kidney and liver from nine COVID-19 patients who died of acute respiratory failure. Snap-frozen samples embedded in OCT were stained with antibodies against complement components and activation products, IgG and spike protein of SARS-CoV-2.\\n\\nFindingsLung deposits of C1q, C4, C3 and C5b-9 were localized in the capillaries of the interalveolar septa and on alveolar cells. IgG displayed a similar even distribution, suggesting classical pathway activation. The spike protein is a potential target of IgG, but its uneven distribution suggests that other viral and tissue molecules may be targeted by IgG. Factor B deposits were also seen in COVID-19 lungs and are consistent with activation of the alternative pathway, whereas MBL and MASP-2 were hardly detectable. Analysis of kidney and liver specimens mirrored findings observed in the lung. Complement deposits were seen on tubules and vessels of the kidney with only mild C5b-9 staining in glomeruli, and on hepatic artery and portal vein of the liver.\\n\\nInterpretationComplement deposits in different organs of deceased COVID-19 patients caused by activation of the classical and alternative pathways support the multi-organ nature of the disease.\\n\\nFundingGrants from the Italian Ministry of Health (COVID-2020-12371808) to PLM and National Institutes of Health HL150146 to NP are gratefully acknowledged.\",\n \"Integrating de novo and inherited variants in over 42,607 autism cases identifies mutations in new moderate risk genes\\nDespite the known heritable nature of autism spectrum disorder (ASD), studies have primarily identified risk genes with de novo variants (DNVs). To capture the full spectrum of ASD genetic risk, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases recruited online by SPARK. In the first stage, we analyzed 19,843 cases with one or both biological parents and found that known ASD or neurodevelopmental disorder (NDD) risk genes explain nearly 70% of the genetic burden conferred by DNVs. In contrast, less than 20% of genetic risk conferred by rare inherited loss-of-function (LoF) variants are explained by known ASD/NDD genes. We selected 404 genes based on the first stage of analysis and performed a meta-analysis with an additional 22,764 cases and 236,000 population controls. We identified 60 genes with exome-wide significance (p < 2.5e-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1, and HNRNPUL2). The association of NAV3 with ASD risk is entirely driven by rare inherited LoFs variants, with an average relative risk of 4, consistent with moderate effect. ASD individuals with LoF variants in the four moderate risk genes (NAV3, ITSN1, SCAF1, and HNRNPUL2, n = 95) have less cognitive impairment compared to 129 ASD individuals with LoF variants in well-established, highly penetrant ASD risk genes (CHD8, SCN2A, ADNP, FOXP1, SHANK3) (59% vs. 88%, p= 1.9e-06). These findings will guide future gene discovery efforts and suggest that much larger numbers of ASD cases and controls are needed to identify additional genes that confer moderate risk of ASD through rare, inherited variants.\",\n \"Characteristics of Patients with Hematologic Malignancies Without Seroconversion Post-COVID19 Third Vaccine Dosing\\nPatients with hematologic malignancies (HM) are at greater risk of severe morbidity and mortality caused by COVID19 and show a lower response to a two-dose COVID19 mRNA vaccine series. The primary objective of this retrospective cohort study is to explore the characteristics of the subset of patients with HM who had little to no change in SARS-CoV-2 spike antibody titer levels after a 3rd vaccine dose (3V) (-/-). As a secondary objective, we seek to compare the cohorts of patients who did and did not seroconvert post-3V to get a better understanding of the demographics and potential drivers of serostatus. A total of 625 patients with HM had two titer results at least 21 days apart pre- and post- the 3V dose. Among the participants who were seronegative prior to 3V (268), 149 (55.6%) seroconverted after the 3V dose and 119 (44.4%) did not. HM diagnosis was significantly associated with seroconversion status (P = .0003) with patients non-Hodgkin lymphoma 6 times the odds of not seroconverting compared to multiple myeloma patients (P = .0010). Among the cohort of patients who remained seronegative post-3V, 107 (90.0%) patients showed no reaction to 3V as indicated by pre- and post- 3V index values. This study focuses on an important subset of patients with HM who are not seroconverting after the COVID mRNA 3V, providing much needed data for clinicians to target and counsel this subset of patients.\",\n \"Virtual Trials: Causally-validated treatment effects efficiently learned from an observational cancer registry\\nRandomized controlled trials (RCTs) offer a clear causal interpretation of treatment effects, but are inefficient in terms of information gain per patient. Moreover, because they are intended to test cohort-level effects, RCTs rarely provide information to support precision medicine, which strives to choose the best treatment for an individual patient. If causal information could be efficiently extracted from widely available real-world data, the rapidity of treatment validation could be increased, and its costs reduced. Moreover, inferences could be made across larger, more diverse patient populations. We created a \\\"virtual trial\\\" by fitting a multilevel Bayesian survival model to treatment and outcome records self-reported by 451 brain cancer patients. The model recovers group-level treatment effects comparable to RCTs representing over 3200 patients. The model additionally discovers the feature-treatment interactions needed to make individual-level predictions for precision medicine. By learning from heterogeneous real-world data, virtual trials can generate more causal estimates with fewer patients than RCTs, and they can do so without artificially limiting the patient population. This demonstrates the value of virtual trials as a complement to large randomized controlled trials, especially in highly heterogeneous or rare diseases.\",\n \"Epigenetic impairment and blunted transcriptional response to Mycobacterium tuberculosis of alveolar macrophages from persons living with HIV\\nPersons living with HIV (PLWH) are at increased risk of tuberculosis (TB). HIV-associated TB is often the result of recent infection with Mycobacterium tuberculosis (Mtb) followed by rapid progression to disease. Alveolar macrophages (AM) are the first cells of the innate immune system that engage Mtb, but how HIV and antiretroviral therapy (ART) impact on the anti-mycobacterial response of AM is not known. To investigate the impact of HIV and ART on the transcriptomic and epigenetic response of AM to Mtb, we obtained AM by bronchoalveolar lavage from 20 PLWH receiving ART, 16 control subjects who were HIV-free (HC), and 14 subjects who received ART as pre-exposure prophylaxis (PrEP) to prevent HIV infection.\\n\\nFollowing in-vitro challenge with Mtb, AM from each group displayed overlapping but distinct profiles of significantly up- and down-regulated genes in response to Mtb. Compared to HC subjects, AM isolated from PLWH and PrEP subjects presented a substantially weaker transcriptional response. Further investigation of chromatin structure revealed that AM from control subjects challenged with Mtb responded with pronounced accessibility changes in over ten thousand regions. In stark contrast, AM obtained from PLWH and PrEP subjects displayed no significant changes in their chromatin state in response to Mtb. Collectively, these results revealed a previously unknown adverse effect of ART on the epigenetic landscape and transcriptional responsiveness of AM.\",\n \"Response of human liver tissue to innate immune stimuli\\nPrecision-cut human liver slice cultures (PCLS) has become an important alternative immunological platform in preclinical testing. To further evaluate the capacity of PCLS, we investigated the innate immune response to TLR3 agonist (poly-I:C) and TLR4 agonist (LPS) with the normal and pathological liver tissue. Pathological liver tissue was obtained from patients with active chronic HCV infection, and patients with former chronic HCV infection cured by recent Direct-Acting Antiviral (DAA) drug therapy. We found that hepatic innate immunity was not suppressed but enhanced in the HCV-infected tissue, compared with the healthy controls. Furthermore, despite recent HCV elimination, DAA-cured liver tissue manifested ongoing abnormalities in liver immunity. Sustained abnormal immune gene expression in DAA-cured samples were identified from direct ex vivo measurements and with TLR3 and TLR4 stimulation assays. Those genes that were up-regulated in chronic HCV-infected liver tissue were enriched in expression in the liver non-parenchymal cell compartment. These results demonstrated the utility of PCLS in studying the liver pathology and innate immunity.\",\n \"The relationship between wild-type transthyretin amyloid load and ligamentum flavum thickness in lumbar stenosis patients\\nBackgroundOne key contributor to lumbar stenosis is thickening of the ligamentum flavum (LF), a process still poorly understood. Wild-type transthyretin amyloid (ATTRwt) has been found in the LF of patients undergoing decompression surgery, suggesting that amyloid may play a role. However, it is unclear whether within patients harboring ATTRwt, the amount of amyloid is associated with LF thickness.\\n\\nMethodsFrom an initial cohort of 324 consecutive lumbar stenosis patients whose LF specimens from decompression surgery were sent for analysis (2018-2019), 33 patients met the following criteria: (1) Congo red-positive amyloid in the LF; (2) ATTRwt by mass spectrometry-based proteomics; and (3) an available preoperative MRI. Histological specimens were digitized, and amyloid load quantified through Trainable Weka Segmentation (TWS) machine learning. LF thicknesses were manually measured on axial T2-weighted preoperative MRI scans at each lumbar level, L1-S1. The sum of thicknesses at every lumbar LF level (L1-S1) equals \\\"lumbar LF burden.\\\"\\n\\nResultsPatients had a mean age of 72.7 years (range 59-87), were mostly male (61%) and white (82%); and predominantly had surgery at L4-L5 levels (73%). Amyloid load was positively correlated with LF thickness (R=0.345, p=0.0492) at the levels of surgical decompression. Furthermore, amyloid load was positively correlated with lumbar LF burden (R=0.383, p=0.0279).\\n\\nConclusionsAmyloid load is positively correlated with LF thickness and lumbar LF burden across all lumbar levels, in a dose-dependent manner. Further studies are needed to validate these findings, uncover the underlying pathophysiology, and pave the way towards using therapies that slow LF thickening.\",\n \"Psychological, endocrine and polygenic predictors of emotional well-being during the COVID-19 pandemic\\nStress is an established risk factor for somatic and mental disorders. The COVID-19 pandemic and the related countermeasures severely affect the lives of families. Prenatal stress, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and genetic factors might impact the well-being of individuals.\\n\\nThe present work is part of an ongoing birth cohort study and aims to investigate maternal perceived stress, early childhood HPA axis activity and polygenic risk scores (PRSs) as predictors of emotional well-being during the COVID-19 pandemic. All participants are part of the ongoing birth cohort study POSEIDON. Emotional well-being of children (n = 259) and mothers (n = 211) was assessed during the COVID-19 pandemic using the CRISIS questionnaire. Furthermore, associations between previously assessed maternal perceived stress (Perceived Stress Scale), childrens salivary and morning urine cortisol measures at 45 months, PRSs for depression, schizophrenia, loneliness and current emotional well-being were investigated.\\n\\nA positive association between the childs and the mothers emotional well-being was found. A worse emotional well-being was observed in both children and mothers during the pandemic compared to before. Childrens emotional well-being improved over the course of the pandemic, while mothers well-being worsened. Maternal perceived stress, salivary and morning urine cortisol and PRSs were not significantly associated with the assessed emotional wellbeing.\\n\\nThe present study confirms that emotional well-being of children and mothers is negatively affected by the COVID-19 pandemic, with differences in development over time. Future studies should examine which mechanisms contribute to stress-related associations and at which age they can be identified.\",\n \"Pausing methotrexate improves immunogenicity of COVID-19 vaccination in patients with rheumatic diseases\\nObjectiveTo study the effect of methotrexate (MTX) and its discontinuation on the humoral immune response after COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD).\\n\\nMethodsNeutralising SARS-CoV-2 antibodies were measured after second vaccination in 64 rheumatic patients on methotrexate therapy, 31 of whom temporarily paused medication without a fixed regimen. The control group consisted of 21 AIRD patients without immunosuppressive medication.\\n\\nResultsMTX patients showed a significantly lower median antibody response compared to AIRD patients without immunosuppressive therapy (p< 0.001). Young age (<60 years) and MTX-hold after vaccination were found to be the main factors influencing antibody response after vaccination, while BMI or MTX dose demonstrated no effect. For patients taking MTX, age correlated negatively with immune response (r=-0.49; p<0.001) and all patients with antibody levels (14 %) below the cut-off were older than 60 years. Patients who held MTX during at least one vaccination showed significantly higher median neutralising antibody levels after second vaccination, compared to patients who continued MTX therapy during both vaccinations (68.82 %, 92.73 %, p=<0.001). This effect was particularly pronounced in patients older than 60 years (p=0.0016). The impact of the time period after vaccination was greater than of the time before vaccination with the critical cut-off being 10 days.\\n\\nConclusionMTX reduces the immunogenicity of SARS-CoV-2 vaccination in an age-dependent manner. Our data further suggest that holding MTX for at least 10 days after vaccination significantly improves the antibody response in patients over 60 years of age.\",\n \"Prenatal alcohol consumption and child IQ and cognition: a Mendelian randomization study\\nBackgroundPrevious studies using Mendelian randomization have found that fetal alcohol exposure may be associated with lower IQ and test scores in childhood.\\n\\nObjectivesWe aim to replicate and extend these findings in Generation R Study, a birth cohort based in Rotterdam, the Netherlands.\\n\\nMethodsWe used data from Generation R which recruited pregnant women between 2002 and 2006. Alcohol use was assessed via questionnaire during each trimester. IQ was measured in the children between ages 5 and 8 using the Snijders-Oomen Non-Verbal Intelligence Test. Scores from a national standardized test administered around age 12 were used as a measure of cognition. We estimated the associations between ten genetic variants in the mothers previously found to be related to alcohol consumption and metabolism and each of the outcomes. In the children, we also estimated the association between the same genetic variants as well as two polygenic scores for alcohol consumption and the outcomes.\\n\\nResultsMaternal genetic variants were not found to be related to either outcome but wide confidence intervals did not preclude important effects. A few genetic variants in the children were suggestive of a decrease in IQ. Likewise, one genetic variant and the genetic score had estimates and confidence intervals consistent with increases in standardized test scores.\\n\\nConclusionsOur results provide slight support for associations between genetic variants in children related to maternal prenatal alcohol consumption and IQ and cognition outcomes. These findings are in line with two previous studies on this topic.\",\n \"Polygenic effect on accelerated tau pathology accumulation in Alzheimer's disease: Implications for patient selection in clinical trials\\nProgression of fibrillar tau is a key driver of dementia symptoms in Alzheimers disease (AD), but predictors of the rate of tau accumulation at patient-level are missing. Here we combined the to-date largest number of genetic risk variants of AD (n=85 lead SNPs) from recent GWAS to generate a polygenic score (PGS) predicting the rate of change in fibrillar tau. We found that a higher PGS was associated with higher rates of PET-assessed fibrillar-tau accumulation over a mean of 1.8 yrs (range = 0.6 - 4 yrs). This, in turn, mediated effects of the PGS on faster rates of cognitive decline. Sensitivity analysis showed that the effects were similar for men and women but pronounced in individuals with elevated levels of beta-amyloid and strongest for lead SNPs expressed in microglia. Together, our results demonstrate that the PGS predicts tau progression in Alzheimers disease, which could afford sample size savings by up to 34% when used alone and up to 61% when combined with APOE {varepsilon}4 genotype in clinical trials targeting tau pathology.\",\n \"Age and Sex Differences in the Genetics of Cardiomyopathy\\nAimsCardiomyopathy is a clinically and genetically heterogeneous disorder with age and sex-related differences in severity and outcomes. The aim of our study was to identify age and sex-related differences in the genetic architecture of cardiomyopathy.\\n\\nMethods and ResultsWe analyzed whole genome sequence data from 471 pediatric and 926 adult cardiomyopathy patients from our Heart Centre Biobank and from the Genomics England cohort. Overall yield of rare deleterious coding variants was higher in pediatric compared to adult onset cardiomyopathy, but not different by sex. MYH7, TNNT2, MYL3, and VCL variants were more frequent in pediatric patients; TTN and OBSCN variants were more frequent in adult patients, with MYH7 (Odds ratio 3.6; CI 2.1-6.3) and OBSCN (Odds ratio 5.5, CI 2.0-21.4) remaining significant after adjusting for multiple testing. Variants in early-onset cardiomyopathy clustered in highly constrained coding regions compared to those in adult patients (p=3.9x10-3). There were also differences between pediatric and adult patients in variant location within MYH7 and TTN genes. When analyzed by sex, variants in female compared to male patients were in more highly constrained coding regions (p=0.002).\\n\\nConclusionOur findings highlight under-appreciated genetic differences in early versus late onset cardiomyopathy. Variants in childhood cardiomyopathy and in female patients were in highly constrained coding regions of the genome suggesting greater deleterious effects and strong purifying selection in the general population. Knowledge of the affected gene, variant location within the gene, and variant constraint scores may be useful in predicting early versus late onset cardiomyopathy.\",\n \"OCT2Hist: Non-Invasive Virtual Biopsy Using Optical Coherence Tomography\\nHistological haematoxylin and eosin-stained (H&E) tissue sections are used as the gold standard for pathologic detection of cancer, tumour margin detection, and disease diagnosis1. Producing H&E sections, however, is invasive and time-consuming. Non-invasive optical imaging modalities, such as optical coherence tomography (OCT), permit label-free, micron-scale 3D imaging of biological tissue microstructure with significant depth (up to 1mm) and large fields-of-view2, but are difficult to interpret and correlate with clinical ground truth without specialized training3. Here we introduce the concept of a virtual biopsy, using generative neural networks to synthesize virtual H&E sections from OCT images. To do so we have developed a novel technique, \\\"optical barcoding\\\", which has allowed us to repeatedly extract the 2D OCT slice from a 3D OCT volume that corresponds to a given H&E tissue section, with very high alignment precision down to 25 microns. Using 1,005 prospectively collected human skin sections from Mohs surgery operations of 71 patients, we constructed the largest dataset of H&E images and their corresponding precisely aligned OCT images, and trained a conditional generative adversarial network4 on these image pairs. Our results demonstrate the ability to use OCT images to generate high-fidelity virtual H&E sections and entire 3D H&E volumes. Applying this trained neural network to in vivo OCT images should enable physicians to readily incorporate OCT imaging into their clinical practice, reducing the number of unnecessary biopsy procedures.\",\n \"Impact of inspiratory vs expiratory incentive spirometry on obstructive, restrictive, and mixed ventilatory impairments: Study protocol. Effect of incentive spirometry on respiratory impairments.\\nBackgroundRespiratory impairments are adjusted reduction in pulmonary function that manifests with adverse effects on an individuals state of health. The basis for identifying these impairments requires differentiation between normal and abnormal ventilatory capacity to avoid inaccurate and potentially harmful drug prescriptions and a mismatch of diagnoses. Incentive Spirometry (IS) is a technique designed to help patients achieve a pre-set volume of airflow; the volume is determined from predicted values or baseline measurements.\\n\\nMethodsFifty-four (54) patients with Obstructive, Restrictive, or Mixed type of respiratory impairments attending the respiratory clinic of Lagos State University Teaching Hospital, Ikeja (LASUTH) will be assessed for eligibility for the study. The study design will be a double-blind, randomized control trial with six intervention groups and three placebo control groups.\\n\\nThe studys independent variable will be an Inspiratory Incentive Spirometry (IIS) and Expiratory Incentive Spirometry (EIS), while Obstructive, Restrictive, and Mixed respiratory impairments will serve as the dependent variable for the study. Baseline Pulmonary Function Test (PFT) will be assessed on entry into the study, and after every procedure, six minutes walk (6MWT) test and CAT assessment test will be assessed at every two (2) weeks interval of the study. Data will be analyzed using descriptive and inferential statistics of repeated ANOVA; P<0.05.\\n\\nDiscussionThe study outcome will determine the relationship between inspiratory and expiratory incentive spirometry on respiratory impairments and deduce the best fit device for the respective impairment.\\n\\nTrial Registrationwww.pactr.org: PACTR202005904039357\",\n \"Adaptive, Unlabeled and Real-time Approximate-Learning Platform (AURA) for Personalized Epileptic Seizure Forecasting\\nA high performance event detection system is all you need for some predictive studies. Here, we present AURA: an Adaptive forecasting model trained with Unlabeled, Real-time data using internally generated Approximate labels on-the-fly. By harnessing the correlated nature of time-series data, a pair of detection and prediction models are coupled together such that the detection model generates labels automatically, which are then used to train the prediction model. AURA relies on several simple principles and assumptions: (i) the performance of an event prediction/forecasting model in the target application remains below the performance of an event detection model, (ii) detected events are treated as weak labels and deemed reliable enough for online training of a predictive model, and (iii) system performance and/or system responsive feedback characteristics can be tuned for a subject-under-test. For example, in medical patient monitoring, this enables personalizing forecasting models. Seizure prediction is identified as an ideal test case of AURA, as pre-ictal brainwaves are patient-specific and tailoring models to individual patients can significantly improve forecasting performance. AURA is used to generate an individual forecasting model for 10 patients, showing an average relative improvement in sensitivity by 14.30% and reduction in false alarms by 19.61%. This paper presents a proof-of-concept for the feasibility of online transfer-learning on a stream of time-series neurophysiological data that pave the way towards a low-power neuromorphic neuromodulation system.\",\n \"The common H202D variant in GDF-15 does not affect its bioactivity but can significantly interfere with measurement of its circulating levels\\nGenetic variants in proteins can interfere with measurement of their circulating concentrations. Given the growing biomedical importance of GDF-15, we wished to establish whether a common histidine to aspartate variant present in position 6 of the mature GDF-15 protein (H202D variant) interfered with its measurement by two commonly used immunoassays. We first examined the detectability of recombinant monomers, homodimers and heterodimers of GDF-15 by assays and/or reagents used in two widely used immunoassays (Roche Elecsys(R) GDF-15 and the R&D antibody combinations used in their Quantikine(R) and DuoSet(R) ELISAs). The Roche assay detected the H and D containing peptides similarly but the assays based on the R&D reagents consistently underreported concentrations of the D-containing variant peptide. Measurements of plasma concentrations of GDF-15 in genotyped human participants showed that the R&D reagents reported values in heterozygotes were [~]25% lower, and in homozygotes, 50% lower than the Roche assay. We finally studied the activation of the GDF-15 receptor, GFRAL-Ret, in a cell based assay and found that the activities of the HH and DD containing GDF-15 peptide were indistinguishable. These results have implications for the interpretation of genetic epidemiological studies which have used the R&D reagents to measure GDF-15, and for the emerging clinical use of GDF-15 as a diagnostic and prognostic biomarker. We provide correction equations, which may be of utility for the analysis of data generated with the R&D reagents where the genotype of the participants is known.\",\n \"Quantitative Digitography Solves the Remote Measurement Problem in Parkinson's disease\\nBackgroundAssessment of motor signs in Parkinsons disease (PD) has required an in-person examination. However, 50% of people with PD do not have access to a neurologist. Wearable sensors can provide remote measures of some motor signs but require continuous data acquisition for several days. A major unmet need is reliable metrics of all cardinal motor signs, including rigidity, from a simple short active task that can be performed remotely or in the clinic.\\n\\nObjectiveInvestigate whether thirty seconds of repetitive alternating finger tapping (RAFT) on a portable quantitative digitography (QDG) device, which measures amplitude and timing, produces reliable metrics of all cardinal motor signs in PD\\n\\nMethodsNinety-six individuals with PD and forty-two healthy controls performed a thirty-second QDG-RAFT task and clinical motor assessment. Eighteen individuals were followed longitudinally with repeated assessments for an average of three years and up to six years.\\n\\nResultsQDG-RAFT metrics differentiated individuals with PD from controls and provided validated metrics for total motor disability (MDS-UPDRS III) and for rigidity, bradykinesia, tremor, gait impairment and freezing of gait (FOG). Additionally, QDG-RAFT tracked disease progression over several years off therapy, and differentiated akinetic rigid from tremor dominant phenotypes, as well as people with from those without FOG.\\n\\nConclusionsQDG is a reliable technology, which will improve access to care, allows complex remote disease management, and accurate monitoring of disease progression over time in PD. QDG-RAFT also provides the comprehensive PD motor metrics needed for therapeutic trials.\",\n \"Reproducible in vivo detection of locus coeruleus pathology in Parkinson's disease\\nBackgroundPatients with Parkinsons disease undergo a loss of melanized neurons in substantia nigra pars compacta and locus coeruleus. There are very few in vivo studies of locus coeruleus pathology in Parkinsons disease with magnetic resonance imaging. Existing studies have used varying methodologies, and reproducibility has not been established for any approach.\\n\\nObjectivesWe used neuromelanin-sensitive magnetic resonance imaging to examine the reproducibility of locus coeruleus and substantia nigra pars compacta degeneration in discovery and validation cohorts.\\n\\nMethodsTwo cohorts, discovery and validation, recruited from the Emory Movement Disorders Clinic were scanned on two different magnetic resonance imaging scanners. In cohort 1, imaging data from 19 controls and 22 Parkinsons disease patients were acquired with a Siemens Trio 3 Tesla scanner using a 2D gradient echo sequence with magnetization transfer preparation pulse. Cohort 2 consisted of 33 controls and 39 Parkinsons disease patients were scanned on a Siemens Prisma 3 Tesla scanner with a similar imaging protocol. Nigral and locus coeruleus volumes were segmented in both cohorts.\\n\\nResultsNigral volume (Cohort 1: p=0.0148; Cohort 2: p=0.0011) and locus coeruleus volume (Cohort 1: p=0.0412; Cohort 2: p=0.0056) were significantly reduced in the Parkinsons disease group as compared to controls in both cohorts.\\n\\nInterpretationSubstantia nigra pars compacta volume and locus coeruleus volume were significantly reduced in Parkinsons disease compared to controls in both cohorts. This imaging approach robustly detects Parkinsons disease effects on these structures suggesting its use as a potential diagnostic biomarker of Parkinsons disease.\",\n \"Surveillance of potential pathogens and antibiotic resistance in wastewater and surface water from Boston, USA and Vellore, India using long-read metagenomic sequencing\\nEnvironmental sampling (wastewater) could be an efficient surveillance strategy to capture global emerging trends in the spread of antibiotic resistance. Long-read DNA sequencing can resolve the genetic context of antibiotic resistance genes (ARGs) and is a promising tool for non-culture-based monitoring of antibiotic-resistant pathogens and ARGs in environmental samples, but has not been rigorously validated against conventional methods. We tested long-read sequencing using the portable Nanopore MinION for surveying pathogens, ARGs, and antibiotic-resistant pathogens in municipal wastewater, hospital wastewater, and surface water collected from Boston, USA and Vellore, India. We compared detection of enteric pathogens by assembly of long reads, with and without short-read polishing, and unassembled raw long reads for ARGs to multiplex real-time PCR. Using real-time PCR as a benchmark, long-read metagenomics was 49% sensitive and 75% specific at pathogen detection in assembled contigs, and 16% sensitive and 100% specific at detecting 28 clinically relevant resistance genes in raw long reads. Short-read polishing did not substantially improve pathogen identification or impact ARG identification in the assembled contigs, demonstrating that short-read polishing is not required, which greatly reduces costs. The high specificity of ARG detection supports portable long-read sequencing as a valuable tool to profile ARGs and antibiotic-resistant pathogens for environmental surveillance programs.\",\n \"Distinctive modularity and resilience of structural covariance network in first-episode antipsychotic-naive psychoses\\nObjectiveDivergent findings in structural brain alterations in psychoses suggest that often-observed regions may exist within a network of susceptible regions. We built structural covariance networks (SCN) of volumes, cortical thickness, and surface area using the Human Connectome Project atlas-based parcellation of 358 regions on structural MRI data from 79 first-episode antipsychotic-naive psychosis patients (FEAP) and 68 controls.\\n\\nMethodsUsing graph theoretic methods, we obtained representative graph metrics of integration, segregation, resilience, centrality, importance, community structure, and hub distribution for all 3-morphometric features. We compared networks for resilience by simulated removal (\\\"attacks\\\") of nodes and hubs, and simulated replacement of correlations among nodes in FEAP with that of controls using DeltaCon metric.\\n\\nResultsVolume and thickness SCNs of FEAP showed differences in many graph metrics in opposite directions compared to controls but not surface area SCN. Network resilience did not show differences in the replacement simulation and hub \\\"attacks, but betweenness centrality-based node \\\"attacks\\\" showed FEAP network disintegrating with relatively fewer node removals with preserved global efficiency compared to controls. In FEAP, communities consisted of regions from different lobes and hubs were more distributed than in controls.\\n\\nConclusionsOur findings suggest decreased heterogeneity and less differentiated community structure of FEAP network that may not be attributed to illness chronicity and medications. Contribution of cortical thickness but not surface area suggests that disease/developmental processes may preferentially affect cortical thickness. Near-similar resilience of FEAP and control networks may shield controls from developing illness but may prevent fuller long-term recovery in FEAP.\",\n \"Alpha globin gene copy number and hypertension risk among Black Americans\\nBACKGROUNDAlpha globin is expressed in the endothelial cells of human resistance arteries where it binds to endothelial nitric oxide synthase and limits release of the vasodilator nitric oxide. Genomic deletion of the alpha globin gene (HBA) is common among Black Americans and could lead to increased endothelial nitric oxide signaling and reduced risk of hypertension.\\n\\nMETHODSCommunity-dwelling US adults aged 45 years or older were enrolled and examined from 2003 to 2007, followed by telephone every 6 months, and reexamined from 2013 to 2016. At both visits, trained personnel performed standardized, in-home blood pressure measurements and pill bottle review. Prevalent hypertension was defined as systolic blood pressure [≥] 140mmHg or diastolic blood pressure [≥] 90mmHg or anti-hypertensive medication use. Droplet digital PCR was used to determine HBA copy number. The associations of HBA copy number with prevalent hypertension, resistant hypertension, and incident hypertension were estimated using multivariable regression.\\n\\nRESULTSAmong 9,684 Black participants, 7,439 (77%) had hypertension at baseline and 1,044 of those had treatment-resistant hypertension. 1,000 participants were not hypertensive at baseline and participated in a follow up visit; 517 (52%) developed hypertension over median 9.2 years follow-up. Increased HBA copy number was not associated with prevalent hypertension (PR=1.00; 95%CI 0.98,1.02), resistant hypertension (PR=0.95; 95%CI 0.86,1.05), or incident hypertension (RR=0.96; 95%CI 0.86,1.07).\\n\\nCONCLUSIONSThere were no associations between increased HBA copy number and risk of hypertension. These findings suggest that genetic variation in alpha globin gene expression does not modify the risk of hypertension among Black American adults.\",\n \"AugmentA: Patient-specific Augmented Atrial model Generation Tool\\nDigital twins of patients hearts are a promising tool to assess arrhythmia vulnerability and to personalize therapy. However, the process of building personalized computational models can be challenging and requires a high level of human interaction. A pipeline to standardize the generation of a patients atrial digital twin from clinical data is therefore desirable. We propose a patient-specific Augmented Atria generation pipeline (AugmentA) as a highly automated framework which, starting from clinical geometrical data, provides ready-to-use atrial personalized computational models. AugmentA consists firstly of a preprocessing step applied to the input geometry. Secondly, the atrial orifices are identified and labelled using only one reference point per atrium. If the user chooses to fit a statistical shape model (SSM) to the input geometry, it is first rigidly aligned with the given mean shape before a nonrigid fitting procedure is applied. AugmentA automatically generates the fiber orientation and finds local conduction velocities by minimizing the error between the simulated and clinical local activation time (LAT) map. The pipeline was tested on a cohort of 29 patients on both segmented magnetic resonance images (MRI) and electroanatomical maps of the left atrium. Moreover, the pipeline was applied to a bi-atrial volumetric mesh derived from MRI. The pipeline robustly integrated fiber orientation and anatomical region annotations in 38.4{+/-}5.7 s. The error between insilico and clinical LAT maps was on average 12.7 ms. In conclusion, AugmentA offers an automated and comprehensive pipeline delivering atrial digital twins from clinical data in procedural time.\",\n \"Pediatric Nemaline Myopathy: A systematic review using individual patient data\\nContextNemaline myopathy (NM) is a skeletal muscle disease that affects 1 in 50,000 live births.\\n\\nObjectiveDevelop a narrative synthesis of the findings of a systematic review of the latest case descriptions of patients with nemaline myopathy.\\n\\nData SourcesA systematic search of MEDLINE, Embase, CINAHL, Web of Science, and Scopus was performed using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines using the keywords pediatric, child, nemaline myopathy, nemaline rod, rod myopathy.\\n\\nStudy SelectionCase studies focused on pediatric NM and published in English between January 1, 2010 and December 31, 2020 in order to represent the most recent findings.\\n\\nData ExtractionInformation was collected about the age of first signs, earliest presenting neuromuscular signs and symptoms, systems affected, progression, death, pathological description, and genetic changes.\\n\\nResultsOf a total of 385 records, 55 case reports or series were reviewed, covering 101 pediatric patients from 23 countries. We review varying presentations in children ranging in severity despite being caused by the same mutation, in addition to current and future clinical considerations relevant to the care of patients with nemaline myopathy.\\n\\nLimitationsThe results are limited by findings shared in the literature, which varied in their detail and sometimes lacked histological or genetic results. Trends and correlations may be altered by information available.\\n\\nConclusionsThis review synthesizes genetic, histopathologic, and disease presentation findings from pediatric nemaline myopathy case reports. These data strengthen our understanding of the wide spectrum of disease seen in nemaline myopathy. Future studies are needed to identify the underlying molecular mechanism of pathology, to improve diagnostics, and to develop better methods to improve quality of life for these patients.\",\n \"Clinical improvement of DM1 patients reflected by reversal of disease-induced gene expression in blood\\nMyotonic dystrophy type 1 (DM1) is an incurable multisystem disease caused by a CTG-repeat expansion in the DM1 protein kinase (DMPK) gene. The OPTIMISTIC clinical trial demonstrated positive and heterogenous effects of cognitive behavioral therapy (CBT) on the capacity for activity and social participations in DM1 patients. Here, we performed mRNA sequencing of full blood for 27 patients of the OPTIMISTIC cohort before and after the CBT intervention. We identified 608 genes for which their expression was significantly associated with the disease causing CTG-repeat expansion, as well as 1176 genes significantly associated with the average clinical response towards the intervention. Remarkably, all 97 genes significantly associated with both returned to more normal levels in patients who benefited most from CBT. This trend was consistent with the difference observed between DM1 patients and controls in an earlier study of blood mRNA expression levels, singling these genes out as candidate biomarkers for therapy response. Together these results highlight the ability to find disease relevant information in full blood of DM1 patients, opening new avenues to monitor therapy effects.\",\n \"SARS-CoV-2 evolution and immune escape in immunocompromised patients treated with exogenous antibodies\\nBackgroundSARS-CoV-2 mutations conferring escape from neutralizing antibodies can arise in immunocompromised patients with prolonged infection, but the conditions that facilitate immune escape are still not fully understood.\\n\\nMethodsWe characterized endogenous immune responses, within-host SARS-CoV-2 evolution, and autologous neutralization of the viral variants that arose in five immunocompromised patients with prolonged infection and B cell deficiencies.\\n\\nResultsIn two patients treated with the monoclonal antibody bamlanivimab, viral resistance to autologous serum arose early and persisted for several months, accompanied by ongoing evolution in the spike protein. These patients exhibited deficiencies in both T and B cell arms, and one patient succumbed to disease. In contrast, we did not observe spike mutations in immunologically important regions in patients who did not receive exogenous antibodies or who received convalescent plasma and had intact T cell responses to SARS-CoV-2.\\n\\nConclusionsOur results underscore the potential importance of multiple factors - the absence of an effective endogenous immune response, persistent virus replication, and selective pressure such as single-agent bamlanivimab - in promoting the emergence of SARS-CoV-2 mutations associated with immune evasion. These findings highlight the need for larger clinical studies in immunocompromised populations to better understand the ramifications of different therapies. Our results also confirm that patients with B cell deficiencies can elicit effector T cells and may suggest an important role for T cells in controlling infection, which is relevant to vaccines and therapeutics.\",\n \"Wastewater monitoring outperforms case numbers as a tool to track COVID-19 incidence dynamics when test positivity rates are high\\nWastewater-based epidemiology (WBE) has been shown to coincide with, or anticipate, confirmed COVID-19 case numbers. During periods with high test positivity rates, however, case numbers may be underreported, whereas wastewater does not suffer from this limitation. Here we investigated how the dynamics of new COVID-19 infections estimated based on wastewater monitoring or confirmed cases compare to true COVID-19 incidence dynamics. We focused on the first pandemic wave in Switzerland (February to April, 2020), when test positivity ranged up to 26%. SARS-CoV-2 RNA loads were determined 2-4 times per week in three Swiss wastewater treatment plants (Lugano, Lausanne and Zurich). Wastewater and case data were combined with a shedding load distribution and an infection-to-case confirmation delay distribution, respectively, to estimate incidence dynamics. Finally, the estimates were compared to reference incidence dynamics determined by a validated compartmental model. Incidence dynamics estimated based on wastewater data were found to better track the timing and shape of the reference infection peak compared to estimates based on confirmed cases. In contrast, case confirmations provided a better estimate of the subsequent decline in infections. Under a regime of high-test positivity rates, WBE thus provides critical information that is complementary to clinical data to monitor the pandemic trajectory.\",\n \"Optimal symptom combinations to aid COVID-19 case identification: analysis from a community-based, prospective, observational cohort\\nObjectivesDiagnostic work-up following any COVID-19 associated symptom will lead to extensive testing, potentially overwhelming laboratory capacity whilst primarily yielding negative results. We aimed to identify optimal symptom combinations to capture most cases using fewer tests with implications for COVID-19 vaccine developers across different resource settings and public health.\\n\\nMethodsUK and US users of the COVID-19 Symptom Study app who reported new-onset symptoms and an RT-PCR test within seven days of symptom onset were included. Sensitivity, specificity, and number of RT-PCR tests needed to identify one case (test per case [TPC]) were calculated for different symptom combinations. A multi-objective evolutionary algorithm was applied to generate combinations with optimal trade-offs between sensitivity and specificity.\\n\\nFindingsUK and US cohorts included 122,305 (1,202 positives) and 3,162 (79 positive) individuals. Within three days of symptom onset, the COVID-19 specific symptom combination (cough, dyspnoea, fever, anosmia/ageusia) identified 69% of cases requiring 47 TPC. The combination with highest sensitivity (fatigue, anosmia/ageusia, cough, diarrhoea, headache, sore throat) identified 96% cases requiring 96 TPC.\\n\\nInterpretationWe confirmed the significance of COVID-19 specific symptoms for triggering RT-PCR and identified additional symptom combinations with optimal trade-offs between sensitivity and specificity that maximize case capture given different resource settings.\\n\\nHighlightsO_LIWidely recommended symptoms identified only [~]70% COVID-19 cases\\nC_LIO_LIAdditional symptoms increased case finding to > 90% but tests needed doubled\\nC_LIO_LIOptimal symptom combinations maximise case capture considering available resources\\nC_LIO_LIImplications for COVID-19 vaccine efficacy trials and wider public health\\nC_LI\",\n \"Survival rate of positive peritoneal cytology in endometrial cancer; a systematic review and meta-analysis\\nBackgroundThe impact of positive peritoneal cytology on survival rate of endometrial cancer patients in different stages and histopathology is still controversial. We performed a systematic review and meta-analysis to investigate the influence of positive peritoneal cytology (PPC) on survival rate of patients with endometrial carcinoma.\\n\\nMethodsA systematic literature search of PubMed, Embase, Scopus, and Cochrane databases was conducted up to November 24, 2020. The quality of included studies was evaluated by Quality in prognosis study (QUIPS) tool.\\n\\nResultsInitially, 3014 articles were found, of which 65 met the inclusion criteria for qualitative analysis and 27 studies on 75897 patients with endometrial cancer were included in the meta-analysis. PPC was associated with a lower overall survival in endometrial cancer (HR= 2.102; 95% CI:1.629-2.711; P< 0.001). The findings also identified PPC as an independent prognostic factor for both disease-free survival (HR= 3.052; 95% CI: 2.348-2967; P< 0.001) and cancer specific survival (HR= 3.461; 95% CI: 2.280-5.254; P< 0.001). In addition, we meta-analyzed the studies in 21 subgroups based on staging and histopathology of the endometrial cancer which all identified PPC as a non-prognostic factor for cancer of endometrium.\\n\\nConclusionPPC is an independent prognostic factor for endometrial cancer survival rate in all staging and histopathologic subgroups.\",\n \"IL-13 is a driver of COVID-19 severity\\nImmune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here we report that elevated interleukin-13 (IL-13) was associated with the need for mechanical ventilation in two independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab had less severe disease. In SARS-CoV-2 infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, in the lung, hyaluronan synthase 1 (Has1) was the most downregulated gene and hyaluronan accumulation was decreased. Blockade of the hyaluronan receptor, CD44, reduced mortality in infected mice, supporting the importance of hyaluronan as a pathogenic mediator, and indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and hyaluronan has important implications for therapy of COVID-19 and potentially other pulmonary diseases.\\n\\nSummaryL-13 levels are elevated in patients with severe COVID-19. In a mouse model of disease, IL-13 neutralization results in reduced disease and lung hyaluronan deposition. Similarly, blockade of hyaluronans receptor, CD44, reduces disease, highlighting a novel mechanism for IL-13-mediated pathology.\",\n \"Cardiovascular Complications of Modern Multiple Myeloma Therapy: Analysis of FDA Adverse Event Reporting System\\nPurposeMultiple myeloma accounts for over 15% of hematological malignancies. In attempt to tackle this malady, the FDA approved four drugs in 2015 which has propagated further development of new anti-multiple myeloma since. However, the health safety of these new agents is still ill-defined. The aim of this study is to delineate the cardiovascular adverse events of these drugs.\\n\\nMethodsWe searched the cardiac adverse events of the newly approved FDA drugs since 2015 using the U.S. Food and Drug Administration Adverse Events Reporting System database (FAERS). We calculated the reporting odds ratio (ROR) with 95% confidence for four drugs that have the highest incidence of cardiovascular adverse events.\\n\\nResultsAmong the medications that have approved for MM Between 2015-2020, four novel drugs showed the highest incidence of cardiotoxicity. ROR (95% CI) for atrial fibrillation due to elotuzumab, Ixazomib, daratumumab, and panobinostat compared to other FAERS drugs was 5.8 (4.4-7.7), 1.93 (1.5-2.3), 4.8 (4.2-5.6), and 5.7 (4.1-8.1), respectively. The ROR (95% CI) for cardiac failure was 8.2 (6.4-10.5), 4.7 (4.1-5.4), 5.8 (4.9-6.7), and 5.6 (3.8-8.1) and ROR (95% CI) for coronary disease was 2.7 (1.9-3.9), 2.7 (2.3-3.2), 2,3 (1.9-2.8), and 4.6 (3.2-6.6) due to elotuzumab, Ixazomib, daratumumab, and panobinostat versus all other drugs in FAERS.\\n\\nConclusionsThe newly approved multiple myeloma therapy (elotuzumab, Ixazomib, daratumumab, panobinostat) are significantly associated with cardiotoxicity. These results highlight the importance of considering the cardiac history of patients with multiple myeloma when utilizing these novel agents.\",\n \"Rapid, Near Point-of-Care Assay for HLA-B*57:01 Genotype Associated with Severe Hypersensitivity Reaction to Abacavir\\nObjectiveThe nucleoside reverse transcriptase inhibitor abacavir is commonly used to treat young children with HIV infection. Abacavir can trigger a severe hypersensitivity reaction in people who are homozygous or heterozygous for HLA-B*57:01. Testing for HLA-B*57:01 prior to abacavir initiation is standard-of-care in high-resource settings, but current tests are too costly for resource-limited settings. To address this gap, we developed an inexpensive, simple-to-use rapid assay to detect HLA-B*57:01.\\n\\nMethodsWe designed and optimized a multiplexed PCR to amplify HLA-B*57 subtypes and the human beta-globin gene. Subsequently, probes annealed to the amplicon and were ligated when specific for the HLA-B*57:01 allele. Ligated products were detected by immunocapture in a lateral flow strip. Cell lines with known HLA genotypes were used to optimize the assay. The assay was then evaluated by comparing the genotype of clinical specimens (n=60) enriched for individuals with HLA-B*57:01 by the new assay to that from sequencing.\\n\\nResultsThe optimized multiplex PCR for B*57 and beta-globin resulted in a 40-minute, 35-cycle amplification, followed by a 20-minute ligation reaction and 15-minute detection step. Evaluation of the HLA-B*57:01 oligonucleotide ligation assay using clinical specimens had a sensitivity of 100% (n=27/27 typed as B*57:01) and specificity of 100% (n=33/33 typed as non-B*57:01) by visual interpretation of lateral flow strips.\\n\\nConclusionsThis rapid and economical assay can accurately detect the presence of HLA-B*57:01 in clinical specimens. Use of this assay could expand access to HLA-B*57:01 genotyping and facilitate safe same-day initiation of abacavir-based treatment.\",\n \"Genetic variants associated with cross-disorder and disorder-specific risk for psychiatric disorders are enriched at epigenetically active sites in peripheral lymphoid cells\\nMultiple psychiatric disorders have been associated with abnormalities in both the innate and adaptive immune systems. The role of these abnormalities in pathogenesis, and whether they are driven by psychiatric risk variants, remains unclear. We tested for enrichment of GWAS variants associated with multiple psychiatric disorders (cross-disorder or trans-diagnostic risk), or 5 specific disorders (cis-diagnostic risk), in regulatory elements in immune cells. We used three independent epigenetic datasets representing multiple organ systems and immune cell subsets. Trans-diagnostic and cis-diagnostic risk variants (for schizophrenia and depression) were enriched at epigenetically active sites in brain tissues and in lymphoid cells (T, B and NK cells), especially stimulated CD4+ T cells. There was no evidence for enrichment of either trans-risk or cis-risk variants for schizophrenia or depression in myeloid cells. This suggests a model where stimuli (e.g. infection) activate T cells to unmask the effects of psychiatric risk variants, contributing to the pathogenesis of mental health disorders.\",\n \"Revisiting the diagnostic criteria for emergence from the minimally conscious state: An empirical investigation\\nObjectiveTo determine whether consistent command-following (CCF) should be added to the diagnostic criteria for emergence from the minimally conscious state (MCS)\\n\\nDesignRetrospective cohort study\\n\\nSettingInpatient rehabilitation hospital\\n\\nParticipantsPatients with severe acquired brain injury and disorders of consciousness (DoC) admitted to a specialized rehabilitation program\\n\\nMain Outcome MeasureDifference between time to recovery of CCF and time to recovery of functional object use [FOU] or functional communication [FC] (the two existing criteria for emergence from MCS) as measured by the Coma Recovery Scale - Revised [CRS-R]).\\n\\nResultsOf 214 patients (median [interquartile range] age: 53 [34, 66] years, male: 134 (62.6%), traumatic etiology: 115 (53.7%), admission CRS-R total score: 10 [7, 13]) admitted to rehabilitation without CCF, FO, or FC, 162 (75.7%) recovered CCF and FOU or FC during the eight-week observation period. On average, recovery of CCF, FOU, and FC was observed within one day of one another, approximately 46 [38.25, 58] days post-injury. One hundred and sixteen patients (71.6%) recovered FOU or FC prior to or at the same time as CCF.\\n\\nConclusionsIn patients recovering from DoC, CCF reemerges around the same time as FOU and FC. This finding likely reflects the shared dependency of these behaviors on cognitive procecess (e.g., language comprehension, attention, motor control) that are essential for effective interpersonal interaction and social participation. Our results support the addition of CCF to the existing diagnostic criteria for emergence from MCS.\",\n \"Correlation between faecal microbial taxa and ulcerative colitis in different phases of disease activity in a north Indian cohort\\nBackground and AimsA link between gut microbiota and Ulcerative colitis (UC) has been established in several studies. However, only a few studies have examined specific changes in microbiota associated with different phases of disease activity in UC. In this study, we attempted to identify differentially abundant taxa between (i) UC patients and healthy controls and (ii) different phases of disease activity, in a genetically distinct north Indian (NI) population.\\n\\nMethods16S rRNA (V3-V4) sequencing of 105 patients with UC [newly diagnosed (n=14); patients in remission (n=36) and active disease (relapse, n=55)]; and 36 healthy controls was performed and analysed.\\n\\nResultsLower gut microbial diversity; enrichment of lactate-producing bacteria namely Streptococcus, Bifidobacterium and Lactobacillus; and depletion of butyrate-producing bacteria (e.g., Lachnospiraceae and Ruminococcaceae), were observed among UC patients. Subgroup analysis revealed differential abundance of Escherichia-Shigella, Streptococcus, Enterococcus and Faecalibacterium in newly diagnosed UC patients. No discrete microbial features were observed between patients in remission and those with active disease. Co-occurrence network analysis revealed a mutualistic association between opportunistic pathogens and Bifidobacterium and Lactobacillus and antagonistic relationship with butyrate-producers.\\n\\nConclusionThis first faecal microbiome study among NI UC cohort elucidated dysanaerobiosis; loss of short chain fatty acid producers and enrichment of inflammation associated microbes; population specific differential microbial genera; and a potential microbial signature for early dysbiosis.\",\n \"IL-1 and IL-6 inhibitor hypersensitivity link to common HLA-DRB1*15 alleles\\nIn Saper et al (2019), we described systemic JIA patients who developed a high-fatality diffuse lung disease (DLD) while on IL-1 or IL-6 inhibitors. We observed severe delayed drug hypersensitivity reactions (DHR) in a significant subset. Because alleles of the human leukocyte antigen (HLA) loci can mediate DHR, we investigated HLA genotype association with these DHR. We typed subjects treated with these inhibitors: 34 sJIA/DHR/DLD, 11 sJIA/DHR without DLD, 18 drug-tolerant sJIA, and 19 Kawasaki disease (KD) patients in an anti-IL-1(anakinra) trial. We also accessed genotypes from a large sJIA case/control cohort.\\n\\nWe first compared White subjects with sJIA/DHR to 550 ancestry-matched sJIA subjects. We found striking enrichments of HLA-DRB1*15:01, HLA-DQA1*01:02, and DQB1*06:02, alleles in near-complete linkage (White individuals). HLA-DRB 1*15:01 (as haplotype proxy) was increased in White sJIA subjects with DHR/DLD versus sJIA drug-tolerant controls and was observed upon inclusion of sJIA+DHR-only and KD+DHR White subjects. In our entire cohort regardless of ancestry, 75% carried HLA-DRB 1*15:01 or the structurally related DRB1*15:03 and DRB1*15:06, which were absent among drug-tolerant subjects (p=5 x 10-13; Odds Ratio lower bound=20.11).\\n\\nPatients who harbor HLA-DRB1*15 alleles are at high risk of developing DHR to anti-IL-1/IL-6. Our data also suggest DHR maybe a trigger/enhancer of DLD in sJIA patients and support performing prospective HLA screening in sJIA, its adult-onset counterpart, and other inflammatory conditions where these drugs are used, such as KD.\",\n \"SplitStrains, a tool to identify and separate mixed Mycobacterium tuberculosis infections from WGS data\\nThe occurrence of multiple strains of a bacterial pathogen such as M. tuberculosis or C. difficile within a single human host, referred to as a mixed infection, has important implications for both healthcare and public health. However, methods for detecting it, and especially determining the proportion and identities of the underlying strains, from WGS (whole-genome sequencing) data, have been limited.\\n\\nIn this paper we introduce SplitStrains, a novel method for addressing these challenges. Grounded in a rigorous statistical model, SplitStrains not only demonstrates superior performance in proportion estimation to other existing methods on both simulated as well as real M. tuberculosis data, but also successfully determines the identity of the underlying strains.\\n\\nWe conclude that SplitStrains is a powerful addition to the existing toolkit of analytical methods for data coming from bacterial pathogens, and holds the promise of enabling previously inaccessible conclusions to be drawn in the realm of public health microbiology.\\n\\nAuthor summaryWhen multiple strains of a pathogenic organism are present in a patient, it may be necessary to not only detect this, but also to identify the individual strains. However, this problem has not yet been solved for bacterial pathogens processed via whole-genome sequencing. In this paper, we propose the SplitStrains algorithm for detecting multiple strains in a sample, identifying their proportions, and inferring their sequences, in the case of Mycobacterium tuberculosis. We test it on both simulated and real data, with encouraging results. We believe that our work opens new horizons in public health microbiology by allowing a more precise detection, identification and quantification of multiple infecting strains within a sample.\",\n \"Novel Application of a Multistate Model to Evaluate the Opioid Use Disorder Care Cascade: A Retrospective Cohort Study\\nBackgroundEvaluating the opioid use disorder (OUD) care cascade can improve OUD treatment retention and care.\\n\\nObjectivesTo identify risk and protective factors for retention among patients in OUD treatment.\\n\\nMethodsWe conducted a retrospective cohort study among patients diagnosed with OUD using data from the Rhode Island (RI) All-Payer Claims Database from 2011 to 2019. Patients who initiated treatment (Stage 2) were classified into sub-stages of retention (Stage 3) corresponding to multistate modeling states capturing early retention (sub-stage 1), short and long-term retention (sub-stage 2), and short and long-term disengagement (sub-stage 3). The association of baseline characteristics with state transitions were evaluated.\\n\\nResultsA cohort of 6,939 RI residents diagnosed with OUD included 41% aged 40 to 60 years, 57.6% male, and 70.8% Medicaid beneficiaries. In sub-stage 1, cannabis (Relative risk ratios (RRR) = 1.16; 95% confidence interval (CI) = 1.04,1.29) and cocaine use disorders (RRR=1.15; 95% CI=1.05,1.25) increased early disengagement risk after engagement. Medicaid beneficiaries were less likely to experience early disengagement (RRR=0.81; 95% CI =0.76,0.87). In sub-stage 2, alcohol (RRR=1.29; 95% CI=1.13,1.47) or cocaine use disorders (RRR=1.18; 95% CI=1.01,1.40) increased risk of disengagement among patients in the retention states. In sub-stage 3, tobacco (RRR=1.10; 95% CI=1.01,1.21) and alcohol (RRR=1.14; 95% CI=1.03,1.27) use disorders were associated with re-engagement from disengaged states.\\n\\nConclusionThe multistate model applied to a cohort of patients initiating medication for OUD led to the identification of factors associated with treatment engagement and retention. These results may guide strategies to sustain treatment among OUD patients.\",\n \"Linking common and rare disease genetics through gene regulatory networks\\nGenetic variants identified through genome-wide association studies (GWAS) are typically non-coding and exert small regulatory effects on downstream genes, but which downstream genes are ultimately impacted and how they confer risk remains mostly unclear. Conversely, variants that cause rare Mendelian diseases are often coding and have a more direct impact on disease development. We demonstrate that common and rare genetic diseases can be linked by studying the gene regulatory networks impacted by common disease-associated variants. We implemented this in the Downstreamer method and applied it to 44 GWAS traits and find that predicted downstream \\\"key genes\\\" are enriched with Mendelian disease genes, e.g. key genes for height are enriched for genes that cause skeletal abnormalities and Ehlers-Danlos syndromes. We find that 82% of these key genes are located outside of GWAS loci, suggesting that they result from complex trans regulation rather than being impacted by disease-associated variants in cis. Finally, we discuss the challenges in reconstructing gene regulatory networks and provide a roadmap to improve identification of these highly connected genes for common traits and diseases.\",\n \"Association between Systemic Lupus Erythematosus and Coronary Heart Disease: a retrospective case-control analysis and Mendelian Randomization Study\\nObjectivesTo appraise the causal effect of systemic lupus erythematosus (SLE) for risk of Coronary heart disease (CHD).\\n\\nMethodsWe selected single nucleotide polymorphisms (SNPs) associated with SLE as instrumental variables (IVs) from three independent genome-wide association studies (GWAS), the three largest to date for SLE of European ancestry. Then we conducted two-sample Mendelian randomization (2SMR) analyses to estimate the effects of IVs on the odds of CHD and traditional coronary risk factors (including high LDL cholesterol levels, low HDL cholesterol levels, Apolipoprotein A-I, Apolipoprotein B, diabetes mellitus, and hypertension). Additionally, we searched for common risk loci between SLE and premature coronary atherosclerosis. Furthermore, we retrospectively reviewed the lipid profile of treatment-naive SLE patients and age-matched healthy controls.\\n\\nResultsGenetically predicted SLE did not increase the odds of CHD. Nevertheless, we found mild causal relationships between SLE and decreased HDL cholesterol levels, and between SLE and decreased apolipoprotein A-I. There was one common risk locus (rs597808) between SLE and premature coronary atherosclerosis at a genome-wide significance level (P<5 x 10-8). Retrospective analysis showed decreased HDL-cholesterol (0.98{+/-}0.516mmol/L vs. 1.46{+/-}0.307mmol/L in female, 0.76{+/-}0.199mmol/L vs. 1.19{+/-}0.257mmol/L in male; both P<0.001) and apolipoprotein A-I (1.06{+/-}0.314g/L vs. 1.37{+/-}0.205g/L in female, 0.87{+/-}0.174g/L vs. 1.24{+/-}0.200g/L in male; both P<0.001) in naive SLE patients.\\n\\nConclusionSLE may accelerate coronary atherosclerosis in young patients by reducing HDL cholesterol and apolipoprotein A-I intrinsically, but it seems not to play a predominant role in CHD development in old patients.\",\n \"Genetic links in angioimmunoblastic T-cell lymphoma (AITL), clonal hematopoiesis and concomitant hematologic malignancies provide insights into the cell of origin, etiology and biomarker discovery for AITL\\nWe generated and compared the mutation profiles through targeted sequencing of the primary tumors and matched bone marrow/peripheral blood samples in 25 patients with angioimmunoblastic T-cell lymphoma (AITL) and 2 with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Our results provided strong evidence that AITL/PTCL-NOS, clonal hematopoiesis (CH) as well as other concomitant myeloid and even B-cell hematologic neoplasms (CHN), frequently arose from common mutated hematopoietic stem cell clones. Aberrant AID/APOBEC activity-associated substitutions and tobacco smoking-associated substitutions were enriched in the early CH-associated mutations and late non-CH associated mutations during AITL/PTCL-NOS development, respectively. Moreover, survival analysis showed that the presence of CH harboring [≥] 2 pathogenic TET2 variants with [≥] 15% of allele burden conferred higher risk for CHN (P = 0.0034, hazard ratio = 10.81). These findings provide insights into the cell origin and etiology of AITL, and provide a novel stratification biomarker for CHN risk in AITL/PTCL-NOS patients.\",\n \"Pharmacokinetics/pharmacodynamics by Race: Analysis of a Peginterferon Beta-1a Phase I Study\\nBackgroundBlack/African-American participants are underrepresented in clinical trials but can experience a greater burden of disease, such as multiple sclerosis, than other racial groups in the United States. A phase 1, open-label, 2-period crossover study that demonstrated bioequivalence of subcutaneous (SC) and intramuscular (IM) injection of peginterferon beta-1a in healthy volunteers enrolled a similar proportion of Black/African-American and White participants, enabling a subgroup analysis comparing these groups.\\n\\nMethodsPeginterferon beta-1a 125 g was administered by SC or IM (1:1) injection, followed by a 28-day washout period before a second injection using the alternate method. Primary endpoints were maximum observed concentration (Cmax) and area under the concentration-time curve from Hour 0 to infinity (AUCinf). Secondary endpoints included safety, tolerability, and additional pharmacokinetic and pharmacodynamic parameters.\\n\\nFindingsThis analysis included 70 (51.5%) Black and 59 (43.3%) White participants. Black participants exhibited a 29.8% higher geometric mean Cmax of peginterferon beta-1a than White participants following SC administration and demonstrated similar values following IM administration. Black participants displayed 31.0% versus 11.8% higher geometric mean AUCinf values than White participants with SC versus IM administration. Neopterin dynamics and safety signals were similar between groups, with numerically fewer adverse events reported among Black participants.\\n\\nConclusionsNo clinically meaningful differences were identified between Black and White participants in pharmacokinetics/pharmacodynamics or safety related to peginterferon beta-1a administration, indicating that no change in dosing regimen is warranted for Black patients with MS.\\n\\nFundingFunding for medical writing support was provided by Biogen Inc. (Cambridge, MA, USA).\",\n \"Increasing test specificity without impairing sensitivity - lessons learned from SARS-CoV-2 serology\\nBackgroundSerological tests are widely used in various medical disciplines for diagnostic and monitoring purposes. Unfortunately, the sensitivity and specificity of test systems is often poor, leaving room for false positive and false negative results. However, conventional methods used to increase specificity decrease sensitivity and vice versa. Using SARS-CoV-2 serology as an example, we propose here a novel testing strategy: the \\\"Sensitivity Improved Two-Test\\\" or \\\" SIT2\\\" algorithm.\\n\\nMethodsSIT2 involves confirmatory re-testing of samples with results falling in a predefined retesting-zone of an initial screening test, with adjusted cut-offs to increase sensitivity. We verified and compared the performance of SIT2 to single tests and orthogonal testing (OTA) in an Austrian cohort (1,117 negative, 64 post-COVID positive samples) and validated the algorithm in an independent British cohort (976 negatives, 536 positives).\\n\\nResultsThe specificity of SIT2 was superior to single tests and non-inferior to OTA. The sensitivity was maintained or even improved using SIT2 when compared to single tests or OTA. SIT2 allowed correct identification of infected individuals even when a live virus neutralization assay could not detect antibodies. Compared to single testing or OTA, SIT2 significantly reduced total test errors to 0.46% (0.24-0.65) or 1.60% (0.94-2.38) at both 5% or 20% seroprevalence.\\n\\nConclusionFor SARS-CoV-2 serology, SIT2 proved to be the best diagnostic choice at both 5% and 20% seroprevalence in all tested scenarios. It is an easy to apply algorithm and can potentially be helpful for the serology of other infectious diseases.\",\n \"Raman spectroscopy on blood serum probes of patients with end-stage liver disease\\nRaman spectroscopy has shown to be a promising method for the examination of biomedical samples. However, until now, its efficacy has not been established in clinical diagnostics. In this study, Raman spectroscopys potential application in medical laboratories is evaluated for a large variety (38) of biomarkers. Given 234 serum samples from a cohort of patients with different stages of liver disease, we performed Raman spectroscopy at 780nm excitation wavelength. The Raman spectra were analyzed in combination with the results of routine diagnostics using specifically developed complex mathematical algorithms, including fluorescence filtering, frequency subset selection and several overfitting circumventing strategies, such as independent validation. With the results of this cohort, which were validated in 328 independent samples, a significant proof-of-concept study was completed. This study highlights the need to prevent overfitting and to use independent data for validation. The results reveal that Raman spectroscopy has high potential for use in medical laboratory diagnostics to simultaneously quantify multiple biomarkers.\",\n \"Autoantibodies Detected in MIS-C Patients due to Administration of Intravenous Immunoglobulin\\nThe autoantibody profile associated with known autoimmune diseases in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that adults with COVID-19 had a moderate prevalence of autoantibodies against the lung antigen KCNRG, and SLE-associated Smith autoantigen. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute insulin-dependent diabetes. While autoantibodies associated with SLE/Sjogrens syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring in vivo decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Together these findings demonstrate that administration of high-dose IVIG is responsible for the detection of several autoantibodies in MIS-C and KD. Further studies are needed to investigate autoantibody production in MIS-C patients, independently from IVIG administration.\",\n \"Plasma biomarkers associated with survival and thrombosis in hospitalized COVID-19 patients\\nSevere coronavirus disease-19 (COVID-19) has been associated with fibrin-mediated hypercoagulability and thromboembolic complications. To evaluate potential biomarkers of coagulopathy and disease severity in COVID-19, we measured plasma levels of eight biomarkers potentially associated with coagulation, fibrinolysis, and platelet function in 43 controls and 63 COVID-19 patients, including 47 patients admitted to the intensive care unit (ICU) and 16 non-ICU patients. COVID-19 patients showed significantly elevated levels of fibrinogen, tissue plasminogen activator (t-PA), and its inhibitor plasminogen activation inhibitor 1 (PAI-1), as well as ST2 (the receptor for interleukin 33) and von Willebrand factor (vWF) compared to the control group. We found that higher levels of t-PA, ST2, and vWF at the time of admission were associated with lower survival rates, and that thrombotic events were more frequent in patients with initial higher levels of vWF. These results support a predictive role of specific biomarkers such as t-PA and vWF in the pathophysiology of COVID-19. The data provide support for the case that hypercoagulability in COVID-19 is fibrin-mediated, but also highlights the important role that vWF may play in the genesis of thromboses in the pathophysiology of COVID-19. Interventions designed to enhance fibrinolysis and reduce platelet aggregation might prove to be useful adjuncts in the treatment of coagulopathy in a subset of COVID-19 patients.\",\n \"Analysis of MRI-derived spleen iron in the UK Biobank identifies genetic variation linked to iron homeostasis and erythrocyte morphology\\nAging, and the pathogenesis of many common diseases, involves iron homeostasis. A key role in iron homeostasis is played by the spleen, which is the largest filter of the blood and performs iron reuptake from old or damaged erythrocytes. Despite this important role, spleen iron content has not been measured previously in a large, population-based cohort. In this study, we quantify spleen iron in 41,764 participants of the UK Biobank using magnetic resonance imaging (MRI). We find that epidemiologic and environmental factors such as increased age, higher red meat consumption and lower alcohol intake correlate with higher spleen iron. Through genome-wide association study, we identify genetic associations between spleen iron and common variation at seven loci, including in two hereditary spherocytosis (HS) genes, ANK1 and SPTA1. HS-causing mutations in these genes are associated with lower reticulocyte volume and increased reticulocyte percentage, while our common alleles are associated with increased expression of ANK1 and SPTA1 in blood and with larger reticulocyte volume and reduced reticulocyte percentage. As genetic modifiers, these common alleles may explain mild spherocytosis phenotypes observed in some HS allele carriers. Further, we identify an association between spleen iron and MS4A7, which colocalizes with a quantitative trait locus for MS4A7 alternative splicing in whole blood, and with monocyte count and fraction. Through quantification of spleen iron in a large human cohort, we extend our understanding of epidemiological and genetic factors associated with iron recycling and erythrocyte morphology.\",\n \"COVID-19 mortality risk correlates inversely with vitamin D3 status, and a mortality rate close to zero could theoretically be achieved at 50 ng/ml 25(OH)D3: Results of a systematic review and meta-analysis\\nBackgroundMuch research shows that blood calcidiol (25(OH)D3) levels correlate strongly with SARS-CoV-2 infection severity. There is open discussion regarding whether low D3 is caused by the infection or if deficiency negatively affects immune defense. The aim of this study was to collect further evidence on this topic.\\n\\nMethodsSystematic literature search was performed to identify retrospective cohort as well as clinical studies on COVID-19 mortality rates versus D3 blood levels. Mortality rates from clinical studies were corrected for age, sex and diabetes. Data were analyzed using correlation and linear regression.\\n\\nResultsOne population study and seven clinical studies were identified, which reported D3 blood levels pre-infection or on the day of hospital admission. They independently showed a negative Pearson correlation of D3 levels and mortality risk (r(17)=-.4154, p=.0770/r(13)=-.4886, p=.0646). For the combined data, median (IQR) D3 levels were 23.2 ng/ml (17.4 - 26.8), and a significant Pearson correlation was observed (r(32)=-.3989, p=.0194). Regression suggested a theoretical point of zero mortality at approximately 50 ng/ml D3.\\n\\nConclusionsThe two datasets provide strong evidence that low D3 is a predictor rather than a side effect of the infection. Despite ongoing vaccinations, we recommend raising serum 25(OH)D levels to above 50 ng/ml to prevent or mitigate new outbreaks due to escape mutations or decreasing antibody activity.\\n\\nTrial registrationNot applicable.\",\n \"Structural and diffusion weighted brain imaging biomarkers for ADHD and its symptomology in very young (4-7-year-old) children\\nThe current study aimed to identify the key neurobiology of Attention-Deficit/Hyperactivity Disorder (ADHD), as it relates to ADHD diagnostic category and symptoms of hyperactive/impulsive behavior and inattention. To do so, we adapted a predictive modeling approach to identify the key structural and diffusion weighted brain imaging measures, and their relative standing with respect to teacher ratings of executive function - EF (measured by the Metacognition Index of the Behavior Rating Inventory of Executive Function- BRIEF), negativity and emotion regulation - ER (measured by the Emotion Regulation Checklist, ERC), in a critical young age range (ages 4 to 7, mean age 5.52 years, 82.2% Hispanic/Latino), where initial contact with educators and clinicians typically take place. Teacher ratings of EF and ER were predictive of both ADHD diagnostic category and symptoms of hyperactive/impulsive behavior and inattention. Among the neural measures evaluated, the current study identified the critical importance of the largely understudied diffusion weighted imaging measures for the underlying neurobiology of ADHD and its associated symptomology. Specifically, our analyses implicated the inferior frontal gyrus, the pericallosal sulcus, and the caudate as critical predictors of ADHD diagnostic category and its associated symptomology, above and beyond teacher ratings of EF and ER. Collectively, the current set of findings have implications for theories of ADHD, the relative utility of neurobiological measures with respect to teacher ratings of EF and ER, and the developmental trajectory of its underlying neurobiology.\",\n \"Non-invasively measured brain activity and radiological progression in diffuse glioma\\nNon-invasively measured brain activity is related to progression-free survival in glioma patients, suggesting its potential as a marker of glioma progression. We therefore assessed the relationship between brain activity and increasing tumor volumes on routine clinical magnetic resonance imaging (MRI) in glioma patients. Postoperative magnetoencephalography (MEG) was recorded in 45 diffuse glioma patients. Brain activity was estimated using three measures (absolute broadband power, offset and slope) calculated at three spatial levels: global average, averaged across the peritumoral areas, and averaged across the homologues of these peritumoral areas in the contralateral hemisphere. Tumors were segmented on MRI. Changes in tumor volume between the two scans surrounding the MEG were calculated and correlated with brain activity. Brain activity was compared between patient groups classified into having increasing or stable tumor volume. Results show that brain activity was significantly increased in the tumor hemisphere in general, and in peritumoral regions specifically. However, none of the measures and spatial levels of brain activity correlated with changes in tumor volume, nor did they differ between patients with increasing versus stable tumor volumes. Longitudinal studies in more homogeneous subgroups of glioma patients are necessary to further explore the clinical potential of non-invasively measured brain activity.\",\n \"Clinical Outcome of Neurological patients with COVID-19: the impact of Healthcare organization improvement between waves.\\nObjectiveThe aim of this study is to evaluate the differences of clinical presentations and the impact of healthcare organization on outcomes of neurological COVID-19 patients admitted during the first and second pandemic waves.\\n\\nMethodsIn this single center cohort study, we included all patients with SARS-CoV-2 infection admitted to a Neuro-COVID Unit. Demographic, clinical and laboratory data were compared between patients admitted during the first and second waves of COVID-19 pandemic.\\n\\nResults223 patients were included, of whom 112 and 111 hospitalized during the first and second pandemic waves, respectively. Patients admitted during the second wave were younger and exhibited pulmonary COVID-19 severity, resulting in less oxygen support (n=41, 36.9% vs n=79, 70.5%, p<0.001) and lower mortality rates (14.4% vs 31.3%, p=0.004). The different healthcare strategies and early steroid treatment emerged as significant predictors of mortality independently from age, premorbid conditions and COVID-19 severity in cox regression analyses.\\n\\nConclusionsDifferences in healthcare strategies during the second phase of COVID-19 pandemic probably explain the differences in clinical outcomes independently of disease severity, underlying the importance of standardized early management of neurological patients with SARS-CoV-2 infection.\",\n \"Validity of the Web-based, Self-directed, NeuroCognitive Performance Test in MCI\\nDigital cognitive tests offer several potential advantages over established paper-pencil tests but have not yet been fully evaluated for the clinical evaluation of mild cognitive impairment. The NeuroCognitive Performance Test (NCPT) is a web-based, self-directed, modular battery intended for repeated assessments of multiple cognitive domains. Using a sample of 101 MCI subjects, we report in this study that the NCPT composite is significantly correlated with both a composite measure of established tests (r=0.77, p<0.0001) as well as with the ADAS-Cog (r=0.55, p<0.0001). Both test batteries had a similar factor structure that included a large \\\"g\\\" component with a high eigenvalue. Further, both the NCPT and established tests significantly (p< 0.01) predicted the UPSA and FAQ, measures of daily functioning. Despite limitations such as a relatively small sample, absence of control group and cross-sectional nature, these findings are consistent with the growing literature on the promise of self-directed, web-based cognitive assessments for MCI.\",\n \"Automation of plate inoculation and reading reduces process time in the clinical microbiology laboratory, compared to a manual workflow\\nWe evaluated the benefits of automation for clinical microbiology laboratory workflow and compared the time required for culture inoculation and plate reading between manual processes and BD Kiestra (but Kiestra) automation. Kiestra automation consists of different modules, each of which facilitate different tasks and work together from specimen inoculation to results reporting. We tracked the steps and measured the associated times-to-completion for both manual and automated workflows, including number of plate touches, hands-on-time (HOT), total technologist time (TTT), and walk-away time (WAT). Manual and automated processes both included 90 samples, and a total of 180 agar plates. There were three media quantity protocols used to mimic common laboratory samples: 1) 30 urine specimens on one biplate; 2) 30 urine specimens divided across two plates; and 3) 30 blood or wound specimens divided across three plates; all cultures incubated for a minimum of 18 hours prior to reading or imaging. Automation reduced HOT by 85% and overall plate touches by 88%. Automated inoculation (through implementation of the BD InoqulA module) resulted in a 100% reduction in plate touches and created 81.5-minutes of WAT. Automation of culture reading (through implementation of the BD ReadA incubation/plate imaging module and BD Synapsys Informatics) reduced HOT by 53%. Overall, laboratory automation resulted in shorter TTT and created WAT when compared to manual processes. Automation can facilitate increased processing capacity, more efficient use of the labor force, and reduced time to results in the clinical microbiology laboratory.\",\n \"Herpesvirus Reactivations in Critically-Ill COVID-19 Patients with Autoantibodies Neutralizing Type I Interferons\\nAutoantibodies neutralizing the antiviral action of type I interferons (IFNs) have been associated with pre-disposition to severe COVID-19. Here, we screened for such autoantibodies in 103 critically-ill COVID-19 patients in a tertiary intensive care unit in Switzerland. Eleven patients (10.7%), but no healthy donors, had neutralizing anti-IFN or anti-IFN/anti-IFN{omega} IgG in plasma/serum, but anti-IFN IgM or IgA was rare. One patient had non-neutralizing anti-IFN IgG. Strikingly, all patients with plasma anti-IFN IgG also had anti-IFN IgG in tracheobronchial secretions, identifying these autoantibodies at anatomical sites relevant for SARS-CoV-2 infection. Longitudinal analyses revealed patient heterogeneity in terms of increasing, decreasing, or stable anti-IFN IgG levels throughout the length of hospitalization. Notably, presence of anti-IFN autoantibodies in this critically-ill COVID-19 cohort appeared to predict herpesvirus (herpes simplex viruses types 1 and 2, HSV-1/-2; and/or cytomegalovirus, CMV) reactivations, which are linked to worse clinical outcomes. Indeed, all seven tested COVID-19 patients with anti-IFN IgG in our cohort (100%) suffered from one or more herpesvirus reactivations, and analysis revealed that these patients were substantially more likely to experience CMV reactivation than COVID-19 patients without anti-IFN autoantibodies, even when adjusting for systemic steroid treatment (odds ratio 7.28, 95%-CI 1.14-46.31, p=0.036). As the IFN system deficiency caused by neutralizing anti-IFN autoantibodies likely directly and indirectly exacerbates herpesvirus reactivations in critically-ill patients, early diagnosis of anti-IFN IgG could be rapidly used to inform risk-group stratification and treatment options.\",\n \"Transdiagnostic connectome-based prediction of craving\\nCraving is a central construct in the study of motivation and human behavior and is also a clinical symptom of substance and non-substance-related addictive disorders. Thus, craving represents a target for transdiagnostic modeling. We applied connectome-based predictive modeling (CPM) to functional connectivity data in a large (N=274) transdiagnostic sample of individuals with and without substance-use-related conditions, to predict self-reported craving. CPM is a machine-learning approach used to identify neural signatures in functional connectivity data related to a specific phenotype. Functional connectomes were derived from three guided imagery conditions of personalized appetitive, stress, and neutral-relaxing experiences. Craving was rated before and after each imagery condition. CPM successfully predicted craving, thereby identifying a transdiagnostic craving network comprised primarily of the posterior cingulate cortex, hippocampus, visual cortex, and primary sensory areas. Findings suggest that craving may be associated with difficulties directing attention away from internal self-related processing, represented in the default mode network.\",\n \"A multiplexed Cas13-based assay with point-of-care attributes for simultaneous COVID-19 diagnosis and variant surveillance\\nPoint-of-care (POC) nucleic acid detection technologies are poised to aid gold-standard technologies in controlling the COVID-19 pandemic, yet shortcomings in the capability to perform critically needed complex detection--such as multiplexed detection for viral variant surveillance--may limit their widespread adoption. Herein, we developed a robust multiplexed CRISPR-based detection using LwaCas13a and PsmCas13b to simultaneously diagnose SARS-CoV-2 infection and pinpoint the causative SARS-CoV-2 variant of concern (VOC)-- including globally dominant VOCs Delta (B.1.617.2) and Omicron (B.1.1.529)--all while maintaining high levels of accuracy upon the detection of multiple SARS-CoV-2 gene targets. The platform has several attributes suitable for POC use: premixed, freeze-dried reagents for easy use and storage; convenient direct-to-eye or smartphone-based readouts; and a one-pot variant of the multiplexed detection. To reduce reliance on proprietary reagents and enable sustainable use of such a technology in low- and middle-income countries, we locally produced and formulated our own recombinase polymerase amplification reaction and demonstrated its equivalent efficiency to commercial counterparts. Our tool--CRISPR-based detection for simultaneous COVID-19 diagnosis and variant surveillance which can be locally manufactured--may enable sustainable use of CRISPR diagnostics technologies for COVID- 19 and other diseases in POC settings.\",\n \"An overview of the National COVID-19 Chest Imaging Database: data quality and cohort analysis\\nThe National COVID-19 Chest Imaging Database (NCCID) is a centralised database containing chest X-rays, chest Computed Tomography (CT) scans and cardiac Magnetic Resonance Images (MRI) from patients across the UK, jointly established by NHSX, the British Society of Thoracic Imaging (BSTI), Royal Surrey NHS Foundation Trust (RSNFT) and Faculty. The objective of the initiative is to support a better understanding of the coronavirus SARS-CoV-2 disease (COVID-19) and development of machine learning (ML) technologies that will improve care for patients hospitalised with a severe COVID-19 infection. The NCCID is now accumulating data from 20 NHS Trusts and Health Boards across England and Wales, with a total contribution of approximately 25,000 imaging studies in the training set (at time of writing) and is actively being used as a research tool by several organisations. This paper introduces the training dataset, including a snapshot analysis performed by NHSX covering: the completeness of clinical data, the availability of image data for the various use-cases (diagnosis, prognosis and longitudinal risk) and potential model confounders within the imaging data. The aim is to inform both existing and potential data users of the NCCIDs suitability for developing diagnostic/prognostic models. In addition, a cohort analysis was performed to measure the representativeness of the NCCID to the wider COVID-19 affected population. Three major aspects were included: geographic, demographic and temporal coverage, revealing good alignment in some categories, e.g., sex and identifying areas for improvements to data collection methods, particularly with respect to geographic coverage. All analyses and discussions are focused on the implications for building ML tools that will generalise well to the clinical use cases.\",\n \"Automation improves repeatability of retinal oximetry measurements\\nPurposeRetinal oximetry is a technique based on spectrophotometry where images are analyzed with software capable of calculating vessel oxygen saturation and vessel diameter. In this study, the effect of automation of measurements of retinal vessel oxygen saturation and vessel diameter is explored.\\n\\nMethodsUntil now, operators have had to choose each vessel segment to be measured explicitly. A new, automatic version of the software automatically selects the vessels once the operator defines a measurement area.\\n\\nFive operators analyzed image pairs from the right eye of 23 healthy subjects with semiautomated retinal oximetry analysis software, Oxymap Analyzer (v2.5.1), and an automated version (v3.0). Inter- and intra-operator variability was investigated using the intraclass correlation coefficient (ICC) between oxygen saturation measurements of vessel segments in the same area of the retina.\\n\\nResultsFor manual saturation measurements, the inter-rater ICC was 0.80 for arterioles and venules. For automated saturation measurements, the inter-rater ICC was 0.97 for arterioles and 0.96 for venules. For manual diameter measurements, the inter-rater ICC was 0.71 for arterioles and venules. For automated diameter measurements the inter-rater ICC was 0.97 for arterioles and 0.95 for venules. The inter-rater ICCs were different (p < 0.01) between the semiautomated and automated version in all instances.\\n\\nConclusionAutomated measurements of retinal oximetry values are more repeatable compared to measurements where vessels are selected manually.\",\n \"Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder\\nABBSTRACTDYRK1A-related intellectual disability (ID) is among the most frequent monogenic form of ID. We refined the description of this disorder by reporting clinical and molecular data of forty individuals with ID harboring DYRK1A variants. We developed a combination of tools to interpret missense variants, which remains a major challenge in human genetics: i) a specific DYRK1A clinical score, ii) amino acid conservation data generated from one hundred of DYRK1A sequences across different taxa, iii) in vitro overexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins, and iv) a specific blood DNA methylation signature. This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, yet reported as pathogenic, and showed it does not cause obvious phenotype in mice, emphasizing the need to take care when interpreting variants, even those occurring de novo.\",\n \"A novel syndrome caused by the constitutional gain-of-function variant p.Glu1099Lys in NSD2\\nPurposeNSD2 dimethylates histone H3 at lysine 36 (H3K36me2) and is located in the Wolf-Hirschhorn syndrome (WHS) region. Recent descriptions delineated loss-of-function (LoF) variants in NSD2 with a distinct disorder. The oncogenic missense variant p.Glu1099Lys occures somatically in leukemia and has a gain-of-function (GoF) effect.\\n\\nMethodsWe describe two unrelated individuals carrying c.3295G>A, p.Glu1099Lys as heterozygous de novo germline variants identified by exome sequencing of blood DNA and subsequently confirmed in two ectodermal tissues. We use omics data from the Cancer Cell Line Encyclopedia to analyze the GoF effect.\\n\\nResultsClinically these individuals are characterized by intellectual disability, coarse/ square facial gestalt, abnormalities of the hands and organomegaly. We confirmed increased K36me2 methylation in lines with either NSD2 GoF variants or duplications. Cells with GoF variants showed increased DNA promoter methylation and dysregulated RNA expression, influencing cellular modules involved in white blood cell activation, cell growth and organ development.\\n\\nConclusionNSD2 GoF caused by the missense variant p.Glu1099Lys leads to a novel syndromic phenotype distinct from both the previously described LoF phenotypes. Other variants causing NSD2 hyperactivation or overexpression may cause a similar phenotype. This syndrome should be distinguished from the recently named Rauch-Steindl syndrome caused by NSD2 haploinsufficiency.\",\n \"Patient and physician shared decision making behaviors in oncology: Evidence on adequate measurement properties of the iSHARE questionnaires\\nObjectivesWe have developed two questionnaires to assess the shared decision making (SDM) process in oncology; the iSHAREpatient and iSHAREphysician. In this study, we aimed to determine: scores, construct validity, test-retest agreement (iSHAREpatient), and inter-rater (iSHAREpatient-iSHAREphysician) agreement.\\n\\nMethodsPhysicians from seven Dutch hospitals recruited cancer patients, and completed the iSHAREphysician and SDM-Questionnaire-physician version. Their patients completed the: iSHAREpatient, 9-item SDM-Questionnaire, Decisional Conflict Scale, Combined Outcome Measure for Risk communication And treatment Decision making Effectiveness, and Perceived Efficacy in Patient-Physician Interactions. We formulated, respectively, one (iSHAREphysician) and 10 (iSHAREpatient) a priori hypotheses regarding correlations between the iSHARE questionnaires and questionnaires assessing related constructs. To assess test-retest agreement patients completed the iSHAREpatient again 1-2 weeks later.\\n\\nResultsIn total, 151 treatment decision making processes with unique patients were rated. Dimension and total iSHARE scores were high both in patients and physicians. The hypothesis on the iSHAREphysician and 9/10 hypotheses on the iSHAREpatient were confirmed. Test-retest and inter-rater agreement were >.60 for most items.\\n\\nConclusionsThe iSHARE questionnaires show high scores, have good construct validity, substantial test-retest agreement, and moderate inter-rater agreement.\\n\\nPractice implicationsResults from the iSHARE questionnaires can inform both physician- and patient-directed efforts to improve SDM in clinical practice.\",\n \"Daily tenofovir disoproxil fumarate/emtricitabine and hydroxychloroquine for pre-exposure prophylaxis of COVID-19: a double-blind placebo controlled randomized trial in healthcare workers\\nObjectiveTo assess the effect of hydroxychloroquine (HCQ), Tenofovir disoproxil fumarate/Emtricitabine (TDF/FTC), and their combination as pre-exposure prophylaxis on the risk of symptomatic COVID-19.\\n\\nMethodsEPICOS is a double-blind, placebo-controlled randomized trial conducted in 51 hospitals in Spain, Bolivia, and Venezuela. Healthcare workers with negative SARS-CoV-2 IgM/IgG test were randomly assigned to: daily TDF/FTC plus HCQ for 12 weeks, TDF/FTC plus HCQ placebo, HCQ plus TDF/FTC placebo and TDF/FTC placebo plus HCQ placebo. The primary outcome was laboratory-confirmed, symptomatic COVID-19. We also studied any (symptomatic or asymptomatic) COVID-19 infection. We compared group-specific 14-week risks via differences and ratios with 95% confidence intervals (CI).\\n\\nResultsOf 1002 individuals screened, 926 (92.4%) were eligible; 64.2% recruited in Spain, 22.3% in Bolivia, and 13.6% in Venezuela. Median age was 38 years (range 18 - 68), 62.5% were female, 62.3% worked at inpatient care, and comorbidities were rare. Compared with the placebo group, 14-week risk ratios (95% CI) of symptomatic COVID-19 were 0.39 (0.00, 1.98) for TDF+HCQ, 0.34 (0.00, 2.06) for TDF, and 0.49 (0.00, 2.29) for HCQ. Corresponding risk ratios of any COVID-19 were 0.51 (0.21, 1.00) for TDF+HCQ, 0.81 (0.44, 1.49) for TDF, and 0.73 (0.41, 1.38) for HCQ. Adverse events were generally mild.\\n\\nConclusionA beneficial effect of TDF/FTC and HCQ, alone or in combination, as pre-exposure prophylaxis for COVID-19 cannot be ruled out but effect estimates are imprecise because the target sample size was not met. These findings support launching randomized trials of TDF/FTC for the early treatment of COVID-19.\",\n \"Persistence of functional memory B cells recognizing SARS-CoV-2 variants despite loss of specific IgG\\nWhile some COVID-19 patients maintain SARS-CoV-2-specific serum IgGs for more than 6 months post-infection, others, especially mild cases, eventually lose IgG levels. We aimed to assess the persistence of SARS-CoV-2-specific B cells in patients who have lost specific IgGs and analyzed the reactivity of the immunoglobulins produced by these B cells. Circulating IgG memory B cells specific for SARS-CoV-2 were detected in all 16 patients 1-8 months post-infection, and 11 participants had specific IgA B cells. Four patients lost specific serum IgG after 5-8 months but had SARS-CoV-2-specific-B-cell levels comparable to those of seropositive donors. Immunoglobulins produced after in vitro differentiation blocked receptor-binding domain (RBD) binding to the cellular receptor ACE-2, indicating neutralizing activity. Memory-B-cell-derived IgGs recognized the RBD of B.1.1.7 similarly to the wild-type, while reactivity to B.1.351 and P.1. decreased by 30% and 50%, respectively. Memory-B-cell differentiation into antibody-producing cells is a more sensitive method for detecting previous infection than measuring serum antibodies. Circulating SARS-CoV-2 IgG memory B cells persist, even in the absence of specific serum IgG; produce neutralizing antibodies; and show differential cross-reactivity to emerging variants of concern. These features of SARS-CoV-2-specific memory B cells will help to understand and promote long-term protection.\",\n \"Weakly supervised and transfer learning for adenocarcinoma classification in transurethral resection of the prostate whole slide images\\nThe transurethral resection of the prostate (TUR-P) is generally considered an option for benign prostatic diseases especially nodular hyperplasia patients who have moderate to severe urinary problems that have not responded to medication. Importantly, incidental prostate cancer are diagnosed at the time of TUR-P for benign prostatic disease. Since diagnosing a large number of cases containing TUR-P specimens which are characterized by a very large volume of tissue fragments by pathologists using a conventional microscope is time-consuming and limited in terms of human resources. Thus, it is necessary to develop new techniques which can rapidly and accurately screen large numbers of TUR-P specimens. Computational pathology applications which can assist pathologists in detecting prostate adenocarcinoma from TUR-P whole slide images (WSIs) would be of great benefit for routine histopathological workflow. In this study, we trained deep learning models to classify TUR-P WSIs into prostate adenocarcinoma and benign (non-neoplastic) lesions using transfer and weakly supervised learning. We evaluated the models on TUR-P, needle biopsy, and The Cancer Genome Atlas (TCGA) public dataset test sets, achieving an ROC-AUC up to 0.984 in TUR-P test sets for adenocarcinoma. The results demonstrate the high promising potential of deployment in a practical TUR-P histopathological diagnostic workflow system.\",\n \"Sensitivity of rapid antigen testing and RT-PCR performed on nasopharyngeal swabs versus saliva samples in COVID-19 hospitalized patients: results of a prospective comparative trial (RESTART).\\nObjectivesSaliva sampling could serve as an alternative non-invasive sample for SARS-CoV-2 diagnosis while rapid antigen testing (RAT) might help to mitigate the shortage of reagents sporadically encountered with RT-PCR. Thus, in the RESTART study we compared antigen and RT-PCR testing methods on nasopharyngeal (NP) swabs and salivary samples.\\n\\nMethodsWe conducted a prospective observational study among COVID-19 hospitalized patients between 10th December 2020 and 1st February 2021. Paired saliva and NP samples were investigated by RT-PCR (Cobas 6800, Roche-Switzerland) and by two rapid antigen tests: One Step Immunoassay Exdia(R) COVID-19 Ag (Precision Biosensor, Korea) and Standard Q(R) COVID-19 Rapid Antigen Test (Roche-Switzerland).\\n\\nResultsA total of 58 paired NP-saliva specimens were collected. Thirty-two of 58 (55%) patients were hospitalized in the intensive care unit and the median duration of symptoms was 11 days (IQR 5-19). NP and salivary RT-PCR exhibited sensitivity of 98% and 69% respectively whereas the specificity of these RT-PCRs assays were of 100%. NP RAT exhibited much lower diagnostic performances with sensitivities of 35% and 41% for the Standard Q(R) and Exdia(R) assays respectively, when a wet-swab approach was used (i.e. when the swab was diluted in the viral transport medium (VTM) before testing). The sensitivity of the dry-swab approach was slightly better (47%). These antigen tests exhibited very low sensitivity (4 and 8%) when applied to salivary swabs.\\n\\nConclusionsNasopharyngeal RT-PCR is the most accurate test for COVID-19 diagnosis in hospitalized patients. RT-PCR on salivary samples may be used when nasopharyngeal swabs are contraindicated. RAT are not appropriate for hospitalized patients.\",\n \"Interaction studies of risk proteins in human induced neurons reveal convergent biology and novel mechanisms underlying autism spectrum disorders\\nSequencing studies of autism spectrum disorders (ASDs) have identified numerous risk genes with enriched expression in the human brain, but it is still unclear how these genes converge into cell type-specific networks and how their encoded proteins mechanistically contribute to ASDs. To address this question, we performed brain cell type-specific interaction proteomics to build a protein-protein interaction network for 13 ASD risk genes in human excitatory neurons derived from iPS cells. The network contains many (>90%) reproducible interactions not reported in the literature and is enriched for transcriptionally perturbed genes observed in layer 2/3 cortical neurons of ASD patients, indicating that it can be explored for ASD-relevant biological discovery. We leveraged the network dataset to show that the brain-specific isoform of ANK2 is important for its interactions with synaptic proteins and characterized a PTEN-AKAP8L interaction that influences neuronal growth through the mTOR pathway. The IGF2BP1-3 complex emerges as a point of convergence in the network, and we showed that this complex is involved in a transcriptional circuit concentrating both common and rare variant risk of ASDs. Finally, we found the network itself enriched for ASD rare variant risk, indicating that it can complement genetic datasets for prioritizing additional risk genes. Our findings establish brain cell type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in ASDs and illustrate how both individual and convergent interactions lead to biological insights into the disease.\",\n \"Recovery Time and Its Predictors among Women Admitted with Obstetric Fistula in Jimma University Medical Center Southwest, Ethiopia: A Retrospective Cohort Study\\nBackgroundObstetric fistula is one of the most shocking medical disabilities that women face as a result of problems caused by a lack of surgical intervention.\\n\\nMethodsFrom January 2011 to February 2017, a retrospective analysis was undertaken on obstetric fistula participants who received undergone surgical repair at the Jimma University Medical Center.\\n\\nResults81.4% of fistula patients were reported to have recovered. The results of lognormal inverse-Gaussian frailty model revealed that weight [≥]50kg ([FE]= 0.86, 95% CI: 0.747, 0.99), divorced ([FE]=1.2, 95% CI: 1.028, 1.413), urban residence ([FE]= 1.56, 95% CI: 01.046, 2.317), urine incontinence >3 months ([FE]=1.2, 95% CI: 1.056, 1.371), no antenatal care ([FE]=1.189, 95% CI:1.023, 1.382), duration of labor <2days ([FE]= 0.86, 95% CI: 0.758, 0.986), health center delivery ([FE]= 0.76, 95% CI: 0.576, 0.989), vaginal delivery ([FE]= 1.5, 95% CI: 1.125, 1.996), and partially damaged urethra ([FE]=1.59, 95% CI: 1.168, 2.166) and recto-vaginal fistula([FE]= 0.735, 95%CI: 0.6045, 0.894) were associated with the recovery time.\\n\\nConclusionPatients with a weight < 50 kg, delivery at a health center, labor lasting <2 days, urinary incontinence lasting <3 months, antenatal care follow-up, cesarean section delivery, urethra status not damaged, and recto-vaginal fistula had a faster recovery period.\",\n \"Regional medical inter-institutional cooperation in medical provider network constructed using patient claims data from Japan\\nThe aging world population requires a sustainable and high-quality healthcare system. To examine the efficiency of medical cooperation, medical provider and physician networks were constructed using patient claims data. Previous studies have shown that these networks contain information on medical cooperation. However, the usage patterns of multiple medical providers in a series of medical services have not been considered. In addition, these studies used only general network features to represent medical cooperation, but their expressive ability was low. To overcome these limitations, we analyzed the medical provider network to examine its overall contribution to the quality of healthcare provided by cooperation between medical providers in a series of medical services. This study focused on: i) the method of feature extraction from the network, ii) incorporation of the usage pattern of medical providers, and iii) expressive ability of the statistical model. Femoral neck fractures were selected as the target disease. To build the medical provider networks, we analyzed the patient claims data from a single prefecture in Japan between January 1, 2014 and December 31, 2019. We considered four types of models: a model using node strength and linear regression to a model using feature representation by node2vec and regression tree ensemble, which is a machine learning method. The results showed that a stronger medical provider reduces the duration of hospital stay. The overall contribution of the medical cooperation to the duration of hospital stay extracted from the medical provider network using node2vec is approximately 20%, which is approximately 20 times higher than the model using strength.\",\n \"Common Data Elements, Scalable Data Management Infrastructure and Analytics Workflows for Large-scale Neuroimaging Studies\\n1.Neuroscience studies require considerable bioinformatic support and expertise. Numerous high-dimensional and multimodal datasets must be preprocessed and integrated to create robust and reproducible analysis pipelines. We describe a common data elements and scalable data management infrastructure that allows multiple analytics workflows to facilitate preprocessing, analysis and sharing of large-scale multi-level data. The process uses the Brain Imaging Data Structure (BIDS) format and supports MRI, fMRI, EEG, clinical and laboratory data. The infrastructure provides support for other datasets such as Fitbit and flexibility for developers to customize the integration of new types of data. Exemplar results from 200+ participants and 11 different pipelines demonstrate the utility of the infrastructure.\",\n \"Point-of-Care Ultrasound (POCUS) Predicts Clinical Outcomes in Patients with COVID-19.\\nIntroductionPoint-of-care ultrasound (POCUS) may detect the cardiopulmonary manifestations of COVID-19 and expediently predict patient outcomes.\\n\\nMethodsWe conducted a prospective cohort study at four medical centers from 3/2020-1/2021 to evaluate POCUS findings and clinical outcomes with COVID-19. Our inclusion criteria included adult patients hospitalized for COVID-19 who received cardiac or lung POCUS with a 12-zone protocol. Images were interpreted by two reviewers blinded to clinical outcomes. Our primary outcome was ICU admission incidence. Secondary outcomes included intubation and supplemental oxygen usage.\\n\\nResultsN=160 patients (N=201 scans) were included. Scans were collected a median 23 hours (IQR:7-80) from emergency department triage. Triage POCUS findings associated with ICU admission included B-lines (OR 4.41 [95% CI:1.71-14.30]; p<0.01) or consolidation (OR 2.49 [95% CI:1.35-4.86]; p<0.01). B-lines were associated with intubation (OR 3.10 [95% CI:1.15-10.27]; p=0.02) and supplemental oxygen usage (OR 3.74 [95% CI:1.63-8.63; p<0.01).\\n\\nConsolidations present on triage were associated with the need for oxygen at discharge (OR 2.16 [95% CI: 1.01-4.70]; p=0.047). A normal lung triage scan was protective for ICU admission (OR 0.28 [95% CI:0.09-0.75; p<0.01) or need for supplemental oxygen during the hospitalization (OR 0.26 [95% CI:0.11-0.61]; p<0.01). Triage cardiac POCUS scans were not associated with any outcomes.\\n\\nDiscussionLung POCUS findings detected early in the hospitalization may provide expedient risk stratification for important COVID-19 clinical outcomes, including ICU admission, intubation, or need for oxygen on discharge. A normal admission scan appears protective against adverse outcomes, which may aid in triage decisions of patients.\",\n \"Using brain cell-type-specific protein interactomes to interpret genetic data in schizophrenia\\nGenetics have nominated many schizophrenia risk genes that lack functional interpretation. To empower such interpretation, we executed interaction proteomics for six risk genes in human induced neurons and found the resulting protein network to be enriched for common variant risk of schizophrenia in Europeans and East Asians. The network is down-regulated in layer 5/6 cortical neurons of patients and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and also contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in patients with schizophrenia and bipolar disease. Our findings establish brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and psychiatric diseases.\\n\\nOne Sentence SummaryNeuronal protein interactomes is an organizing framework for integrating genetic and transcriptomic data in schizophrenia.\"\n]","isConversational":false},"cluster":{"kind":"number","value":10,"string":"10"}}},{"rowIdx":228,"cells":{"query":{"kind":"string","value":"Microbiota of Chronic Prostatitis/Chronic Pelvic Pain Syndrome are Distinct from Interstitial Cystitis/Bladder Pain Syndrome\nUrologic chronic pelvic pain syndrome patients include men chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and patients, mainly women, with interstitial cystitis/bladder pain syndrome (IC/BPS or IC). CP/CPPS is marked by severe chronic pelvic pain of unknown etiology that is differentially associated with prostatic inflammation. Microbes are known to modulate sensory responses, and microbiota are increasingly understood to drive normal biological processes and pathogenesis, including inflammation. Recent studies have linked fecal dysbiosis with chronic pelvic pain in IC/BPS, suggesting a role for microbiota in modulating UCPPS pain. Similarly, dysbiosis has been reported in CP/CPPS patients, but the relationship between with the dysbiosis of IC/BPS patients is unclear. Here, we characterized the fecal microbiota of men with CP/CPPS and women and men with IC/BPS. Similar to recent reports, we identified fecal dysbiosis in men with CP/CPPS relative to healthy controls among specific phyla and overall differences in diversity and richness. Interestingly, we also observed differences between CP/CPPS microbiota and IC/BPS microbiota that were not likely due to sex differences. These findings suggest that CP/CPPS is marked by changes in the gut microbiome, but these changes differ from IC/BPS. Taken together, UCPPS appears associated with distinct dybioses among CP/CPPS and IC/BPS, raising the possibility of distinct contributions to underlying pelvic pain mechanisms and/or etiologies."},"positive":{"kind":"list like","value":["Molecular portrait of prostate tissue probed by MALDI Imaging Mass Spectrometry\nBenign prostatic hyperplasia (BPH) is the most common condition in aging men, associated with lower urinary tract symptoms. BPH has been suggested to be a risk factor for certain urologic cancers, but the current evidence is inconsistent. The gold-standard method for the diagnosis of BPH is histopathology. Histopathology displays the cellular morphologies of tissues wherein characteristic changes pertaining specifically to BPH can be identified. However, the onset of BPH might be associated with minimal phenotypic changes in cellular morphologies in tissues that histopathology might not be able to detect successfully. Therefore, to understand the onset of a disease and its pathogenesis it is important to investigate the detailed molecular profiles associated with the disease that might help in the diagnosis and to understand the insights of the disease pathogenesis. Over the last decade, imaging mass spectrometry has been used to explore the spatial distribution and expression profiles of several molecules with their two-dimensional heterogeneity retained across the tissues. In the present study, using MALDI mass spectrometry based tissue imaging platform, we observed the expression of several proteins across human prostate tissue sections diagnosed with BPH. The proteins were identified and characterized using tissue proteomics approach. We could successfully identify the on-tissue distribution of ribonuclease T2, vinculin, isoform 2 of tropomyosin alpha-3 chain and mitochondrial citrate synthase proteins using this approach. Therefore, imaging mass spectrometry might be a potential tool to complement the findings of histopathology in diagnosis of BPH in human prostate tissues.","Radical versus partial nephrectomy and survival from stage T1 renal cell carcinoma in three prospective cohorts\nBackgroundWhether or not a survival difference exists between radical and partial nephrectomy for stage T1 renal cell carcinoma (RCC) is controversial. We therefore aimed to evaluate cancer-specific, other cause, and overall survival among patients undergoing radical or partial nephrectomy for stage pT1 RCC.\n\nMaterials and methodsWe identified 330 participants with pT1a-b RCC diagnosed between 2000-2015 in three prospective cohort studies and compared treatment with radical nephrectomy (N=196) versus partial nephrectomy (N=134). The primary outcome was overall survival. Secondary outcomes were other-cause and cancer-specific mortality. Kaplan-Meier plots were used to visualize overall survival for the two treatment groups. Cox proportional hazards regression was utilized to compare outcomes between groups, and Fine and Gray competing risks regression was used to compare cancer-specific and other cause mortality between groups. Multivariable models adjusted for age, tumor size, sex, year of diagnosis, body mass index, history of smoking, history of hypertension, surgical technique, and pathological differentiation.\n\nResultsDuring a median follow-up of eight years, overall survival was 84%. We did not detect a statistically significant difference in overall survival between partial and radical nephrectomy (Hazard Ratio (HR) = 0.84, 95% Confidence Interval: 0.40-1.78). There was no significant difference in cause-specific or other cause mortality between groups. This study had 80% power to detect an HR [≥]2.20.\n\nConclusionsThese results did not suggest a difference in long-term survival outcomes between radical and partial nephrectomy.","Protocol for 18F-PSMA PET imaging in staging and management of prostate cancer - a retrospective cohort study\nBackgroundMRI, bone scan, and CT staging is recommended in the staging of prostate cancer. However, prostate-specific membrane antigen positron emission tomography (PSMA PET) could be superior in detection of local and distant prostate cancer cells. Most PSMA PET scans for prostate cancer are performed with a Gallium-68 ligand, with the Fluorine-18 (18F) ligand being introduced more recently. Methods: We will conduct a retrospective review of electronic patient records for all consecutive patients who underwent preoperative 18F-PSMA PET scan for prostate cancer from its introduction at our centre in 2019. We will compare PET scans with other imaging modalities and evaluate its use in diagnosis and management decisions for prostate cancer.\n\nConclusionsUnderstanding the role of 18F-PSMA PET in diagnosis and management could influence the diagnostic pathway of primary and secondary prostate cancer.\n\nTrial registrationNot applicable.","Gut-bladder axis syndrome associated with recurrent UTIs in humans\nRecurrent urinary tract infections (rUTIs) are a major health burden worldwide, with history of infection being a significant risk factor. While the gut is a known reservoir for uropathogenic bacteria, the role of the microbiota in rUTI remains unclear. We conducted a year-long study of women with and without history of rUTIs, from whom we collected urine, blood and monthly fecal samples for multi-omic interrogation. The rUTI gut microbiome was significantly depleted in microbial richness and butyrate-producing bacteria compared to controls, reminiscent of other inflammatory conditions, though Escherichia coli gut and bladder dynamics were comparable between cohorts. Blood samples revealed signals of differential systemic immunity, leading us to hypothesize that rUTI susceptibility is in part mediated through a syndrome involving the gut-bladder axis, comprising gut dysbiosis and differential immune response to bacterial bladder colonization, manifesting in symptoms. This work highlights the potential for microbiome therapeutics to prevent and treat rUTIs.","The relationship between ethnicity and stone composition in a large multi-ethnic London NHS Trust\nPurposeFew studies have examined kidney stone composition of an ethnically diverse group living in the same location, we aimed to study this in an ethnically diverse NHS trust.\n\nMethodsWe reviewed all patients (n=312) with laboratory stone analysis and compared their ethnicity with their stone composition.\n\nResultsUsing a Chi Squared analysis there was no significant difference between stone composition in different ethnic groups (p=0.07). Uric acid stones were more common in the White-other group at 22.0% compared to 10.3% for White British, 5.2% for Asian and 9.52% for Black patients. Calcium oxalate stone were more common in the Asian population with 71.9% and Black population at 76.1%, compared with 56.7% in the White British population and 52.6% in the White-other population. Calcium phosphate stones were found commonly in the White British population (26.8%) compared to 18.6% for White-other, 16.7% for Asian and 9.5% for Black patients. Cystine and Struvite stones were found at low levels of between 0-3.4% in each group. Repeat stone formers with calcium oxalate, uric acid or cystine stones formed the same stone again 100.0% of the time. The odds for the Black population having a stone analysed (OR 0.62, CI 0.39-0.97, p=0.04) was significantly lower than the local population, and for the Asian population this was significantly higher (OR 1.31, CI1.05-1.62, p=0.01),\n\nConclusionUric acid stones are found more frequently in the White-other population and calcium oxalate stones are found more frequently in the Asian and black population. However, these results were not statistically significant. The odds ratio of having a stone was significantly higher in the Asian population and lower in the Black population.","Non-muscle Invasive Bladder Cancer Molecular Subtypes Predict Differential Response to Intravesical Bacillus Calmette-Guerin\nThe recommended treatment for patients with high-risk non-muscle invasive bladder cancer (HR-NMIBC) is tumor resection followed by adjuvant Bacillus Calmette-Guerin (BCG) bladder instillations. However, only 50% of patients benefit from this therapy. In case of progression to advanced disease, patients must undergo a radical cystectomy with significant morbidity and have a poor clinical outcome. Identifying tumors least likely to respond to BCG can translate into alternative treatments, such as early radical cystectomy or novel targeted or immunotherapies. Here we present molecular profiling of 132 BCG-naive, HR-NMIBC patients, and 44 post-BCG recurrences (34 matched), which uncovered three distinct BCG Response Subtypes (BRS1-3). Patients with BRS3 tumors have reduced recurrence and progression-free survival compared to BRS1-2. BRS3 tumors expressed high EMT-basal markers and had an immunosuppresive profile, which was confirmed with spatial proteomics. Tumors which recurred post-BCG were enriched for BRS3. BRS stratification was validated in a second cohort of 151 BCG-naive HR-NMIBC patients and the molecular subtypes outperformed guideline recommended risk stratification based on clinicopathological variables. For clinical application, we validated that a commercially approved assay was able to accurately predict BRS3 tumors (AUROC 0.86). Our findings provide a potential clinical tool for improved identification of HR-NMIBC patients at the highest risk of progression, which can be used to select patients for early radical cystectomy or novel subtype-directed therapies.\n\nOne Sentence SummaryMolecular subtypes are predictive of response to intravesical Bacillus Calmette-Guerin immunotherapy in non-muscle invasive bladder cancer.","Innate immune responses in patients treated with SBRT irradiation enhances prostate cancer remissions\nStereotactic body radiation therapy (SBRT) is a curative therapeutic modality employing large fractional doses of highly conformal radiation therapy for cancer treatment. To understand the mechanisms underlying clinical responses to radiation therapy, SBRT offers a unique window for high-throughput analysis of post-radiation molecular events to inform predictive biomarker discovery and strategies for multi-disciplinary therapeutics. We performed longitudinal analysis of plasma proteins and metabolites from patients treated with prostate SBRT, comparing cohorts of patients in clinical remission to cohorts experiencing PSA-determined cancer progression. We observed onset of post-SBRT DNA Damage Response (DDR), cell cycle arrest, and immune response signaling in patients within one hour of treatment and innate immune response signaling that persisted for up to three months following treatment. Furthermore, patients in remission experienced more robust immune responses and metabolite elevations consistent with a pro-inflammatory, M1-mediated innate immune activation in the short-term following SBRT, whereas patients with disease progression had less robust immune responses and M2-mediated metabolite elevations. We interpret these data to support a critical role for innate immune activation in the clinical outcomes of patients receiving radiation therapy for prostate cancer potentially improving future multidisciplinary therapeutic strategies.\n\nOne Sentence SummaryFollowing SBRT, proteomic and metabolomic profiles reveal a robust immune activation that correlates with prostate cancer remission","Creation of synthetic contrast-enhanced computed tomography images using deep neural networks to screen for renal cell carcinoma\nObjectivesTo elucidate if synthetic contrast enhanced computed tomography (CECT) images created from plain CT images using deep neural networks (DNN) could be used for screening, clinical diagnosis, and postoperative follow-up of small-diameter renal tumors by comparing the concordance rate between real and synthetic CECT images and the diagnoses according to 10 urologists.\n\nMethodsThis retrospective, multicenter study included 155 patients (artificial intelligence training cohort [n=99], validation cohort [n=56]) who underwent surgery for small-diameter ([≤]40 mm) renal tumors, with the pathological diagnosis of renal cell carcinoma, during 2010-2020. Preoperatively, dynamic plain CT and CECT images were obtained. We created a learned DNN using pix2pix. We examined the quality of the synthetic CECT images created using this DNN and compared them with real CECT images using the zero-mean normalized cross-correlation parameter. We assessed concordance rates between real and synthetic images and diagnoses according to 10 urologists by creating a receiver operating characteristic curve and calculating the area under the curve (AUC).\n\nResultsThe synthetic CECT images were highly concordant with the real CECT images, regardless of the existence or morphology of the renal tumor. Regarding the concordance rate, a greater AUC was obtained with synthetic CECT (AUC=0.892) than with only CT (AUC=0.720; p<0.001).\n\nConclusionsThis study is the first to use DNN to create a high-quality synthetic CECT image that was highly concordant with a real CECT image. Synthetic CECT images could be used for urological diagnoses and clinical screening.","NOVEL PLASMA GLYCOPROTEIN BIOMARKERS PREDICT PROGRESSION-FREE SURVIVAL IN SURGICALLY RESECTED CLEAR CELL RENAL CELL CARCINOMA\nIntroductionLimited data exists on utilization of protein post-translational modifications as biomarkers for clear cell renal cell carcinoma (ccRCC). We employed high-throughput glycoproteomics to evaluate differential expression of glycoprotein-isoforms as novel markers for ccRCC progression-free survival (PFS).\n\nMethodsPlasma samples were obtained from 77 patients treated surgically for ccRCC. Glycoproteomic analyses were carried out after liquid chromatography tandem mass spectrometry. Age-adjusted Cox proportional hazard models were constructed to evaluate PFS. Optimized Harrells c-index was employed to dichotomize the collective for the construction of Kaplan-Meier curves.\n\nResultsThe average length of follow-up was 3.4 (range: 0.04-9.83) years. Glycoproteomic analysis identified 39 glycopeptides and 14 non-glycosylated peptides that showed statistically significant (false discovery rate p [≤]0.05) differential expression associated with PFS. Five of the glycosylated peptides conferred continuous hazard ratio of > 6 (range 6.3-11.6). These included prothrombin A2G2S glycan motif (HR=6.47, P=9.53E-05), immunoglobulin J chain FA2G2S2 motif (HR=10.69, P=0.001), clusterin A2G2 motif (HR=7.38, P=0.002), complement component C8A A2G2S2 motif (HR=11.59, P=0.002), and apolipoprotein M glycopeptide with non-fucosylated and non-sialylated hybrid-type glycan (HR=6.30, P=0.003). Kaplan-Meier curves based on dichotomous expression of these five glycopeptides resulted in hazard ratios of 3.9-10.7, all with p-value < 0.03. Kaplan-Meyer plot using the multivariable model comprising 3 of the markers yielded HR of 11.96 (p <0.0001).\n\nConclusionDifferential glyco-isoform abundance of plasma proteins may be a useful source of biomarkers for the clinical course and prognosis of ccRCC.","Estimating Under-diagnosis of Patients in Chronically-ill Populations\nDiagnosis coding in administrative data is known to be inconsistent and incomplete, introducing inaccurate assessment of patients health outcomes. The under-diagnosis of members with a target chronic condition reduces the correlation of that chronic condition with associated events. Yet, only a few studies have evaluated the extent of under-reporting of chronic conditions in administrative data. In this study, we developed a novel framework to identify latent members, or those who have not yet been identified with a target chronic condition through claims-based diagnosis but are likely to have some degree of the condition. We applied our innovative approach to estimate the prevalence of a chronic-related event, based on the population of observed and latent members. We provided a detailed illustration that treats incontinence as our target chronic condition while examining four types of incontinence-related events: urinary-tract infections (UTIs), slips and falls, dermatitis, and behavioral disruptions. All analysis relied on the 5% Medicare sample for a continuously enrolled cohort between 2014-2018. Using our novel approach, we were able to increase our identification of incontinence from the 11.2% diagnosed in 2018 to an estimated prevalence in 2018 of 34.7% among fee-for-service Medicare beneficiaries over the age of 65. Similarly, our estimation of UTIs associated with those with incontinence increased from 38% to 68%, from 20% to 41% for IAD, 22% to 54% for slips and falls, and from 26% to 57% for behavior disruptions.","Comparing survival in urinary tract cancer patients with various second primary malignancies: A population-based study\nPurposeWe aimed to identify the patterns and combinations of second primary malignancies (SPMs) observed in patients with malignant neoplasms of the urinary tract (MNUT) and to explore the independent risk factors for survival outcomes in these patients.\n\nMaterials and MethodsWe analysed the data of MNUT patients with SPM in 25 hospitals in Shanghai between 2002 and 2015. A life table was used to calculate the survival rates, Kaplan-Meier analysis was used to determine the survival status of MNUT patients, and Cox regression analysis was used to perform multivariate analysis of survival risk factors in MNUT patients with SPM.\n\nResultsAmong the 154 patients included, the first primary malignancy (PM) most commonly occurred in the bladder (50.65%) and kidney (41.56%), and the SPM most commonly occurred in the lung (22.73%) and stomach (13.64%). The most common combinations included the bladder + lung and bladder + stomach. The Cox regression results showed that age older than 60 years (HR = 2.36 [95% CI 1.30-4.28] vs. age [≤]60 years, p = 0.005), TNM 1 stage III+IV disease (HR = 2.19 [95% CI 1.37-4.57] vs. I+ II), p = 0.037), TNM 2 stage III+IV disease (HR = 7.43 [95% CI 1.49-19.68] vs. I + II), p <0.001), and SPM in the lung (HR = 4.36 [95% CI 1.74-18.69], p = 0.047) were associated with a significantly worse cancer-specific survival.\n\nConclusionThe survival of MNUT patients with SPM may be related to the SPM site, first and second PM staging and latency time.","Glucose and lipid profiles in men with non-obstructive azoospermia\nThe impact of a low testosterone level among men with non-obstructive azoospermia with various testicular histopathological patterns on the regulation of glucose and lipid metabolism is less well known than among the general population. The aim of this retrospective study was to examine the association between testicular histopathology and components of the metabolic profile among men with non-obstructive azoospermia. Participants were divided into two groups: men with non-obstructive azoospermia and men with obstructive azoospermia. Testicular biopsies were performed among those with non-obstructive azoospermia. We included 115 patients in this study: 83 (72.2%) had non-obstructive azoospermia and 32 (27.8%) had obstructive azoospermia. The plasma glucose concentration, glycated hemoglobin level, and lipid profile were similar between patients with non-obstructive azoospermia and those with obstructive azoospermia. Upon subgroup analysis of patients with non-obstructive azoospermia, those with Sertoli-cell-only syndrome had the lowest testosterone (431 {+/-} 238 ng/dL; P=0.039) and highest follicle-stimulating hormone (23.4 {+/-} 18.2 mIU/mL; P=0.002) concentrations. They also had the highest triglyceride concentration (163 {+/-} 114 mg/dL; P=0.001). Interestingly, patients with Sertoli-cell-only syndrome had a lower fasting plasma glucose concentration (92 {+/-} 11 mg/dL; P<0.001) and glycated hemoglobin level (5.9 {+/-} 0.8%; P=0.022) than those with histopathological patterns of maturation arrest and hypospermatogenesis. In conclusion, differences in glucose and lipid metabolism are evident between men with non-obstructive azoospermia with different spermatogenesis patterns.","Impact of Transition from Conventional Open Radical Cystectomy to Laparoscopic Radical Cystectomy for Neobladder: A Retrospective Study\nBackgroundEarly operative recovery and good Quality of life are important goals of radical cystectomy. We compare the pre, peri and post operative data between Open radical cystectomy (ORC) and Laparoscopic radical cystectomy (LRC) surgery of neobladder.\n\nPatients and MethodsRetrospective analysis of 13 male consecutive patients who underwent radical cystectomy by a single surgeon was done. Diagnosis of all patients was of invasive bladder cancer. Abdominal and preoperative staging was done using computed tomography. None of them received neoadjuvant chemotherapy. All the patients received same standard template bilateral pelvic lympadenenectomy. The urinary diversion included orthotopic neobladder. All patients were consented prior to study participation.\n\nResultsOf the 13 male patients, six had ORC with neobladder while 7 underwent LRC surgery. Baseline characteristics (age, BMI, comorbidities, tumour grade, lymph node status) were similar in both groups. Incision length was significantly smaller in LRC as compared to ORC group (p <0.0001). Although the operative time was longer in LRC group as compared to ORC it was sufficed by reduced time for analgesics, shorter hospital stay (p<0.05), besides earlier time to liquid intake with immediate removal of nasogastric tube (p<0.001). No major complications were observed in the LRC unlike ORC group where one patient died at 30 days.\n\nConclusionsBased on the observations of our small study sample peri and postoperative outcomes are promising for LRC compared to ORC for patients undergoing neobladder in terms of the smaller incision length associated with less pain and complications, with speedy recovery without jeopardizing oncological outcomes. Transition of surgeon from ORC to LRC was advantageous to patients.","The predictive significance of prognostic nutritional index and serum albumin/globulin ratio on the overall survival of penile cancer patients undergoing penectomy\nObjectiveTo assess the value of using the prognostic nutritional index (PNI) and serum albumin/globulin ratio (AGR) in predicting the overall survival (OS) of patients with penile cancer (PC) undergoing penectomy.\n\nMaterials and methodsA retrospective analysis of 123 patients who were admitted to our hospital due to PC from April 2010 to September 2021 and underwent penectomy were included in the study. The optimal cut-off value of PNI and AGR was determined by receiver operating characteristic curve analysis. Kaplan-Meier analysis and the Cox proportional hazard model were used to evaluate the correlation between PNI, AGR, and OS in patients with PC.\n\nResultsThe best cut-off values of PNI and AGR were set to 49.03 (95% confidence interval 0.705-0.888, Youden index=0.517, sensitivity=57.9%, specificity=93.7%, P<0.001) and 1.28 (95% confidence interval 0.610-0.860, Youden index=0.404, sensitivity=84.1%, specificity=56.2%, P=0.003). Kaplan-Meier analysis showed that the OS of the patients in the high PNI group and the high AGR group was significantly higher than that of the patients in the low PNI group and the low AGR group (P<0.001). Univariate analysis showed that patient age, clinical N stage, pathological stage, PNI, and SII are all predictors of OS in patients with PC (P<0.05). Multivariate analysis showed that pathological stage (P=0.005), PNI (P=0.021), and AGR (P=0.004) are independent prognostic factors for predicting OS in patients with PC undergoing penectomy.\n\nConclusionsBoth PNI score and serum AGR are independent prognostic factors for predicting OS in patients with PC undergoing penectomy.","Intraoperative calculus or hemorrhage in transurethral seminal vesiculoscopy as a risk factor for recurrent hemospermia\nWe summarized our experience regarding Transurethral Seminal Vesiculoscopy (TUSV) and analyzed both recurrence status and risk factors for recurrence. From January 2010 to December 2020, 48 patients with intractable hemospermia received successful TUSV at Taichung Invalids General Hospital. For the intraoperative findings, the five-year Disease-free Survival rates (DFS) were 74.1% in the no calculus group compared to 37.1% in the calculus group with a significant difference (log-rank p = 0.015), 75.0% in the no hemorrhage or no blood clot group compared to 43.2% in the hemorrhage or blood clot group with significant difference (log-rank p = 0.032). Univariate analysis showed intraoperative calculus (p = 0.040; HR: 2.94, 95% CI: 1.05-8.21) to be significantly associated with recurrence (p < 0.05). Patients with intractable hemospermia who were diagnosed with stones or blood clots found during TUSV experienced a higher rate of hemospermia recurrence."],"string":"[\n \"Molecular portrait of prostate tissue probed by MALDI Imaging Mass Spectrometry\\nBenign prostatic hyperplasia (BPH) is the most common condition in aging men, associated with lower urinary tract symptoms. BPH has been suggested to be a risk factor for certain urologic cancers, but the current evidence is inconsistent. The gold-standard method for the diagnosis of BPH is histopathology. Histopathology displays the cellular morphologies of tissues wherein characteristic changes pertaining specifically to BPH can be identified. However, the onset of BPH might be associated with minimal phenotypic changes in cellular morphologies in tissues that histopathology might not be able to detect successfully. Therefore, to understand the onset of a disease and its pathogenesis it is important to investigate the detailed molecular profiles associated with the disease that might help in the diagnosis and to understand the insights of the disease pathogenesis. Over the last decade, imaging mass spectrometry has been used to explore the spatial distribution and expression profiles of several molecules with their two-dimensional heterogeneity retained across the tissues. In the present study, using MALDI mass spectrometry based tissue imaging platform, we observed the expression of several proteins across human prostate tissue sections diagnosed with BPH. The proteins were identified and characterized using tissue proteomics approach. We could successfully identify the on-tissue distribution of ribonuclease T2, vinculin, isoform 2 of tropomyosin alpha-3 chain and mitochondrial citrate synthase proteins using this approach. Therefore, imaging mass spectrometry might be a potential tool to complement the findings of histopathology in diagnosis of BPH in human prostate tissues.\",\n \"Radical versus partial nephrectomy and survival from stage T1 renal cell carcinoma in three prospective cohorts\\nBackgroundWhether or not a survival difference exists between radical and partial nephrectomy for stage T1 renal cell carcinoma (RCC) is controversial. We therefore aimed to evaluate cancer-specific, other cause, and overall survival among patients undergoing radical or partial nephrectomy for stage pT1 RCC.\\n\\nMaterials and methodsWe identified 330 participants with pT1a-b RCC diagnosed between 2000-2015 in three prospective cohort studies and compared treatment with radical nephrectomy (N=196) versus partial nephrectomy (N=134). The primary outcome was overall survival. Secondary outcomes were other-cause and cancer-specific mortality. Kaplan-Meier plots were used to visualize overall survival for the two treatment groups. Cox proportional hazards regression was utilized to compare outcomes between groups, and Fine and Gray competing risks regression was used to compare cancer-specific and other cause mortality between groups. Multivariable models adjusted for age, tumor size, sex, year of diagnosis, body mass index, history of smoking, history of hypertension, surgical technique, and pathological differentiation.\\n\\nResultsDuring a median follow-up of eight years, overall survival was 84%. We did not detect a statistically significant difference in overall survival between partial and radical nephrectomy (Hazard Ratio (HR) = 0.84, 95% Confidence Interval: 0.40-1.78). There was no significant difference in cause-specific or other cause mortality between groups. This study had 80% power to detect an HR [≥]2.20.\\n\\nConclusionsThese results did not suggest a difference in long-term survival outcomes between radical and partial nephrectomy.\",\n \"Protocol for 18F-PSMA PET imaging in staging and management of prostate cancer - a retrospective cohort study\\nBackgroundMRI, bone scan, and CT staging is recommended in the staging of prostate cancer. However, prostate-specific membrane antigen positron emission tomography (PSMA PET) could be superior in detection of local and distant prostate cancer cells. Most PSMA PET scans for prostate cancer are performed with a Gallium-68 ligand, with the Fluorine-18 (18F) ligand being introduced more recently. Methods: We will conduct a retrospective review of electronic patient records for all consecutive patients who underwent preoperative 18F-PSMA PET scan for prostate cancer from its introduction at our centre in 2019. We will compare PET scans with other imaging modalities and evaluate its use in diagnosis and management decisions for prostate cancer.\\n\\nConclusionsUnderstanding the role of 18F-PSMA PET in diagnosis and management could influence the diagnostic pathway of primary and secondary prostate cancer.\\n\\nTrial registrationNot applicable.\",\n \"Gut-bladder axis syndrome associated with recurrent UTIs in humans\\nRecurrent urinary tract infections (rUTIs) are a major health burden worldwide, with history of infection being a significant risk factor. While the gut is a known reservoir for uropathogenic bacteria, the role of the microbiota in rUTI remains unclear. We conducted a year-long study of women with and without history of rUTIs, from whom we collected urine, blood and monthly fecal samples for multi-omic interrogation. The rUTI gut microbiome was significantly depleted in microbial richness and butyrate-producing bacteria compared to controls, reminiscent of other inflammatory conditions, though Escherichia coli gut and bladder dynamics were comparable between cohorts. Blood samples revealed signals of differential systemic immunity, leading us to hypothesize that rUTI susceptibility is in part mediated through a syndrome involving the gut-bladder axis, comprising gut dysbiosis and differential immune response to bacterial bladder colonization, manifesting in symptoms. This work highlights the potential for microbiome therapeutics to prevent and treat rUTIs.\",\n \"The relationship between ethnicity and stone composition in a large multi-ethnic London NHS Trust\\nPurposeFew studies have examined kidney stone composition of an ethnically diverse group living in the same location, we aimed to study this in an ethnically diverse NHS trust.\\n\\nMethodsWe reviewed all patients (n=312) with laboratory stone analysis and compared their ethnicity with their stone composition.\\n\\nResultsUsing a Chi Squared analysis there was no significant difference between stone composition in different ethnic groups (p=0.07). Uric acid stones were more common in the White-other group at 22.0% compared to 10.3% for White British, 5.2% for Asian and 9.52% for Black patients. Calcium oxalate stone were more common in the Asian population with 71.9% and Black population at 76.1%, compared with 56.7% in the White British population and 52.6% in the White-other population. Calcium phosphate stones were found commonly in the White British population (26.8%) compared to 18.6% for White-other, 16.7% for Asian and 9.5% for Black patients. Cystine and Struvite stones were found at low levels of between 0-3.4% in each group. Repeat stone formers with calcium oxalate, uric acid or cystine stones formed the same stone again 100.0% of the time. The odds for the Black population having a stone analysed (OR 0.62, CI 0.39-0.97, p=0.04) was significantly lower than the local population, and for the Asian population this was significantly higher (OR 1.31, CI1.05-1.62, p=0.01),\\n\\nConclusionUric acid stones are found more frequently in the White-other population and calcium oxalate stones are found more frequently in the Asian and black population. However, these results were not statistically significant. The odds ratio of having a stone was significantly higher in the Asian population and lower in the Black population.\",\n \"Non-muscle Invasive Bladder Cancer Molecular Subtypes Predict Differential Response to Intravesical Bacillus Calmette-Guerin\\nThe recommended treatment for patients with high-risk non-muscle invasive bladder cancer (HR-NMIBC) is tumor resection followed by adjuvant Bacillus Calmette-Guerin (BCG) bladder instillations. However, only 50% of patients benefit from this therapy. In case of progression to advanced disease, patients must undergo a radical cystectomy with significant morbidity and have a poor clinical outcome. Identifying tumors least likely to respond to BCG can translate into alternative treatments, such as early radical cystectomy or novel targeted or immunotherapies. Here we present molecular profiling of 132 BCG-naive, HR-NMIBC patients, and 44 post-BCG recurrences (34 matched), which uncovered three distinct BCG Response Subtypes (BRS1-3). Patients with BRS3 tumors have reduced recurrence and progression-free survival compared to BRS1-2. BRS3 tumors expressed high EMT-basal markers and had an immunosuppresive profile, which was confirmed with spatial proteomics. Tumors which recurred post-BCG were enriched for BRS3. BRS stratification was validated in a second cohort of 151 BCG-naive HR-NMIBC patients and the molecular subtypes outperformed guideline recommended risk stratification based on clinicopathological variables. For clinical application, we validated that a commercially approved assay was able to accurately predict BRS3 tumors (AUROC 0.86). Our findings provide a potential clinical tool for improved identification of HR-NMIBC patients at the highest risk of progression, which can be used to select patients for early radical cystectomy or novel subtype-directed therapies.\\n\\nOne Sentence SummaryMolecular subtypes are predictive of response to intravesical Bacillus Calmette-Guerin immunotherapy in non-muscle invasive bladder cancer.\",\n \"Innate immune responses in patients treated with SBRT irradiation enhances prostate cancer remissions\\nStereotactic body radiation therapy (SBRT) is a curative therapeutic modality employing large fractional doses of highly conformal radiation therapy for cancer treatment. To understand the mechanisms underlying clinical responses to radiation therapy, SBRT offers a unique window for high-throughput analysis of post-radiation molecular events to inform predictive biomarker discovery and strategies for multi-disciplinary therapeutics. We performed longitudinal analysis of plasma proteins and metabolites from patients treated with prostate SBRT, comparing cohorts of patients in clinical remission to cohorts experiencing PSA-determined cancer progression. We observed onset of post-SBRT DNA Damage Response (DDR), cell cycle arrest, and immune response signaling in patients within one hour of treatment and innate immune response signaling that persisted for up to three months following treatment. Furthermore, patients in remission experienced more robust immune responses and metabolite elevations consistent with a pro-inflammatory, M1-mediated innate immune activation in the short-term following SBRT, whereas patients with disease progression had less robust immune responses and M2-mediated metabolite elevations. We interpret these data to support a critical role for innate immune activation in the clinical outcomes of patients receiving radiation therapy for prostate cancer potentially improving future multidisciplinary therapeutic strategies.\\n\\nOne Sentence SummaryFollowing SBRT, proteomic and metabolomic profiles reveal a robust immune activation that correlates with prostate cancer remission\",\n \"Creation of synthetic contrast-enhanced computed tomography images using deep neural networks to screen for renal cell carcinoma\\nObjectivesTo elucidate if synthetic contrast enhanced computed tomography (CECT) images created from plain CT images using deep neural networks (DNN) could be used for screening, clinical diagnosis, and postoperative follow-up of small-diameter renal tumors by comparing the concordance rate between real and synthetic CECT images and the diagnoses according to 10 urologists.\\n\\nMethodsThis retrospective, multicenter study included 155 patients (artificial intelligence training cohort [n=99], validation cohort [n=56]) who underwent surgery for small-diameter ([≤]40 mm) renal tumors, with the pathological diagnosis of renal cell carcinoma, during 2010-2020. Preoperatively, dynamic plain CT and CECT images were obtained. We created a learned DNN using pix2pix. We examined the quality of the synthetic CECT images created using this DNN and compared them with real CECT images using the zero-mean normalized cross-correlation parameter. We assessed concordance rates between real and synthetic images and diagnoses according to 10 urologists by creating a receiver operating characteristic curve and calculating the area under the curve (AUC).\\n\\nResultsThe synthetic CECT images were highly concordant with the real CECT images, regardless of the existence or morphology of the renal tumor. Regarding the concordance rate, a greater AUC was obtained with synthetic CECT (AUC=0.892) than with only CT (AUC=0.720; p<0.001).\\n\\nConclusionsThis study is the first to use DNN to create a high-quality synthetic CECT image that was highly concordant with a real CECT image. Synthetic CECT images could be used for urological diagnoses and clinical screening.\",\n \"NOVEL PLASMA GLYCOPROTEIN BIOMARKERS PREDICT PROGRESSION-FREE SURVIVAL IN SURGICALLY RESECTED CLEAR CELL RENAL CELL CARCINOMA\\nIntroductionLimited data exists on utilization of protein post-translational modifications as biomarkers for clear cell renal cell carcinoma (ccRCC). We employed high-throughput glycoproteomics to evaluate differential expression of glycoprotein-isoforms as novel markers for ccRCC progression-free survival (PFS).\\n\\nMethodsPlasma samples were obtained from 77 patients treated surgically for ccRCC. Glycoproteomic analyses were carried out after liquid chromatography tandem mass spectrometry. Age-adjusted Cox proportional hazard models were constructed to evaluate PFS. Optimized Harrells c-index was employed to dichotomize the collective for the construction of Kaplan-Meier curves.\\n\\nResultsThe average length of follow-up was 3.4 (range: 0.04-9.83) years. Glycoproteomic analysis identified 39 glycopeptides and 14 non-glycosylated peptides that showed statistically significant (false discovery rate p [≤]0.05) differential expression associated with PFS. Five of the glycosylated peptides conferred continuous hazard ratio of > 6 (range 6.3-11.6). These included prothrombin A2G2S glycan motif (HR=6.47, P=9.53E-05), immunoglobulin J chain FA2G2S2 motif (HR=10.69, P=0.001), clusterin A2G2 motif (HR=7.38, P=0.002), complement component C8A A2G2S2 motif (HR=11.59, P=0.002), and apolipoprotein M glycopeptide with non-fucosylated and non-sialylated hybrid-type glycan (HR=6.30, P=0.003). Kaplan-Meier curves based on dichotomous expression of these five glycopeptides resulted in hazard ratios of 3.9-10.7, all with p-value < 0.03. Kaplan-Meyer plot using the multivariable model comprising 3 of the markers yielded HR of 11.96 (p <0.0001).\\n\\nConclusionDifferential glyco-isoform abundance of plasma proteins may be a useful source of biomarkers for the clinical course and prognosis of ccRCC.\",\n \"Estimating Under-diagnosis of Patients in Chronically-ill Populations\\nDiagnosis coding in administrative data is known to be inconsistent and incomplete, introducing inaccurate assessment of patients health outcomes. The under-diagnosis of members with a target chronic condition reduces the correlation of that chronic condition with associated events. Yet, only a few studies have evaluated the extent of under-reporting of chronic conditions in administrative data. In this study, we developed a novel framework to identify latent members, or those who have not yet been identified with a target chronic condition through claims-based diagnosis but are likely to have some degree of the condition. We applied our innovative approach to estimate the prevalence of a chronic-related event, based on the population of observed and latent members. We provided a detailed illustration that treats incontinence as our target chronic condition while examining four types of incontinence-related events: urinary-tract infections (UTIs), slips and falls, dermatitis, and behavioral disruptions. All analysis relied on the 5% Medicare sample for a continuously enrolled cohort between 2014-2018. Using our novel approach, we were able to increase our identification of incontinence from the 11.2% diagnosed in 2018 to an estimated prevalence in 2018 of 34.7% among fee-for-service Medicare beneficiaries over the age of 65. Similarly, our estimation of UTIs associated with those with incontinence increased from 38% to 68%, from 20% to 41% for IAD, 22% to 54% for slips and falls, and from 26% to 57% for behavior disruptions.\",\n \"Comparing survival in urinary tract cancer patients with various second primary malignancies: A population-based study\\nPurposeWe aimed to identify the patterns and combinations of second primary malignancies (SPMs) observed in patients with malignant neoplasms of the urinary tract (MNUT) and to explore the independent risk factors for survival outcomes in these patients.\\n\\nMaterials and MethodsWe analysed the data of MNUT patients with SPM in 25 hospitals in Shanghai between 2002 and 2015. A life table was used to calculate the survival rates, Kaplan-Meier analysis was used to determine the survival status of MNUT patients, and Cox regression analysis was used to perform multivariate analysis of survival risk factors in MNUT patients with SPM.\\n\\nResultsAmong the 154 patients included, the first primary malignancy (PM) most commonly occurred in the bladder (50.65%) and kidney (41.56%), and the SPM most commonly occurred in the lung (22.73%) and stomach (13.64%). The most common combinations included the bladder + lung and bladder + stomach. The Cox regression results showed that age older than 60 years (HR = 2.36 [95% CI 1.30-4.28] vs. age [≤]60 years, p = 0.005), TNM 1 stage III+IV disease (HR = 2.19 [95% CI 1.37-4.57] vs. I+ II), p = 0.037), TNM 2 stage III+IV disease (HR = 7.43 [95% CI 1.49-19.68] vs. I + II), p <0.001), and SPM in the lung (HR = 4.36 [95% CI 1.74-18.69], p = 0.047) were associated with a significantly worse cancer-specific survival.\\n\\nConclusionThe survival of MNUT patients with SPM may be related to the SPM site, first and second PM staging and latency time.\",\n \"Glucose and lipid profiles in men with non-obstructive azoospermia\\nThe impact of a low testosterone level among men with non-obstructive azoospermia with various testicular histopathological patterns on the regulation of glucose and lipid metabolism is less well known than among the general population. The aim of this retrospective study was to examine the association between testicular histopathology and components of the metabolic profile among men with non-obstructive azoospermia. Participants were divided into two groups: men with non-obstructive azoospermia and men with obstructive azoospermia. Testicular biopsies were performed among those with non-obstructive azoospermia. We included 115 patients in this study: 83 (72.2%) had non-obstructive azoospermia and 32 (27.8%) had obstructive azoospermia. The plasma glucose concentration, glycated hemoglobin level, and lipid profile were similar between patients with non-obstructive azoospermia and those with obstructive azoospermia. Upon subgroup analysis of patients with non-obstructive azoospermia, those with Sertoli-cell-only syndrome had the lowest testosterone (431 {+/-} 238 ng/dL; P=0.039) and highest follicle-stimulating hormone (23.4 {+/-} 18.2 mIU/mL; P=0.002) concentrations. They also had the highest triglyceride concentration (163 {+/-} 114 mg/dL; P=0.001). Interestingly, patients with Sertoli-cell-only syndrome had a lower fasting plasma glucose concentration (92 {+/-} 11 mg/dL; P<0.001) and glycated hemoglobin level (5.9 {+/-} 0.8%; P=0.022) than those with histopathological patterns of maturation arrest and hypospermatogenesis. In conclusion, differences in glucose and lipid metabolism are evident between men with non-obstructive azoospermia with different spermatogenesis patterns.\",\n \"Impact of Transition from Conventional Open Radical Cystectomy to Laparoscopic Radical Cystectomy for Neobladder: A Retrospective Study\\nBackgroundEarly operative recovery and good Quality of life are important goals of radical cystectomy. We compare the pre, peri and post operative data between Open radical cystectomy (ORC) and Laparoscopic radical cystectomy (LRC) surgery of neobladder.\\n\\nPatients and MethodsRetrospective analysis of 13 male consecutive patients who underwent radical cystectomy by a single surgeon was done. Diagnosis of all patients was of invasive bladder cancer. Abdominal and preoperative staging was done using computed tomography. None of them received neoadjuvant chemotherapy. All the patients received same standard template bilateral pelvic lympadenenectomy. The urinary diversion included orthotopic neobladder. All patients were consented prior to study participation.\\n\\nResultsOf the 13 male patients, six had ORC with neobladder while 7 underwent LRC surgery. Baseline characteristics (age, BMI, comorbidities, tumour grade, lymph node status) were similar in both groups. Incision length was significantly smaller in LRC as compared to ORC group (p <0.0001). Although the operative time was longer in LRC group as compared to ORC it was sufficed by reduced time for analgesics, shorter hospital stay (p<0.05), besides earlier time to liquid intake with immediate removal of nasogastric tube (p<0.001). No major complications were observed in the LRC unlike ORC group where one patient died at 30 days.\\n\\nConclusionsBased on the observations of our small study sample peri and postoperative outcomes are promising for LRC compared to ORC for patients undergoing neobladder in terms of the smaller incision length associated with less pain and complications, with speedy recovery without jeopardizing oncological outcomes. Transition of surgeon from ORC to LRC was advantageous to patients.\",\n \"The predictive significance of prognostic nutritional index and serum albumin/globulin ratio on the overall survival of penile cancer patients undergoing penectomy\\nObjectiveTo assess the value of using the prognostic nutritional index (PNI) and serum albumin/globulin ratio (AGR) in predicting the overall survival (OS) of patients with penile cancer (PC) undergoing penectomy.\\n\\nMaterials and methodsA retrospective analysis of 123 patients who were admitted to our hospital due to PC from April 2010 to September 2021 and underwent penectomy were included in the study. The optimal cut-off value of PNI and AGR was determined by receiver operating characteristic curve analysis. Kaplan-Meier analysis and the Cox proportional hazard model were used to evaluate the correlation between PNI, AGR, and OS in patients with PC.\\n\\nResultsThe best cut-off values of PNI and AGR were set to 49.03 (95% confidence interval 0.705-0.888, Youden index=0.517, sensitivity=57.9%, specificity=93.7%, P<0.001) and 1.28 (95% confidence interval 0.610-0.860, Youden index=0.404, sensitivity=84.1%, specificity=56.2%, P=0.003). Kaplan-Meier analysis showed that the OS of the patients in the high PNI group and the high AGR group was significantly higher than that of the patients in the low PNI group and the low AGR group (P<0.001). Univariate analysis showed that patient age, clinical N stage, pathological stage, PNI, and SII are all predictors of OS in patients with PC (P<0.05). Multivariate analysis showed that pathological stage (P=0.005), PNI (P=0.021), and AGR (P=0.004) are independent prognostic factors for predicting OS in patients with PC undergoing penectomy.\\n\\nConclusionsBoth PNI score and serum AGR are independent prognostic factors for predicting OS in patients with PC undergoing penectomy.\",\n \"Intraoperative calculus or hemorrhage in transurethral seminal vesiculoscopy as a risk factor for recurrent hemospermia\\nWe summarized our experience regarding Transurethral Seminal Vesiculoscopy (TUSV) and analyzed both recurrence status and risk factors for recurrence. From January 2010 to December 2020, 48 patients with intractable hemospermia received successful TUSV at Taichung Invalids General Hospital. For the intraoperative findings, the five-year Disease-free Survival rates (DFS) were 74.1% in the no calculus group compared to 37.1% in the calculus group with a significant difference (log-rank p = 0.015), 75.0% in the no hemorrhage or no blood clot group compared to 43.2% in the hemorrhage or blood clot group with significant difference (log-rank p = 0.032). Univariate analysis showed intraoperative calculus (p = 0.040; HR: 2.94, 95% CI: 1.05-8.21) to be significantly associated with recurrence (p < 0.05). Patients with intractable hemospermia who were diagnosed with stones or blood clots found during TUSV experienced a higher rate of hemospermia recurrence.\"\n]","isConversational":false},"negative":{"kind":"list like","value":["Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis\nProteoglycans are complex macromolecules formed of glycosaminoglycan chains covalently linked to core proteins through a linker tetrasaccharide common to heparan sulfate proteoglycans (HSPG) and chondroitin sulfate proteoglycans (CSPG). Biosynthesis of a single proteoglycan requires the expression of dozens of genes, which together create the large structural and functional diversity reflected by the numerous diseases or syndromes associated to their genetic variability. Among proteoglycans, HSPG are the most structurally and functionally complex. To decrease this complexity, we retrieved and linked information on pathogenic variants, polymorphism, expression, and literature databases for 50 genes involved in the biosynthesis of HSPG core proteins, heparan sulfate (HS) chains, and their linker tetrasaccharide. This resulted in a new gene organization and biosynthetic pathway representation in which the phenotypic continuum of disorders as linkeropathies and other pathologies could be predictable. Moreover, ubiquitous NDST1, GLCE, HS2ST1, and HS6ST1 appeared to generate ubiquitous heparan sulfate (HS) sequences essential for normal development and homeostasis, whereas the tissue restricted NDST2-4, HS6ST2-3, and HS3ST1-6 appeared to generate specialized HS sequences mainly involved in responsiveness to stimuli. Supported by data on genetic polymorphism and clinical variants, we afford a new vision of HSPG involvement in homeostasis, disease, vulnerability to disease, and behavioral disorders.","Delta/ Omicron and Omicron/BA.2 co-infections occurring in Immunocompromised hosts\nConcomitant infection of multiple SARS-CoV-2 variants has become an increasing concern, as this scenario increases the likelihood of recombinant variants. Detecting co-infection of SARS-CoV-2 variants is difficult to detect by whole genome sequencing approaches, but genotyping methods facilitate detection. We describe 2 cases of Delta/Omicron and 2 cases of Omicron sublineage BA.1/ BA.2 co-infection as detected by a multiplex genotyping fragment analysis method. Findings were confirmed by whole genome sequencing. Review of the patient characteristics revealed co-morbidities and conditions which weaken the immune system and may make them more susceptible to harboring SARS-CoV-2 variant co-infections.","Sibling Experiences of Adverse Childhood Experiences: A Scoping Review.\nAdverse childhood experiences (ACEs) are traumatic events during childhood known to affect health and wellbeing across the life-span. The purpose of this scoping review was to understand what we currently know about the experiences of siblings living with ACEs. Sibling relationships are unique, and for some the most enduring we experience. These relationships can be categorised by love and warmth, however, can also be a point of escalating conflict and problems. This scoping review was conducted following Arksey and OMalleys (2005) methodological framework, complemented by the PAGER framework (Bradbury-Jones et al, 2021), offering a structured approach to the reviews analysis and reporting through presenting the Patterns, Advances, Gaps, and Evidence for practice and Research. In June 2020 we searched 12 databases, with 11,469 results. Articles were screened for eligibility by the review team leaving a total of 148 articles meeting the inclusion criteria. Findings highlighted five main patterns: (1) the influence of birth order (older siblings shielding younger); (2) the influence of sibling relationships (lack of research exploring sibling types outside of biological siblings); (3) identifying siblings experiencing ACEs (when one sibling experiences adversity, it is likely that their other siblings also do, or experience vicariously); (4) siblings who cause harm (siblings harming other siblings is often normalised and minimised, especially by parents); (5) focus on individual ACEs (the majority of studies explore ACEs in isolation). Our findings suggest future research would benefit from an increase in theoretical understanding and exploration of different types of sibling relationships (full, step, half).","Clinical features of UK Biobank subjects carrying protein truncating variants in genes implicated in schizophrenia pathogenesis\nThe SCHEMA consortium has identified ten genes in which protein truncating variants (PTVs) confer substantial risk of schizophrenia. Exome-sequenced participants in the UK Biobank who carried PTVs in these genes were studied to determine to what extent they demonstrated features of schizophrenia or had neuropsychiatric impairment. Following automated quality control and visual inspection of reads, 251 subjects were identified as having well-supported PTVs in one of these genes. The frequency of PTVs in CACNA1G was higher than had been observed in SCHEMA cases, casting doubt on its role in schizophrenia pathogenesis, but otherwise rates were similar to those observed in SCHEMA controls. Numbers were too small to allow formal statistical analysis but in general carriers of PTVs did not appear to have high rates of psychiatric illness or reduced educational or occupational functioning. One subject with a PTV in SETD1A had a diagnosis of schizophrenia. one with a PTV in HERC1 had psychotic depression and two subjects seemed to have developmental disorders, one with a PTV in GRIN2A and one with a PTV in RBCC1. There seemed to be somewhat increased rates of affective disorders among carriers of PTVs in HERC1 and RB1CC1. Carriers of PTVs did not appear to have subclinical manifestations of schizophrenia. Although PTVs in these genes can substantially increase schizophrenia risk, their effect seems to be dichotomous and most carriers appear psychiatrically well.\n\nThis research has been conducted using the UK Biobank Resource.","Phenotypic distinctions of BLM- and RMI1-associated Bloom syndrome\nBloom syndrome (BS) is an autosomal recessive disease with characteristic clinical features of primary microcephaly, growth deficiency, skin lesions, cancer predisposition, and immunodeficiency. Here, we report the clinical and molecular findings of eight patients from six families diagnosed with BS. We identified causative mutations in all families, three different homozygous mutations in BLM and one causative homozygous mutation in RMI1. The homozygous c.581_582delTT (p.Phe194*) and c.3164G>C (p.Cys1055Ser) mutations in BLM have already been reported in BS patients, while the c.572_573delGA (p.Arg191Lysfs*4) is novel. Interestingly, whole-exome sequencing revealed a homozygous loss-of-function mutation in RMI1 in two BS patients of a consanguineous Turkish family. All BS patients had primary microcephaly, intrauterine growth delay, and short stature, presenting the phenotypic hallmarks of BS. However, a narrow face, skin lesions, and upper airway infections were observed only in some of the patients. Overall, patients with homozygous BLM mutations had a more severe BS phenotype compared to patients carrying the homozygous RMI1 mutation, especially in terms of immunodeficiency and associated recurrent infections. Low-level immunoglobulins were observed in all BLM-mutated patients, emphasizing the immunodeficiency profile of the disease, which should be considered as an important phenotypic characteristic of BS, especially in the current Covid-19 pandemic era.","AImmune: a new blood-based machine learning approach to improving immune profiling analysis on COVID-19 patients\nA massive number of transcriptomic profiles of blood samples from COVID-19 patients has been produced since pandemic COVID-19 begins, however, these big data from primary studies have not been well integrated by machine learning approaches. Taking advantage of modern machine learning arthrograms, we integrated and collected single cell RNA-seq (scRNA-seq) data from three independent studies, identified genes potentially available for interpretation of severity, and developed a high-performance deep learning-based deconvolution model AImmune that can predict the proportion of seven different immune cells from the bulk RNA-seq results of human peripheral mononuclear cells. This novel approach which can be used for clinical blood testing of COVID-19 on the ground that previous research shows that mRNA alternations in blood-derived PBMCs may serve as a severity indicator. Assessed on real-world data sets, the AImmune model outperformed the most recognized immune profiling model CIBERSORTx. The presented study showed the results obtained by the true scRNA-seq route can be consistently reproduced through the new approach AImmune, indicating a potential replacing the costly scRNA-seq technique for the analysis of circulating blood cells for both clinical and research purposes.","Knowledge, Attitude, and Practices of Health Professionals Working in A Major Health Care System Regarding Social Determinants of Health (SDOH) and Community Health Workers (CHWs)\nIntroductionSocial Determinants of Health (SDOH) play a key role in impacting the health outcomes of any population. Community Health Workers (CHWs) play an important role in health promotion, disease prevention, and management of chronic illnesses. This study aims at exploring the knowledge, attitude, and practices of health care professionals towards CHWs to fully integrate in them for mitigation of SDOH.\n\nMaterials and MethodsA cross-sectional study utilizing an anonymous survey questionnaire across 4 clinical sites was carried out from June 2016 to November 2017 in a major healthcare system (Presbyterian) in Albuquerque, New Mexico. Descriptive statistics (means, standard deviations, and proportions) were collected. Categorical variables were analyzed using Chi-squared and Fishers exact test; a p-value of <0.05 was considered statistically significant, using SAS 9.4 statistical software.\n\nResultsAlmost half of the health professionals had no knowledge about the social determinants of health. Almost a quarter of the health professionals did not know the role of CHWs in healthcare, however, 100% of the respondents across all clinic and practice locations and regardless of their role or scope of the practice believed that greater involvement of CHWs would improve patient outcomes.\n\nConclusionThere is a knowledge deficit among health care providers about the social determinants of health (SDOH).More educational and teaching opportunities on SDOH and CHWs to all health professionals should be provided to all health professionals so the clinical team can help manage SDOH in addition to providing clinical care.","Association between SARS-Cov-2 infection during pregnancy and adverse pregnancy outcomes: a re-analysis of data from Wei et al. (2021).\nBackgroundWei et al. have published a meta-analysis (MA) which aimed to \"evaluate the association between SARS-CoV-2 infection during pregnancy and adverse pregnancy outcomes\".\n\nUsing classical random-effects model, they found that SARS-CoV-2 infection was associated with preeclampsia, preterm birth and stillbirth.\n\nPerforming MA with low event rates or with few studies may be challenging as MA relies on several within and between study distributional assumptions.\n\nMethodsto assess the robustness of the results provided by Wei et al., we performed a sensitivity analysis using several frequentist and Bayesian meta-analysis methods. We also estimated fragility indexes.\n\nResultsFor eclampsia (patients with Covid-19 vs without), the confidence intervals of most frequentist models contain 1. All beta-binomial models (Bayesian) lead to credible intervals containing 1. The prediction interval, based on DL method ranges from 0.75 to 2.38. The fragility index is 2 for the DL method.\n\nFor preterm, the confidence (credible) intervals exclude 1. The prediction interval is broad, ranging from 0.84 to 20.61. The fragility index ranges from 27 to 10.\n\nFor stillbirth, the confidence intervals of most frequentist models contain 1. Six Bayesian MA models lead to credible intervals containing 1.The prediction interval ranges from 0.52 to 8.49. The fragility index is 3.\n\nInterpretationGiven the available data and the results of our broad sensitivity analysis, we can only suggest that SARS-CoV-2 infection during pregnancy is associated to preterm, and may be associated to preeclampsia. For stillbirth, more data are needed as none of the Bayesian analyses are conclusive.","Comparative analysis unveils novel changes in serum metabolites and metabolomic networks of retinopathy of prematurity infants\nBackgroundAdvances in mass spectrometry are providing new insights into the role of metabolomics in the aetiology of many diseases. Studies in retinopathy of prematurity (ROP), for instance, overlooked the role of metabolic alterations in disease development. Here, we employed comprehensive metabolic profiling and gold-standard metabolic analysis to explore major metabolites and metabolic pathways significantly affected in early stages of pathogenesis toward ROP.\n\nMethodsThis is a multicentre, retrospective case-control study. We collected serums from 57 ROP cases and 57 strictly baseline matched non-ROP controls. Non-targeted ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) from Metabolon, Inc. was used to detect the metabolites in serum samples. Machine learning was used to unravel most affected metabolites and pathways in ROP development.\n\nResultsCompared to non-ROP controls, we found a significant metabolic perturbation in the ROP serums, featured with an increase in lipid, nucleotide, carbohydrate metabolites and a lower level of peptides. Machine leaning helped to distinguish a cluster of metabolic pathways (glycometabolism, redox homeostasis, lipid metabolism and arginine pathway) that were strongly related to the development of ROP. In addition, we found that the severity of ROP was related to the level of creatinine and ribitol.\n\nConclusionIn the current study, our results suggested a strong link between metabolic profiling and retinal neovascularization during ROP pathogenesis. These findings provided an insight into identifying novel metabolic biomarkers for ROP diagnosis and prevention.","AKI Risk Score (AKI-RiSc): Developing an Interpretable Clinical Score for Early Identification of Acute Kidney Injury for Patients Presenting to the Emergency Department\nBackgroundAcute kidney injury (AKI) in hospitalised patients is a common syndrome associated with poorer patient outcomes. Clinical risk scores can be used for the early identification of patients at risk of AKI.\n\nMethodsWe conducted a retrospective study using electronic health records of Singapore General Hospital emergency department patients who were admitted from 2008 to 2016. The primary outcome was inpatient AKI of any stage within 7 days of admission based on Kidney Disease Improving Global Outcome (KDIGO) 2012 guidelines. AutoScore, a machine learning based algorithm, was used to generate point based clinical scores from the study sample which was divided into training, validation and testing cohorts. Model performance was evaluated using area under the curve (AUC).\n\nResultsAmong the 119,468 admissions, 10,693 (9.0%) developed AKI. 8,491 were stage 1 (79.4%), 906 stage 2 (8.5%) and 1,296 stage 3 (12.1%). The AKI Risk Score (AKI-RiSc) was a summation of the integer scores of 6 variables: serum creatinine, serum bicarbonate, pulse, systolic blood pressure, and diastolic blood pressure. AUC of AKI-RiSc was 0.730 (95% CI: 0.713 - 0.747), outperforming an existing AKI Prediction Score model which achieved AUC of 0.665 (95% CI: 0.646 - 0.679) when evaluated on the same test cohort. At a cut-off of 4 points, AKI-RiSc had a sensitivity of 82.5% and specificity of 46.7%.\n\nConclusionAKI-RiSc is a simple point based clinical score that can be easily implemented on the ground for early identification of AKI in high-risk patients and potentially be applied in healthcare settings internationally.","The impact of the coronavirus disease 2019 (COVID-19) outbreak on cancer practice in Japan: using an administrative database\nBackgroundRecent researches reported the impact of the coronavirus disease 2019 (COVID - 19) pandemic on the clinical practice of specific type cancers. The aim of this study was to reveal the impact of the COVID-19 outbreak on the clinical practice of various cancers.\n\nMethodsWe included hospitalized patients aged 18 years or older diagnosed between July 2018 and June 2020 with one of the top 12 most common cancers in Japan (colon/rectum, lung, gastric, breast, bladder & urinary tract, pancreas, non-Hodgkin lymphoma, liver, prostate, esophagus, uterus, and gallbladder & biliary tract) using Diagnostic Procedure Combination data, an administrative database in Japan. The intervention was defined April 2020 based on a declaration of emergency from Japanese government. The change volume of number of monthly admissions with each cancer was tested by interrupted time series (ITS) analysis, and monthly cases with radical surgery or chemotherapy for each cancer were descripted.\n\nResults403,344 cases were included during the study period. The most common cancer was colon/rectum (20.5%), followed by lung (17.5%). In almost cancer cases, the number of admissions decreased in May 2020. In particular, colorectal, lung, gastric, breast, uterine, or esophageal cancer cases decreased by over 10%. The number of admissions with surgery or chemotherapy decreased in colorectal, lung, gastric, breast, uterine, or esophageal cancer. ITS analysis indicated that cases with gastric or esophageal cancer were affected more than other type of cancer.\n\nConclusionsThe COVID-19 outbreak has a negative impact on the number of admission cases with cancer; the magnitude of impact varied by cancer diagnosis.","Allelic Complexity of KMT2A Partial Tandem Duplications in Acute Myeloid Leukemia and Myelodysplastic Syndromes\nKMT2A partial tandem duplication (KMT2A-PTD) at 11q23.3 is associated with adverse risk in AML and MDS, is a potential therapeutic target, and is an attractive marker of measurable residual disease. High initial KMT2A-PTD RNA levels have been linked to poor prognosis, but mechanisms regulating KMT2A-PTD expression are not well understood. While it has been reported that KMT2A-PTD affects only a single allele, it has been theorized but not proven that duplications or genomic gains of a monoallelic KMT2A-PTD may occur, thereby potentially driving high expression and disease progression. Copy neutral loss of heterozygosity (CN-LOH) of 11q has also been described and is known to be associated with mutations in CBL but has not been reported to involve KMT2A-PTD. In this study, we identified 94 patients with KMT2A-PTDs using targeted DNA next-generation sequencing (NGS) and found that 16% (15/94) had complex secondary events, including CN-LOH and selective gain involving the KMT2A-PTD allele. High copy numbers indicating complexity were significantly enriched in AML versus MDS and correlated with higher RNA expression. Moreover, in serial samples, complexity was associated with relapse and secondary transformation. Taken together, we provide approaches to integrate quantitative and allelic assessment of KMT2A-PTDs into targeted DNA NGS and demonstrate that secondary genetic events occur in KMT2A-PTD by multiple mechanisms that may be linked to myeloid disease progression by driving increased expression from the affected allele.","Robotic-Assisted Gait for lower-limb Rehabilitation: Evidence of Altered Neural Mechanisms in Stroke\nRobotic-Assisted Gait training (RAGT) offers an innovative therapeutic option for restoration of functional gait in stroke survivors, complementing existing physical rehabilitation strategies. However, there is a limited understanding of the neurophysiological response induced by this training in end-users. Neural desynchronization and Cortico-Muscular Coherence (CMC) are two biomarkers that define the level of muscle-cortex association during gait phases and can be used to estimate induced users adaptation during RAGT. In this study, we measure Event-Related Spectral Perturbation (ERSP) and CMC from three healthy individuals and three stroke survivors during overground-gait with and without an exoskeleton. Results show that (1) the use of the exoskeleton in healthy individuals is associated with a different and more refined motor-control represented in a high{theta} -desynchronization, (2) altered and noisy ERSP and lower and non-focal {beta}-CMC patterns are observed in Stroke patients when performing overground-gait both with and without the Exoskeleton, and (3) Exoskeleton use in stroke survivors is associated with a reduction in swing-time during gait-cycle, but this effect is not correlated with an increment of{theta} -desynchronization and/or {beta}-CMC. ERSP and CMC demonstrated evidence of neural modulation in able-bodied users during RAGT, which could not be detected in subacute stroke survivors during RAGT. These results suggest that the gait-parameters changes observed during exoskeleton use in subacute stroke survivors are unlikely to be neurally driven.","A novel age-informed approach for genetic association analysis in Alzheimer's disease\nIntroductionMany Alzheimers disease (AD) genetic association studies disregard age or incorrectly account for it, hampering variant discovery.\n\nMethodUsing simulated data, we compared the statistical power of several models: logistic regression on AD diagnosis adjusted and not adjusted for age; linear regression on a score integrating case-control status and age; and multivariate Cox regression on age-at-onset. We applied these models to real exome-wide data of 11,127 sequenced individuals (54% cases) and replicated suggestive associations in 21,631 genotype-imputed individuals (51% cases).\n\nResultsModelling variable AD risk across age results in 10-20% statistical power gain compared to logistic regression without age adjustment, while incorrect age adjustment leads to critical power loss. Applying our novel AD-age score and/or Cox regression, we discovered and replicated novel variants associated with AD on KIF21B, USH2A, RAB10, RIN3 and TAOK2 genes.\n\nDiscussionOur AD-age score provides a simple means for statistical power gain and is recommended for future AD studies.","Empirical networks for localized COVID-19 interventions using WiFi infrastructure at university campuses\nInfectious diseases, like COVID-19, pose serious challenges to university campuses, which typically adopt closure as a non-pharmaceutical intervention to control spread and ensure a gradual return to normalcy. Intervention policies, such as remote instruction (RI) where large classes are offered online, reduce potential contact but also have broad side-effects on campus by hampering the local economy, students learning outcomes, and community wellbeing. In this paper, we demonstrate that university policymakers can mitigate these tradeoffs by leveraging anonymized data from their WiFi infrastructure to learn community mobility --- a methodology we refer to as WiFi mobility models (WO_SCPLOWIC_SCPLOWMO_SCPLOWOBC_SCPLOW). This approach enables policymakers to explore more granular policies like localized closures (LC). WO_SCPLOWIC_SCPLOWMO_SCPLOWOBC_SCPLOW can construct contact networks that capture behavior in various spaces, highlighting new potential transmission pathways and temporal variation in contact behavior. Additionally, WO_SCPLOWIC_SCPLOWMO_SCPLOWOBC_SCPLOW enables us to design LC policies that close super-spreader locations on campus. By simulating disease spread with contact networks from WO_SCPLOWIC_SCPLOWMO_SCPLOWOBC_SCPLOW, we find that LC maintains the same reduction in cumulative infections as RI while showing greater reduction in peak infections and internal transmission. Moreover, LC reduces campus burden by closing fewer locations, forcing fewer students into completely online schedules, and requiring no additional isolation. WO_SCPLOWIC_SCPLOWMO_SCPLOWOBC_SCPLOW can empower universities to conceive and assess a variety of closure policies to prevent future outbreaks.","Novelty-induced frontal-STN networks in Parkinson's disease\nNovelty detection is a primitive subcomponent of cognitive control that is deficient in Parkinsons disease (PD) patients with cognitive dysfunction. Here, we studied novelty-response mechanisms in PD. In participants with PD, we recorded from cortical circuits with scalp-based electroencephalography (EEG) and from subcortical circuits using intraoperative neurophysiology during surgeries for implantation of deep-brain stimulation (DBS) electrodes. We report three major results. First, novel auditory stimuli triggered midfrontal low-frequency rhythms; of these, 1-4 Hz \"delta\" rhythms were linked to novelty-associated slowing whereas 4-7 Hz \"theta\" rhythms were specifically attenuated in PD. Second, 32% of subthalamic nucleus (STN) neurons were response-modulated; nearly all (94%) of these were also modulated by novel stimuli. Third, response-modulated STN neurons were coherent with midfrontal 1-4 Hz activity. These findings link scalp-based measurements of neural activity with neuronal activity in the STN. Our results provide insight into midfrontal cognitive control mechanisms and how purported hyperdirect fronto-basal ganglia circuits evaluate new information.","Exon variants associated with asthma and allergy\nRecent biobank based exon sequencing studies included thousands of traits while the mutational spectrum of asthma and allergy associated genes is still unknown.\n\nMethodsMeta-analysis of exome data from 281,104 UK Biobank samples that were analyzed for association of mostly rare variants with asthma, allergic rhinitis and atopic dermatitis. Variants of interest (VOI) were tabulated, shared genes annotated and compared to earlier GWAS, WGBS, WES and selected candidate gene studies.\n\nResults354 VOI were significantly associated with the traits examined. They cluster mainly in two large regions on chromosome 6 and 17 while there is basically no overlap of atopic dermatitis with both other diseases. After exclusion of the two atopic dermatitis variants, 321 unique VOI remain in 122 unique genes. 30 genes are shared by the group of 87 genes with increased and the group of 65 genes with decreased risk for allergic disease. 85% of genes identified earlier by common SNPs in GWAS can not be replicated.\n\nDiscussionMost identified genes are involved in interferon {gamma} and IL33 signaling pathway. They highlight already known but also new pharmacological targets, including the IL33 receptor ST2/IL1RL1, TLR1, ALOX15, GSDMA, BTNL2, IL13 and IKZF3. Future pharmacological studies will need to included these VOI for stratification of the study population.","Damaging missense variants in IGF1R implicate a role for IGF-1 resistance in the aetiology of type 2 diabetes\nType 2 diabetes (T2D) is a chronic metabolic disorder with a significant genetic component. While large-scale population studies have identified hundreds of common genetic variants associated with T2D susceptibility, the role of rare (minor allele frequency < 0.1%) protein coding variation is less clear. To this end, we performed a gene burden analysis of 18,691 genes in 418,436 (n=32,374 T2D cases) individuals sequenced by the UK Biobank (UKBB) study to assess the impact of rare genetic variants on T2D risk. Our analysis identified T2D associations at exome-wide significance (P < 6.9x10-7) with rare, damaging variants within previously identified genes including GCK, GIGYF1, HNF1A, and TNRC6B. In addition, individuals with rare, damaging missense variants in the genes ZEB2 (N=31 carriers; OR=5.5 [95% CI=2.5-12.0]; p=6.4x10-7), MLXIPL (N=245; OR=2.3 [1.6-3.2]; p=3.2x10-7), and IGF1R (N=394; OR=2.4 [1.8-3.2]; p=1.3x10-10) have higher risk of T2D. Carriers of damaging missense variants within IGF1R were also shorter (-2.2cm [-1.8-2.7]; p=1.2x10-19) and had higher circulating protein levels of insulin-like growth factor-1 (IGF-1; 2.3 nmol/L [1.7-2.9] p=2.8x10-14), indicating relative IGF-1 resistance. A likely causal role of IGF-1 resistance on T2D was further supported by Mendelian randomisation analyses using common variants. Our results increase our understanding of the genetic architecture of T2D and highlight a potential therapeutic benefit of targeting the Growth Hormone/IGF-1 axis.","Decoding molecular programs in melanoma brain metastases\nThe systemic dissemination of tumor cells and the spatiotemporal development of organ- metastases are associated with loss of therapeutic control and decreased overall survival (OS). The emergence of solitary or multiple brain metastases is frequently observed in melanoma patients and responsible for disease progression and dismal prognosis. Here, we used whole transcriptome and methylome profiling as well as targeted sequencing (TargetSeq) of intraoperative/snap frozen or archived melanoma brain metastases to unravel molecular subgroups and subclonal heterogeneity. We discovered that E-cadherin (Ecad)/BRAFV600E/K, CD271/NRASQ61L/R/K, and tumor infiltrated lymphocytes (TIL)-status molecularly subdivided tumors into proliferative/pigmented and invasive/stem-like irrespective of the intracranial location. Moreover, we identified 46 differentially methylated regions in promoters of 14 genes, subdividing MBM into BRAFmut and NRASmut subgroups. We observed that therapy-resistant, migratory CD271+/Ecadneg subclones derived from Ecad+tumors in an epithelial-mesenchymal transition (EMT)-like process and fostered intracranial progression. Hence, CD271high MBM present a therapy-resistant, progressive subset of tumors that are refractory to conventional therapeutic strategies. The knockdown of CD271 or SOX4 in in vitro established, MBM-derived cell lines decreased cell migration, proliferation, and number of suspension cells that were shed by cell lines of progressive tumors. In summary, we propose that an Ecad-to-CD271 switch of MBM is a rate-limiting process that potentially determines intracranial progression in melanoma patients. The therapeutic control of this process may prevent intracranial progression, increasing patients overall survival.","Multi-contrast magnetic resonance imaging of visual white matter pathways in glaucoma patients\nPurposeGlaucoma is a disorder that involves visual field loss caused by retinal ganglion cell damage. Previous diffusion magnetic resonance imaging (dMRI) studies have demonstrated that retinal ganglion cell damage affects tissues in the optic tract (OT) and optic radiation (OR). However, because previous studies have used a simple diffusion tensor model to analyze dMRI data, the microstructural interpretation of white matter tissue changes remains uncertain. In this study, we used a multi-contrast MRI approach to further clarify the type of microstructural damage that occurs in glaucoma patients.\n\nMethodsWe collected multi-shell dMRI data from 17 glaucoma patients and 30 controls using 3T MRI. Using the dMRI data, we estimated three types of tissue property metrics: intracellular volume fraction (ICVF), orientation dispersion index (ODI), and isotropic volume fraction (IsoV). Quantitative T1 (qT1) data, which may be relatively specific to myelin, were collected from all subjects.\n\nResultsIn the OT, all four metrics showed significant differences between the glaucoma and control groups. In the OR, only the ICVF showed significant between-group differences. ICVF was significantly correlated with qT1 in the OR of glaucoma patients, although qT1 did not show any abnormality at the group level.\n\nConclusionsOur results suggest that at the group level, tissue changes in the glaucoma patients OR might be explained by axonal damage, which is reflected in the intracellular diffusion signals, rather than myelin damage. The significant correlation between ICVF and qT1 suggests that myelin damage might also occur in a smaller number of severe cases.","Ivacaftor, not ivacaftor/lumacaftor, is associated with lower pulmonary inflammation in preschool cystic fibrosis\nAirway inflammation is a key driver of cystic fibrosis (CF) lung disease. The advent of cystic fibrosis transmembrane conductance regulator (CFTR) modulators has the potential to transform the care of CF, however the direct effect of these therapies on lung inflammation is unknown. Here, we profile airway inflammation in bronchoalveolar lavage (BAL) of preschool aged children with CF on CFTR modulator therapy (ivacaftor or ivacaftor/lumacaftor), untreated children with CF, and age-matched healthy controls. We show that children treated with ivacaftor have lower pulmonary concentrations of inflammatory mediators CCL3, CXCL9, CCL2, IL-8, IL-1{beta}, and IL-6 relative to untreated children with CF. Conversely, there was no significant effect of lumacaftor/ivacaftor treatment on airway inflammation. This is the first work to illustrate a difference in early life airway inflammation with CFTR treatment, highlights the effectiveness of ivacaftor in early life, and suggests that BAL inflammatory profile may represent a biomarker of therapeutic response to treatment.","Single EV analysis (sEVA) of mutated proteins allows detection of stage 1 pancreatic cancer\nTumor cell derived extracellular vesicles (EV) are being explored as circulating biomarkers for cancer detection. Up to now however, clinical results have been mixed for a number of reasons including the predominant use of bulk measurements, the inability to differentiate tumor from host cell derived vesicles, the general absence of uniquely identifying biomarkers and the unknown frequency of stochastically distributed biomarkers into single circulating vesicles. We hypothesized that a single EV analysis (sEVA) technique could potentially improve diagnostic accuracy necessary to detect early cancers but the actual biomarker frequency and practical detection limits are currently unknown. Using pancreatic cancer, we carefully analyzed the composition of putative cancer markers in 11 established and new patient derived models. In parental PDAC cells positive for KRASmut and/or P53mut proteins only [~]40% of EVs were also positive (range: 30-64%). This rate of positivity increased to 57% when additional PDAC biomarkers were considered (MUC1, EGFR, FG-P4OH) in cell lines. In a blinded study involving 16 patients with surgically proven stage 1 PDAC, KRASmut and P53mut protein was detectable at much lower levels, generally in < 0.1% of vesicles. With the analytical capabilities of sEVA however, 15 of the 16 patients with stage 1 PDAC expressed low levels of biomarker positive EV. Using a modeling approach, we estimate that the current PDAC detection limit is at [~]0.1 cm3 tumor volume, below clinical imaging capabilities. These findings establish the potential for single-EV analysis for early cancer detection.","Structural connectivity of subthalamic nucleus stimulation for improving freezing of gait\nGait impairments such as freezing of gait (FOG) are among the most common and disabling symptoms of Parkinsons disease (PD). While the efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with early or advanced PD has been proven in large randomised controlled trials, its effect on gait impairments is still insufficiently understood. Moreover, there is uncertainty about pathways that need to be modulated to improve gait impairments. In this bi-centric study, we investigated how STN-DBS alters FOG in 47 subjects with PD. We assessed freezing prevalence and severity using the Freezing of Gait Questionnaire and Item 14 of the Unified Parkinsons Disease Rating Scale-II. Using a model of publicly available basal-ganglia pathways we determined a connectivity profile for postoperative changes in FOG. Compared to preoperative baseline, freezing of gait significantly improved six months postoperatively, marked by reduced frequency and duration of freezing episodes. We found that optimal stimulation sites for improving freezing of gait structurally connected to primary and supplementary motor areas, the dorsolateral prefrontal cortex and to the globus pallidus. Stimulation of the lenticular fasciculus was associated with worsening of freezing of gait. Our findings highlight the need for optimal identification and characterisation for network structures that can be implemented in stereotactic planning and can additionally pose a target for postoperative stimulation strategies.","Impact of shaggy aorta on intraoperative cerebral embolism during carotid artery stenting\nBackgroundCareful selection of patients for carotid stenting is necessary. We suggest that patients with a shaggy aorta syndrome may have a higher risk of perioperative embolic complications.\n\nMethodsThe study is a subanalysis of the SIBERIA Trial. We included 72 patients undergoing transfemoral carotid artery stenting. All patients had an MRI DWI and a clinical neurological examination two days before and on the second and 30th days after the intervention.\n\nResults46 patients had shaggy aorta syndrome. Intraoperative embolisms were recorded in 82.6% and 46.1% of patients with and without shaggy aorta syndrome, respectively (p=0.001). New asymptomatic ischemic brain lesions in the postoperative period occurred in 78.3% and in 26.9% of patients with and without shaggy aorta syndrome, respectively (p=0.000). 3 (6.5%) cases of stroke within 30 days after the procedure were observed only in patients with shaggy aorta syndrome. Shaggy aorta syndrome (OR 5.54 [1.83:16.7], p=0.001) and aortic arch ulceration (OR 6.67 [1.19: 37.3], p = 0.02) were independently associated with cerebral embolism. Shaggy aorta syndrome (OR 9.77 [3.14-30.37], p=0.000) and aortic arch ulceration (OR 12.9 [2.3: 72.8], p = 0.003) were independently associated with ipsilateral new asymptomatic ischemic brain lesions.\n\nConclusionsShaggy aorta syndrome and aortic arch ulceration significantly increase the odds of intraoperative embolism and new asymptomatic ischemic brain lesions. Carotid endarterectomy or transcervical carotid stent should be selected in the presence of aortic ulceration.","An automated Dashboard to improve laboratory COVID-19 diagnostics management\nBackgroundIn response to the CoVID-19 pandemic, our microbial diagnostic laboratory located in a university hospital has implemented several distinct SARS-CoV-2 RT-PCR systems in a very short time. Thanks to our automated molecular diagnostic platform, more than 140000 SARS-CoV-2 RT-PCR tests were achieved over 12 months, with peaks higher than 1500 daily tests. A dashboard was developed to give access to Key Performance Indicators (KPIs) to improve laboratory operational management.\n\nMethodsRT-PCR data extraction of four respiratory viruses - SARS-CoV-2, influenza A and B and RSV - from our laboratory information system (LIS), was automated. Important KPIs were identified and the visualization was achieved using an in-house dashboard based on the open-source language R (Shiny). Information is updated every 4 hours.\n\nResultsThe dashboard is organized into three main parts. The \"Filter\" page presents all the KPIs, divided into five sections: i) general and gender-related indicators, ii) number of tests and positivity rate, iii) cycle threshold and viral load, iv) test durations, and v) not valid results. Filtering allows to select a given period, a dedicated instrument, a given specimen, or a requester for instance. The \"Comparison\" page allows a custom charting of all the available variables, which represents more than 182 combinations. The \"Data\" page gives the user access to the raw data in table format, with the possibility of filtering, allowing for a deeper analysis and data download in Excel format.\n\nConclusionsThe dashboard, that gives a rapid access to a huge number of up-to-date information, represents a reliable and user-friendly tool improving the decision-making process, resource planning and quality management. The dashboard represent an added value for diagnosric laboratories during a pandemic, where rapid and efficient adaptation is mandatory.","Comparison of Phase Angle Using Bioelectrical Impedance Analysis According to Device Type and Examination Posture\nBackgroundBioelectrical impedance analysis (BIA) is gaining popularity as a body composition assessment tool for patients. Although it has been studied and validated in different populations, age groups, and clinical settings, including critically ill patients, there are concerns about BIA reproducibility and reliability in different device types and postures. This study aimed to evaluate the reliability of BIA according to different devices, postures, and lead types.\n\nMethodsCross-sectional observational data of 74 healthy volunteers (32 women and 42 men) were collected. We used two types of devices, three types of postures (standing, sitting, and lying), and two lead types (clamp lead and adhesive lead) to measure the whole-body phase angle (phA) at a single frequency of 50 kHz. The measurements were validated using the intraclass correlation coefficient (ICC) and Bland-Altman plot analysis.\n\nResultsAll phA measurements recorded with two types of devices, three different postures, and two types of leads were equivalent to each other (mean ICC = 0.9932, 95% confidence interval (CI) 0.9905-0.0053). The average mean difference in phA was 0.31 (95% CI 0.16- 0.46). The largest phA value was measured using BWA with an adhesive-type lead in the lying position. There were no differences between standing and sitting positions.\n\nConclusionThis is the first study to show the consistency and reliability of BIA in measuring phA using different devices, lead types, and postures. This could provide the confidence that BIA can be used in various clinical settings.","Age-based differences in quantity and frequency of consumption when screening for harmful alcohol use\nAimsSurvey questions on usual quantity and frequency of alcohol consumption are regularly used in screening tools to identify drinkers requiring intervention. The aim of this study is to examine age-based differences in quantity and frequency of alcohol consumption on the Alcohol Use Disorders Identification Test (AUDIT) and how this relates to the prediction of harmful or dependent drinking\n\nDesignCross sectional survey\n\nSettingAustralia.\n\nParticipantsData was taken from 17,399 respondents who reported any alcohol consumption in the last year and were aged 18 and over from the 2016 National Drug Strategy Household Survey, a broadly representative cross-sectional survey on substance use.\n\nMeasurementRespondents were asked about their frequency of consumption, usual quantity per occasion and the other items of the AUDIT.\n\nFindingsIn older drinkers, quantity per occasion ({beta}=0.53 (0.43, 0.64 95%CI in 43-47 year olds as an example) is a stronger predictor of dependence than frequency per occasion ({beta}=0.24 (0.17, 0.31). In younger drinkers the reverse was true with frequency a stronger predictor ({beta}=0.54 (0.39, 0.69) in 23-27 year olds) than quantity ({beta}=0.26 (0.18, 0.34) in 23-27 year olds). Frequency of consumption was not a significant predictor of dependence in respondents aged 73 and over ({beta}=-0.03 (-0.08, 0.02)). Similar patterns were found when predicting harmful drinking. Despite this, since frequency of consumption increased steadily with age, the question on frequency was responsible for at least 65% of AUDIT scores in drinkers aged 53 and over.\n\nConclusionsThe items with a weaker association with dependent or harmful drinking in younger and older drinkers are the same items with the strongest influence on overall AUDIT scores. Further investigation into age-specific scoring of screening tools is recommended.","Automated Detection of Candidate Subjects with Cerebral Microbleeds using Machine Learning\nCerebral microbleeds (CMBs) appear as small, circular, well defined hypointense lesions of a few mm in size on T2*-weighted gradient recalled echo (T2*-GRE) images and appear enhanced on susceptibility weighted images (SWI). Due to their small size, contrast variations and other mimics (e.g. blood vessels), CMBs are highly challenging to detect automatically. In large datasets (e.g. the UK Biobank dataset), exhaustively labelling CMBs manually is difficult and time consuming. Hence it would be useful to preselect candidate CMB subjects in order to focus on those for manual labelling, which is essential for training and testing automated CMB detection tools on these datasets. In this work, we aim to detect CMB candidate subjects from a larger dataset, UK Biobank, using a machine learning-based, computationally light pipeline. For our evaluation, we used 3 different datasets, with different intensity characteristics, acquired with different scanners. They include the UK Biobank dataset and two clinical datasets with different pathological conditions. We developed and evaluated our pipelines on different types of images, consisting of SWI or GRE images. We also used the UK Biobank dataset to compare our approach with alternative CMB preselection methods using non-imaging factors and/or imaging data. Finally, we evaluated the pipelines generalisability across datasets. Our method provided subject-level detection accuracy > 80% on all the datasets (withindataset results), and showed good generalisability across datasets, providing a consistent accuracy of over 80%, even when evaluated across different modalities.","Characterizing Sleep Disorders in an Autism-Specific Collection of Electronic Health Records\nBackgroundSleep problems are common in individuals with autism spectrum disorder (ASD). This study reviews one detailed approach to querying the electronic health record (EHR).\n\nMethodsWe developed methods for identifying individuals with ASD and defined their sleep problems using International Classification of Diseases (ICD) codes or key words. We examined treatment responses to melatonin.\n\nResultsSleep problems were documented in 86% of patients and using specific keywords yielded more sleep diagnoses than ICD codes alone. About two-thirds of patients benefitted from melatonin.\n\nConclusionsOur study provides a framework for using deidentified medical records to characterize sleep, a common co-occurring condition, in ASD. Using specific keywords could be helpful in future work that queries the EHR.","Frequent Cocaine Use is Associated with Larger HIV Latent Reservoir Size\nBackgroundWith the success of combination antiretroviral therapy, HIV is now treated as a chronic disease, including among drug users. Cocaine--one of the most frequently abused illicit drugs among persons living with HIV (PLWH)-- slows the decline of viral production after ART, and is associated with higher HIV viral load, more rapid HIV progression, and increased mortality. We examined the impact of cocaine use on the CD4+ T-cell HIV Latent Reservoir (HLR) in virally suppressed PLWH.\n\nMethodsCD4+ T-cell genomic DNA was isolated from peripheral blood mononuclear cells collected from 434 women of diverse ancestry (i.e., 75% Black, 14% Hispanic, 12% White) who self-reported cocaine use (i.e., 160 cocaine users, 59 prior users, 215 non-users). Participants had to have an undetectable HIV RNA viral load measured by commercial assay for at least 6 months. The Intact Proviral HIV DNA Assay (IPDA) provided estimates of intact provirus per 106 CD4+ T-cells.\n\nResultsThe HLR size differed by cocaine use (i.e., median [interquartile range]: 72 [14, 193] for never users, for prior users 165 [63, 387], 184 [28, 502] for current users), which was statistically significantly larger in both prior (p=0.023) and current (p=0.001) cocaine users compared with never users.\n\nConclusionOur study is the first to provide evidence that cocaine use may contribute to a larger replication competent HLR in CD4* T-cells among virologically suppressed women living with HIV. Our findings are important, because women are under-represented in HIV reservoir studies and in studies of the impact of cocaine use on outcomes among PLWH.","A rapid assessment of wastewater for genomic surveillance of SARS-CoV-2 variants at sewershed scale in Louisville, KY\nIn this communication, we report on the genomic surveillance of SARS-CoV-2 using wastewater samples in Jefferson County, KY. In February 2021, we analyzed seven wastewater samples for SARS-CoV-2 genomic surveillance. Variants observed in smaller catchment areas, such as neighborhood manhole locations, were not necessarily consistent when compared to associated variant results in downstream treatment plants, suggesting catchment size or population could impact the ability to detect diversity.","Obesity may hamper SARS-CoV-2 vaccine immunogenicity\nBackgroundThe first goal of the study was to analyse the antibody titre 7 days after the second dose of BNT162b2 vaccine in a group of 248 healthcare workers (HCW). The second goal was to analyse how the antibody titre changes in correlation with age, gender and BMI.\n\nMethodsParticipants were assigned to receive the priming dose at baseline and booster dose at day 21. Blood and nasopharyngeal swabs were collected at baseline and 7 days after second dose of vaccine.\n\nFindings248 HWCs were analysed, 158 women (63.7%) and 90 men (36.3%). After the second dose of BNT162b2 vaccine, 99.5% of participants developed a humoral immune response.\n\nThe geometric mean concentration of antibodies among the vaccinated subjects after booster dose (285.9 AU/mL 95% CI: 249.5-327.7); was higher than that of human convalescent sera (39.4 AU/mL, 95% CI: 33.1-46.9), with p<0.0001. The antibody titre was found to be higher in young and female participants. A strong correlation of BMI classes with antibody titres was noticed: humoral response was more efficient in the group with under- and normal-weight vs the group with pre- and obesity participants (p<0.0001 at T1).\n\nInterpretationThese findings imply that females, lean and young people have an increased capacity to mount humoral immune responses compared to males, overweight and the older population. Although further studies are needed, this data may have important implications for the development of vaccination strategies for COVID-19, particularly in obese people.\n\nFundingNone","Helmet noninvasive ventilation for COVID-19 patients (Helmet-COVID): study protocol for a multicenter randomized controlled trial\nIntroductionNoninvasive ventilation delivered by helmet is has been used for respiratory support of patients with acute hypoxemic respiratory failure due to COVID-19 pneumonia. The aim of this study is to compare helmet noninvasive ventilation with usual care versus usual care alone to reduce the mortality.\n\nMethods and analysisThis is a multicenter, pragmatic, parallel, randomized controlled trial that compares helmet noninvasive ventilation with usual care to usual care alone in 1:1 ratio. A total of 320 patients will be enrolled in this study. The primary outcome is 28-day all-cause mortality. The primary outcome will be compared between the two study groups in the intention-to-treat and per-protocol cohorts. An interim analysis will be conducted for both safety and effectiveness.\n\nEthics and disseminationApprovals are obtained from the Institutional Review Boards (IRBs) of each participating institution. Our findings will be published in peer-review journals and presented at relevant conferences and meetings.\n\nTrial registration numberNCT04477668 registered on July 20, 2020\n\nArticle SummaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIThis trial compares helmet NIV to usual care for respiratory support of patients with acute hypoxemic respiratory failure due to COVID-19 pneumonia.\nC_LIO_LIThe trial is a multi-center, pragmatic, parallel randomized controlled trial.\nC_LIO_LIThe main limitation is the unblinded design due to the nature of the intervention.\nC_LI","Identification of shared and differentiating genetic risk for autism spectrum disorder, attention deficit hyperactivity disorder and case subgroups.\nAttention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable neurodevelopmental disorders with a considerable overlap in their genetic etiology. We dissected their shared and distinct genetic architecture by cross-disorder analyses of large data sets, including samples with information on comorbid diagnoses. We identified seven loci shared by the disorders and the first five genome-wide significant loci differentiating the disorders. All five differentiating loci showed opposite allelic directions in the two disorders separately as well as significant associations with variation in other traits e.g. educational attainment, items of neuroticism and regional brain volume. Integration with brain transcriptome data identified and prioritized several significantly associated genes. Genetic correlation of the shared liability across ASD-ADHD was strong for other psychiatric phenotypes while the ASD-ADHD differentiating liability correlated most strongly with cognitive traits. Polygenic score analyses revealed that individuals diagnosed with both ASD and ADHD are double-burdened with genetic risk for both disorders and show distinctive patterns of genetic association with other traits when compared to the ASD-only and ADHD-only subgroups. The results provide novel insights into the biological foundation for developing just one or both of the disorders and for driving the psychopathology discriminatively towards either ADHD or ASD.","Use of Convalescent Plasma Therapy among Hospitalized Coronavirus Disease 2019 (COVID-19) Patients: A Single-Center Experience\nCOVID-19 Disease has strained our healthcare system. Convalescent plasma has been used to treat emerging infectious diseases -Influenza A/B, SARS-CoV, Ebola virus and now SARS-CoV 2.\n\nOBJECTIVEThis study aims to determine the outcome and clinical course of COVID-19 patients who received convalescent plasma transfusion at Cardinal Santos Medical Center.\n\nMETHODSThis is a retrospective cohort analytical study of 75 patients who received convalescent plasma.\n\nRESULTSMedian time from admission to CP transfusion was 3 days. Majority of patients received additional therapies including dexamethasone (100%); Remdesivir (95%); antibiotics (100%), tocilizumab (65%); hemoperfusion (88%) or combination of these. Among the survivors, the median LOS was 15 days while non-survivors have a median LOS of 6 days. One patient (1.33%) had mild transfusion reaction. Four patients (5.33%) developed DVT despite anti-coagulation. There was improvement in the inflammatory markers (LDH pvalue 0.04, CRP pvalue 0.00, Ferritin pvalue 0.0001). There was improvement in the pulmonary parameters -increase in mean PaO2, mean SaO2, and mean PFR; and decrease in mean FiO2 and mean RR post-treatment. Median LOS is 14 days for the CP group vs 11 days for the non-CP group. Mortality rate among the CP group is 25.33% while the non-CP group was 26.67%. LOS and mortality rate did not reach statistical significance.\n\nCONCLUSIONSThere was no significant difference in mortality and length of hospital stay in patients given CP vs controls. CP might have a role in the improvement of inflammatory markers and pulmonary status.","Cell-Mediated Immune Response after COVID 19 Vaccination in Patients with Inflammatory Bowel Disease\nIntroductionMost patients with IBD mount an antibody response to mRNA COVID-19 vaccines, but few studies have evaluated the cell mediated immune response (CMIR).\n\nMethodsWe performed a prospective study (HERCULES) to evaluate CMIR among patients with IBD and healthy controls (HC) after completion of the primary series of mRNA COVID-19 vaccines.\n\nResultsOne hundred 158 patients with IBD and 20 HC were enrolled. The majority (89%) of IBD patients developed a CMIR which was not different than HC (94%, p=0.6667). There was no significant difference (p=0.5488) in CMIR response between those not immunosuppressed (median 255 Spike T cells/million PBMC, IQR 146, 958) and immunosuppressed (median 377, IQR 123, 1440). There was also no correlation between antibody responses and CMIR (p=0.5215)\n\nDiscussionMost patients with IBD achieved CMIR to a COVID-19 vaccine. Future studies are needed evaluating sustained CMIR and clinical outcomes.","Trends in clinical characteristics and associations of severe non-respiratory events related to SARS-CoV-2\nBackgroundThe 2019 novel coronavirus (SARS-CoV-2) is reported to result in both respiratory and non-respiratory severe health outcomes, but quantitative assessment of the risk - while adjusting for underlying risk driven by comorbidities - is not yet established.\n\nMethodsA retrospective observational study using electronic health records of 9,344,021 individuals across the U.S. with at-least 1 year of clinical history and followed up throughout 2020.\n\nResults131,329 individuals were associated with SARS-CoV-2 infection by January 6, 2021 in three distinct surges. While the age and number of preexisting conditions had decreased throughout the pandemic, the characteristics of those who experienced severe health events did not.\n\nDuring the second surge, between June 7 and November 18, 2020, 425,988 individuals in the base cohort were admitted to emergency rooms or hospitals. Among them, 15,486 were detected with SAR-CoV-2 within few days of admission. Significant adjusted odds ratios were observed between SARS-CoV-2 infection and the following severe health events: respiratory (4.38, 95% confidence interval 4.16- 4.62), bacterial pneumonia (3.25, 2.76-3.83), sepsis (1.71, 1.53-1.91), renal (1.69, 1.57-1.83), hematologic/immune (1.32, 1.20-1.45), neurological (1.23, 1.09-1.38).\n\nConclusionsSARS-CoV-2 infection among hospitalized patients is associated with non-negligible increased risk of severe events including multiple non-respiratory ones. These associations, which complement recent studies, are persistent even after accounting for sources of selection and confounding bias, increasing the confidence they are not spurious.","Epigenetic impairment and blunted transcriptional response to Mycobacterium tuberculosis of alveolar macrophages from persons living with HIV\nPersons living with HIV (PLWH) are at increased risk of tuberculosis (TB). HIV-associated TB is often the result of recent infection with Mycobacterium tuberculosis (Mtb) followed by rapid progression to disease. Alveolar macrophages (AM) are the first cells of the innate immune system that engage Mtb, but how HIV and antiretroviral therapy (ART) impact on the anti-mycobacterial response of AM is not known. To investigate the impact of HIV and ART on the transcriptomic and epigenetic response of AM to Mtb, we obtained AM by bronchoalveolar lavage from 20 PLWH receiving ART, 16 control subjects who were HIV-free (HC), and 14 subjects who received ART as pre-exposure prophylaxis (PrEP) to prevent HIV infection.\n\nFollowing in-vitro challenge with Mtb, AM from each group displayed overlapping but distinct profiles of significantly up- and down-regulated genes in response to Mtb. Compared to HC subjects, AM isolated from PLWH and PrEP subjects presented a substantially weaker transcriptional response. Further investigation of chromatin structure revealed that AM from control subjects challenged with Mtb responded with pronounced accessibility changes in over ten thousand regions. In stark contrast, AM obtained from PLWH and PrEP subjects displayed no significant changes in their chromatin state in response to Mtb. Collectively, these results revealed a previously unknown adverse effect of ART on the epigenetic landscape and transcriptional responsiveness of AM.","Comparative and Integrated Analysis of Plasma Extracellular Vesicles Isolations Methods in Healthy Volunteers and Patients Following Myocardial Infarction\nPlasma extracellular vesicle (EV) number and composition are altered following myocardial infarction (MI), but to properly understand the significance of these changes it is essential to appreciate how the different isolation methods affect EV characteristics, proteome and sphingolipidome. Here, we compared plasma EV isolated from platelet-poor plasma from four healthy donors and six MI patients at presentation and 1-month post-MI using ultracentrifugation, polyethylene glycol precipitation, acoustic trapping, size-exclusion chromatography (SEC) or immunoaffinity capture. The isolated EV were evaluated by Nanoparticle Tracking Analysis, Western blot, transmission electron microscopy, an EV-protein array, untargeted proteomics (LC-MS/MS) and targeted sphingolipidomics (LC-MS/MS). The application of the five different plasma EV isolation methods in patients presenting with MI showed that the choice of plasma EV isolation method influenced the ability to distinguish elevations in plasma EV concentration following MI, enrichment of EV-cargo (EV-proteins and sphingolipidomics) and associations with the size of the infarct determined by cardiac magnetic resonance imaging 6 months-post-MI. Despite the selection bias imposed by each method, a core of EV associated proteins and lipids was detectable using all approaches. However, this study highlights how each isolation method comes with its own idiosyncrasies and makes the comparison of data acquired by different techniques in clinical studies problematic.","Blood cytokine analysis suggests that SARS-CoV-2 infection results in a sustained tumour promoting environment in cancer patients\nCytokines, chemokines and (angiogenic) growth factors (CCGs) have been shown to play an intricate role in the progression of both solid and haematological malignancies. Recent studies have shown that SARS-CoV-2 infection leads to worse outcome in cancer patients, especially in haematological malignancy patients. Here, we investigated how SARS-CoV-2 infection impacts the already altered CCG levels in solid or haematological malignancies, specifically whether there is a protective effect or rather a potentially higher risk for major COVID-19 complications in cancer patients due to elevated CCGs linked to cancer progression. Serially analysing immune responses with 55 CCGs in cancer patients under active treatment with or without SARS-CoV-2 infection, we first showed that cancer patients without SARS-CoV-2 infection (n=54) demonstrate elevated levels of 35 CCGs compared to the non-cancer, non-infected control group of health care workers (n=42). Of the 35 CCGs, 19 were common to both solid and haematological malignancy groups and comprised previously described cytokines such as IL-6, TNF-, IL-1Ra, IL-17A, and VEGF, but also several less well described cytokines/chemokines such as Fractalkine, Tie-2, and T cell chemokine CTACK. Importantly, we show here that 7 CCGs are significantly altered in SARS-CoV-2 exposed cancer patients (n=52). Of these TNF-, IFN-{beta}, TSLP and sVCAM-1, identified to be elevated in haematological cancers, are also known tumour-promoting factors. Longitudinal analysis conducted over 3 months showed persistence of several tumour-promoting CCGs in SARS-CoV-2 exposed cancer patients. These data urge for increased vigilance for haematological malignancy patients as a part of long COVID follow-up.","Specific concussion curriculum: Does it improve residents' comfort, Knowledge and In-Training Examination Scores? A pilot study.\nBackgroundConcussion is defined as aberrant brain function consequent to traumatic injury characterized by disorientation or loss of consciousness or memory. If concussions are not recognized and treated appropriately, they can cause significant morbidity. Because [~]20% of sports-related concussions occur in juveniles, pediatricians must be able to treat this injury. Our primary objective was to assess the comfort and competence of pediatric residents in managing patients with concussions. Secondary objective was to assess the change in the In-Training Examination (ITE) scores after instituting a novel multimodal concussion curriculum.\n\nMethodFrom February to June 2019, all pediatric residents (N = 24) were required to complete a multimodal concussion curriculum, including board review-style questions, lectures, and rotation in a concussion clinic. Residents voluntarily participated in a pre-and post-curriculum survey. ITE scores from 2018 and 2019 were compared.\n\nResultsTwenty-three of 24 (96%) residents completed both pre- and post-curriculum surveys; of those, 17 (74%) had matched identifiers. Most residents (82%) want more education about concussion management. Residents scores on knowledge-based questions increased an average of 0.64 questions, with PGY-1 showing the most improvement. The proportion of residents who correctly answered the ITE head injury/concussion questions increased from 0.33 to 0.88. The concussion clinic was identified as the most helpful tool.\n\nConclusionTo better educate pediatric residents about concussions, we propose a unique multimodal curriculum. We found improved self-assessed comfort and performance on knowledge-based questions and the ITE. We recommend that pediatric and other residency training programs consider implementing this type of curriculum.","Altered reward network responses to social touch in major depression\nIntroductionAffective touch is highly rewarding and an integral part of social relationships. Major depressive disorder (MDD) is characterized by severe impairments in reward processing, but the neural effects of social touch in MDD are still elusive.\n\nObjectiveWe aimed to determine whether the neural processing of social touch is impaired in MDD and to assess the impact of antidepressant therapy.\n\nMethodsBefore and after antidepressant treatment, 53 MDD patients and 41 healthy controls underwent functional magnetic resonance imaging (fMRI) while receiving social touch. We compared neural responses to social touch in the reward network, behavioral ratings of touch comfort and general aversion to interpersonal touch in MDD patients to controls. Additionally, we examined the effect of treatment response on those measures.\n\nResultsClinical symptoms decreased after treatment and 43.4% of patients were classified as responders. Patients reported higher aversion to social touch and lower comfort ratings during the fMRI paradigm than controls. Patients showed reduced responses to social touch in the nucleus accumbens, caudate nucleus and putamen than controls, both before and after treatment. Non-responders exhibited blunted response in the caudate nucleus and the insula compared to responders, again irrespective of treatment.\n\nConclusionsThese findings confirm our hypothesis that interpersonal touch as an indicator of social reward processing is impaired in MDD. Persistent dysfunctional processing of social touch despite clinical improvements may constitute a latent risk factor for social withdrawal and isolation. New treatment approaches are necessary to specifically target social reward processing and disturbed body awareness in MDD.","Competitive fitness of emerging SARS-CoV-2 variants is linked to their Distinctiveness relative to preceding lineages from that region\nThe COVID-19 pandemic has seen the persistent emergence of fitter Variants of Concern (VOCs) that have successfully out-competed circulating strains, but the determinants of viral fitness remain unknown. Here we define Distinctiveness of SARS-CoV-2 sequences based on a proteome-wide comparison with all prior sequences from the same geographical region. From the perspective of viral evolution, Distinctiveness captures \"regional herd exposure\" and has the advantage over the canonical concept of mutation, which relies foremost on the reference ancestral sequence that is invariant over time. By assessing the correlation between Distinctiveness and change in prevalence for all circulating lineages in each region when a new lineage is introduced, we find that the relative Distinctiveness of emergent SARS-CoV-2 lineages is associated with their competitive fitness (Pearson r = 0.67). Further, by assessing the Delta variant in India versus Brazil, we show that the same lineage can have different Distinctiveness-contributing positions in different geographical regions depending on the other variants that previously circulated in those regions. Finally, analysis of Omicron lineages in India and USA shows the BA.1 and BA.2 sub-lineages have comparable distinctiveness, suggesting that they may have similar levels of competitive fitness. Overall, our study proposes that augmenting the ongoing surveillance of highly mutated variants with real-time assessment of Distinctiveness can aid in achieving robust pandemic preparedness.","Cause-specific student absenteeism monitoring in K-12 schools for detection of increased influenza activity in the surrounding community - Dane County, Wisconsin, 2014-2020\nBackgroundSchools are primary venues of influenza amplification with secondary spread to communities. We assessed K-12 student absenteeism monitoring as a means for early detection of influenza activity in the community.\n\nMaterials and MethodsBetween September 2014 and March 2020, we conducted a prospective observational study of all-cause (a-TOT), illness-associated (a-I), and influenza-like illness-associated (a-ILI) absenteeism within the Oregon School District (OSD), Dane County, Wisconsin. Absenteeism was reported through the electronic student information system. Students were visited at home where pharyngeal specimens were collected for influenza RT-PCR testing. Surveillance of medically-attended laboratory-confirmed influenza (MAI) occurred in five primary care clinics in and adjoining OSD. Poisson general additive log linear regression models of daily counts of absenteeism and MAI were compared using correlation analysis.\n\nFindingsInfluenza was detected in 723 of 2,378 visited students, and in 1,327 of 4,903 MAI patients. Over six influenza seasons, a-ILI was significantly correlated with MAI in the community (r = 0.57; 95% CI: 0.53--0.63) with a one-day lead time and a-I was significantly correlated with MAI in the community (r = 0.49; 0.44-0.54) with a 10-day lead time, while a-TOT performed poorly (r = 0.27; 0.21--0.33), following MAI by six days.\n\nDiscussionSurveillance using cause-specific absenteeism was feasible and performed well over a study period marked by diverse presentations of seasonal influenza. Monitoring a-I and a-ILI can provide early warning of seasonal influenza in time for community mitigation efforts.","Biomarker-guided neuromodulation aids memory in traumatic brain injury\nTraumatic brain injury (TBI) is a leading cause of cognitive disability in adults, often characterized by marked deficits in episodic memory and executive function. Prior studies have found that direct electrical stimulation of the temporal cortex yielded improved memory in epilepsy patients, but it is not clear if these results generalize to patients with a specific history of TBI. Here we asked whether applying closed-loop, direct electrical stimulation to lateral temporal cortex could reliably improve memory in a TBI cohort. Among a larger group of patients undergoing neurosurgical evaluation for refractory epilepsy, we recruited a subset patients with a history of moderate-to-severe TBI. By analyzing neural data from indwelling electrodes as patients studied and recalled lists of words, we trained personalized machine-learning classifiers to predict momentary fluctuations in mnemonic function in each patient. We subsequently used these classifiers to trigger high-frequency stimulation of the lateral temporal cortex (LTC) at moments when memory was predicted to fail. This strategy yielded a 19% boost in recall performance on stimulated as compared with non-stimulated lists (P = 0.012). These results provide a proof-of-concept for using closed-loop stimulation of the brain in treatment of TBI-related memory impairment.","Recurrent aphthous stomatitis affects quality of life\nRecurrent aphthous stomatitis are recurrent oral ulcers that can affect important daily activities, such as oral hygiene and eating. In this prospective case-control study (n=62), we show that, during ulcer episodes, patients report a poorer quality of life compared to ulcer-free periods, and that this impact is positively associated with the number and size of lesions. Our results suggest that, if intervened locally, general relief of the condition could be achieved.","Physical activity and health: Findings from Finnish monozygotic twin pairs discordant for physical activity\nGenetic and early environmental differences including early health habits associate with future health. To provide insight on the causal nature of these associations, monozygotic (MZ) twin pairs discordant for health habits provide an interesting natural experiment. Twin pairs discordant for leisure-time physical activity (LTPA) in early adult life are thus a powerful study design to investigate the associations between long-term LTPA and indicators of health and wellbeing. We have used this study design by identifying 17 LTPA discordant twin pairs from two Finnish twin cohorts and summarize key findings of these studies in this paper. The carefully characterized rare long-term LTPA discordant MZ twin pairs have participated in multi-dimensional clinical examinations. The occurrence of type 2 diabetes and death has been evaluated on the basis of prospective questionnaire data and register follow-up among a larger number of twin pairs. Key findings highlight that, compared to less active twins in such MZ twin pairs, the twins with higher long-term LTPA have higher physical fitness, reduced body fat, reduced visceral fat, reduced liver fat, increased lumen diameters of conduit arteries to the lower limbs, increased bone mineral density in loaded bone areas, increased high-density lipoprotein cholesterol levels and reduced occurrence of type 2 diabetes. However, we have not been able to document differences in the life expectancy between the less and more active twin siblings of the LTPA discordant MZ twin pairs. The findings are in agreement with intervention studies but not with all observational studies in which genetic factors are not controlled for.","Performance evaluation of a multinational data platform for critical care in Asia\nObjectiveWe aimed to evaluate the quality of a multinational intensive care unit (ICU) network of registries of critically ill patients established in seven Asian low and middle income countries (LMICs).\n\nMethodsThe Critical Care Asia federated registry platform enables ICUs to collect clinical, outcome and process data for aggregate and unit-level analysis. The evaluation used the standardised criteria of the Directory of Clinical Databases (DoCDat) and a framework for data quality assurance in medical registries. Six reviewers assessed structure, coverage, reliability and validity of the ICU registry data. Case mix and process measures on patient episodes from June to December 2020 were analysed.\n\nResultsData on 20,507 consecutive patient episodes from 97 ICUs in Afghanistan, Bangladesh, India, Malaysia, Nepal, Pakistan and Vietnam were included. The quality level achieved according to the ten prespecified DoCDat criteria was high (average score 3.4 out of 4) as was the structural and organizational performance -- comparable to ICU registries in high-income countries. Identified strengths were types of variables included, reliability of coding, data completeness and validation. Potential improvements include extension of national coverage.\n\nConclusionThe Critical Care Asia platform evaluates well using standardised frameworks for data quality and equally to registries in resource-rich settings.\n\nFundingThis work was undertaken as part of the existing Wellcome Innovations Flagship award, Collaboration for Research, Improvement and Training in Critical CARE in ASIA (ref. 215522/Z/19/Z). The funder had no role in the decision to publish or in the preparation of this manuscript.","The French Early Breast Cancer Cohort (FRESH): a resource for breast cancer research and evaluations of oncology practices based on the French National Healthcare System Database (SNDS)\nBackgroundBreast cancer (BC) is the most frequent cancer and the leading cause of cancer-related death in women. The French National Cancer Institute has created a national cancer cohort to promote cancer research and improve our understanding of cancer using the National Health Data System (SNDS). This cohort amalgamates all cancer sites, with no detailed separate data for early BC.\n\nObjectivesWe describe the French Early Breast Cancer Cohort (FRESH).\n\nMethodsAll French women aged 18 years or over, with early-stage BC newly diagnosed between January 1, 2011 and December 31, 2017, treated by surgery and registered in the general health insurance coverage plan were included in the cohort. Patients with suspected locoregional or distant metastases at diagnosis were excluded. BC treatments (surgery, chemotherapy, targeted therapy, radiotherapy, endocrine therapy), and diagnostic procedures (biopsy, cytology, imaging) were extracted from hospital discharge reports, outpatient care notes or pharmacy drug delivery data. BC subtype was inferred from the treatments received.\n\nResultsWe included 235,368 patients with early BC in the cohort (median age: 60 years). BC subtype distribution was as follows: luminal (80.2%), triple-negative (TNBC, 9.5%); HER2+ (10.3%), or unidentifiable (n=44,388, 18.9% of the cohort). Most patients underwent radiotherapy (n=200,685, 85.3%) and endocrine therapy (n=165,655, 70.4%), and 38.3% (n=90,252) received chemotherapy. Treatments and care pathways are described.\n\nConclusionThe FRESH Cohort is an unprecedented population-based resource facilitating future large-scale real-life studies aiming to improve care pathways and quality of care for BC patients.","Towards fast, routine blood sample quality evaluation by Probe Electrospray Ionization (PESI) metabolomics\nAO_SCPLOWBSTRACTC_SCPLOWPESI-MS enables with its greatly simplified handling and fast result delivery the application field for high-throughput use in routine settings. In health care and research, pre-analytical errors often remain undetected and disrupt diagnosis, treatment, clinical studies and biomarker validations incurring high costs. This proof-of-principle study investigates the suitability of PESI-MS for robust, routine sample quality evaluation.\n\nOne of the most common pre-analytical quality issues in blood sampling are prolonged transportations times from bedside to laboratory promptly changing the metabolome. Here, human blood (n=50) was processed immediately or with a time delay of 3 h. The developed sample preparation method delivers ready-to-measure extracts in <8 min. PESI-MS spectra were measured in both ionization modes in 2 min from as little as 2 {micro}l plasma allowing 3 replicate measurements. The mass spectra contained 1200 stable features covering a broad chemical space covering major metabolic classes (e.g. fatty acids, lysolipids, lipids). The time delay of 3 h was predictable by using 18 features with AUC > 0.95 with various machine learning and was robust against loss of single features.\n\nOur results serve as first proof of principle for the unique advantages of PESI-MS in sample quality assessments. The results pave the way towards a fully automated, cost-efficient, user-friendly, robust and fast quality assessment of human blood samples from minimal sample amounts.\n\nGO_SCPLOWRAPHICALC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWABSTRACTC_SCPLOW\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=38 SRC=\"FIGDIR/small/21254782v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (15K):\norg.highwire.dtl.DTLVardef@182233forg.highwire.dtl.DTLVardef@d801f9org.highwire.dtl.DTLVardef@169a2aaorg.highwire.dtl.DTLVardef@3673bb_HPS_FORMAT_FIGEXP M_FIG C_FIG","Preliminary Rasch analysis of the Multidimensional Assessment of Interoceptive Awareness in adults with stroke\nPurposeThe Multidimensional Assessment of Interoceptive Awareness (MAIA) measures interoceptive body awareness, which includes aspects such as attention regulation, self-regulation, and body listening. Our purpose was to validate the MAIA in adults with stroke using Rasch Measurement Theory.\n\nMethodsThe original MAIA has 32 items grouped into eight separately scored subscales that measure aspects of body awareness. Using Rasch Measurement Theory, we evaluated the unidimensionality of the entire scale and investigated person and item fit, person separation reliability, targeting, local item dependence, and principal components analysis of residuals.\n\nResultsForty-one adults with chronic stroke (average 3.8 years post-stroke, 13 women, and average age, 57{+/-}13 years) participated in the study. Overall fit (X2=62.26, p=0.26) and item fit were obtained after deleting 3 items and rescoring 26 items. One participant did not fit the model (2.44%). There were no floor (0.00%) or ceiling effects (0.00%). Local item dependence was found in 42 pairs. The person separation reliability was 0.91, and the person mean location was 0.06{+/-}1.12 logits.\n\nConclusionsThe MAIA demonstrated good targeting and reliability, as well as good item and person fit in adults with chronic stroke. A study with a larger sample size is needed to validate our findings.","COVID-19 associated autoimmunity is a feature of severe respiratory disease - a Bayesian analysis.\nBackgroundSerological and clinical features with similarities to systemic autoimmunity have been reported in severe COVID-19, but there is a lack of studies that include contemporaneous controls who do not have COVID-19.\n\nMethodsObservational cohort study of adult patients admitted to an intensive care unit with acute respiratory failure. Patients were divided into COVID+ and COVID- based on SARS-CoV-2 PCR from nasopharyngeal swabs and/or endotracheal aspirates. No COVID-19 specific interventions were given. The primary clinical outcome was death in the ICU within 3 months; secondary outcomes included in-hospital death and disease severity measures. Measurements including autoantibodies, were done longitudinally. ANOVA and Fishers exact test were used with =0.05, with a false discovery rate of q=0.05. Bayesian analysis was performed to provide credible estimates of the possible states of nature compatible with our results.\n\nResults22 COVID+ and 20 COVID- patients were recruited, 69% males, median age 60.5 years. Overall, 64% had anti-nuclear antibodies, 38% had antigen-specific autoantibodies, 31% had myositis related autoantibodies, and 38% had high levels of anti-cytokine autoantibodies. There were no statistically significant differences between COVID+ and COVID- for any of the clinical or autoantibody parameters. A specific pattern of anti-nuclear antibodies was associated with worse clinical severity for both cohorts.\n\nConclusionsSevere COVID+ patients have similar humoral autoimmune features as comparably ill COVID- patients, suggesting that autoantibodies are a feature of critical illness regardless of COVID-19 status. The clinical significance of autoimmune serology and the correlation with severity in critical illness remains to be elucidated.","Virtually in Synch: A Pilot Study on Affective Dimensions of Dancing with Parkinson's during COVID- 19\nLoss of social supports and community programs due to lockdowns and other measures associated with COVID-19 has been linked with concerns over mental health and feelings of isolation. These challenges can be particularly acute for the elderly and people living with chronic or pervasive health conditions. Dance for PD, a program specifically developed for people living with Parkinsons Disease, formerly offered in hundreds of locations around the globe, either halted or shifted to a virtual format. Our study investigates the transition of these dance-based programs to an online environment, with the aim of determining the extent to which a virtual format provides affective support or other benefits. Given the increased incidence of mental health problems and social isolation associated with COVID-19, this investigation aims to contribute to the development of better supports for vulnerable populations while helping us understand the specific contributions of dance-based programs in a virtual environment.","Lesion Symptom Mapping of Domain-Specific Cognitive Impairments using Routine Imaging in Stroke\nBackground and PurposeThis large-scale lesion-symptom mapping study aimed to investigate the necessary neuro-anatomical substrates of 5 cognitive domains frequently affected post stroke: Language, Attention, Praxis, Number, and Memory. This study aims to demonstrate the validity of using routine clinical brain imaging from a large, real-world patient cohort for lesion-symptom mapping.\n\nMethodsBehavioural cognitive screening data from the Oxford Cognitive Screen and routine clinical neuroimaging from 573 acute patients was used in voxel-based lesion-symptom mapping analyses. Patients were classed as impaired or not on each of the subtests within 5 cognitive domains.\n\nResultsDistinct patterns of lesion damage were associated with different domains. Language functions were associated with damage to left hemisphere fronto-temporal areas. Visuo-spatial functions were associated with damage to posterior occipital areas (Visual Field) and the right temporo-parietal region (Visual Neglect). Different memory impairments were linked to distinct voxel clusters within the left insular and opercular cortices. Deficits which were not associated with localised voxels (e.g. praxis, executive function) represent distributed functions.\n\nConclusionThe standardised, brief Oxford Cognitive Screen was able to reliably differentiate distinct neural correlates critically involved in supporting domain-specific cognitive abilities. By demonstrating and replicating known brain anatomy correlates within real-life clinical cohorts using routine CT scans, we open up VLSM techniques to a wealth of clinically relevant studies which can capitalise on using existing clinical brain imaging.","Dopamine D1 agonist effects in late-stage Parkinson's disease\nAO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSCurrent pharmacotherapy has limited efficacy and/or intolerable side effects in late-stage Parkinsons disease (LsPD) patients whose daily life depends primarily on caregivers and palliative care. Clinical metrics inadequately gauge efficacy in LsPD patients.\n\nObjectiveExplore if a D1/5 dopamine agonist will have efficacy in LsPD that will be detected most sensitively by caregivers in a phase I study.\n\nMethodsA double-blind controlled phase Ia/b study compared the D1/5 agonist PF-06412562 to levodopa/carbidopa in six LsPD patients. Throughout the study, caregivers were with the patients. Assessments included standard quantitative scales of motor function (MDS-UPDRS-III), alertness (Glasgow Coma and Stanford Sleepiness Scales), and cognition (Severe Impairment and Frontal Assessment Batteries) at baseline (Day 1) and thrice daily during drug testing (Days 2 and 3). Clinicians and caregivers completed clinical impression of change questionnaires, and caregivers participated in a qualitative exit interview. Blinded triangulation of quantitative and qualitative data was used to integrate findings.\n\nResultsNeither traditional scales, nor clinician impression of change, detected consistent differences between treatments in the five participants who completed the study. Conversely, the overall caregiver data strongly favored PF-06412562 over levodopa in four of five patients. The most meaningful improvements converged on motor, alertness, and engagement.\n\nConclusionD1/5 agonists may offer potential benefit for LsPD patients. Caregiver perspectives with mixed method analyses may overcome limitations in standard rater/clinician-based evaluations. Further studies are warranted and need to integrate caregiver input as an essential component of outcome evaluations.\n\nTrial Registration#ClinicalTrials.gov: NCT03665454","Cystatin C is a glucocorticoid response gene predictive of cancer immunotherapy failure\nThe secreted protein Cystatin C (CyC) is a cysteine protease inhibitor of incompletely characterized biomedical function, used clinically for estimation of glomerular filtration rate. Plasma CyC is elevated in many patients, especially when they receive glucocorticoid (GC) treatment. Here we empirically connect GCs with systemic regulation of CyC. First, we leveraged genome-wide association and structural equation modeling to determine the genetics of the latent trait CyC production in UK Biobank. Using multi-modal genomic, transcriptional, and experimental approaches, we demonstrated that CyC is a direct target of GC receptor, with GC-responsive CyC secretion exhibited by macrophages and cancer cells in vitro. Elevated serum CyC levels were positively correlated with GC levels in a murine model of cancer progression. Consistent with the coupling of CyC levels to GC signaling in a disease relevant manner, CyC predicted elevated all-cause and cancer-specific mortality in humans. These associations were orthogonally confirmed by a polygenic score (PGS) capturing germline predisposition to CyC production. This PGS predicted checkpoint immunotherapy failure in a combined clinical trial cohort of 685 metastatic cancer patients, with available germline exome sequencing. Taken together, our results demonstrate that CyC captures biomedically-relevant variations in endogenous GC activity, raising the possibility that CyC may be a direct effector of GC-induced immunosuppression and therefore a target for combination cancer immunotherapy.","Comparative efficacy of interferential therapy, bronchodilators, and body positioning on asthma control and quality of life of patients with bronchial asthma: Study protocol\nBackgroundInterferential therapy (IFT) is the application of two medium frequency currents to the skin to stimulate and activate different systems in the body using specific frequencies and frequency ranges. IFT aims to reduce myalgia in the chest and upper back, reduce muscular fatigue and induce mucus expectoration. This study is designed to compare the efficacy of IFT on asthma control and quality of life of asthma patients pre-and post-administration of bronchodilators and determine the most influential body position in its application.\n\nMethodsForty-eight (48) patients aged 18 years and above with bronchial Asthma attending the respiratory clinic at the Lagos State University Teaching Hospital, Ikeja (LASUTH) will be assessed for the study eligibility. The study design will be a double-blinded, randomized control trial with four intervention groups and four parallel placebo control groups. IFT will be administered as an intervention to patients on short and long-acting bronchodilators in an assigned fundamental body position for 20 minutes. Six continuous outcome variables at different points will be utilized as an outcome measure. Baseline Pulmonary Function Test (PFT) will be assessed on entry into the study, Quality of life and asthma control will be evaluated every two (2) weeks of the study. Data obtained will be analyzed using descriptive and inferential statistics of repeated ANOVA; P<0.05.\n\nDiscussionThe study outcome will compare the efficacy of IFT on Bronchial Asthma, identify its effect in different body positions, and compare the relationship between its application and the bronchodilator medication frequently used by the patients.\n\nTrial Registrationhttps://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=10942:\n\nPACTR202005807526130","Using Artificial Intelligence-based models to predict the risk of Mucormycosis among COVID-19 Survivors: An Experience from India\nIntroductionIndia reported a severe public health challenge not only due to the COVID-19 outbreak but also the increasing number of associated mucormycosis cases since 2021. This study aimed at developing artificial intelligence-based models to predict the risk of mucormycosis among the patients at the time of discharge from the hospital.\n\nMethodsThe dataset included 1229 COVID-19 positive patients, and additional 214 inpatients, COVID-19 positive as well as infected with mucormycosis. We used logistic regression, decision tree, and random forest, and the extreme gradient boosting algorithm. All our models were evaluated with 5-fold validation to derive a reliable estimate of the model error.\n\nResultsThe logistic regression, XGBoost, and random forest performed equally well with AUROC 95.0, 94.0, and 94.0 respectively. This study also determined the top five variables namely obesity, anosmia, de novo diabetes, myalgia, and nasal discharge, which showed a positive impact on the risk of mucormycosis.\n\nConclusionThe developed model has the potential to predict the patients at high risk and thus, consequently initiating preventive care or aiding in early detection of mucormycosis infection. Thus, this study holds potential for early treatment and better management of patients suffering from COVID-19 associated mucormycosis.","Structural differences in adolescent brains can predict alcohol misuse\nAlcohol misuse during adolescence (AAM) has been linked with disruptive structural development of the brain and alcohol use disorder. Using machine learning (ML), we analyze the link between AAM phenotypes and adolescent brain structure (T1-weighted imaging and DTI) at ages 14, 19, and 22 in the IMAGEN dataset (n [~] 1182). ML predicted AAM at age 22 from brain structure with a balanced accuracy of 78% on independent test data. Therefore, structural differences in adolescent brains could significantly predict AAM. Using brain structure at age 14 and 19, ML predicted AAM at age 22 with a balanced accuracy of 73% and 75%, respectively. These results showed that structural differences preceded alcohol misuse behavior in the dataset. The most informative features were located in the white matter tracts of the corpus callosum and internal capsule, brain stem, and ventricular CSF. In the cortex, they were spread across the occipital, frontal, and temporal lobes and in the cingulate cortex. Our study also demonstrates how the choice of the phenotype for AAM, the ML method, and the confound correction technique are all crucial decisions in an exploratory ML study analyzing psychiatric disorders with weak effect sizes such as AAM.","A Study On Clinical Profile And Semiology In Complex Partial Seizures And Its Radiological Correlation\nBackgroundEpilepsy is the second most common and frequently encountered neurological disorder which poses huge threat to known healthcare systems worldwide also causing financial, socio economic burden to the community. Complex Partial Seizures are a form of focal epileptic seizures that may impair consciousness.\n\nAim and objectivesOur motivation for the study was to understand the extent of patients with complex partial seizures associated with medial temporal lobe sclerosis.\n\nMaterials and methodsWe performed a cross sectional study about patients with complex partial seizures in Thanjavur medical college and hospital about their clinical profile and neuro-radiological correlation.\n\nStatistical analysis and resultsThrough our multimodal study with EEG, MRI on N=118 (female / male, age range, Most common age group-10-20 years, mean age of 23 years, SD-14 years, 66% males), we observed that atypical febrile seizures and fever provoked seizures has more association (18%) to complex partial seizures and to medial temporal lobe sclerosis in comparison to 12% in an earlier study.\n\nConclusionWe believe this study summarizes the complex partial seizure features, origin, and their link to Medial Temporal lobe Sclerosis in our subject pool from Thajavur, India.\n\nLimitationThere are some limitations to our study, especially with no video EEG monitoring and no invasive EEG recording. We aim to improve them in our future studies.","Intra-individual reproducibility as essential determinant of clinical utility of smartphone-based neurological disability tests\nTechnological advances, lack of medical professionals, high cost of face-to face encounters and disasters such as COVID19 pandemic, fuel the telemedicine revolution. Numerous smartphone apps have been developed to measure neurological functions. However, their psychometric properties are seldom determined. Lacking such data, it is unclear which designs underlie eventual clinical utility of the smartphone tests.\n\nWe have developed the smartphone Neurological Function Tests Suite (NeuFun-TS) and are systematically evaluating their psychometric properties against the gold-standard of complete neurological examination digitalized into NeurExTM App. This paper examines the fifth, and thus far the most complex NeuFun-TS test, the \"Spiral tracing\". We generated 40 features in the training cohort (22 healthy donors [HD] and 105 multiple sclerosis [MS] patients) and compared their intraclass correlation coefficient, fold-change between HD and MS and correlations with relevant clinical and imaging outcomes. We assembled the best features into machine-learning models and examined their performance in the independent validation cohort (56 MS patients).\n\nWe show that by aggregating multiple neurological functions, complex tests such as spiral tracing are susceptible to intra-individual variations, decreasing their reproducibility and thus, clinical utility. Simple tests, reproducibly measuring single function(s) that can be aggregated to increase sensitivity are preferable in app design.","The inhibition of Macrophage Migration Inhibitory Factor by ISO-1 attenuates trauma-induced multiorgan dysfunction in rats\nBackgroundMulti organ dysfunction syndrome caused by systemic inflammation after trauma is responsible for a high number of deaths worldwide. The cytokine Migration Inhibitory Factor (MIF) is recognized as a modulator of inflammatory response, however, its role in trauma is unknown. The aim of this study was to investigate (a) the levels of MIF in serum of trauma patients and of rats after hemorrhagic shock, (b) the potential of the MIF tautomerase activity inhibitor ISO-1 to reduce multi organ dysfunction syndrome in an acute and chronic hemorrhagic shock rat model and (c) whether treatment with ISO-1 attenuates NF-{kappa}B and NLRP3 activation in hemorrhagic shock.\n\nMethodsThe serum MIF-levels in trauma patients and rats with hemorrhagic shock were measured by Enzyme-Linked Immunosorbent Assays. Acute and chronic hemorrhagic shock rat models were performed to determine the influence of ISO-1 on multi organ dysfunction syndrome. The activation of NF-{kappa}B and NLRP3 pathways were analyzed by western blot.\n\nResultsWe demonstrated that (a) MIF levels are increased in serum of trauma patients on arrival in the emergency room and in serum of rats after hemorrhagic shock, (b) hemorrhagic shock caused organ damage and low blood pressure (after resuscitation) in rats, while (c) treatment of hemorrhagic shock rats with ISO-1 attenuated organ injury and dysfunction in acute and chronic hemorrhagic shock rat models and (d) decreased the activation of NF-{kappa}B and NLRP3 pathways.\n\nConclusionOur results point to a role of MIF in the pathophysiology of the organ injury and dysfunction caused by trauma/hemorrhage and indicate that MIF tautomerase activity inhibitors may have potential in the therapy of the multi organ dysfunction syndrome after trauma and/or hemorrhage.","Identification of B.1.346 lineage of SARS-CoV-2 in Japan: Genomic evidence of re-entry of Clade 20C\nObjectivesWhole SARS-CoV-2 genome sequencing from COVID-19 patients is useful for infection control and regional trends evaluation. We report a lineage data collected from hospitals in the Kanto region of Japan.\n\nMethodsWe performed whole genome sequencing in specimens of 198 COVID-19 patients at 13 collaborating hospitals in the Kanto region. Phylogenetic analysis and fingerprinting of the nucleotide substitutions underwent to differentiate and classify the viral lineages.\n\nResultsMore than 90% of the strains belonged to Clade 20B and two lineages (B.1.1.284 and B.1.1.214) have been detected predominantly in the Kanto region. However, one sample from a COVID-19 patient in November 2020, belonged to the B.1.346 lineage of Clade 20C, which has been prevalent in western United States. The patient had no history of overseas travel and no contact with anyone who had travelled abroad, suggesting that this strain appeared likely to have been imported from western United States, across the strict quarantine barrier.\n\nConclusionB.1.1.284 and B.1.1.214 have been identified predominantly in the Kanto region and B.1.346 of clade 20C in one patient was probably imported from western United States. These results illustrate that a decentralized network of hospitals can be significantly advantageous for monitoring regional molecular epidemiologic trends.\n\nHighlights{middle dot} Whole SARS-CoV-2 genome sequencing is useful for infection control\n{middle dot} B.1.1.284 and B.1.1.214 have been identified predominantly in the Kanto region\n{middle dot} B.1.346 of Clade 20C was detected in one COVID-19 patient in November\n{middle dot} Molecular genomic data sharing provides benefits to public health against COVID-19","Stroke recovery phenotyping through network trajectory approaches and graph neural networks\nStroke is a leading cause of neurological injury characterized by impairments in multiple neurological domains including cognition, language, sensory and motor functions. Clinical recovery in these domains is tracked using a wide range of measures that may be continuous, ordinal, interval or categorical in nature, which presents challenges for standard multivariate regression approaches. This has hindered stroke researchers ability to achieve an integrated picture of the complex time-evolving interactions amongst symptoms. Here we use tools from network science and machine learning that are particularly well-suited to extracting underlying patterns in such data, and may assist in prediction of recovery patterns. To demonstrate the utility of this approach, we analyzed data from the NINDS tPA trial using the Trajectory Profile Clustering (TPC) method to identify distinct stroke recovery patterns for 11 different neurological domains at 5 discrete time points. Our analysis identified 3 distinct stroke trajectory profiles that align with clinically relevant stroke syndromes, characterized both by distinct clusters of symptoms, as well as differing degrees of symptom severity. We then validated our approach using graph neural networks to determine how well our model performed predictively for stratifying patients into these trajectory profiles at early vs. later time points post-stroke. We demonstrate that trajectory profile clustering is an effective method for identifying clinically relevant recovery subtypes in multidimensional longitudinal datasets, and for early prediction of symptom progression subtypes in individual patients. This paper is the first work introducing network trajectory approaches for stroke recovery phenotyping, and is aimed at enhancing the translation of such novel computational approaches for practical clinical application.","The Sequence Effect Worsens over Time in Parkinson's disease and Responds to Open and Closed-Loop Subthalamic Nucleus Deep Brain Stimulation\nBackgroundThe sequence effect is the progressive deterioration in speech, limb movement, and gait that leads to an inability to communicate, manipulate objects or walk without freezing of gait. Many studies have demonstrated a lack of improvement of the sequence effect from dopaminergic medication, however few studies have studied the metric over time or investigated the effect of open and closed-loop deep brain stimulation in people with PD.\n\nObjectiveTo investigate whether the sequence effect worsens over time and/or is improved on clinical (open-loop) and closed-loop deep brain stimulation (DBS).\n\nMethodsTwenty-one people with PD with bilateral STN DBS performed thirty seconds of instrumented repetitive wrist flexion extension and the MDS-UPDRS III off therapy, prior to activation of DBS and every six months for up to three years. A sub-cohort of ten people performed the task during randomized presentations of different intensities of STN DBS.\n\nResultsThe sequence effect was highly correlated with the overall MDS-UPDRS III score and the bradykinesia sub-score and worsened over three years. Increasing intensities of STN open-loop DBS improved the sequence effect and one subject demonstrated improvement on both open-loop and even further improvement on closed-loop DBS.\n\nConclusionsSequence effect in limb bradykinesia worsened over time off therapy due to disease progression but improved on open and closed-loop DBS. These results demonstrate that DBS is a useful treatment of the debilitating effects of the sequence effect in limb bradykinesia and that closed-loop DBS may offer added improvement.","Clonality and timing of relapsing colorectal cancer metastasis revealed through whole-genome single-cell sequencing\nBACKGROUNDRecurrence of tumor cells following local and systemic therapy is a significant hurdle in cancer. Most patients with metastatic colorectal cancer (mCRC) will relapse, despite resection of the metastatic lesions. A better understanding of the evolutionary history of recurrent lesions is thus required to identify the spatial and temporal patterns of metastatic progression and expose the genetic determinants of therapeutic resistance.\n\nMETHODSUtilizing a robust Bayesian phylogenetic approach, we analyzed a unique single-cell whole-genome sequencing dataset comprising 60 cells sampled from metastatic and recurrent hepatic lesions of a patient with a long-term disease course to investigate the origin, timing, and clonality of a colorectal metastatic relapse. We further tracked the changes in the size of the malignant cell population and evaluated the impact of the treatment strategy on the mutational landscape of this tumor.\n\nRESULTSOur results suggest that the recurrent lesion originated from the clonal expansion of a single drug-resistant metastatic lineage, which began to expand around one year before surgical resection of the relapse. We additionally observed substantial variability in the substitution rates along the tumor cell phylogeny and found a large number of mutations specific to the ancestral lineage that gave rise to the relapse, including non-silent mutations in CRC genes. Moreover, our results point to a substantial contribution of chemotherapy exposure to the overall mutational burden.\n\nCONCLUSIONSOur study suggests that resistant colorectal metastatic clones can quickly grow, even under strong drug-imposed pressure, highlighting the importance of profiling the genomic landscape of tumor lesions to identify mutations potentially contributing to treatment failure.","Deep Learning Prediction of Biomarkers from Echocardiogram Videos\nLaboratory blood testing is routinely used to assay biomarkers to provide information on physiologic state beyond what clinicians can evaluate from interpreting medical imaging. We hypothesized that deep learning interpretation of echocardiogram videos can provide additional value in understanding disease states and can predict common biomarkers results. Using 70,066 echocardiograms and associated biomarker results from 39,460 patients, we developed EchoNet-Labs, a video-based deep learning algorithm to predict anemia, elevated B-type natriuretic peptide (BNP), troponin I, and blood urea nitrogen (BUN), and abnormal levels in ten additional lab tests. On held-out test data across different healthcare systems, EchoNet-Labs achieved an area under the curve (AUC) of 0.80 in predicting anemia, 0.82 in predicting elevated BNP, 0.75 in predicting elevated troponin I, and 0.69 in predicting elevated BUN. We further demonstrate the utility of the model in predicting abnormalities in 10 additional lab tests. We investigate the features necessary for EchoNet-Labs to make successful predictions and identify potential prediction mechanisms for each biomarker using well-known and novel explainability techniques. These results show that deep learning applied to diagnostic imaging can provide additional clinical value and identify phenotypic information beyond current imaging interpretation methods.","Mental Disorder Prevalence Among Populations Impacted by Coronavirus Pandemics: A Multilevel Meta-Analytic Study of COVID-19, MERS & SARS\nObjectiveThrough a systematic review and meta-analysis of research on COVID-19, severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS) pandemics, we investigated whether mental disorder prevalence: (a) was elevated among populations impacted by coronavirus pandemics (relative to unselected populations reported in the literature), and (b) varied by disorder (undifferentiated psychiatric morbidity, anxiety, depressive, posttraumatic stress disorders [PTSD]) and impacted population (community, infected/recovered, healthcare provider, quarantined).\n\nMethodFrom 68 publications (N=87,586 participants), 808 estimates were included in a series of multilevel meta-analyses/regressions including random effects to account for estimates nested within studies.\n\nResultsMedian summary point prevalence estimates varied by disorder and population. Psychiatric morbidity (20%-56%), PTSD (10-26%) and depression (9-27%) were most prevalent in most populations. The highest prevalence of each disorder was found among infected/recovered adults (18-56%), followed by healthcare providers (11-28%) and community adults (11-20%). Prevalence estimates were often notably higher than reported for unselected samples. Sensitivity analyses demonstrated that overall prevalence estimates moderately varied by pandemic, study location, and mental disorder measure type.\n\nConclusionCoronavirus pandemics are associated with multiple mental disorders in several impacted populations. Needed are investigations of causal links between specific pandemic-related stressors, threats, and traumas and mental disorders.","Development of a vocal biomarker for fatigue monitoring in people with COVID-19\nObjectiveTo develop a vocal biomarker for fatigue monitoring in people with COVID-19.\n\nDesignProspective cohort study.\n\nSettingPredi-COVID data between May 2020 and May 2021.\n\nParticipantsA total of 1772 voice recordings was used to train an AI-based algorithm to predict fatigue, stratified by gender and smartphones operating system (Android/iOS). The recordings were collected from 296 participants tracked for two weeks following SARS-CoV-2 infection.\n\nprimary and secondary outcome measuresFour machine learning algorithms (Logistic regression, k-nearest neighbors, support vector machine, and soft voting classifier) were used to train and derive the fatigue vocal biomarker. A t-test was used to evaluate the distribution of the vocal biomarker between the two classes (Fatigue and No fatigue).\n\nResultsThe final study population included 56% of women and had a mean ({+/-}SD) age of 40 ({+/-}13) years. Women were more likely to report fatigue (P<.001). We developed four models for Android female, Android male, iOS female, and iOS male users with a weighted AUC of 79%, 85%, 86%, 82%, and a mean Brier Score of 0.15, 0.12, 0.17, 0.12, respectively. The vocal biomarker derived from the prediction models successfully discriminated COVID-19 participants with and without fatigue (t-test P<.001).\n\nConclusionsThis study demonstrates the feasibility of identifying and remotely monitoring fatigue thanks to voice. Vocal biomarkers, digitally integrated into telemedicine technologies, are expected to improve the monitoring of people with COVID-19 or Long-COVID.","Mendelian gene identification through mouse embryo viability screening\nThe diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful.\n\nA full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property. Here we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid or late gestation lethal.\n\nWe studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes, and found that the members of the early gestation lethal category show distinctive characteristics and a strong enrichment for genes linked with recessive forms of inherited metabolic disease.\n\nBased on these findings, we explored a gene similarity approach for novel gene discovery focused on this subset of lethal genes. Finally, we investigated unsolved cases from the 100,000 Genomes Project recruited under this disease category to look for signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes and highlight two novel candidates with phenotypic overlap between the patients and the mouse knockout.","Automatic Identification of Tinnitus Malingering Based on Overt and Covert Behavioral Responses During Psychoacoustic Testing\nTinnitus, or ringing in the ears, is a prevalent condition that imposes a substantial health and financial burden on the patient and to society. The diagnosis of tinnitus, like pain, relies on patient self-report. Subjective self-report measures can complicate the distinction between actual and fraudulent claims and obscure accurate severity assessments. In this study, we combined tablet-based self-directed hearing assessments with neural network classifiers to objectively determine tinnitus severity, and to differentiate participants with tinnitus (N=24) from a malingering cohort, who were instructed to feign an imagined tinnitus percept (N=28). We identified clear differences between the groups, both in their overt rating of tinnitus severity but also covert differences in their fingertip movement trajectories on the tablet surface as they performed the reporting assay. Using only 10 minutes of data, we achieved 81% accuracy classifying patients vs malingerers (ROC AUC=0.88) with leave-one-participant-out cross validation. Objective measurements of tinnitus will improve estimates of tinnitus prevalence and help to prioritize and direct funds for tinnitus compensation.","A mixed methods study of seasonal influenza vaccine hesitancy in adults with chronic respiratory conditions\nBackgroundSeasonal influenza vaccination is recommended for patients with chronic respiratory conditions, but uptake is suboptimal. We undertook a comprehensive mixed methods study in order to examine the barriers and enablers to influenza vaccination in patients with chronic respiratory conditions.\n\nMethodsMixed methods including a survey (n=429) which assessed socio-demographics and the psychological factors associated with vaccine uptake (i.e. confidence, complacency, constraints, calculation and collective responsibility) with binary logistic regression analysis. We also undertook focus groups and interviews (n=59) to further explore barriers and enablers to uptake using thematic analysis.\n\nResultsThe survey analysis identified that older participants were more likely to accept the vaccine, as were those with higher perceptions of collective responsibility around vaccination, lower levels of complacency, and lower levels of constraints. Thematic analysis showed that concerns over vaccine side effects, lack of tailored information and knowledge, and a lack of trust and rapport with healthcare professionals were key barriers. In contrast, the importance of feeling protected, acceptance of being part of an at-risk group, and feeling a reduced sense of vulnerability after vaccination were seen as key enablers.\n\nConclusionsOur findings showed that the decision to accept a vaccine against influenza is influenced by multiple sociodemographic and psychological factors. Future interventions should provide clear and transparent information about side effects and be tailored to patients with chronic respiratory conditions. Interactions between patients and their healthcare providers have a particularly important role to play in helping patients address their concerns and feel confident in vaccination.","Justification, safety, and efficacy of a third dose of mRNA vaccine in maintenance hemodialysis patients: a prospective observational study\nBackgroundPatients on maintenance hemodialysis (MHD) are at high risk of infection with SARS-Cov-2 and death due to COVID-19. This vulnerable population has been prioritized for vaccination, but the level of protection achieved in these immunocompromised patients is unclear.\n\nObjectivesTo evaluate the protection of MHD patients against COVID-19 after 2 doses (2D) of BNT162b2, and the safety and impact on immune responses of a 3rd dose (3D).\n\nDesignProspective observational.\n\nSetting, Patients, intervention and measurementsREIN national registry was used to compare the severity of 1474 cases of COVID-19 diagnosed in MHD patients after 0, 1 or 2 doses of mRNA vaccine. Anti-spike receptor binding domain (RBD) IgG and interferon gamma-producing CD4+ and CD8+ specific-T cells were measured after 2D and 3D of BNT162b2 in a monocentric cohort of 75 MHD patients.\n\nResultsVaccination reduced disease severity but 11% of MHD patients infected after 2D still died. Tolerance to 3D of BNT162b2 was excellent. MHD patients with humoral response similar to healthy volunteers after 2D did not generate more immune effectors after 3D and had more side effects. In contrast, 2/3 of MHD patients with suboptimal response after 2D reached optimal titer of anti-RBD IgG and/or developed spike-specific CD8+ T cells after 3D. Presence of spike-specific CD4+ T cells after 2D was associated with response to 3D in multivariate analysis (OR=4.80 [1.23-21.54]; p=0.029).\n\nLimitationsLimited number of patients injected with 3D.\n\nConclusionStandard scheme of vaccination provides insufficient protection to some MHD patients. Anti-RBD IgG and specific CD4+ T cells should be measured after 2D. Among patients with suboptimal humoral response, those with specific CD4+ T cells could benefit of a 3rd dose of vaccine.\n\nRegistrationNCT04881396\n\nFunding SourceNone","Nusinersen in adult patients with 5q spinal muscular atrophy: a multicenter observational cohorts study\nObjectiveTo assess safety and efficacy of nusinersen in adult 5q spinal muscular atrophy (SMA) patients.\n\nMethodsPatients older than 15 years and followed at least for 6 months with one motor scale (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb module, RULM) in five referral centers were included. Clinical and patients global impression of change (CGI-C and PGI-C) were recorded in treated patients at the last visit. Functional scales (Egen Klassification, EK2; Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, ALSFRS-R) and the percent-predicted forced vital capacity were collected when available.\n\nResultsSeventy-nine SMA patients (39 treated with nusinersen) were included. Compared with untreated patients, treated patients showed a significant improvement of 2 points ({+/-}0.46) in RULM (p<0.001) after six months. After a mean follow-up of 16 months, nusinersen treatment was associated with a significant improvement in HFMSE (OR=1.15, p=0.006), 6MWT (OR=1.07, p<0.001), and EK2 (OR=0.81, p=0.001).\n\nCompared with untreated patients, more treated patients experienced clinically meaningful improvements in all scales, but these differences were statistically significant only for RULM (p=0.033), ALSFRS-R (p=0.005), and EK2 (p<0.001). According to the CGI-C and PGI-C, 64.1% and 61.5% of treated patients improved with treatment. Being non-sitter was associated with less response to treatment, while longer time of treatment was associated with better response. Most treated patients (77%) presented at least one adverse event, mostly mild.\n\nConclusionsNusinersen treatment associates to some improvements in adult SMA patients. Most severely affected patients with complex spines are probably those with the most unfavorable risk-benefit ratio.","Fraction of COVID-19 hospitalizations and deaths attributable to chronic diseases\nAimTo estimate the fraction of hospitalizations and deaths from COVID-19 attributable to chronic diseases due to poor nutrition and smoking in Mexico.\n\nMethodsWe used data from the Mexican surveillance system of COVID-19. We considered six chronic diseases (obesity, COPD, hypertension, diabetes, cardiovascular disease, and chronic kidney disease) to define a multimorbidity variable: no diseases, 1 disease, 2 diseases, or 3 or more diseases. We calibrated the database using bias quantification methods to consider the undiagnosed cases of chronic diseases. To estimate the risks of hospitalization and death due to chronic diseases, we fitted Poisson regression models with robust standard errors, adjusting for possible confounders. Using these risks, we calculated attributable fractions using the population attributable fraction (PAF).\n\nResultsChronic diseases accounted for to 25.4% (24.8%, 26.1%), 28.3% (27.8%, 28.7%) and 15.3% (14.9%,15.7%) of the hospitalizations among adults below 40 years, 40 to 59, and 60 years and older respectively (95% CI). For COVID-19-related deaths, 50.1% (48.6%, 51.5%), 40.5% (39.7%, 41.3%), and 18.7% (18.0%, 19.5%) were attributable to chronic diseases in adults under 40 years, 40 to 59, and 60 years and older, respectively.\n\nConclusionChronic diseases linked to malnutrition and tobacco use contributed to a higher burden of hospitalization and deaths from COVID-19 in Mexico, particularly among younger adults. Medical and structural interventions to curb chronic disease incidence and facilitate disease control are urgently needed.","Psychometric properties of the Copenhagen Burnout Inventory (CBI) in Italian physicians\nBackgroundAssessing burnout in physicians is relevant as it can adversely affect both their mental and physical health by also decreasing the quality of care, especially since the onset of the COVID-19 pandemic. This study aimed at standardizing the Copenhagen Burnout Inventory (CBI), a psychometrically sound, worldwide-spread tool, in Italian physicians.\n\nMethodsNine-hundred and fifteen Italian physicians were web-administered the CBI, Patient Health Questionnaire-8 (PHQ-8), Generalized Anxiety Disorder-7 (GAD-7) and General Self-Efficacy Scale (GSE). The present CBI is a self-report questionnaire including 18 Likert items (range=19-90) assessing Personal, Work-related and Client-related Burnout. Client-related adaptation was performed. Construct validity, factorial structure (Confirmatory Factor Analysis) and internal consistency were tested. Diagnostic accuracy was assessed simultaneously against the PHQ-8, GAD-7 and GSE.\n\nResultsAll CBI measures yielded optimal internal consistency (Cronbachs =.90-.96). The CBI met its original three-factor model (CFI=.94; TLI=.93; RMSEA=.09; SRMR=.04), was positively related with the PHQ-8 (r=.76) and GAD-7 (r.=73), whereas negatively with the GSE (r=-.39), and yielded optimal diagnostics (AUC=.93; sensitivity=.91 and specificity=.85 at the optimal cut-off of 69/90).\n\nDiscussionThe CBI is a valid, reliable and normed tool to assess burnout levels in physicians, whose use is encouraged in both clinical practice and research as being short-lived, easy to use and openly accessible.","Identification and Mitigation of High-Risk Pregnancy with the Community Maternal Danger Score Mobile Application in Gboko, Nigeria\nIntroductionNigeria constitutes 1% of the worlds population yet accounts for 10% of global maternal mortality. Risk analyses within rural regions of Nigeria are not routinely conducted, yet could help inform access to skilled birth care. The objectives of this study were to assess the proportion of women at risk for mortality or morbidity in Benue State, Nigeria by analysing data collected during routine antenatal visits and through the Community Maternal Danger Score (CMDS), a validated risk-analysis tool.\n\nMethodsTwo cohorts, comprised of pregnant women presenting to primary healthcare centres within Gboko, Benue State between 2015-2017 and 2020-2021, were included in this study. The 2015-2017 cohort had their risk assessed retrospectively through analysis of routinely collected data. Identification of risk was based on their age, parity, and disease status (HIV and diabetes). The 2020-2021 cohort had their risk assessed prospectively using the CMDS.\n\nResultsRoutinely collected data from 2015-2017 demonstrated that up to 14.9% of women in Gboko were at risk for mortality or morbidity. The CMDS reported that up to 21.5% of women were at a similar level of risk; a significant difference of 6.6% (p=0.006). The CMDS was more efficient in obtaining and assessing this data, and the identification was available in real-time for midwives and pregnant women.\n\nConclusionRoutine data collected in Gboko identifies a high proportion of pregnant women at risk for mortality or morbidity. The CMDS is an evidence-based risk analysis tool that expands on this assessment by also estimating individual and community-level risk, which allows for more efficient mitigation and prevention strategies of maternal mortality.","Epigenetic aging and perceived psychological stress in old age\nAdverse effects of psychological stress on physical and mental health, especially in older age, are well documented. How perceived stress relates to the epigenetic clock measure, DNA methylation age acceleration (DNAmAA), is less well understood and existing studies reported inconsistent results.\n\nDNAmAA was estimated from five epigenetic clocks (7-CpG, Horvaths, Hannums, PhenoAge and GrimAge DNAmAA). Cohens Perceived Stress Scale (PSS) was used as marker of psychological stress.\n\nWe analyzed data from 1,100 Berlin Aging Study II (BASE-II) participants assessed as part of the GendAge study (mean age = 75.6 years, SD = 3.8 years, 52.1% women).\n\nIn a first step, we replicated well-established associations of perceived stress with morbidity, frailty, and symptoms of depression in the BASE-II cohort studied here. In a second step, we did not find any statistically significant association of perceived stress with any of the five epigenetic clocks in multiple linear regression analyses that adjusted for covariates.\n\nAlthough the body of literature suggests an association between higher DNAmAA and stress or trauma during early childhood, the current study found no evidence for an association of perception of stress with DNAmAA in older people. We discuss possible reasons for the lack of associations and highlight directions for future research.","Nationwide surveillance of methicillin-resistant Staphylococcus aureus isolated from bloodstream infections in Japan in 2019\nSynopsisO_ST_ABSObjectivesC_ST_ABSSome single-centre studies have reported that MRSA carrying the staphylococcal cassette chromosome mec (SCCmec) type IV has been increasing in bloodstream infections (BSIs) in Japan. Therefore, we conducted nationwide surveillance for MRSA BSI to investigate the extent of such change across Japan.\n\nMethodsWe recruited 51 Japanese hospitals from the Japanese Association for Infectious Diseases. MRSA isolates detected in two or more sets of blood cultures were collected between January and September 2019 and subjected to antimicrobial susceptibility testing. Whole-genome sequencing was also performed to determine SCCmec typing and multilocus typing and detect drug-resistance and virulence genes.\n\nResultsTwo hundred seventy MRSA isolates were collected from 45 hospitals. The major combination types were ST8 with SCCmec type IV (ST8-IV) (30.7%), ST1-IV (29.6%), ST2725-IV (9.5%), ST764-II (8.1%), and ST5-II (7.8%). However, there were regional differences among the most major types. The most common types in western, eastern, and northern Japan were ST1-IV, ST8-IV, and ST5-II, respectively. ST8-IV, ST1-IV, and ST2725-IV exhibited greater susceptibility to clindamycin and minocycline than ST764-II and ST5-II, but erm(A) was detected in 93.8% and 100% of ST1-IV and ST2725-IV, respectively. Based on drug-resistance and virulence genes, characteristics of ST8-IV were different from those of ST1-IV and ST2725-IV. In addition, there were two major ST8-IV types with different characteristics.\n\nConclusionsThis study revealed that SCCmec type IV replaced SCCmec type II in MRSA BSI. In addition, SCCmec type IV was divided into several types with different characteristics.","A mixed-methods study of risk factors and experiences of healthcare workers tested for the novel coronavirus in Canada\nObjectivesWe aimed to investigate the contribution of occupational and non-work-related factors to the risk of novel coronavirus (SARS-CoV-2) infection among healthcare workers (HCWs) in Vancouver Coastal Health, British Columbia, Canada. We also aimed to examine how HCWs described their experiences.\n\nMethodsWe conducted a matched case-control study using data from online and phone questionnaires with optional open-ended questions completed by HCWs who sought SARS-CoV-2 testing between March 2020 and March 2021. Conditional logistic regression and thematic analysis were utilized.\n\nResultsData from 1340 HCWs were included. Free-text responses were provided by 257 respondents. Adjusting for age, gender, race, occupation, and number of weeks since pandemic was declared, community exposure to a known COVID-19 case (adjusted odds ratio -aOR: 2.45; 95% CI 1.67-3.59), and difficulty accessing personal protective equipment -PPE- (aOR: 1.84; 95% CI 1.07-3.17) were associated with higher infection odds. Care-aides/licensed practical nurses had substantially higher risk (aOR: 2.92; 95% CI 1.49-5.70) than medical staff who had the lowest risk. Direct COVID-19 patient care was not associated with elevated risk. HCWs experiences reflected the phase of the pandemic when they were tested. Suboptimal communication, mental stress, and situations perceived as unsafe were common sources of dissatisfaction.\n\nConclusionsCommunity exposures and occupation were important determinants of infection among HCWs in our study. The availability of PPE and clear communication enhanced a sense of safety. Varying levels of risk between occupational groups call for wider targeting of infection prevention measures. Strategies for mitigating community exposure and supporting HCW resilience are required.","Tuberculostearic acid, a potential parameter for scoring system construction for Tuberculous meningitis diagnosis\nThis study aimed to validate the value of tuberculostearic acid (TBSA) whether it could implicate the existence of M. tuberculosis and assist for clinical diagnosis of Tuberculous Meningitis (TBM). Gas Chromatography/mass spectrometry was used to detect TBSA in the chemically pretreated cerebrospinal fluid of suspected TBM patients. In total, 140 patients were admitted for our study included 27 confirm TBM patients and 50 TBSA positive patients. Sensitivity of 0.7407 (CI 95%: 0.5372-0.8889) and specificity of 0.7345 (CI 95%: 0.6432-0.8132) were calculated. The Lancet consensus scoring system was also applied to evaluate the possibility of TBM in suspected patients, finding that TBSA positive patients showed a similar distributive grouping as the definite TBM patients. Our study implicates that the prospective use of TBSA is worth combining into a scoring system for characterizing the features of Mtb, showing a great potential of TBM diagnosis by TBSA in the future.","IL-1 and IL-6 inhibitor hypersensitivity link to common HLA-DRB1*15 alleles\nIn Saper et al (2019), we described systemic JIA patients who developed a high-fatality diffuse lung disease (DLD) while on IL-1 or IL-6 inhibitors. We observed severe delayed drug hypersensitivity reactions (DHR) in a significant subset. Because alleles of the human leukocyte antigen (HLA) loci can mediate DHR, we investigated HLA genotype association with these DHR. We typed subjects treated with these inhibitors: 34 sJIA/DHR/DLD, 11 sJIA/DHR without DLD, 18 drug-tolerant sJIA, and 19 Kawasaki disease (KD) patients in an anti-IL-1(anakinra) trial. We also accessed genotypes from a large sJIA case/control cohort.\n\nWe first compared White subjects with sJIA/DHR to 550 ancestry-matched sJIA subjects. We found striking enrichments of HLA-DRB1*15:01, HLA-DQA1*01:02, and DQB1*06:02, alleles in near-complete linkage (White individuals). HLA-DRB 1*15:01 (as haplotype proxy) was increased in White sJIA subjects with DHR/DLD versus sJIA drug-tolerant controls and was observed upon inclusion of sJIA+DHR-only and KD+DHR White subjects. In our entire cohort regardless of ancestry, 75% carried HLA-DRB 1*15:01 or the structurally related DRB1*15:03 and DRB1*15:06, which were absent among drug-tolerant subjects (p=5 x 10-13; Odds Ratio lower bound=20.11).\n\nPatients who harbor HLA-DRB1*15 alleles are at high risk of developing DHR to anti-IL-1/IL-6. Our data also suggest DHR maybe a trigger/enhancer of DLD in sJIA patients and support performing prospective HLA screening in sJIA, its adult-onset counterpart, and other inflammatory conditions where these drugs are used, such as KD.","Assessment of private variants in PRKN, PARK7 and PINK1 in Parkinson's disease\nRecessive mutations in PRKN, PARK7 and PINK1 are established causes of early-onset Parkinsons disease (EOPD). Previous studies have interrogated the role of heterozygous variants in these genes but mainly focused on rare (minor allele frequency [MAF] <1%) damaging variants or established mutations. Here, we assessed heterozygous private PRKN, PARK7 and PINK1 variants in PD risk in four large-scale PD case-control datasets by performing gene-wise burden analyses using sequencing data totaling 5,829 PD cases and 7,221 controls, and summary allele counts from 9,501 PD cases and 48,207 controls. Results showed no significant burden in all three genes after meta-analyses. Burden in EOPD (age at onset <50 years) and late-onset PD ([≥]50 years) remained nonsignificant. In summary, we found no evidence to support the association of the excess burden of heterozygous private variants in PRKN, PARK7, and PINK1 with PD risk in the European population. Larger, more diverse cohorts are needed to accurately determine their role in PD.","The Anorexia Nervosa Care Pathway: Closing the Treatment Gap to Improve Care for Patients Admitted to Medical Hospitals\nIntroductionMedical complications of malnutrition and refeeding account for approximately half of deaths in anorexia nervosa (AN). The AN Care Pathway (ANCP) was introduced at our institution in 2016 to improve quality of care of patients admitted for medical observation and management. We report results from our review of medical complications and report the impact and adoption of the ANCP.\n\nMethodsThe ANCP was developed in response to a need to improve quality of medical monitoring of patients with severe AN using Squire Guidelines and the Plan-Do-Study-Act cycle. All patients admitted to a medical hospital with AN between 2010-2020 were included after hospital inpatient enquiry and medical records were reviewed. Descriptive statistics were calculated using Stata (Statcorp).\n\nResultsFifty-one patients (63 admissions) were included. Median BMI was 13.8 kg/m (11.9-22.5). After ANCP implementation in 2016, compliance with recommended daily ECG, thiamine and blood tests improved from 30% (n=8/27) to 86% (n=21/36). We report a high rate of medical complications of severe AN including anaemia (n=24, 47%), neutropoenia (n=18, 35%), abnormal liver bloods (n=15, 29%) and half developed refeeding syndrome. One-third patients had cardiovascular compromise including reduced cardiac contractility (n=13, 25%), pericardial effusion (n=7, 14%) and one death. Low BMI was associated with cardiovascular complications (mean BMI 13.5 kg/m vs 15.5 kg/m, p=0.01) and neutropoenia (mean BMI 13.4 kg/m vs 15.4 kg/m, p=0.02).\n\nConclusionIntroduction of the ANCP improved quality of care during medical stabilisation. We report a high rate of medical complications of severe AN in patients admitted to a medical hospital. Use of multidisciplinary care protocols may contribute to quality improvement and improved consistency of care for this vulnerable population.","Prolonged SARS-CoV-2 RNA virus shedding and lymphopenia are hallmarks of COVID-19 in cancer patients with poor prognosis\nPatients with cancer are at higher risk of severe coronavirus infectious disease 2019 (COVID-19), but the mechanisms underlying virus-host interactions during cancer therapies remain elusive. When comparing nasopharyngeal swabs from cancer and non-cancer patients for RT-qPCR cycle thresholds measuring acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 1063 patients (58% with cancer, 89% COVID-19+), we found that malignant disease favors the magnitude and duration of viral RNA shedding concomitant with prolonged serum elevations of type 1 IFN that anticorrelated with anti-RBD IgG antibodies. Chronic viral RNA carriers exhibited the typical immunopathology of severe COVID-19 at the early phase of infection including circulation of immature neutrophils, depletion of non-conventional monocytes and a general lymphopenia that, however, was accompanied by a rise in plasmablasts, activated follicular T helper cells, and non-naive Granzyme B+ FasL+, EomehighTCF-1high, PD-1+CD8+ Tc1 cells. Virus-induced lymphopenia worsened cancer-associated lymphocyte loss, and low lymphocyte counts correlated with chronic SARS-CoV-2 RNA shedding, COVID-19 severity and a higher risk of cancer-related death in the first and second surge of the pandemic. Lymphocyte loss correlated with significant changes in metabolites from the polyamine and biliary salt pathways as well as increased blood DNA from Enterobacteriaceae and Micrococcaceae gut family members in long term viral carriers. We surmise that cancer therapies may exacerbate the paradoxical association between lymphopenia and COVID-19-related immunopathology, and that the prevention of COVID-19-induced lymphocyte loss may reduce cancer-associated death.","Molecular Mechanism of Parosmia\nThe molecular stimuli that trigger a parosmic response have been identified. Parosmia is a debilitating disease in which familiar smells become distorted and unpleasant. Often a result of post infectious smell loss, incidences are increasing as the number of COVID-19 cases escalates worldwide. Little is understood of its pathophysiology, but the prevailing hypothesis for the underlying mechanism is a mis-wiring of olfactory sensory neurons. We identified 15 different molecular triggers in coffee using GC-Olfactometry as a relatively rapid screening tool for assessment of both quantitative olfactory loss and parosmia. This provides evidence for peripheral causation, but places constraints on the mis-wiring theory.","The influence of baseline clinical status and surgical strategy on early good to excellent result in spinal lumbar arthrodesis: a machine learning approach\nAimsTo create, using a machine learning (ML) approach, a preoperative model from baseline demographic and health-related quality of life scores (HRQOL) to predict a good to excellent early clinical outcome.\n\nPatients and MethodsA single spine surgery center retrospective review of prospectively collected data from January 2016 to December 2020 from the institutional registry (SpineREG) was performed. The inclusion criteria were age [≥] 18 years, both sexes, lumbar arthrodesis procedure, a complete follow up assessment (ODI, SF-36 and COMI back) and the capability to read and understand the Italian language. A delta of improvement of the ODI higher than 12.7/100 was considered a \"good early outcome\". A combined target model of ODI ({Delta} [≥] 12.7/100), SF-36 PCS ({Delta} [≥] 6/100) and COMI back ({Delta} [≥] 2.2/10) was considered an \"excellent early outcome\". The performance of the ML models was evaluated in terms of sensitivity, i.e., True Positive Rate (TPR), specificity, i.e., True Negative Rate (TNR), accuracy and area under the receiver operating characteristic curve (AUC ROC).\n\nResultsA total of 1243 patients were included in this study. The model for predicting ODI at 6 months follow up showed a good balance between sensitivity (74.3%) and specificity (79.4%), while providing a good accuracy (75.8%) with ROC AUC = 0.842. The combined target model showed a sensitivity of 74.2% and specificity of 71.8%, with an accuracy of 72.8%, and a ROC AUC = 0.808.\n\nConclusionThe results of our study suggest that a machine learning approach showed high performance in predicting early good to excellent clinical results.","Patient-specific forecasting of post-radiotherapy prostate-specific antigen kinetics enables early prediction of biochemical relapse\nThe detection of prostate cancer recurrence after external beam radiotherapy relies on the measurement of a sustained rise of serum prostate-specific antigen (PSA). However, this biochemical relapse may take years to occur, thereby delaying the delivery of a secondary treatment to patients with recurring tumors. To address this issue, here we propose to use patient-specific forecasts of PSA dynamics to early predict biochemical relapse. Our forecasts are based on mechanistic models of prostate cancer response to external beam radio-therapy, which are fit to patient-specific PSA data collected during standard post-treatment monitoring. Our results show a remarkable performance of our models in recapitulating the observed changes in PSA and yielding short-term predictions over approximately one year (cohort median RMSE of 0.10 to 0.47 ng/mL and 0.13 to 1.41 ng/mL, respectively). Additionally, we identify three model-based biomarkers that enable an accurate identification of biochemical relapse (AUC > 0.80) significantly earlier than standard practice (p < 0.01).","A novel morphometric signature of brain alterations in type 2 diabetes: patterns of changed cortical gyrification\nType 2 diabetes is a chronic disease that creates atrophic signatures in the brain, including decreases of total and regional volume of grey matter, white matter, and cortical thickness. However, there is a lack of studies assessing cortical gyrification in type 2 diabetes. Changes in this emerging feature has been associated mainly with genetic legacy, but environmental factors may also play a role. Here, we investigated alterations of the gyrification index and classical morphometric measures in type 2 diabetes, a disease with complex etiology with both underlying genetic and more preponderant environmental factors.\n\nIn this cross-sectional study we analyzed brain anatomical magnetic resonance images of 86 participants with type 2 diabetes and 40 healthy control participants, to investigate structural alterations in type 2 diabetes, including whole-brain volumetric measures, local alterations of grey matter volume, cortical thickness and the gyrification index.\n\nWe found concordant significant decrements in total and regional grey matter volume, and cortical thickness. Surprisingly, the cortical gyrification index was found to be mainly increased in cortical sensory areas in type 2 diabetes. Moreover, it correlated with features of metabolic control. Our findings challenge the classical neurodevelopmental association of gyrification mostly with genetic determinants. While we found mainly increased gyrification in more genetically constrained sensory areas in type 2 diabetes, our correlation results concurrently suggest an influence of metabolic control in alterations of gyrification in type 2 diabetes. Further studies should address causal influences of genetic and/or environmental factors in patterns of cortical gyrification in type 2 diabetes.","Methylome analysis for prediction of long and short-term survival in glioblastoma patients from the Nordic trial\nPatients with glioblastoma (GBM) have a short survival, but even among patients receiving the same therapies and with good prognostic factors, one can find those with exceptionally short and long survival.\n\nIn the Nordic trial, patients with GBM, 60 years or older, were randomized between 2 radiotherapy arms or TMZ. We selected 59 patients, equally distributed between the 3 treatment arms and MGMT promoter methylation status, with good prognostic factors, but with short or long survival. We performed methylation profiling with the Illumina Infinium Methylation EPIC BeadChip arrays in conjunction with a methylation-based CNS tumor classifier, analysis of differentially methylated CpG sites (DMCs) and pathway enrichment analysis.\n\nSamples classified as non-GBM IDH wildtype were excluded and in the analysis of long vs. short survivors with documented progression or tumor-related death, we found DMCs in the TMZ, MGMT promoter methylated group (123,510), as well as in the 60Gy, MGMT promoter unmethylated group (4,086) and 34Gy, MGMT promoter methylated group (39,649). The joint analysis of the RT arms revealed 319 DMCs in the MGMT unmethylated group but no differences for MGMT promoter methylated samples, or in any of the analyses independent of MGMT status. Interestingly, in the long-term survivors with methylated MGMT promoter treated with TMZ we found hypermethylation of the Wnt signaling and the platelet activation, signaling and aggregation pathways.\n\nWe identified DMCs for both TMZ and RT treated patients. Further systematic analysis of larger patient cohorts is necessary for confirmation of their predictive properties.","Calculating variant penetrance using family history of disease and population data\nPurposeGenetic penetrance is the probability of a phenotype manifesting if one harbours a specific pathogenic variant. For most Mendelian genes, penetrance is incomplete and may be age-dependent. Accurate penetrance estimates are important in many biomedical fields including genetic counselling, disease research, and for gene therapy. The main methods for its estimation are limited in situations where large family pedigrees are not available, the disease is rare, late onset, or complex.\n\nMethodsHere we present a novel method for penetrance estimation in autosomal dominant phenotypes. It uses population-scale data regarding the distribution of a variant among unrelated people affected (cases) and unaffected (controls) by an associated phenotype and can be operated using samples of affected people only by considering family disease history.\n\nResultsThe method is validated within simulation studies. Candidate variant-disease case studies yield estimates which align with existing disease knowledge and estimates derived using established methods.\n\nConclusionWe have presented a valid method for penetrance estimation in autosomal dominant traits which avoids kinship-specific penetrance estimates and the ascertainment biases that can arise when sampling rare variants among control populations. It can be accessed from our public web server (https://adpenetrance.rosalind.kcl.ac.uk) and is available as an open-source R library (https://github.com/ThomasPSpargo/adpenetrance).","Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein\nPurposeAlthough haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized the clinical, molecular and functional spectra of ANKRD11 missense variants.\n\nMethodsWe collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants by in silico analyses and cell-based experiments.\n\nResultsWe identified 29 individuals with (mostly de novo) ANKRD11 missense variants, who presented with syndromic neurodevelopmental disorders and were phenotypically similar to individuals with KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in Repression Domain 2. Cellularly, most variants caused reduced ANKRD11 stability. One variant resulted in decreased proteasome degradation and loss of ANKRD11 transcriptional activity.\n\nConclusionOur study indicates that pathogenic heterozygous missense variants in ANKRD11 cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges, as the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping.","Predictors for participation in DNA self-sampling of childhood cancer survivors in Switzerland\nResearch on germline genetic variants relies on a sufficient number of eligible participants which is difficult to achieve for rare diseases such as childhood cancer. With self-collection kits using saliva or buccal swabs, participants can contribute genetic samples conveniently from their home. We identified determinants of participation in DNA self-collection in this cross-sectional study.\n\nWe invited 928 childhood cancer survivors in Switzerland with a median age of 26.5 years (interquartile range 18.8-36.5), of which 463 (50%) participated. Foreign nationality (odds ratio [OR] 0.5, 95%-confidence interval [CI] 0.4-0.7), survivors aged 30-39 years at study versus other age groups (OR 0.5, CI 0.4-0.8), and those with a known cancer predisposition syndrome (OR 0.5, CI 0.3-1.0) participated less. Survivors with a second primary neoplasm (OR 1.9, CI 1.0-3.8) or those living in a French or Italian speaking region (OR 1.3, 1.0-1.8) tended to participate more.\n\nWe showed that half of survivors participate in germline DNA self-sampling relying completely on mailing of sample kits. Foreign nationality, age 30-39 years, and cancer predisposition syndromes were associated with less participation. More targeted recruitment strategies may be advocated for these subgroups. To increase participation in DNA self-sampling, understanding and perceptions of survivors need to be better understood.","Association between telecommuting environment and low back pain among Japanese telecommuting workers: A cross-sectional study\nObjectivesWe evaluated the relationship between telecommuting environment and low back pain (LBP) among desk-based workers in Japan.\n\nMethodsThis cross-sectional study included 3,663 desk-based, telecommuting workers. LBP was assessed using a 0-10 numerical rating scale. The telecommuting environment was evaluated using subjective questions. Mixed-effects logistic regression analysis was used to evaluate this association.\n\nResultsThe results of mixed-effects logistic model revealed that not having a place or room to concentrate on work, desk not well-lit enough for work, lack of space on the desk to work, not having enough legroom, and uncomfortable temperature and humidity conditions in the workspace were significantly associated with higher odds of LBP.\n\nConclusionsOur findings suggest that telecommuting environment is associated with the prevalence of LBP.","NEW CORONAVIRUS IN PREGNANT WOMEN. Maternal and perinatal outcomes.\nObjectivesTo report the maternal and neonatal results of patients infected with COVID-19 in Panama.\n\nMethodsThe study is based on the analysis of pregnant women with COVID-19, in 5 hospitals in the Republic of Panama. The inclusion criteria were: Patients with or without symptoms, positive RT-PCR for SARS-CoV-2 in the period from March 23 to 6 months after, whose births were attended in one of those 5 hospitals and who signed the consent. Data was obtained at the time of diagnosis of the infection and at the time of termination of pregnancy for the mother and newborn.\n\nResults253 patients met the inclusion criteria. Most were diagnosed in the third trimester (89.3%). 10.3% of the patients presented in a severe form of COVID-19. The most frequent complication was pre-eclampsia and if we add gestational hypertension they represent 21.2%; most of the patients terminated the pregnancy by caesarean section (58%). 26.9% (95% CI 21.3-32.9%) of the births were premature, and perinatal mortality was 5.4% (95% CI 3.0-9.0%). There was a need for mechanical ventilation in 5.9% (95% CI 3.6-9.6%) of the cohort and there were four maternal deaths (1.6% - 95% CI 0.6-4.0%).\n\nConclusionsThis study of pregnant women infected with COVID-19 and diagnosed with RT-PCR shows serious maternal complications such as high admission to the ICU, need for mechanical ventilation and one death in every 64 infected. Frequent obstetric complications such as hypertension, premature rupture of membranes, high rate of prematurity and perinatal lethality were also seen.","Social connectedness as a determinant of mental health: A scoping review\nPublic health and epidemiologic research have established that social connectedness promotes overall health. Yet there have been no recent reviews of findings from research examining social connectedness as a determinant of mental health. The goal of this review was to evaluate recent longitudinal research probing the effects of social connectedness on depression and anxiety symptoms and diagnoses in the general population. A scoping review was performed of PubMed and PsychInfo databases from January 2015 to December 2020 following PRISMA-ScR guidelines using a defined search strategy. The search yielded 56 articles representing 52 unique studies. In research with other than pregnant women, 84% (16 of 19) studies reported that social support benefited symptoms of depression with the remaining 16% (3 of 19) reporting minimal or no evidence that lower levels of social support predict depression at follow-up. In research with pregnant women, 80% (21 of 26 studies) found that low social support increased postpartum depressive symptoms. Among 3 of 4 studies that focused on loneliness, feeling lonely at baseline was related to adverse outcomes at follow-up including higher risks of major depressive disorder, depressive symptom severity, generalized anxiety disorder, and lower levels of physical activity. In 5 of 7 reports, smaller social network size predicted depressive symptoms or disorder at follow-up. In summary, most recent relevant longitudinal studies have demonstrated that social support protects adults in the general population from depressive symptoms and disorders. The results, which were largely consistent across settings, exposure measures, and populations, support efforts to improve clinical detection of high-risk patients, including adults with low social support and elevated loneliness.","Predictability and Stability Testing to Assess Clinical Decision Instrument Performance for Children After Blunt Torso Trauma\nObjectiveThe Pediatric Emergency Care Applied Research Network (PECARN) has developed a clinical-decision instrument (CDI) to identify children at very low risk of intra-abdominal injury. However, the CDI has not been externally validated. We sought to vet the PECARN CDI with the Predictability Computability Stability (PCS) data science framework, potentially increasing its chance of a successful external validation.\n\nMaterials & MethodsWe performed a secondary analysis of two prospectively collected datasets: PECARN (12,044 children from 20 emergency departments) and an independent external validation dataset from the Pediatric Surgical Research Collaborative (PedSRC; 2,188 children from 14 emergency departments). We used PCS to reanalyze the original PECARN CDI along with new interpretable PCS CDIs we developed using the PECARN dataset. External validation was then measured on the PedSRC dataset.\n\nResultsThree predictor variables (abdominal wall trauma, Glasgow Coma Scale Score <14, and abdominal tenderness) were found to be stable. Using only these variables, we developed a PCS CDI which had a lower sensitivity than the original PECARN CDI on internal PECARN validation but performed the same on external PedSRC validation (sensitivity 96.8% and specificity 44%).\n\nConclusionThe PCS data science framework vetted the PECARN CDI and its constituent predictor variables prior to external validation. In this case, the PECARN CDI with 7 predictors, and our PCS-based CDI with 3 stable predictors, had identical performance on independent external validation. This suggests that both CDIs will generalize well to new populations, offering a potential strategy to increase the chance of a successful (costly) prospective validation.","Delirium and Neuropsychological Outcomes in Critically Ill Patients with COVID-19: an Institutional Case Series\nObjectiveTo characterize the clinical course of delirium for COVID-19 patients in the intensive care unit, including post-discharge cognitive outcomes.\n\nPatients and MethodsA retrospective chart review was conducted for patients diagnosed with COVID-19 (n=148) admitted to an intensive care unit at Michigan Medicine between March 1, 2020 and May 31, 2020. A validated chart review method was used to identify presence of delirium, and various measures (e.g., Family Confusion Assessment Method, Short Blessed Test, Patient-Health Questionnaire-9) were used to determine neuropsychological outcomes between 1-2 months after hospital discharge.\n\nResultsDelirium was identified in 108/148 (73%) patients in the study cohort, with median (interquartile range) duration lasting 10 (4 - 17) days. In the delirium cohort, 50% (54/108) of patients were African American, and delirious patients were more likely to be female (76/108, 70%) (absolute standardized differences >.30). Sedation regimens, inflammation, deviation from delirium prevention protocols, and hypoxic-ischemic injury were likely contributing factors, and the most common disposition for delirious patients was a skilled care facility (41/108, 38%). Among patients who were delirious during hospitalization, 4/17 (24%) later screened positive for delirium at home based on caretaker assessment, 5/22 (23%) demonstrated signs of questionable cognitive impairment or cognitive impairment consistent with dementia, and 3/25 (12%) screened positive for depression within two months after discharge.\n\nConclusionPatients with COVID-19 commonly experience a prolonged course of delirium in the intensive care unit, likely with multiple contributing factors. Furthermore, neuropsychological impairment may persist after discharge.","FastMix: A Versatile Multi-Omics Data Integration Pipeline for Cell Type-Specific Biomarker Inference\nWe developed a novel analytic pipeline - FastMix - to integrate flow cytometry, bulk transcriptomics, and clinical covariates for statistical inference of cell type-specific gene expression signatures. FastMix addresses the \"large p, small n\" problem via a carefully designed linear mixed effects model (LMER), which is applicable for both cross-sectional and longitudinal studies. With a novel moment-based estimator, FastMix runs and converges much faster than competing methods for big data analytics. The pipeline also includes a cutting-edge flow cytometry data analysis method for identifying cell population proportions. Simulation studies showed that FastMix produced smaller type I/II errors with more accurate parameter estimation than competing methods. When applied to real transcriptomics and flow cytometry data in two vaccine studies, FastMix-identified cell type-specific signatures were largely consistent with those obtained from the single cell RNA-seq data, with some unique interesting findings.","Deep brain stimulation in the bed nucleus of the stria terminalis: A symptom provocation study in patients with obsessive-compulsive disorder\nBackgroundDeep brain stimulation (DBS) is an emerging therapy for treatment-resistant obsessive-compulsive disorder (OCD), and several targets for electrode implantation and contact selection have been proposed, including the bed nucleus of the stria terminalis (BST). Selecting the active electrode contacts (patients typically have four to choose from in each hemisphere), and thus the main locus of stimulation, can be a taxing process. Here, we investigated whether contact selection based purely on their neuroanatomical position in the BST is a worthwhile approach. For the first time, we also compared the effects of uni- versus bilateral BST stimulation.\n\nMethodsNine OCD patients currently receiving DBS participated in a double-blind, randomized symptom provocation study to compare no versus BST stimulation. Primary outcomes were anxiety and mood ratings in response to disorder-relevant trigger images, as well as ratings of obsessions, compulsions, tendency to avoid and overall wellbeing. Furthermore, we asked whether patients preferred the electrode contacts in the BST over their regular stimulation contacts as a new treatment setting after the end of the task.\n\nResultsWe found no statistically significant group differences between the four conditions (no, left, right and bilateral BST stimulation). Exploratory analyses, as well as follow-up data, did indicate that (bilateral) bipolar stimulation in the BST was beneficial for some patients, particularly for those who had achieved unsatisfactory effects through the typical contact selection procedure.\n\nConclusionsDespite its limitations, this study suggests that selection of stimulation contacts in the BST is a viable option for DBS in treatment-resistant OCD patients.","COVID-19 Prevention Facilitators and Barriers among Specific Ethnic Minority Communities in Rural Ohio\nObjectiveTo assess knowledge, beliefs, and behaviors concerning COVID-19 among Guatemalan, Marshallese, and Amish populations in rural Ohio; identify individual, interpersonal, community, and structural level challenges within each community; and provide population-specific recommendations to prevent and mitigate further SARS-CoV-2 transmission among these rural communities.\n\nMethodsWe conducted 30 key informant interviews in four rural counties in Ohio, in May 2020. Three teams of two investigators conducted interviews with local health department staff, community members, meat packing plant management, and community leaders from three communities disproportionately affected by the COVID-19 pandemic [Guatemalan (N=12), Marshallese (N=7), Amish (N=11)]. We used the Social Ecological Model to identify and categorize themes.\n\nResultsEmerging and overall themes were identified and defined. Investigators identified COVID-19 knowledge gaps, myths, and misinformation, food insecurity, community cohesion, stigma, community culture and norms, lack of workplace safety policies, and access to testing as key themes to COVID-19 prevention.\n\nConclusionsUnderstanding specific barriers and identifying facilitators that most effectively provide resources, healthcare services, education, and social support tailored to specific communities would help deter SARS-CoV-2 transmission.","Biallelic and de novo variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy\nThe vacuolar H+-ATPase is a large multi-subunit proton pump, composed of an integral membrane V0 domain, involved in proton translocation, and a peripheral V1 domain, catalysing ATP hydrolysis. This complex is widely distributed on the membrane of various subcellular organelles, such as endosomes and lysosomes, and plays a critical role in cellular processes ranging from autophagy to protein trafficking and endocytosis. Variants in ATP6V0A1, the brain-enriched isoform in the V0 domain, have been recently associated with developmental delay and epilepsy in four individuals. Here we identified 17 individuals from 14 unrelated families with both with new and previously characterised variants in this gene, representing the largest cohort to date. Five affected subjects with biallelic variants in this gene presented with a phenotype of early-onset progressive myoclonus epilepsy with ataxia, while 12 individuals carried de novo missense variants and showed severe developmental and epileptic encephalopathy. The R740Q mutation, which alone accounts for almost 50% of the mutations identified among our cases, leads to failure of lysosomal hydrolysis by directly impairing acidification of the endolysosomal compartment, causing autophagic dysfunction and severe developmental defect in C. elegans. Altogether, our findings further expand the neurological phenotype associated with variants in this gene and provide a direct link with endolysosomal acidification in the pathophysiology of ATP6V0A1-related conditions.","A Randomized Trial of Otilimab in Severe COVID-19 Pneumonia (OSCAR)\nBACKGROUNDIncreasing age is a risk factor for COVID-19 severity and mortality; emerging science implicates GM-CSF and dysregulated myeloid cell responses in the pathophysiology of severe COVID-19.\n\nMETHODSWe conducted a large, global, double-blind, randomized, placebo-controlled study evaluating a single 90 mg infusion of otilimab (human anti-GM-CSF monoclonal) plus standard of care in adults hospitalized with severe COVID-19 respiratory failure and systemic inflammation, stratified by age and clinical status. Primary outcome was the proportion of patients alive and free of respiratory failure at Day 28; secondary endpoints included all-cause mortality at Day 60.\n\nRESULTSOverall, 806 patients were randomized (1:1); 71% of patients receiving otilimab were alive and free of respiratory failure at Day 28 versus 67% receiving placebo, although this did not reach statistical significance (model-adjusted difference 5.3% [95% CI -0.8, 11.4]; p=0.09). However, there was a benefit in the pre-defined [≥]70-year age group (model-adjusted difference 19.1% [95% CI 5.2, 33.1]; nominal p=0.009); these patients also had a reduction of 14.4% (95% CI 0.9, 27.9%; nominal p=0.04) in model-adjusted all-cause mortality at Day 60. Safety findings were comparable between otilimab and placebo, and consistent with severe COVID-19.\n\nCONCLUSIONSAlthough not statistically significant in the overall population, otilimab demonstrated a substantial benefit in patients aged [≥]70, possibly reflecting a population that could benefit from therapeutic blocking of GM-CSF in severe COVID-19 where myeloid cell dysregulation is predominant. These findings are being confirmed in a further cohort of patients aged [≥]70 in Part 2 of this study. (ClinicalTrials.gov number: NCT04376684).","Repeated introductions and intensive community transmission fueled a mumps virus outbreak in Washington State\nIn 2016/2017, Washington State experienced a mumps outbreak despite high childhood vaccination rates, with cases more frequently detected among school-aged children and members of the Marshallese community. We sequenced 166 mumps virus genomes collected during outbreaks in Washington and other US states, and apply phylodynamic approaches to trace mumps introductions and transmission within Washington. We uncover that mumps was introduced into Washington at least 13 times, primarily from Arkansas, sparking multiple co-circulating transmission chains. Neither vaccination status nor age were strong determinants of transmission. Instead, the outbreak in Washington was overwhelmingly sustained by transmission within the Marshallese community. Our findings underscore the utility of genomic data to clarify epidemiologic factors driving transmission, and pinpoint contact networks as critical determinants of mumps transmission. These results imply that contact structures and historic disparities may leave populations at increased risk for respiratory virus disease even when a vaccine is effective and widely used.","Longitudinal changes in physical activity during and after the first national lockdown due to the COVID-19 pandemic in England\nBackgroundRecent studies have shown reduced physical activity at early stages of the COVID-19 pandemic. However, there is a lack of investigation on longitudinal changes in physical activity beyond lockdowns and stay at home orders. Moreover, it is unclear if there is heterogeneity in physical activity growth trajectories. This study aimed to explore longitudinal patterns of physical activity and factors associated with them.\n\nMethodsData were from the UCL COVID -19 Social Study. The analytical sample consisted of 35,915 adults in England who were followed up for 22 weeks from 24th March to 23rd August 2020. Data were analysed using growth mixture models.\n\nFindingsOur analyses identified six classes of growth trajectories, including three stable classes showing little change over time (62.4% in total), two classes showing decreasing physical activity (28.6%), and one class showing increasing physical activity over time (9%). A range of factors were found to be associated the class membership of physical activity trajectories, such as age, gender, education, income, employment status, and health.\n\nInterpretationThere is substantial heterogeneity in longitudinal changes in physical activity during the COVID-19 pandemic. However, a substantial proportion of our sample showed persistent physical inactivity or decreasing physical activity. Given the well-established linked between physical activity and health, persistent or increased physical inactivity is likely to have both immediate and long-term implications for peoples physical and mental health, as well as general wellbeing. More efforts are needed to promote physical activity during the pandemic and beyond.\n\nFundingNuffield Foundation, UK Research and Innovation, Wellcome Trust","Quality control and removal of technical variation of NMR metabolic biomarker data in ~120,000 UK Biobank participants\nMetabolic biomarker data quantified by nuclear magnetic resonance (NMR) spectroscopy has recently become available in UK Biobank. Here, we describe procedures for quality control and removal of technical variation for this biomarker data, comprising 249 circulating metabolites, lipids, and lipoprotein sub-fractions on approximately 121,000 participants. We identify and characterise technical and biological factors associated with individual biomarkers and find that linear effects on individual biomarkers can combine in a non-linear fashion for 61 composite biomarkers and 81 biomarker ratios. We create an R package, ukbnmr, for extracting and normalising the metabolic biomarker data, then use ukbnmr to remove unwanted variation from the UK Biobank data. We make available code for re-deriving the 61 composite biomarkers and 81 ratios, and for further derivation of 76 additional biomarker ratios of potential biological significance. Finally, we demonstrate that removal of technical variation leads to increased signal for genetic and epidemiological studies of the NMR metabolic biomarkers in UK Biobank.","Impact of low-dose intrathecal morphine on orthopedic surgery: a protocol of a systematic review and meta-analysis of randomized controlled trials\nIntroductionPatients undergoing orthopedic surgery usually suffer considerably from peri-operative pain and intrathecal morphine (ITM) has recently been used as an effective analgesic method. The intrathecal morphine dose achieving optimal analgesia for orthopedic surgery while minimizing side effects has not yet been determined. There is currently a lack of literature synthesis on the safety and effects of low-dose ITM on orthopedic surgery.\n\nMethods and analysisA thorough literature search will be performed on multiple electronic databases and trial registries until January 11th 2022, and reference lists will be examined. Two independent reviewers will select studies, extract data and assess the risk of bias and quality of the included studies. We will select randomized controlled trials comparing low-dose ITM (<100g) with high-dose ITM (<200g) or placebo treatment or other comparatives. We will assess the risk of bias using the Cochrane risk of bias tool and Jadad score will be applied to assess the quality of each included trial. We will also use Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) to determine the confidence in effect estimates. Publication bias will be evaluated by visually inspecting funnel plots and Egger regression asymmetry test in estimations of more than 10 trials. Standard meta-analysis will be performed using R package meta.\n\nEthics and disseminationThe results of this systematic review and meta-analysis will be disseminated through peer-reviewed journal and related conferences. The data used in this meta-analysis will not contain individual patient data and ethical approval is therefore not required.","Multi-cohort transcriptomic subtyping of B-cell acute lymphoblastic leukemia\nAcute lymphoblastic leukemia (ALL) is the most common childhood cancer and comprises multiple genetically distinguishable subtypes. To detect subtypes, current pipelines include fusion calling, polymorphisms, candidate gene copy numbers and cytogenetics but these approaches have limitations. RNA-seq provides a functional genome-wide snapshot that enables classification of ALL subtypes, however, typical mRNA-seq clustering analyses lack the rigor of quantitative modelling. Furthermore, high-dimensional gene expression data across cohorts and countries contain biases that previous transcriptomics studies have not addressed. Our aim was to integrate easy-to-interpret reliable transcriptome-wide biomarkers into subtyping pipelines. We analyzed 2,046 samples from two continents, carefully adjusted for biases and applied a rigorous machine learning design with independent replication. Six ALL subtypes that covered 32% of patients were robustly detected by mRNA-seq (PPV [≥] 87%). Five other frequent subtypes were distinguishable in 40% of patients, although overlapping transcriptional profiles led to lower accuracy (52% [≤] PPV [≤] 73%). Based on these findings, we developed the Allspice tool that predicts ALL subtypes and driver genes from unadjusted mRNA-seq read counts as encountered in real-world settings. Allspice also includes quantitative classification and safety metrics to help determine the most plausible genetic drivers for cases where other findings are inconclusive.","Alpha-1 adrenoreceptor antagonism mitigates extracellular mitochondrial DNA accumulation in lung fibrosis models and in patients with IPF\nIdiopathic Pulmonary Fibrosis is increasingly associated with adrenergic innervation and endogenous innate immune ligands such as mitochondrial DNA (mtDNA). Interestingly, a connection between these entities has not been explored. Here we report that noradrenaline (NA) derived from the lungs adrenergic nerve supply drives the accumulation of SMA-expressing fibroblasts via a mechanism involving 1 adrenoreceptors and mtDNA. Using the bleomycin model of lung fibrosis we compared the effect of lung specific adrenergic denervation achieved via the inhalational administration of the sympathetic neurotoxin 6-hydroxydopamine to surgically mediated adrenal ablation and found that NA derived from local but not adrenal sources drives lung fibrosis. Bleomycin induced the appearance of a SMA+ fibroblast population co-expressing the adrenoreceptor alpha-1D (ADRA1D). Therapeutic delivery of the 1 adrenoreceptor antagonist terazosin reversed these changes and suppressed the accumulation of extracellular mtDNA. TGF{beta}1-stimulated normal human lung fibroblasts treated with TGF{beta}1 and Noradrenaline expressed ADRA1D and developed reduced SMA expression and extracellular mtDNA concentrations when treated with terazosin. IPF patients prescribed 1 adrenoreceptor antagonists for non-pulmonary indications showed improved survival and reduced concentrations of plasma mtDNA. These findings link nerve-derived NA and 1 adrenoreceptor antagonism with mtDNA accumulation and lung fibrogenesis in mouse models, cultured cells, and humans with IPF. Further study of this neuro-innate connection may yield new avenues for investigation in the clinical and basic science realms.","Fusion of Imaging and Non-Imaging Data for Disease Trajectory Prediction for COVID-19 Patients\nABSTRCATO_ST_ABSPurposeC_ST_ABSThis study investigates whether graph-based fusion of imaging data with non-imaging EHR data can improve the prediction of disease trajectory for COVID-19 patients, beyond the prediction performance of only imaging or non-imaging EHR data.\n\nMaterials and MethodsWe present a novel graph-based framework for fine-grained clinical outcome prediction (discharge, ICU admission, or death) that fuses imaging and non-imaging information using a similarity-based graph structure. Node features are represented by image embedding and edges are encoded with clinical or demographic similarity.\n\nResultsOur experiments on data collected from Emory Healthcare network indicate that our fusion modeling scheme performs consistently better than predictive models using only imaging or non-imaging features, with f1-scores of 0.73, 0.77, and 0.66 for discharge from hospital, mortality, and ICU admission, respectively. External validation was performed on data collected from Mayo Clinic. Our scheme highlights known biases in the model prediction such as bias against patients with alcohol abuse history and bias based on insurance status.\n\nConclusionThe study signifies the importance of fusion of multiple data modalities for accurate prediction of clinical trajectory. Proposed graph structure can model relationships between patients based on non-imaging EHR data and graph convolutional networks can fuse this relationship information with imaging data to effectively predict future disease trajectory more effectively than models employing only imaging or non-imaging data. Forecasting clinical events can enable intelligent resource allocation in hospitals. Our graph-based fusion modeling frameworks can be easily extended to other prediction tasks to efficiently combine imaging data with non-imaging clinical data.","How do we measure the adequacy of cancer pain management? Testing the performance of 4 commonly used measures and steps towards measurement refinement\nAlthough pain is the most common and disabling cancer symptom requiring management, the best index of cancer pain management adequacy is unknown. While the Pain Management Index is most commonly used, other indices have included relief, satisfaction, and pain intensity. We evaluated their correlations and agreement, compared their biopsychosocial correlates, and investigated whether they represented a single construct reflecting the adequacy of cancer pain management in 269 people with advanced cancer and pain. Despite moderate-to-severe average pain in 52.8% of participants, 85.1% had PMI scores suggesting adequate analgesia, pain relief was moderate and satisfaction was high. Correlations and agreement were low-to-moderate, suggesting low construct validity. Although the correlates of pain management adequacy were multidimensional, including lower pain interference, neuropathic and nociceptive pain, and catastrophizing, shorter cancer duration, and greater physical symptoms, no single index captured this multidimensionality. Principal component analysis demonstrated a single underlying construct, thus we constructed the Adequacy of Cancer Pain Management from factor loadings. It had somewhat better agreement, however correlates were limited to pain interference and neuropathic pain. This study demonstrates the psychometric shortcomings of commonly used indices. We provide suggestions for future research to improve measurement, a critical step in optimizing cancer pain management.\n\nPerspectiveThe Pain Management Index and other commonly used indices of cancer pain management adequacy have poor construct validity. This study provides suggestions to improve the measurement of the adequacy of cancer pain management.","WHAT ABOUT USING SNIFFIN STICKS 12 SCREENING TEST TO IDENTIFY POST-COVID-19 OLFACTORY DISORDERS?\nBackgroundOlfactory impairment is a major sequela of SARS-CoV-2 infection and has a negative impact on daily life quality. Olfactory loss can be assessed in many ways but seems to be little realized in a daily clinical practice. The sniffin Sticks test - 12 items (SST-12) can be used in quick olfactory disorders screening. Its use in a post-covid19 situation was the main objective of this work.\n\nMethodologyConsecutive patients consulting to the ENT department with post-Covid-19 olfactory loss were included. The clinical examination included an analog scale for the self-assessment of olfactory recovery (VAS), self-reported salt and sugar intake, a nasofibroscopy, the complete Sniffin Stick Test (SST) and the SST-12.\n\nResultsAmong the 54 patients included, based on the SST-12, 14,8% (n=8) of the patients could be classified as normosmic (SST-12[≥]11), 48,1% (n=26) as hyposmic (6< SST-12<10) and 37% (n=20) as functional anosmic (SST-12[≤]6). We report excellent and significant correlations between SST-12 and SST or VAS assessments. Salt and Sugar increased intake seems significantly related to SST-12 results.\n\nConclusionsSST-12 is a reliable way to screen post-COVID-19 olfactory disorders could be used in a daily clinical practice and might be used to prevent bad diet habits and so cardiovascular risk.","THE ADDED VALUE OF 18F-FDG PET/CT IN THE ASSESSMENT OF ONSET AND STEROID RESISTANT POLIMYALGIA RHEUMATICA\nPMR is a common inflammatory rheumatic disease. Although its clinical characteristics are fully recognized, no specific test for its diagnosis has been established to date. Several studies have described a wide variety of diseases that present with polymyalgic symptoms. A 18FDG-PET/CT scan could help to deal with these differential diagnoses. The goal of our study is to describe the findings of the 18FDG-PET/CT scan in a cohort of PMR patients and to detail how the 18FDG-PET/CT scan improves accuracy when diagnosing other underlying conditions. This cross-sectional study enrolled patients with a diagnosis of PMR who underwent to a 18FDG-PET/CT scan to rule out other diagnosis. The 18FDG-PET/CT scan was performed either following clinical criteria at the onset of clinical symptoms or when the patient became PMR steroid resistant. Patients demographic, clinical and analytical data at the moment of the 18FDG-PET/CT scan were recorded. The final diagnosis was confirmed according to clinical judgement. A total of 103 patients with PMR were included. In 49.51% of patients, the 18FDG-PET/CT scan was ordered to study resistance to steroid therapy. The final diagnoses of patients were PMR in 70.9% patients, large vessel vasculitis in 15.5%, neoplasms 4.8% and another diagnosis in the rest. The 18FDG-PET/CT scan is a very useful technique for the study of Polymyalgia Rheumatica, not only to help in the diagnostic process, but also due to its role in the identification of a variety of PMR-like patrons.","Multi-scalar data integration links glomerular angiopoietin-tie signaling pathway activation with progression of diabetic kidney disease\nDiabetes is the leading cause of chronic kidney disease. Prognostic biomarkers reflective of underlying molecular mechanisms are critically needed for effective management of diabetic kidney disease (DKD). In the Clinical Phenotyping and Resource Biobank study, an unbiased, machine learning approach identified a three-marker panel from plasma proteomics which, when added to standard clinical parameters, improved the prediction of outcome of end-stage kidney disease (ESKD) or 40% decline in baseline glomerular filtration rate (GFR) in a discovery DKD group (N=58) and was validated in an independent group (N=68) who also had kidney transcriptomic profiles available. Of the three markers, plasma angiopoietin 2 (ANGPT2) remained significantly associated with composite outcome in 210 Chinese Cohort Study of Chronic Kidney Disease participants with DKD. The glomerular transcriptional Angiopoietin/Tie (ANG-TIE) activation scores, derived from the expression of 154 literature-curated ANG-TIE signaling mediators, positively correlated with plasma ANGPT2 levels and outcome, explained by substantially higher TEK receptor expression in glomeruli and higher ANG-TIE activation scores in endothelial cells in DKD by single cell RNA sequencing. Our work suggests that activation of glomerular ANG-TIE signaling in the kidneys underlies the association of plasma ANGPT2 with disease progression, thereby providing potential targets to prevent DKD progression.","Art therapy as treatment modality for persons living with dementia- a protocol for a scoping review of systematic reviews\nObjectiveTo establish a robust understanding of the state of the evidence on the effectiveness and/or efficacy of art therapy (AT) as a non-pharmacological treatment (NPT) modality for persons living with dementia (PLWD).\n\nBackgroundOver the past decade, AT has received increased attention from health care professionals and researchers as having a potential role to play within treatment plans for PLWD.(1-4)\n\nInclusion criteriaThis scoping review will include systematic reviews from health-related disciplines conducted within the last 20 years that report the effectiveness and/or efficacy of AT as an NPT modality for PLWD and Mild Cognitive Impairment (MCI). Study outcomes must include cognition, quality of life, emotional and psychological well-being, and/or neuropsychiatric symptoms (NPS).\n\nMethodsA scoping review of systematic reviews was selected to outline different types of evidence and to identify gaps in the literature. The proposed review will be guided by the methodological framework proposed by the Joanna Briggs Institute. We will therefore specify the research question, identify relevant studies, select eligible studies, extract, collate, and summarize our results. We will not conduct a quality appraisal of the included studies as this review aims to explore the general scope of research conducted that assesses AT effectiveness and efficacy in PLWD.","Prodromal Progressive Supranuclear Palsy: insights from the UK Biobank\nBackgroundProdromal Parkinsons Disease is well described but prodromal Progressive Supranuclear Palsy (PSP) is much less understood. The diagnosis of PSP is typically delayed by an average of three years after symptom onset. Understanding the changes that occur in the prodromal and pre-diagnostic period will aid earlier diagnosis, clarify the natural history, and aid the design of early disease-modifying therapy trials.\n\nObjectivesTo determine motor and cognitive markers of prodromal PSP, with Parkinsons disease as a comparator condition, in a large prospective cohort.\n\nMethodsBaseline UK Biobank data from 502,504 individuals were collected between 2006 and 2010. Subsequent PSP and Parkinsons disease cases were identified from primary and secondary care electronic health records diagnostic coding data and death registry, with 5,404 matched controls.\n\nResults176 PSP cases (time to diagnosis 7.8{+/-}2.8 years) and 2,526 Parkinsons disease cases (time to diagnosis 7.8{+/-}2.9 years) were identified. At baseline, those later diagnosed with PSP had slower reaction times, weaker hand grip, lower fluid intelligence, poorer prospective memory, worse self-rated health score and lower digit recall than controls. They had higher mortality than both Parkinsons disease and control groups.\n\nConclusionsMotor slowing, cognitive dysfunction, and postural instability are clinical diagnostic features of PSP and are typically symptomatic three years before diagnosis. However, objective markers of these features are evident over seven years before diagnosis. This suggests a long prodromal course in PSP with subtle changes in motor and cognitive function.","Two Pools of ATP Detected in the Brains of Pediatric Patients with Myelin Oligodendrocyte Glycoprotein Antibody Disorders (MOGAD) by 3D 31P MR Spectroscopic Imaging (MRSI) at 7T\nOver the past four decades, ATP, the obligatory energy molecule for keeping all cells alive and functioning, was thought to contribute only one set of 31P MR signals in the human brain. Here we report for the first time the simultaneous detection of two pools of ATP in the human brain by high-resolution 3D 31P MRSI at ultrahigh field 7T. These two ATP pools differ in cytosolic Mg2+ concentration (1:0.5 ratio), with a resonance separation of 0.5 ppm at {beta}-ATP, a well-established imaging marker of intracellular Mg2+ concentration. Mg2+ is a cofactor of ATPase and its deficiency is associated with immune dysfunction, free radical damage, perturbations in Ca2+ homeostasis, and development of atherosclerosis, dyslipidemia and a number of neurological disorders, such as cerebral vasospasm, stroke, migraine, Alzheimers disease, and Parkinsons disease. Our study documents reduced Mg levels in the brain of patients with myelin oligodendrocyte glycoprotein antibody disorders (MOGAD), which is an idiopathic, inflammatory, demyelinating condition of the central nervous system (CNS) more common in pediatric patients. Low-Mg2+ ATP signals were detected mostly in the white matter regions in MOGAD, suggesting an association between Mg2+ deficiency and compromised functions of oligodendrocytes in maintenance and generation of the axonal myelin sheath. This preliminary study demonstrates the utility of the 7T 3D 31P MSRI for probing altered energy metabolism at reduced availability of Mg2+ rather than ATP itself. The potential correlation between [Mg2+] and disease progression over time should be assessed in larger cohorts.\n\nAuthor ApprovalYes","COVID-19 Bimodal Clinical and Pathological Phenotypes\nBackgroundPatients with coronavirus disease-2019 (COVID-19) present varying clinical complications. Different viral load and host response related to genetic and immune background are probably the reasons for these differences. We aimed to sought clinical and pathological correlation that justifies the different clinical outcomes among COVID-19 autopsies cases.\n\nMethodsMinimally invasive autopsy was performed on forty-seven confirmed COVID-19 patients from May-July, 2020. Electronic medical record of all patients was collected and a comprehensive histopathological evaluation was performed. Immunohistochemistry, immunofluorescence, special stain, western blotting and post-mortem real-time reverse transcriptase polymerase chain reaction on fresh lung tissue were performed.\n\nResultsWe show that 5/47 (10,6%) patients present a progressive decline in oxygenation index for acute respiratory distress syndrome (PaO2/FiO2 ratio), low compliance levels, interstitial fibrosis, high -SMA+ cells/protein expression, high collagens I/III deposition and NETs(P<0.05), named as fibrotic phenotype (N=5). Conversely, 10/47 (21,2%) patients demonstrated progressive increase in PaO2/FiO2 ratio, high pulmonary compliance levels, preserved elastic framework, increase thrombus formation and high platelets and D-dimer levels at admission (P<0.05), named as thrombotic phenotype. While 32/47 (68,1%) had a mixed phenotypes between both ones.\n\nConclusionsWe believe that categorization of patients based on these two phenotypes can be used to develop prognostic tools and potential therapies since the PaO2/FiO2 ratio variation and D-dimer levels correlate with the underlying fibrotic or thrombotic pathologic process, respectively; which may indicate possible clinical outcome of the patient.","Uncovering interpretable potential confounders in electronic medical records\nRandomized clinical trials (RCT) are the gold standard for informing treatment decisions. Observational studies are often plagued by selection bias, and expert-selected covariates may insufficiently adjust for confounding. We explore how unstructured clinical text can be used to reduce selection bias and improve medical practice. We develop a framework based on natural language processing to uncover interpretable potential confounders from text. We validate our method by comparing the estimated hazard ratio (HR) with and without the confounders against established RCTs. We apply our method to four cohorts built from localized prostate and lung cancer datasets from the Stanford Cancer Institute and show that our method shifts the HR estimate towards the RCT results. The uncovered terms can also be interpreted by oncologists for clinical insights. We present this proof-of-concept study to enable more credible causal inference using observational data, uncover meaningful insights from clinical text, and inform high-stakes medical decisions.","Higher Limbic and Basal Ganglia volumes in surviving COVID-negative patients and the relations to fatigue.\nBackgroundAmong systemic abnormalities caused by the novel coronavirus, little is known about the critical attack on the central nervous system (CNS). Few studies have shown cerebrovascular pathologies that indicate CNS involvement in acute patients. However, replication studies are necessary to verify if these effects persist in COVID-19 survivors more conclusively. Furthermore, recent studies indicate fatigue is highly prevalent among long-COVID patients. How morphometry in each group relate to work-related fatigue need to be investigated.\n\nMethodCOVID survivors were MRI scanned two weeks after hospital discharge. We hypothesized, these survivors will demonstrate altered gray matter volume (GMV) and experience higher fatigue levels when compared to healthy controls, leading to stronger correlation of GMV with fatigue. Voxel-based morphometry was performed on T1-weighted MRI images between 46 survivors and 30 controls. Unpaired two-sample t-test and multiple linear regression were performed to observe group differences and correlation of fatigue with GMV.\n\nResultsThe COVID group experienced significantly higher fatigue levels and GMV of this group was significantly higher within the Limbic System and Basal Ganglia when compared to healthy controls. Moreover, while a significant positive correlation was observed across the whole group between GMV and self-reported fatigue, COVID subjects showed stronger effects within the Posterior Cingulate, Precuneus and Superior Parietal Lobule.\n\nConclusionBrain regions with GMV alterations in our analysis align with both single case acute patient reports and current group level neuroimaging findings. We also newly report a stronger positive correlation of GMV with fatigue among COVID survivors within brain regions associated with fatigue, indicating a link between structural abnormality and brain function in this cohort."],"string":"[\n \"Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis\\nProteoglycans are complex macromolecules formed of glycosaminoglycan chains covalently linked to core proteins through a linker tetrasaccharide common to heparan sulfate proteoglycans (HSPG) and chondroitin sulfate proteoglycans (CSPG). Biosynthesis of a single proteoglycan requires the expression of dozens of genes, which together create the large structural and functional diversity reflected by the numerous diseases or syndromes associated to their genetic variability. Among proteoglycans, HSPG are the most structurally and functionally complex. To decrease this complexity, we retrieved and linked information on pathogenic variants, polymorphism, expression, and literature databases for 50 genes involved in the biosynthesis of HSPG core proteins, heparan sulfate (HS) chains, and their linker tetrasaccharide. This resulted in a new gene organization and biosynthetic pathway representation in which the phenotypic continuum of disorders as linkeropathies and other pathologies could be predictable. Moreover, ubiquitous NDST1, GLCE, HS2ST1, and HS6ST1 appeared to generate ubiquitous heparan sulfate (HS) sequences essential for normal development and homeostasis, whereas the tissue restricted NDST2-4, HS6ST2-3, and HS3ST1-6 appeared to generate specialized HS sequences mainly involved in responsiveness to stimuli. Supported by data on genetic polymorphism and clinical variants, we afford a new vision of HSPG involvement in homeostasis, disease, vulnerability to disease, and behavioral disorders.\",\n \"Delta/ Omicron and Omicron/BA.2 co-infections occurring in Immunocompromised hosts\\nConcomitant infection of multiple SARS-CoV-2 variants has become an increasing concern, as this scenario increases the likelihood of recombinant variants. Detecting co-infection of SARS-CoV-2 variants is difficult to detect by whole genome sequencing approaches, but genotyping methods facilitate detection. We describe 2 cases of Delta/Omicron and 2 cases of Omicron sublineage BA.1/ BA.2 co-infection as detected by a multiplex genotyping fragment analysis method. Findings were confirmed by whole genome sequencing. Review of the patient characteristics revealed co-morbidities and conditions which weaken the immune system and may make them more susceptible to harboring SARS-CoV-2 variant co-infections.\",\n \"Sibling Experiences of Adverse Childhood Experiences: A Scoping Review.\\nAdverse childhood experiences (ACEs) are traumatic events during childhood known to affect health and wellbeing across the life-span. The purpose of this scoping review was to understand what we currently know about the experiences of siblings living with ACEs. Sibling relationships are unique, and for some the most enduring we experience. These relationships can be categorised by love and warmth, however, can also be a point of escalating conflict and problems. This scoping review was conducted following Arksey and OMalleys (2005) methodological framework, complemented by the PAGER framework (Bradbury-Jones et al, 2021), offering a structured approach to the reviews analysis and reporting through presenting the Patterns, Advances, Gaps, and Evidence for practice and Research. In June 2020 we searched 12 databases, with 11,469 results. Articles were screened for eligibility by the review team leaving a total of 148 articles meeting the inclusion criteria. Findings highlighted five main patterns: (1) the influence of birth order (older siblings shielding younger); (2) the influence of sibling relationships (lack of research exploring sibling types outside of biological siblings); (3) identifying siblings experiencing ACEs (when one sibling experiences adversity, it is likely that their other siblings also do, or experience vicariously); (4) siblings who cause harm (siblings harming other siblings is often normalised and minimised, especially by parents); (5) focus on individual ACEs (the majority of studies explore ACEs in isolation). Our findings suggest future research would benefit from an increase in theoretical understanding and exploration of different types of sibling relationships (full, step, half).\",\n \"Clinical features of UK Biobank subjects carrying protein truncating variants in genes implicated in schizophrenia pathogenesis\\nThe SCHEMA consortium has identified ten genes in which protein truncating variants (PTVs) confer substantial risk of schizophrenia. Exome-sequenced participants in the UK Biobank who carried PTVs in these genes were studied to determine to what extent they demonstrated features of schizophrenia or had neuropsychiatric impairment. Following automated quality control and visual inspection of reads, 251 subjects were identified as having well-supported PTVs in one of these genes. The frequency of PTVs in CACNA1G was higher than had been observed in SCHEMA cases, casting doubt on its role in schizophrenia pathogenesis, but otherwise rates were similar to those observed in SCHEMA controls. Numbers were too small to allow formal statistical analysis but in general carriers of PTVs did not appear to have high rates of psychiatric illness or reduced educational or occupational functioning. One subject with a PTV in SETD1A had a diagnosis of schizophrenia. one with a PTV in HERC1 had psychotic depression and two subjects seemed to have developmental disorders, one with a PTV in GRIN2A and one with a PTV in RBCC1. There seemed to be somewhat increased rates of affective disorders among carriers of PTVs in HERC1 and RB1CC1. Carriers of PTVs did not appear to have subclinical manifestations of schizophrenia. Although PTVs in these genes can substantially increase schizophrenia risk, their effect seems to be dichotomous and most carriers appear psychiatrically well.\\n\\nThis research has been conducted using the UK Biobank Resource.\",\n \"Phenotypic distinctions of BLM- and RMI1-associated Bloom syndrome\\nBloom syndrome (BS) is an autosomal recessive disease with characteristic clinical features of primary microcephaly, growth deficiency, skin lesions, cancer predisposition, and immunodeficiency. Here, we report the clinical and molecular findings of eight patients from six families diagnosed with BS. We identified causative mutations in all families, three different homozygous mutations in BLM and one causative homozygous mutation in RMI1. The homozygous c.581_582delTT (p.Phe194*) and c.3164G>C (p.Cys1055Ser) mutations in BLM have already been reported in BS patients, while the c.572_573delGA (p.Arg191Lysfs*4) is novel. Interestingly, whole-exome sequencing revealed a homozygous loss-of-function mutation in RMI1 in two BS patients of a consanguineous Turkish family. All BS patients had primary microcephaly, intrauterine growth delay, and short stature, presenting the phenotypic hallmarks of BS. However, a narrow face, skin lesions, and upper airway infections were observed only in some of the patients. Overall, patients with homozygous BLM mutations had a more severe BS phenotype compared to patients carrying the homozygous RMI1 mutation, especially in terms of immunodeficiency and associated recurrent infections. Low-level immunoglobulins were observed in all BLM-mutated patients, emphasizing the immunodeficiency profile of the disease, which should be considered as an important phenotypic characteristic of BS, especially in the current Covid-19 pandemic era.\",\n \"AImmune: a new blood-based machine learning approach to improving immune profiling analysis on COVID-19 patients\\nA massive number of transcriptomic profiles of blood samples from COVID-19 patients has been produced since pandemic COVID-19 begins, however, these big data from primary studies have not been well integrated by machine learning approaches. Taking advantage of modern machine learning arthrograms, we integrated and collected single cell RNA-seq (scRNA-seq) data from three independent studies, identified genes potentially available for interpretation of severity, and developed a high-performance deep learning-based deconvolution model AImmune that can predict the proportion of seven different immune cells from the bulk RNA-seq results of human peripheral mononuclear cells. This novel approach which can be used for clinical blood testing of COVID-19 on the ground that previous research shows that mRNA alternations in blood-derived PBMCs may serve as a severity indicator. Assessed on real-world data sets, the AImmune model outperformed the most recognized immune profiling model CIBERSORTx. The presented study showed the results obtained by the true scRNA-seq route can be consistently reproduced through the new approach AImmune, indicating a potential replacing the costly scRNA-seq technique for the analysis of circulating blood cells for both clinical and research purposes.\",\n \"Knowledge, Attitude, and Practices of Health Professionals Working in A Major Health Care System Regarding Social Determinants of Health (SDOH) and Community Health Workers (CHWs)\\nIntroductionSocial Determinants of Health (SDOH) play a key role in impacting the health outcomes of any population. Community Health Workers (CHWs) play an important role in health promotion, disease prevention, and management of chronic illnesses. This study aims at exploring the knowledge, attitude, and practices of health care professionals towards CHWs to fully integrate in them for mitigation of SDOH.\\n\\nMaterials and MethodsA cross-sectional study utilizing an anonymous survey questionnaire across 4 clinical sites was carried out from June 2016 to November 2017 in a major healthcare system (Presbyterian) in Albuquerque, New Mexico. Descriptive statistics (means, standard deviations, and proportions) were collected. Categorical variables were analyzed using Chi-squared and Fishers exact test; a p-value of <0.05 was considered statistically significant, using SAS 9.4 statistical software.\\n\\nResultsAlmost half of the health professionals had no knowledge about the social determinants of health. Almost a quarter of the health professionals did not know the role of CHWs in healthcare, however, 100% of the respondents across all clinic and practice locations and regardless of their role or scope of the practice believed that greater involvement of CHWs would improve patient outcomes.\\n\\nConclusionThere is a knowledge deficit among health care providers about the social determinants of health (SDOH).More educational and teaching opportunities on SDOH and CHWs to all health professionals should be provided to all health professionals so the clinical team can help manage SDOH in addition to providing clinical care.\",\n \"Association between SARS-Cov-2 infection during pregnancy and adverse pregnancy outcomes: a re-analysis of data from Wei et al. (2021).\\nBackgroundWei et al. have published a meta-analysis (MA) which aimed to \\\"evaluate the association between SARS-CoV-2 infection during pregnancy and adverse pregnancy outcomes\\\".\\n\\nUsing classical random-effects model, they found that SARS-CoV-2 infection was associated with preeclampsia, preterm birth and stillbirth.\\n\\nPerforming MA with low event rates or with few studies may be challenging as MA relies on several within and between study distributional assumptions.\\n\\nMethodsto assess the robustness of the results provided by Wei et al., we performed a sensitivity analysis using several frequentist and Bayesian meta-analysis methods. We also estimated fragility indexes.\\n\\nResultsFor eclampsia (patients with Covid-19 vs without), the confidence intervals of most frequentist models contain 1. All beta-binomial models (Bayesian) lead to credible intervals containing 1. The prediction interval, based on DL method ranges from 0.75 to 2.38. The fragility index is 2 for the DL method.\\n\\nFor preterm, the confidence (credible) intervals exclude 1. The prediction interval is broad, ranging from 0.84 to 20.61. The fragility index ranges from 27 to 10.\\n\\nFor stillbirth, the confidence intervals of most frequentist models contain 1. Six Bayesian MA models lead to credible intervals containing 1.The prediction interval ranges from 0.52 to 8.49. The fragility index is 3.\\n\\nInterpretationGiven the available data and the results of our broad sensitivity analysis, we can only suggest that SARS-CoV-2 infection during pregnancy is associated to preterm, and may be associated to preeclampsia. For stillbirth, more data are needed as none of the Bayesian analyses are conclusive.\",\n \"Comparative analysis unveils novel changes in serum metabolites and metabolomic networks of retinopathy of prematurity infants\\nBackgroundAdvances in mass spectrometry are providing new insights into the role of metabolomics in the aetiology of many diseases. Studies in retinopathy of prematurity (ROP), for instance, overlooked the role of metabolic alterations in disease development. Here, we employed comprehensive metabolic profiling and gold-standard metabolic analysis to explore major metabolites and metabolic pathways significantly affected in early stages of pathogenesis toward ROP.\\n\\nMethodsThis is a multicentre, retrospective case-control study. We collected serums from 57 ROP cases and 57 strictly baseline matched non-ROP controls. Non-targeted ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) from Metabolon, Inc. was used to detect the metabolites in serum samples. Machine learning was used to unravel most affected metabolites and pathways in ROP development.\\n\\nResultsCompared to non-ROP controls, we found a significant metabolic perturbation in the ROP serums, featured with an increase in lipid, nucleotide, carbohydrate metabolites and a lower level of peptides. Machine leaning helped to distinguish a cluster of metabolic pathways (glycometabolism, redox homeostasis, lipid metabolism and arginine pathway) that were strongly related to the development of ROP. In addition, we found that the severity of ROP was related to the level of creatinine and ribitol.\\n\\nConclusionIn the current study, our results suggested a strong link between metabolic profiling and retinal neovascularization during ROP pathogenesis. These findings provided an insight into identifying novel metabolic biomarkers for ROP diagnosis and prevention.\",\n \"AKI Risk Score (AKI-RiSc): Developing an Interpretable Clinical Score for Early Identification of Acute Kidney Injury for Patients Presenting to the Emergency Department\\nBackgroundAcute kidney injury (AKI) in hospitalised patients is a common syndrome associated with poorer patient outcomes. Clinical risk scores can be used for the early identification of patients at risk of AKI.\\n\\nMethodsWe conducted a retrospective study using electronic health records of Singapore General Hospital emergency department patients who were admitted from 2008 to 2016. The primary outcome was inpatient AKI of any stage within 7 days of admission based on Kidney Disease Improving Global Outcome (KDIGO) 2012 guidelines. AutoScore, a machine learning based algorithm, was used to generate point based clinical scores from the study sample which was divided into training, validation and testing cohorts. Model performance was evaluated using area under the curve (AUC).\\n\\nResultsAmong the 119,468 admissions, 10,693 (9.0%) developed AKI. 8,491 were stage 1 (79.4%), 906 stage 2 (8.5%) and 1,296 stage 3 (12.1%). The AKI Risk Score (AKI-RiSc) was a summation of the integer scores of 6 variables: serum creatinine, serum bicarbonate, pulse, systolic blood pressure, and diastolic blood pressure. AUC of AKI-RiSc was 0.730 (95% CI: 0.713 - 0.747), outperforming an existing AKI Prediction Score model which achieved AUC of 0.665 (95% CI: 0.646 - 0.679) when evaluated on the same test cohort. At a cut-off of 4 points, AKI-RiSc had a sensitivity of 82.5% and specificity of 46.7%.\\n\\nConclusionAKI-RiSc is a simple point based clinical score that can be easily implemented on the ground for early identification of AKI in high-risk patients and potentially be applied in healthcare settings internationally.\",\n \"The impact of the coronavirus disease 2019 (COVID-19) outbreak on cancer practice in Japan: using an administrative database\\nBackgroundRecent researches reported the impact of the coronavirus disease 2019 (COVID - 19) pandemic on the clinical practice of specific type cancers. The aim of this study was to reveal the impact of the COVID-19 outbreak on the clinical practice of various cancers.\\n\\nMethodsWe included hospitalized patients aged 18 years or older diagnosed between July 2018 and June 2020 with one of the top 12 most common cancers in Japan (colon/rectum, lung, gastric, breast, bladder & urinary tract, pancreas, non-Hodgkin lymphoma, liver, prostate, esophagus, uterus, and gallbladder & biliary tract) using Diagnostic Procedure Combination data, an administrative database in Japan. The intervention was defined April 2020 based on a declaration of emergency from Japanese government. The change volume of number of monthly admissions with each cancer was tested by interrupted time series (ITS) analysis, and monthly cases with radical surgery or chemotherapy for each cancer were descripted.\\n\\nResults403,344 cases were included during the study period. The most common cancer was colon/rectum (20.5%), followed by lung (17.5%). In almost cancer cases, the number of admissions decreased in May 2020. In particular, colorectal, lung, gastric, breast, uterine, or esophageal cancer cases decreased by over 10%. The number of admissions with surgery or chemotherapy decreased in colorectal, lung, gastric, breast, uterine, or esophageal cancer. ITS analysis indicated that cases with gastric or esophageal cancer were affected more than other type of cancer.\\n\\nConclusionsThe COVID-19 outbreak has a negative impact on the number of admission cases with cancer; the magnitude of impact varied by cancer diagnosis.\",\n \"Allelic Complexity of KMT2A Partial Tandem Duplications in Acute Myeloid Leukemia and Myelodysplastic Syndromes\\nKMT2A partial tandem duplication (KMT2A-PTD) at 11q23.3 is associated with adverse risk in AML and MDS, is a potential therapeutic target, and is an attractive marker of measurable residual disease. High initial KMT2A-PTD RNA levels have been linked to poor prognosis, but mechanisms regulating KMT2A-PTD expression are not well understood. While it has been reported that KMT2A-PTD affects only a single allele, it has been theorized but not proven that duplications or genomic gains of a monoallelic KMT2A-PTD may occur, thereby potentially driving high expression and disease progression. Copy neutral loss of heterozygosity (CN-LOH) of 11q has also been described and is known to be associated with mutations in CBL but has not been reported to involve KMT2A-PTD. In this study, we identified 94 patients with KMT2A-PTDs using targeted DNA next-generation sequencing (NGS) and found that 16% (15/94) had complex secondary events, including CN-LOH and selective gain involving the KMT2A-PTD allele. High copy numbers indicating complexity were significantly enriched in AML versus MDS and correlated with higher RNA expression. Moreover, in serial samples, complexity was associated with relapse and secondary transformation. Taken together, we provide approaches to integrate quantitative and allelic assessment of KMT2A-PTDs into targeted DNA NGS and demonstrate that secondary genetic events occur in KMT2A-PTD by multiple mechanisms that may be linked to myeloid disease progression by driving increased expression from the affected allele.\",\n \"Robotic-Assisted Gait for lower-limb Rehabilitation: Evidence of Altered Neural Mechanisms in Stroke\\nRobotic-Assisted Gait training (RAGT) offers an innovative therapeutic option for restoration of functional gait in stroke survivors, complementing existing physical rehabilitation strategies. However, there is a limited understanding of the neurophysiological response induced by this training in end-users. Neural desynchronization and Cortico-Muscular Coherence (CMC) are two biomarkers that define the level of muscle-cortex association during gait phases and can be used to estimate induced users adaptation during RAGT. In this study, we measure Event-Related Spectral Perturbation (ERSP) and CMC from three healthy individuals and three stroke survivors during overground-gait with and without an exoskeleton. Results show that (1) the use of the exoskeleton in healthy individuals is associated with a different and more refined motor-control represented in a high{theta} -desynchronization, (2) altered and noisy ERSP and lower and non-focal {beta}-CMC patterns are observed in Stroke patients when performing overground-gait both with and without the Exoskeleton, and (3) Exoskeleton use in stroke survivors is associated with a reduction in swing-time during gait-cycle, but this effect is not correlated with an increment of{theta} -desynchronization and/or {beta}-CMC. ERSP and CMC demonstrated evidence of neural modulation in able-bodied users during RAGT, which could not be detected in subacute stroke survivors during RAGT. These results suggest that the gait-parameters changes observed during exoskeleton use in subacute stroke survivors are unlikely to be neurally driven.\",\n \"A novel age-informed approach for genetic association analysis in Alzheimer's disease\\nIntroductionMany Alzheimers disease (AD) genetic association studies disregard age or incorrectly account for it, hampering variant discovery.\\n\\nMethodUsing simulated data, we compared the statistical power of several models: logistic regression on AD diagnosis adjusted and not adjusted for age; linear regression on a score integrating case-control status and age; and multivariate Cox regression on age-at-onset. We applied these models to real exome-wide data of 11,127 sequenced individuals (54% cases) and replicated suggestive associations in 21,631 genotype-imputed individuals (51% cases).\\n\\nResultsModelling variable AD risk across age results in 10-20% statistical power gain compared to logistic regression without age adjustment, while incorrect age adjustment leads to critical power loss. Applying our novel AD-age score and/or Cox regression, we discovered and replicated novel variants associated with AD on KIF21B, USH2A, RAB10, RIN3 and TAOK2 genes.\\n\\nDiscussionOur AD-age score provides a simple means for statistical power gain and is recommended for future AD studies.\",\n \"Empirical networks for localized COVID-19 interventions using WiFi infrastructure at university campuses\\nInfectious diseases, like COVID-19, pose serious challenges to university campuses, which typically adopt closure as a non-pharmaceutical intervention to control spread and ensure a gradual return to normalcy. Intervention policies, such as remote instruction (RI) where large classes are offered online, reduce potential contact but also have broad side-effects on campus by hampering the local economy, students learning outcomes, and community wellbeing. In this paper, we demonstrate that university policymakers can mitigate these tradeoffs by leveraging anonymized data from their WiFi infrastructure to learn community mobility --- a methodology we refer to as WiFi mobility models (WO_SCPLOWIC_SCPLOWMO_SCPLOWOBC_SCPLOW). This approach enables policymakers to explore more granular policies like localized closures (LC). WO_SCPLOWIC_SCPLOWMO_SCPLOWOBC_SCPLOW can construct contact networks that capture behavior in various spaces, highlighting new potential transmission pathways and temporal variation in contact behavior. Additionally, WO_SCPLOWIC_SCPLOWMO_SCPLOWOBC_SCPLOW enables us to design LC policies that close super-spreader locations on campus. By simulating disease spread with contact networks from WO_SCPLOWIC_SCPLOWMO_SCPLOWOBC_SCPLOW, we find that LC maintains the same reduction in cumulative infections as RI while showing greater reduction in peak infections and internal transmission. Moreover, LC reduces campus burden by closing fewer locations, forcing fewer students into completely online schedules, and requiring no additional isolation. WO_SCPLOWIC_SCPLOWMO_SCPLOWOBC_SCPLOW can empower universities to conceive and assess a variety of closure policies to prevent future outbreaks.\",\n \"Novelty-induced frontal-STN networks in Parkinson's disease\\nNovelty detection is a primitive subcomponent of cognitive control that is deficient in Parkinsons disease (PD) patients with cognitive dysfunction. Here, we studied novelty-response mechanisms in PD. In participants with PD, we recorded from cortical circuits with scalp-based electroencephalography (EEG) and from subcortical circuits using intraoperative neurophysiology during surgeries for implantation of deep-brain stimulation (DBS) electrodes. We report three major results. First, novel auditory stimuli triggered midfrontal low-frequency rhythms; of these, 1-4 Hz \\\"delta\\\" rhythms were linked to novelty-associated slowing whereas 4-7 Hz \\\"theta\\\" rhythms were specifically attenuated in PD. Second, 32% of subthalamic nucleus (STN) neurons were response-modulated; nearly all (94%) of these were also modulated by novel stimuli. Third, response-modulated STN neurons were coherent with midfrontal 1-4 Hz activity. These findings link scalp-based measurements of neural activity with neuronal activity in the STN. Our results provide insight into midfrontal cognitive control mechanisms and how purported hyperdirect fronto-basal ganglia circuits evaluate new information.\",\n \"Exon variants associated with asthma and allergy\\nRecent biobank based exon sequencing studies included thousands of traits while the mutational spectrum of asthma and allergy associated genes is still unknown.\\n\\nMethodsMeta-analysis of exome data from 281,104 UK Biobank samples that were analyzed for association of mostly rare variants with asthma, allergic rhinitis and atopic dermatitis. Variants of interest (VOI) were tabulated, shared genes annotated and compared to earlier GWAS, WGBS, WES and selected candidate gene studies.\\n\\nResults354 VOI were significantly associated with the traits examined. They cluster mainly in two large regions on chromosome 6 and 17 while there is basically no overlap of atopic dermatitis with both other diseases. After exclusion of the two atopic dermatitis variants, 321 unique VOI remain in 122 unique genes. 30 genes are shared by the group of 87 genes with increased and the group of 65 genes with decreased risk for allergic disease. 85% of genes identified earlier by common SNPs in GWAS can not be replicated.\\n\\nDiscussionMost identified genes are involved in interferon {gamma} and IL33 signaling pathway. They highlight already known but also new pharmacological targets, including the IL33 receptor ST2/IL1RL1, TLR1, ALOX15, GSDMA, BTNL2, IL13 and IKZF3. Future pharmacological studies will need to included these VOI for stratification of the study population.\",\n \"Damaging missense variants in IGF1R implicate a role for IGF-1 resistance in the aetiology of type 2 diabetes\\nType 2 diabetes (T2D) is a chronic metabolic disorder with a significant genetic component. While large-scale population studies have identified hundreds of common genetic variants associated with T2D susceptibility, the role of rare (minor allele frequency < 0.1%) protein coding variation is less clear. To this end, we performed a gene burden analysis of 18,691 genes in 418,436 (n=32,374 T2D cases) individuals sequenced by the UK Biobank (UKBB) study to assess the impact of rare genetic variants on T2D risk. Our analysis identified T2D associations at exome-wide significance (P < 6.9x10-7) with rare, damaging variants within previously identified genes including GCK, GIGYF1, HNF1A, and TNRC6B. In addition, individuals with rare, damaging missense variants in the genes ZEB2 (N=31 carriers; OR=5.5 [95% CI=2.5-12.0]; p=6.4x10-7), MLXIPL (N=245; OR=2.3 [1.6-3.2]; p=3.2x10-7), and IGF1R (N=394; OR=2.4 [1.8-3.2]; p=1.3x10-10) have higher risk of T2D. Carriers of damaging missense variants within IGF1R were also shorter (-2.2cm [-1.8-2.7]; p=1.2x10-19) and had higher circulating protein levels of insulin-like growth factor-1 (IGF-1; 2.3 nmol/L [1.7-2.9] p=2.8x10-14), indicating relative IGF-1 resistance. A likely causal role of IGF-1 resistance on T2D was further supported by Mendelian randomisation analyses using common variants. Our results increase our understanding of the genetic architecture of T2D and highlight a potential therapeutic benefit of targeting the Growth Hormone/IGF-1 axis.\",\n \"Decoding molecular programs in melanoma brain metastases\\nThe systemic dissemination of tumor cells and the spatiotemporal development of organ- metastases are associated with loss of therapeutic control and decreased overall survival (OS). The emergence of solitary or multiple brain metastases is frequently observed in melanoma patients and responsible for disease progression and dismal prognosis. Here, we used whole transcriptome and methylome profiling as well as targeted sequencing (TargetSeq) of intraoperative/snap frozen or archived melanoma brain metastases to unravel molecular subgroups and subclonal heterogeneity. We discovered that E-cadherin (Ecad)/BRAFV600E/K, CD271/NRASQ61L/R/K, and tumor infiltrated lymphocytes (TIL)-status molecularly subdivided tumors into proliferative/pigmented and invasive/stem-like irrespective of the intracranial location. Moreover, we identified 46 differentially methylated regions in promoters of 14 genes, subdividing MBM into BRAFmut and NRASmut subgroups. We observed that therapy-resistant, migratory CD271+/Ecadneg subclones derived from Ecad+tumors in an epithelial-mesenchymal transition (EMT)-like process and fostered intracranial progression. Hence, CD271high MBM present a therapy-resistant, progressive subset of tumors that are refractory to conventional therapeutic strategies. The knockdown of CD271 or SOX4 in in vitro established, MBM-derived cell lines decreased cell migration, proliferation, and number of suspension cells that were shed by cell lines of progressive tumors. In summary, we propose that an Ecad-to-CD271 switch of MBM is a rate-limiting process that potentially determines intracranial progression in melanoma patients. The therapeutic control of this process may prevent intracranial progression, increasing patients overall survival.\",\n \"Multi-contrast magnetic resonance imaging of visual white matter pathways in glaucoma patients\\nPurposeGlaucoma is a disorder that involves visual field loss caused by retinal ganglion cell damage. Previous diffusion magnetic resonance imaging (dMRI) studies have demonstrated that retinal ganglion cell damage affects tissues in the optic tract (OT) and optic radiation (OR). However, because previous studies have used a simple diffusion tensor model to analyze dMRI data, the microstructural interpretation of white matter tissue changes remains uncertain. In this study, we used a multi-contrast MRI approach to further clarify the type of microstructural damage that occurs in glaucoma patients.\\n\\nMethodsWe collected multi-shell dMRI data from 17 glaucoma patients and 30 controls using 3T MRI. Using the dMRI data, we estimated three types of tissue property metrics: intracellular volume fraction (ICVF), orientation dispersion index (ODI), and isotropic volume fraction (IsoV). Quantitative T1 (qT1) data, which may be relatively specific to myelin, were collected from all subjects.\\n\\nResultsIn the OT, all four metrics showed significant differences between the glaucoma and control groups. In the OR, only the ICVF showed significant between-group differences. ICVF was significantly correlated with qT1 in the OR of glaucoma patients, although qT1 did not show any abnormality at the group level.\\n\\nConclusionsOur results suggest that at the group level, tissue changes in the glaucoma patients OR might be explained by axonal damage, which is reflected in the intracellular diffusion signals, rather than myelin damage. The significant correlation between ICVF and qT1 suggests that myelin damage might also occur in a smaller number of severe cases.\",\n \"Ivacaftor, not ivacaftor/lumacaftor, is associated with lower pulmonary inflammation in preschool cystic fibrosis\\nAirway inflammation is a key driver of cystic fibrosis (CF) lung disease. The advent of cystic fibrosis transmembrane conductance regulator (CFTR) modulators has the potential to transform the care of CF, however the direct effect of these therapies on lung inflammation is unknown. Here, we profile airway inflammation in bronchoalveolar lavage (BAL) of preschool aged children with CF on CFTR modulator therapy (ivacaftor or ivacaftor/lumacaftor), untreated children with CF, and age-matched healthy controls. We show that children treated with ivacaftor have lower pulmonary concentrations of inflammatory mediators CCL3, CXCL9, CCL2, IL-8, IL-1{beta}, and IL-6 relative to untreated children with CF. Conversely, there was no significant effect of lumacaftor/ivacaftor treatment on airway inflammation. This is the first work to illustrate a difference in early life airway inflammation with CFTR treatment, highlights the effectiveness of ivacaftor in early life, and suggests that BAL inflammatory profile may represent a biomarker of therapeutic response to treatment.\",\n \"Single EV analysis (sEVA) of mutated proteins allows detection of stage 1 pancreatic cancer\\nTumor cell derived extracellular vesicles (EV) are being explored as circulating biomarkers for cancer detection. Up to now however, clinical results have been mixed for a number of reasons including the predominant use of bulk measurements, the inability to differentiate tumor from host cell derived vesicles, the general absence of uniquely identifying biomarkers and the unknown frequency of stochastically distributed biomarkers into single circulating vesicles. We hypothesized that a single EV analysis (sEVA) technique could potentially improve diagnostic accuracy necessary to detect early cancers but the actual biomarker frequency and practical detection limits are currently unknown. Using pancreatic cancer, we carefully analyzed the composition of putative cancer markers in 11 established and new patient derived models. In parental PDAC cells positive for KRASmut and/or P53mut proteins only [~]40% of EVs were also positive (range: 30-64%). This rate of positivity increased to 57% when additional PDAC biomarkers were considered (MUC1, EGFR, FG-P4OH) in cell lines. In a blinded study involving 16 patients with surgically proven stage 1 PDAC, KRASmut and P53mut protein was detectable at much lower levels, generally in < 0.1% of vesicles. With the analytical capabilities of sEVA however, 15 of the 16 patients with stage 1 PDAC expressed low levels of biomarker positive EV. Using a modeling approach, we estimate that the current PDAC detection limit is at [~]0.1 cm3 tumor volume, below clinical imaging capabilities. These findings establish the potential for single-EV analysis for early cancer detection.\",\n \"Structural connectivity of subthalamic nucleus stimulation for improving freezing of gait\\nGait impairments such as freezing of gait (FOG) are among the most common and disabling symptoms of Parkinsons disease (PD). While the efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with early or advanced PD has been proven in large randomised controlled trials, its effect on gait impairments is still insufficiently understood. Moreover, there is uncertainty about pathways that need to be modulated to improve gait impairments. In this bi-centric study, we investigated how STN-DBS alters FOG in 47 subjects with PD. We assessed freezing prevalence and severity using the Freezing of Gait Questionnaire and Item 14 of the Unified Parkinsons Disease Rating Scale-II. Using a model of publicly available basal-ganglia pathways we determined a connectivity profile for postoperative changes in FOG. Compared to preoperative baseline, freezing of gait significantly improved six months postoperatively, marked by reduced frequency and duration of freezing episodes. We found that optimal stimulation sites for improving freezing of gait structurally connected to primary and supplementary motor areas, the dorsolateral prefrontal cortex and to the globus pallidus. Stimulation of the lenticular fasciculus was associated with worsening of freezing of gait. Our findings highlight the need for optimal identification and characterisation for network structures that can be implemented in stereotactic planning and can additionally pose a target for postoperative stimulation strategies.\",\n \"Impact of shaggy aorta on intraoperative cerebral embolism during carotid artery stenting\\nBackgroundCareful selection of patients for carotid stenting is necessary. We suggest that patients with a shaggy aorta syndrome may have a higher risk of perioperative embolic complications.\\n\\nMethodsThe study is a subanalysis of the SIBERIA Trial. We included 72 patients undergoing transfemoral carotid artery stenting. All patients had an MRI DWI and a clinical neurological examination two days before and on the second and 30th days after the intervention.\\n\\nResults46 patients had shaggy aorta syndrome. Intraoperative embolisms were recorded in 82.6% and 46.1% of patients with and without shaggy aorta syndrome, respectively (p=0.001). New asymptomatic ischemic brain lesions in the postoperative period occurred in 78.3% and in 26.9% of patients with and without shaggy aorta syndrome, respectively (p=0.000). 3 (6.5%) cases of stroke within 30 days after the procedure were observed only in patients with shaggy aorta syndrome. Shaggy aorta syndrome (OR 5.54 [1.83:16.7], p=0.001) and aortic arch ulceration (OR 6.67 [1.19: 37.3], p = 0.02) were independently associated with cerebral embolism. Shaggy aorta syndrome (OR 9.77 [3.14-30.37], p=0.000) and aortic arch ulceration (OR 12.9 [2.3: 72.8], p = 0.003) were independently associated with ipsilateral new asymptomatic ischemic brain lesions.\\n\\nConclusionsShaggy aorta syndrome and aortic arch ulceration significantly increase the odds of intraoperative embolism and new asymptomatic ischemic brain lesions. Carotid endarterectomy or transcervical carotid stent should be selected in the presence of aortic ulceration.\",\n \"An automated Dashboard to improve laboratory COVID-19 diagnostics management\\nBackgroundIn response to the CoVID-19 pandemic, our microbial diagnostic laboratory located in a university hospital has implemented several distinct SARS-CoV-2 RT-PCR systems in a very short time. Thanks to our automated molecular diagnostic platform, more than 140000 SARS-CoV-2 RT-PCR tests were achieved over 12 months, with peaks higher than 1500 daily tests. A dashboard was developed to give access to Key Performance Indicators (KPIs) to improve laboratory operational management.\\n\\nMethodsRT-PCR data extraction of four respiratory viruses - SARS-CoV-2, influenza A and B and RSV - from our laboratory information system (LIS), was automated. Important KPIs were identified and the visualization was achieved using an in-house dashboard based on the open-source language R (Shiny). Information is updated every 4 hours.\\n\\nResultsThe dashboard is organized into three main parts. The \\\"Filter\\\" page presents all the KPIs, divided into five sections: i) general and gender-related indicators, ii) number of tests and positivity rate, iii) cycle threshold and viral load, iv) test durations, and v) not valid results. Filtering allows to select a given period, a dedicated instrument, a given specimen, or a requester for instance. The \\\"Comparison\\\" page allows a custom charting of all the available variables, which represents more than 182 combinations. The \\\"Data\\\" page gives the user access to the raw data in table format, with the possibility of filtering, allowing for a deeper analysis and data download in Excel format.\\n\\nConclusionsThe dashboard, that gives a rapid access to a huge number of up-to-date information, represents a reliable and user-friendly tool improving the decision-making process, resource planning and quality management. The dashboard represent an added value for diagnosric laboratories during a pandemic, where rapid and efficient adaptation is mandatory.\",\n \"Comparison of Phase Angle Using Bioelectrical Impedance Analysis According to Device Type and Examination Posture\\nBackgroundBioelectrical impedance analysis (BIA) is gaining popularity as a body composition assessment tool for patients. Although it has been studied and validated in different populations, age groups, and clinical settings, including critically ill patients, there are concerns about BIA reproducibility and reliability in different device types and postures. This study aimed to evaluate the reliability of BIA according to different devices, postures, and lead types.\\n\\nMethodsCross-sectional observational data of 74 healthy volunteers (32 women and 42 men) were collected. We used two types of devices, three types of postures (standing, sitting, and lying), and two lead types (clamp lead and adhesive lead) to measure the whole-body phase angle (phA) at a single frequency of 50 kHz. The measurements were validated using the intraclass correlation coefficient (ICC) and Bland-Altman plot analysis.\\n\\nResultsAll phA measurements recorded with two types of devices, three different postures, and two types of leads were equivalent to each other (mean ICC = 0.9932, 95% confidence interval (CI) 0.9905-0.0053). The average mean difference in phA was 0.31 (95% CI 0.16- 0.46). The largest phA value was measured using BWA with an adhesive-type lead in the lying position. There were no differences between standing and sitting positions.\\n\\nConclusionThis is the first study to show the consistency and reliability of BIA in measuring phA using different devices, lead types, and postures. This could provide the confidence that BIA can be used in various clinical settings.\",\n \"Age-based differences in quantity and frequency of consumption when screening for harmful alcohol use\\nAimsSurvey questions on usual quantity and frequency of alcohol consumption are regularly used in screening tools to identify drinkers requiring intervention. The aim of this study is to examine age-based differences in quantity and frequency of alcohol consumption on the Alcohol Use Disorders Identification Test (AUDIT) and how this relates to the prediction of harmful or dependent drinking\\n\\nDesignCross sectional survey\\n\\nSettingAustralia.\\n\\nParticipantsData was taken from 17,399 respondents who reported any alcohol consumption in the last year and were aged 18 and over from the 2016 National Drug Strategy Household Survey, a broadly representative cross-sectional survey on substance use.\\n\\nMeasurementRespondents were asked about their frequency of consumption, usual quantity per occasion and the other items of the AUDIT.\\n\\nFindingsIn older drinkers, quantity per occasion ({beta}=0.53 (0.43, 0.64 95%CI in 43-47 year olds as an example) is a stronger predictor of dependence than frequency per occasion ({beta}=0.24 (0.17, 0.31). In younger drinkers the reverse was true with frequency a stronger predictor ({beta}=0.54 (0.39, 0.69) in 23-27 year olds) than quantity ({beta}=0.26 (0.18, 0.34) in 23-27 year olds). Frequency of consumption was not a significant predictor of dependence in respondents aged 73 and over ({beta}=-0.03 (-0.08, 0.02)). Similar patterns were found when predicting harmful drinking. Despite this, since frequency of consumption increased steadily with age, the question on frequency was responsible for at least 65% of AUDIT scores in drinkers aged 53 and over.\\n\\nConclusionsThe items with a weaker association with dependent or harmful drinking in younger and older drinkers are the same items with the strongest influence on overall AUDIT scores. Further investigation into age-specific scoring of screening tools is recommended.\",\n \"Automated Detection of Candidate Subjects with Cerebral Microbleeds using Machine Learning\\nCerebral microbleeds (CMBs) appear as small, circular, well defined hypointense lesions of a few mm in size on T2*-weighted gradient recalled echo (T2*-GRE) images and appear enhanced on susceptibility weighted images (SWI). Due to their small size, contrast variations and other mimics (e.g. blood vessels), CMBs are highly challenging to detect automatically. In large datasets (e.g. the UK Biobank dataset), exhaustively labelling CMBs manually is difficult and time consuming. Hence it would be useful to preselect candidate CMB subjects in order to focus on those for manual labelling, which is essential for training and testing automated CMB detection tools on these datasets. In this work, we aim to detect CMB candidate subjects from a larger dataset, UK Biobank, using a machine learning-based, computationally light pipeline. For our evaluation, we used 3 different datasets, with different intensity characteristics, acquired with different scanners. They include the UK Biobank dataset and two clinical datasets with different pathological conditions. We developed and evaluated our pipelines on different types of images, consisting of SWI or GRE images. We also used the UK Biobank dataset to compare our approach with alternative CMB preselection methods using non-imaging factors and/or imaging data. Finally, we evaluated the pipelines generalisability across datasets. Our method provided subject-level detection accuracy > 80% on all the datasets (withindataset results), and showed good generalisability across datasets, providing a consistent accuracy of over 80%, even when evaluated across different modalities.\",\n \"Characterizing Sleep Disorders in an Autism-Specific Collection of Electronic Health Records\\nBackgroundSleep problems are common in individuals with autism spectrum disorder (ASD). This study reviews one detailed approach to querying the electronic health record (EHR).\\n\\nMethodsWe developed methods for identifying individuals with ASD and defined their sleep problems using International Classification of Diseases (ICD) codes or key words. We examined treatment responses to melatonin.\\n\\nResultsSleep problems were documented in 86% of patients and using specific keywords yielded more sleep diagnoses than ICD codes alone. About two-thirds of patients benefitted from melatonin.\\n\\nConclusionsOur study provides a framework for using deidentified medical records to characterize sleep, a common co-occurring condition, in ASD. Using specific keywords could be helpful in future work that queries the EHR.\",\n \"Frequent Cocaine Use is Associated with Larger HIV Latent Reservoir Size\\nBackgroundWith the success of combination antiretroviral therapy, HIV is now treated as a chronic disease, including among drug users. Cocaine--one of the most frequently abused illicit drugs among persons living with HIV (PLWH)-- slows the decline of viral production after ART, and is associated with higher HIV viral load, more rapid HIV progression, and increased mortality. We examined the impact of cocaine use on the CD4+ T-cell HIV Latent Reservoir (HLR) in virally suppressed PLWH.\\n\\nMethodsCD4+ T-cell genomic DNA was isolated from peripheral blood mononuclear cells collected from 434 women of diverse ancestry (i.e., 75% Black, 14% Hispanic, 12% White) who self-reported cocaine use (i.e., 160 cocaine users, 59 prior users, 215 non-users). Participants had to have an undetectable HIV RNA viral load measured by commercial assay for at least 6 months. The Intact Proviral HIV DNA Assay (IPDA) provided estimates of intact provirus per 106 CD4+ T-cells.\\n\\nResultsThe HLR size differed by cocaine use (i.e., median [interquartile range]: 72 [14, 193] for never users, for prior users 165 [63, 387], 184 [28, 502] for current users), which was statistically significantly larger in both prior (p=0.023) and current (p=0.001) cocaine users compared with never users.\\n\\nConclusionOur study is the first to provide evidence that cocaine use may contribute to a larger replication competent HLR in CD4* T-cells among virologically suppressed women living with HIV. Our findings are important, because women are under-represented in HIV reservoir studies and in studies of the impact of cocaine use on outcomes among PLWH.\",\n \"A rapid assessment of wastewater for genomic surveillance of SARS-CoV-2 variants at sewershed scale in Louisville, KY\\nIn this communication, we report on the genomic surveillance of SARS-CoV-2 using wastewater samples in Jefferson County, KY. In February 2021, we analyzed seven wastewater samples for SARS-CoV-2 genomic surveillance. Variants observed in smaller catchment areas, such as neighborhood manhole locations, were not necessarily consistent when compared to associated variant results in downstream treatment plants, suggesting catchment size or population could impact the ability to detect diversity.\",\n \"Obesity may hamper SARS-CoV-2 vaccine immunogenicity\\nBackgroundThe first goal of the study was to analyse the antibody titre 7 days after the second dose of BNT162b2 vaccine in a group of 248 healthcare workers (HCW). The second goal was to analyse how the antibody titre changes in correlation with age, gender and BMI.\\n\\nMethodsParticipants were assigned to receive the priming dose at baseline and booster dose at day 21. Blood and nasopharyngeal swabs were collected at baseline and 7 days after second dose of vaccine.\\n\\nFindings248 HWCs were analysed, 158 women (63.7%) and 90 men (36.3%). After the second dose of BNT162b2 vaccine, 99.5% of participants developed a humoral immune response.\\n\\nThe geometric mean concentration of antibodies among the vaccinated subjects after booster dose (285.9 AU/mL 95% CI: 249.5-327.7); was higher than that of human convalescent sera (39.4 AU/mL, 95% CI: 33.1-46.9), with p<0.0001. The antibody titre was found to be higher in young and female participants. A strong correlation of BMI classes with antibody titres was noticed: humoral response was more efficient in the group with under- and normal-weight vs the group with pre- and obesity participants (p<0.0001 at T1).\\n\\nInterpretationThese findings imply that females, lean and young people have an increased capacity to mount humoral immune responses compared to males, overweight and the older population. Although further studies are needed, this data may have important implications for the development of vaccination strategies for COVID-19, particularly in obese people.\\n\\nFundingNone\",\n \"Helmet noninvasive ventilation for COVID-19 patients (Helmet-COVID): study protocol for a multicenter randomized controlled trial\\nIntroductionNoninvasive ventilation delivered by helmet is has been used for respiratory support of patients with acute hypoxemic respiratory failure due to COVID-19 pneumonia. The aim of this study is to compare helmet noninvasive ventilation with usual care versus usual care alone to reduce the mortality.\\n\\nMethods and analysisThis is a multicenter, pragmatic, parallel, randomized controlled trial that compares helmet noninvasive ventilation with usual care to usual care alone in 1:1 ratio. A total of 320 patients will be enrolled in this study. The primary outcome is 28-day all-cause mortality. The primary outcome will be compared between the two study groups in the intention-to-treat and per-protocol cohorts. An interim analysis will be conducted for both safety and effectiveness.\\n\\nEthics and disseminationApprovals are obtained from the Institutional Review Boards (IRBs) of each participating institution. Our findings will be published in peer-review journals and presented at relevant conferences and meetings.\\n\\nTrial registration numberNCT04477668 registered on July 20, 2020\\n\\nArticle SummaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIThis trial compares helmet NIV to usual care for respiratory support of patients with acute hypoxemic respiratory failure due to COVID-19 pneumonia.\\nC_LIO_LIThe trial is a multi-center, pragmatic, parallel randomized controlled trial.\\nC_LIO_LIThe main limitation is the unblinded design due to the nature of the intervention.\\nC_LI\",\n \"Identification of shared and differentiating genetic risk for autism spectrum disorder, attention deficit hyperactivity disorder and case subgroups.\\nAttention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable neurodevelopmental disorders with a considerable overlap in their genetic etiology. We dissected their shared and distinct genetic architecture by cross-disorder analyses of large data sets, including samples with information on comorbid diagnoses. We identified seven loci shared by the disorders and the first five genome-wide significant loci differentiating the disorders. All five differentiating loci showed opposite allelic directions in the two disorders separately as well as significant associations with variation in other traits e.g. educational attainment, items of neuroticism and regional brain volume. Integration with brain transcriptome data identified and prioritized several significantly associated genes. Genetic correlation of the shared liability across ASD-ADHD was strong for other psychiatric phenotypes while the ASD-ADHD differentiating liability correlated most strongly with cognitive traits. Polygenic score analyses revealed that individuals diagnosed with both ASD and ADHD are double-burdened with genetic risk for both disorders and show distinctive patterns of genetic association with other traits when compared to the ASD-only and ADHD-only subgroups. The results provide novel insights into the biological foundation for developing just one or both of the disorders and for driving the psychopathology discriminatively towards either ADHD or ASD.\",\n \"Use of Convalescent Plasma Therapy among Hospitalized Coronavirus Disease 2019 (COVID-19) Patients: A Single-Center Experience\\nCOVID-19 Disease has strained our healthcare system. Convalescent plasma has been used to treat emerging infectious diseases -Influenza A/B, SARS-CoV, Ebola virus and now SARS-CoV 2.\\n\\nOBJECTIVEThis study aims to determine the outcome and clinical course of COVID-19 patients who received convalescent plasma transfusion at Cardinal Santos Medical Center.\\n\\nMETHODSThis is a retrospective cohort analytical study of 75 patients who received convalescent plasma.\\n\\nRESULTSMedian time from admission to CP transfusion was 3 days. Majority of patients received additional therapies including dexamethasone (100%); Remdesivir (95%); antibiotics (100%), tocilizumab (65%); hemoperfusion (88%) or combination of these. Among the survivors, the median LOS was 15 days while non-survivors have a median LOS of 6 days. One patient (1.33%) had mild transfusion reaction. Four patients (5.33%) developed DVT despite anti-coagulation. There was improvement in the inflammatory markers (LDH pvalue 0.04, CRP pvalue 0.00, Ferritin pvalue 0.0001). There was improvement in the pulmonary parameters -increase in mean PaO2, mean SaO2, and mean PFR; and decrease in mean FiO2 and mean RR post-treatment. Median LOS is 14 days for the CP group vs 11 days for the non-CP group. Mortality rate among the CP group is 25.33% while the non-CP group was 26.67%. LOS and mortality rate did not reach statistical significance.\\n\\nCONCLUSIONSThere was no significant difference in mortality and length of hospital stay in patients given CP vs controls. CP might have a role in the improvement of inflammatory markers and pulmonary status.\",\n \"Cell-Mediated Immune Response after COVID 19 Vaccination in Patients with Inflammatory Bowel Disease\\nIntroductionMost patients with IBD mount an antibody response to mRNA COVID-19 vaccines, but few studies have evaluated the cell mediated immune response (CMIR).\\n\\nMethodsWe performed a prospective study (HERCULES) to evaluate CMIR among patients with IBD and healthy controls (HC) after completion of the primary series of mRNA COVID-19 vaccines.\\n\\nResultsOne hundred 158 patients with IBD and 20 HC were enrolled. The majority (89%) of IBD patients developed a CMIR which was not different than HC (94%, p=0.6667). There was no significant difference (p=0.5488) in CMIR response between those not immunosuppressed (median 255 Spike T cells/million PBMC, IQR 146, 958) and immunosuppressed (median 377, IQR 123, 1440). There was also no correlation between antibody responses and CMIR (p=0.5215)\\n\\nDiscussionMost patients with IBD achieved CMIR to a COVID-19 vaccine. Future studies are needed evaluating sustained CMIR and clinical outcomes.\",\n \"Trends in clinical characteristics and associations of severe non-respiratory events related to SARS-CoV-2\\nBackgroundThe 2019 novel coronavirus (SARS-CoV-2) is reported to result in both respiratory and non-respiratory severe health outcomes, but quantitative assessment of the risk - while adjusting for underlying risk driven by comorbidities - is not yet established.\\n\\nMethodsA retrospective observational study using electronic health records of 9,344,021 individuals across the U.S. with at-least 1 year of clinical history and followed up throughout 2020.\\n\\nResults131,329 individuals were associated with SARS-CoV-2 infection by January 6, 2021 in three distinct surges. While the age and number of preexisting conditions had decreased throughout the pandemic, the characteristics of those who experienced severe health events did not.\\n\\nDuring the second surge, between June 7 and November 18, 2020, 425,988 individuals in the base cohort were admitted to emergency rooms or hospitals. Among them, 15,486 were detected with SAR-CoV-2 within few days of admission. Significant adjusted odds ratios were observed between SARS-CoV-2 infection and the following severe health events: respiratory (4.38, 95% confidence interval 4.16- 4.62), bacterial pneumonia (3.25, 2.76-3.83), sepsis (1.71, 1.53-1.91), renal (1.69, 1.57-1.83), hematologic/immune (1.32, 1.20-1.45), neurological (1.23, 1.09-1.38).\\n\\nConclusionsSARS-CoV-2 infection among hospitalized patients is associated with non-negligible increased risk of severe events including multiple non-respiratory ones. These associations, which complement recent studies, are persistent even after accounting for sources of selection and confounding bias, increasing the confidence they are not spurious.\",\n \"Epigenetic impairment and blunted transcriptional response to Mycobacterium tuberculosis of alveolar macrophages from persons living with HIV\\nPersons living with HIV (PLWH) are at increased risk of tuberculosis (TB). HIV-associated TB is often the result of recent infection with Mycobacterium tuberculosis (Mtb) followed by rapid progression to disease. Alveolar macrophages (AM) are the first cells of the innate immune system that engage Mtb, but how HIV and antiretroviral therapy (ART) impact on the anti-mycobacterial response of AM is not known. To investigate the impact of HIV and ART on the transcriptomic and epigenetic response of AM to Mtb, we obtained AM by bronchoalveolar lavage from 20 PLWH receiving ART, 16 control subjects who were HIV-free (HC), and 14 subjects who received ART as pre-exposure prophylaxis (PrEP) to prevent HIV infection.\\n\\nFollowing in-vitro challenge with Mtb, AM from each group displayed overlapping but distinct profiles of significantly up- and down-regulated genes in response to Mtb. Compared to HC subjects, AM isolated from PLWH and PrEP subjects presented a substantially weaker transcriptional response. Further investigation of chromatin structure revealed that AM from control subjects challenged with Mtb responded with pronounced accessibility changes in over ten thousand regions. In stark contrast, AM obtained from PLWH and PrEP subjects displayed no significant changes in their chromatin state in response to Mtb. Collectively, these results revealed a previously unknown adverse effect of ART on the epigenetic landscape and transcriptional responsiveness of AM.\",\n \"Comparative and Integrated Analysis of Plasma Extracellular Vesicles Isolations Methods in Healthy Volunteers and Patients Following Myocardial Infarction\\nPlasma extracellular vesicle (EV) number and composition are altered following myocardial infarction (MI), but to properly understand the significance of these changes it is essential to appreciate how the different isolation methods affect EV characteristics, proteome and sphingolipidome. Here, we compared plasma EV isolated from platelet-poor plasma from four healthy donors and six MI patients at presentation and 1-month post-MI using ultracentrifugation, polyethylene glycol precipitation, acoustic trapping, size-exclusion chromatography (SEC) or immunoaffinity capture. The isolated EV were evaluated by Nanoparticle Tracking Analysis, Western blot, transmission electron microscopy, an EV-protein array, untargeted proteomics (LC-MS/MS) and targeted sphingolipidomics (LC-MS/MS). The application of the five different plasma EV isolation methods in patients presenting with MI showed that the choice of plasma EV isolation method influenced the ability to distinguish elevations in plasma EV concentration following MI, enrichment of EV-cargo (EV-proteins and sphingolipidomics) and associations with the size of the infarct determined by cardiac magnetic resonance imaging 6 months-post-MI. Despite the selection bias imposed by each method, a core of EV associated proteins and lipids was detectable using all approaches. However, this study highlights how each isolation method comes with its own idiosyncrasies and makes the comparison of data acquired by different techniques in clinical studies problematic.\",\n \"Blood cytokine analysis suggests that SARS-CoV-2 infection results in a sustained tumour promoting environment in cancer patients\\nCytokines, chemokines and (angiogenic) growth factors (CCGs) have been shown to play an intricate role in the progression of both solid and haematological malignancies. Recent studies have shown that SARS-CoV-2 infection leads to worse outcome in cancer patients, especially in haematological malignancy patients. Here, we investigated how SARS-CoV-2 infection impacts the already altered CCG levels in solid or haematological malignancies, specifically whether there is a protective effect or rather a potentially higher risk for major COVID-19 complications in cancer patients due to elevated CCGs linked to cancer progression. Serially analysing immune responses with 55 CCGs in cancer patients under active treatment with or without SARS-CoV-2 infection, we first showed that cancer patients without SARS-CoV-2 infection (n=54) demonstrate elevated levels of 35 CCGs compared to the non-cancer, non-infected control group of health care workers (n=42). Of the 35 CCGs, 19 were common to both solid and haematological malignancy groups and comprised previously described cytokines such as IL-6, TNF-, IL-1Ra, IL-17A, and VEGF, but also several less well described cytokines/chemokines such as Fractalkine, Tie-2, and T cell chemokine CTACK. Importantly, we show here that 7 CCGs are significantly altered in SARS-CoV-2 exposed cancer patients (n=52). Of these TNF-, IFN-{beta}, TSLP and sVCAM-1, identified to be elevated in haematological cancers, are also known tumour-promoting factors. Longitudinal analysis conducted over 3 months showed persistence of several tumour-promoting CCGs in SARS-CoV-2 exposed cancer patients. These data urge for increased vigilance for haematological malignancy patients as a part of long COVID follow-up.\",\n \"Specific concussion curriculum: Does it improve residents' comfort, Knowledge and In-Training Examination Scores? A pilot study.\\nBackgroundConcussion is defined as aberrant brain function consequent to traumatic injury characterized by disorientation or loss of consciousness or memory. If concussions are not recognized and treated appropriately, they can cause significant morbidity. Because [~]20% of sports-related concussions occur in juveniles, pediatricians must be able to treat this injury. Our primary objective was to assess the comfort and competence of pediatric residents in managing patients with concussions. Secondary objective was to assess the change in the In-Training Examination (ITE) scores after instituting a novel multimodal concussion curriculum.\\n\\nMethodFrom February to June 2019, all pediatric residents (N = 24) were required to complete a multimodal concussion curriculum, including board review-style questions, lectures, and rotation in a concussion clinic. Residents voluntarily participated in a pre-and post-curriculum survey. ITE scores from 2018 and 2019 were compared.\\n\\nResultsTwenty-three of 24 (96%) residents completed both pre- and post-curriculum surveys; of those, 17 (74%) had matched identifiers. Most residents (82%) want more education about concussion management. Residents scores on knowledge-based questions increased an average of 0.64 questions, with PGY-1 showing the most improvement. The proportion of residents who correctly answered the ITE head injury/concussion questions increased from 0.33 to 0.88. The concussion clinic was identified as the most helpful tool.\\n\\nConclusionTo better educate pediatric residents about concussions, we propose a unique multimodal curriculum. We found improved self-assessed comfort and performance on knowledge-based questions and the ITE. We recommend that pediatric and other residency training programs consider implementing this type of curriculum.\",\n \"Altered reward network responses to social touch in major depression\\nIntroductionAffective touch is highly rewarding and an integral part of social relationships. Major depressive disorder (MDD) is characterized by severe impairments in reward processing, but the neural effects of social touch in MDD are still elusive.\\n\\nObjectiveWe aimed to determine whether the neural processing of social touch is impaired in MDD and to assess the impact of antidepressant therapy.\\n\\nMethodsBefore and after antidepressant treatment, 53 MDD patients and 41 healthy controls underwent functional magnetic resonance imaging (fMRI) while receiving social touch. We compared neural responses to social touch in the reward network, behavioral ratings of touch comfort and general aversion to interpersonal touch in MDD patients to controls. Additionally, we examined the effect of treatment response on those measures.\\n\\nResultsClinical symptoms decreased after treatment and 43.4% of patients were classified as responders. Patients reported higher aversion to social touch and lower comfort ratings during the fMRI paradigm than controls. Patients showed reduced responses to social touch in the nucleus accumbens, caudate nucleus and putamen than controls, both before and after treatment. Non-responders exhibited blunted response in the caudate nucleus and the insula compared to responders, again irrespective of treatment.\\n\\nConclusionsThese findings confirm our hypothesis that interpersonal touch as an indicator of social reward processing is impaired in MDD. Persistent dysfunctional processing of social touch despite clinical improvements may constitute a latent risk factor for social withdrawal and isolation. New treatment approaches are necessary to specifically target social reward processing and disturbed body awareness in MDD.\",\n \"Competitive fitness of emerging SARS-CoV-2 variants is linked to their Distinctiveness relative to preceding lineages from that region\\nThe COVID-19 pandemic has seen the persistent emergence of fitter Variants of Concern (VOCs) that have successfully out-competed circulating strains, but the determinants of viral fitness remain unknown. Here we define Distinctiveness of SARS-CoV-2 sequences based on a proteome-wide comparison with all prior sequences from the same geographical region. From the perspective of viral evolution, Distinctiveness captures \\\"regional herd exposure\\\" and has the advantage over the canonical concept of mutation, which relies foremost on the reference ancestral sequence that is invariant over time. By assessing the correlation between Distinctiveness and change in prevalence for all circulating lineages in each region when a new lineage is introduced, we find that the relative Distinctiveness of emergent SARS-CoV-2 lineages is associated with their competitive fitness (Pearson r = 0.67). Further, by assessing the Delta variant in India versus Brazil, we show that the same lineage can have different Distinctiveness-contributing positions in different geographical regions depending on the other variants that previously circulated in those regions. Finally, analysis of Omicron lineages in India and USA shows the BA.1 and BA.2 sub-lineages have comparable distinctiveness, suggesting that they may have similar levels of competitive fitness. Overall, our study proposes that augmenting the ongoing surveillance of highly mutated variants with real-time assessment of Distinctiveness can aid in achieving robust pandemic preparedness.\",\n \"Cause-specific student absenteeism monitoring in K-12 schools for detection of increased influenza activity in the surrounding community - Dane County, Wisconsin, 2014-2020\\nBackgroundSchools are primary venues of influenza amplification with secondary spread to communities. We assessed K-12 student absenteeism monitoring as a means for early detection of influenza activity in the community.\\n\\nMaterials and MethodsBetween September 2014 and March 2020, we conducted a prospective observational study of all-cause (a-TOT), illness-associated (a-I), and influenza-like illness-associated (a-ILI) absenteeism within the Oregon School District (OSD), Dane County, Wisconsin. Absenteeism was reported through the electronic student information system. Students were visited at home where pharyngeal specimens were collected for influenza RT-PCR testing. Surveillance of medically-attended laboratory-confirmed influenza (MAI) occurred in five primary care clinics in and adjoining OSD. Poisson general additive log linear regression models of daily counts of absenteeism and MAI were compared using correlation analysis.\\n\\nFindingsInfluenza was detected in 723 of 2,378 visited students, and in 1,327 of 4,903 MAI patients. Over six influenza seasons, a-ILI was significantly correlated with MAI in the community (r = 0.57; 95% CI: 0.53--0.63) with a one-day lead time and a-I was significantly correlated with MAI in the community (r = 0.49; 0.44-0.54) with a 10-day lead time, while a-TOT performed poorly (r = 0.27; 0.21--0.33), following MAI by six days.\\n\\nDiscussionSurveillance using cause-specific absenteeism was feasible and performed well over a study period marked by diverse presentations of seasonal influenza. Monitoring a-I and a-ILI can provide early warning of seasonal influenza in time for community mitigation efforts.\",\n \"Biomarker-guided neuromodulation aids memory in traumatic brain injury\\nTraumatic brain injury (TBI) is a leading cause of cognitive disability in adults, often characterized by marked deficits in episodic memory and executive function. Prior studies have found that direct electrical stimulation of the temporal cortex yielded improved memory in epilepsy patients, but it is not clear if these results generalize to patients with a specific history of TBI. Here we asked whether applying closed-loop, direct electrical stimulation to lateral temporal cortex could reliably improve memory in a TBI cohort. Among a larger group of patients undergoing neurosurgical evaluation for refractory epilepsy, we recruited a subset patients with a history of moderate-to-severe TBI. By analyzing neural data from indwelling electrodes as patients studied and recalled lists of words, we trained personalized machine-learning classifiers to predict momentary fluctuations in mnemonic function in each patient. We subsequently used these classifiers to trigger high-frequency stimulation of the lateral temporal cortex (LTC) at moments when memory was predicted to fail. This strategy yielded a 19% boost in recall performance on stimulated as compared with non-stimulated lists (P = 0.012). These results provide a proof-of-concept for using closed-loop stimulation of the brain in treatment of TBI-related memory impairment.\",\n \"Recurrent aphthous stomatitis affects quality of life\\nRecurrent aphthous stomatitis are recurrent oral ulcers that can affect important daily activities, such as oral hygiene and eating. In this prospective case-control study (n=62), we show that, during ulcer episodes, patients report a poorer quality of life compared to ulcer-free periods, and that this impact is positively associated with the number and size of lesions. Our results suggest that, if intervened locally, general relief of the condition could be achieved.\",\n \"Physical activity and health: Findings from Finnish monozygotic twin pairs discordant for physical activity\\nGenetic and early environmental differences including early health habits associate with future health. To provide insight on the causal nature of these associations, monozygotic (MZ) twin pairs discordant for health habits provide an interesting natural experiment. Twin pairs discordant for leisure-time physical activity (LTPA) in early adult life are thus a powerful study design to investigate the associations between long-term LTPA and indicators of health and wellbeing. We have used this study design by identifying 17 LTPA discordant twin pairs from two Finnish twin cohorts and summarize key findings of these studies in this paper. The carefully characterized rare long-term LTPA discordant MZ twin pairs have participated in multi-dimensional clinical examinations. The occurrence of type 2 diabetes and death has been evaluated on the basis of prospective questionnaire data and register follow-up among a larger number of twin pairs. Key findings highlight that, compared to less active twins in such MZ twin pairs, the twins with higher long-term LTPA have higher physical fitness, reduced body fat, reduced visceral fat, reduced liver fat, increased lumen diameters of conduit arteries to the lower limbs, increased bone mineral density in loaded bone areas, increased high-density lipoprotein cholesterol levels and reduced occurrence of type 2 diabetes. However, we have not been able to document differences in the life expectancy between the less and more active twin siblings of the LTPA discordant MZ twin pairs. The findings are in agreement with intervention studies but not with all observational studies in which genetic factors are not controlled for.\",\n \"Performance evaluation of a multinational data platform for critical care in Asia\\nObjectiveWe aimed to evaluate the quality of a multinational intensive care unit (ICU) network of registries of critically ill patients established in seven Asian low and middle income countries (LMICs).\\n\\nMethodsThe Critical Care Asia federated registry platform enables ICUs to collect clinical, outcome and process data for aggregate and unit-level analysis. The evaluation used the standardised criteria of the Directory of Clinical Databases (DoCDat) and a framework for data quality assurance in medical registries. Six reviewers assessed structure, coverage, reliability and validity of the ICU registry data. Case mix and process measures on patient episodes from June to December 2020 were analysed.\\n\\nResultsData on 20,507 consecutive patient episodes from 97 ICUs in Afghanistan, Bangladesh, India, Malaysia, Nepal, Pakistan and Vietnam were included. The quality level achieved according to the ten prespecified DoCDat criteria was high (average score 3.4 out of 4) as was the structural and organizational performance -- comparable to ICU registries in high-income countries. Identified strengths were types of variables included, reliability of coding, data completeness and validation. Potential improvements include extension of national coverage.\\n\\nConclusionThe Critical Care Asia platform evaluates well using standardised frameworks for data quality and equally to registries in resource-rich settings.\\n\\nFundingThis work was undertaken as part of the existing Wellcome Innovations Flagship award, Collaboration for Research, Improvement and Training in Critical CARE in ASIA (ref. 215522/Z/19/Z). The funder had no role in the decision to publish or in the preparation of this manuscript.\",\n \"The French Early Breast Cancer Cohort (FRESH): a resource for breast cancer research and evaluations of oncology practices based on the French National Healthcare System Database (SNDS)\\nBackgroundBreast cancer (BC) is the most frequent cancer and the leading cause of cancer-related death in women. The French National Cancer Institute has created a national cancer cohort to promote cancer research and improve our understanding of cancer using the National Health Data System (SNDS). This cohort amalgamates all cancer sites, with no detailed separate data for early BC.\\n\\nObjectivesWe describe the French Early Breast Cancer Cohort (FRESH).\\n\\nMethodsAll French women aged 18 years or over, with early-stage BC newly diagnosed between January 1, 2011 and December 31, 2017, treated by surgery and registered in the general health insurance coverage plan were included in the cohort. Patients with suspected locoregional or distant metastases at diagnosis were excluded. BC treatments (surgery, chemotherapy, targeted therapy, radiotherapy, endocrine therapy), and diagnostic procedures (biopsy, cytology, imaging) were extracted from hospital discharge reports, outpatient care notes or pharmacy drug delivery data. BC subtype was inferred from the treatments received.\\n\\nResultsWe included 235,368 patients with early BC in the cohort (median age: 60 years). BC subtype distribution was as follows: luminal (80.2%), triple-negative (TNBC, 9.5%); HER2+ (10.3%), or unidentifiable (n=44,388, 18.9% of the cohort). Most patients underwent radiotherapy (n=200,685, 85.3%) and endocrine therapy (n=165,655, 70.4%), and 38.3% (n=90,252) received chemotherapy. Treatments and care pathways are described.\\n\\nConclusionThe FRESH Cohort is an unprecedented population-based resource facilitating future large-scale real-life studies aiming to improve care pathways and quality of care for BC patients.\",\n \"Towards fast, routine blood sample quality evaluation by Probe Electrospray Ionization (PESI) metabolomics\\nAO_SCPLOWBSTRACTC_SCPLOWPESI-MS enables with its greatly simplified handling and fast result delivery the application field for high-throughput use in routine settings. In health care and research, pre-analytical errors often remain undetected and disrupt diagnosis, treatment, clinical studies and biomarker validations incurring high costs. This proof-of-principle study investigates the suitability of PESI-MS for robust, routine sample quality evaluation.\\n\\nOne of the most common pre-analytical quality issues in blood sampling are prolonged transportations times from bedside to laboratory promptly changing the metabolome. Here, human blood (n=50) was processed immediately or with a time delay of 3 h. The developed sample preparation method delivers ready-to-measure extracts in <8 min. PESI-MS spectra were measured in both ionization modes in 2 min from as little as 2 {micro}l plasma allowing 3 replicate measurements. The mass spectra contained 1200 stable features covering a broad chemical space covering major metabolic classes (e.g. fatty acids, lysolipids, lipids). The time delay of 3 h was predictable by using 18 features with AUC > 0.95 with various machine learning and was robust against loss of single features.\\n\\nOur results serve as first proof of principle for the unique advantages of PESI-MS in sample quality assessments. The results pave the way towards a fully automated, cost-efficient, user-friendly, robust and fast quality assessment of human blood samples from minimal sample amounts.\\n\\nGO_SCPLOWRAPHICALC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWABSTRACTC_SCPLOW\\n\\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=38 SRC=\\\"FIGDIR/small/21254782v1_ufig1.gif\\\" ALT=\\\"Figure 1\\\">\\nView larger version (15K):\\norg.highwire.dtl.DTLVardef@182233forg.highwire.dtl.DTLVardef@d801f9org.highwire.dtl.DTLVardef@169a2aaorg.highwire.dtl.DTLVardef@3673bb_HPS_FORMAT_FIGEXP M_FIG C_FIG\",\n \"Preliminary Rasch analysis of the Multidimensional Assessment of Interoceptive Awareness in adults with stroke\\nPurposeThe Multidimensional Assessment of Interoceptive Awareness (MAIA) measures interoceptive body awareness, which includes aspects such as attention regulation, self-regulation, and body listening. Our purpose was to validate the MAIA in adults with stroke using Rasch Measurement Theory.\\n\\nMethodsThe original MAIA has 32 items grouped into eight separately scored subscales that measure aspects of body awareness. Using Rasch Measurement Theory, we evaluated the unidimensionality of the entire scale and investigated person and item fit, person separation reliability, targeting, local item dependence, and principal components analysis of residuals.\\n\\nResultsForty-one adults with chronic stroke (average 3.8 years post-stroke, 13 women, and average age, 57{+/-}13 years) participated in the study. Overall fit (X2=62.26, p=0.26) and item fit were obtained after deleting 3 items and rescoring 26 items. One participant did not fit the model (2.44%). There were no floor (0.00%) or ceiling effects (0.00%). Local item dependence was found in 42 pairs. The person separation reliability was 0.91, and the person mean location was 0.06{+/-}1.12 logits.\\n\\nConclusionsThe MAIA demonstrated good targeting and reliability, as well as good item and person fit in adults with chronic stroke. A study with a larger sample size is needed to validate our findings.\",\n \"COVID-19 associated autoimmunity is a feature of severe respiratory disease - a Bayesian analysis.\\nBackgroundSerological and clinical features with similarities to systemic autoimmunity have been reported in severe COVID-19, but there is a lack of studies that include contemporaneous controls who do not have COVID-19.\\n\\nMethodsObservational cohort study of adult patients admitted to an intensive care unit with acute respiratory failure. Patients were divided into COVID+ and COVID- based on SARS-CoV-2 PCR from nasopharyngeal swabs and/or endotracheal aspirates. No COVID-19 specific interventions were given. The primary clinical outcome was death in the ICU within 3 months; secondary outcomes included in-hospital death and disease severity measures. Measurements including autoantibodies, were done longitudinally. ANOVA and Fishers exact test were used with =0.05, with a false discovery rate of q=0.05. Bayesian analysis was performed to provide credible estimates of the possible states of nature compatible with our results.\\n\\nResults22 COVID+ and 20 COVID- patients were recruited, 69% males, median age 60.5 years. Overall, 64% had anti-nuclear antibodies, 38% had antigen-specific autoantibodies, 31% had myositis related autoantibodies, and 38% had high levels of anti-cytokine autoantibodies. There were no statistically significant differences between COVID+ and COVID- for any of the clinical or autoantibody parameters. A specific pattern of anti-nuclear antibodies was associated with worse clinical severity for both cohorts.\\n\\nConclusionsSevere COVID+ patients have similar humoral autoimmune features as comparably ill COVID- patients, suggesting that autoantibodies are a feature of critical illness regardless of COVID-19 status. The clinical significance of autoimmune serology and the correlation with severity in critical illness remains to be elucidated.\",\n \"Virtually in Synch: A Pilot Study on Affective Dimensions of Dancing with Parkinson's during COVID- 19\\nLoss of social supports and community programs due to lockdowns and other measures associated with COVID-19 has been linked with concerns over mental health and feelings of isolation. These challenges can be particularly acute for the elderly and people living with chronic or pervasive health conditions. Dance for PD, a program specifically developed for people living with Parkinsons Disease, formerly offered in hundreds of locations around the globe, either halted or shifted to a virtual format. Our study investigates the transition of these dance-based programs to an online environment, with the aim of determining the extent to which a virtual format provides affective support or other benefits. Given the increased incidence of mental health problems and social isolation associated with COVID-19, this investigation aims to contribute to the development of better supports for vulnerable populations while helping us understand the specific contributions of dance-based programs in a virtual environment.\",\n \"Lesion Symptom Mapping of Domain-Specific Cognitive Impairments using Routine Imaging in Stroke\\nBackground and PurposeThis large-scale lesion-symptom mapping study aimed to investigate the necessary neuro-anatomical substrates of 5 cognitive domains frequently affected post stroke: Language, Attention, Praxis, Number, and Memory. This study aims to demonstrate the validity of using routine clinical brain imaging from a large, real-world patient cohort for lesion-symptom mapping.\\n\\nMethodsBehavioural cognitive screening data from the Oxford Cognitive Screen and routine clinical neuroimaging from 573 acute patients was used in voxel-based lesion-symptom mapping analyses. Patients were classed as impaired or not on each of the subtests within 5 cognitive domains.\\n\\nResultsDistinct patterns of lesion damage were associated with different domains. Language functions were associated with damage to left hemisphere fronto-temporal areas. Visuo-spatial functions were associated with damage to posterior occipital areas (Visual Field) and the right temporo-parietal region (Visual Neglect). Different memory impairments were linked to distinct voxel clusters within the left insular and opercular cortices. Deficits which were not associated with localised voxels (e.g. praxis, executive function) represent distributed functions.\\n\\nConclusionThe standardised, brief Oxford Cognitive Screen was able to reliably differentiate distinct neural correlates critically involved in supporting domain-specific cognitive abilities. By demonstrating and replicating known brain anatomy correlates within real-life clinical cohorts using routine CT scans, we open up VLSM techniques to a wealth of clinically relevant studies which can capitalise on using existing clinical brain imaging.\",\n \"Dopamine D1 agonist effects in late-stage Parkinson's disease\\nAO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSCurrent pharmacotherapy has limited efficacy and/or intolerable side effects in late-stage Parkinsons disease (LsPD) patients whose daily life depends primarily on caregivers and palliative care. Clinical metrics inadequately gauge efficacy in LsPD patients.\\n\\nObjectiveExplore if a D1/5 dopamine agonist will have efficacy in LsPD that will be detected most sensitively by caregivers in a phase I study.\\n\\nMethodsA double-blind controlled phase Ia/b study compared the D1/5 agonist PF-06412562 to levodopa/carbidopa in six LsPD patients. Throughout the study, caregivers were with the patients. Assessments included standard quantitative scales of motor function (MDS-UPDRS-III), alertness (Glasgow Coma and Stanford Sleepiness Scales), and cognition (Severe Impairment and Frontal Assessment Batteries) at baseline (Day 1) and thrice daily during drug testing (Days 2 and 3). Clinicians and caregivers completed clinical impression of change questionnaires, and caregivers participated in a qualitative exit interview. Blinded triangulation of quantitative and qualitative data was used to integrate findings.\\n\\nResultsNeither traditional scales, nor clinician impression of change, detected consistent differences between treatments in the five participants who completed the study. Conversely, the overall caregiver data strongly favored PF-06412562 over levodopa in four of five patients. The most meaningful improvements converged on motor, alertness, and engagement.\\n\\nConclusionD1/5 agonists may offer potential benefit for LsPD patients. Caregiver perspectives with mixed method analyses may overcome limitations in standard rater/clinician-based evaluations. Further studies are warranted and need to integrate caregiver input as an essential component of outcome evaluations.\\n\\nTrial Registration#ClinicalTrials.gov: NCT03665454\",\n \"Cystatin C is a glucocorticoid response gene predictive of cancer immunotherapy failure\\nThe secreted protein Cystatin C (CyC) is a cysteine protease inhibitor of incompletely characterized biomedical function, used clinically for estimation of glomerular filtration rate. Plasma CyC is elevated in many patients, especially when they receive glucocorticoid (GC) treatment. Here we empirically connect GCs with systemic regulation of CyC. First, we leveraged genome-wide association and structural equation modeling to determine the genetics of the latent trait CyC production in UK Biobank. Using multi-modal genomic, transcriptional, and experimental approaches, we demonstrated that CyC is a direct target of GC receptor, with GC-responsive CyC secretion exhibited by macrophages and cancer cells in vitro. Elevated serum CyC levels were positively correlated with GC levels in a murine model of cancer progression. Consistent with the coupling of CyC levels to GC signaling in a disease relevant manner, CyC predicted elevated all-cause and cancer-specific mortality in humans. These associations were orthogonally confirmed by a polygenic score (PGS) capturing germline predisposition to CyC production. This PGS predicted checkpoint immunotherapy failure in a combined clinical trial cohort of 685 metastatic cancer patients, with available germline exome sequencing. Taken together, our results demonstrate that CyC captures biomedically-relevant variations in endogenous GC activity, raising the possibility that CyC may be a direct effector of GC-induced immunosuppression and therefore a target for combination cancer immunotherapy.\",\n \"Comparative efficacy of interferential therapy, bronchodilators, and body positioning on asthma control and quality of life of patients with bronchial asthma: Study protocol\\nBackgroundInterferential therapy (IFT) is the application of two medium frequency currents to the skin to stimulate and activate different systems in the body using specific frequencies and frequency ranges. IFT aims to reduce myalgia in the chest and upper back, reduce muscular fatigue and induce mucus expectoration. This study is designed to compare the efficacy of IFT on asthma control and quality of life of asthma patients pre-and post-administration of bronchodilators and determine the most influential body position in its application.\\n\\nMethodsForty-eight (48) patients aged 18 years and above with bronchial Asthma attending the respiratory clinic at the Lagos State University Teaching Hospital, Ikeja (LASUTH) will be assessed for the study eligibility. The study design will be a double-blinded, randomized control trial with four intervention groups and four parallel placebo control groups. IFT will be administered as an intervention to patients on short and long-acting bronchodilators in an assigned fundamental body position for 20 minutes. Six continuous outcome variables at different points will be utilized as an outcome measure. Baseline Pulmonary Function Test (PFT) will be assessed on entry into the study, Quality of life and asthma control will be evaluated every two (2) weeks of the study. Data obtained will be analyzed using descriptive and inferential statistics of repeated ANOVA; P<0.05.\\n\\nDiscussionThe study outcome will compare the efficacy of IFT on Bronchial Asthma, identify its effect in different body positions, and compare the relationship between its application and the bronchodilator medication frequently used by the patients.\\n\\nTrial Registrationhttps://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=10942:\\n\\nPACTR202005807526130\",\n \"Using Artificial Intelligence-based models to predict the risk of Mucormycosis among COVID-19 Survivors: An Experience from India\\nIntroductionIndia reported a severe public health challenge not only due to the COVID-19 outbreak but also the increasing number of associated mucormycosis cases since 2021. This study aimed at developing artificial intelligence-based models to predict the risk of mucormycosis among the patients at the time of discharge from the hospital.\\n\\nMethodsThe dataset included 1229 COVID-19 positive patients, and additional 214 inpatients, COVID-19 positive as well as infected with mucormycosis. We used logistic regression, decision tree, and random forest, and the extreme gradient boosting algorithm. All our models were evaluated with 5-fold validation to derive a reliable estimate of the model error.\\n\\nResultsThe logistic regression, XGBoost, and random forest performed equally well with AUROC 95.0, 94.0, and 94.0 respectively. This study also determined the top five variables namely obesity, anosmia, de novo diabetes, myalgia, and nasal discharge, which showed a positive impact on the risk of mucormycosis.\\n\\nConclusionThe developed model has the potential to predict the patients at high risk and thus, consequently initiating preventive care or aiding in early detection of mucormycosis infection. Thus, this study holds potential for early treatment and better management of patients suffering from COVID-19 associated mucormycosis.\",\n \"Structural differences in adolescent brains can predict alcohol misuse\\nAlcohol misuse during adolescence (AAM) has been linked with disruptive structural development of the brain and alcohol use disorder. Using machine learning (ML), we analyze the link between AAM phenotypes and adolescent brain structure (T1-weighted imaging and DTI) at ages 14, 19, and 22 in the IMAGEN dataset (n [~] 1182). ML predicted AAM at age 22 from brain structure with a balanced accuracy of 78% on independent test data. Therefore, structural differences in adolescent brains could significantly predict AAM. Using brain structure at age 14 and 19, ML predicted AAM at age 22 with a balanced accuracy of 73% and 75%, respectively. These results showed that structural differences preceded alcohol misuse behavior in the dataset. The most informative features were located in the white matter tracts of the corpus callosum and internal capsule, brain stem, and ventricular CSF. In the cortex, they were spread across the occipital, frontal, and temporal lobes and in the cingulate cortex. Our study also demonstrates how the choice of the phenotype for AAM, the ML method, and the confound correction technique are all crucial decisions in an exploratory ML study analyzing psychiatric disorders with weak effect sizes such as AAM.\",\n \"A Study On Clinical Profile And Semiology In Complex Partial Seizures And Its Radiological Correlation\\nBackgroundEpilepsy is the second most common and frequently encountered neurological disorder which poses huge threat to known healthcare systems worldwide also causing financial, socio economic burden to the community. Complex Partial Seizures are a form of focal epileptic seizures that may impair consciousness.\\n\\nAim and objectivesOur motivation for the study was to understand the extent of patients with complex partial seizures associated with medial temporal lobe sclerosis.\\n\\nMaterials and methodsWe performed a cross sectional study about patients with complex partial seizures in Thanjavur medical college and hospital about their clinical profile and neuro-radiological correlation.\\n\\nStatistical analysis and resultsThrough our multimodal study with EEG, MRI on N=118 (female / male, age range, Most common age group-10-20 years, mean age of 23 years, SD-14 years, 66% males), we observed that atypical febrile seizures and fever provoked seizures has more association (18%) to complex partial seizures and to medial temporal lobe sclerosis in comparison to 12% in an earlier study.\\n\\nConclusionWe believe this study summarizes the complex partial seizure features, origin, and their link to Medial Temporal lobe Sclerosis in our subject pool from Thajavur, India.\\n\\nLimitationThere are some limitations to our study, especially with no video EEG monitoring and no invasive EEG recording. We aim to improve them in our future studies.\",\n \"Intra-individual reproducibility as essential determinant of clinical utility of smartphone-based neurological disability tests\\nTechnological advances, lack of medical professionals, high cost of face-to face encounters and disasters such as COVID19 pandemic, fuel the telemedicine revolution. Numerous smartphone apps have been developed to measure neurological functions. However, their psychometric properties are seldom determined. Lacking such data, it is unclear which designs underlie eventual clinical utility of the smartphone tests.\\n\\nWe have developed the smartphone Neurological Function Tests Suite (NeuFun-TS) and are systematically evaluating their psychometric properties against the gold-standard of complete neurological examination digitalized into NeurExTM App. This paper examines the fifth, and thus far the most complex NeuFun-TS test, the \\\"Spiral tracing\\\". We generated 40 features in the training cohort (22 healthy donors [HD] and 105 multiple sclerosis [MS] patients) and compared their intraclass correlation coefficient, fold-change between HD and MS and correlations with relevant clinical and imaging outcomes. We assembled the best features into machine-learning models and examined their performance in the independent validation cohort (56 MS patients).\\n\\nWe show that by aggregating multiple neurological functions, complex tests such as spiral tracing are susceptible to intra-individual variations, decreasing their reproducibility and thus, clinical utility. Simple tests, reproducibly measuring single function(s) that can be aggregated to increase sensitivity are preferable in app design.\",\n \"The inhibition of Macrophage Migration Inhibitory Factor by ISO-1 attenuates trauma-induced multiorgan dysfunction in rats\\nBackgroundMulti organ dysfunction syndrome caused by systemic inflammation after trauma is responsible for a high number of deaths worldwide. The cytokine Migration Inhibitory Factor (MIF) is recognized as a modulator of inflammatory response, however, its role in trauma is unknown. The aim of this study was to investigate (a) the levels of MIF in serum of trauma patients and of rats after hemorrhagic shock, (b) the potential of the MIF tautomerase activity inhibitor ISO-1 to reduce multi organ dysfunction syndrome in an acute and chronic hemorrhagic shock rat model and (c) whether treatment with ISO-1 attenuates NF-{kappa}B and NLRP3 activation in hemorrhagic shock.\\n\\nMethodsThe serum MIF-levels in trauma patients and rats with hemorrhagic shock were measured by Enzyme-Linked Immunosorbent Assays. Acute and chronic hemorrhagic shock rat models were performed to determine the influence of ISO-1 on multi organ dysfunction syndrome. The activation of NF-{kappa}B and NLRP3 pathways were analyzed by western blot.\\n\\nResultsWe demonstrated that (a) MIF levels are increased in serum of trauma patients on arrival in the emergency room and in serum of rats after hemorrhagic shock, (b) hemorrhagic shock caused organ damage and low blood pressure (after resuscitation) in rats, while (c) treatment of hemorrhagic shock rats with ISO-1 attenuated organ injury and dysfunction in acute and chronic hemorrhagic shock rat models and (d) decreased the activation of NF-{kappa}B and NLRP3 pathways.\\n\\nConclusionOur results point to a role of MIF in the pathophysiology of the organ injury and dysfunction caused by trauma/hemorrhage and indicate that MIF tautomerase activity inhibitors may have potential in the therapy of the multi organ dysfunction syndrome after trauma and/or hemorrhage.\",\n \"Identification of B.1.346 lineage of SARS-CoV-2 in Japan: Genomic evidence of re-entry of Clade 20C\\nObjectivesWhole SARS-CoV-2 genome sequencing from COVID-19 patients is useful for infection control and regional trends evaluation. We report a lineage data collected from hospitals in the Kanto region of Japan.\\n\\nMethodsWe performed whole genome sequencing in specimens of 198 COVID-19 patients at 13 collaborating hospitals in the Kanto region. Phylogenetic analysis and fingerprinting of the nucleotide substitutions underwent to differentiate and classify the viral lineages.\\n\\nResultsMore than 90% of the strains belonged to Clade 20B and two lineages (B.1.1.284 and B.1.1.214) have been detected predominantly in the Kanto region. However, one sample from a COVID-19 patient in November 2020, belonged to the B.1.346 lineage of Clade 20C, which has been prevalent in western United States. The patient had no history of overseas travel and no contact with anyone who had travelled abroad, suggesting that this strain appeared likely to have been imported from western United States, across the strict quarantine barrier.\\n\\nConclusionB.1.1.284 and B.1.1.214 have been identified predominantly in the Kanto region and B.1.346 of clade 20C in one patient was probably imported from western United States. These results illustrate that a decentralized network of hospitals can be significantly advantageous for monitoring regional molecular epidemiologic trends.\\n\\nHighlights{middle dot} Whole SARS-CoV-2 genome sequencing is useful for infection control\\n{middle dot} B.1.1.284 and B.1.1.214 have been identified predominantly in the Kanto region\\n{middle dot} B.1.346 of Clade 20C was detected in one COVID-19 patient in November\\n{middle dot} Molecular genomic data sharing provides benefits to public health against COVID-19\",\n \"Stroke recovery phenotyping through network trajectory approaches and graph neural networks\\nStroke is a leading cause of neurological injury characterized by impairments in multiple neurological domains including cognition, language, sensory and motor functions. Clinical recovery in these domains is tracked using a wide range of measures that may be continuous, ordinal, interval or categorical in nature, which presents challenges for standard multivariate regression approaches. This has hindered stroke researchers ability to achieve an integrated picture of the complex time-evolving interactions amongst symptoms. Here we use tools from network science and machine learning that are particularly well-suited to extracting underlying patterns in such data, and may assist in prediction of recovery patterns. To demonstrate the utility of this approach, we analyzed data from the NINDS tPA trial using the Trajectory Profile Clustering (TPC) method to identify distinct stroke recovery patterns for 11 different neurological domains at 5 discrete time points. Our analysis identified 3 distinct stroke trajectory profiles that align with clinically relevant stroke syndromes, characterized both by distinct clusters of symptoms, as well as differing degrees of symptom severity. We then validated our approach using graph neural networks to determine how well our model performed predictively for stratifying patients into these trajectory profiles at early vs. later time points post-stroke. We demonstrate that trajectory profile clustering is an effective method for identifying clinically relevant recovery subtypes in multidimensional longitudinal datasets, and for early prediction of symptom progression subtypes in individual patients. This paper is the first work introducing network trajectory approaches for stroke recovery phenotyping, and is aimed at enhancing the translation of such novel computational approaches for practical clinical application.\",\n \"The Sequence Effect Worsens over Time in Parkinson's disease and Responds to Open and Closed-Loop Subthalamic Nucleus Deep Brain Stimulation\\nBackgroundThe sequence effect is the progressive deterioration in speech, limb movement, and gait that leads to an inability to communicate, manipulate objects or walk without freezing of gait. Many studies have demonstrated a lack of improvement of the sequence effect from dopaminergic medication, however few studies have studied the metric over time or investigated the effect of open and closed-loop deep brain stimulation in people with PD.\\n\\nObjectiveTo investigate whether the sequence effect worsens over time and/or is improved on clinical (open-loop) and closed-loop deep brain stimulation (DBS).\\n\\nMethodsTwenty-one people with PD with bilateral STN DBS performed thirty seconds of instrumented repetitive wrist flexion extension and the MDS-UPDRS III off therapy, prior to activation of DBS and every six months for up to three years. A sub-cohort of ten people performed the task during randomized presentations of different intensities of STN DBS.\\n\\nResultsThe sequence effect was highly correlated with the overall MDS-UPDRS III score and the bradykinesia sub-score and worsened over three years. Increasing intensities of STN open-loop DBS improved the sequence effect and one subject demonstrated improvement on both open-loop and even further improvement on closed-loop DBS.\\n\\nConclusionsSequence effect in limb bradykinesia worsened over time off therapy due to disease progression but improved on open and closed-loop DBS. These results demonstrate that DBS is a useful treatment of the debilitating effects of the sequence effect in limb bradykinesia and that closed-loop DBS may offer added improvement.\",\n \"Clonality and timing of relapsing colorectal cancer metastasis revealed through whole-genome single-cell sequencing\\nBACKGROUNDRecurrence of tumor cells following local and systemic therapy is a significant hurdle in cancer. Most patients with metastatic colorectal cancer (mCRC) will relapse, despite resection of the metastatic lesions. A better understanding of the evolutionary history of recurrent lesions is thus required to identify the spatial and temporal patterns of metastatic progression and expose the genetic determinants of therapeutic resistance.\\n\\nMETHODSUtilizing a robust Bayesian phylogenetic approach, we analyzed a unique single-cell whole-genome sequencing dataset comprising 60 cells sampled from metastatic and recurrent hepatic lesions of a patient with a long-term disease course to investigate the origin, timing, and clonality of a colorectal metastatic relapse. We further tracked the changes in the size of the malignant cell population and evaluated the impact of the treatment strategy on the mutational landscape of this tumor.\\n\\nRESULTSOur results suggest that the recurrent lesion originated from the clonal expansion of a single drug-resistant metastatic lineage, which began to expand around one year before surgical resection of the relapse. We additionally observed substantial variability in the substitution rates along the tumor cell phylogeny and found a large number of mutations specific to the ancestral lineage that gave rise to the relapse, including non-silent mutations in CRC genes. Moreover, our results point to a substantial contribution of chemotherapy exposure to the overall mutational burden.\\n\\nCONCLUSIONSOur study suggests that resistant colorectal metastatic clones can quickly grow, even under strong drug-imposed pressure, highlighting the importance of profiling the genomic landscape of tumor lesions to identify mutations potentially contributing to treatment failure.\",\n \"Deep Learning Prediction of Biomarkers from Echocardiogram Videos\\nLaboratory blood testing is routinely used to assay biomarkers to provide information on physiologic state beyond what clinicians can evaluate from interpreting medical imaging. We hypothesized that deep learning interpretation of echocardiogram videos can provide additional value in understanding disease states and can predict common biomarkers results. Using 70,066 echocardiograms and associated biomarker results from 39,460 patients, we developed EchoNet-Labs, a video-based deep learning algorithm to predict anemia, elevated B-type natriuretic peptide (BNP), troponin I, and blood urea nitrogen (BUN), and abnormal levels in ten additional lab tests. On held-out test data across different healthcare systems, EchoNet-Labs achieved an area under the curve (AUC) of 0.80 in predicting anemia, 0.82 in predicting elevated BNP, 0.75 in predicting elevated troponin I, and 0.69 in predicting elevated BUN. We further demonstrate the utility of the model in predicting abnormalities in 10 additional lab tests. We investigate the features necessary for EchoNet-Labs to make successful predictions and identify potential prediction mechanisms for each biomarker using well-known and novel explainability techniques. These results show that deep learning applied to diagnostic imaging can provide additional clinical value and identify phenotypic information beyond current imaging interpretation methods.\",\n \"Mental Disorder Prevalence Among Populations Impacted by Coronavirus Pandemics: A Multilevel Meta-Analytic Study of COVID-19, MERS & SARS\\nObjectiveThrough a systematic review and meta-analysis of research on COVID-19, severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS) pandemics, we investigated whether mental disorder prevalence: (a) was elevated among populations impacted by coronavirus pandemics (relative to unselected populations reported in the literature), and (b) varied by disorder (undifferentiated psychiatric morbidity, anxiety, depressive, posttraumatic stress disorders [PTSD]) and impacted population (community, infected/recovered, healthcare provider, quarantined).\\n\\nMethodFrom 68 publications (N=87,586 participants), 808 estimates were included in a series of multilevel meta-analyses/regressions including random effects to account for estimates nested within studies.\\n\\nResultsMedian summary point prevalence estimates varied by disorder and population. Psychiatric morbidity (20%-56%), PTSD (10-26%) and depression (9-27%) were most prevalent in most populations. The highest prevalence of each disorder was found among infected/recovered adults (18-56%), followed by healthcare providers (11-28%) and community adults (11-20%). Prevalence estimates were often notably higher than reported for unselected samples. Sensitivity analyses demonstrated that overall prevalence estimates moderately varied by pandemic, study location, and mental disorder measure type.\\n\\nConclusionCoronavirus pandemics are associated with multiple mental disorders in several impacted populations. Needed are investigations of causal links between specific pandemic-related stressors, threats, and traumas and mental disorders.\",\n \"Development of a vocal biomarker for fatigue monitoring in people with COVID-19\\nObjectiveTo develop a vocal biomarker for fatigue monitoring in people with COVID-19.\\n\\nDesignProspective cohort study.\\n\\nSettingPredi-COVID data between May 2020 and May 2021.\\n\\nParticipantsA total of 1772 voice recordings was used to train an AI-based algorithm to predict fatigue, stratified by gender and smartphones operating system (Android/iOS). The recordings were collected from 296 participants tracked for two weeks following SARS-CoV-2 infection.\\n\\nprimary and secondary outcome measuresFour machine learning algorithms (Logistic regression, k-nearest neighbors, support vector machine, and soft voting classifier) were used to train and derive the fatigue vocal biomarker. A t-test was used to evaluate the distribution of the vocal biomarker between the two classes (Fatigue and No fatigue).\\n\\nResultsThe final study population included 56% of women and had a mean ({+/-}SD) age of 40 ({+/-}13) years. Women were more likely to report fatigue (P<.001). We developed four models for Android female, Android male, iOS female, and iOS male users with a weighted AUC of 79%, 85%, 86%, 82%, and a mean Brier Score of 0.15, 0.12, 0.17, 0.12, respectively. The vocal biomarker derived from the prediction models successfully discriminated COVID-19 participants with and without fatigue (t-test P<.001).\\n\\nConclusionsThis study demonstrates the feasibility of identifying and remotely monitoring fatigue thanks to voice. Vocal biomarkers, digitally integrated into telemedicine technologies, are expected to improve the monitoring of people with COVID-19 or Long-COVID.\",\n \"Mendelian gene identification through mouse embryo viability screening\\nThe diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful.\\n\\nA full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property. Here we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid or late gestation lethal.\\n\\nWe studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes, and found that the members of the early gestation lethal category show distinctive characteristics and a strong enrichment for genes linked with recessive forms of inherited metabolic disease.\\n\\nBased on these findings, we explored a gene similarity approach for novel gene discovery focused on this subset of lethal genes. Finally, we investigated unsolved cases from the 100,000 Genomes Project recruited under this disease category to look for signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes and highlight two novel candidates with phenotypic overlap between the patients and the mouse knockout.\",\n \"Automatic Identification of Tinnitus Malingering Based on Overt and Covert Behavioral Responses During Psychoacoustic Testing\\nTinnitus, or ringing in the ears, is a prevalent condition that imposes a substantial health and financial burden on the patient and to society. The diagnosis of tinnitus, like pain, relies on patient self-report. Subjective self-report measures can complicate the distinction between actual and fraudulent claims and obscure accurate severity assessments. In this study, we combined tablet-based self-directed hearing assessments with neural network classifiers to objectively determine tinnitus severity, and to differentiate participants with tinnitus (N=24) from a malingering cohort, who were instructed to feign an imagined tinnitus percept (N=28). We identified clear differences between the groups, both in their overt rating of tinnitus severity but also covert differences in their fingertip movement trajectories on the tablet surface as they performed the reporting assay. Using only 10 minutes of data, we achieved 81% accuracy classifying patients vs malingerers (ROC AUC=0.88) with leave-one-participant-out cross validation. Objective measurements of tinnitus will improve estimates of tinnitus prevalence and help to prioritize and direct funds for tinnitus compensation.\",\n \"A mixed methods study of seasonal influenza vaccine hesitancy in adults with chronic respiratory conditions\\nBackgroundSeasonal influenza vaccination is recommended for patients with chronic respiratory conditions, but uptake is suboptimal. We undertook a comprehensive mixed methods study in order to examine the barriers and enablers to influenza vaccination in patients with chronic respiratory conditions.\\n\\nMethodsMixed methods including a survey (n=429) which assessed socio-demographics and the psychological factors associated with vaccine uptake (i.e. confidence, complacency, constraints, calculation and collective responsibility) with binary logistic regression analysis. We also undertook focus groups and interviews (n=59) to further explore barriers and enablers to uptake using thematic analysis.\\n\\nResultsThe survey analysis identified that older participants were more likely to accept the vaccine, as were those with higher perceptions of collective responsibility around vaccination, lower levels of complacency, and lower levels of constraints. Thematic analysis showed that concerns over vaccine side effects, lack of tailored information and knowledge, and a lack of trust and rapport with healthcare professionals were key barriers. In contrast, the importance of feeling protected, acceptance of being part of an at-risk group, and feeling a reduced sense of vulnerability after vaccination were seen as key enablers.\\n\\nConclusionsOur findings showed that the decision to accept a vaccine against influenza is influenced by multiple sociodemographic and psychological factors. Future interventions should provide clear and transparent information about side effects and be tailored to patients with chronic respiratory conditions. Interactions between patients and their healthcare providers have a particularly important role to play in helping patients address their concerns and feel confident in vaccination.\",\n \"Justification, safety, and efficacy of a third dose of mRNA vaccine in maintenance hemodialysis patients: a prospective observational study\\nBackgroundPatients on maintenance hemodialysis (MHD) are at high risk of infection with SARS-Cov-2 and death due to COVID-19. This vulnerable population has been prioritized for vaccination, but the level of protection achieved in these immunocompromised patients is unclear.\\n\\nObjectivesTo evaluate the protection of MHD patients against COVID-19 after 2 doses (2D) of BNT162b2, and the safety and impact on immune responses of a 3rd dose (3D).\\n\\nDesignProspective observational.\\n\\nSetting, Patients, intervention and measurementsREIN national registry was used to compare the severity of 1474 cases of COVID-19 diagnosed in MHD patients after 0, 1 or 2 doses of mRNA vaccine. Anti-spike receptor binding domain (RBD) IgG and interferon gamma-producing CD4+ and CD8+ specific-T cells were measured after 2D and 3D of BNT162b2 in a monocentric cohort of 75 MHD patients.\\n\\nResultsVaccination reduced disease severity but 11% of MHD patients infected after 2D still died. Tolerance to 3D of BNT162b2 was excellent. MHD patients with humoral response similar to healthy volunteers after 2D did not generate more immune effectors after 3D and had more side effects. In contrast, 2/3 of MHD patients with suboptimal response after 2D reached optimal titer of anti-RBD IgG and/or developed spike-specific CD8+ T cells after 3D. Presence of spike-specific CD4+ T cells after 2D was associated with response to 3D in multivariate analysis (OR=4.80 [1.23-21.54]; p=0.029).\\n\\nLimitationsLimited number of patients injected with 3D.\\n\\nConclusionStandard scheme of vaccination provides insufficient protection to some MHD patients. Anti-RBD IgG and specific CD4+ T cells should be measured after 2D. Among patients with suboptimal humoral response, those with specific CD4+ T cells could benefit of a 3rd dose of vaccine.\\n\\nRegistrationNCT04881396\\n\\nFunding SourceNone\",\n \"Nusinersen in adult patients with 5q spinal muscular atrophy: a multicenter observational cohorts study\\nObjectiveTo assess safety and efficacy of nusinersen in adult 5q spinal muscular atrophy (SMA) patients.\\n\\nMethodsPatients older than 15 years and followed at least for 6 months with one motor scale (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb module, RULM) in five referral centers were included. Clinical and patients global impression of change (CGI-C and PGI-C) were recorded in treated patients at the last visit. Functional scales (Egen Klassification, EK2; Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, ALSFRS-R) and the percent-predicted forced vital capacity were collected when available.\\n\\nResultsSeventy-nine SMA patients (39 treated with nusinersen) were included. Compared with untreated patients, treated patients showed a significant improvement of 2 points ({+/-}0.46) in RULM (p<0.001) after six months. After a mean follow-up of 16 months, nusinersen treatment was associated with a significant improvement in HFMSE (OR=1.15, p=0.006), 6MWT (OR=1.07, p<0.001), and EK2 (OR=0.81, p=0.001).\\n\\nCompared with untreated patients, more treated patients experienced clinically meaningful improvements in all scales, but these differences were statistically significant only for RULM (p=0.033), ALSFRS-R (p=0.005), and EK2 (p<0.001). According to the CGI-C and PGI-C, 64.1% and 61.5% of treated patients improved with treatment. Being non-sitter was associated with less response to treatment, while longer time of treatment was associated with better response. Most treated patients (77%) presented at least one adverse event, mostly mild.\\n\\nConclusionsNusinersen treatment associates to some improvements in adult SMA patients. Most severely affected patients with complex spines are probably those with the most unfavorable risk-benefit ratio.\",\n \"Fraction of COVID-19 hospitalizations and deaths attributable to chronic diseases\\nAimTo estimate the fraction of hospitalizations and deaths from COVID-19 attributable to chronic diseases due to poor nutrition and smoking in Mexico.\\n\\nMethodsWe used data from the Mexican surveillance system of COVID-19. We considered six chronic diseases (obesity, COPD, hypertension, diabetes, cardiovascular disease, and chronic kidney disease) to define a multimorbidity variable: no diseases, 1 disease, 2 diseases, or 3 or more diseases. We calibrated the database using bias quantification methods to consider the undiagnosed cases of chronic diseases. To estimate the risks of hospitalization and death due to chronic diseases, we fitted Poisson regression models with robust standard errors, adjusting for possible confounders. Using these risks, we calculated attributable fractions using the population attributable fraction (PAF).\\n\\nResultsChronic diseases accounted for to 25.4% (24.8%, 26.1%), 28.3% (27.8%, 28.7%) and 15.3% (14.9%,15.7%) of the hospitalizations among adults below 40 years, 40 to 59, and 60 years and older respectively (95% CI). For COVID-19-related deaths, 50.1% (48.6%, 51.5%), 40.5% (39.7%, 41.3%), and 18.7% (18.0%, 19.5%) were attributable to chronic diseases in adults under 40 years, 40 to 59, and 60 years and older, respectively.\\n\\nConclusionChronic diseases linked to malnutrition and tobacco use contributed to a higher burden of hospitalization and deaths from COVID-19 in Mexico, particularly among younger adults. Medical and structural interventions to curb chronic disease incidence and facilitate disease control are urgently needed.\",\n \"Psychometric properties of the Copenhagen Burnout Inventory (CBI) in Italian physicians\\nBackgroundAssessing burnout in physicians is relevant as it can adversely affect both their mental and physical health by also decreasing the quality of care, especially since the onset of the COVID-19 pandemic. This study aimed at standardizing the Copenhagen Burnout Inventory (CBI), a psychometrically sound, worldwide-spread tool, in Italian physicians.\\n\\nMethodsNine-hundred and fifteen Italian physicians were web-administered the CBI, Patient Health Questionnaire-8 (PHQ-8), Generalized Anxiety Disorder-7 (GAD-7) and General Self-Efficacy Scale (GSE). The present CBI is a self-report questionnaire including 18 Likert items (range=19-90) assessing Personal, Work-related and Client-related Burnout. Client-related adaptation was performed. Construct validity, factorial structure (Confirmatory Factor Analysis) and internal consistency were tested. Diagnostic accuracy was assessed simultaneously against the PHQ-8, GAD-7 and GSE.\\n\\nResultsAll CBI measures yielded optimal internal consistency (Cronbachs =.90-.96). The CBI met its original three-factor model (CFI=.94; TLI=.93; RMSEA=.09; SRMR=.04), was positively related with the PHQ-8 (r=.76) and GAD-7 (r.=73), whereas negatively with the GSE (r=-.39), and yielded optimal diagnostics (AUC=.93; sensitivity=.91 and specificity=.85 at the optimal cut-off of 69/90).\\n\\nDiscussionThe CBI is a valid, reliable and normed tool to assess burnout levels in physicians, whose use is encouraged in both clinical practice and research as being short-lived, easy to use and openly accessible.\",\n \"Identification and Mitigation of High-Risk Pregnancy with the Community Maternal Danger Score Mobile Application in Gboko, Nigeria\\nIntroductionNigeria constitutes 1% of the worlds population yet accounts for 10% of global maternal mortality. Risk analyses within rural regions of Nigeria are not routinely conducted, yet could help inform access to skilled birth care. The objectives of this study were to assess the proportion of women at risk for mortality or morbidity in Benue State, Nigeria by analysing data collected during routine antenatal visits and through the Community Maternal Danger Score (CMDS), a validated risk-analysis tool.\\n\\nMethodsTwo cohorts, comprised of pregnant women presenting to primary healthcare centres within Gboko, Benue State between 2015-2017 and 2020-2021, were included in this study. The 2015-2017 cohort had their risk assessed retrospectively through analysis of routinely collected data. Identification of risk was based on their age, parity, and disease status (HIV and diabetes). The 2020-2021 cohort had their risk assessed prospectively using the CMDS.\\n\\nResultsRoutinely collected data from 2015-2017 demonstrated that up to 14.9% of women in Gboko were at risk for mortality or morbidity. The CMDS reported that up to 21.5% of women were at a similar level of risk; a significant difference of 6.6% (p=0.006). The CMDS was more efficient in obtaining and assessing this data, and the identification was available in real-time for midwives and pregnant women.\\n\\nConclusionRoutine data collected in Gboko identifies a high proportion of pregnant women at risk for mortality or morbidity. The CMDS is an evidence-based risk analysis tool that expands on this assessment by also estimating individual and community-level risk, which allows for more efficient mitigation and prevention strategies of maternal mortality.\",\n \"Epigenetic aging and perceived psychological stress in old age\\nAdverse effects of psychological stress on physical and mental health, especially in older age, are well documented. How perceived stress relates to the epigenetic clock measure, DNA methylation age acceleration (DNAmAA), is less well understood and existing studies reported inconsistent results.\\n\\nDNAmAA was estimated from five epigenetic clocks (7-CpG, Horvaths, Hannums, PhenoAge and GrimAge DNAmAA). Cohens Perceived Stress Scale (PSS) was used as marker of psychological stress.\\n\\nWe analyzed data from 1,100 Berlin Aging Study II (BASE-II) participants assessed as part of the GendAge study (mean age = 75.6 years, SD = 3.8 years, 52.1% women).\\n\\nIn a first step, we replicated well-established associations of perceived stress with morbidity, frailty, and symptoms of depression in the BASE-II cohort studied here. In a second step, we did not find any statistically significant association of perceived stress with any of the five epigenetic clocks in multiple linear regression analyses that adjusted for covariates.\\n\\nAlthough the body of literature suggests an association between higher DNAmAA and stress or trauma during early childhood, the current study found no evidence for an association of perception of stress with DNAmAA in older people. We discuss possible reasons for the lack of associations and highlight directions for future research.\",\n \"Nationwide surveillance of methicillin-resistant Staphylococcus aureus isolated from bloodstream infections in Japan in 2019\\nSynopsisO_ST_ABSObjectivesC_ST_ABSSome single-centre studies have reported that MRSA carrying the staphylococcal cassette chromosome mec (SCCmec) type IV has been increasing in bloodstream infections (BSIs) in Japan. Therefore, we conducted nationwide surveillance for MRSA BSI to investigate the extent of such change across Japan.\\n\\nMethodsWe recruited 51 Japanese hospitals from the Japanese Association for Infectious Diseases. MRSA isolates detected in two or more sets of blood cultures were collected between January and September 2019 and subjected to antimicrobial susceptibility testing. Whole-genome sequencing was also performed to determine SCCmec typing and multilocus typing and detect drug-resistance and virulence genes.\\n\\nResultsTwo hundred seventy MRSA isolates were collected from 45 hospitals. The major combination types were ST8 with SCCmec type IV (ST8-IV) (30.7%), ST1-IV (29.6%), ST2725-IV (9.5%), ST764-II (8.1%), and ST5-II (7.8%). However, there were regional differences among the most major types. The most common types in western, eastern, and northern Japan were ST1-IV, ST8-IV, and ST5-II, respectively. ST8-IV, ST1-IV, and ST2725-IV exhibited greater susceptibility to clindamycin and minocycline than ST764-II and ST5-II, but erm(A) was detected in 93.8% and 100% of ST1-IV and ST2725-IV, respectively. Based on drug-resistance and virulence genes, characteristics of ST8-IV were different from those of ST1-IV and ST2725-IV. In addition, there were two major ST8-IV types with different characteristics.\\n\\nConclusionsThis study revealed that SCCmec type IV replaced SCCmec type II in MRSA BSI. In addition, SCCmec type IV was divided into several types with different characteristics.\",\n \"A mixed-methods study of risk factors and experiences of healthcare workers tested for the novel coronavirus in Canada\\nObjectivesWe aimed to investigate the contribution of occupational and non-work-related factors to the risk of novel coronavirus (SARS-CoV-2) infection among healthcare workers (HCWs) in Vancouver Coastal Health, British Columbia, Canada. We also aimed to examine how HCWs described their experiences.\\n\\nMethodsWe conducted a matched case-control study using data from online and phone questionnaires with optional open-ended questions completed by HCWs who sought SARS-CoV-2 testing between March 2020 and March 2021. Conditional logistic regression and thematic analysis were utilized.\\n\\nResultsData from 1340 HCWs were included. Free-text responses were provided by 257 respondents. Adjusting for age, gender, race, occupation, and number of weeks since pandemic was declared, community exposure to a known COVID-19 case (adjusted odds ratio -aOR: 2.45; 95% CI 1.67-3.59), and difficulty accessing personal protective equipment -PPE- (aOR: 1.84; 95% CI 1.07-3.17) were associated with higher infection odds. Care-aides/licensed practical nurses had substantially higher risk (aOR: 2.92; 95% CI 1.49-5.70) than medical staff who had the lowest risk. Direct COVID-19 patient care was not associated with elevated risk. HCWs experiences reflected the phase of the pandemic when they were tested. Suboptimal communication, mental stress, and situations perceived as unsafe were common sources of dissatisfaction.\\n\\nConclusionsCommunity exposures and occupation were important determinants of infection among HCWs in our study. The availability of PPE and clear communication enhanced a sense of safety. Varying levels of risk between occupational groups call for wider targeting of infection prevention measures. Strategies for mitigating community exposure and supporting HCW resilience are required.\",\n \"Tuberculostearic acid, a potential parameter for scoring system construction for Tuberculous meningitis diagnosis\\nThis study aimed to validate the value of tuberculostearic acid (TBSA) whether it could implicate the existence of M. tuberculosis and assist for clinical diagnosis of Tuberculous Meningitis (TBM). Gas Chromatography/mass spectrometry was used to detect TBSA in the chemically pretreated cerebrospinal fluid of suspected TBM patients. In total, 140 patients were admitted for our study included 27 confirm TBM patients and 50 TBSA positive patients. Sensitivity of 0.7407 (CI 95%: 0.5372-0.8889) and specificity of 0.7345 (CI 95%: 0.6432-0.8132) were calculated. The Lancet consensus scoring system was also applied to evaluate the possibility of TBM in suspected patients, finding that TBSA positive patients showed a similar distributive grouping as the definite TBM patients. Our study implicates that the prospective use of TBSA is worth combining into a scoring system for characterizing the features of Mtb, showing a great potential of TBM diagnosis by TBSA in the future.\",\n \"IL-1 and IL-6 inhibitor hypersensitivity link to common HLA-DRB1*15 alleles\\nIn Saper et al (2019), we described systemic JIA patients who developed a high-fatality diffuse lung disease (DLD) while on IL-1 or IL-6 inhibitors. We observed severe delayed drug hypersensitivity reactions (DHR) in a significant subset. Because alleles of the human leukocyte antigen (HLA) loci can mediate DHR, we investigated HLA genotype association with these DHR. We typed subjects treated with these inhibitors: 34 sJIA/DHR/DLD, 11 sJIA/DHR without DLD, 18 drug-tolerant sJIA, and 19 Kawasaki disease (KD) patients in an anti-IL-1(anakinra) trial. We also accessed genotypes from a large sJIA case/control cohort.\\n\\nWe first compared White subjects with sJIA/DHR to 550 ancestry-matched sJIA subjects. We found striking enrichments of HLA-DRB1*15:01, HLA-DQA1*01:02, and DQB1*06:02, alleles in near-complete linkage (White individuals). HLA-DRB 1*15:01 (as haplotype proxy) was increased in White sJIA subjects with DHR/DLD versus sJIA drug-tolerant controls and was observed upon inclusion of sJIA+DHR-only and KD+DHR White subjects. In our entire cohort regardless of ancestry, 75% carried HLA-DRB 1*15:01 or the structurally related DRB1*15:03 and DRB1*15:06, which were absent among drug-tolerant subjects (p=5 x 10-13; Odds Ratio lower bound=20.11).\\n\\nPatients who harbor HLA-DRB1*15 alleles are at high risk of developing DHR to anti-IL-1/IL-6. Our data also suggest DHR maybe a trigger/enhancer of DLD in sJIA patients and support performing prospective HLA screening in sJIA, its adult-onset counterpart, and other inflammatory conditions where these drugs are used, such as KD.\",\n \"Assessment of private variants in PRKN, PARK7 and PINK1 in Parkinson's disease\\nRecessive mutations in PRKN, PARK7 and PINK1 are established causes of early-onset Parkinsons disease (EOPD). Previous studies have interrogated the role of heterozygous variants in these genes but mainly focused on rare (minor allele frequency [MAF] <1%) damaging variants or established mutations. Here, we assessed heterozygous private PRKN, PARK7 and PINK1 variants in PD risk in four large-scale PD case-control datasets by performing gene-wise burden analyses using sequencing data totaling 5,829 PD cases and 7,221 controls, and summary allele counts from 9,501 PD cases and 48,207 controls. Results showed no significant burden in all three genes after meta-analyses. Burden in EOPD (age at onset <50 years) and late-onset PD ([≥]50 years) remained nonsignificant. In summary, we found no evidence to support the association of the excess burden of heterozygous private variants in PRKN, PARK7, and PINK1 with PD risk in the European population. Larger, more diverse cohorts are needed to accurately determine their role in PD.\",\n \"The Anorexia Nervosa Care Pathway: Closing the Treatment Gap to Improve Care for Patients Admitted to Medical Hospitals\\nIntroductionMedical complications of malnutrition and refeeding account for approximately half of deaths in anorexia nervosa (AN). The AN Care Pathway (ANCP) was introduced at our institution in 2016 to improve quality of care of patients admitted for medical observation and management. We report results from our review of medical complications and report the impact and adoption of the ANCP.\\n\\nMethodsThe ANCP was developed in response to a need to improve quality of medical monitoring of patients with severe AN using Squire Guidelines and the Plan-Do-Study-Act cycle. All patients admitted to a medical hospital with AN between 2010-2020 were included after hospital inpatient enquiry and medical records were reviewed. Descriptive statistics were calculated using Stata (Statcorp).\\n\\nResultsFifty-one patients (63 admissions) were included. Median BMI was 13.8 kg/m (11.9-22.5). After ANCP implementation in 2016, compliance with recommended daily ECG, thiamine and blood tests improved from 30% (n=8/27) to 86% (n=21/36). We report a high rate of medical complications of severe AN including anaemia (n=24, 47%), neutropoenia (n=18, 35%), abnormal liver bloods (n=15, 29%) and half developed refeeding syndrome. One-third patients had cardiovascular compromise including reduced cardiac contractility (n=13, 25%), pericardial effusion (n=7, 14%) and one death. Low BMI was associated with cardiovascular complications (mean BMI 13.5 kg/m vs 15.5 kg/m, p=0.01) and neutropoenia (mean BMI 13.4 kg/m vs 15.4 kg/m, p=0.02).\\n\\nConclusionIntroduction of the ANCP improved quality of care during medical stabilisation. We report a high rate of medical complications of severe AN in patients admitted to a medical hospital. Use of multidisciplinary care protocols may contribute to quality improvement and improved consistency of care for this vulnerable population.\",\n \"Prolonged SARS-CoV-2 RNA virus shedding and lymphopenia are hallmarks of COVID-19 in cancer patients with poor prognosis\\nPatients with cancer are at higher risk of severe coronavirus infectious disease 2019 (COVID-19), but the mechanisms underlying virus-host interactions during cancer therapies remain elusive. When comparing nasopharyngeal swabs from cancer and non-cancer patients for RT-qPCR cycle thresholds measuring acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 1063 patients (58% with cancer, 89% COVID-19+), we found that malignant disease favors the magnitude and duration of viral RNA shedding concomitant with prolonged serum elevations of type 1 IFN that anticorrelated with anti-RBD IgG antibodies. Chronic viral RNA carriers exhibited the typical immunopathology of severe COVID-19 at the early phase of infection including circulation of immature neutrophils, depletion of non-conventional monocytes and a general lymphopenia that, however, was accompanied by a rise in plasmablasts, activated follicular T helper cells, and non-naive Granzyme B+ FasL+, EomehighTCF-1high, PD-1+CD8+ Tc1 cells. Virus-induced lymphopenia worsened cancer-associated lymphocyte loss, and low lymphocyte counts correlated with chronic SARS-CoV-2 RNA shedding, COVID-19 severity and a higher risk of cancer-related death in the first and second surge of the pandemic. Lymphocyte loss correlated with significant changes in metabolites from the polyamine and biliary salt pathways as well as increased blood DNA from Enterobacteriaceae and Micrococcaceae gut family members in long term viral carriers. We surmise that cancer therapies may exacerbate the paradoxical association between lymphopenia and COVID-19-related immunopathology, and that the prevention of COVID-19-induced lymphocyte loss may reduce cancer-associated death.\",\n \"Molecular Mechanism of Parosmia\\nThe molecular stimuli that trigger a parosmic response have been identified. Parosmia is a debilitating disease in which familiar smells become distorted and unpleasant. Often a result of post infectious smell loss, incidences are increasing as the number of COVID-19 cases escalates worldwide. Little is understood of its pathophysiology, but the prevailing hypothesis for the underlying mechanism is a mis-wiring of olfactory sensory neurons. We identified 15 different molecular triggers in coffee using GC-Olfactometry as a relatively rapid screening tool for assessment of both quantitative olfactory loss and parosmia. This provides evidence for peripheral causation, but places constraints on the mis-wiring theory.\",\n \"The influence of baseline clinical status and surgical strategy on early good to excellent result in spinal lumbar arthrodesis: a machine learning approach\\nAimsTo create, using a machine learning (ML) approach, a preoperative model from baseline demographic and health-related quality of life scores (HRQOL) to predict a good to excellent early clinical outcome.\\n\\nPatients and MethodsA single spine surgery center retrospective review of prospectively collected data from January 2016 to December 2020 from the institutional registry (SpineREG) was performed. The inclusion criteria were age [≥] 18 years, both sexes, lumbar arthrodesis procedure, a complete follow up assessment (ODI, SF-36 and COMI back) and the capability to read and understand the Italian language. A delta of improvement of the ODI higher than 12.7/100 was considered a \\\"good early outcome\\\". A combined target model of ODI ({Delta} [≥] 12.7/100), SF-36 PCS ({Delta} [≥] 6/100) and COMI back ({Delta} [≥] 2.2/10) was considered an \\\"excellent early outcome\\\". The performance of the ML models was evaluated in terms of sensitivity, i.e., True Positive Rate (TPR), specificity, i.e., True Negative Rate (TNR), accuracy and area under the receiver operating characteristic curve (AUC ROC).\\n\\nResultsA total of 1243 patients were included in this study. The model for predicting ODI at 6 months follow up showed a good balance between sensitivity (74.3%) and specificity (79.4%), while providing a good accuracy (75.8%) with ROC AUC = 0.842. The combined target model showed a sensitivity of 74.2% and specificity of 71.8%, with an accuracy of 72.8%, and a ROC AUC = 0.808.\\n\\nConclusionThe results of our study suggest that a machine learning approach showed high performance in predicting early good to excellent clinical results.\",\n \"Patient-specific forecasting of post-radiotherapy prostate-specific antigen kinetics enables early prediction of biochemical relapse\\nThe detection of prostate cancer recurrence after external beam radiotherapy relies on the measurement of a sustained rise of serum prostate-specific antigen (PSA). However, this biochemical relapse may take years to occur, thereby delaying the delivery of a secondary treatment to patients with recurring tumors. To address this issue, here we propose to use patient-specific forecasts of PSA dynamics to early predict biochemical relapse. Our forecasts are based on mechanistic models of prostate cancer response to external beam radio-therapy, which are fit to patient-specific PSA data collected during standard post-treatment monitoring. Our results show a remarkable performance of our models in recapitulating the observed changes in PSA and yielding short-term predictions over approximately one year (cohort median RMSE of 0.10 to 0.47 ng/mL and 0.13 to 1.41 ng/mL, respectively). Additionally, we identify three model-based biomarkers that enable an accurate identification of biochemical relapse (AUC > 0.80) significantly earlier than standard practice (p < 0.01).\",\n \"A novel morphometric signature of brain alterations in type 2 diabetes: patterns of changed cortical gyrification\\nType 2 diabetes is a chronic disease that creates atrophic signatures in the brain, including decreases of total and regional volume of grey matter, white matter, and cortical thickness. However, there is a lack of studies assessing cortical gyrification in type 2 diabetes. Changes in this emerging feature has been associated mainly with genetic legacy, but environmental factors may also play a role. Here, we investigated alterations of the gyrification index and classical morphometric measures in type 2 diabetes, a disease with complex etiology with both underlying genetic and more preponderant environmental factors.\\n\\nIn this cross-sectional study we analyzed brain anatomical magnetic resonance images of 86 participants with type 2 diabetes and 40 healthy control participants, to investigate structural alterations in type 2 diabetes, including whole-brain volumetric measures, local alterations of grey matter volume, cortical thickness and the gyrification index.\\n\\nWe found concordant significant decrements in total and regional grey matter volume, and cortical thickness. Surprisingly, the cortical gyrification index was found to be mainly increased in cortical sensory areas in type 2 diabetes. Moreover, it correlated with features of metabolic control. Our findings challenge the classical neurodevelopmental association of gyrification mostly with genetic determinants. While we found mainly increased gyrification in more genetically constrained sensory areas in type 2 diabetes, our correlation results concurrently suggest an influence of metabolic control in alterations of gyrification in type 2 diabetes. Further studies should address causal influences of genetic and/or environmental factors in patterns of cortical gyrification in type 2 diabetes.\",\n \"Methylome analysis for prediction of long and short-term survival in glioblastoma patients from the Nordic trial\\nPatients with glioblastoma (GBM) have a short survival, but even among patients receiving the same therapies and with good prognostic factors, one can find those with exceptionally short and long survival.\\n\\nIn the Nordic trial, patients with GBM, 60 years or older, were randomized between 2 radiotherapy arms or TMZ. We selected 59 patients, equally distributed between the 3 treatment arms and MGMT promoter methylation status, with good prognostic factors, but with short or long survival. We performed methylation profiling with the Illumina Infinium Methylation EPIC BeadChip arrays in conjunction with a methylation-based CNS tumor classifier, analysis of differentially methylated CpG sites (DMCs) and pathway enrichment analysis.\\n\\nSamples classified as non-GBM IDH wildtype were excluded and in the analysis of long vs. short survivors with documented progression or tumor-related death, we found DMCs in the TMZ, MGMT promoter methylated group (123,510), as well as in the 60Gy, MGMT promoter unmethylated group (4,086) and 34Gy, MGMT promoter methylated group (39,649). The joint analysis of the RT arms revealed 319 DMCs in the MGMT unmethylated group but no differences for MGMT promoter methylated samples, or in any of the analyses independent of MGMT status. Interestingly, in the long-term survivors with methylated MGMT promoter treated with TMZ we found hypermethylation of the Wnt signaling and the platelet activation, signaling and aggregation pathways.\\n\\nWe identified DMCs for both TMZ and RT treated patients. Further systematic analysis of larger patient cohorts is necessary for confirmation of their predictive properties.\",\n \"Calculating variant penetrance using family history of disease and population data\\nPurposeGenetic penetrance is the probability of a phenotype manifesting if one harbours a specific pathogenic variant. For most Mendelian genes, penetrance is incomplete and may be age-dependent. Accurate penetrance estimates are important in many biomedical fields including genetic counselling, disease research, and for gene therapy. The main methods for its estimation are limited in situations where large family pedigrees are not available, the disease is rare, late onset, or complex.\\n\\nMethodsHere we present a novel method for penetrance estimation in autosomal dominant phenotypes. It uses population-scale data regarding the distribution of a variant among unrelated people affected (cases) and unaffected (controls) by an associated phenotype and can be operated using samples of affected people only by considering family disease history.\\n\\nResultsThe method is validated within simulation studies. Candidate variant-disease case studies yield estimates which align with existing disease knowledge and estimates derived using established methods.\\n\\nConclusionWe have presented a valid method for penetrance estimation in autosomal dominant traits which avoids kinship-specific penetrance estimates and the ascertainment biases that can arise when sampling rare variants among control populations. It can be accessed from our public web server (https://adpenetrance.rosalind.kcl.ac.uk) and is available as an open-source R library (https://github.com/ThomasPSpargo/adpenetrance).\",\n \"Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein\\nPurposeAlthough haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized the clinical, molecular and functional spectra of ANKRD11 missense variants.\\n\\nMethodsWe collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants by in silico analyses and cell-based experiments.\\n\\nResultsWe identified 29 individuals with (mostly de novo) ANKRD11 missense variants, who presented with syndromic neurodevelopmental disorders and were phenotypically similar to individuals with KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in Repression Domain 2. Cellularly, most variants caused reduced ANKRD11 stability. One variant resulted in decreased proteasome degradation and loss of ANKRD11 transcriptional activity.\\n\\nConclusionOur study indicates that pathogenic heterozygous missense variants in ANKRD11 cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges, as the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping.\",\n \"Predictors for participation in DNA self-sampling of childhood cancer survivors in Switzerland\\nResearch on germline genetic variants relies on a sufficient number of eligible participants which is difficult to achieve for rare diseases such as childhood cancer. With self-collection kits using saliva or buccal swabs, participants can contribute genetic samples conveniently from their home. We identified determinants of participation in DNA self-collection in this cross-sectional study.\\n\\nWe invited 928 childhood cancer survivors in Switzerland with a median age of 26.5 years (interquartile range 18.8-36.5), of which 463 (50%) participated. Foreign nationality (odds ratio [OR] 0.5, 95%-confidence interval [CI] 0.4-0.7), survivors aged 30-39 years at study versus other age groups (OR 0.5, CI 0.4-0.8), and those with a known cancer predisposition syndrome (OR 0.5, CI 0.3-1.0) participated less. Survivors with a second primary neoplasm (OR 1.9, CI 1.0-3.8) or those living in a French or Italian speaking region (OR 1.3, 1.0-1.8) tended to participate more.\\n\\nWe showed that half of survivors participate in germline DNA self-sampling relying completely on mailing of sample kits. Foreign nationality, age 30-39 years, and cancer predisposition syndromes were associated with less participation. More targeted recruitment strategies may be advocated for these subgroups. To increase participation in DNA self-sampling, understanding and perceptions of survivors need to be better understood.\",\n \"Association between telecommuting environment and low back pain among Japanese telecommuting workers: A cross-sectional study\\nObjectivesWe evaluated the relationship between telecommuting environment and low back pain (LBP) among desk-based workers in Japan.\\n\\nMethodsThis cross-sectional study included 3,663 desk-based, telecommuting workers. LBP was assessed using a 0-10 numerical rating scale. The telecommuting environment was evaluated using subjective questions. Mixed-effects logistic regression analysis was used to evaluate this association.\\n\\nResultsThe results of mixed-effects logistic model revealed that not having a place or room to concentrate on work, desk not well-lit enough for work, lack of space on the desk to work, not having enough legroom, and uncomfortable temperature and humidity conditions in the workspace were significantly associated with higher odds of LBP.\\n\\nConclusionsOur findings suggest that telecommuting environment is associated with the prevalence of LBP.\",\n \"NEW CORONAVIRUS IN PREGNANT WOMEN. Maternal and perinatal outcomes.\\nObjectivesTo report the maternal and neonatal results of patients infected with COVID-19 in Panama.\\n\\nMethodsThe study is based on the analysis of pregnant women with COVID-19, in 5 hospitals in the Republic of Panama. The inclusion criteria were: Patients with or without symptoms, positive RT-PCR for SARS-CoV-2 in the period from March 23 to 6 months after, whose births were attended in one of those 5 hospitals and who signed the consent. Data was obtained at the time of diagnosis of the infection and at the time of termination of pregnancy for the mother and newborn.\\n\\nResults253 patients met the inclusion criteria. Most were diagnosed in the third trimester (89.3%). 10.3% of the patients presented in a severe form of COVID-19. The most frequent complication was pre-eclampsia and if we add gestational hypertension they represent 21.2%; most of the patients terminated the pregnancy by caesarean section (58%). 26.9% (95% CI 21.3-32.9%) of the births were premature, and perinatal mortality was 5.4% (95% CI 3.0-9.0%). There was a need for mechanical ventilation in 5.9% (95% CI 3.6-9.6%) of the cohort and there were four maternal deaths (1.6% - 95% CI 0.6-4.0%).\\n\\nConclusionsThis study of pregnant women infected with COVID-19 and diagnosed with RT-PCR shows serious maternal complications such as high admission to the ICU, need for mechanical ventilation and one death in every 64 infected. Frequent obstetric complications such as hypertension, premature rupture of membranes, high rate of prematurity and perinatal lethality were also seen.\",\n \"Social connectedness as a determinant of mental health: A scoping review\\nPublic health and epidemiologic research have established that social connectedness promotes overall health. Yet there have been no recent reviews of findings from research examining social connectedness as a determinant of mental health. The goal of this review was to evaluate recent longitudinal research probing the effects of social connectedness on depression and anxiety symptoms and diagnoses in the general population. A scoping review was performed of PubMed and PsychInfo databases from January 2015 to December 2020 following PRISMA-ScR guidelines using a defined search strategy. The search yielded 56 articles representing 52 unique studies. In research with other than pregnant women, 84% (16 of 19) studies reported that social support benefited symptoms of depression with the remaining 16% (3 of 19) reporting minimal or no evidence that lower levels of social support predict depression at follow-up. In research with pregnant women, 80% (21 of 26 studies) found that low social support increased postpartum depressive symptoms. Among 3 of 4 studies that focused on loneliness, feeling lonely at baseline was related to adverse outcomes at follow-up including higher risks of major depressive disorder, depressive symptom severity, generalized anxiety disorder, and lower levels of physical activity. In 5 of 7 reports, smaller social network size predicted depressive symptoms or disorder at follow-up. In summary, most recent relevant longitudinal studies have demonstrated that social support protects adults in the general population from depressive symptoms and disorders. The results, which were largely consistent across settings, exposure measures, and populations, support efforts to improve clinical detection of high-risk patients, including adults with low social support and elevated loneliness.\",\n \"Predictability and Stability Testing to Assess Clinical Decision Instrument Performance for Children After Blunt Torso Trauma\\nObjectiveThe Pediatric Emergency Care Applied Research Network (PECARN) has developed a clinical-decision instrument (CDI) to identify children at very low risk of intra-abdominal injury. However, the CDI has not been externally validated. We sought to vet the PECARN CDI with the Predictability Computability Stability (PCS) data science framework, potentially increasing its chance of a successful external validation.\\n\\nMaterials & MethodsWe performed a secondary analysis of two prospectively collected datasets: PECARN (12,044 children from 20 emergency departments) and an independent external validation dataset from the Pediatric Surgical Research Collaborative (PedSRC; 2,188 children from 14 emergency departments). We used PCS to reanalyze the original PECARN CDI along with new interpretable PCS CDIs we developed using the PECARN dataset. External validation was then measured on the PedSRC dataset.\\n\\nResultsThree predictor variables (abdominal wall trauma, Glasgow Coma Scale Score <14, and abdominal tenderness) were found to be stable. Using only these variables, we developed a PCS CDI which had a lower sensitivity than the original PECARN CDI on internal PECARN validation but performed the same on external PedSRC validation (sensitivity 96.8% and specificity 44%).\\n\\nConclusionThe PCS data science framework vetted the PECARN CDI and its constituent predictor variables prior to external validation. In this case, the PECARN CDI with 7 predictors, and our PCS-based CDI with 3 stable predictors, had identical performance on independent external validation. This suggests that both CDIs will generalize well to new populations, offering a potential strategy to increase the chance of a successful (costly) prospective validation.\",\n \"Delirium and Neuropsychological Outcomes in Critically Ill Patients with COVID-19: an Institutional Case Series\\nObjectiveTo characterize the clinical course of delirium for COVID-19 patients in the intensive care unit, including post-discharge cognitive outcomes.\\n\\nPatients and MethodsA retrospective chart review was conducted for patients diagnosed with COVID-19 (n=148) admitted to an intensive care unit at Michigan Medicine between March 1, 2020 and May 31, 2020. A validated chart review method was used to identify presence of delirium, and various measures (e.g., Family Confusion Assessment Method, Short Blessed Test, Patient-Health Questionnaire-9) were used to determine neuropsychological outcomes between 1-2 months after hospital discharge.\\n\\nResultsDelirium was identified in 108/148 (73%) patients in the study cohort, with median (interquartile range) duration lasting 10 (4 - 17) days. In the delirium cohort, 50% (54/108) of patients were African American, and delirious patients were more likely to be female (76/108, 70%) (absolute standardized differences >.30). Sedation regimens, inflammation, deviation from delirium prevention protocols, and hypoxic-ischemic injury were likely contributing factors, and the most common disposition for delirious patients was a skilled care facility (41/108, 38%). Among patients who were delirious during hospitalization, 4/17 (24%) later screened positive for delirium at home based on caretaker assessment, 5/22 (23%) demonstrated signs of questionable cognitive impairment or cognitive impairment consistent with dementia, and 3/25 (12%) screened positive for depression within two months after discharge.\\n\\nConclusionPatients with COVID-19 commonly experience a prolonged course of delirium in the intensive care unit, likely with multiple contributing factors. Furthermore, neuropsychological impairment may persist after discharge.\",\n \"FastMix: A Versatile Multi-Omics Data Integration Pipeline for Cell Type-Specific Biomarker Inference\\nWe developed a novel analytic pipeline - FastMix - to integrate flow cytometry, bulk transcriptomics, and clinical covariates for statistical inference of cell type-specific gene expression signatures. FastMix addresses the \\\"large p, small n\\\" problem via a carefully designed linear mixed effects model (LMER), which is applicable for both cross-sectional and longitudinal studies. With a novel moment-based estimator, FastMix runs and converges much faster than competing methods for big data analytics. The pipeline also includes a cutting-edge flow cytometry data analysis method for identifying cell population proportions. Simulation studies showed that FastMix produced smaller type I/II errors with more accurate parameter estimation than competing methods. When applied to real transcriptomics and flow cytometry data in two vaccine studies, FastMix-identified cell type-specific signatures were largely consistent with those obtained from the single cell RNA-seq data, with some unique interesting findings.\",\n \"Deep brain stimulation in the bed nucleus of the stria terminalis: A symptom provocation study in patients with obsessive-compulsive disorder\\nBackgroundDeep brain stimulation (DBS) is an emerging therapy for treatment-resistant obsessive-compulsive disorder (OCD), and several targets for electrode implantation and contact selection have been proposed, including the bed nucleus of the stria terminalis (BST). Selecting the active electrode contacts (patients typically have four to choose from in each hemisphere), and thus the main locus of stimulation, can be a taxing process. Here, we investigated whether contact selection based purely on their neuroanatomical position in the BST is a worthwhile approach. For the first time, we also compared the effects of uni- versus bilateral BST stimulation.\\n\\nMethodsNine OCD patients currently receiving DBS participated in a double-blind, randomized symptom provocation study to compare no versus BST stimulation. Primary outcomes were anxiety and mood ratings in response to disorder-relevant trigger images, as well as ratings of obsessions, compulsions, tendency to avoid and overall wellbeing. Furthermore, we asked whether patients preferred the electrode contacts in the BST over their regular stimulation contacts as a new treatment setting after the end of the task.\\n\\nResultsWe found no statistically significant group differences between the four conditions (no, left, right and bilateral BST stimulation). Exploratory analyses, as well as follow-up data, did indicate that (bilateral) bipolar stimulation in the BST was beneficial for some patients, particularly for those who had achieved unsatisfactory effects through the typical contact selection procedure.\\n\\nConclusionsDespite its limitations, this study suggests that selection of stimulation contacts in the BST is a viable option for DBS in treatment-resistant OCD patients.\",\n \"COVID-19 Prevention Facilitators and Barriers among Specific Ethnic Minority Communities in Rural Ohio\\nObjectiveTo assess knowledge, beliefs, and behaviors concerning COVID-19 among Guatemalan, Marshallese, and Amish populations in rural Ohio; identify individual, interpersonal, community, and structural level challenges within each community; and provide population-specific recommendations to prevent and mitigate further SARS-CoV-2 transmission among these rural communities.\\n\\nMethodsWe conducted 30 key informant interviews in four rural counties in Ohio, in May 2020. Three teams of two investigators conducted interviews with local health department staff, community members, meat packing plant management, and community leaders from three communities disproportionately affected by the COVID-19 pandemic [Guatemalan (N=12), Marshallese (N=7), Amish (N=11)]. We used the Social Ecological Model to identify and categorize themes.\\n\\nResultsEmerging and overall themes were identified and defined. Investigators identified COVID-19 knowledge gaps, myths, and misinformation, food insecurity, community cohesion, stigma, community culture and norms, lack of workplace safety policies, and access to testing as key themes to COVID-19 prevention.\\n\\nConclusionsUnderstanding specific barriers and identifying facilitators that most effectively provide resources, healthcare services, education, and social support tailored to specific communities would help deter SARS-CoV-2 transmission.\",\n \"Biallelic and de novo variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy\\nThe vacuolar H+-ATPase is a large multi-subunit proton pump, composed of an integral membrane V0 domain, involved in proton translocation, and a peripheral V1 domain, catalysing ATP hydrolysis. This complex is widely distributed on the membrane of various subcellular organelles, such as endosomes and lysosomes, and plays a critical role in cellular processes ranging from autophagy to protein trafficking and endocytosis. Variants in ATP6V0A1, the brain-enriched isoform in the V0 domain, have been recently associated with developmental delay and epilepsy in four individuals. Here we identified 17 individuals from 14 unrelated families with both with new and previously characterised variants in this gene, representing the largest cohort to date. Five affected subjects with biallelic variants in this gene presented with a phenotype of early-onset progressive myoclonus epilepsy with ataxia, while 12 individuals carried de novo missense variants and showed severe developmental and epileptic encephalopathy. The R740Q mutation, which alone accounts for almost 50% of the mutations identified among our cases, leads to failure of lysosomal hydrolysis by directly impairing acidification of the endolysosomal compartment, causing autophagic dysfunction and severe developmental defect in C. elegans. Altogether, our findings further expand the neurological phenotype associated with variants in this gene and provide a direct link with endolysosomal acidification in the pathophysiology of ATP6V0A1-related conditions.\",\n \"A Randomized Trial of Otilimab in Severe COVID-19 Pneumonia (OSCAR)\\nBACKGROUNDIncreasing age is a risk factor for COVID-19 severity and mortality; emerging science implicates GM-CSF and dysregulated myeloid cell responses in the pathophysiology of severe COVID-19.\\n\\nMETHODSWe conducted a large, global, double-blind, randomized, placebo-controlled study evaluating a single 90 mg infusion of otilimab (human anti-GM-CSF monoclonal) plus standard of care in adults hospitalized with severe COVID-19 respiratory failure and systemic inflammation, stratified by age and clinical status. Primary outcome was the proportion of patients alive and free of respiratory failure at Day 28; secondary endpoints included all-cause mortality at Day 60.\\n\\nRESULTSOverall, 806 patients were randomized (1:1); 71% of patients receiving otilimab were alive and free of respiratory failure at Day 28 versus 67% receiving placebo, although this did not reach statistical significance (model-adjusted difference 5.3% [95% CI -0.8, 11.4]; p=0.09). However, there was a benefit in the pre-defined [≥]70-year age group (model-adjusted difference 19.1% [95% CI 5.2, 33.1]; nominal p=0.009); these patients also had a reduction of 14.4% (95% CI 0.9, 27.9%; nominal p=0.04) in model-adjusted all-cause mortality at Day 60. Safety findings were comparable between otilimab and placebo, and consistent with severe COVID-19.\\n\\nCONCLUSIONSAlthough not statistically significant in the overall population, otilimab demonstrated a substantial benefit in patients aged [≥]70, possibly reflecting a population that could benefit from therapeutic blocking of GM-CSF in severe COVID-19 where myeloid cell dysregulation is predominant. These findings are being confirmed in a further cohort of patients aged [≥]70 in Part 2 of this study. (ClinicalTrials.gov number: NCT04376684).\",\n \"Repeated introductions and intensive community transmission fueled a mumps virus outbreak in Washington State\\nIn 2016/2017, Washington State experienced a mumps outbreak despite high childhood vaccination rates, with cases more frequently detected among school-aged children and members of the Marshallese community. We sequenced 166 mumps virus genomes collected during outbreaks in Washington and other US states, and apply phylodynamic approaches to trace mumps introductions and transmission within Washington. We uncover that mumps was introduced into Washington at least 13 times, primarily from Arkansas, sparking multiple co-circulating transmission chains. Neither vaccination status nor age were strong determinants of transmission. Instead, the outbreak in Washington was overwhelmingly sustained by transmission within the Marshallese community. Our findings underscore the utility of genomic data to clarify epidemiologic factors driving transmission, and pinpoint contact networks as critical determinants of mumps transmission. These results imply that contact structures and historic disparities may leave populations at increased risk for respiratory virus disease even when a vaccine is effective and widely used.\",\n \"Longitudinal changes in physical activity during and after the first national lockdown due to the COVID-19 pandemic in England\\nBackgroundRecent studies have shown reduced physical activity at early stages of the COVID-19 pandemic. However, there is a lack of investigation on longitudinal changes in physical activity beyond lockdowns and stay at home orders. Moreover, it is unclear if there is heterogeneity in physical activity growth trajectories. This study aimed to explore longitudinal patterns of physical activity and factors associated with them.\\n\\nMethodsData were from the UCL COVID -19 Social Study. The analytical sample consisted of 35,915 adults in England who were followed up for 22 weeks from 24th March to 23rd August 2020. Data were analysed using growth mixture models.\\n\\nFindingsOur analyses identified six classes of growth trajectories, including three stable classes showing little change over time (62.4% in total), two classes showing decreasing physical activity (28.6%), and one class showing increasing physical activity over time (9%). A range of factors were found to be associated the class membership of physical activity trajectories, such as age, gender, education, income, employment status, and health.\\n\\nInterpretationThere is substantial heterogeneity in longitudinal changes in physical activity during the COVID-19 pandemic. However, a substantial proportion of our sample showed persistent physical inactivity or decreasing physical activity. Given the well-established linked between physical activity and health, persistent or increased physical inactivity is likely to have both immediate and long-term implications for peoples physical and mental health, as well as general wellbeing. More efforts are needed to promote physical activity during the pandemic and beyond.\\n\\nFundingNuffield Foundation, UK Research and Innovation, Wellcome Trust\",\n \"Quality control and removal of technical variation of NMR metabolic biomarker data in ~120,000 UK Biobank participants\\nMetabolic biomarker data quantified by nuclear magnetic resonance (NMR) spectroscopy has recently become available in UK Biobank. Here, we describe procedures for quality control and removal of technical variation for this biomarker data, comprising 249 circulating metabolites, lipids, and lipoprotein sub-fractions on approximately 121,000 participants. We identify and characterise technical and biological factors associated with individual biomarkers and find that linear effects on individual biomarkers can combine in a non-linear fashion for 61 composite biomarkers and 81 biomarker ratios. We create an R package, ukbnmr, for extracting and normalising the metabolic biomarker data, then use ukbnmr to remove unwanted variation from the UK Biobank data. We make available code for re-deriving the 61 composite biomarkers and 81 ratios, and for further derivation of 76 additional biomarker ratios of potential biological significance. Finally, we demonstrate that removal of technical variation leads to increased signal for genetic and epidemiological studies of the NMR metabolic biomarkers in UK Biobank.\",\n \"Impact of low-dose intrathecal morphine on orthopedic surgery: a protocol of a systematic review and meta-analysis of randomized controlled trials\\nIntroductionPatients undergoing orthopedic surgery usually suffer considerably from peri-operative pain and intrathecal morphine (ITM) has recently been used as an effective analgesic method. The intrathecal morphine dose achieving optimal analgesia for orthopedic surgery while minimizing side effects has not yet been determined. There is currently a lack of literature synthesis on the safety and effects of low-dose ITM on orthopedic surgery.\\n\\nMethods and analysisA thorough literature search will be performed on multiple electronic databases and trial registries until January 11th 2022, and reference lists will be examined. Two independent reviewers will select studies, extract data and assess the risk of bias and quality of the included studies. We will select randomized controlled trials comparing low-dose ITM (<100g) with high-dose ITM (<200g) or placebo treatment or other comparatives. We will assess the risk of bias using the Cochrane risk of bias tool and Jadad score will be applied to assess the quality of each included trial. We will also use Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) to determine the confidence in effect estimates. Publication bias will be evaluated by visually inspecting funnel plots and Egger regression asymmetry test in estimations of more than 10 trials. Standard meta-analysis will be performed using R package meta.\\n\\nEthics and disseminationThe results of this systematic review and meta-analysis will be disseminated through peer-reviewed journal and related conferences. The data used in this meta-analysis will not contain individual patient data and ethical approval is therefore not required.\",\n \"Multi-cohort transcriptomic subtyping of B-cell acute lymphoblastic leukemia\\nAcute lymphoblastic leukemia (ALL) is the most common childhood cancer and comprises multiple genetically distinguishable subtypes. To detect subtypes, current pipelines include fusion calling, polymorphisms, candidate gene copy numbers and cytogenetics but these approaches have limitations. RNA-seq provides a functional genome-wide snapshot that enables classification of ALL subtypes, however, typical mRNA-seq clustering analyses lack the rigor of quantitative modelling. Furthermore, high-dimensional gene expression data across cohorts and countries contain biases that previous transcriptomics studies have not addressed. Our aim was to integrate easy-to-interpret reliable transcriptome-wide biomarkers into subtyping pipelines. We analyzed 2,046 samples from two continents, carefully adjusted for biases and applied a rigorous machine learning design with independent replication. Six ALL subtypes that covered 32% of patients were robustly detected by mRNA-seq (PPV [≥] 87%). Five other frequent subtypes were distinguishable in 40% of patients, although overlapping transcriptional profiles led to lower accuracy (52% [≤] PPV [≤] 73%). Based on these findings, we developed the Allspice tool that predicts ALL subtypes and driver genes from unadjusted mRNA-seq read counts as encountered in real-world settings. Allspice also includes quantitative classification and safety metrics to help determine the most plausible genetic drivers for cases where other findings are inconclusive.\",\n \"Alpha-1 adrenoreceptor antagonism mitigates extracellular mitochondrial DNA accumulation in lung fibrosis models and in patients with IPF\\nIdiopathic Pulmonary Fibrosis is increasingly associated with adrenergic innervation and endogenous innate immune ligands such as mitochondrial DNA (mtDNA). Interestingly, a connection between these entities has not been explored. Here we report that noradrenaline (NA) derived from the lungs adrenergic nerve supply drives the accumulation of SMA-expressing fibroblasts via a mechanism involving 1 adrenoreceptors and mtDNA. Using the bleomycin model of lung fibrosis we compared the effect of lung specific adrenergic denervation achieved via the inhalational administration of the sympathetic neurotoxin 6-hydroxydopamine to surgically mediated adrenal ablation and found that NA derived from local but not adrenal sources drives lung fibrosis. Bleomycin induced the appearance of a SMA+ fibroblast population co-expressing the adrenoreceptor alpha-1D (ADRA1D). Therapeutic delivery of the 1 adrenoreceptor antagonist terazosin reversed these changes and suppressed the accumulation of extracellular mtDNA. TGF{beta}1-stimulated normal human lung fibroblasts treated with TGF{beta}1 and Noradrenaline expressed ADRA1D and developed reduced SMA expression and extracellular mtDNA concentrations when treated with terazosin. IPF patients prescribed 1 adrenoreceptor antagonists for non-pulmonary indications showed improved survival and reduced concentrations of plasma mtDNA. These findings link nerve-derived NA and 1 adrenoreceptor antagonism with mtDNA accumulation and lung fibrogenesis in mouse models, cultured cells, and humans with IPF. Further study of this neuro-innate connection may yield new avenues for investigation in the clinical and basic science realms.\",\n \"Fusion of Imaging and Non-Imaging Data for Disease Trajectory Prediction for COVID-19 Patients\\nABSTRCATO_ST_ABSPurposeC_ST_ABSThis study investigates whether graph-based fusion of imaging data with non-imaging EHR data can improve the prediction of disease trajectory for COVID-19 patients, beyond the prediction performance of only imaging or non-imaging EHR data.\\n\\nMaterials and MethodsWe present a novel graph-based framework for fine-grained clinical outcome prediction (discharge, ICU admission, or death) that fuses imaging and non-imaging information using a similarity-based graph structure. Node features are represented by image embedding and edges are encoded with clinical or demographic similarity.\\n\\nResultsOur experiments on data collected from Emory Healthcare network indicate that our fusion modeling scheme performs consistently better than predictive models using only imaging or non-imaging features, with f1-scores of 0.73, 0.77, and 0.66 for discharge from hospital, mortality, and ICU admission, respectively. External validation was performed on data collected from Mayo Clinic. Our scheme highlights known biases in the model prediction such as bias against patients with alcohol abuse history and bias based on insurance status.\\n\\nConclusionThe study signifies the importance of fusion of multiple data modalities for accurate prediction of clinical trajectory. Proposed graph structure can model relationships between patients based on non-imaging EHR data and graph convolutional networks can fuse this relationship information with imaging data to effectively predict future disease trajectory more effectively than models employing only imaging or non-imaging data. Forecasting clinical events can enable intelligent resource allocation in hospitals. Our graph-based fusion modeling frameworks can be easily extended to other prediction tasks to efficiently combine imaging data with non-imaging clinical data.\",\n \"How do we measure the adequacy of cancer pain management? Testing the performance of 4 commonly used measures and steps towards measurement refinement\\nAlthough pain is the most common and disabling cancer symptom requiring management, the best index of cancer pain management adequacy is unknown. While the Pain Management Index is most commonly used, other indices have included relief, satisfaction, and pain intensity. We evaluated their correlations and agreement, compared their biopsychosocial correlates, and investigated whether they represented a single construct reflecting the adequacy of cancer pain management in 269 people with advanced cancer and pain. Despite moderate-to-severe average pain in 52.8% of participants, 85.1% had PMI scores suggesting adequate analgesia, pain relief was moderate and satisfaction was high. Correlations and agreement were low-to-moderate, suggesting low construct validity. Although the correlates of pain management adequacy were multidimensional, including lower pain interference, neuropathic and nociceptive pain, and catastrophizing, shorter cancer duration, and greater physical symptoms, no single index captured this multidimensionality. Principal component analysis demonstrated a single underlying construct, thus we constructed the Adequacy of Cancer Pain Management from factor loadings. It had somewhat better agreement, however correlates were limited to pain interference and neuropathic pain. This study demonstrates the psychometric shortcomings of commonly used indices. We provide suggestions for future research to improve measurement, a critical step in optimizing cancer pain management.\\n\\nPerspectiveThe Pain Management Index and other commonly used indices of cancer pain management adequacy have poor construct validity. This study provides suggestions to improve the measurement of the adequacy of cancer pain management.\",\n \"WHAT ABOUT USING SNIFFIN STICKS 12 SCREENING TEST TO IDENTIFY POST-COVID-19 OLFACTORY DISORDERS?\\nBackgroundOlfactory impairment is a major sequela of SARS-CoV-2 infection and has a negative impact on daily life quality. Olfactory loss can be assessed in many ways but seems to be little realized in a daily clinical practice. The sniffin Sticks test - 12 items (SST-12) can be used in quick olfactory disorders screening. Its use in a post-covid19 situation was the main objective of this work.\\n\\nMethodologyConsecutive patients consulting to the ENT department with post-Covid-19 olfactory loss were included. The clinical examination included an analog scale for the self-assessment of olfactory recovery (VAS), self-reported salt and sugar intake, a nasofibroscopy, the complete Sniffin Stick Test (SST) and the SST-12.\\n\\nResultsAmong the 54 patients included, based on the SST-12, 14,8% (n=8) of the patients could be classified as normosmic (SST-12[≥]11), 48,1% (n=26) as hyposmic (6< SST-12<10) and 37% (n=20) as functional anosmic (SST-12[≤]6). We report excellent and significant correlations between SST-12 and SST or VAS assessments. Salt and Sugar increased intake seems significantly related to SST-12 results.\\n\\nConclusionsSST-12 is a reliable way to screen post-COVID-19 olfactory disorders could be used in a daily clinical practice and might be used to prevent bad diet habits and so cardiovascular risk.\",\n \"THE ADDED VALUE OF 18F-FDG PET/CT IN THE ASSESSMENT OF ONSET AND STEROID RESISTANT POLIMYALGIA RHEUMATICA\\nPMR is a common inflammatory rheumatic disease. Although its clinical characteristics are fully recognized, no specific test for its diagnosis has been established to date. Several studies have described a wide variety of diseases that present with polymyalgic symptoms. A 18FDG-PET/CT scan could help to deal with these differential diagnoses. The goal of our study is to describe the findings of the 18FDG-PET/CT scan in a cohort of PMR patients and to detail how the 18FDG-PET/CT scan improves accuracy when diagnosing other underlying conditions. This cross-sectional study enrolled patients with a diagnosis of PMR who underwent to a 18FDG-PET/CT scan to rule out other diagnosis. The 18FDG-PET/CT scan was performed either following clinical criteria at the onset of clinical symptoms or when the patient became PMR steroid resistant. Patients demographic, clinical and analytical data at the moment of the 18FDG-PET/CT scan were recorded. The final diagnosis was confirmed according to clinical judgement. A total of 103 patients with PMR were included. In 49.51% of patients, the 18FDG-PET/CT scan was ordered to study resistance to steroid therapy. The final diagnoses of patients were PMR in 70.9% patients, large vessel vasculitis in 15.5%, neoplasms 4.8% and another diagnosis in the rest. The 18FDG-PET/CT scan is a very useful technique for the study of Polymyalgia Rheumatica, not only to help in the diagnostic process, but also due to its role in the identification of a variety of PMR-like patrons.\",\n \"Multi-scalar data integration links glomerular angiopoietin-tie signaling pathway activation with progression of diabetic kidney disease\\nDiabetes is the leading cause of chronic kidney disease. Prognostic biomarkers reflective of underlying molecular mechanisms are critically needed for effective management of diabetic kidney disease (DKD). In the Clinical Phenotyping and Resource Biobank study, an unbiased, machine learning approach identified a three-marker panel from plasma proteomics which, when added to standard clinical parameters, improved the prediction of outcome of end-stage kidney disease (ESKD) or 40% decline in baseline glomerular filtration rate (GFR) in a discovery DKD group (N=58) and was validated in an independent group (N=68) who also had kidney transcriptomic profiles available. Of the three markers, plasma angiopoietin 2 (ANGPT2) remained significantly associated with composite outcome in 210 Chinese Cohort Study of Chronic Kidney Disease participants with DKD. The glomerular transcriptional Angiopoietin/Tie (ANG-TIE) activation scores, derived from the expression of 154 literature-curated ANG-TIE signaling mediators, positively correlated with plasma ANGPT2 levels and outcome, explained by substantially higher TEK receptor expression in glomeruli and higher ANG-TIE activation scores in endothelial cells in DKD by single cell RNA sequencing. Our work suggests that activation of glomerular ANG-TIE signaling in the kidneys underlies the association of plasma ANGPT2 with disease progression, thereby providing potential targets to prevent DKD progression.\",\n \"Art therapy as treatment modality for persons living with dementia- a protocol for a scoping review of systematic reviews\\nObjectiveTo establish a robust understanding of the state of the evidence on the effectiveness and/or efficacy of art therapy (AT) as a non-pharmacological treatment (NPT) modality for persons living with dementia (PLWD).\\n\\nBackgroundOver the past decade, AT has received increased attention from health care professionals and researchers as having a potential role to play within treatment plans for PLWD.(1-4)\\n\\nInclusion criteriaThis scoping review will include systematic reviews from health-related disciplines conducted within the last 20 years that report the effectiveness and/or efficacy of AT as an NPT modality for PLWD and Mild Cognitive Impairment (MCI). Study outcomes must include cognition, quality of life, emotional and psychological well-being, and/or neuropsychiatric symptoms (NPS).\\n\\nMethodsA scoping review of systematic reviews was selected to outline different types of evidence and to identify gaps in the literature. The proposed review will be guided by the methodological framework proposed by the Joanna Briggs Institute. We will therefore specify the research question, identify relevant studies, select eligible studies, extract, collate, and summarize our results. We will not conduct a quality appraisal of the included studies as this review aims to explore the general scope of research conducted that assesses AT effectiveness and efficacy in PLWD.\",\n \"Prodromal Progressive Supranuclear Palsy: insights from the UK Biobank\\nBackgroundProdromal Parkinsons Disease is well described but prodromal Progressive Supranuclear Palsy (PSP) is much less understood. The diagnosis of PSP is typically delayed by an average of three years after symptom onset. Understanding the changes that occur in the prodromal and pre-diagnostic period will aid earlier diagnosis, clarify the natural history, and aid the design of early disease-modifying therapy trials.\\n\\nObjectivesTo determine motor and cognitive markers of prodromal PSP, with Parkinsons disease as a comparator condition, in a large prospective cohort.\\n\\nMethodsBaseline UK Biobank data from 502,504 individuals were collected between 2006 and 2010. Subsequent PSP and Parkinsons disease cases were identified from primary and secondary care electronic health records diagnostic coding data and death registry, with 5,404 matched controls.\\n\\nResults176 PSP cases (time to diagnosis 7.8{+/-}2.8 years) and 2,526 Parkinsons disease cases (time to diagnosis 7.8{+/-}2.9 years) were identified. At baseline, those later diagnosed with PSP had slower reaction times, weaker hand grip, lower fluid intelligence, poorer prospective memory, worse self-rated health score and lower digit recall than controls. They had higher mortality than both Parkinsons disease and control groups.\\n\\nConclusionsMotor slowing, cognitive dysfunction, and postural instability are clinical diagnostic features of PSP and are typically symptomatic three years before diagnosis. However, objective markers of these features are evident over seven years before diagnosis. This suggests a long prodromal course in PSP with subtle changes in motor and cognitive function.\",\n \"Two Pools of ATP Detected in the Brains of Pediatric Patients with Myelin Oligodendrocyte Glycoprotein Antibody Disorders (MOGAD) by 3D 31P MR Spectroscopic Imaging (MRSI) at 7T\\nOver the past four decades, ATP, the obligatory energy molecule for keeping all cells alive and functioning, was thought to contribute only one set of 31P MR signals in the human brain. Here we report for the first time the simultaneous detection of two pools of ATP in the human brain by high-resolution 3D 31P MRSI at ultrahigh field 7T. These two ATP pools differ in cytosolic Mg2+ concentration (1:0.5 ratio), with a resonance separation of 0.5 ppm at {beta}-ATP, a well-established imaging marker of intracellular Mg2+ concentration. Mg2+ is a cofactor of ATPase and its deficiency is associated with immune dysfunction, free radical damage, perturbations in Ca2+ homeostasis, and development of atherosclerosis, dyslipidemia and a number of neurological disorders, such as cerebral vasospasm, stroke, migraine, Alzheimers disease, and Parkinsons disease. Our study documents reduced Mg levels in the brain of patients with myelin oligodendrocyte glycoprotein antibody disorders (MOGAD), which is an idiopathic, inflammatory, demyelinating condition of the central nervous system (CNS) more common in pediatric patients. Low-Mg2+ ATP signals were detected mostly in the white matter regions in MOGAD, suggesting an association between Mg2+ deficiency and compromised functions of oligodendrocytes in maintenance and generation of the axonal myelin sheath. This preliminary study demonstrates the utility of the 7T 3D 31P MSRI for probing altered energy metabolism at reduced availability of Mg2+ rather than ATP itself. The potential correlation between [Mg2+] and disease progression over time should be assessed in larger cohorts.\\n\\nAuthor ApprovalYes\",\n \"COVID-19 Bimodal Clinical and Pathological Phenotypes\\nBackgroundPatients with coronavirus disease-2019 (COVID-19) present varying clinical complications. Different viral load and host response related to genetic and immune background are probably the reasons for these differences. We aimed to sought clinical and pathological correlation that justifies the different clinical outcomes among COVID-19 autopsies cases.\\n\\nMethodsMinimally invasive autopsy was performed on forty-seven confirmed COVID-19 patients from May-July, 2020. Electronic medical record of all patients was collected and a comprehensive histopathological evaluation was performed. Immunohistochemistry, immunofluorescence, special stain, western blotting and post-mortem real-time reverse transcriptase polymerase chain reaction on fresh lung tissue were performed.\\n\\nResultsWe show that 5/47 (10,6%) patients present a progressive decline in oxygenation index for acute respiratory distress syndrome (PaO2/FiO2 ratio), low compliance levels, interstitial fibrosis, high -SMA+ cells/protein expression, high collagens I/III deposition and NETs(P<0.05), named as fibrotic phenotype (N=5). Conversely, 10/47 (21,2%) patients demonstrated progressive increase in PaO2/FiO2 ratio, high pulmonary compliance levels, preserved elastic framework, increase thrombus formation and high platelets and D-dimer levels at admission (P<0.05), named as thrombotic phenotype. While 32/47 (68,1%) had a mixed phenotypes between both ones.\\n\\nConclusionsWe believe that categorization of patients based on these two phenotypes can be used to develop prognostic tools and potential therapies since the PaO2/FiO2 ratio variation and D-dimer levels correlate with the underlying fibrotic or thrombotic pathologic process, respectively; which may indicate possible clinical outcome of the patient.\",\n \"Uncovering interpretable potential confounders in electronic medical records\\nRandomized clinical trials (RCT) are the gold standard for informing treatment decisions. Observational studies are often plagued by selection bias, and expert-selected covariates may insufficiently adjust for confounding. We explore how unstructured clinical text can be used to reduce selection bias and improve medical practice. We develop a framework based on natural language processing to uncover interpretable potential confounders from text. We validate our method by comparing the estimated hazard ratio (HR) with and without the confounders against established RCTs. We apply our method to four cohorts built from localized prostate and lung cancer datasets from the Stanford Cancer Institute and show that our method shifts the HR estimate towards the RCT results. The uncovered terms can also be interpreted by oncologists for clinical insights. We present this proof-of-concept study to enable more credible causal inference using observational data, uncover meaningful insights from clinical text, and inform high-stakes medical decisions.\",\n \"Higher Limbic and Basal Ganglia volumes in surviving COVID-negative patients and the relations to fatigue.\\nBackgroundAmong systemic abnormalities caused by the novel coronavirus, little is known about the critical attack on the central nervous system (CNS). Few studies have shown cerebrovascular pathologies that indicate CNS involvement in acute patients. However, replication studies are necessary to verify if these effects persist in COVID-19 survivors more conclusively. Furthermore, recent studies indicate fatigue is highly prevalent among long-COVID patients. How morphometry in each group relate to work-related fatigue need to be investigated.\\n\\nMethodCOVID survivors were MRI scanned two weeks after hospital discharge. We hypothesized, these survivors will demonstrate altered gray matter volume (GMV) and experience higher fatigue levels when compared to healthy controls, leading to stronger correlation of GMV with fatigue. Voxel-based morphometry was performed on T1-weighted MRI images between 46 survivors and 30 controls. Unpaired two-sample t-test and multiple linear regression were performed to observe group differences and correlation of fatigue with GMV.\\n\\nResultsThe COVID group experienced significantly higher fatigue levels and GMV of this group was significantly higher within the Limbic System and Basal Ganglia when compared to healthy controls. Moreover, while a significant positive correlation was observed across the whole group between GMV and self-reported fatigue, COVID subjects showed stronger effects within the Posterior Cingulate, Precuneus and Superior Parietal Lobule.\\n\\nConclusionBrain regions with GMV alterations in our analysis align with both single case acute patient reports and current group level neuroimaging findings. We also newly report a stronger positive correlation of GMV with fatigue among COVID survivors within brain regions associated with fatigue, indicating a link between structural abnormality and brain function in this cohort.\"\n]","isConversational":false},"cluster":{"kind":"number","value":10,"string":"10"}}}],"truncated":false,"partial":false},"paginationData":{"pageIndex":2,"numItemsPerPage":100,"numTotalItems":229,"offset":200,"length":100}},"jwt":"eyJhbGciOiJFZERTQSJ9.eyJyZWFkIjp0cnVlLCJwZXJtaXNzaW9ucyI6eyJyZXBvLmNvbnRlbnQucmVhZCI6dHJ1ZX0sImlhdCI6MTc3Nzk3MTI5Nywic3ViIjoiL2RhdGFzZXRzL0hpZXVtYW4vbWVkcnhpdlAyUCIsImV4cCI6MTc3Nzk3NDg5NywiaXNzIjoiaHR0cHM6Ly9odWdnaW5nZmFjZS5jbyJ9.E-xBtzCuyE2orU3yAoYby4Ht-xN1F0yMzilBbgcImSGcl9KtVLNK1eLzDrtKIpdYTJZPR1VIkm76aNvbjx79DA","displayUrls":true,"splitSizeSummaries":[{"config":"default","split":"train","numRows":229,"numBytesParquet":29948619}]},"discussionsStats":{"closed":0,"open":0,"total":0},"fullWidth":true,"hasGatedAccess":true,"hasFullAccess":true,"isEmbedded":false,"savedQueries":{"community":[],"user":[]}}">
query stringlengths 526 2k | positive listlengths 2 31 | negative listlengths 120 120 | cluster int64 0 10 |
|---|---|---|---|
Estimating the direct Disability-Adjusted Life Years (DALYs) associated with SARS-CoV-2 (COVID-19) in the Republic of Ireland: The first full year
ObjectivesBurden of Disease frameworks facilitate estimation of the health impact of diseases to be translated into a single measure, such as the Disability-Adjusted-Life-Ye... | [
"Cognitive predictors of vaccine hesitancy and COVID-19 mitigation behaviors in a population representative sample\nWith the continued threat of COVID-19, predictors of vaccination hesitancy and mitigation behaviors are critical to identify. Prior studies have found that cognitive factors are associated with some C... | [
"SARS-CoV-2 specific memory B-cells from individuals with diverse disease severities recognize SARS-CoV-2 variants of concern.\nIn this investigation we examined the magnitude, breadth, and durability of SARS-CoV-2 specific antibodies in two distinct B-cell compartments: long-lived plasma cell-derived antibodies in... | 8 |
Longitudinal changes in home-based arts engagement during and following the first national lockdown due to the COVID-19 pandemic in the United Kingdom
AimsThis study aimed to examine potential heterogeneity in longitudinal changes in home-based arts engagement during the first national lockdown and following gradual ea... | [
"Maliqua: A study within Malakit, a project on malaria and gold miners in French Guiana\nMalaria is endemic in French Guiana, especially within the gold mining community working illegally. Gold miners travel to remote camps in the forest to carry out their activities, exposing themselves to the presumed contaminati... | [
"Herpesvirus Reactivations in Critically-Ill COVID-19 Patients with Autoantibodies Neutralizing Type I Interferons\nAutoantibodies neutralizing the antiviral action of type I interferons (IFNs) have been associated with pre-disposition to severe COVID-19. Here, we screened for such autoantibodies in 103 critically-... | 8 |
DEVELOPMENT OF DISASTER EDUCATION IN THE INITIAL HANDLING OF MULTI-AGENT-BASED EMERGENCIES IN THE PRE-HOSPITAL AREA.
BackgroundDisaster risk reduction involves several sectors, legal, social, structural, economic, technological, educational, environmental health, with improved preparedness will be able to reduce the im... | [
"The MU Study of Seropositivity and Risk for SARS-CoV-2 and COVID-19: Crucial Behavioral and Immunological Data from Midwestern College Students\nObjectiveWe describe our Fall 2020 study of college students COVID-19 related behaviors, attitudes, and antibody test results.\n\nParticipantsThe study included 1,446 ran... | [
"Predictors of suicidal thoughts and behavior in children: results from penalized logistic regression analyses in the ABCD study\nDespite numerous efforts to predict suicide risk in children, the ability to reliably identify youth that will engage in suicide thoughts or behaviors (STB) has remained remarkably unsuc... | 6 |
When efficacy and adherence conflict: preferences and patterns of response to mask-wearing and social distancing public health advice during the COVID-19 pandemic
With recurring waves of the Covid-19 pandemic, a dilemma facing public health leadership is whether to provide public advice that is medically optimal (e.g.,... | [
"Detection and quantification of enteric pathogens in aerosols near open wastewater canals in cities with poor sanitation\nUrban sanitation infrastructure is inadequate in many low-income countries, leading to the presence of highly concentrated, uncontained fecal waste streams in densely populated areas. Combined ... | [
"Development of a rapid SARS-CoV-2 neutralisation test by detecting antibodies that block interaction of spike protein receptor-binding domain (RBD) with angiotensin-converting enzyme 2 (ACE2)\nThe urgent need for a rapid and reliable Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) neutralising antibod... | 9 |
Did national holidays accelerate COVID-19 diffusion in Bangladesh? A case study
Bangladesh registered 1573828 confirmed cases of COVID-19 and the death toll crossed the grim milestone of 27946 across the country as of 9th December, 2021. Despite the enforcement of stringent COVID-19 measures, including nationwide lockd... | [
"Effectiveness of whole virus COVID-19 vaccine at protecting health care personnel against SARS-CoV-2 infections in Lima, Peru\nIn February 2021, Peru launched a vaccination campaign among healthcare personnel using BBIBP-CorV inactivated whole virus (BBIBP-CorV) COVID-19 vaccine. Two doses of BBIBP-CorV vaccine ar... | [
"Testing out of quarantine\nSince SARS-CoV-2 emerged, a 14-day quarantine has been recommended based on COVID-19\"s incubation period. Using an RT-PCR or rapid antigen test to \"test out\" of quarantine is a frequently proposed strategy to shorten duration without increasing risk. We calculated the probability that... | 4 |
Elderly acceptance of telemedicine use in Hong Kong during and after the COVID-19 pandemic: a cross-sectional cohort survey
BackgroundTelemedicine services worldwide have experienced an unprecedented boom since the beginning of the COVID-19 pandemic. Multiple studies have noted telemedicine as an effective alternative ... | [
"Tobacco and Nicotine Use in the United States Army Trainee Soldiers Environment\nTobacco and nicotine use rates within the United States military population are high, and rates among young trainee soldiers are not improving over time. Trainee soldiers are heavily influenced by role models in their environment, and... | [
"An immune dysfunction score for stratification of patients with acute infection based on whole blood gene expression\nDysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of deaths globally each year. To alleviate this burden, improved prognostication and biomarkers o... | 8 |
Quantification of abdominal fat from computed tomography using deep learning and its association with electronic health records in an academic biobank
ObjectiveThe objective was to develop a fully automated algorithm for abdominal fat segmentation and deploy this method at scale and associated with diagnoses in an acad... | [
"Functional connectivity directionality between large-scale resting-state networks in children and adolescence from the Healthy Brain Network sample\nMental disorders often emerge during adolescence and have been associated with age-related differences in connection strengths of brain networks (static functional co... | [
"Heart rate and heart rate variability in patients with chronic inflammatory joint disease: The role of pain duration and the insular cortex\nChronic inflammatory joint diseases (CIJD) have been linked to increased cardiovascular morbidity and mortality. A decisive reason could be a dysregulation of the autonomic n... | 0 |
COLI-NET: Fully Automated COVID-19 Lung and Infection Pneumonia Lesion Detection and Segmentation from Chest CT Images
BackgroundWe present a deep learning (DL)-based automated whole lung and COVID-19 pneumonia infectious lesions (COLI-Net) detection and segmentation from chest CT images.
MethodsWe prepared 2358 (3472... | [
"Volumetric lung cancer screening reduces unnecessary low-dose computed tomography scans: results from a single-centre prospective trial on 4,119 subjects\nPurposeTo compare low-dose computed tomography (LDCT) outcome and volume-doubling time (VDT) derived from measured volume (MV) and estimated volume (EV) of pulm... | [
"Neutralising antibody activity against SARS-CoV-2 variants, including Omicron, in an elderly cohort vaccinated with BNT162b2\nSARS-CoV-2 variants threaten the effectiveness of tools we have developed to mitigate against serious COVID-19. This is especially true in clinically vulnerable sections of society includin... | 2 |
Quantitative susceptibility mapping improves the detection of calcified carotid vessels by multi-contrast MRI using computed tomography angiography as the reference standard
The objective of this study was to evaluate initial feasibility and improvement in the detection of calcified carotid arteries by including quanti... | [
"Class dependency based learning using Bi-LSTM coupled with the transfer learning of VGG16 for the diagnosis of Tuberculosis from chest x-rays\nTuberculosis is an infectious disease that is leadingto the death of millions of people across the world. The mortalityrate of this disease is high in patients suffering fr... | [
"Inexpensive and colorimetric RNA detection by E. coli cell-free protein synthesis platform at room temperature\nWe report colorimetric detection of SARS-CoV-2 viral RNA by an in vitro transcription/translation assay with crude E. coli extracts at room temperature, with the aid of body heat. Clinically-relevant con... | 5 |
Combining Tumor Segmentation Masks with PET/CT Images and Clinical Data in a Deep Learning Framework for Improved Prognostic Prediction in Head and Neck Squamous Cell Carcinoma
PET/CT images provide a rich data source for clinical prediction models in head and neck squamous cell carcinoma (HNSCC). Deep learning models ... | [
"Head and Neck Cancer Primary Tumor Auto Segmentation using Model Ensembling of Deep Learning in PET-CT Images\nAuto-segmentation of primary tumors in oropharyngeal cancer using PET/CT images is an unmet need that has the potential to improve radiation oncology workflows. In this study, we develop a series of deep ... | [
"Radiological follow-up of adults hospitalised with pneumonia and SARS-CoV-2 infection, in Bristol UK, during the COVID19 pandemic\nFor patients with pneumonia and COVID19 repeating chest radiography is recommend in current British Thoracic Society (BTS) guidelines. Over two distinct time periods during the COVID19... | 9 |
A systematic review of previous MRI studies demonstrating the relationship between season and brain volume
IntroductionSpecific diseases such as Alzheimers, schizophrenia and multiple sclerosis have been associated with environmental changes, including changes in season. The relationship between changes in season or ph... | [
"Radiographic Imaging of Power Injectable Medical Access Ports as a Supplemental Identification Tool\nPurposeOur aims were to describe characteristic radiographic features of two power injectable medical access ports (MAPs) on various imaging modalities for rapid and precise identification; and to demonstrate the v... | [
"Elevated mucosal antibody responses against SARS-CoV-2 are correlated with lower viral load and faster decrease in systemic COVID-19 symptoms\nMucosal antibodies play a key role in protection against SARS-CoV-2 exposure, but their role during primary infection is not well understood. We assessed mucosal antibody r... | 3 |
Insights on Telemedicine Use by Physiatrists Before, During, and Beyond the COVID-19 Pandemic
PurposeTo determine if physiatrists increased their use of telemedicine during the first 11 months of the COVID-19 pandemic and if changes are expected to persist post-pandemic. And to identify key tasks which require video fo... | [
"Higher knee hypertension in patients with hemiplegia correlates lower lateral and medial meniscus volume in the paretic leg\nStroke is a disease with high morbidity and disability rate. After stroke, slower walking velocity, shorter step length, higher cadence, larger step width, and longer stance phase duration c... | [
"Reliability of Spike Gene Target Failure for ascertaining SARS-CoV-2 lineage B.1.1.7 prevalence in a hospital setting\nThe appearance of the SARS-CoV-2 lineage B.1.1.7 in the UK in late 2020, associated with faster transmission, sparked the need to find effective ways to monitor its spread. The set of mutations th... | 8 |
Implicit and explicit motor learning interventions for gait in people after stroke: a process evaluation of a randomized controlled trial
BackgroundGait training within stroke rehabilitation can be applied using implicit or explicit motor learning approaches. Explicit learning is a more conscious approach to learning, ... | [
"Resting-state network plasticity induced by music therapy after traumatic brain injury\nTraumatic brain injury (TBI) is characterized by a complex pattern of abnormalities in resting-state functional connectivity (rsFC) and network dysfunction, which can potentially be ameliorated by rehabilitation. In our previou... | [
"An automated Dashboard to improve laboratory COVID-19 diagnostics management\nBackgroundIn response to the CoVID-19 pandemic, our microbial diagnostic laboratory located in a university hospital has implemented several distinct SARS-CoV-2 RT-PCR systems in a very short time. Thanks to our automated molecular diagn... | 6 |
Walking Activities during the Acute Stroke Hospital Stay May Benefit Cerebrovascular Health
PurposePhysical activity within the hospital post-stroke is recommended for cardiovascular and musculoskeletal health, but no studies have examined cerebrovascular health. We hypothesized individuals who walked farther distances... | [
"A Patient-Reported Measure of Locomotor Function Derived from the Functional Assessment Questionnaire\nBackgroundLocomotor function is often impaired in children diagnosed with cerebral palsy (CP). Improving locomotor function is a common goal of treatment. The current gold standard for assessing locomotor functio... | [
"Process evaluation protocol for the SLEEP study: a hybrid digital CBT-I intervention for working people with insomnia\nIntroduction: The Supporting Employees with Insomnia and Emotional Regulation Problems (SLEEP) pilot uses hybrid digital Cognitive Behavioural Therapy for Insomnia (CBT-I) to help working people a... | 5 |
An individual participant data meta-analysis of prognostic blood biomarkers in IPF
BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with variable disease trajectory. Blood biomarkers reflecting disease severity that can accurately predict outcomes are urgently needed. Through systema... | [
"Development of Childhood Asthma Prediction Models using Machine Learning Approaches\nBackgroundWheeze is common in early life and often transient. It is difficult to identify which children will experience persistent symptoms and subsequently develop asthma. Machine learning approaches have the potential for bette... | [
"Prevalence of multimorbidity combinations and their association with medical costs and poor health among U.S. adults\nBackgroundMultimorbidity is common, but the prevalence and burden of the specific combinations of co-occurring disease has not been systematically examined at the population level in the U.S. The o... | 10 |
Quantitative Trait Loci on Chromosome 21 have Pleiotropic Effects on %FEV1 and Allergen Polysensitization; asthma related traits in the EGEA study
To investigate whether the 21q21 region may contain a quantitative trait locus (QTL) with pleiotropic effect on % predicted FEV1 (forced expiratory volume in 1 second) and S... | [
"Anti-CELA1 KF4 Antibody Prevents Emphysema by Inhibiting Stretch-Mediated Remodeling\nEmphysema is a major contributor to the morbidity and mortality of chronic obstructive pulmonary disease (COPD), and there are no disease modifying therapies. Three leading pathophysiologic models are the altered protease/antipro... | [
"Extended Invariant Information Clustering is Effective for Leave-One- Site-Out Cross-Validation in Resting State Functional Connectivity Modelling\nHerein, we propose a new deep neural network model based on invariant information clustering (IIC), proposed by Ji et al., to improve the modeling performance of the l... | 1 |
Targeted screening for lung cancer with autoantibodies.
Earlier detection of lung cancer is possible, but difficult and costly to achieve. Screening with Low Dose Computed Tomography (LDCT)scanning has been shown to reduce mortality by 20-25% over the past decade but uptake amongst those most likely to suffer the disea... | [
"Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY disease (CLARITY): Statistical analysis plan for a randomised controlled Bayesian adaptive sample size trial\nThe CLARITY trial (Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY Disease) investigates the ... | [
"HeartNet: Self Multi-Head Attention Mechanism via Convolutional Network with Adversarial Data Synthesis for ECG-based Arrhythmia Classification\nAO_SCPLOWBSTRACTC_SCPLOWCardiovascular disease is now one of the leading causes of morbidity and mortality in humans. Electrocardiogram (ECG) is a reliable tool for monit... | 1 |
Ex-vivo mucolytic and anti-inflammatory activity of BromAc in tracheal aspirates from COVID-19
COVID-19 is a lethal disease caused by the pandemic SARS-CoV-2, which continues to be a public health threat. COVID-19 is principally a respiratory disease and is often associated with sputum retention, for which there are li... | [
"Use of Baricitinib in Treatment of COVID-19: A Systematic Review\nObjectivesTo assess the role of baricitinib alone or in combination with other therapies as a treatment for patients with COVID-19.\n\nMethodsSystematic literature search was conducted in the WHO COVID-19 Coronavirus disease database to find clinica... | [
"Comorbidity Risk Factors Contributing to COVID-19 Related Deaths in Florida, March 1, 2020-January 16, 2021\nObjectivesTo assess the association of specific comorbid conditions to COVID-19 deaths in Florida among decedents 16 to 64 years of age.\n\nMethodsThis report uses Florida vital statistics death data over t... | 2 |
Genetic landscape of rare autoinflammatory disease variants in Qatar and Middle Eastern populations through the integration of whole-genome and exome datasets
Rare monogenic autoinflammatory diseases are a group of recurrent inflammatory genetic disorders caused due to genetic variants in over 37 genes. While a number ... | [
"Cytokines (IL-17, IL-23 and IL-33) in Systemic lupus erythematosus in Trinidad and Tobago.\nSystemic lupus erythematosus (SLE) is the most common autoimmune disease. It is characterized by the presence of hundreds of autoantibodies against many organs and tissues, including the presence of a large number of autoan... | [
"From Delta to Omicron SARS-CoV-2 variant: switch to saliva sampling for higher detection rate\nBackgroundReal-time polymerase chain reaction (RT-PCR) testing on a nasopharyngeal swab is the current standard for SARS-CoV-2 virus detection. Since collection of this sample type is experienced uncomfortable by patient... | 10 |
Physical Activity Moderates Inflammatory Gene Expression in Rheumatoid Arthritis
BackgroundWhile general population studies have shown associations between greater physical activity and lower inflammatory markers, effects of physical activity on inflammatory pathways in rheumatoid arthritis (RA) remain unknown. We aime... | [
"Multi-modal single-cell sequencing identifies cellular immunophenotypes associated with juvenile dermatomyositis disease activity\nJuvenile dermatomyositis (JDM) is a rare autoimmune condition with insufficient biomarkers and treatments, in part, due to incomplete knowledge of the cell types mediating disease. We ... | [
"Premature Atrial Stimulation Accentuates Conduction Abnormalities in Cardiac Surgery Patients that Develop Postoperative Atrial Fibrillation\nBACKGROUNDpostoperative atrial fibrillation (POAF) is a common cardiac surgery complication that is associated with increased complications and negative outcomes, but the as... | 10 |
Mitochondria-mediated Maternal-fetal Interactions and Consequences of Mitochondrial Dysregulation Indicate New Roles for Mitochondria in Hypertensive Pregnancies
Oxidative stress, placental mitochondrial morphological alterations, and impaired bioenergetics are associated with hypertensive disorders of pregnancy. Here ... | [
"SARS-CoV-2 infects, replicates, elevates angiotensin II and activates immune cells in human testes\nAlthough much has been published since the first cases of COVID-19, there remain unanswered questions regarding SARS-CoV-2 impact on testes and the potential consequences for reproductive health. We investigated tes... | [
"Amygdala connectivity as a predisposing neural feature of stress-induced behaviour during the COVID-2019 outbreak in Hubei\nThe amygdala plays an important role in the regulation of stress and anxiety. However, little is known about the relationship between amygdala connectivity and subsequent stress-induced behav... | 0 |
Assessment of menstrual hygiene practice and associated factor among High school female students in Harar Eastern Ethiopia 2019
BackgroundMenstruation is a visible manifestation of cyclic uterine bleeding as a result of the interaction of different hormones. During menstruation, girls face gender problems. These are, e... | [
"Unmasking Seasonal Cycles in Human Fertility: How holiday sex and fertility cycles shape birth seasonality\nThe mechanisms of human birth seasonality have been debated for over 150 years1. In particular, the question of whether sexual activity or fertility variations drive birth seasonality has remained open and c... | [
"Aerosol decontamination and spatial separation using a free-space LED-based UV-C light curtain\nBackgroundThe SARS-CoV-2 pandemic demonstrated the vulnerability of our societies to aerosol transmitted pathogens. With no less than 260mio known cases and > 5mio deaths, SARS-CoV-2 is a global catastrophe leading to h... | 7 |
Variability in physical inactivity responses of university students during COVID-19 pandemic: A monitoring of daily step counts using a smartphone application
This study investigated the changes in physical inactivity of university students during the COVID-19 pandemic, with reference to their academic calendar. We use... | [
"Transgender Swimmer in College Athletics\nThere is current scientific and legal controversy about sports competition eligibility regulations for transgender athletes. To better understand and contextualize the effect of androgen-suppression treatment on swimming performance, we compared the gender-related differen... | [
"Using DeepLabCut for tracking body landmarks in videos of children with dyskinetic cerebral palsy: a working methodology\nMarkerless motion tracking is a promising technique to capture human movements and postures. It could be a clinically feasible tool to objectively assess movement disorders within severe dyskin... | 9 |
The effect of including the Nordic Hamstring exercise on sprint and jump performance in athletes: protocol of a systematic review and meta-analyses
The Nordic Hamstring exercise reduces hamstring strain injuries in football and other sports, but the exercise is not well adopted in practice. Barriers from practitioners ... | [
"The heart of an endurance athlete: impact of and recovery after an ultra-endurance event.\nAimsAcute bouts of ultra-endurance exercise may cause an acute reduction in cardiac function, causing a physiological cascade which releases cardiac biomarkers. This study set out to determine the cardiac stress and recovery... | [
"KIM-1/TIM-1 is a Receptor for SARS-CoV-2 in Lung and Kidney\nSARS-CoV-2 precipitates respiratory distress by infection of airway epithelial cells and is often accompanied by acute kidney injury. We report that Kidney Injury Molecule-1/T cell immunoglobulin mucin domain 1 (KIM-1/TIM-1) is expressed in lung and kidn... | 10 |
Hepatic resection versus transarterial chemoembolization for the intermediate stage hepatocellular carcinoma：A cohort study
BackgroundThe selection criterion for hepatic resection(HR) in intermediate-stage(IM) hepatocellular carcinoma(HCC) is still controversial. We used real-world data to evaluate the overall survival... | [
"Post operative acute kidney injury in abdominal Surgeries. A retrospective analysis of single center in western India.\nAIMThe aim of our study was to evaluate the incidence and causative factors for acute kidney injury in abdominal surgeries.\n\nMaterial and MethodsAll the abdominal surgeries performed between Ap... | [
"Reliability and validity of the Japanese version of the Mental Health Literacy Scale (MHLS) among undergraduate and graduate students in the medical field\nObjectiveMental health literacy (MHL) is a fundamental basis of reducing stigma towards mental disorders and promoting early help-seeking. However, there is no... | 10 |
Prophylactic Antibiotics in Arteriovenous Fistulae: A systematic Review
BackgroundThe aim of this study is to establish and evaluate whether the use of prophylactic antibiotics in the creation of any autogenous arteriovenous fistula in hemodialysis patients is indicated, evidence-based and/or recommended.
MethodsA sys... | [
"Development of machine learning models for the prediction of complications after colorectal and small intestine surgery in psychiatric and non-psychiatric patient collectives (P-Study)\nPsychiatric and psychosomatic diseases are an increasingly cumbersome burden for the medical system. Indeed, hospital costs assoc... | [
"Saving Lives with Pre-Financed Rules-Based Disaster Aid: Evidence from Mexico\nDeveloping economies are not disproportionately exposed to natural disasters, but they experience significantly more deaths. Exploiting a discontinuity in the eligibility rules to Mexicos pre-financed indexed disaster fund (Fonden), I s... | 6 |
How hostile is prolonged brain death for donor organs in transplantation? A time course analysis using clinical samples
Organ donation after brain death (DBD) is an important source of transplanted organs, as chronic undersupply means many patients die whilst awaiting transplant. Improving organ quality and graft survi... | [
"Human cytomegalovirus strain diversity and dynamics reveal the donor lung as a major contributor after transplantation\nMixed human cytomegalovirus (HCMV) strain infections are frequent in lung transplant recipients (LTRs). To date, the influence of the donor (D) and recipient (R) HCMV-serostatus on intra-host HCM... | [
"Mortality among Care Home Residents in England during the first and second waves of the COVID-19 pandemic: an analysis of 4.3 million adults over the age of 65\nBackgroundResidents in care homes have been severely impacted by the COVID-19 pandemic. We describe trends in risk of mortality among care home residents ... | 9 |
Early prediction of renal graft function: Analysis of a multi-centre, multi-level data set
IntroductionLong-term graft survival rates after renal transplantation are still moderate. We aimed to build an early predictor of an established long-term outcomes marker, the glomerular filtration rate (eGFR) one year post-tran... | [
"COVID-19 in 823 Transplant patients: A Systematic Scoping Review\nBackgroundManagement of COVID-19 in transplant patients is a big challenge. Data on immunosuppression management, clinical picture, and outcomes are lacking.\n\nObjectivesTo summarize the current literature on COVID-19 in transplant patients especia... | [
"Multi-trait genome-wide association study identifies new loci associated with sleep apnoea risk\nBackgroundSleep apnoea is a disorder characterised by periods of halted breathing during sleep. Despite its association with severe health conditions such as cardiovascular disease, liver problems and metabolic syndrom... | 10 |
Microbiota of Chronic Prostatitis/Chronic Pelvic Pain Syndrome are Distinct from Interstitial Cystitis/Bladder Pain Syndrome
Urologic chronic pelvic pain syndrome patients include men chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and patients, mainly women, with interstitial cystitis/bladder pain syndrome ... | [
"Molecular portrait of prostate tissue probed by MALDI Imaging Mass Spectrometry\nBenign prostatic hyperplasia (BPH) is the most common condition in aging men, associated with lower urinary tract symptoms. BPH has been suggested to be a risk factor for certain urologic cancers, but the current evidence is inconsist... | [
"Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis\nProteoglycans are complex macromolecules formed of glycosaminoglycan chains covalently linked to core proteins through a linker tetrasaccharide common to heparan sulfate proteoglycans ... | 10 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.