bluuebunny/crossref_metadata_2025_split huggingface dataset:
Findings and insights from the genetic investigation of age of first reported occurrence for complex disorders in the UK Biobank and FinnGen
Authors: Feng Yen-Chen A. , Ge Tian , Cordioli Mattia ,   FinnGen, Ganna Andrea , Smoller Jordan W. , Neale Benjamin M. 
Published: November 2020

AbstractAge of onset contains information on the timing of events relevant to disease etiology, but there has not been a systematic investigation of its heritability from GWAS data. Here, we characterize the genetic architecture of age of first occurrence and its genomic relationship with disease susceptibility for a wide range of complex disorders in the UK Biobank. For diseases with a sufficient sample size, we discover that age of first occurrence has non-trivial genetic contributions, some with specific genetic risk factors not associated with susceptibility to the disease. Through genetic correlation analysis, we show that an earlier health-event occurrence is correlated with a higher polygenic risk of disease susceptibility. An independent genetic investigation of the FinnGen cohort replicates the pattern of heritability and genetic correlation estimates. We then demonstrate that incorporating disease onset age with susceptibility may improve genetic risk prediction and stratification.
Timing the SARS-CoV-2 Index Case in Hubei Province
Authors: Pekar Jonathan , Worobey Michael , Moshiri Niema , Scheffler Konrad , Wertheim Joel O. 
Published: November 2020

AbstractUnderstanding when SARS-CoV-2 emerged is critical to evaluating our current approach to monitoring novel zoonotic pathogens and understanding the failure of early containment and mitigation efforts for COVID-19. We employed a coalescent framework to combine retrospective molecular clock inference with forward epidemiological simulations to determine how long SARS-CoV-2 could have circulated prior to the time of the most recent common ancestor. Our results define the period between mid-October and mid-November 2019 as the plausible interval when the first case of SARS-CoV-2 emerged in Hubei province. By characterizing the likely dynamics of the virus before it was discovered, we show that over two-thirds of SARS-CoV-2-like zoonotic events would be self-limited, dying out without igniting a pandemic. Our findings highlight the shortcomings of zoonosis surveillance approaches for detecting highly contagious pathogens with moderate mortality rates.
Comparing COVID-19 vaccine allocation strategies in India: a mathematical modelling study
Authors: Foy Brody H , Wahl Brian , Mehta Kayur , Shet Anita , Menon Gautam I , Britto Carl 
Published: November 2020

ABSTRACTBackgroundThe development and widespread use of an effective SARS-CoV-2 vaccine could help prevent substantial morbidity and mortality associated with COVID-19 infection and mitigate many of the secondary effects associated with non-pharmaceutical interventions. The limited availability of an effective and licensed vaccine will task policymakers around the world, including in India, with decisions regarding optimal vaccine allocation strategies. Using mathematical modelling we aimed to assess the impact of different age-specific COVID-19 vaccine allocation strategies within India on SARS CoV-2-related mortality and infection.MethodsWe used an age-structured, expanded SEIR model with social contact matrices to assess different age-specific vaccine allocation strategies in India. We used state-specific age structures and disease transmission coefficients estimated from confirmed Indian incident cases of COVID-19 between 28 January and 31 August 2020. Simulations were used to investigate the relative reduction in mortality and morbidity of vaccinate allocation strategies based on prioritizing different age groups, and the interactions of these strategies with several concurrent non-pharmacologic interventions (i.e., social distancing, mandated masks, lockdowns). Given the uncertainty associated with current COVID-19 vaccine development, we also varied several vaccine characteristics (i.e., efficacy, type of immunity conferred, and rollout speed) in the modelling simulations.ResultsIn nearly all scenarios, prioritizing COVID-19 vaccine allocation for older populations (i.e., >60yrs old) led to the greatest relative reduction in deaths, regardless of vaccine efficacy, control measures, rollout speed, or immunity dynamics. However, preferential vaccination of this target group often produced higher total symptomatic infection counts and more pronounced estimates of peak incidence than strategies which targeted younger adults (i.e., 20-40yrs or 40-60yrs) or the general population irrespective of age. Vaccine efficacy, immunity type, target coverage and rollout speed all significantly influenced overall strategy effectiveness, with the time taken to reach target coverage significantly affecting the relative mortality benefit comparative to no vaccination.ConclusionsOur findings support global recommendations to prioritize COVID-19 vaccine allocation for older age groups. Including younger adults in the prioritisation group can reduce overall infection rates, although this benefit was countered by the larger mortality rates in older populations. Ultimately an optimal vaccine allocation strategy will depend on vaccine characteristics, strength of concurrent non-pharmaceutical interventions, and region-specific goals such as reducing mortality, morbidity, or peak incidence.
Metabolic correlates of late midlife cognitive function: findings from the 1946 British Birth Cohort
Authors: Green Rebecca , Lord Jodie , Xu Jin , Maddock Jane , Kim Min , Dobson Richard , Legido-Quigley Cristina , Wong Andrew , Richards Marcus , Proitsi Petroula 
Published: November 2020

AbstractInvestigating associations between metabolites and late midlife cognitive function could reveal potential markers and mechanistic insights relevant to early dementia. Here, we aimed to systematically explore the metabolic underpinnings of cognitive outcomes across the 7th decade of life, while untangling influencing life course factors. Using levels of 1019 metabolites detected by liquid chromatography-mass spectrometry and quantified at age 60-64, we evaluated relationships between metabolites and cognitive outcomes in the British 1946 Birth Cohort (N=1740). We conducted pathway and network analyses to allow for greater insight into underlying mechanisms, and sequentially adjusted for life course factors including social factors, childhood cognition and lifestyle influences. After adjusting for multiple tests, 155 metabolites, 10 pathways and 5 network modules demonstrated relationships with cognitive outcomes. Integrating these, we identified thirty-five “hub” metabolites that were influential in their module and associated with our outcomes. Notably, we report relationships between a module comprised of acylcarnitines and processing speed that were independent of life course factors, revealing palmitoylcarnitine as a hub (final model: ß =-0.10, 95%CI =-0.15--0.052, p=5.99×10−5). Two modules additionally demonstrated associations with several cognitive outcomes that were partly explained by life course factors: one enriched in nucleosides and amino acids, and another in vitamin A and C metabolites. Our other findings, including a module enriched in sphingolipid pathways, were entirely explained by life course factors - particularly social factors and childhood cognition. These results highlight potential metabolic mechanisms underlying cognitive function in late midlife, suggesting marker candidates and life course relationships for further study.
The Contrasting Role of Nasopharyngeal Angiotensin Converting Enzyme 2 (ACE2) Expression in SARS-CoV-2 Infection: A Cross-Sectional Study of People Tested for COVID-19 in British Columbia
Authors: Nikiforuk Aidan M. , Kuchinski Kevin S. , Twa David D.W. , Lukac Christine D. , Sbihi Hind , Basham C. Andrew , Steidl Christian , Prystajecky Natalie A. , Jassem Agatha N. , Krajden Mel , Patrick David M , Sekirov Inna 
Published: November 2020

SummaryBackgroundAngiotensin converting enzyme 2 (ACE2) serves as the host receptor for SARS-CoV-2, with a critical role in viral infection. We aim to understand population level variation of nasopharyngealACE2expression in people tested for COVID-19 and the relationship betweenACE2expression and SARS-CoV-2 viral RNA load, while adjusting for expression of the complementary protease, Transmembrane serine protease 2 (TMPRSS2), solubleACE2, age, and biological sex.MethodsA cross-sectional study of n=424 participants aged 1-104 years referred for COVID-19 testing was performed in British Columbia, Canada. Participants who tested negative or positive for COVID-19 were matched by age and biological sex. Viral and host gene expression was measured by quantitative reverse-transcriptase polymerase chain reaction. Bivariate analysis and multiple linear regression were performed to understand the role of nasopharyngealACE2expression in SARS-CoV-2 infection. TheACE2gene was targeted to measure expression of transmembrane and soluble transcripts.FindingsAnalysis shows no association between age and nasopharyngealACE2expression in those who tested negative for COVID-19 (P=0·092). Mean expression of transmembrane (P=1·2e-4), solubleACE2(P<0·0001) andTMPRSS2(P<0·0001) differed between COVID-19-negative and -positive groups. In bivariate analysis of COVID-19-positive participants, expression of transmembraneACE2positively correlated with SARS-CoV-2 RNA viral load (P<0·0001), expression of solubleACE2negatively correlated (P<0·0001), and no correlation was found withTMPRSS2 (P=0·694). Multivariable analysis showed that the greatest viral RNA loads were observed in participants with high transmembraneACE2expression (B=0·886, 95%CI:[0·596 to 1·18]), while expression of solubleACE2may protect against high viral RNA load in the upper respiratory tract (B= −0·0990, 95%CI:[−0·176 to −0·0224]).InterpretationNasopharyngealACE2expression plays a dual, contrasting role in SARS-CoV-2 infection of the upper respiratory tract. TransmembraneACE2positively correlates, while solubleACE2negatively correlates with viral RNA load after adjusting for age, biological sex and expression of TMPRSS2.FundingThis project (COV-55) was funded by Genome British Columbia as part of their COVID-19 rapid response initiative.
Optimal symptom combinations to aid COVID-19 case identification: analysis from a community-based, prospective, observational cohort
Authors: Antonelli M , Capdevila J , Chaudhari A , Granerod J , Canas LS , Graham MS , Klaser K , Modat M , Molteni E , Murray B , Sudre CH , Davies R , May A , Nguyen LH , Drew DA , Joshi A , Chan AT , Cramer JP , Spector T , Wolf J , Ourselin S , Steves CJ , Loeliger AE 
Published: November 2020

AbstractObjectivesDiagnostic 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.MethodsUK 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.FindingsUK 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.InterpretationWe 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.HighlightsWidely recommended symptoms identified only ∼70% COVID-19 casesAdditional symptoms increased case finding to > 90% but tests needed doubledOptimal symptom combinations maximise case capture considering available resourcesImplications for COVID-19 vaccine efficacy trials and wider public health
Differential homeostatic regulation of glycinergic and GABAergic nanocolumns at mixed inhibitory synapses
Authors: Yang Xiaojuan , Le Corronc Hervé , Legendre Pascal , Triller Antoine , Specht Christian G 
Published: November 2020

AbstractSuper-resolution imaging of synapses has revealed that key synaptic proteins are dynamically organized within sub-synaptic domains (SSDs). At mixed inhibitory synapses in spinal cord neurons, both GlyRs and GABAARs reside at the same post-synaptic density (PSD). To examine how the different inhibitory receptors are organized and regulated, we carried out dual-color direct stochastic optical reconstruction microscopy (dSTORM). We found that endogenous GlyRs and GABAARs as well as their common scaffold protein gephyrin form SSDs that align with pre-synaptic RIM1/2, thus forming trans-synaptic nanocolumns. Strikingly, GlyRs and GABAARs occupy different sub-synaptic spaces, exhibiting only a partial overlap at mixed inhibitory synapses. When network activity was increased by pharmacological treatment using the K+channel blocker 4-aminopyridine (4-AP), the GABAAR copy numbers of as well as the number of GABAAR SSDs were reduced, while GlyRs remained largely unchanged. This differential regulation is likely the result of changes in gephyrin phosphorylation that preferentially occurred outside of the SSDs. The total gephyrin content was not altered by 4-AP application. The activity-dependent regulation of GABAARs versus GlyRs suggests that different signaling pathways control their respective sub-synaptic organization. Whereas gephyrin serves as a scaffold protein that upholds GlyR numbers at SSDs, it may act as a switch regulating GABAARs via its phosphorylation state. Taken together, our data reinforce the notion that the precise sub-synaptic organization of GlyRs, GABAARs and gephyrin has functional consequences for the homeostatic regulation of mixed inhibitory synapses.HighlightsAlignment of sub-synaptic domains (SSDs) in trans-synaptic nanocolumns at inhibitory synapses Differential spatial organization of SSDs formed by GlyRs and GABAARs at mixed inhibitory synapses Activity-dependent regulation of GABAARs but not GlyRs at mixed inhibitory synapses Gephyrin phosphorylation is compartmentalized in SSDs within the synaptic scaffold
Rapid Detection of VanA/B-Producing Vancomycin-Resistant enterococci using Lateral Flow Immunoassay from colonies and blood culture
Authors: Oueslati Saoussen , Volland Hervé , Cattoir Vincent , Bernabeu Sandrine , Girlich Delphine , Dulac Duncan , Plaisance Marc , Boutigny Laure , Dortet Laurent , Simon Stéphanie , Naas Thierry 
Published: November 2020

AbstractVancomycin-resistant enterococci (VRE) have become one of the most important nosocomial pathogens worldwide associated with increased treatment costs, prolonged hospital stay, and high mortality. Rapid detection is crucial to reduce their spread and prevent infections and outbreaks. The lateral flow immunoassay NG-Test VanB (NG Biotech) was evaluated for the rapid detection of VanB-producing vancomycin-resistant enterococci (VanB-VRE) using 104 well-characterized enterococcal isolates. The sensitivity and specificity were both 100%, when bacterial cells were grown in the presence of vancomycin used as VanB inducer. The NG-Test VanB is an efficient, rapid, and easy to implement assay in clinical microbiology laboratories for the confirmation of VanB-VREs either from colonies or from positive blood cultures. Together with the NG-Test VanA, they could complete/replace the already existing panel of tests available for confirmation of acquired vancomycin resistance in enterococci, especially from selective media (rectal screenings) or from antibiograms (infections), with a sensitivity and specificity of both of 100%. The rapid detection in less than 15 minutes will result in more efficient management of carriers and infected patients.
Estimating the effectiveness of routine asymptomatic PCR testing at different frequencies for the detection of SARS-CoV-2 infections
Authors: Hellewell Joel , Russell Timothy W. ,   The SAFER Investigators and Field Study Team,   The Crick COVID-19 Consortium,   CMMID COVID-19 working group, Beale Rupert , Kelly Gavin , Houlihan Catherine , Nastouli Eleni , Kucharski Adam J. 
Published: November 2020

AbstractBackgroundRoutine asymptomatic testing using RT-PCR of people who interact with vulnerable populations, such as medical staff in hospitals or care workers in care homes, has been employed to help prevent outbreaks among vulnerable populations. Although the peak sensitivity of RT-PCR can be high, the probability of detecting an infection will vary throughout the course of an infection. The effectiveness of routine asymptomatic testing will therefore depend on testing frequency and how PCR detection varies over time.MethodsWe fitted a Bayesian statistical model to a dataset of twice weekly PCR tests of UK healthcare workers performed by self-administered nasopharyngeal swab, regardless of symptoms. We jointly estimated times of infection and the probability of a positive PCR test over time following infection, we then compared asymptomatic testing strategies by calculating the probability that a symptomatic infection is detected before symptom onset and the probability that an asymptomatic infection is detected within 7 days of infection.FindingsWe estimated that the probability that the PCR test detected infection peaked at 77% (54 - 88%) 4 days after infection, decreasing to 50% (38 - 65%) by 10 days after infection. Our results suggest a substantially higher probability of detecting infections 1–3 days after infection than previously published estimates. We estimated that testing every other day would detect 57% (33-76%) of symptomatic cases prior to onset and 94% (75-99%) of asymptomatic cases within 7 days if test results were returned within a day.InterpretationOur results suggest that routine asymptomatic testing can enable detection of a high proportion of infected individuals early in their infection, provided that the testing is frequent and the time from testing to notification of results is sufficiently fast.FundingWellcome Trust, National Institute for Health Research (NIHR) Health Protection Research Unit, Medical Research Council (UKRI)
Asymptomatic SARS-CoV-2 testing: predictors of effectiveness; risk of increasing transmission
Authors: Skittrall Jordan P. 
Published: November 2020

AbstractTesting asymptomatic people for SARS-CoV-2 aims to reduce COVID-19 transmission. Screening programs’ effectiveness depends upon testing strategy, sample handling logistics, test sensitivity, and individual behavior, in addition to dynamics of viral transmission. We investigated the interaction between these factors to determine how to optimize reduction of transmission. We show that under idealistic assumptions 70% of transmission may be averted, but under realistic assumptions only 7% may be averted. We show that programs that overwhelm laboratory capacity or reduce isolation of those with minor symptoms have increased transmission compared with those that do not: programs need to be designed to avoid these issues. Our model allows optimal selection of whom to test, quantifies the balance between accuracy and timeliness, and quantifies potential impacts of behavioral interventions.One Sentence SummaryPrograms that overwhelm laboratory capacity or reduce isolation of those with minor symptoms have impaired effectiveness.
Seroprevalence of SARS-CoV-2 infection in the craft and manual worker population of Qatar
Authors: Al-Thani Mohamed H. , Farag Elmoubasher , Bertollini Roberto , Al Romaihi Hamad Eid , Abdeen Sami , Abdelkarim Ashraf , Daraan Faisal , Ismail Ahmed , Mostafa Nahid , Sahl Mohamed , Suliman Jinan , Tayar Elias , Kasem Hasan Ali , Agsalog Meynard J. A. , Akkarathodiyil Bassam K. , Alkhalaf Ayat A. , Alakshar Mohamed Morhaf M. H. , Al-Qahtani Abdulsalam Ali A. H. , Al-Shedifat Monther H. A. , Ansari Anas , Ataalla Ahmad Ali , Chougule Sandeep , Gopinathan Abhilash K. K. V. , Poolakundan Feroz J. , Ranbhise Sanjay U. , Saefan Saed M. A. , Thaivalappil Mohamed M. , Thoyalil Abubacker S. , Umar Inayath M. , Kanaani Zaina Al , Khal Abdullatif Al , Kuwari Einas Al , Butt Adeel A. , Coyle Peter , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Rahim Hanan F. Abdul , Yassine Hadi M. , Nasrallah Gheyath K. , Kuwari Mohamed G. Al , Chaghoury Odette , Chemaitelly Hiam , Abu-Raddad Laith J. ,   the Craft and Manual Workers Seroprevalence Study Group
Published: November 2020

ABSTRACTBackgroundQatar experienced a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic that disproportionately affected the craft and manual worker (CMW) population who comprise 60% of the total population. This study aimed to assess the proportions of ever and/or current infection in this population.MethodsA cross-sectional population-based survey was conducted during July 26-September 09, 2020 to assess both anti-SARS-CoV-2 positivity through serological testing and polymerase chain reaction (PCR) positivity through PCR testing. Associations with antibody and PCR positivity were identified through regression analyses.ResultsStudy included 2,641 participants, 69.3% of whom were <40 years of age. Anti-SARS-CoV-2 positivity was estimated at 55.3% (95% CI: 53.3-57.3%) and was significantly associated with nationality, geographic location, educational attainment, occupation, presence of symptoms in the two weeks preceding the survey, and previous infection diagnosis. PCR positivity was assessed at 11.3% (95% CI: 9.9-12.8%) and was significantly associated with geographic location, contact with an infected person, and reporting two or more symptoms. Infection positivity (antibody and/or PCR positive) was assessed at 60.6% (95% CI: 9.9-12.8%). The proportion of antibody-positive CMWs that had a prior SARS-CoV-2 diagnosis was 9.3% (95% CI: 7.9-11.0%). Only seven infections were ever severe and one was ever critical—an infection severity rate of 0.5% (95% CI: 0.2-1.0%).ConclusionsSix in every 10 CMWs have been infected, suggestive of reaching the herd immunity threshold. Infection severity was low with only one in every 200 infections progressing to be severe or critical. Only one in every 10 infections had been previously diagnosed suggestive of mostly asymptomatic or minimally mild infections.