bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum proteome analysis of systemic JIA and related pulmonary alveolar proteinosis identifies distinct inflammatory programs and biomarkers
Authors: Chen Guangbo , Deutsch Gail , Schulert Grant , Zheng Hong , Jang SoRi , Trapnell Bruce , Lee Pui , Macaubas Claudia , Ho Katherine , Schneider Corinne , Saper Vivian E. , de Jesus Adriana Almeida , Krasnow Mark , Grom Alexei , Goldbach-Mansky Raphaela , Khatri Purvesh , Mellins Elizabeth D , Canna Scott W. 
Published: January 2021

AbstractObjectivesRecent observations in systemic Juvenile Idiopathic Arthritis (sJIA) suggest an increasing incidence of high-mortality interstitial lung disease, characterized by a variant of pulmonary alveolar proteinosis (PAP). Co-occurrence of macrophage activation syndrome (MAS) and PAP in sJIA suggested a shared pathology, but sJIA-PAP patients also commonly experience features of drug reaction such as atypical rashes and eosinophilia. We sought to investigate immunopathology and identify biomarkers in sJIA, MAS, and sJIA-PAP.MethodsWe used SOMAscan to measure >1300 analytes in sera from healthy controls and patients with sJIA, MAS, sJIA-PAP and other related diseases. We verified selected findings by ELISA and lung immunostaining. Because the proteome of a sample may reflect multiple states (sJIA, MAS, sJIA-PAP), we used regression modeling to identify subsets of altered proteins associated with each state. We tested key findings in a validation cohort.ResultsProteome alterations in active sJIA and MAS overlapped substantially, including known sJIA biomarkers like SAA and S100A9, and novel elevations of heat shock proteins and glycolytic enzymes. IL-18 was elevated in all sJIA groups, particularly MAS and sJIA-PAP. We also identified an MAS-independent sJIA-PAP signature notable for elevated ICAM5, MMP7, and allergic/eosinophilic chemokines, which were all previously associated with lung damage. Immunohistochemistry localized ICAM5 and MMP7 in sJIA-PAP lung. ICAM5’s ability to distinguish sJIA-PAP from sJIA/MAS was independently validated.ConclusionsSerum proteins support an sJIA-to-MAS continuum, help distinguish sJIA, sJIA/MAS, and sJIA-PAP, and suggest etiologic hypotheses. Select biomarkers, such as ICAM5, could aid in early detection and management of sJIA-PAP.
Impact of COVID-19 Pandemic on Inpatient Rehabilitation and the Original Infection Control Measures for Rehabilitation Team
Authors: Igawa Yukimasa , Sugimoto Takahiro , Horimoto Hiromasa , Moriya Yusuke , Okada Masaki , Yamada Yasuyuki 
Published: January 2021

AbstractObjectiveThis study aimed to investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on inpatient rehabilitation, and to determine the effectiveness of the original infection control measures implemented for the rehabilitation team.MethodsIn this single-center, retrospective, observational study, we calculated multiple rehabilitation indices of patients discharged from our rehabilitation ward between February 28 and May 25, 2020 when Hokkaido was initially affected by COVID-19, and compared them with those calculated during the same period in 2019. Fisher’s exact test and the Mann-Whitney U test were used for statistical analysis. We also verified the impact of implementing the original infection control measures for the rehabilitation team on preventing nosocomial infections.ResultsA total of 93 patients (47 of 2020 group, 46 of 2019 group) were included. The median age was 87 and 88 years, respectively, with no differences in age, sex, and main disease between the groups. Training time per day in the ward in 2020 was significantly lower than that in 2019 (p = 0.013). No significant differences were found in the qualitative evaluation indices of Functional Independence Measure (FIM) score at admission, FIM gain, length of ward stay, FIM efficiency, and rate of discharge to home. None of the patients or staff members had confirmed COVID-19 during the study period.ConclusionsEarly COVID-19 pandemic in Hokkaido affected the quantitative index for inpatient rehabilitation but not the qualitative indices. No symptomatic nosocomial COVID-19 infections were observed with our infection control measures.
Weighted burden analysis in 200 000 exome-sequenced UK Biobank subjects characterises effects of rare genetic variants on BMI
Authors: Curtis David 
Published: January 2021

AbstractIntroductionA number of genes have been identified in which rare variants can cause obesity. Here we analyse a sample of exome sequenced subjects from UK Biobank using BMI as a phenotype.MethodsThere were 199,807 exome sequenced subjects for whom BMI was recorded. Weighted burden analysis of rare, functional variants was carried out, incorporating population principal components and sex as covariates. For selected genes, additional analyses were carried out to clarify the contribution of different categories of variant. Statistical significance was summarised as the signed log 10 of the p value (SLP), given a positive sign if the weighted burden score was positively correlated with BMI.ResultsTwo genes were exome-wide significant,MC4R(SLP = 15.79) andPCSK1(SLP = 6.61). InMC4R, disruptive variants were associated with an increase in BMI of 2.72 units and probably damaging nonsynonymous variants with an increase of 2.02 units. InPCSK1, disruptive variants were associated with a BMI increase of 2.29 and protein-altering variants with an increase of 0.34. Results for other genes were not formally significant after correction for multiple testing, althoughSIRT1, ZBED6andNPC2were noted to be of potential interest.ConclusionBecause the UK Biobank consists of a self-selected sample of relatively healthy volunteers, the effect sizes noted may be underestimates. The results demonstrate the effects of very rare variants on BMI and suggest that other genes and variants will be definitively implicated when the sequence data for additional subjects becomes available.This research has been conducted using the UK Biobank Resource.
Association of pre-pandemic high-density lipoprotein cholesterol with risk of COVID-19 hospitalisation and death: the UK Biobank cohort study
Authors: Lassale Camille , Hamer Mark , Hernáez Álvaro , Gale Catharine R. , Batty G. David 
Published: January 2021

AbstractObjectiveThere is growing evidence of, and biological plausibility for, elevated levels of high-density lipoprotein cholesterol (HDL-C), being related to lower rates of severe infection. Accordingly, we tested whether pre-pandemic HDL-C within the normal range is associated with subsequent COVID-19 hospitalisations and death.ApproachWe analysed data on 317,306 participants from UK Biobank, a prospective cohort study, baseline data for which were collected between 2006 and 2010. Follow-up for COVID-19 was via hospitalisation records and a national mortality registry.ResultsAfter controlling for a series of confounding factors which included health behaviours, inflammatory markers, and socio-economic status, higher levels of HDL-C were related to a lower risk of later hospitalisation for COVID-19. The effect was linear (p-value for trend 0.001) such that a 0.2 mmol/L increase in HDL-C was associated with a corresponding 9% reduction in risk (odds ratio; 95% confidence interval: 0.91; 0.86, 0.96). A very similar pattern of association was apparent when COVID-19 mortality was the outcome of interest (odds ratio per 0.2 mmol/l increase in HDL-C: 0.90; 0.81, 1.00); again, a stepwise effect was evident (p-value for trend 0.03).ConclusionsThese novel results for HDL-C and COVID-19 events warrant testing in other studies.
Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder
Authors: Courraud Jeremie , Chater-Diehl Eric , Durand Benjamin , Vincent Marie , del Mar Muniz Moreno Maria , Boujelbene Imène , Drouot Nathalie , Genschik Loréline , Schaefer Elise , Nizon Mathilde , Gerard Bénédicte , Abramowicz Marc , Cogné Benjamin , Bronicki Lucas , Burglen Lydie , Barth Magalie , Charles Perrine , Colin Estelle , Coubes Christine , David Albert , Delobel Bruno , Demurger Florence , Passemard Sandrine , Denommé Anne-Sophie , Faivre Laurence , Feger Claire , Fradin Mélanie , Francannet Christine , Genevieve David , Goldenberg Alice , Guerrot Anne-Marie , Isidor Bertrand , Johannesen Katrine M. , Keren Boris , Kibæk Maria , Kuentz Paul , Mathieu-Dramard Michele , Demeer Bénédicte , Metreau Julia , Møller Rikke Steensbjerre , Moutton Sébastien , Pasquier Laurent , Pilekær Sørensen Kristina , Perrin Laurence , Renaud Mathilde , Saugier Pascale , Svane Joane , Thevenon Julien , Them Frederic Tran Mau , Tronhjem Cathrine Elisabeth , Vitobello Antonio , Layet Valerie , Birling Marie-Christine , Drunat Severine , Bayat Allan , Dubourg Christèle , Chehadeh Salima El , Fagerberg Christina , Mignot Cyril , Guipponi Michel , Bienvenu Thierry , Herault Yann , Thompson Julie , Willems Marjolaine , Mandel Jean-Louis , Weksberg Rosanna , Piton Amélie 
Published: January 2021

ABBSTRACTDYRK1A-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 harboringDYRK1Avariants. We developed a combination of tools to interpret missense variants, which remains a major challenge in human genetics: i) a specificDYRK1Aclinical score, ii) amino acid conservation data generated from one hundred of DYRK1A sequences across different taxa, iii)in vitrooverexpression 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 occurringde novo.
Adjustment for energy intake in nutritional research: a causal inference perspective
Authors: Tomova Georgia D , Arnold Kellyn F , Gilthorpe Mark S , Tennant Peter WG 
Published: January 2021

ABSTRACTBackgroundFour models are commonly used to adjust for energy intake when estimating the causal effect of a dietary component on an outcome; (1) the ‘standard model’ adjusts for total energy intake, (2) the ‘energy partition model’ adjusts for remaining energy intake, (3) the ‘nutrient density model’ rescales the exposure as a proportion of total energy, and (4) the ‘residual model’ indirectly adjusts for total energy by using a residual. It remains underappreciated that each approach evaluates a different estimand and only partially accounts for proxy confounding by common dietary causes.ObjectiveTo clarify the implied causal estimand and interpretation of each model and evaluate their performance in reducing dietary confounding.DesignSemi-parametric directed acyclic graphs and Monte Carlo simulations were used to identify the estimands and interpretations implied by each model and explore their performance in the absence or presence of dietary confounding.ResultsThe ‘standard model’ and the mathematically identical ‘residual model’ estimate theaverage relative causal effect(i.e., a ‘substitution’ effect) but provide biased estimates even in the absence of confounding. The ‘energy partition model’ estimates thetotal causal effectbut only provides unbiased estimates in the absence of confounding or when all other nutrients have equal effects on the outcome. The ‘nutrient density model’ has an obscure interpretation but attempts to estimate the average relative causal effect rescaled as a proportion of total energy intake. Accurate estimates of both the total and average relative causal effects may instead be estimated by simultaneously adjusting for all dietary components, an approach we term the ‘all-components model’.ConclusionLack of awareness of the estimand differences and accuracy of the four modelling approaches may explain some of the apparent heterogeneity among existing nutritional studies and raise serious questions regarding the validity of meta-analyses where different estimands have been inappropriately pooled.
Integrating Operant and Cognitive Behavioral Economics to Inform Infectious Disease Response: Prevention, Testing, and Vaccination in the COVID-19 Pandemic
Authors: Strickland Justin C. , Reed Derek D. , Hursh Steven R. , Schwartz Lindsay P. , Foster Rachel N.S. , Gelino Brett W. , LeComte Robert S. , Oda Fernanda S. , Salzer Allyson R. , Schneider Tadd D. , Dayton Lauren , Latkin Carl , Johnson Matthew W. 
Published: January 2021

AbstractThe role of human behavior to thwart transmission of infectious diseases like COVID-19 is evident. Yet, many areas of psychological and behavioral science are limited in the ability to mobilize to address exponential spread or provide easily translatable findings for policymakers. Here we describe how integrating methods from operant and cognitive approaches to behavioral economics can provide robust policy relevant data. Adapting well validated methods from behavioral economic discounting and demand frameworks, we evaluate in four crowdsourced samples (total N = 1,366) behavioral mechanisms underlying engagement in preventive health behaviors. We find that people are more likely to social distance when specified activities are framed as high risk, that describing delay until testing (rather than delay until results) increases testing likelihood, and that framing vaccine safety in a positive valence improves vaccine acceptance. These findings collectively emphasize the flexibility of methods from diverse areas of behavioral science for informing public health crisis management.
Outcomes and phenotypic expression of rare variants in hypertrophic cardiomyopathy genes amongst UK Biobank participants
Authors: de Marvao Antonio , McGurk Kathryn A , Zheng Sean L , Thanaj Marjola , Bai Wenjia , Duan Jinming , Biffi Carlo , Mazzarotto Francesco , Statton Ben , Dawes Timothy JW , Savioli Nicolò , Halliday Brian P , Xu Xiao , Buchan Rachel J , Baksi A John , Quinlan Marina , Tokarczuk Paweł , Tayal Upasana , Francis Catherine , Whiffin Nicola , Theotokis Pantazis I , Zhang Xiaolei , Jang Mikyung , Berry Alaine , Pantazis Antonis , Barton Paul JR , Rueckert Daniel , Prasad Sanjay K , Walsh Roddy , Ho Carolyn Y , Cook Stuart A , Ware James S , O’Regan Declan P 
Published: January 2021

AbstractBackgroundHypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.MethodsWe compared outcomes and cardiovascular phenotypes in UK Biobank participants with whole exome sequencing stratified by sarcomere-encoding variant status.ResultsThe prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n=5,727; 1 in 35), of which 0.24% (n=474, 1 in 423) were pathogenic or likely pathogenic variants (SARC-P/LP). SARC-P/LP variants were associated with increased risk of death or major adverse cardiac events compared to controls (HR 1.68, 95% CI 1.37-2.06, p<0.001), mainly due to heart failure (HR 4.40, 95% CI 3.22-6.02, p<0.001) and arrhythmia (HR 1.55, 95% CI 1.18-2.03, p=0.002). In 21,322 participants with cardiac magnetic resonance imaging, SARC-P/LP were associated with increased left ventricular maximum wall thickness (10.9±2.7 vs 9.4±1.6 mm, p<0.001) and concentric remodelling (mass/volume ratio: 0.63±0.12 vs 0.58±0.09 g/mL, p<0.001), but hypertrophy (≥13mm) was only present in 16% (n=7/43, 95% CI 7-31%). Other rare sarcomere-encoding variants had a weak effect on wall thickness (9.5±1.7 vs 9.4±1.6 mm, p=0.002) with no combined excess cardiovascular risk (HR 1.00 95% CI 0.92-1.08, p=0.9).ConclusionsIn the general population, SARC-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and a sub-clinical cardiomyopathic phenotype. In contrast, rare sarcomeric variants that do not meet criteria to be classified as P/LP appear to have minimal clinical impact.
Counterfactual inference for single-cell gene expression analysis
Authors: Park Yongjin , Kellis Manolis 
Published: January 2021

AbstractFinding a causal gene is a fundamental problem in genomic medicine. We present a causal inference framework that prioritizes disease genes by adjusting confounders without prior knowledge of control variables. We demonstrate that our method substantially improves statistical power in simulations and real-world data analysis of 70k brain cells collected for dissecting Alzheimer’s disease. We identified that 215 causal genes are differentially regulated by the disease in various cell types, including highly relevant genes with a proper cell type context. Genes found in different types enrich distinctive pathways, implicating the importance of cell types in understanding multifaceted disease mechanisms.
Genomic Epidemiology of SARS-CoV-2 in Esteio, Rio Grande do Sul, Brazil
Authors: Franceschi Vinícius Bonetti , Caldana Gabriel Dickin , de Menezes Mayer Amanda , Cybis Gabriela Bettella , Neves Carla Andretta Moreira , Ferrareze Patrícia Aline Gröhs , Demoliner Meriane , de Almeida Paula Rodrigues , Gularte Juliana Schons , Hansen Alana Witt , Weber Matheus Nunes , Fleck Juliane Deise , Zimerman Ricardo Ariel , Kmetzsch Lívia , Spilki Fernando Rosado , Thompson Claudia Elizabeth 
Published: January 2021

AbstractBrazil is the third country most affected by Covid-19 pandemic. In spite of this, viral evolution in municipality resolution is poorly understood in Brazil and it is crucial to understand the epidemiology of viral spread. We identified four main circulating lineages in Esteio (Southern Brazil) and their relationship with global, national and regional lineages using phylogenetics and phylodynamics inferences from 21 SARS-CoV-2 genome sequences. We provided a comprehensive view of viral mutations from a time- and age-representative sampling from May to October 2020, in Esteio (RS, Brazil), highlighting two frequent mutations in Spike glycoprotein (D614G and V1176F), an emergent mutation (E484K) in Spike Receptor Binding Domain (RBD) characteristic of the South African lineage B.1.351, and the adjacent replacement of 2 amino acids in Nucleocapsid phosphoprotein (R203K and G204R). A significant viral diversity was evidenced with the identification of 80 different SNPs. The E484K replacement was found in two genomes (9.5%) from samples obtained in mid-October, which is to our best knowledge the earliest description of E484K harboring SARS-CoV-2 in South Brazil. This mutation identified in a small municipality from the RS state demonstrates that it was probably widely distributed in the Brazilian territory, but went unnoticed so far by the lack of genomic surveillance in Brazil. The introduction of E484K mutants shows temporal correlation with later increases in new cases in our state. Importantly, since it has been associated with immune evasion and enhanced interaction with hACE-2, lineages containing this substitution must be the subject of intense surveillance. Our date demonstrates multiple introductions of the most prevalent lineages (B.1.1.33 and B.1.1.248) and the major role of community transmission in viral spreading and the establishment of Brazilian lineages. This represents an important contribution to the epidemiology of SARS-CoV-2.
Cohort Profile: The Birhan Health and Demographic Surveillance System
Authors: Bekele Delayehu , Hunegnaw Bezawit Mesfin , Bekele Chalachew , Van Wickle Kimiko , Tadesse Fisseha , Goddard Frederick G. B. , Mohammed Yahya , Unninayar Sarah , Chan Grace J. 
Published: January 2021

AbstractThe Birhan health and demographic surveillance system (HDSS) was established to determine the magnitude and causes of morbidity and mortality in Ethiopia among pregnant and postpartum women and children. Located in the North Shewa Zone of the Amhara Region, the site includes 16 kebeles (villages) and spans two woredas (districts), Angolela Tera and Kewet/Shewa Robit. The initial census was conducted in May 2018, and core demographic and health events are updated every three months. The site has 18,933 households and a population of 77,766. Over 82.6% of the population is rural.During the baseline census, all households were geocoded; household members were enumerated; and data were collected on sociodemographic status, housing construction material, economics and asset ownership, care seeking behaviors, and water and sanitation access. During each subsequent round, data on key demographic events such as births, deaths, marital status changes, in-migration, or out-migration were collected for all enumerated household members. Pregnancy surveillance was conducted among married women of reproductive age 15-49 using a pregnancy screening questionnaire and confirmed by urine pregnancy tests. Morbidity and immunization status data for children aged under two years were collected during each round.
Listening to Bluetooth Beacons for Epidemic Risk Mitigation
Authors: Barthe Gilles , Viti Roberta De , Druschel Peter , Garg Deepak , Gomez-Rodriguez Manuel , Ingo Pierfrancesco , Kremer Heiner , Lentz Matthew , Lorch Lars , Mehta Aastha , Schölkopf Bernhard 
Published: January 2021

AbstractDuring the ongoing COVID-19 pandemic, there have been burgeoning efforts to develop and deploy digital contact tracing systems to expedite contact tracing and risk notification. Unfortunately, the success of these systems has been limited, partly owing to poor interoperability with manual contact tracing, low adoption rates, and a societally sensitive trade-off between utility and privacy. In this work, we introduce a new privacy-preserving and inclusive system for epidemic risk assessment and notification that aims to address the above limitations. Rather than capturing pairwise encounters between user devices as done by existing systems, our system captures encounters between user devices and beacons placed in strategic locations where infection clusters may originate. Epidemiological simulations using an agent-based model demonstrate several beneficial properties of our system. By achieving bidirectional interoperability with manual contact tracing, our system may help reduce the effective reproduction number already at adoption levels of 10%. The use of location and environmental information provided by beacons allows our system to achieve significantly higher sensitivity and specificity than existing systems and thus may improve the efficacy of contact tracing under limited isolation and testing resources. Moreover, to achieve high utility, it is sufficient to deploy beacons in a small fraction of strategic locations. Finally, our simulations also show that existing systems could inherit these beneficial properties if they integrated the beacons used by our system.