bluuebunny/crossref_metadata_2025_split huggingface dataset:
The general impact of haploinsufficiency on brain connectivity underlies the pleiotropic effect of neuropsychiatric CNVs
Authors: Moreau Clara , Huguet Guillaume , Urchs Sebastian , Douard Elise , Sharmarke Hanad , Orban Pierre , Labbe Aurélie , Modenato Claudia , Martin-Brevet Sandra , Kuldeep Kumar , Martin Charles-Olivier , Jizi Khadije , Younis Nadine , Tamer Petra , Martineau Jean-Louis , Silva Ana Isabel , Jønch Aia E. , Lin Amy , Foundation Simons VIP , Hall Jeremy , van den Bree Marianne B.M. , Owen Michael J. , Linden David E. J. , Maillard Anne. M. , Lippé Sarah , Greenwood Celia , Bearden Carrie E. , Thompson Paul M. , Bellec Pierre , Jacquemont Sebastien 
Published: March 2020

AbstractCopy number variants (CNVs) are among the most highly penetrant genetic risk factors for neuropsychiatric disorders. Their impact on brain connectivity remains mostly unstudied. Because they confer risk for overlapping conditions, we hypothesized that they may converge on shared connectivity patterns.We performed connectome-wide analyses using resting-state functional MRI data from 436 carriers of neuropsychiatric CNVs at the 1q21.1, 15q11.2, 16p11.2, 22q11.2 loci, 4 “neutral effect” CNVs, 66 carriers of scarcer neuropsychiatric CNVs, 756 individuals with idiopathic autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder, and 5,377 controls. Neuropsychiatric CNVs showed global shifts of mean connectivity. The effect size of CNVs on relative connectivity (adjusted for the mean) was correlated with the known level of neuropsychiatric risk conferred by CNVs. Individuals with idiopathic schizophrenia and ASD had similarities in connectivity with neuropsychiatric CNVs. We reported a linear relationship between connectivity and intolerance to haploinsufficiency measured for all genes encompassed by CNVs across 18 loci. This profile involved the thalamus, the basal ganglia, somatomotor and frontoparietal networks and was correlated with lower general intelligence and higher autism severity scores. An exploratory factor analysis confirmed the contribution of these regions to three latent components shared across CNVs and neuropsychiatric disorders.We posit that deleting genes intolerant to haploinsufficiency reorganize connectivity along general dimensions irrespective of where deletions occur in the genome. This haploinsufficiency brain signature opens new avenues to understand polygenicity in psychiatric conditions and the pleiotropic effect of CNVs on cognition and risk for neuropsychiatric disorders.One sentence summaryNeuropsychiatric CNVs across the genome reorganize brain connectivity architecture along dominant patterns contributing to complex idiopathic conditions.
Identification of a super-spreading chain of transmission associated with COVID-19
Authors: Hu Ke , Zhao Yang , Wang Mengmei , Zeng Qiqi , Wang Xiaorui , Wang Ming , Zheng Zhishui , Li Xiaochen , Zhang Yunting , Wang Tao , Zeng Shaolin , Jiang Yan , Liu Dan , Yu Wenzhen , Hu Fang , Qin Hongyu , Hao Jingcan , Yuan Jian , Shang Rui , Jiang Meng , Ding Xi , Zhang Binghong , Shi Bingyin , Zhang Chengsheng 
Published: March 2020

AbstractBackgroundSuper-spreading events were associated with the outbreaks of SARS and MERS, but their association with the outbreak of COVID-19 remains unknown. Here, we report a super-spreading transmission chain of SARS-CoV-2 involving an index patient, seven cancer patients, 40 health care workers and four family members.MethodsWe conducted a retrospective study to identify the index patient and the exposed individuals linked to a chain of transmission associated with COVID-19. We collected and analyzed the data on demographic features, exposure history, clinical presentation, laboratory investigation, radiological examination, and disease outcome of these patients.ResultsWe identified the index patient and another presumptive “super-spreader”, who initiated and amplified a super-spreading transmission chain associated with COVID-19, respectively. There were 31 female and 21 male patients in this cohort, and the median age was 37 years (range: 22-79 years). Each of them had an exposure history with the index patient or his close contacts. Approximately 87% (45/52) of the patients had fever or other symptoms, 96% (50/52) had abnormal chest CT-scan findings, 86% of the tested patients (39/45) were positive for SARS-CoV-2 in the nasopharyngeal or throat swab specimen, 85% of the tested patients (29/34) were positive for SARS-CoV-2-specific IgM and/or IgG, 15% of the RT-PCR positive patients were tested negative for the specific IgM and/or IgG at the convalescent phase, and 15% of the RT-PCR negative patients were tested positive for the specific IgM and/or IgG. The severe patients experienced a significant decrease in oximetry saturation, lymphocyte, and platelet counts, along with a significant increase in C-reactive protein, D-dimer, and lactate dehydrogenase. All six fatal cases had comorbidities and five of the seven cancer patients (71%) died within 2-20 days of the disease onset.ConclusionsThe super-spreading events were associated with the outbreak of COVID-19 in Wuhan and its impact on disease transmission warrants further investigation. Cancer patients appeared highly vulnerable to COVID-19. The finding that a significant portion of SARS-CoV-2 infected patients were tested negative for the serum specific IgM and IgG at the convalescent phase should be addressed by additional studies.
Characteristics of patients with COVID-19 during epidemic ongoing outbreak in Wuhan, China
Authors: Luo Xiaomin , Xia Hongxia , Yang Weize , Wang Benchao , Guo Tangxi , Xiong Jun , Jiang Zongping , Liu Yu , Yan Xiaojie , Zhou W , Ye Lu , Zhang Bicheng 
Published: March 2020

AbstractBackgroundSince Dec 2019, SARS-CoV-2 has caused about fifty thousand patients and over two thousand deaths in Wuhan, China. We reported characteristics of patients with COVID-19 during epidemic ongoing outbreak in Wuhan.MethodsData of COVID-19 patients with clinical outcome in a designated hospital in Wuhan, were retrospectively collected from electronic medical records. Characteristics were compared between patients who died or recovered, and between patients with different disease severity.ResultsBy Feb 25, 2020, 403 patients were enrolled, 100 died and 303 recovered. Most of non-survivors tended to be males, old aged, or with chronic diseases. Duration from illness onset to admission was 9 (7-12) days. Patients with severe or critical illness had more days from onset to admission compared to those with ordinary illness. Lymphopenia, anemia, hypoproteinemia, and abnormal serum sodium were presented in 52.6%, 54.6%, 69.8%, and 21.8% cases, respectively. Patients who died or with severe/critical illness showed increased white blood cell and neutrophil count, serum total bilirubin, creatinine, hypersensitive troponin I, D-dimer, procalcitonin, and C-reactive protein, and decreased red blood cell, lymphocyte, platelet count, and serum albumin on admission compared to those who recovered or with ordinary illness. Complications of acute organ injury and secondary infection were common in patients with COVID-19, especially in non-survivors.ConclusionsMultiple homeostasis disturbances were common in patients with severe or critical illness at admission. Early support should be provided, especially for old men with chronic disease, which is vital to control disease progression and reduce mortality of COVID-19 during epidemic ongoing outbreak.
Inherited rare, deleterious variants in ATM increase lung adenocarcinoma risk
Authors: Selvan Myvizhi Esai , Zauderer Marjorie G. , Rudin Charles M. , Jones Siân , Mukherjee Semanti , Offit Kenneth , Onel Kenan , Rennert Gad , Velculescu Victor E. , Lipkin Steven M. , Klein Robert J. , Gümüş Zeynep H. 
Published: March 2020

ABSTRACTIntroductionLung cancer is the leading cause of cancer deaths in the world, and adenocarcinoma (LUAD) is its most prevalent subtype. Symptoms often appear in advanced disease when treatment options are limited. Identifying genetic risk factors will enable better identification of high-risk individuals.MethodsTo identify LUAD risk genes, we performed a case-control association study for gene-level burden of rare, deleterious variants (RDVs) in germline whole-exome sequencing (WES) data of 1,083 LUAD patients and 7,650 controls, split into discovery and validation cohorts. Of these, we performed WES on 97 patients and acquired the rest from multiple public databases. We annotated all rare variants for pathogenicity conservatively, using ACMG guidelines and ClinVar curation, and investigated gene-level RDV burden using penalized logistic regression. All statistical tests were two-sided.ResultsWe discovered and replicated the finding that the burden of germline ATM RDVs was significantly higher in LUAD patients versus controls (ORcombined=4.6; p=1.7e-04; 95% CI=2.2–9.5; 1.21% of cases; 0.24% of controls). Germline ATM RDVs were also enriched in an independent clinical cohort of 1,594 patients from the MSK-IMPACT study (0.63%). Additionally, we observed that an Ashkenazi Jewish (AJ) founder ATM variant, rs56009889, was statistically significantly more frequent in AJ cases versus AJ controls in our cohort (ORcombined, AJ=2.7, p=6.9e-03, 95% CI=1.3–5.3).ConclusionsOur results indicate that ATM is a moderate-penetrance LUAD risk gene, and that LUAD may be part of the ATM-related cancer syndrome spectrum. Individuals with ATM RDVs are at elevated LUAD risk and can benefit from increased surveillance (particularly CT scanning), early detection and chemoprevention programs, improving prognosis.
Multi-omic approach to identify phenotypic modifiers underlying cerebral demyelination in X-linked adrenoleukodystrophy
Authors: Richmond Phillip A. , van der Kloet Frans , Vaz Frederic M. , Lin David , Uzozie Anuli , Graham Emma , Kobor Michael , Mostafavi Sara , Moerland Perry D. , Lange Philipp F. , van Kampen Antoine H. C. , Wasserman Wyeth , Engelen Marc , Kemp Stephan , van Karnebeek Clara 
Published: March 2020

AbstractX-linked adrenoleukodystrophy (ALD) is a peroxisomal metabolic disorder with a highly complex clinical presentation. ALD is caused by mutations in the ABCD1 gene, and is characterized by the accumulation of very long-chain fatty acids in plasma and tissues. Disease-causing mutations are ‘loss of function’ mutations, with no prognostic value with respect to the clinical outcome of an individual. All male patients with ALD develop spinal cord disease and a peripheral neuropathy in adulthood, although age of onset is highly variable. However, the lifetime prevalence to develop progressive white matter lesions, termed cerebral ALD (CALD), is only about 60%. Early identification of transition to CALD is critical since it can be halted by allogeneic hematopoietic stem cell therapy only in an early stage. The primary goal of this study is to identify molecular markers which may be prognostic of cerebral demyelination from a simple blood sample, with the hope that blood-based assays can replace the current protocols for diagnosis. We collected six well-characterized brother pairs affected by ALD and discordant for the presence of CALD and performed multi-omic profiling of blood samples including genome, epigenome, transcriptome, metabolome/lipidome, and proteome profiling. In our analysis we identify discordant genomic alleles present across all families as well as differentially abundant molecular features across the omics technologies. The analysis was focused on univariate modeling to discriminate the two phenotypic groups, but was unable to identify statistically significant candidate molecular markers. Our study highlights the issues caused by a large amount of inter-individual variation, and supports the emerging hypothesis that cerebral demyelination is a complex mix of environmental factors and/or heterogeneous genomic alleles. We confirm previous observations about the role of immune response, specifically auto-immunity and the potential role of PFN1 protein overabundance in CALD in a subset of the families. We envision our methodology as well as dataset has utility to the field for reproducing previous or enabling future modifier investigations.
Effects of voluntary event cancellation and school closure as countermeasures against COVID-19 outbreak in Japan
Authors: Sugishita Yoshiyuki , Kurita Junko , Sugawara Tamie , Ohkusa Yasushi 
Published: March 2020

AbstractBackgroundTo control the COVID-19 outbreak in Japan, sports and entertainment events were canceled and schools were closed throughout Japan from February 26 through March 19. That policy has been designated as voluntary event cancellation and school closure (VECSC).ObjectThis study assesses VECSC effectiveness based on predicted outcomes. Method: A simple susceptible–infected–recovery model was applied to data of patients with symptoms in Japan during January 14 through March 25. The respective reproduction numbers were estimated before VECSC (R), during VECSC (Re), and after VECSC (Ra).ResultsResults suggest R before VECSC as 1.987 [1.908, 2.055], Re during VECSC as 1.122 [0.980, 1.260], and Ra after VECSC as 3.086 [2.529, 3.739].Discussion and ConclusionResults demonstrated that VECSC can reduce COVID-19 infectiousness considerably, but the value of R rose to exceed 2.5 after VECSC.
Supervised Machine Learning for the Early Prediction of Acute Respiratory Distress Syndrome (ARDS)
Authors: Le Sidney , Pellegrini Emily , Green-Saxena Abigail , Summers Charlotte , Hoffman Jana , Calvert Jacob , Das Ritankar 
Published: March 2020

ABSTRACTPurposeAcute respiratory distress syndrome (ARDS) is a serious respiratory condition with high mortality and associated morbidity. The objective of this study is to develop and evaluate a novel application of gradient boosted tree models trained on patient health record data for the early prediction of ARDS.Materials and Methods9919 patient encounters were retrospectively analyzed from the Medical Information Mart for Intensive Care III (MIMIC-III) data base. XGBoost gradient boosted tree models for early ARDS prediction were created using routinely collected clinical variables and numerical representations of radiology reports as inputs. XGBoost models were iteratively trained and validated using 10-fold cross validation.ResultsOn a hold-out test set, algorithm classifiers attained area under the receiver operating characteristic curve (AUROC) values of 0.905, 0.827, 0.810, and 0.790 when tested for the prediction of ARDS at 0-, 12-, 24-, and 48-hour windows prior to onset, respectively.ConclusionSupervised machine learning predictions may help predict patients with ARDS up to 48 hours prior to onset.
An exploratory randomized controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI)
Authors: Li Yueping , Xie Zhiwei , Lin Weiyin , Cai Weiping , Wen Chunyan , Guan Yujuan , Mo Xiaoneng , Wang Jian , Wang Yaping , Peng Ping , Chen Xudan , Hong Wenxin , Xiao Guangming , Liu Jinxin , Zhang Lieguang , Hu Fengyu , Li Feng , Zhang Fuchun , Deng Xilong , Li Linghua 
Published: March 2020

AbstractBackgroundAntiviral therapies against the novel coronavirus SARS-CoV-2, which has caused a global pandemic of respiratory illness called COVID-19, are still lacking.MethodsOur study (NCT04252885, named ELACOI), was an exploratory randomized (2:2:1) controlled trial assessing the efficacy and safety of lopinavir/ritonavir (LPV/r) or arbidol monotherapy for treating patients with mild/moderate COVID-19.FindingsThis study successfully enrolled 86 patients with mild/moderate COVID-19 with 34 randomly assigned to receive LPV/r, 35 to arbidol and 17 with no antiviral medication as control. Baseline characteristics of the three groups were comparable. The primary endpoints, the average time of positive-to-negative conversion of SARS-CoV-2 nucleic acid and conversion rates at days 7 and 14, were similar between groups (all P>0.05). There were no differences between groups in the secondary endpoints, the rates of antipyresis, cough alleviation, or improvement of chest CT at days 7 or 14 (all P>0.05). At day 7, eight (23.5%) patients in the LPV/r group, 3 (8.6%) in the arbidol group and 2(11.8%) in the control group showed a deterioration in clinical status from moderate to severe/critical(P =0.206). Overall, 12 (35.3%) patients in the LPV/r group and 5 (14.3%) in the arbidol group experienced adverse events during the follow-up period. No apparent adverse event occurred in the control group.ConclusionsLPV/r or arbidol monotherapy present little benefit for improving the clinical outcome of patients hospitalized with mild/moderate COVID-19 over supportive care.FundingThis study was supported by project 2018ZX10302103-002, 2017ZX10202102-003-004 and Infectious Disease Specialty of Guangzhou High-level Clinical Key Specialty (2019-2021).
Profiling virus-specific Tcf1+ T cell repertoires during acute and chronic viral infection
Authors: Yermanos Alexander , Sandu Ioana , Pedrioli Alessandro , Borsa Mariana , Wagen Franziska , Oetiker Nathalie , Welten Suzanne P.M. , Pallmer Katharina , Reddy Sai , Oxenius Annette 
Published: March 2020

AbstractCD8 T cells play a crucial role in providing protection from viral infections. It has recently been established that a subset of CD8 T cells expressing Tcf1 are responsible for sustaining exhausted T cells during chronic lymphocytic choriomeningitis virus (LCMV) infection. Many of these studies, however, have been performed using T cell receptor (TCR) transgenic mice, in which CD8 T cells express a monoclonal TCR specific for the LCMV glycoprotein. To investigate whether the Tcf1+ and Tcf1-repertoires are naturally composed of similar or different clones in wild-type mice exposed to acute or chronic LCMV infection, we performed TCR repertoire sequencing of virus-specific CD8 T cells, including Tcf1+ and Tcf1-populations. Our analysis revealed that the Tcf1+ TCR repertoire is maintained at an equal or higher degree of clonal diversity despite harboring fewer cells. Additionally, within the same animal, there was extensive clonal overlap between the Tcf1+ and Tcf1-repertoires in both chronic and acute LCMV infection. We could further detect these virus-specific clones in longitudinal blood samples earlier in the infection. With respect to common repertoire parameters (clonal overlap, germline gene usage, and clonal expansion), we found minor differences between the virus-specific TCR repertoire of acute and chronic LCMV infection 40 days post infection. Overall, our results indicate that the Tcf1+ population emerging during chronic LCMV infection is not clonally distinct from the Tcf1-population, supporting the notion that the Tcf1+ pool is indeed a fuel for the more exhausted Tcf1-population within the heterogenous repertoire of LCMV-specific CD8 T cells.
A functional non-coding RNA is produced fromxbp-1mRNA
Authors: Liu Xiao , Beaudoin Jean-Denis , Davison Carrie Ann , Kosmaczewski Sara G. , Meyer Benjamin I. , Giraldez Antonio J. , Hammarlund Marc 
Published: March 2020

AbstractThexbp-1mRNA encodes the XBP-1 transcription factor, a critical part of the unfolded protein response. Here we report that an RNA fragment produced fromxbp-1mRNA cleavage is a biologically active non-coding RNA (ncRNA) inCaenorhabditis elegansneurons, providing the first example of ncRNA derived from mRNA cleavage. We show that thexbp-1ncRNA is crucial for axon regenerationin vivo, and that it acts independently of the protein-coding function of thexbp-1transcript. Structural analysis indicates that the function of thexbp-1ncRNA depends on a single RNA stem; and this stem forms only in the cleavedxbp-1ncRNA fragment. Disruption of this stem abolishes the non-coding but not coding function of the endogenousxbp-1transcript. Thus, cleavage of thexbp-1mRNA bifurcates it into a coding and a non-coding pathway; modulation of the two pathways may allow neurons to fine-tune their response to injury and other stresses.Graphic abstract
High COVID-19 incidence among Norwegian travellers returned from Lombardy: implications for travel restrictions
Authors: Brynildsrud Ola , Eldholm Vegard 
Published: March 2020

On February 27th, three cases of COVID-19 were reported among Norwegians that had recently returned from Lombardy, Italy. Travellers from the region rapidly became the most common source of imported infections in the earliest stage of the Norwegian COVID-19 epidemic. The situation was exacerbated by the unfortunate temporal overlap between the Norwegian winter holidays and intense epidemic spread of COVID-19 in Northern Italy, resulting in a large number of infected travellers. Here we combined flight data on travels between Norway and Lombardy with patient-level data to determine the fraction of travellers returning to Norway that had been infected with SARS-CoV-2.Travellers returning to Norway from Lombardy contracted COVID-19 at incidence rates up to 0.02 per person-day in the period spanning February 21st and March 1st, with a clear uptick in transmission in the middle of the period.This shows an example of the infection risk in tourist destinations being several fold higher than elsewhere in the region. In Norway, this is also supported by high rates of infections among tourists returning from Austria in February and March, despite a low number of reported cases in the country at the time.The massive COVID-19 prevalence among travellers suggest that mandatory quarantine of returning travellers or suspension of non-essential international flights is essential if the aim is to control or suppress the COVID-19 pandemic.