bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rare variant analysis of 4,241 pulmonary arterial hypertension cases from an international consortium implicateFBLN2,PDGFDand rarede novovariants in PAH
Authors: Zhu Na , Swietlik Emilia M. , Welch Carrie L. , Pauciulo Michael W. , Hagen Jacob J. , Zhou Xueya , Guo Yicheng , Karten Johannes , Pandya Divya , Tilly Tobias , Lutz Katie A. , Rosenzweig Erika , Krishnan Usha , Coleman Anna W. , Gonzaga-Juaregiu Claudia , Lawrie Allan , Trembath Richard C. , Wilkins Martin R. ,   Regeneron Genetics Center,   PAH Biobank Enrolling Centers’ Investigators,   NIHR BioResource for Translational Research - Rare Diseases,   National Cohort Study of Idiopathic and Heritable PAH, Morrell Nicholas W. , Shen Yufeng , Gräf Stefan , Nichols William C. , Chung Wendy K. 
Published: May 2020

AbstractBackgroundGroup 1 pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy and heart failure. Recent high-throughput sequencing studies have identified additional PAH risk genes and suggested differences in genetic causes by age of onset. However, known risk genes explain only 15-20% of non-familial idiopathic PAH cases.MethodsTo identify new risk genes, we utilized an international consortium of 4,241 PAH cases with 4,175 sequenced exomes (n=2,572 National Biological Sample and Data Repository for PAH; n=469 Columbia University Irving Medical Center, enriched for pediatric trios) and 1,134 sequenced genomes (UK NIHR Bioresource – Rare Diseases Study). Most of the cases were adult-onset disease (93%), and 55% idiopathic (IPAH) and 35% associated with other diseases (APAH). We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 2,789 cases and 18,819 controls (11,101 unaffected parents from the Simons Powering Autism Research for Knowledge study and 7,718 gnomAD individuals). We analyzedde novovariants in 124 pediatric trios.ResultsSeven genes with rare deleterious variants were significantly associated (false discovery rate <0.1) with IPAH, including three known genes (BMPR2,GDF2, andTBX4), two recently identified candidate genes (SOX17,KDR), and two new candidate genes (FBLN2, fibulin 2;PDGFD, platelet-derived growth factor D). The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most of the variants occur in conserved protein domains. Variants in known PAH gene,ACVRL1, showed association with APAH. Predicted deleteriousde novovariants in pediatric cases exhibited a significant burden compared to the background mutation rate (2.5x, p=7.0E-6). At least eight novel candidate genes carryingde novovariants have plausible roles in lung/heart development.ConclusionsRare variant analysis of a large international consortium identifies two new candidate genes -FBLN2andPDGFD. The new genes have known functions in vasculogenesis and remodeling but have not been previously implicated in PAH. Trio analysis predicts that ~15% of pediatric IPAH may be explained byde novovariants.
The evolution of virulence inPseudomonas aeruginosaduring chronic wound infection
Authors: Vanderwoude Jelly , Fleming Derek , Azimi Sheyda , Trivedi Urvish , Rumbaugh Kendra P. , Diggle Stephen P. 
Published: May 2020

ABSTRACTOpportunistic pathogens are associated with a number of chronic human infections, yet the evolution of virulence in these organisms during chronic infection remains poorly understood. Here, we tested the evolution of virulence in the human opportunistic pathogenPseudomonas aeruginosain a murine chronic wound model using a two-part serial passage and sepsis experiment, and found that virulence evolved in different directions in each line of evolution. We also assessedP. aeruginosaadaptation to a chronic wound after 42 days of evolution, and found that morphological diversity in our evolved populations was limited compared to that previously described in cystic fibrosis (CF) infections. Using whole genome sequencing, we found that genes previously implicated inP. aeruginosapathogenesis (lasR, pilR, fleQ, rpoN, andpvcA), acquired mutations during the course of evolution in wounds, with some mutations evolving in parallel across all lines of evolution. Our findings highlight that (i)P. aeruginosaheterogeneity may be less extensive in chronic wounds than in CF lungs; (ii) genes involved inP. aeruginosapathogenesis acquire mutations during chronic wound infection; (iii) similar genetic adaptations are employed byP. aeruginosaacross multiple infection environments, and (iv) current models of virulence may not adequately explain the diverging evolutionary trajectories observed in an opportunistic pathogen during chronic wound infection.
Targeted sequencing of Parkinson’s disease loci genes highlightsSYT11, FGF20and other associations
Authors: Rudakou Uladzislau , Yu Eric , Krohn Lynne , Ruskey Jennifer A. , Asayesh Farnaz , Dauvilliers Yves , Spiegelman Dan , Greenbaum Lior , Fahn Stanley , Waters Cheryl H. , Dupré Nicolas , Rouleau Guy A. , Hassin-Baer Sharon , Fon Edward A. , Alcalay Roy N. , Gan-Or Ziv 
Published: May 2020

AbstractGenome-wide association studies (GWAS) have identified numerous loci associated with Parkinson’s disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson’s disease in 2,657 patients and 3,647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency < 0.01) using optimized sequence Kernel association tests (SKAT-O). The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants inSYT11, FGF20andGCH1associated with Parkinson’s disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that theSYT11GWAS association is driven by variants in the nearbyGBAgene. However, the association ofSYT11was mainly driven by a rare 3’ UTR variant (rs945006601) and was independent ofGBAvariants (p=5.23E-05 after exclusion of allGBAvariant carriers). The association ofFGF20was driven by a rare 5’ UTR variant (rs1034608171) located in the promoter region. The previously reported association ofGCH1with Parkinson’s Disease is driven by rare nonsynonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified twoLRRK2variants, p.Arg793Met and p.Gln1353Lys, in ten and eight controls, respectively, but not in patients. We identified common variants associated with Parkinson’s disease inMAPT, TMEM175, BST1,SNCAandGPNMBwhich are all in strong linkage disequilibrium (LD) with known GWAS hits in their respective loci. A common codingPM20D1variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson’s disease (OR 0.73, 95% CI 0.60-0.89, p=1.161E-03). This variant is not in LD with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest thatSYT11, FGF20, and potentiallyPM20D1, BST1andGPNMBshould be considered for future studies as possible Parkinson’s disease-related genes.
Detection of Circulating Tumor-specific DNA Methylation Markers in the Blood of Patients with Pituitary Tumors
Authors: Wells Michael , Asmaro Karam P. , Sabedot Thais S. , Malta Tathiane M. , Mosella Maritza S. , Nelson Kevin , Snyder James , deCarvalho Ana , Mukherjee Abir , Chitale Dhananjay , Robin Adam , Rosenblum Mark , Mikkelsen Thomas , Poisson Laila M. , Lee Ian Y. , Walbert Tobias , Bhan Arti , Kalkanis Steven , Rock Jack , Noushmehr Houtan , Castro Ana Valeria 
Published: May 2020

AbstractGenome-wide DNA methylation aberrations are pervasive and associated with clinicopathological features across pituitary tumors (PT) subtypes. The feasibility to detect CpG methylation abnormalities in circulating cell-free DNA (cfDNA) has been reported in central nervous system tumors other than PT. Here, we aimed to profile and identify methylome-based signatures in the serum of patients harboring PT (n =13). Our analysis indicated that serum cfDNA methylome from patients with PT are distinct from the counterparts in patients with other tumors (gliomas, meningiomas, colorectal carcinomas, n =134) and nontumor conditions (n = 4). Furthermore, the serum methylome patterns across PT was associated with functional status and adenohypophyseal cell lineage PT subtypes, recapitulating epigenetic features reported in PT-tissue. A machine learning algorithm using serum PT-specific signatures generated a score that distinguished PT from non-PT conditions with 100% accuracy in our validation set. These preliminary results underpin the potential clinical application of a liquid biopsy-based DNA methylation profiling as a noninvasive approach to identify clinically relevant epigenetic markers that can be used in the management of PT.
Mortality and use of angiotensin converting enzyme inhibitors in Covid 19 disease – a systematic review
Authors: Nunes José Pedro L. 
Published: May 2020

AbstractBackgroundInterest exits concerning the use of angiotensin converting enzyme inhibitors (ACEi) in patients with Covid-19 disease.ObjectivesTo perform a systematic review on mortality associated to the use of ACEi in patients with Covid 19 disease.MethodsSearch in Medline (PubMed), in ISI Web of Knowledge and in medRxiv database; use of other sources.ResultsA total of 33 articles were evaluated. Concerning the papers used to produce the meta-analyses, seven studies were selected, five of which were used. These five studies involved a total number of 944 patients treated with ACEi and 5173 not treated with ACEi. Increased mortality was seen in association to the use of ACEi in the context of Covid-19 disease (ACEi users versus non-users; odds ratio, 1.48; 95% confidence interval [CI], 1.02 to 2.15; P=0.04). When compared to mortality in patients treated with angiotensin receptor blockers, mortality of patients treated with ACEi was not significantly different (odds ratio, 0.96; 95% confidence interval [CI], 0.76 to 1.21; P=0.74). Concerning the remaining reports, different types of data adjustments were used by several authors, after which increased mortality was not seen in association to the use of ACEi in this context.ConclusionsACEi use could act as a marker of increased mortality risk in some but not all Covid-19 disease settings. The data now presented do not prove a causal relation but argue in favor of carrying out clinical trials studying ACEi in Covid-19 patients, in order to establish the safety of ACEi use in this context.
Novel indicators for evaluating topological threats to populations from pandemics applied to COVID-19
Authors: Adachi Shun 
Published: May 2020

ABSTRACTBACKGROUNDTo deal with pandemics, evaluating the temporal status of an outbreak is important. However, prevailing standards in this respect are mostly empirical and arbitrary. As an alternative, we focus on a novel approach which configures indicators that evaluate topological threats to populations due to the COVID-19 pandemic.METHODSWe extended the current PzDom model to calculate a threshold of the model for accelerated growth, an indicator of growth extent Re(v), covariance Re(s), a topological number E(l), and expected sums of possibly increasing numbers of infected people. We term this the exPzDom model.RESULTSThe indicators in the exPzDom model adhere well to the empirical dynamics of SARS-CoV-2 infected people and align appropriately with actual policies instituted by the Japanese government.CONCLUSIONSThe described indicators could be leveraged pursuant of objective evaluation based on mathematics. Further testing of the reliability and robustness of exPzDom model in other pandemic contexts is warranted.
Resting-state network plasticity induced by music therapy after traumatic brain injury
Authors: Martínez-Molina Noelia , Siponkoski Sini-Tuuli , Kuusela Linda , Laitinen Sari , Holma Milla , Ahlfors Mirja , Jordan-Kilkki Päivi , Ala-Kauhaluoma Katja , Melkas Susanna , Pekkola Johanna , Rodriguez-Fornells Antoni , Laine Matti , Ylinen Aarne , Rantanen Pekka , Koskinen Sanna , Cowley Benjamin Ultan , Särkämö Teppo 
Published: May 2020

AbstractTraumatic 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 previous randomized controlled trial, we found that a 3-month neurological music therapy intervention enhanced executive function (EF) and increased grey matter volume in the right inferior frontal gyrus (IFG) in patients with moderate-to-severe TBI (N=40). Extending this study, we performed longitudinal rsFC analyses of resting-state fMRI data using a ROI-to-ROI approach assessing within-network and between-network rsFC in the frontoparietal (FPN), dorsal attention (DAN), default mode (DMN), and salience (SAL) networks, which all have been associated with cognitive impairment after TBI. We also performed a seed-based connectivity analysis between the right IFG and whole-brain rsFC. The results showed that neurological music therapy increased the coupling between the FPN and DAN as well as between these networks and primary sensory networks. By contrast, the DMN was less connected with sensory networks after the intervention. Similarly, there was a shift towards a less connected state within the FPN and SAL networks, which are typically hyperconnected following TBI. Improvements in EF were correlated with rsFC within the FPN and between the DMN and sensorimotor networks. Finally, in the seed-based connectivity analysis, the right IFG showed increased rsFC with the right inferior parietal and left frontoparietal (Rolandic operculum) regions. Together, these results indicate that the rehabilitative effects of neurological music therapy after TBI are underpinned by a pattern of within- and between-network connectivity changes in cognitive networks as well as increased connectivity between frontal and parietal regions associated with music processing.
Loneliness during lockdown: trajectories and predictors during the COVID-19 pandemic in 35,712 adults in the UK
Authors: Bu Feifei , Steptoe Andrew , Fancourt Daisy 
Published: May 2020

AbstractThere are increasing worries that lockdowns and “stay-at-home” orders due to the COVID-19 pandemic could lead to a rise in loneliness, which is recognised as a major public health concern. But profiles of loneliness during the pandemic and risk factors remain unclear.Data from 35,712 UK adults in the UCL COVID-19 Social Study (a panel study collecting data weekly during the pandemic) were analysed from 21/03/2020-03/05/2020. The sample was well-stratified and weighted to population proportions of gender, age, ethnicity, education and geographical location. Growth mixture modelling was used to identify the latent classes of loneliness growth trajectories and their predictors.Analyses revealed four classes, with the baseline loneliness level ranging from low to high. In the first six weeks of lockdown, loneliness levels increased in the highest loneliness group, decreased in the lowest loneliness group, and stayed relatively constant in the middle two groups. Younger adults (OR = 2.17–6.81), women (OR = 1.59), people with low income (OR = 1.3), the economically inactive (OR = 1.3–2.04) and people with mental health conditions (OR = 5.32) were more likely to be in highest loneliness class relative to the lowest. Further, living with others or in a rural area, and having more close friends or greater social support were protective.Perceived levels of loneliness in the first few weeks of lockdown during COVID-19 were relatively stable in the UK, but for many people these levels were high with no signs of improvement. Results suggest that more efforts are needed to address loneliness, especially amongst young people.
SARS-CoV-2 Seroprevalence Among All Workers in a Teaching Hospital in Spain: Unmasking The Risk
Authors: Isabel Galán M , Velasco María , Luisa Casas M , José Goyanes M , Rodríguez-Caravaca Gil , Emilio Losa Juan , Noguera Carmen , Castilla Virgilio ,   Working Group Alcorcon COVID-19 investigators
Published: May 2020

ABSTRACTBackgroundHealth-care workers (HCW) are at increased risk for SARS-CoV-2 infection, but few studies have evaluated prevalence of antibodies against SARS-CoV-2 among them.ObjectiveTo determine the seroprevalence against SARS-CoV-2 in all HCW.MethodsCross-sectional study (April 14th- 27th, 2020) of all HCW at Hospital Universitario Fundación Alcorcón, a second level teaching hospital in Madrid, Spain. SARS-CoV-2 IgG was measured by ELISA. HCW were classified by professional category, working area, and risk for SARS-CoV-2 exposure.ResultsAmong 2919 HCW, 2590 (90.5%) were evaluated. Mean age was 43.8 years (SD 11.1) and 73.9% were females. Globally, 818 (31.6%) workers were IgG positive, with no differences for age, sex or previous diseases. Among them, 48.5% did not report previous symptoms. Seropositivity was more frequent in high (33.1%) and medium (33.8%) than in low-risk areas (25.8%, p = 0.007), but no difference was found for hospitalization areas attending COVID-19 and non-COVID-19 patients (35.5 vs 38.3% p = NS). HCW with a previous SARS-CoV2 PCR positive test were IgG seropositive in 90.8%. By multivariate logistic regression analysis, seropositivity was associated with being physicians (OR 2.37, CI95% 1.61–3.49), nurses (OR 1.67, CI95% 1.14–2.46), or nurse- assistants (OR 1.84, CI95% 1.24–2.73), HCW working at COVID-19 hospitalization areas (OR 1.71, CI95% 1.22–2.40), non-COVID-19 hospitalization areas (OR 1.88, CI95% 1.30–2.73), and at the Emergency Room (OR 1.51, CI95% 1.01–2.27)ConclusionsSeroprevalence uncovered a high rate of infection previously unnoticed among HCW. Patients not suspected of having COVID-19 as well as asymptomatic HCW may be a relevant source for nosocomial SARS-CoV-2 transmission.
Can medication mitigate the need for a strict lock down?: A mathematical study of control strategies for COVID-19 infection
Authors: Ali Mohsin , Imran Mudassar , Khan Adnan 
Published: May 2020

AbstractWe formulate a deterministic epidemic model to study the effects of medication on the transmission dynamics of Corona Virus Disease (COVID-19). We are especially interested in how the availability of medication could change the necessary quarantine measures for effective control of the disease. We model the transmission by extending the SEIR model to include asymptomatic, quarantined, isolated and medicated population compartments. We calculate the basic reproduction number R0 and show that for R0 < 1 the disease dies out and for R0 > 1 the disease is endemic. Using sensitivity analysis we establish that R0 is most sensitive to the rates of quarantine and medication. We also study how the effectiveness and the rate of medication along with the quarantine rate affect R0. We devise optimal quarantine, medication and isolation strategies, noting that availability of medication reduces the duration and severity of the lock-down needed for effective disease control. Our study also reinforces the idea that with the availability of medication, while the severity of the lock downs can be eased over time some social distancing protocols need to be observed, at least till a vaccine is found. We also analyze the COVID-109 outbreak data for four different countries, in two of these, India and Pakistan the curve is still rising, and in he other two, Italy and Spain, the epidemic curve is now falling due to effective quarantine measures. We provide estimates of R0 and the proportion of asymptomatic individuals in the population for these countries.
Serum proteomics in COVID-19 patients: Altered coagulation and complement status as a function of IL-6 level
Authors: D’Alessandro Angelo , Thomas Tiffany , Dzieciatkowska Monika , Hill Ryan C. , Francis Richard O , Hudson Krystalyn E. , Zimring James C. , Hod Eldad A. , Spitalnik Steven L. , Hansen Kirk C. 
Published: May 2020

AbstractOver 5 million people around the world have tested positive for the beta coronavirus SARS-CoV-2 as of May 29, 2020, a third of which in the United States alone. These infections are associated with the development of a disease known as COVID-19, which is characterized by several symptoms, including persistent dry cough, shortness of breath, chills, muscle pain, headache, loss of taste or smell, and gastrointestinal distress. COVID-19 has been characterized by elevated mortality (over 100 thousand people have already died in the US alone), mostly due to thromboinflammatory complications that impair lung perfusion and systemic oxygenation in the most severe cases. While the levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) have been associated with the severity of the disease, little is known about the impact of IL-6 levels on the proteome of COVID-19 patients. The present study provides the first proteomics analysis of sera from COVID-19 patients, stratified by circulating levels of IL-6, and correlated to markers of inflammation and renal function. As a function of IL-6 levels, we identified significant dysregulation in serum levels of various coagulation factors, accompanied by increased levels of anti-fibrinolytic components, including several serine protease inhibitors (SERPINs). These were accompanied by up-regulation of the complement cascade and antimicrobial enzymes, especially in subjects with the highest levels of IL-6, which is consistent with an exacerbation of the acute phase response in these subjects. Although our results are observational, they highlight a clear increase in the levels of inhibitory components of the fibrinolytic cascade in severe COVID-19 disease, providing potential clues related to the etiology of coagulopathic complications in COVID-19 and paving the way for potential therapeutic interventions, such as the use of pro-fibrinolytic agents.