bluuebunny/crossref_metadata_2025_split huggingface dataset:
rareSurvival: rare variant association analysis for “time-to-event” outcomes
Authors: Syed Hamzah , Jorgensen Andrea L. , Morris Andrew P. 
Published: December 2021

AbstractSummaryRare variants have been proposed as contributing to the “missing heritability” of complex human traits. There has been much recent development of methodology to investigate association of complex traits with multiple rare variants within pre-defined “units” from sequence and array-based studies of the exome or genome. However, software for modelling time to event outcomes for rare variant associations has been under developed in comparison with binary and quantitative traits. We introduce a new command line application, rareSurvival, used for the analysis of rare variants with time to event outcomes. The program is compatible with high performance computing (HPC) clusters for batch processing. rareSurvival implements statistical methodology, which are a combination of widely used survival and gene-based analysis techniques such as the Cox proportional hazards model and the burden test. We introduce a novel piece of software that will be at the forefront of efforts to discover rare variants associated with a variety of complex diseases with survival endpoints.Availability & ImplementationrareSurvival is implemented in C#, available on Linux, Windows and Mac OS X operating systems. It is freely available (GNU General Public License, version 3) to download from https://www.liverpool.ac.uk/translational-medicine/research/statistical-genetics/software/. Download Mono for Linux or Mac OS X to run software.Contacthamzah.syed@liverpool.ac.ukSupplementary informationLinks to additional figures and tables are available at Bioinformatics online.
In the back of your mind: Cortical mapping of paraspinal afferent inputs
Authors: Cole David M. , Stämpfli Philipp , Gandia Robert , Schibli Louis , Gantner Sandro , Schuetz Philipp , Meier Michael L. 
Published: December 2021

AbstractTopographic organization is a hallmark of vertebrate cortex architecture, characterized by ordered projections of the body’s sensory surfaces onto brain systems. High-resolution functional magnetic resonance imaging (fMRI) has proven itself as a valuable tool to investigate the cortical landscape and its (mal-)adaptive plasticity with respect to various body part representations, in particular extremities such as the hand and fingers. Less is known, however, about the cortical representation of the human back. We therefore validated a novel, MRI-compatible method of mapping cortical representations of sensory afferents of the back, using vibrotactile stimulation at varying frequencies and paraspinal locations, in conjunction with fMRI. We expected high-frequency stimulation to be associated with differential neuronal activity in the primary somatosensory cortex (S1) compared to low-frequency stimulation and that somatosensory representations would differ across the thoracolumbar axis. We found significant differences between neural representations of high- and low-frequency stimulation and between representations of thoracic and lumbar paraspinal locations, in several bilateral S1 sub-regions, and in regions of the primary motor cortex (M1). High-frequency stimulation preferentially activated Brodmann Area (BA) regions BA3a and BA4p, while low-frequency stimulation was more encoded in BA3b and BA4a. Moreover, we found clear topographic differences in S1 for representations of the upper and lower back during high-frequency stimulation. We present the first neurobiological validation of a method for establishing detailed cortical maps of the human back, which might serve as a novel tool to evaluate the pathological significance of neuroplastic changes in clinical conditions such as chronic low back pain.Key pointsDetailed investigations of cortical representations of somatosensory paraspinal afferents along the thoracolumbar axis are lacking.Using fMRI combined with a novel vibrotactile stimulation device (“pneuVID”) we investigated different sensorimotor cortical representations of the back and explored topographic differences between the upper and lower back.We found differential sub-regional sensorimotor neural representations of high- and low-frequency stimulation, as well as revealing initial evidence of the somatotopy of upper and lower paraspinal representations.The current approach might serve as a promising tool to elucidate the role of cortical reorganisation in the pathophysiology of clinical conditions such as chronic low back pain.
Pentosan polysulfate inhibits attachment and infection by SARS-CoV-2 in vitro: insights into structural requirements for binding
Authors: Bertini Sabrina , Alekseeva Anna , Elli Stefano , Pagani Isabel , Zanzoni Serena , Eisele Giorgio , Krishnan Ravi , Maag Klaus P , Reiter Christian , Lenhart Dominik , Gruber Rudolf , Yates Edwin A , Vicenzi Elisa , Naggi Annamaria , Bisio Antonella , Guerrini Marco 
Published: December 2021

AbstractTwo years since the outbreak of the novel coronavirus SARS-CoV-2 pandemic, there remain few clinically effective drugs to complement vaccines. One is the anticoagulant, heparin, which in 2004 was found able to inhibit invasion of SARS CoV (CoV-1) and which has been employed during the current pandemic to prevent thromboembolic complications and moderate potentially damaging inflammation. Heparin has also been shown experimentally to inhibit SARS-CoV-2 attachment and infection in susceptible cells. At high therapeutic doses however, heparin increases the risk of bleeding and prolonged use can cause heparin-induced thrombocytopenia, a serious side-effect. One alternative, with structural similarities to heparin is the plant-derived, semi-synthetic polysaccharide, pentosan polysulfate (PPS). PPS is an established drug for the oral treatment of interstitial cystitis, is well-tolerated and exhibits weaker anticoagulant effects than heparin. In an established Vero cell model, PPS and its fractions of varying molecular weights, inhibited invasion by SARS-CoV-2. Intact PPS and its size-defined fractions were characterized by molecular weight distribution and chemical structure using NMR spectroscopy and LC-MS, then employed to explore the structural basis of interactions with SARS-CoV-2 spike protein receptor-binding domain (S1 RBD) and the inhibition of Vero cell invasion. PPS was as effective as unfractionated heparin, but more effective at inhibiting cell infection than low molecular weight heparin (on a weight/volume basis). Isothermal titration calorimetry and viral plaque-forming assays demonstrated size-dependent binding to S1 RBD and inhibition of Vero cell invasion, suggesting the potential application of PPS as a novel inhibitor of SARS-CoV-2 infection.
Cerebellar GABA change during visuomotor adaptation relates to adaptation performance and cerebellar network connectivity: A Magnetic Resonance Spectroscopic Imaging study
Authors: Nettekoven Caroline R , Mitchell Leah , Clarke William T , Emir Uzay , Campbell Jon , Johansen-Berg Heidi , Jenkinson Ned , Stagg Charlotte J 
Published: December 2021

AbstractMotor adaptation is crucial for performing accurate movements in a changing environment and relies on the cerebellum. Although cerebellar involvement has been well characterized, the neurochemical changes in the cerebellum underpinning human motor adaptation remain unknown.We used a novel Magnetic Resonance Spectroscopic Imaging (MRSI) technique to measure changes in the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the human cerebellum during visuomotor adaptation. Participants used their right hand to adapt to a rotated cursor in the scanner, compared with a control task requiring no adaptation. We spatially resolved adaptation-driven GABA changes at the cerebellar nuclei and cerebellar cortex in the left and the right cerebellar hemisphere independently and found that simple right-hand movements increase GABA in the right cerebellar nuclei and decreases GABA in the left. When isolating adaptation-driven GABA changes, we found an increase in GABA in the left cerebellar nuclei and decrease in GABA in the right cerebellar nuclei. Early adaptation-driven GABA change in the right cerebellar nuclei correlated with adaptation performance: Participants showing greater GABA decrease adapted better, suggesting early GABA change is behaviourally relevant. Early GABA change also correlated with functional connectivity change in a cerebellar network: Participants showing greater decreases in GABA showed greater strength increases in cerebellar network connectivity. Results were specific to GABA, to adaptation and to the cerebellar network.This study provides first evidence for plastic changes in cerebellar neurochemistry during motor adaptation. Characterising these naturally occurring neurochemical changes may provide a basis for developing therapeutic interventions to facilitate human motor adaptation.Significance StatementDespite motor adaptation being fundamental to maintaining accurate movements, its neurochemical basis remains poorly understood, perhaps because measuring neurochemicals in the human cerebellum is technically challenging. Using a novel magnetic resonance spectroscopic imaging method, this study provides evidence for GABA changes in the left and right cerebellar nuclei driven by both simple movement and motor adaptation. The adaptation-driven GABA change in the right cerebellar nuclei correlated with adaptation performance, and with functional connectivity change in a cerebellar network. These results show the first evidence for plastic changes in cerebellar neurochemistry during a cerebellar learning task. This provides the basis for developing therapeutic interventions that facilitate these naturally occurring changes to amplify cerebellar-dependent learning.
Economic burden and catastrophic health expenditure associated with COVID-19 hospitalisations in Kerala, South India
Authors: Thomas Ronnie , Jacob Quincy Mariam , Eliza Sharon Raj , Mini Malathi , Jose Jobinse , Sobha A 
Published: December 2021

AbstractIntroductionCatastrophic health expenditure during COVID-19 hospitalization has altered the economic picture of households especially in low resource settings with high rates of COVID-19 infection. This study aimed to estimate the Out of Pocket (OOP) expenditure and the proportion of households that incurred catastrophic health expenditures due to COVID-19 hospitalisation in Kerala, South India.Materials and MethodsA cross-sectional study was conducted among a representative sample of 155 COVID-19 hospitalised patients in Kottayam district over four months, using a pretested interview schedule. The direct medical and non-medical costs incurred by the study participant during hospitalisation and the total monthly household expenditure were obtained from the respective COVID-19 affected households. Catastrophic health expenditure was defined as direct medical expenditure exceeding 40% of effective household income.ResultsFrom the study, median and mean Out of Pocket (OOP) expenditures were obtained as USD 93.57 and USD 502.60 respectively. The study revealed that 49.7% of households had Catastrophic health expenditure, with 32.9% having incurred Distress financing. Multivariate analysis revealed being Below poverty line, hospitalisation in private healthcare facility and presence of co-morbid conditions as significant determinants of Catastrophic health expenditure.ConclusionHigh levels of Catastrophic health expenditure and distress financing revealed by the study unveils major unaddressed challenges in the road to Universal health coverage.
Associations between intimate partner violence and mental health in German men and women: a cross-sectional analysis of the German Health Interview and Examination Survey for Adults (DEGS1)
Authors: Graßkemper Lena , Costa Diogo 
Published: December 2021

AbstractThis work explores the cross-sectional associations between Intimate Partner Violence (IPV) and anxiety, depressive symptoms, stress symptoms, and health-related quality of life (HRQoL), in a representative sample of German adult men (n=2,789) and women (n=3,149), and considers their involvement as victims or perpetrators of physical and psychological IPV. In this sample, physical IPV victimization was associated with anxiety and stress among men. Psychological IPV victimization was associated with depression among men, and with stress among both sexes. Physical IPV perpetration was significantly associated only with women’s depressive and stress symptoms. Psychological IPV perpetration was associated with stress for both men and women. The mental component of HRQoL was significantly lower for men and women involved in any type of IPV. These results support the need to consider the mental health consequences of IPV involvement for both men and women.
A nationwide deep learning pipeline to predict stroke and COVID-19 death in atrial fibrillation
Authors: Handy Alex , Wood Angela , Sudlow Cathie , Tomlinson Christopher , Kee Frank , Thygesen Johan H , Mamouei Mohammad , Sofat Reecha , Dobson Richard , Ip Samantha , Denaxas Spiros 
Published: December 2021

ABSTRACTDeep learning (DL) and machine learning (ML) models trained on long-term patient trajectories held as medical codes in electronic health records (EHR) have the potential to improve disease prediction. Anticoagulant prescribing decisions in atrial fibrillation (AF) offer a use case where the benchmark stroke risk prediction tool (CHA2DS2-VASc) could be meaningfully improved by including more information from a patient’s medical history. In this study, we design and build the first DL and ML pipeline that uses the routinely updated, linked EHR data for 56 million people in England accessed via NHS Digital to predict first ischaemic stroke in people with AF, and as a secondary outcome, COVID-19 death. Our pipeline improves first stroke prediction in AF by 17% compared to CHA2DS2-VASc (0.61 (0.57-0.65) vs 0.52 (0.52-0.52) area under the receiver operating characteristics curves, 95% confidence interval) and provides a generalisable, opensource framework that other researchers and developers can build on.
SARS-CoV-2 vaccine effectiveness and breakthrough infections in maintenance dialysis patients
Authors: Manley Harold J. , Aweh Gideon N. , Hsu Caroline M. , Weiner Daniel E. , Miskulin Dana , Harford Antonia M. , Johnson Doug , Lacson Eduardo K. 
Published: December 2021

AbstractBackgroundSARS-CoV-2 vaccine effectiveness during the Delta period and immunogenicity threshold associated with protection against COVID-19 related hospitalization or death in the dialysis population is unknown.MethodsA retrospective, observational study assessed SARS-CoV-2 vaccine effectiveness and immunogenicity threshold in all adult maintenance dialysis patients without COVID-19 history treated between February 1 and October 2, 2021. All COVID-19 infections, composite of hospitalization or death following COVID-19 and available SARS-CoV-2 anti-spike immunoglobulin (Ig) G values were extracted from electronic medical record. COVID-19 cases per 10,000 days at risk and vaccine effectiveness during pre-Delta and Delta periods were determined.ResultsOf 15,718 patients receiving dialysis during the study period, 11,191 (71%) were fully vaccinated, 733 (5%) were partially vaccinated and 3,794 (24%) were unvaccinated. 967 COVID-19 were cases identified: 511 (53%) occurred in unvaccinated patients and 579 (60%) occurred during the Delta period. COVID-19 related hospitalization or death was less likely among vaccinated versus unvaccinated patients for all vaccines (adjusted HR 0.19 [0.12, 0.30]) and for BNT162b2/Pfizer, mRNA-1273/Moderna, and Ad26.COV2.S/Janssen (adjusted HR=0.25 [0.16, 0.40], 0.14 [0.08, 0.22], and 0.34 [0.17, 0.68] respectively). Among those with anti-spike IgG levels, those with IgG level ≥ 7 had significantly lower risk of a COVID-19 diagnosis (HR=0.25 [0.15, 0.42]) and none experienced a COVID-related hospitalization or death.ConclusionsAmong maintenance dialysis patients, SARS-CoV-2 vaccination was associated with a lower risk of COVID-19 diagnosis and associated hospitalization or death. Among vaccinated patients, low anti-spike IgG level is associated with worse COVID-19 related outcomes.Significance StatementSARS-CoV-2 vaccine effectiveness and association between antibody levels and clinical outcomes in maintenance dialysis patients is not known. Between February 1 and October 2, 2021, vaccine effectiveness was 85% against COVID-19 infection and 81% against composite of COVID-related hospitalization or death. COVID-19 case rates and severe outcomes were higher during the Delta dominant period (June 27-October 2, 2021). Increasing time (weeks) since full vaccination status was associated with increased risk for COVID-19 related hospitalization or death. Anti-spike IgG level ≥ 7 had lower risk of a COVID-19 diagnosis and no COVID-related hospitalization or death. Our findings supports utilization of SARS-CoV-2 vaccination and suggests that monitoring SARS-CoV-2 antibody levels and administering additional vaccine doses to maintain adequate immunity will be beneficial.
Cardiovascular Complications of Modern Multiple Myeloma Therapy: Analysis of FDA Adverse Event Reporting System
Authors: Al-Yafeai Zaki , Ananthaneni Anil , Ghoweba Mohamed , Abduljabar Hamzah , Aziz David , Grewal Udhayvir 
Published: December 2021

AbstractPurposeMultiple 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.MethodsWe 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.ResultsAmong 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.ConclusionsThe 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.
Cortical and thalamic influences on striatal involvement in instructed, serial reversal learning; implications for the organisation of flexible behaviour
Authors: Williams Brendan , Christakou Anastasia 
Published: December 2021

AbstractCognitive flexibility is essential for enabling an individual to respond adaptively to changes in their environment. Evidence from human and animal research suggests that the control of cognitive flexibility is dependent on an array of neural architecture. Cortico-basal ganglia circuits have long been implicated in cognitive flexibility. In particular, the role of the striatum is pivotal, acting as an integrative hub for inputs from the prefrontal cortex and thalamus, and modulation by dopamine and acetylcholine. Striatal cholinergic modulation has been implicated in the flexible control of behaviour, driven by input from the centromedian-parafascicular nuclei of the thalamus. However, the role of this system in humans is not clearly defined as much of the current literature is based on animal work. Here, we aim to investigate the roles corticostriatal and thalamostriatal connectivity in serial reversal learning. Functional connectivity between the left centromedian-parafascicular nuclei and the associative dorsal striatum was significantly increased for negative feedback compared to positive feedback. Similar differences in functional connectivity were observed for the right lateral orbitofrontal cortex, but these were localised to when participants switched to using an alternate response strategy following reversal. These findings suggest that connectivity between the centromedian-parafascicular nuclei and the striatum may be used to generally identify potential changes in context based on negative outcomes, and the effect of this signal on striatal output may be influenced by connectivity between the lateral orbitofrontal cortex and the striatum.
MIAAIM: Multi-omics image integration and tissue state mapping using topological data analysis and cobordism learning
Authors: Hess Joshua M. , Ilieş Iulian , Schapiro Denis , Iskra John J. , Abdelmoula Walid M. , Regan Michael S. , Theocharidis Georgios , Wu Chin Lee , Veves Aristidis , Agar Nathalie Y.R. , Sluder Ann E. , Poznansky Mark C. , Reeves Patrick M. , Sîrbulescu Ruxandra F. 
Published: December 2021

ABSTRACTHigh-parameter tissue imaging enables detailed molecular analysis of single cells in their spatial environment. However, the comprehensive characterization and mapping of tissue states through multimodal imaging across different physiological and pathological conditions requires data integration across multiple imaging systems. Here, we introduce MIAAIM (Multi-omics Image Alignment and Analysis by Information Manifolds) a modular, reproducible computational framework for aligning data across bioimaging technologies, modeling continuities in tissue states, and translating multimodal measures across tissue types. We demonstrate MIAAIM’s workflows across diverse imaging platforms, including histological stains, imaging mass cytometry, and mass spectrometry imaging, to link cellular phenotypic states with molecular microenvironments in clinical biopsies from multiple tissue types with high cellular complexity. MIAAIM provides a robust foundation for the development of computational methods to integrate multimodal, high-parameter tissue imaging data and enable downstream computational and statistical interrogation of tissue states.
Inductive inference of novel protein-molecule interactions using Heterogeneous Graph Transformer (HGT) AutoEncoder
Authors: Arrigoni Alberto 
Published: December 2021

1AbstractProtein-molecule interactions are promoted by the physicochemical characteristics of the actors involved, but structural information alone does not capture expression patterns, localization and pharmacokinetics. In this work we propose an integrative strategy for protein-molecule interaction discovery that combines different layers of information through the use of convolutional operators on graph, and frame the problem as missing link prediction task on an heterogeneous graph constituted by three node types: 1) molecules 2) proteins 3) diseases. Physicochemical information of the actors are encoded using shallow embedding techniques (SeqVec, Mol2Vec, Doc2Vec respectively) and are supplied as feature vectors to a Graph AutoEncoer (GAE) that uses a Heterogeneous Graph Transformer (HGT) in the encoder module. We show in this work that HGT Autoencoder can be used to accurately recapitulate the proteinmolecule interactions set and propose novel relationships in inductive settings that are grounded in biological and functional information extracted from the graph.