bluuebunny/crossref_metadata_2025_split huggingface dataset:
COVID-19 vaccine hesitancy January-May 2021 among 18-64 year old US adults by employment and occupation
Authors: King Wendy C. , Rubinstein Max , Reinhart Alex , Mejia Robin J. 
Published: April 2021

AbstractCOVID-19 vaccine hesitancy threatens pandemic control efforts. We evaluated vaccine hesitancy in the US by employment status and occupation category during the COVID-19 vaccine rollout. US adults 18-64 years completed an online COVID-19 survey 3,179,174 times from January 6-May 19, 2021. Data was aggregated by month. Survey weights matched the sample to the US population age, gender, and state profile. Weighted percentages and 95% confidence intervals (95%CI) were calculated. Changes in vaccine hesitancy from January-May varied widely by employment status (e.g., -7.8% [95%CI, -8.2--7.5] among those working outside the home, a 26.6% decrease; -13.3% [95%CI, -13.7--13.0] among those not working for pay, a 44.9% decrease), and occupation category (e.g., -15.9% [95%CI, -17.7--14.2] in production, a 39.3% decrease; -1.4% [95%CI, -3.8--1.0] in construction/extraction, a 3.0% decrease). April 20-May 19, 2021, vaccine hesitancy ranged from 7.3% (95%CI, 6.7-7.8) in computer/mathematical professions to 45.2% (95%CI, 43.2-46.8) in construction/extraction. Hesitancy was 9.0% (95%CI, 8.6-9.3) among educators and 14.5% (95%CI, 14.0-15.0) among healthcare practitioners/technicians. While the prevalence of reasons for hesitancy differed by occupation, over half of employed hesitant participants reported concern about side effects (51.7%) and not trusting COVID-19 vaccines (51.3%), whereas only 15.0% didn’t like vaccines in general. Over a third didn’t believe they needed the vaccine, didn’t trust the government, and/or were waiting to see if it was safe. In this massive national survey of adults 18-64 years, vaccine hesitancy varied widely by occupation. Reasons for hesitancy indicate messaging about safety and addressing trust are paramount.
Mild and severe SARS-CoV-2 infection induces respiratory and intestinal microbiome changes in the K18-hACE2 transgenic mouse model
Authors: Seibert Brittany , Joaquín Cáceres C. , Cardenas-Garcia Stivalis , Carnaccini Silvia , Geiger Ginger , Rajao Daniela S. , Ottesen Elizabeth , Perez Daniel R. 
Published: April 2021

ABSTRACTTransmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and declining economies around the world. K18-hACE2 mice develop disease resembling severe SARS-CoV-2 infection in a virus dose-dependent manner. The relationship between SARS-CoV-2 and the intestinal or respiratory microbiome is not fully understood. In this context, we characterized the cecal and lung microbiome of SARS-CoV-2 challenged K18-hACE2 transgenic mice in the presence or absence of treatment with the Mproinhibitor GC376. Cecum microbiome showed decreased Shannon and Inv Simpson diversity index correlating with SARS-CoV-2 infection dosage and a difference of Bray-Curtis dissimilarity distances among control and infected mice. Bacterial phyla such as Firmicutes, particularly Lachnospiraceae and Oscillospiraceae, were significantly less abundant while Verrucomicrobiota, particularly the family Akkermansiaceae, were increasingly more prevalent during peak infection in mice challenged with a high virus dose. In contrast to the cecal microbiome, the lung microbiome showed similar microbial diversity among the control, low and high challenge virus groups, independent of antiviral treatment. Bacterial phyla in the lungs such as Bacteroidota decreased while Firmicutes and Proteobacteria were significantly enriched in mice challenged with a high dose of SARS-CoV-2. In summary, we identified changes in the cecal and lung microbiome of K18-hACE2 mice with severe clinical signs of SARS-CoV-2 infection.IMPORTANCEThe COVID-19 pandemic has resulted in millions of deaths. The host’s respiratory and intestinal microbiome can affect directly or indirectly the immune system during viral infections. We characterized the cecal and lung microbiome in a relevant mouse model challenged with a low and high dose of SARS-CoV-2 in the presence or absence of an antiviral Mproinhibitor, GC376. Decreased microbial diversity and taxonomic abundances of the phyla Firmicutes, particularly Lachnospiraceae, correlating with infection dosage was observed in the cecum. In addition, microbes within the family Akkermansiaceae were increasingly more prevalent during peak infection, which is observed in other viral infections. The lung microbiome showed similar microbial diversity to the control, independent of antiviral treatment. Decreased Bacteroidota and increased Firmicutes and Proteobacteria were observed in the lungs in a virus dose-dependent manner. These studies add to a better understanding of the complexities associated with the intestinal microbiome during respiratory infections.
Establishment of a publicly available core genome multilocus sequence typing scheme forClostridium perfringens
Authors: Abdel-Glil Mostafa Y. , Thomas Prasad , Linde Jörg , Jolley Keith A. , Harmsen Dag , Wieler Lothar H. , Neubauer Heinrich , Seyboldt Christian 
Published: April 2021

AbstractClostridium perfringensis a spore-forming anaerobic pathogen responsible for a variety of histotoxic and intestinal infections in humans and animals. High-resolution genotyping aiming to identify bacteria at strain level has become increasingly important in modern microbiology to understand pathogen transmission pathways and to tackle infection sources. This study aimed at establishing a publicly available genome-wide multilocus sequence-typing scheme forC. perfringens. 1,431 highly conserved core genes (1.34 megabases; 50% of the reference genome genes) were indexed for a core-genome-based MLST scheme forC. perfringens. As an example, we applied the scheme to 87 poultry and 73 non-poultry strains (total=160). The genotyping results of the 160 genomes were congruent in terms of resolution and tree topology between allele-based and single-nucleotide-polymorphism-based core-genome typing. For the analysis of poultry strains ofC. perfringensconcerning the country of isolation, NetB-toxin gene carriage and clinical disease, we used 60 allelic differences as a clustering threshold. The results showed that poultry strains from a single country formed a cluster (n=17 clusters including 46 strains). Two clusters included six strains from four different countries. These strains werenetB-positive, as were seven strains from Denmark and two strains from Finland, possibly indicating common sources ofnetB-positive strains. In terms of clinical presentation, different clusters of strains were associated with cases of suspected necrotic enteritis. Strains from sick birds grouped with strains from healthy birds or meat samples showing that potentially virulent strains are widespread and that host-related factors contribute significantly to NE. In summary, a publicly available scheme and an allele nomenclature database for genomic typing ofC. perfringenshas been established and can be used for broad-based and standardised epidemiological studies.
Regional atrophy and cognitive decline depend on definition of subjective cognitive decline
Authors: Morrison Cassandra , Dadar Mahsa , Shafiee Neda , Villeneuve Sylvia , Collins D. Louis ,   for Alzheimer’s Disease Neuroimaging Initiative
Published: April 2021

AbstractBackgroundPeople with subjective cognitive decline (SCD) may be at increased risk for Alzheimer’s disease (AD). However, not all studies have observed this increased risk. Inconsistencies may be related to different methods used to define SCD. The current project examined whether four methods of defining SCD (applied to the same sample) results in different patterns of atrophy and future cognitive decline between cognitively normal older adults with (SCD+) and without SCD (SCD-).MethodsMRI scans and questionnaire data for 273 cognitively normal older adults from Alzheimer’s Disease Neuroimaging Initiative were examined. To operationalize SCD we used four common methods: Cognitive Change Index (CCI), Everyday Cognition Scale (ECog), ECog + Worry, and Worry only. A previously validated MRI analysis method (SNIPE) was used to measure hippocampal volume and grading. Deformation-based morphometry was performed to examine volume at regions known to be vulnerable to AD. Logistic regressions were completed to determine whether diagnostic method was associated with volume differences between SCD- and SCD+. Linear mixed effects models were performed to examine the relationship between the definitions of SCD and future cognitive decline.ResultsResults varied between the four methods of defining SCD. Left hippocampal grading was lower in SCD+ than SCD-when using the CCI (p=.041) and Worry (p=.021) definitions. The right (p=.008) and left (p=.003) superior temporal regions were smaller in SCD+ than SCD-, but only with the ECog. SCD+ was associated with greater future cognitive decline measured by Alzheimer’s Disease Assessment Scale, but only with the CCI definition. In contrast, only the ECog definition of SCD was associated with future decline on the Montreal Cognitive Assessment.ConclusionThe current findings suggest that the various methods used to differentiate between SCD- and SCD+ influence whether volume differences and findings of cognitive decline are observed between groups in this retrospective analysis.
HPC framework for in-silico trials on 3D virtual human cardiac population to assess drug-induced arrhythmic risk
Authors: Aguado-Sierra Jazmin , Butakoff Constantine , Brigham Renee , Baron Apollo K. , Houzeaux Guillaume , Guerra Jose M. , Carreras Francesc , Filgueiras-Rama David , Iaizzo Paul A. , Iles Tinen L. , Vazquez Mariano 
Published: April 2021

AbstractCardiotoxicity continues to be a major health issue worldwide due to the imperative need to access new or repurposed drugs that are safe and effective. Accessibility to affordable drugs is also key to ensure access to drugs to all patients who require them. In this work we propose a workflow for an in-silico clinical trial at the 3D biventricular human population level, to assess cardiac pro-arrhythmic risk after administration of a single or a combination of potentially cardiotoxic drugs.The proposed workflow aims at reproducing gender-specific ionic channel characteristics that determine different responses of patients to drug-induced arrhythmia. To that end a “normal” virtual population of human 3D hearts at rest and exercise/stress (increased heart rate) was analyzed under the influence of drugs, using computer electrophysiology simulations. The changes in ECG, calcium concentration as well as activation patterns on 3D geometry were evaluated for the signs of arrhythmia. Hydroxychloroquine and Azithromycin were used to demonstrate the workflow. Additionally a series of experiments on a reanimated swine heart utilizing Visible Heart® methodologies were performed to verify the arrhythmic behaviour observed in the in-silico trial.Our results showed similar results to the recently published clinical trials (21% clinical risk vs 21.8% in-silico trial risk). Evidence of transmurally heterogeneous action potential prolongation after a large dose of hydroxychloroquine was an observed mechanism of arrhythmia, both in the in-vitro and the in-silico model. The proposed workflow for the in-silico clinical drug cardiotoxicity trials allows reproducing the complex behavior of cardiac electrophysiology in a population and verifying drug-induced arrhythmic risk in a matter of a few days as compared to the in-vivo trials. Importantly, our results provided evidence of the normal phenotype variants that produce distinct drug-induced arrhythmogenic outcomes.
Classifying chronic pain using multidimensional pain-agnostic symptom assessments and clustering analysis
Authors: Gilam Gadi , Cramer Eric M. , Webber Kenneth A. , Ziadni Maisa S. , Kao Ming-Chih , Mackey Sean C. 
Published: April 2021

AbstractChronic pain conditions present in various forms, yet all feature symptomatic impairments in physical, mental, and social domains. Rather than assessing symptoms as manifestations of illness, we used them to develop a chronic pain classification system. A cohort of real-world treatment-seeking patients completed a multidimensional patient-reported registry as part of a routine initial evaluation in a multidisciplinary academic pain clinic. We applied hierarchical clustering on a training subset of 11448 patients using nine pain-agnostic symptoms. We then validated a three-cluster solution reflecting a graded scale of severity across all symptoms and eight independent pain-specific measures in additional subsets of 3817 and 1273 patients. Negative affect-related factors were key determinants of cluster assignment. The smallest subset included follow-up assessments that were predicted based on baseline cluster assignment. Findings provide a cost-effective classification system that promises to improve clinical care and alleviate suffering by providing putative markers for personalized diagnosis and prognosis.
Endomembrane targeting of human OAS1 p46 augments antiviral activity
Authors: Soveg Frank W. , Schwerk Johannes , Gokhale Nandan S. , Cerosaletti Karen , Smith Julian R. , Pairo-Castineira Erola , Kell Alison M. , Forero Adriana , Zaver Shivam A. , Esser-Nobis Katharina , Roby Justin A. , Hsiang Tien-Ying , Ozarkar Snehal , Clingan Jonathan M. , McAnarney Eileen T. , Stone Amy E. L. , Malhotra Uma , Speake Cate , Perez Joseph , Balu Chiraag , Allenspach Eric J. , Hyde Jennifer L. , Menachery Vineet D. , Sarkar Saumendra N. , Woodward Joshua J. , Stetson Daniel B. , Baillie J. Kenneth , Buckner Jane H. , Gale Michael , Savan Ram 
Published: April 2021

SUMMARYMany host RNA sensors are positioned in the cytosol to detect viral RNA during infection. However, most positive-strand RNA viruses replicate within a modified organelle co-opted from intracellular membranes of the endomembrane system, which shields viral products from host cell innate immune sensors. Targeting innate RNA sensors to the endomembrane system may enhance their ability to sense viral RNA generated by viruses that use these compartments for replication. Here, we reveal that an isoform of oligoadenylate synthetase 1, OAS1 p46, is prenylated and targeted to the endomembrane system. Membrane localization of OAS1 p46 confers enhanced access to viral replication sites and results in increased antiviral activity against a subset of RNA viruses including flavivirus, picornavirus, and SARS-CoV-2. Finally, our human genetic analysis shows that theOAS1splice-site SNP responsible for production of the OAS1 p46 isoform strongly associates with COVID-19 severity. This study highlights the importance of endomembrane targeting for the antiviral specificity of OAS1 and suggests early control of SARS-CoV-2 replication through OAS1-p46 is an important determinant of COVID-19 severity.
Evaluation of SARS-CoV-2 Entry, Inflammation and New Therapeutics in Human Lung Tissue Cells
Authors: Grau-Expósito Judith , Perea David , Suppi Marina , Massana Núria , Vergara Ander , Soler Maria José , Trinite Benjamin , Blanco Julià , García-Pérez Javier , Alcamí José , Serrano-Mollar Anna , Rosado Joel , Falcó Vicenç , Genescà Meritxell , Buzon Maria J. 
Published: April 2021

AbstractThe development of physiological models that reproduce SARS-CoV-2 infection in primary human cells will be instrumental to identify host-pathogen interactions and potential therapeutics. Here, using cell suspensions directly from primary human lung tissues (HLT), we have developed a rapid platform for the identification of viral targets and the expression of viral entry factors, as well as for the screening of viral entry inhibitors and anti-inflammatory compounds. The direct use of HLT cells, without long-term cell culture andin vitrodifferentiation approaches, preserves main immune and structural cell populations, including the most susceptible cell targets for SARS-CoV-2; alveolar type II (AT-II) cells, while maintaining the expression of proteins involved in viral infection, such as ACE2, TMPRSS2, CD147 and AXL. Further, antiviral testing of 39 drug candidates reveals a highly reproducible method, suitable for different SARS-CoV-2 variants, and provides the identification of new compounds missed by conventional systems, such as VeroE6. Using this method, we also show that interferons do not modulate ACE2 expression, and that stimulation of local inflammatory responses can be modulated by different compounds with antiviral activity. Overall, we present a relevant and rapid method for the study of SARS-CoV-2.Graphical AbstractHighlightsEx vivophysiological systems for the study of SARS-CoV-2-host interactions are scarce. Here, we establish a method using primary human lung tissue (HLT) cells for the rapid analysis of cell tropism and identification of therapeutics.HLT cells preserve main cell subpopulations, including alveolar type-2 cells, and expression of SARS-CoV-2 entry factors ACE2, CD147, TMPRSS2 and AXL.HLT cells are readily susceptible to SARS-CoV-2 infection without the need of cell isolation or further cell differentiation.Antiviral testing in HLT cells allows the rapid identification of new drug candidates against SARS-CoV-2 variants, missed by conventional systems.Local inflammation is supported in HLT cells and offers the identification of relevant anti-inflammatory compounds for SARS-CoV-2 infection.
Anxiety and Depression in Patients with Pulmonary Hypertension and its Impact on Health-Related Quality of Life
Authors: Saleemi Sarfraz , Alameer Reem , Alsulaim Toka , Alghasab Naif S 
Published: April 2021

AbstractBackgroundPulmonary Hypertension (PH) is a chronic progressive disease which affects quality of life. The prevalence of mood disorders in PH patients in Saudi Arabia is not known.ObjectivesThis is a prospective observational study to investigate the prevalence of anxiety and depression in patients with pulmonary hypertension and its effect on health-related quality of life (HRQoL).MethodsForty-two PH patients were evaluated for mood disorders by using Hospital Anxiety and Depression Scale (HADS) and health related quality of life was assessed with The Short Form 36 (SF-36) Health Survey questionnaire.ResultsMean age for the cohort was 42.8 (±13.3) years and 31(73%) were female. Mean pulmonary artery pressure was 46.4 (± 15) mm Hg and 25 (60%) patients had severe PH (mPAP ≥45 mmHg). Thirty-eight (90%) patients were in World Health Organization Functional Class (WHO-FC) II/III and 5 (10%) class IV. HADS anxiety and depression score was positive (11-21) in 4 (10%) and 6 (14%) patients respectively. Presence of anxiety and/or depression affected HRQoL.ConclusionPrevalence of anxiety and depression in PH patients in Saudi Arabia is low (10% and 14% respectively) compared to published studies. The low prevalence may be explained by cultural and social differences and strong family support.
Pathogenic Neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq
Authors: Koster R. , Brandão R.D. , Tserpelis D. , van Roozendaal C.E.P. , van Oosterhoud C.N. , Claes K.B.M. , Paulussen A.D.C. , Sinnema M. , Vreeburg M. , van der Schoot V. , Stumpel C.T.R.M. , Broen M.P.G. , Spruijt L. , Jongmans M.C.J. , Oberstein S.A.J. Lesnik , Plomp A.S. , Misra-Isrie M. , Duijkers F.A. , Louwers M.J. , Szklarczyk R. , Derks K.W.J. , Brunner H.G. , van den Wijngaard A. , van Geel M. , Blok M.J. 
Published: April 2021

AbstractPurposeNeurofibromatosis type 1 (NF1) is caused by loss-of-function variants in the NF1 gene. Approximately 10% of these variants affect RNA splicing and are either missed by conventional DNA diagnostics or are misinterpreted by in silico splicing predictions. A targeted RNAseq-based approach was designed to detect pathogenic RNA splicing and associated pathogenic DNA variants.MethodsRNA was extracted from lymphocytes, followed by targeted NF1 RNAseq. An in-house developed tool (QURNAS) was used to calculate the enrichment score (ERS) for each splicing event.ResultsThis method was thoroughly tested using two different patient cohorts with known pathogenic splice-variants. In both cohorts all 56 normal reference transcript exon splice junctions, 24 previously described and 45 novel non-reference splicing events were detected. Additionally, all expected pathogenic splice-variants were detected. Eleven patients with NF1 symptoms were subsequently tested, three of which have a known NF1 DNA variant with a putative effect on RNA splicing. This effect could be confirmed for all 3. The other eight patients were previously without any molecular confirmation of their NF1-diagnosis. A deep-intronic pathogenic splice variant could now be identified for two of them (25%).ConclusionTargeted NF1 RNAseq can be successfully used to detect pathogenic RNA splicing variants, complementary to DNA based diagnostics.
Little genomic support for cyclophilin A-matrix metalloproteinase-9 pathway as a therapeutic target for cognitive impairment in APOE4 carriers
Authors: Anderson Emma L , Williams Dylan M , Walker Venexia , Davies Neil M 
Published: April 2021

AbstractTherapeutic targets for halting the progression of Alzheimers disease pathology are lacking. Recent evidence suggests that APOE4, but not APOE3, activates the cyclophilin A matrix metalloproteinase-9 (CypA MMP9) pathway in the cerebrospinal fluid, leading to an accelerated breakdown of the blood brain barrier (BBB) and thereby causing neuronal and synaptic dysfunction. Furthermore, blockade of the CypA MMP9 pathway in APOE4 knock-in mice restores BBB integrity and subsequently normalizes neuronal and synaptic function. Thus, CypA has been suggested as a potential target for treating APOE4 mediated neurovascular injury and the resulting neuronal dysfunction and degeneration. The odds of drug targets passing through clinical trials are greatly increased if they are supported by genomic evidence. We found little evidence that CypA or MMP9 affected the risk of Alzheimers disease or cognitive impairment using two-sample Mendelian randomization and polygenic risk score analysis in humans. This casts doubt on whether they are likely to represent effective drug targets for cognitive impairment in APOE4 carriers.
Comparative analysis unveils novel changes in serum metabolites and metabolomic networks of retinopathy of prematurity infants
Authors: Yang Yuhang , Yang Qian , Zhang Yinsheng , Lian Chaohui , He Honghui , Zeng Jian , Zhang Guoming 
Published: April 2021

AbstractBackgroundAdvances in mass spectrometry are providing new insights into the role of metabolomics in the aetiology of many diseases. Studies in retinopathy of prematurity (ROP), for instance, overlooked the role of metabolic alterations in disease development. Here, we employed comprehensive metabolic profiling and gold-standard metabolic analysis to explore major metabolites and metabolic pathways significantly affected in early stages of pathogenesis toward ROP.MethodsThis is a multicentre, retrospective case-control study. We collected serums from 57 ROP cases and 57 strictly baseline matched non-ROP controls. Non-targeted ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) from Metabolon, Inc. was used to detect the metabolites in serum samples. Machine learning was used to unravel most affected metabolites and pathways in ROP development.ResultsCompared to non-ROP controls, we found a significant metabolic perturbation in the ROP serums, featured with an increase in lipid, nucleotide, carbohydrate metabolites and a lower level of peptides. Machine leaning helped to distinguish a cluster of metabolic pathways (glycometabolism, redox homeostasis, lipid metabolism and arginine pathway) that were strongly related to the development of ROP. In addition, we found that the severity of ROP was related to the level of creatinine and ribitol.ConclusionIn the current study, our results suggested a strong link between metabolic profiling and retinal neovascularization during ROP pathogenesis. These findings provided an insight into identifying novel metabolic biomarkers for ROP diagnosis and prevention.