bluuebunny/crossref_metadata_2025_split huggingface dataset:
Model for evaluating cost-effectiveness of surveillance testing for SARS-CoV2
Authors: Silver Jonathan 
Published: December 2020

AbstractTesting people without symptoms for SARS-CoV-2 followed by isolation of those who test positive could mitigate the covid-19 epidemic pending arrival of an effective vaccine. Key questions for such programs are who should be tested, how often, and when should such testing stop. Answers to these questions depend on test and population characteristics. A cost-effectiveness model that provides answers depending on user-adjustable parameter values is described. Key parameters are the value ascribed to preventing a death and the reproduction number (roughly, rate of spread) at the time surveillance testing is initiated. For current rates of spread, cost-effectiveness usually requires a value per life saved greater than $100,000 and depends critically on the extent and frequency of testing.
Clinical Evaluation of a COVID-19 Antibody Lateral Flow Assay using Point of Care Samples
Authors: Lee Won , Straube Steven , Sincic Ryan , Noble Jeanne A. , Montoy Juan Carlos , Kornblith Aaron E. , Prakash Arun , Wang Ralph , Bainton Roland J. , Kurien Philip A. 
Published: December 2020

ABSTRACTIntroductionThe ongoing SARS-CoV-2 pandemic has spurred the development of numerous point of care (PoC) immunoassays. Assessments of performance of available kits are necessary to determine their clinical utility. Previous studies have mostly performed these assessments in a laboratory setting, which raises concerns of translating findings for PoC use. The aim of this study was to assess the performance of a lateral flow immunoassay for the detection of SARS-CoV-2 antibodies using samples collected at PoC.MethodOne lateral flow immunoassay (Humasis®COVID-19 IgG/IgM) was tested. In total, 50 PCR RT-PCR positive and 52 RT-PCR negative samples were collected at PoC. Fifty serum specimens from Dec 2018 to Feb 2019 were used as controls for specificity. Serum samples collected between Dec 2019 to Feb 2020 were used as additional comparators. Clinical data including symptom onset date was collected from patient history and the medical record.ResultsThe overall sensitivity for the kit was 74% (95% CI: 59.7% -85.4%). The sensitivity for IgM and IgG detection >14 days after date of onset was 88% (95% CI: 68.8% -97.5%) and 84% (95% CI: 63.9% – 95.5%), with a negative predictive value (NPV) of 94% for IgM (95% CI: 83.5% - 98.8%) and 93% for IgG (95% CI: 81.8% - 97.9%). The overall specificity was 94% (95% CI: 83.5% - 98.8%). The Immunoglobulin specific specificity was 94% for IgM (95% CI: 83.5% - 98.8%) and 98% for IgG (95% CI: 89.4% - 100.0%), with a positive predictive value (PPV) of 88% for IgM (95% CI: 68.8% - 97.5%) and 95% for IgG (95% CI: 77.2% - 99.9%) respectively for samples collected from patients >14 days after date of onset. Specimen collected during early phase of COVID-19 pandemic (Dec 2019 to Feb 2020) showed 11.8% antibody positivity, and 11.3% of PCR-negative patients demonstrated antibody positivity.DiscussionHumasis®COVID-19 IgG/IgM LFA demonstrates greater than 90% PPV and NPV for samples collected 14 days after the onset of symptoms using samples collected at PoC. While not practical for the diagnosis of acute infection, the use of the lateral flow assays with high specificity may have utility for determining seroprevalence or seroconversion in longitudinal studies.
Mitogen and Stress-Activated Kinases 1 and 2 Mediate Endothelial Dysfunction
Authors: Akbar Naveed , Forteath Calum , Hussain Muhammad S. , Reyskens Kathleen , Belch Jill J. F. , Lang Chim C. , Mordi Ify , Bhalraam U , Arthur J. Simon C. , Khan Faisel 
Published: December 2020

ABSTRACTInflammation promotes endothelial dysfunction. Using translational vascular function testing in myocardial Infarction patients, a situation where inflammation is prevalent, and knock-out (KO) mouse models we demonstrate a role for mitogen-activated-protein-kinases (MAPKs) in endothelial dysfunction. Myocardial infarction significantly lowers mitogen and stress kinase 1/2 (MSK1/2) expression in peripheral blood mononuclear cells and diminished endothelial function. To further understand the role of MSK1/2 in vascular function we developed in vivo animal models to assess vascular responses to vasoactive drugs using laser Doppler imaging. Genetic deficiency of MSK1/2 in mice increased plasma levels of pro-inflammatory cytokines and promoted endothelial dysfunction, through attenuated production of nitric oxide (NO), which were further exacerbated by cholesterol feeding. MSK1/2 are activated by toll-like receptors through MyD88. MyD88 KO showed preserved endothelial function and reduced plasma cytokine expression, despite significant hypercholesterolemia. MSK1/2 kinases interact with MAPK-activated proteins 2/3 (MAPKAP2/3), which limit cytokine synthesis. Cholesterol-fed MAPKAP2/3 KO mice showed reduced plasma cytokine expression and preservation of endothelial function. MSK1/2 plays a significant role in the development of endothelial dysfunction and may provide a novel target for intervention to reduce vascular inflammation. Selective activation of MSK1/2 could reduce pro-inflammatory responses and preserve endothelial function before development of significant vascular disease.Graphical Abstract
Tolerability and Pharmacokinetic Evaluation of Inhaled Dry Powder Hydroxychloroquine in Healthy Volunteers
Authors: de Reus Y.A. , Hagedoorn P. , Sturkenboom M.G.G. , Grasmeijer F. , Bolhuis M.S. , Sibum I. , Kerstjens H.A.M. , Frijlink H.W. , Akkerman O.W. 
Published: December 2020

ABSTRACTRationaleInhaled antimicrobials enable high local concentrations where needed and, compared to orally administration, greatly reduce the potential for systemic side effects. In SARS-CoV-2 infections, hydroxychloroquine (HCQ) administered as dry powder via inhalation could be safer than oral HCQ allowing for higher and therefore more effective pulmonary concentrations without dose limiting toxic effects.ObjectivesTo assess the local tolerability, safety and pharmacokinetic parameters of HCQ inhalations in single ascending doses of 5, 10 and 20 mg using the Cyclops dry powder inhaler.Methods12healthy volunteers were trained in inhaling HCQ correctly. Local tolerability and safety were assessed by pulmonary function tests, ECG and recording adverse events. To estimate systemic exposure, serum samples were collected before and 0.5, 2 and 3.5 h after inhalation.Results and discussionDry powder HCQ inhalations were well tolerated by the participants, except for transient bitter taste in all participants and minor coughing irritation. There was no significant change in QTc-interval or drop in FEV1post inhalation. The serum HCQ concentration remained below 10 µg/L in all samples.ConclusionInhaled dry powder HCQ is safe and well tolerated. Our data support further studies with inhaled HCQ dry powder to evaluate pulmonary pharmacokinetics and efficacy is warranted.
Long Covid and the role of physical activity: a qualitative study
Authors: Humphreys Helen , Kilby Laura , Kudiersky Nik , Copeland Robert 
Published: December 2020

ABSTRACTObjectivesTo explore the lived experience of Long Covid with particular focus on the role of physical activityDesignQualitative study using semi-structured interviewsParticipants18 people living with Long Covid (9 male, 9 female; aged between 18-74; 10 White British, 3 White Other, 3 Asian, 1 Black, 1 mixed ethnicity) recruited via a UK-based research interest database for people with Long CovidSettingTelephone interviews with 17 participants living in the UK and 1 participant living in the USResultsFour themes were generated. Theme one highlights the physical and social isolation experienced by people with Long Covid, compounded by a lack of support and advice from medical professionals. Theme two describes how participants sought information and validation through online sources and communities. Theme three captures the challenges associated with managing physical and cognitive effects of Long Covid including fatigue and ‘brain fog’ whilst trying to resume and maintain activities of daily living and other forms of exercise. Theme four illustrates the battle with self-concept to accept reduced function (even temporarily) and the fear of permanent reduction in physical and cognitive ability.ConclusionsThis study provides insight into the challenges of managing physical activity alongside the extended symptoms associated with Long Covid. Findings highlight the need for greater consensus around physical activity-related advice for people with Long Covid and improved support to resume activities considered important for wellbeing.Article SummaryStrengths and limitations of this studyTo our knowledge, this paper is the first to explore the role of physical activity in the lived experience of Long Covid using a qualitative approachThe study design enabled in-depth inquiry of lived experiences in a diverse sampleInductive thematic analysis ensured descriptions and interpretations of the lived experience were tested and found to be grounded in the dataParticipants were recruited from members of a Long Covid research interest database who registered via an on-line form, meaning study findings might not capture the views of digitally excluded populationsFunding statementThis work was supported by Sheffield Hallam University.Competing interestsAll authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Association between Participation in Government Subsidy Program for Domestic Travel and Symptoms Indicative of COVID-19 Infection
Authors: Miyawaki Atsushi , Tabuchi Takahiro , Tomata Yasutake , Tsugawa Yusuke 
Published: December 2020

ABSTRACTImportanceAs countermeasures against the economic downturn caused by the coronavirus 2019 (COVID-19) pandemic, many countries have introduced or considering financial incentives for people to engage in economic activities such as travel and use restaurants. Japan has implemented a large-scale, nationwide government-funded program that subsidizes up to 50% of all travel expenses since July 2020 with the aim of reviving the travel industry. However, it remains unknown as to how such provision of government subsidies for travel impacted the COVID-19 pandemic.ObjectiveTo investigate the association between participation in government subsidies for domestic travel in Japan and the incidence of COVID-19 infections.Design, Setting, and ParticipantsUsing the data from a large internet survey conducted between August 25 and September 30, 2020, in Japan, we examined whether individuals who used subsidies experienced a higher likelihood of symptoms indicative of the COVID-19 infection.ExposureParticipation in the government subsidy program for domestic travel.Main Outcomes and MeasuresFive symptoms indicative of the COVID-19 infection (high fever, sore throat, cough, headache, and smell and taste disorder) within the past one month of the survey.ResultsOf the 25,482 respondents (50.3% [12,809] women; mean [SD] age, 48.4 [17.4] years), 3,289 (12.9%) participated in the subsidy program at the time of survey. After adjusting for potential confounders, we found that participants in the subsidy program exhibited higher incidence of high fever (adjusted rate, 4.8% for participants vs. 3.7% for non-participants; adjusted odds ratio [aOR], 1.90; 95%CI, 1.42-2.54; p<0.001), sore throat (19.8% vs. 11.3%; aOR, 2.09; 95%CI, 1.37-3.20; p=0.002), cough (19.1% vs. 11.2%; aOR 1.96; 95%CI, 1.27-3.02; p=0.007), headache (29.1% vs. 25.5%; aOR, 1.24; 95%CI, 1.07-1.43; p=0.007), and smell and taste disorder (2.6% vs. 1.8%; aOR 1.98; 95%CI; 1.15-3.40; p=0.01) compared with non-participants.Conclusion and RelevanceThe participants of government subsidies for domestic travel experienced a higher incidence of symptoms indicative of the COVID-19 infection.
Opportunities to catalyze improved healthcare access in pluralistic systems: a cross-sectional study in Haiti
Authors: Klarman Molly B , Schon Justin , Cajusma Youseline , Maples Stace , Beau de Rochars Valery M , Baril Chantale , Nelson Eric J 
Published: December 2020

SUMMARYIntroductionGains to ensure global healthcare access are at risk of stalling because some old resilient challenges require new solutions. Our objective was to study a pluralistic healthcare system that is reliant on both conventional and non-conventional providers to discover opportunities to catalyze renewed progress.MethodsA cross-sectional study was conducted among households with children less than 5 years of age in Haiti. Households were randomly sampled geographically with stratifications for population density. Household questionnaires with standardized cases (intentions) were compared to self-recall of health events (behaviors). The connectedness of households and their providers was determined by network analysis.ResultsA total of 568 households (incorporating 2900 members) and 65 providers were enrolled. Households reported 636 health events in the prior month. Households sought care for 35% (n=220) and treated with home remedies for 44% (n=277). The odds of seeking care increased 217% for severe events (aOR=3.17; 95%CI 1.99-5.05; p< 0.001). The odds of seeking care from a conventional provider increased by 37% with increasing distance (aOR=1.37; 95%CI 1.06-1.79; p=0.016). Despite stating an intention to seek care from conventional providers, there was a lack of congruence in practice that favored non-conventional providers (McNemar’s Chi-squared Test p<0.001). Care was sought from primary providers for 68% (n=150) of cases within a three-tiered network; 25% (n=38/150) were non-conventional.ConclusionAddressing geographic barriers, possibly with technology solutions, should be prioritized to meet healthcare seeking intentions while developing approaches to connect non-conventional providers into healthcare networks when geographic barriers cannot be overcome.Article SummaryThe study is inclusive of both conventional and non-conventional healthcare providers, reflecting Haiti’s pluralistic healthcare system.The study utilized randomized geospatial sampling method to ensure participants were geographically representative of all families in the study area.Employed an unique application of network analysis to observe relationships between families and healthcare providers to identify approaches to increase healthcare access in seemingly change resilient pluralistic systems.A limitation of the approach to compare healthcare seeking intentions and behaviors was that the standardized case scenarios did not cover all health event scenarios.A limitation on enrollment was that non-conventional healthcare providers were more difficult to locate than conventional providers.
Risk factors for severe illness and death in COVID-19: a systematic review and meta-analysis
Authors: Degarege Abraham , Naveed Zaeema , Kabayundo Josiane , Brett-Major David 
Published: December 2020

AbstractObjectivesThis systematic review and meta-analysis synthesized the evidence on the impact of demographics and comorbidities with clinical outcomes of COVID-19, including severe illness, admission to the intensive care unit (ICU), and death.MethodsThe PRISMA guidelines were followed to conduct and report this meta-analysis. The protocol is registered in PROSPERO International prospective register of systematic reviews (ID=CRD42020184440). Two authors independently searched literature from PubMed, Embase, Cochrane library and CINHAL on May 6, 2020; removed duplicates; screened titles, abstracts and full text using criteria; and extracted data from eligible articles. A random-effects model was used to estimate the summary odds ratio (OR). Variations among studies were examined using Cochrane Q and I2.ResultsOut of 4,275 articles obtained from the databases and screened, 71 studies that involved 216,843 patients were abstracted and then, where appropriate, analyzed by meta-analysis. The COVID-19 related outcomes reported were death in 26 studies, severe illness in 41 studies, and admission to ICU in 11 studies. Death was significantly correlated with hypertension (OR 2.60, 95% CI 1.95–3.25, I2 = 52.6%, n= 13 studies), cardiovascular disease (5.16, 4.10–6.22, 0.0%, 6), diabetes (2.11, 1.35–2.87, 67.4%, 12), chronic respiratory disease (2.83, 2.14–3.51, 0.0%, 9), cerebrovascular diseases (5.14, 1.08–9.19, 0.0%, 2), male sex (1.34, 1.18 1.50, 38.7%, 16), age older than 60 (6.09, 3.53 8.66, 95.5%, 6) or 65 years (3.56, 1.21 5.90, 18.2%, 6). Severe illness was also significantly associated with hypertension (1.70, 1.30 –2.10, 47.8%, 21), cardiovascular diseases (2.04, 1.01–3.08, 30.6%, 10), diabetes (1.65, 1.23–2.08, 24.9%, 18), male sex (1.35, 1.23 1.47, 0.0%, 32) and age at least 60 (4.91, 1.35 8.47, 0.0%, 4) or 65 (2.55,1.94 3.17, 24.5%, 9) years. Among hospitalized patients, the odds of admission to ICU was greater in individuals who had cardiovascular diseases (1.36,1.04–1.69, 0.0%, 4), diabetes (1.55, 1.20–1.90, 0.0%, 5) and chronic respiratory disease (1.52, 1.09–1.94, 0.0%, 5) than those who were not having these comorbidities.ConclusionsOlder age and chronic diseases increase the risk of developing severe illness, admission to ICU and death among COVID-19 patients. Special strategies are warranted to prevent SARS-CoV-2 infection and manage COVID-19 cases in those with vulnerabilities.
MACE2K: A Text-Mining Tool to Extract Literature-based Evidence for Variant Interpretation using Machine Learning
Authors: Gupta Samir , Rao Shruti , Miglani Trisha , Iyer Yasaswini , Lin Junxia , Saiyed Ahson M. , Ikwuemesi Ifeoma , McNulty Shannon , Thaxton Courtney , Madhavan Subha 
Published: December 2020

AbstractInterpretation of a given variant’s pathogenicity is one of the most profound challenges to realizing the promise of genomic medicine. A large amount of information about associations between variants and diseases used by curators and researchers for interpreting variant pathogenicity is buried in biomedical literature. The development of text-mining tools that can extract relevant information from the literature will speed up and assist the variant interpretation curation process. In this work, we present a text-mining tool, MACE2k that extracts evidence sentences containing associations between variants and diseases from full-length PMC Open Access articles. We use different machine learning models (classical and deep learning) to identify evidence sentences with variant-disease associations. Evaluation shows promising results with the best F1-score of 82.9% and AUC-ROC of 73.9%. Classical ML models had a better recall (96.6% for Random Forest) compared to deep learning models. The deep learning model, Convolutional Neural Network had the best precision (75.6%), which is essential for any curation task.
Serine Palmitoyltransferase Controls Stemness of Intestinal Progenitors
Authors: Li Ying , Chaurasia Bhagirath , Kaddai Vincent , Wilkerson Joseph L. , Alan Maschek J. , Cox James , Wei Peng , Bensard Claire , Meikle Peter J , Clevers Hans , Shayman James A , Hirabayashi Yoshio , Holland William L. , Rutter Jared , Summers Scott A. 
Published: December 2020

SummaryCancers of the gastrointestinal tract including esophageal adenocarcinomas, colorectal cancers, and cancers of the gastric cardia are common comorbidities of obesity. Excessive delivery of macronutrients to the cells lining the gut can increase one’s risk for these cancer by inducing imbalances in the rate of intestinal stem cell proliferation vs. differentiation, which can produce polyps and other aberrant growths. We demonstrate that serine palmitoyltransferase (SPT), which diverts dietary fatty and amino acids into the sphingolipid biosynthesis pathway, is a critical modulator of intestinal stem cell homeostasis. SPT and other enzymes in the biosynthetic pathway are upregulated in human colon tumors. These enzymes produce sphingolipids that serve as pro-stemness signals that stimulate peroxisome-proliferator activated receptor alpha (PPARα)-mediated induction of fatty acid binding protein-1. This increases fatty acid uptake and oxidation and enhances the stemness program. Serine palmitoyltransferase thus serves as a critical link between dietary macronutrients, epithelial regeneration, and cancer risk.
Efferent control of hearing sensitivity and protection via inner ear supporting cells
Authors: Zhao Hong-Bo , Liu Li-Man , Yu Ning , Zhu Yan , Mei Ling , Chen Jin , Liang Chun 
Published: December 2020

SummaryIt is well-known that medial olivocochlear (MOC) efferent nerves innervate outer hair cells (OHCs) and inhibit OHC electromotility to control hearing sensitivity. Here, we report that the MOC nerve fibers associated with MOC neurotransmitter acetylcholine (ACh) receptors and presynaptic vesicular acetylcholine transporters (VAChT) also innervated the cochlear supporting cells (SCs). Application of ACh could evoke inward currents in SCs and reduced gap junctions (GJs) between them with long-lasting effect. We further found that uncoupling of GJs between SCs shifted OHC electromotility to the left hyperpolarization direction and enhanced the direct effect of ACh on OHC electromotility. Diminution of this control by deficiency of GJs between SCs compromised the regulation of active cochlear amplification and increased susceptibility to noise. These data suggest that the MOC efferent system has functional innervations with SCs. Such efferent innervation may have an important role in the protection of hearing from noise and slow efferent effect.
Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, while the Alzheimer’s R47H mutant does the opposite
Authors: Vilalta Anna , Zhou Ye , Sevalle Jean , Griffin Jennifer K. , Satoh Kanayo , Allendorf David H. , De Suman , Puigdellívol Mar , Bruzas Arturas , Burguillos Miguel A. , Dodd Roger B. , Chen Fusheng , Zhang Yalun , Flagmeier Patrick , Needham Lisa-Maria , Enomoto Masahiro , Qamar Seema , Henderson James , Walter Jochen , Fraser Paul E. , Klenerman David , Lee Steven F. , St George-Hyslop Peter , Brown Guy C. 
Published: December 2020

AbstractMissense mutations (e.g. R47H) of the microglial receptor TREM2 increase risk of Alzheimer’s disease (AD), and the soluble ectodomain of wild-type TREM2 (sTREM2) appears to protect in vivo, but the underlying mechanisms are unclear. We show that Aβ oligomers bind to TREM2, inducing shedding of sTREM2. Wild-type sTREM2 inhibits Aβ oligomerization, fibrillization and neurotoxicity, and disaggregates preformed Aβ oligomers and protofibrils. In contrast, the R47H AD-risk variant of sTREM2 is less able to bind and disaggregate oligomeric Aβ, but rather promotes Aβ protofibril formation and neurotoxicity. Thus, in addition to mediating phagocytosis, wild-type TREM2 may protect against amyloid pathology by Aβ-induced release of sTREM2 that blocks Aβ aggregation and neurotoxicity; while R47H sTREM2 promotes Aβ aggregation into neurotoxic forms, which may explain why the R47H variant gene increases AD risk several fold.