bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Proportion of Randomized Controlled Trials That Inform Clinical Practice: A Longitudinal Cohort Study of Trials Registered on ClinicalTrials.gov
Authors: Hutchinson Nora , Moyer Hannah , Zarin Deborah A. , Kimmelman Jonathan 
Published: May 2022

AbstractBackgroundPrior studies suggest that clinical trials are often hampered by problems in design, conduct and reporting that limit their uptake in clinical practice. We have described “informativeness” as the ability of a trial to guide clinical, policy or research decisions. Little is known about the proportion of initiated trials that inform clinical practice.MethodsWe created a cohort of randomized interventional clinical trials in three disease areas (ischemic heart disease, diabetes mellitus and lung cancer), that were initiated between 1 January 2009 and 31 December 2010 using ClinicalTrials.gov. We restricted inclusion to trials aimed at answering a clinical question related to the treatment or prevention of disease. Our primary outcome was the proportion of clinical trials fulfilling four conditions of informativeness: importance of the clinical question, trial design, feasibility, and reporting of results.ResultsOur study included 125 clinical trials. The proportion meeting four conditions for informativeness was 26.4% (95% CI 18.9 – 35.0). Sixty-seven percent of participants were enrolled in informative trials. The proportion of informative trials did not differ significantly between our three disease areas.ConclusionsOur results suggest that the majority of clinical trials designed to guide clinical practice possess features that may compromise their ability to do so. This highlights opportunities to improve the scientific vetting of clinical research.FundingThis study was funded by the Fonds de recherche Santé Québec postdoctoral research grant (NH). This funding body was not involved in study design, conduct or reporting.
The impact of sampling bias on viral phylogeographic reconstruction
Authors: Liu Pengyu , Song Yexuan , Colijn Caroline , MacPherson Ailene 
Published: May 2022

AbstractGenomic epidemiology plays an ever-increasing role in our understanding of and response to the spread of infectious pathogens. Phylogeography, the reconstruction of the historical location and movement of pathogens from the evolutionary relationships among sampled pathogen sequences, can inform policy decisions related to viral movement among jurisdictions. However, phylogeographic reconstruction is impacted by the fact that the sampling and virus sequencing policies differ among jurisdictions, and these differences can cause bias in phylogeographic reconstructions. Here we assess the potential impacts of geographic-based sampling bias on estimated viral locations in the past, and on whether key viral movements can be detected. We quantify the effect of bias using simulated phylogenies with known geographic histories, and determine the impact of the biased sampling and of the underlying migration rate on the accuracy of estimated past viral locations. We then apply these insights to the geographic spread of Ebolavirus in the 2014-2016 West Africa epidemic. This work highlights how sampling policy can both impact geographic inference and be optimized to best ensure the accuracy of specific features of geographic spread.
Outcomes of open transverse abdominis release for ventral hernias- A systematic review, meta-analysis and meta-regression of factors affecting them
Authors: Vasavada Bhavin B , Patel Hardik 
Published: May 2022

AbstractObjectivesThe primary objectives were to evaluate Surgical Site Occurrences (SSO) and Surgical Site Occurrences requiring procedural Intervention (SSOPI) after open transversus abdominis release and to study various factors affecting it. Secondary objectives were to evaluate Surgical Site Infections (SSI), recurrence rates and overall complications after transversus abdominis release (TAR) and the factors responsible for those.MethodsWe searched PUBMED, SCOPUS and Cochrane databases with keywords “transversus abdominis release” or “TAR” OR “Surgical Site Occurrences” OR “posterior component separation AND “outcomes” as per PRISMA 2020 and MOOSE guidelines. Full texts and English literature studies were included, studies mentioning outcomes for open transversus abdominis release for ventral hernia were included and studies with robotic transversus abdominis release were excluded. Percentage occurrences of SSO, SSOPI, SSI, recurrence and overall complications after TAR were evaluated. Random effect meta-analysis with restricted maximum likehood methods was used for meta-analysis. Heterogeneity was analysed using I2 statistics. Publication bias with eager’s test and funnel plots. Meta0regression analysis was done to evaluate factors affecting the heterogeneity. JASP 0.16.2 software was used for meta-analysis.ResultsTwenty two studies including 5284 patients who underwent TAR for ventral hernia were included in systematic review and meta-analysis. Overall pooled SSO, SSOPI, Overall Complications, SSI and recurrence rates were 21.72% [95% C.I 17.18-26.27%], 9.82% [95% C.I 7.64 −12%], 33.34% [95% C.I. 27.43-39.26%], 9.13% [95% 6.41-11.84] and 1.6% [0.78-2.44] respectively. Heterogeneity was significant in all the analysis. Age (p<0.001),sex (p<0.001), BMI (p<0.001),presence of comorbidities (p<0.001), prior recurrence, defect size (p<0.001) and current or past history of tobacco exposure were associated with SSO in multivariate meta-regression analysis. Defect size (p=0.04) was associated with SSOPI. Age (p=0.011), BMI (p=0.013), comorbidities (p<0.01), tobacco exposure (p=0.018),prior recurrence (p <0.01) and sex (p < 0.01) were associated with overall complications.ConclusionOpen transversus abdominis release is associated with high rates of SSO, SSOPI, SSI and overall complications but recurrence rates are low. Various preoperative factors mentioned may be responsible for heterogeneity across studies.
Laboratory diagnostic of acute kidney injury and its progression: risk of underdiagnosis in female and elderly patients
Authors: Kister Thea Sophie , Schmidt Maria , Heuft Lara , Federbusch Martin , Haase Michael , Kaiser Thorsten 
Published: May 2022

AbstractObjectiveAcute kidney injury (AKI) is a common disease, with high morbidity and mortality rates. In this study, we investigate the potential influence of sex and age on laboratory diagnostic and outcome. It is known that serum creatinine (SCr) has limitations as a laboratory diagnostic parameter for AKI due to its dependence on muscle mass, which may lead to incorrect or delayed diagnosis for certain patient groups, such as women and the elderly.MethodsOverall, 7592 cases with AKI, hospitalized at the University of Leipzig Medical Center (ULMC) between 1st January 2017 and 31st December 2019, were retrospectively analyzed. Diagnosis and staging of AKI was performed according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, based on the level and dynamics of SCr. The impact of sex and age was analyzed by the recalculation of a female to male and an old to young SCr using the CKD-EPI equation.ResultsThe incidence proportion of AKI in our study cohort was 12.0%, with progressive AKI occurring in 19.2% of these cases (n = 1458). Male cases with AKI were overrepresented (59.6%), with a significantly higher first (+3.5 ml/min) and last eGFR (+2.7 ml/min) (p < 0.001). The highest incidence proportion of AKI was found in the [61–81) age group in female (49.5%) and male (52.7%) cases. Males with progressive AKI were overrepresented (p = 0.04). By defining and staging AKI on the basis of relative and absolute changes in SCr level, it is more difficult for patients with low muscle mass and thus a lower baseline SCr to be diagnosed by an absolute SCr increase. AKIN1 and AKIN3 can be diagnosed by a relative or absolute change in SCr. In females, both stages were less frequently detected by an absolute criterion alone (AKIN1 ♀ 20.2%, ♂ 29.5%, p < 0.001; AKIN3 ♀ 13.4%, ♂ 15.2%, p < 0.001). A recalculated SCr for females (to males) and males (to young males) displayed the expected increase in AKI occurrence and severity with age and in general in females.ConclusionOur study illustrates how SCr as the sole parameter for diagnosis and staging of AKI bears the risk of underdiagnosis of patient groups with low muscle mass, such as women and the elderly. A sex- and age-adapted approach might offer advantages.
Modeling islet enhancers using deep learning identifies candidate causal variants at loci associated with T2D and glycemic traits
Authors: Hudaiberdiev Sanjarbek , Taylor D. Leland , Song Wei , Narisu Narisu , Bhuiyan Redwan M. , Taylor Henry J. , Yan Tingfen , Swift Amy J. , Bonnycastle Lori L. ,   DIAMANTE Consortium, Stitzel Michael L. , Erdos Michael R. , Ovcharenko Ivan , Collins Francis S. 
Published: May 2022

AbstractGenetic association studies have identified hundreds of independent signals associated with type 2 diabetes (T2D) and related traits. Despite these successes, the identification of specific causal variants underlying a genetic association signal remains challenging. In this study, we describe a deep learning method to analyze the impact of sequence variants on enhancers. Focusing on pancreatic islets, a T2D relevant tissue, we show that our model learns islet-specific transcription factor (TF) regulatory patterns and can be used to prioritize candidate causal variants. At 101 genetic signals associated with T2D and related glycemic traits where multiple variants occur in linkage disequilibrium, our method nominates a single causal variant for each association signal, including three variants previously shown to alter reporter activity in islet-relevant cell types. For another signal associated with blood glucose levels, we biochemically test all candidate causal variants from statistical fine-mapping using a pancreatic islet beta cell line and show biochemical evidence of allelic effects on TF binding for the model-prioritized variant. To aid in future research, we publicly distribute our model and islet enhancer perturbation scores across ∼67 million genetic variants. We anticipate that deep learning methods like the one presented in this study will enhance the prioritization of candidate causal variants for functional studies.
A homozygous p.(Arg371Ser) mutation in FICD de-regulates AMPylation of the human endoplasmic reticulum chaperone BiP causing infancy-onset diabetes and severe neurodevelopmental delay
Authors: Perera Luke A. , Hattersley Andrew T. , Harding Heather P. , Wakeling Matthew N. , Flanagan Sarah E. , Moshina Ibrahim , Raza Jamal , Gardham Alice , Ron David , De Franco Elisa 
Published: May 2022

ABSTRACTDysfunction of the endoplasmic reticulum (ER) in insulin-producing beta cells results in cell loss and diabetes mellitus. Here we report on 5 individuals from three different consanguineous families with infancy-onset diabetes mellitus and severe neurodevelopmental delay caused by a homozygous p.(Arg371Ser) mutation in FICD. The FICD gene encodes a bifunctional Fic domain-containing enzyme that regulates the ER Hsp70 chaperone, BiP, via catalysis of two antagonistic reactions: inhibitory AMPylation and stimulatory deAMPylation of BiP. Arg371 is a conserved residue in the Fic domain active site. The FICDR371S mutation partially compromises BiP AMPylation in vitro but eliminates all detectable deAMPylation activity. Overexpression of FICDR371S or knock-in of the mutation at the FICD locus of stressed CHO cells result in inappropriately elevated levels of AMPylated BiP. These findings, guided by human genetics, highlight the destructive consequences of de-regulated BiP AMPylation and raise the prospect of tuning FICD’s antagonistic activities towards therapeutic ends.
Self-medication practices and associated factors among COVID-19 recovered patients to prevent future infections: A web-based survey in Bangladesh
Authors: Sujan Md. Safaet Hossain , Haghighathoseini Atefehsadat , Tasnim Rafia , Islam Md. Saiful , Salauddin Sarif Mahammad , Hasan Mohammad Mohiuddin , Uddin Muhammad Ramiz 
Published: May 2022

AbstractBackgroundHuman health is largely affected by self-medication in both ways, adversely and favorably, as evidenced by the COVID-19 pandemic. The fear of spreading COVID-19 among health workers and hospital environments has led many Bangladeshi people to practice self-medicate for as a preventive strategy against this disease. Consequently, this practice entails an improper and injudicious use of medicine to cure self-recognized symptoms. To date, the COVID-19 has no effective treatment. The lack of a cure for COVID-19 and the continual progression of the diseases in educational settings induce a substantial population to practice self-medication. Therefore a study of self-medication practices is necessary for the framework of the pandemic. This study aimed to estimate the prevalence and factors associated with self-medication to prevent or manage future COVID-19 infections among recovered COVID-19 patients.MethodsThis cross-sectional study was conducted from September 2020 to February 2021 using an e-survey along with 360 participants. Data were collected using a pre-tested self-reported questionnaire. Descriptive statistics and correlations analysis were performed in the study.ResultsAmong 360 participants, males were 69.7%, and females 30.3%. The prevalence of self-medication is 11%, and monthly family income, residence, education, occupation, and previous history of SM are the associated factors. Among the participants, 29.7% use antibiotics, and 30% use herbal products or drugs as medication.ConclusionThe present study found SMP is moderately prevalent among COVID-19 recovered patients. To minimize the rate of SMP, adequate health care access systems and public education should be introduced, and media & community should be engaged in rational use of medication.
Dynamics of corticocortical brain functional connectivity relevant to therapeutic response to biologics in inflammatory arthritis
Authors: Abe Nobuya , Sakiyama Kodai , Fujieda Yuichiro , Tha Khin K. , Narita Hisashi , Karino Kohei , Kanda Masatoshi , Kono Michihito , Kato Masaru , Atsumi Tatsuya 
Published: May 2022

ABSTRACTAberrant resting-state static functional connectivity of the brain regions, which could be evaluated by functional magnetic resonance imaging (fMRI), affects clinical courses in inflammatory arthritis (IA) including rheumatoid arthritis and spondyloarthritis. This static methods for assessing brain functional connections would be too simple to estimate the whole picture of resting-state brain function because it fluctuates over time. The effects of resting-state brain connectivity dynamics for clinical course are unknown in patients with IA. Therefore, we aimed to evaluate dynamic functional connectivity for clinical courses of IA in the context of therapeutic responsiveness to biologics using resting-state fMRI data of 64 patients with IA consisting of two cohorts. We determined representative whole-brain dynamic functional connectivity patterns by k-means++ cluster analysis, and evaluated the association of their occurrence probability and therapeutic outcomes with biologics. We determined four distinct clusters of dynamic functional connectivity in IA patients. In the first cohort, occurrence probability of the distinct cluster was associated with favorable therapeutic response in disease activity and patients’ global assessment. This finding was validated by the second cohort. The whole-brain functional coordination of the cluster indicated significantly increased corticocortical connectivity, and probabilistically decreased after therapy in treatment-effective patients compared to -ineffective patients. In conclusion, dynamic functional connectivity, in particular, frequent emergence of corticocortical connections was associated with clinical outcomes in patients with IA. The coherence of corticocortical interactions might affect modulation of pain, which would be relevant to therapeutic satisfaction.SUMMARYEffects of resting-state dynamic connectivity on clinical course of inflammatory arthritis regarding therapeutic responsiveness to biologics were assessed by functional magnetic resonance.Occurrence probability of corticocortical functional connectivity pattern was associated with favorable therapeutic response in disease activity and patients’ global assessment in inflammatory arthritis.
Multi-omic comparative analysis of COVID-19 and bacterial sepsis-induced ARDS
Authors: Batra Richa , Whalen William , Alvarez-Mulett Sergio , Gómez-Escobar Luis G. , Hoffman Katherine L. , Simmons Will , Harrington John , Chetnik Kelsey , Buyukozkan Mustafa , Benedetti Elisa , Choi Mary E. , Suhre Karsten , Schenck Edward , Choi Augustine M.K. , Schmidt Frank , Cho Soo Jung , Krumsiek Jan 
Published: May 2022

AbstractBackgroundAcute respiratory distress syndrome (ARDS), a life-threatening condition characterized by hypoxemia and poor lung compliance, is associated with high mortality. ARDS induced by COVID-19 has similar clinical presentations and pathological manifestations as non-COVID-19 ARDS. However, COVID-19 ARDS is associated with a more protracted inflammatory respiratory failure compared to traditional ARDS. Therefore, a comprehensive molecular comparison of ARDS of different etiologies groups may pave the way for more specific clinical interventions.Methods and FindingsIn this study, we compared COVID-19 ARDS (n=43) and bacterial sepsis-induced (non-COVID-19) ARDS (n=24) using multi-omic plasma profiles covering 663 metabolites, 1,051 lipids, and 266 proteins. To address both between- and within-ARDS group variabilities we followed two approaches. First, we identified 706 molecules differently abundant between the two ARDS etiologies, revealing more than 40 biological processes differently regulated between the two groups. From these processes, we assembled a cascade of therapeutically relevant pathways downstream of sphingosine metabolism. The analysis suggests a possible overactivation of arginine metabolism involved in long-term sequelae of ARDS and highlights the potential of JAK inhibitors to improve outcomes in bacterial sepsis-induced ARDS. The second part of our study involved the comparison of the two ARDS groups with respect to clinical manifestations. Using a data-driven multi-omic network, we identified signatures of acute kidney injury (AKI) and thrombocytosis within each ARDS group. The AKI-associated network implicated mitochondrial dysregulation which might lead to post-ARDS renal-sequalae. The thrombocytosis-associated network hinted at a synergy between prothrombotic processes, namely IL-17, MAPK, TNF signaling pathways, and cell adhesion molecules. Thus, we speculate that combination therapy targeting two or more of these processes may ameliorate thrombocytosis-mediated hypercoagulation.ConclusionWe present a first comprehensive molecular characterization of differences between two ARDS etiologies – COVID-19 and bacterial sepsis. Further investigation into the identified pathways will lead to a better understanding of the pathophysiological processes, potentially enabling novel therapeutic interventions.
Population-based analysis ofPOT1variants in a cutaneous melanoma case-control cohort
Authors: Simonin-Wilmer Irving , Ossio Raul , Leddin Emmett , Harland Mark , Pooley Karen A. , Martil de la Garza Mauricio Gerardo , Obolenski Sofia , Hewinson James , Wong Chi C. , Iyer Vivek , Taylor John C. , Newton-Bishop Julia A. , Bishop D. Timothy , Cisneros G. Andrés , Iles Mark M. , Adams David J. , Robles-Espinoza Carla Daniela 
Published: May 2022

AbstractPathogenic germline variants in the protection of telomeres 1 gene (POT1) have been associated with predisposition to a range of tumor types, including melanoma, glioma, leukemia and cardioangiosarcoma. We sequenced all coding exons of thePOT1gene in 2,929 European-descent melanoma cases and 3,298 controls, identifying 43 protein-changing genetic variants. We performed POT1-telomere binding assays for all missense and stop gained variants, finding nine variants that impair or disrupt protein-telomere complex formation, and we further define the role of variants in the regulation of telomere length and complex formation through molecular dynamics simulations. We determine thatPOT1variants are a minor contributor to melanoma burden in the general population, with only about 0.5% of melanoma cases carrying germline pathogenic variants in this gene, but should be screened in individuals with a strong family history of melanoma and/or multiple malignancies.
Jinhua Qinggan Granules for Nonhospitalized COVID-19 Patients: a Double-Blind, Placebo-Controlled, Randomized Controlled Trial
Authors: Shah Muhammad Raza , Fatima Samreen , Khan Sehrosh Naz , Shafiullah  , Himani Gulshan , Wan Kelvin , Lin Timothy , Lau Johnson Y.N. , Liu Qingquan , Lam Dennis S.C. 
Published: May 2022

AbstractBackgroundKey findings from the World Health Organization Expert Meeting on Evaluation of Traditional Chinese Medicine in treating COVID-19 reported that TCMs are beneficial, particularly for mild-to-moderate cases. The efficacy of Jinhua Qinggan Granules (JHQG) in COVID-19 patients with mild symptoms has yet to be clearly defined.MethodsWe conducted a phase 2/3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with JHQG in mild, nonhospitalized, laboratory-confirmed COVID-19 patients. Participants were randomly assigned to receive 5g/sacket of JHQG or placebo granules orally thrice daily for 10 days. The primary outcomes were the improvement in clinical symptoms and proportion tested negative on viral PCR after treatment. Secondary outcomes were the time to recovery from clinical symptoms and changes in white blood cells (WBC) and acute phase reactants (C-reactive protein (CRP) and ferritin) 10-15 days after treatment.ResultsA total of 300 patients were randomly assigned to receive JHQG (150 patients) and placebo (150 patients). Baseline characteristics were similar in the two groups. In the modified intention-to-treat analysis, JHQG showed greater clinical efficacy (82.67%) after 10 days of treatment compared with the placebo group (10.74%) (rate difference: 71.93%; 95% CI 64.09 - 79.76). The proportion of patients with a negative PCR after treatment were comparable (rate difference: -4.67%; 95% CI -15.76 - 6.42). While all changes in WBC, ferritin, and CRP levels showed a statistically significant decline in JHQG (P≤0.044) after treatment, but not the latter in placebo (P=0.077). The median time to recovery of COVID-19 related symptoms including cough, sputum, sore throat, dyspnea, headache, nasal obstruction, fatigue, and myalgia were shorter in the JHQG group compared to the placebo group (P<0.001 for all). 3 patients experienced mild to moderate adverse events during the treatment period in the JHQG group. Findings were similar between the modified intention-to-treat and the per-protocol analysis that included only patients who reported 100% adherence to the assigned regimen.ConclusionsJHQG is a safe and effective TCM for the treatment of mild COVID-19 patients.Clinical Trial RegistrationThe Trial was prospectively registered on www.clinicaltrials.gov with registration number: NCT04723524.