bluuebunny/crossref_metadata_2025_split huggingface dataset:
Experiment aversion among clinicians and the public — an obstacle to evidence-based medicine and public health
Authors: Vogt Randi L. , Heck Patrick R. , Mestechkin Rebecca M. , Heydari Pedram , Chabris Christopher F. , Meyer Michelle N. 
Published: April 2023

AbstractBackgroundRandomized controlled trials (RCTs) are essential for determining the safety and efficacy of healthcare interventions. However, both laypeople and clinicians often demonstrate experiment aversion: preferring to implement either of two interventions for everyone rather than comparing them to determine which is best. We studied whether clinician and layperson views of pragmatic RCTs for Covid-19 or other interventions became more positive early in the pandemic, which increased both the urgency and public discussion of RCTs.MethodsWe conducted several survey studies with laypeople (totaln=2,909) and two with clinicians (n=895;n=1,254) in 2020 and 2021. Participants read vignettes in which a hypothetical decision-maker who sought to improve health could choose to implement intervention A for all, implement intervention B for all, or experimentally compare A and B and implement the superior intervention. Participants rated and ranked the appropriateness of each decision.ResultsCompared to our pre-pandemic results, we found no decrease in laypeople’s aversion to non-Covid-19 experiments involving catheterization checklists and hypertension drugs. Nor were either laypeople or clinicians less averse to Covid-19 RCTs (concerning corticosteroid drugs, vaccines, intubation checklists, proning, school reopening, and mask protocols), on average. Across all vignettes and samples, levels of experiment aversion ranged from 28% to 57%, while levels of experiment appreciation (in which the RCT is rated higher than the participant’s highest-rated intervention) ranged from only 6% to 35%.ConclusionsAdvancing evidence-based medicine through pragmatic RCTs will require anticipating and addressing experiment aversion among both patients and healthcare professionals.
Redundancy, quality appraisal, and discordance in the results of systematic reviews of early mobilization of critically ill adults. A meta-research protocol
Authors: Gutierrez-Arias Ruvistay , Pieper Dawid , Nydahl Peter , González-Seguel Felipe , Jalil Yorschua , Oliveros Maria-Jose , Torres-Castro Rodrigo , Seron Pamela 
Published: April 2023

ABSTRACTIntroductionIn adult patients in intensive care units (ICU), early mobilization is one of the central non-pharmacological interventions studied for recovery from critical illness. Several systematic reviews (SRs) have been conducted to determine the effect of this intervention on ICU-acquired weakness (ICU-AW) with heterogeneous methodology and results. Redundancy in conducting SRs, unclear justification when leading new SRs or updating, and discordant results of SRs on the same research question may be generating research waste that makes it difficult for clinicians to keep up to date with the best available evidence. Therefore, this meta-research aims to assess the redundancy, methodological and reporting quality, and potential reasons for discordance in the results reported by SRs conducted to determine the effectiveness of early mobilization in critically ill adult patients on different clinical outcomes.MethodsA meta-research of early mobilization SRs in critically ill adult patients will be conducted. A sensitive search of MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCOhost), Cochrane Library, Epistemonikos, and other search resources will be conducted. Two independent reviewers will perform study selection, data extraction, and quality appraisal. Discrepancies will be resolved by consensus or a third reviewer. The redundancy of SRs will be assessed by the degree of overlap of primary studies. In addition, the justification for conducting new SRs will be evaluated with the “Evidence-Based Research” framework. The methodological quality of the SRs will be assessed with the AMSTAR 2 tool and the quality of the reports through compliance with the PRISMA statement. To assess the potential reasons for discordance in the results of the SRs, only SRs that an MA has carried out will be analyzed, considering divergence in results and their interpretation.Expected resultsThe analysis of this meta-research will assess the redundancy in the conducting of SR on the mobilization of critically ill adult patients, their methodological quality, and the quality of the reporting of their findings, as well as the causes of possible discrepancies between their results. These findings could guide the development of better and more timely SRs on the effectiveness of early mobilization of adult critically ill patients. The decrease in waste research could facilitate evidence-based decision-making by stakeholders.Registration numberosf.io/kxwq9
Time-of-day-dependent variation of the hepatic transcriptome and metabolome is disrupted in non-alcoholic fatty liver disease patients
Authors: Johanns Manuel , Haas Joel T. , Raverdy Violetta , Vandel Jimmy , Chevalier-Dubois Julie , Guille Loic , Derudas Bruno , Legendre Benjamin , Caiazzo Robert , Verkindt Helene , Gnemmi Viviane , Leteurtre Emmanuelle , Derhourhi Mehdi , Bonnefond Amélie , Froguel Philippe , Eeckhoute Jérôme , Lassailly Guillaume , Mathurin Philippe , Pattou François , Staels Bart , Lefebvre Philippe 
Published: April 2023

ABSTRACTLiver homeostasis is ensured in part by time-of-day-dependent processes, many of them being paced by the molecular circadian clock. Liver functions are compromised in non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), and clock disruption increases susceptibility to non-alcoholic fatty liver disease (NAFLD) progression in rodent models. We therefore investigated whether time-of-day-dependent transcriptome and metabolome are significantly altered in human NAFL and NASH livers. Liver biopsies, collected within an 8 hour- window from a carefully phenotyped cohort of 290 patients and histologically diagnosed to be either normal, NAFL or NASH hepatic tissues, were analyzed by RNA sequencing and unbiased metabolomic approaches. Time-of-day-dependent gene expression patterns and metabolomes were identified and compared between histologically normal, NAFL and NASH livers. We provide here a first-of-its-kind report of a daytime-resolved human liver transcriptome-metabolome and associated alterations in NAFLD. Transcriptomic analysis showed a robustness of core molecular clock components in NAFL and NASH livers. It also revealed stage-specific, time-of-day- dependent alterations of hundreds of transcripts involved in cell-to-cell communication, intra- cellular signaling and metabolism. Similarly, rhythmic amino acid and lipid metabolomes were affected in pathological livers. Both TNFa and PPARγ signaling are predicted as important contributors to altered rhythmicity. NAFLD progression to NASH perturbs time-of-day-dependent processes in human livers, while core molecular clock component differential expression is maintained.
Immunosuppression with Cyclosporine versus Tacrolimus shows distinctive nephrotoxicity profiles within renal compartments
Authors: Demirci Hasan , Popovic Suncica , Dittmayer Carsten , Yilmaz Duygu Elif , El-Shimy Ismail Amr , Mülleder Michael , Hinze Christian , Persson Pontus B. , Mutig Kerim , Bachmann Sebastian 
Published: April 2023

AbstractCalcineurin inhibitors (CNI) are the backbone for immunosuppression after solid organ transplantation. Although successful in preventing kidney transplant rejection, their nephrotoxic side effects notoriously contribute to allograft injury despite attempts to optimize their application, often with additional medications. Complex renal parenchymal damage occurs for cyclosporine A (CsA) as well as for the currently favoured tacrolimus (Tac). To test for distinct CsA and Tac damaging patterns, we combined multiomics analysis with histopathology from rat kidneys exposed to continuous CNI delivery. Damage forms varied strikingly. Both drugs caused significant albeit differential damage in vasculature and nephron. The glomerular filtration barrier was more affected by Tac than by CsA, showing prominent deteriorations in pore endothelium and podocytes along with impaired VEGF/VEGFR2 signaling and podocyte-specific gene expression. By contrast, proximal tubule epithelia were more severely affected by CsA than by Tac, revealing lysosomal dysfunction and enhanced apoptosis along with impaired proteostasis and oxidative stress. We conclude that pathogenetic alterations in renal microenvironments are specific for either treatment. Should this translate to the clinical setting, CNI choice should reflect individual risk factors for renal vasculature and tubular epithelia. As a step in this direction, we share products identified from multiomics for differential pathognomonic biomarkers.Translational StatementCalcineurin inhibitors (CNI) are first-choice immunosuppressive agents. Their nephrotoxic side effects may often limit their use. Tacrolimus is currently preferred to cyclosporine although its superiority remains unclear. Within the nephron, damage to the filtration barrier is greater for tacrolimus, whereas cyclosporine side effects locate more to the proximal tubular epithelium when compared in our rodent model. We identify the distinctive location and nature of damage by both drugs and unravel involved mechanisms. By detecting differential protein signatures we make available pathognomonic biomarkers for renal allograft health under CNI treatment.
Metabolic signatures of cardiorenal dysfunction in plasma from sickle cell patients, as a function of therapeutic transfusion and hydroxyurea treatment
Authors: D’Alessandro Angelo , Nouraie S. Mehdi , Zhang Yingze , Cendali Francesca , Gamboni Fabia , Reisz Julie A. , Zhang Xu , Bartsch Kyle W. , Galbraith Matthew D. , Espinosa Joaquin M. , Gordeuk Victor R. , Gladwin Mark T 
Published: April 2023

AbstractMetabolomics studies in sickle cell disease (SCD) have been so far limited to tens of samples, owing to technical and experimental limitations. To overcome these limitations, we performed plasma metabolomics analyses on 596 samples from patients with sickle cell sickle cell disease (SCD) enrolled in the WALK-PHaSST study. Clinical covariates informed the biological interpretation of metabolomics data, including genotypes (hemoglobin SS, hemoglobin SC), history of recent transfusion (HbA%), response to hydroxyurea treatment (HbF%). We investigated metabolic correlates to the degree of hemolysis, cardiorenal function, as determined by tricuspid regurgitation velocity (TRV), estimated glomerular filtration rate (eGFR), and overall hazard ratio (unadjusted or adjusted by age). Recent transfusion events or hydroxyurea treatment were associated with elevation in plasma free fatty acids and decreases in acyl-carnitines, urate, kynurenine, indoles, carboxylic acids, and glycine- or taurine-conjugated bile acids. High levels of these metabolites, along with low levels of plasma S1P and L-arginine were identified as top markers of hemolysis, cardiorenal function (TRV, eGFR), and overall hazard ratio. We thus uploaded all omics and clinical data on a novel online portal that we used to identify a potential mechanism of dysregulated red cell S1P synthesis and export as a contributor to the more severe clinical manifestations in patients with the SS genotype compared to SC. In conclusion, plasma metabolic signatures – including low S1P, arginine and elevated kynurenine, acyl-carnitines and bile acids - are associated with clinical manifestation and therapeutic efficacy in SCD patients, suggesting new avenues for metabolic interventions in this patient population.
Validity of Dried Blood Spot Testing for Sexually Transmitted and Blood-Borne Infections: A Narrative Systematic Review
Authors: Cholette François , Périnet Simone , Neufeld Bronwyn , Bryson Maggie , Macri Jennifer , Sibley Kathryn M. , Kim John , Driedger S. Michelle , Becker Marissa L. , Sandstrom Paul , Meyers Adrienne F. A. , Paquette Dana 
Published: April 2023

AbstractObjectiveTesting for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) using dried blood spot (DBS) specimens has been an integral part of bio-behavioural surveillance in Canada for almost two decades. A systematic review was conducted to assess the current evidence regarding the validity of sexually transmitted and blood-borne infection (STBBI) testing using DBS specimens.MethodsA literature search was conducted using a peer-reviewed search strategy. Eligibility criteria included studies reporting use of DBS specimens for STBBI testing in populations 15 years of age or older. The intervention of interest was either commercially available or “in-house” tests used to detect STBBI from DBS specimens. Studies that reported a measure of validity such as sensitivity, specificity, positive and negative predictive values were eligible for inclusion. Quality of studies and risk of bias were assessed using the QUADAS-2 tool.ResultsA total of 6,706 records were identified. Of these records, 169 full-text articles met the criteria for inclusion. The STBBI with the most articles reporting a measure of validity for testing on DBS was HIV (n=73), followed by HCV (n=63), HBV (n=33), syphilis (n=7), HAV (n=5), HSV (n=5), HTLV (n=3), and HPV (n=1). The majority of studies reported high sensitivity (≥90%) and specificity (≥90%). However, the quality of the studies varied greatly. No evidence was found on the validity of chlamydia and gonorrhoea testing using DBS specimens.ConclusionOur findings support the validity of DBS testing for STBBI surveillance where sufficient evidence was available, but validity is highly dependent on thorough method development and validation.
Mandatory membership of community-based mutual health insurance in Senegal: A national survey
Authors: Ridde Valéry , Gaye Ibrahima , Ventelou Bruno , Paul Elisabeth , Faye Adama 
Published: April 2023

ABSTRACTWith the low adhesion to voluntary mutual health insurance, Senegal’s policymakers have sought to understand the feasibility of compulsory health insurance membership. This study aims to measure the acceptability of mandatory membership in community-based mutual health insurance (CBHI) and to understand its possible administrative modalities.The study consists of a national survey among a representative population sample selected by marginal quotas. The survey was conducted in 2022 over the phone, with the random composition method among 914 people. The questionnaire measured the socio-economic characteristics of households, their level of acceptability concerning voluntary and compulsory membership, and their level of confidence in CBHIs and the health system.Respondents preferred voluntary (86 %) over mandatory (70 %) membership of a CBHI. The gap between voluntary and compulsory membership scores was smaller among women (p=0.040), people under 35 (p=0.033) and people with no health coverage (p=0.011). Voluntary or compulsory membership was correlated (p=0.000) to trust in current CBHIs and health systems. No particular preference emerged as for the preferred administrative channel (e.g. death certificate, identity card, etc.) which could enable to enforce the mandatory character.The results confirmed the well-known challenges of building universal health coverage on the basis of CBHIs, a model which is poorly appreciated and whose low performance reduces the acceptability of populations to adhere to it, be it on a voluntary or mandatory basis. Suppose Senegal persists in its health insurance approach. In that case, it will be essential to strengthen the performance and funding of CBHIs, and to gain population trust to enable a mandatory or more systemic membership.
A protocol for a systematic critical realist synthesis of school mindfulness interventions designed to promote pupils’ mental wellbeing
Authors: Abbott Pamela , Nixon Graeme , Stanley Isabel , D’Ambruoso Lucia 
Published: April 2023

AbstractIntroductionThe review described in this protocol will be the first critical realist review of the literature reporting on the impact of mindfulness interventions in schools on the mental wellbeing of pupils. Mindfulness interventions are increasingly being introduced into schools to promote children’s (and teachers’) wellbeing. Findings from impact evaluations, including systematic reviews and metanalysis, suggest that school-based mindfulness interventions promote pupils’ wellbeing. However, there is a need for further evidence on how they work and for whom and under what circumstances.Methods and analysisA critical realist review methodology will be used to provide a causal interdisciplinary understanding of how mindfulness interventions in schools promote the mental wellbeing of pupils. This will be done through a systematic literature review and extrapolating context, agency, intervention, mechanisms, and outcome configurations. This will enable us to understand how in certain contexts, pupils can use the resources offered by a mindfulness intervention to trigger mechanisms that promote their mental wellbeing and what mechanisms in the context support, restrict or prevent change. We will then use retrodiction and retroduction to develop the most plausible interdisciplinary middle-range theory to explain the findings.DiscussionThe review findings will inform a critical realist evaluation of a mindfulness intervention in schools that we will be carrying out. The findings from the review will enable us to inform policymakers and other stakeholders about what conditions need to be in place for mindfulness interventions to promote pupils’ mental wellbeing and for which pupils. We will publish the findings from the review in academic and professional publications, policy briefs, workshops, conferences, and social media.
Inflammatory cytokines and a diverse cervicovaginal microbiome are associated with cervical disease in Hispanics living in Puerto Rico
Authors: Tosado-Rodríguez Eduardo , Mendez Loyda B. , Espino Ana M. , Dorta-Estremera Stephanie , Aquino Edna E. , Romaguera Josefina , Godoy-Vitorino Filipa 
Published: April 2023

AbstractCervical cancer (CC) is women’s fourth most common cancer worldwide. A worrying increase in CC rates in Hispanics suggests that besides Human Papillomaviruses infections, there may be other biological causes promoting the disease. We hypothesized that the cervical microbiome and the epithelial microenvironment favoring inflammation is conducive to disease progression. There is a lack of studies examining the part played by microbial populations in the development of precancerous lesions into cancer in Hispanic women. We aimed to investigate the relationship between the cervicovaginal microbiome and inflammation in Hispanic women living in PR while considering cervical neoplasia and HPV infection. Cervical samples collected from 91 participants coming to clinics in San Juan, underwent 16S rRNA genes (V4 region) profiling, and cytokines were measured using Luminex MAGPIX technology. Cytokines were grouped as inflammatory (IL-1β, TNFα, IFNγ, IL-6), anti-inflammatory (IL-4, IL-10, TGFβ1), and traffic-associated (IL-8, MIP1a, MCP1, IP10). They were related to microbes via an inflammation scoring index based on the quartile and tercile distribution of the cytokine’s concentration. We found significant differences in the diversity and composition of the microbiota according to HPV risk, cervical disease, and cytokine abundance. The most dominant community state type (CST) was CST IV with ∼ 90% dominance in participants with high-grade squamous intraepithelial lesions and high-risk HPV. The increasing concentration of pro-inflammatory cytokines was associated with a decrease inL. crispatus. In contrast, dysbiosis-associated bacteria such asGardnerella,Prevotella,Atopobiumconcomitantly increased with pro-inflammatory cytokines. Our study highlights that the cervical microbiota of Hispanics living in PR is characteristically diverse, regardless of HPV status and that dysbiosis associated with a decrease inLactobacillusmarks inflammatory processes. Therefore, the joint host-microbe interaction analyses via cytokine signaling and microbiota in precancerous lesions is confirmed to have great translational potential.
Multicellular, IVT-derived, unmodified human transcriptome for nanopore-direct RNA analysis
Authors: McCormick Caroline A. , Akeson Stuart , Tavakoli Sepideh , Bloch Dylan , Klink Isabel N. , Jain Miten , Rouhanifard Sara H. 
Published: April 2023

ABSTRACTNanopore direct RNA sequencing (DRS) enables measurements of RNA modifications. Modification-free transcripts are a practical and targeted control for DRS, providing a baseline measurement for canonical nucleotides within a matched and biologically derived sequence context. However, these controls can be challenging to generate and carry nanopore-specific nuances that can impact analysis. We produced DRS datasets using modification-free transcripts fromin vitrotranscription (IVT) of cDNA from six immortalized human cell lines. We characterized variation across cell lines and demonstrated how these may be interpreted. These data will serve as a versatile control and resource to the community for RNA modification analysis of human transcripts.
Where Initial rates are directly proportional to Substrate concentrations with Application in Molar-mass Determination, Zero-order Specificity constant is Inappropriate
Authors: Udema Ikechukwu Iloh 
Published: April 2023

ABSTRACTBackground“High-ranking scientists” employ the initial rate (vi), expression without consideration for the conditions under which theviexpression can be used. The consequence is the suggestion that theviis equal to the product of maximum velocity,Vmax, andsubstrate concentration [S0] divided by the Michaelis-Menten constant,KM.ObjectivesThe main objectives are: 1) to show thatviis not equal toVmax[S0]/KM; 2) to show that the equilibrium dissociation constant,Kd, is strictly proportional to the concentration ([E0]) of the enzyme; and 3) to show that the two standard quasi-steady-state assumptions (sQSSA) and reverse QSSA (rQSSA) have a limited domain of validity.MethodsThe study was experimental and theoretical, supported by the Bernfeld method of enzyme assay.ResultKdis directly proportional to [E0], andviis not equal toVmax[S0]/KM.. AKM-like value that is greater than the putativeKdvalue, 2.482 g/L, is equal to 2.569 g/L. TheKM-like values in other situations are 2.396 and 2.407 g/L; the corresponding equilibrium dissociation constant (Kd) values are, respectively, 2.288 and 2.299 g/L; the molar mass of insoluble potato starch ranges between 62.296 and 65.616 exp. (+6) g/mol.ConclusionThe equations that invalidate the assumption thatviis equal toVmax[S0]/KMwhenever [S0] is much less thanKMwere derived; the proposition thatKdis strictly proportional to [E0] was confirmed; the molar mass of starch could be calculated from the derived equation; and it was shown graphically and mathematically that both the sQSSA and rQSSA domains have a limit of validity; the equation with which to calculate the second order rate constant based on the conditions that validate the rQSSA is not applicable to the sQSSA. AKM-like value that is greater than the putativeKdvalue is possible.GRAPHICAL ABSTRACTThe graphical abstract illustrates three zones: the zone in which the sQSSA is valid, the zone in which the rQSSA is valid, and the zone in which neither assumption is exclusively valid. The curved arrow (oxblood) pointing to the red line depicts a tendency towards conditions that validate the rQSSA if the assay is conducted with an appropriate [S0]/[E0] ratio (< 1 to ≪1) while the red curved arrow pointing to the blue line depicts a tendency towards conditions that validate the sQSSA if the assay is conducted with an appropriate [S0]/[E0] ratio (>1 to ≫1). The enzyme-substrate complex (ES) is in a quasi-steady state with respect to S as depicted by ∂ [ES]/ ∂t≈0, the sQSSA case, while in the rQSSA, it is the S that is in a quasi-steady state with respect to ES as depicted by ∂[S0]/∂t≈0. The double-headed arrow merely shows, artistically, the limit of the data points.