bluuebunny/crossref_metadata_2025_split huggingface dataset:
Examining the evidence for Mendelian randomization homogeneity assumption violation using instrument association with exposure variance
Authors: Lyon Matthew S. , Millard Louise A. C. , Smith George Davey , Hartwig Fernando , Gaunt Tom R. , Tilling Kate 
Published: September 2022

AbstractBackgroundEstimation of the average causal effect using instrumental variable (IV) analyses requires homogeneity of instrument-exposure and/or exposure-outcome relationships. Previous research explored the validity of homogeneity assumptions by testing IV-exposure interaction effects using a set of effect modifiers. However, this approach requires that modifiers are known and measured but evidence for interaction may also be observed through IV association with exposure variance without knowledge of the modifier.MethodsWe explored the utility of testing for IV-exposure variance effects as evidence against homogeneity through simulation. We also evaluated the approach of removing IVs from Mendelian randomization (MR) analyses that show strong association with exposure variance (hence are likely to have heterogeneous effects). Our methodology was applied to evaluate homogeneity assumptions of LDL, urate and glucose on cardiovascular disease, gout, and type 2 diabetes, respectively.ResultsUnder simulation, interaction of IV-exposure and exposure-outcome effects by a single modifier led to bias of the estimated average causal effect (ACE) which could be partially assessed by testing for IV-exposure variance effects. Bias of the ACE attenuated after removing instruments with strong exposure variance effects. In applied analyses, we found no strong evidence of bias from the ACE.ConclusionsWe find no strong evidence against estimating the ACE for LDL, urate and glucose on cardiovascular disease, gout, and type 2 diabetes. These approaches could be used in future MR analyses to gain improved understanding of the causal estimand.Key messagesHomogeneity of the instrument-exposure and/or exposure-outcome effect is necessary to estimate the average causal effect which is important for developing health interventionsPartial evidence against the homogeneity assumption can be obtained from testing for the instrument-exposure variance effect which may suggest the presence of effect modificationThis evidence can be used in two ways: i) as a falsification approach to determine if the homogeneity assumption may be violated. ii) to remove genetic instruments from Mendelian randomization analyses providing an estimate that is closer to the average causal effectAfter removing instruments with exposure variance effects, the Mendelian randomization effect of LDL, urate and glucose on coronary heart disease, gout, and type 2 diabetes, respectively showed little difference suggesting no strong evidence against the average causal effect
Exercise prescription and strategies to promote the cross-education of strength: a scoping review
Authors: Voskuil Caleb C. , Andrushko Justin W. , Huddleston Boglarka S. , Farthing Jonathan P. , Carr Joshua C. 
Published: September 2022

AbstractObjectiveTo perform a scoping review of the literature on the experimental studies examining the role of resistance training frequency, intensity, the type of training, training volume, and adjuvant therapies on the cross-education of strength.Study DesignScoping Review.Literature SearchThe review was preregistered and performed with the search methodology described by the PRISMA extension for scoping reviews. CINAHL, MEDLINE, APA PsycInfo, SPORTDiscus, and Web of Science were systematically searched with grey literature searches and pearling of references thereafter.Study Selection CriteriaExperiments were included in the review if they performed a unilateral resistance training intervention that directly compared the dose of a training variable on the cross-education response in healthy or clinical populations following a minimum of two weeks of training. Experiments must have reported maximal strength outcomes for the untrained limb.Data SynthesisFor each experiment, the study population, intervention methods, the dosage of the training variable being studied, and the outcomes for the untrained, contralateral limb were identified and collectively synthesized.ResultsThe search returned a total of 911 articles, 56 of which qualified for inclusion. The results show that experimental trials have been conducted on resistance training frequency (n = 4), intensity (n = 7), the type of training (n = 25), training volume (n = 3), and adjuvant therapies (n = 17) on the cross-education of strength.ConclusionsThis review synthesizes the available evidence regarding exercise design and prescription strategies to promote the cross-education of strength. It appears that traditional resistance training frequencies (ie., 2-3d/wk) at high intensities are effective at promoting cross- education. Eccentric muscle actions show additive benefits. There is experimental evidence that neuromodulatory techniques can augment cross-education when layered with unilateral resistance training versus training alone.
Drug-Related Problems and associated factors among hospitalized pediatric patients at the University of Gondar Comprehensive and Specialized Hospital
Authors: Amsalu Atalay , Baraki Adhanom Gebreegziabher , Muche Esileman Abdela 
Published: September 2022

AbstractIntroductionDrug-related problem is any event involving drug therapy that interferes with a patient’s desired clinical outcome. Hospitalized pediatric patients are particularly prone to drugrelated problems. Thus, this study aimed to assess drug-related problems and associated factors among patients admitted to the pediatric ward of the University of Gondar Comprehensive and Specialized Hospital, Ethiopia.MethodsA hospital-based cross-sectional study was conducted among pediatric patients admitted to the University of Gondar Comprehensive and Specialized Hospital from May 1, to July 30, 2021. A Simple random sampling technique was employed to select study participants. Odds ratio with 95% confidence interval was computed for each variable for the corresponding P-value to see the strength of association. Those variables which have a P-value of < 0.25 in Bivariable analysis were entered in Multivariable analysis to determine factors associated with drug related problems.ResultsA total of 180 drug-related problems were identified in 145 participants with an overall prevalence of 40.2% [95% CI (35.5-45.4)]. Dose too low (35.56%), needs additional drug (28.89%) and dose too high (21%) were the commonest type of drug-related problems identified. The most important interventions made were dose adjustment (52%) and the addition of drugs (30%). The presence of comorbidity [AOR = 3.32, 95% CI (1.88-5.88)], polypharmacy [AOR = 4.22, 95% CI (2.21-8.10)], and more than 6 days stay in the hospital [AOR =7.59, 95% CI (3.76-15.33)] were independent predictors for the occurrence of drug-related problems.ConclusionDrug-related problems are common among hospitalized pediatrics at the University of Gondar Comprehensive and Specialized Hospital. The presence of comorbidity, polypharmacy and prolonged hospital stay were predictors of drug-related problems. Therefore, health care providers have to work in collaboration with clinical pharmacists and give due attention to those patients with comorbidity, polypharmacy and patients who stayed longer days in the hospital.
Real-world Use of Nirmatrelvir-Ritonavir in COVID-19 Outpatients During the Emergence of Omicron Variants BA.2/BA2.12.1
Authors: Aggarwal Neil R. , Molina Kyle C. , Beaty Laurel E. , Bennett Tellen D. , Carlson Nichole E. , Ginde Adit A. 
Published: September 2022

ABSTRACTBackgroundRitonavir-boosted Nirmatrelvir (NMV-r), a protease inhibitor with in vitro activity against SARS-CoV-2, has been shown to reduce risk of progression to severe COVID-19 among high-risk individuals during the Delta-variant phase. We sought to determine the effectiveness of NMV-r against Omicron lineage variants BA.2/BA2.12.1, and assess for evidence of a clinical rebound effect.MethodsWe conducted a retrospective observational cohort study of non-hospitalized adult patients with SARS-CoV-2 infection from March 26th, 2022 to June 23rd, 2022, using records from a statewide health system linked to vaccine and mortality data. Propensity score matching was performed on NMV-r treated outpatients with outpatients not treated with antiviral therapy. The primary outcome was 28-day all-cause hospitalization; secondary outcomes were COVID-19-related hospitalization, 28-day all-cause mortality, and 28-day ED visits. Logistic regression was used to determine NMV-r treatment effectiveness; subgroup analyses were performed to assess for heterogeneity in treatment effect.ResultsOf 14,953 SARS-CoV-2 infected outpatients, 3,614 NMV-r treated patients were matched to 4,835 untreated outpatients. NMV-r was associated with significantly lower odds of 28-day all-cause hospitalization as compared to no antiviral treatment [31 (0.9%) vs. 64 (1.3%), adjusted odds ratio (aOR): 0.48 (95% CI 0.31-0.75)]. NMV-r was also associated with lower odds of COVID-19 related hospitalization [aOR (95% CI): 0.42 (0.25-0.68)] and 28-day all-cause mortality [aOR (95% CI): 0.05 (0.00-0.38)]. Using ED visits within 28 days as a surrogate for rebound symptoms, we observed no clinically evident rebound effect with NMV-r treatment [140 (3.9%) vs 205 (4.2%), aOR: 0.81 (95% CI 0.65-1.02), p = 0.075].ConclusionReal-world evidence during an Omicron BA.2/BA2.12.1 predominant period demonstrated an association of NMV-r treatment with reduced 28-day hospitalization and all-cause mortality, and without an increase in rebound symptoms as assessed by ED visits within 28 days after treatment.
Drought, armed conflict and population mortality in Somalia, 2014-2018: a statistical analysis
Authors: Warsame Abdihamid , Frison Séverine , Checchi Francesco 
Published: September 2022

AbstractBackgroundDuring 2010-2012, extreme food insecurity and famine in Somalia were estimated to account for 256,000 deaths. Since 2014 Somalia has experienced recurrent below-average rainfall, with consecutive failed rains in late 2016 and 2017 leading to large-scale drought, displacement and epidemics. We wished to estimate mortality across Somalia from 2014 to 2018, and measure the excess death toll attributable to the 2017-2018 drought-triggered crisis.MethodsWe used a statistical approach akin to small-area estimation, and relying solely on existing data. We identified and re-analysed 91 household surveys conducted at the district level and estimating the crude (CDR) and under 5 years death rate (U5DR) over retrospective periods of 3-4 months. We captured datasets of candidate predictors of mortality with availability by district and month. We also reconstructed population denominators by district-month combining alternative census estimates and displacement data. We combined these data inputs into predictive models to estimate CDR and U5DR and combined the predictions with population estimates to project death tolls. Excess mortality was estimated by constructing counterfactual no-crisis scenarios.ResultsBetween 2013 and 2018, Somalia’s population increased from 12.0 to 13.5 million, and internally displaced people or returnees reached 20% of the population. We estimated an excess death toll of 44,700 in the most likely counterfactual scenario, and as high as 163,800 in a pessimistic scenario. By contrast to 2010-2012, excess deaths were widespread across Somalia, including central and northern regions.ConclusionThis analysis suggests that the 2017-2018 crisis had a lower, albeit still very substantial, mortality impact than its 2010-2012 predecessor. Despite modest elevations in death rate, crisis conditions were widespread and affected a population of millions. Humanitarian response to drought-related crises in Somalia needs to be strengthened, target the most vulnerable and emphasise very early interventions.
Polygenic risk scores for the prediction of common cancers in East Asians: A population-based prospective cohort study
Authors: Ho Peh Joo , Tan Iain Bee Huat , Chong Dawn Qingqing , Khor Chiea Chuen , Yuan Jian-Min , Koh Woon-Puay , Dorajoo Rajkumar , Li Jingmei 
Published: September 2022

ABSTRACTBackgroundTo evaluate the utility of polygenic risk scores (PRS) in identifying high-risk individuals, different publicly available PRS for breast (n=65), prostate (n=26), colorectal (n=12) and lung cancers (n=7) were examined in a prospective study of 21,694 Chinese adults.MethodsWe constructed PRS using weights curated in the online PGS Catalog. PRS performance was evaluated by distribution, discrimination, predictive ability, and calibration. Hazard ratios (HR) and corresponding confidence intervals [CI] of the common cancers after 20 years of follow-up were estimated using Cox proportional hazard models for different levels of PRS.ResultsA total of 495 breast, 308 prostate, 332 female-colorectal, 409 male-colorectal, 181 female-lung and 381 male-lung incident cancers were identified. The area under receiver operating characteristic curve for the best performing site-specific PRS were 0.61 (PGS000004, breast), 0.66 (PGS00586, prostate), 0.58 (PGS000148, female-colorectal), 0.60 (PGS000734, male-colorectal) and 0.55 (PGS000740, female-lung), and 0.55 (PGS000392, male-lung), respectively. Compared to the middle quintile, individuals in the highest PRS quintile were 67% more likely to develop cancers of the breast, prostate, and colorectal. For lung cancer, the lowest PRS quintile was associated with 31-45% decreased risk compared to the middle quintile. In contrast, the hazard ratios observed for quintiles 4 (female-lung: 0.91 [0.58-1.44]; male-lung: 1.01 [0.74-1.38]) and 5 (female-lung: 1.00 [0.64-1.56]; male-lung: 1.07 [0.79-1.45]) were not significantly different from that for the middle quintile.ConclusionsSite-specific PRSs can stratify the risk of developing breast, prostate, and colorectal cancers in this East Asian population. Appropriate correction factors may be required to improve calibration.FundingThis work is supported by the National Research Foundation Singapore (NRF-NRFF2017-02), PRECISION Health Research, Singapore (PRECISE) and the Agency for Science, Technology and Research (A*STAR). WP Koh was supported by National Medical Research Council, Singapore (NMRC/CSA/0055/2013). CC Khor was supported by National Research Foundation Singapore (NRF-NRFI2018-01). Rajkumar Dorajoo received a grant from the Agency for Science, Technology and Research Career Development Award (A*STAR CDA - 202D8090), and from Ministry of Health Healthy Longevity Catalyst Award (HLCA20Jan-0022).The Singapore Chinese Health Study was supported by grants from the National Medical Research Council, Singapore (NMRC/CIRG/1456/2016) and the U.S. National Institutes of Health [NIH] (R01 CA144034 and UM1 CA182876).
The Incidence, Predictors, and Mortality Impact of Ventricular Pacing Dependency after Transcatheter Aortic Valve Replacement: A Prospective Cohort
Authors: Apiyasawat Sirin , Chandavimol Mann , Soontornmanokati Natcha , Sirikhamkorn Chulaporn 
Published: September 2022

AbstractBackgroundAtrioventricular conduction disturbance occurs in a significant number of patients underwent transcatheter aortic valve replacement (TAVR). However, not all of the cases persistently depend on ventricular pacing.ObjectiveTo study the incidence, predictors, and outcomes of new ventricular pacing dependency (VpDep) after TAVR.DesignProspective, single-center, cohort trialMethodsThe first 130 consecutive transfemoral TAVR cases, except 3 with prior cardiac electronic implantable devices (CIEDs) who depended on ventricular pacing, were analyzed. The endpoints were VpDep at 1 month and all-cause mortality at the end of follow-up in 2021. The effects of variables on VpDep and all-cause mortality were evaluated using multivariate binary logistic regression and Cox-regression analysis, respectively. First degree atrioventricular block (AVB) was considered severe when PR interval > 300 ms.ResultsOut of 127 patients in the analysis (mean age 82 years, SD 6.3; 62.2% female sex; 67.7% Balloon-expandable device), 7 patients (5.5%) had implanted with CIEDs before TAVR but not ventricular pacing dependent. The incidence of VpDep at 1 month was 7.9% (n=10) among all patients and 34.5% among patients with CIEDs (n=29). VpDep was likely to occur in patients with pre-existing right bundle branch block (OR 21.38; 95% CI 3.25-139.33; P=.001) and severe 1st degree or Mobitz I AVB (OR 14.79; 95% CI 1.65-132.74; P=.016). After a mean follow-up of 25.8 months (SD 21.2), death from any causes occurred in 18 patients (14.2%). VpDep was not associated with excess mortality.ConclusionVpDep at 1 month occurred in 7.9% of all patients underwent TAVR. Pre-existing conduction abnormalities were significantly associated with higher risk of VpDep. Mortality was similar between patients with and without VpDep.Clinical Trial RegistrationThai Clinical Trial Registration; Study ID: TCTR20220726005
FASDetect – A machine learning-based app to screen for the risk of fetal alcohol-spectrum disorder in youth with attention-deficit/hyperactivity disorder symptoms
Authors: Ehrig Lukas , Wagner Ann-Christin , Wolter Heike , Correll Christoph U. , Geisel Olga , Konigorski Stefan 
Published: September 2022

AbstractFetal alcohol-spectrum disorder (FASD) is underdiagnosed and often misdiagnosed as attention-deficit/hyperactivity disorder (ADHD). Here, we developed a screening tool for FASD in youth with ADHD symptoms. To develop the prediction model, medical record data from a German University outpatient unit were assessed including 275 patients aged 0-19 years old with FASD with or without ADHD and 170 patients with ADHD without FASD aged 0-19 years old. We trained 6 machine learning models based on 13 selected variables and evaluated their performance. Random forests yielded the best prediction models with a cross-validated AUC of 0.92 (95% confidence interval [0.84, 0.99]). Follow-up analyses indicated that a random forest model with 6 variables – body length and head circumference at birth, IQ, socially intrusive behaviour, poor memory and sleep disturbance – yielded equivalent predictive accuracy. We implemented the prediction model in a web-based app called FASDetect – a user-friendly, clinically scalable FASD risk calculator that is freely available at https://fasdetect.dhc-lab.hpi.de.
RUNX1-deficient human megakaryocytes demonstrate thrombopoietic and platelet half-life and functional defects: Therapeutic implications
Authors: Lee Kiwon , Ahn Hyun Sook , Estevez Brian , Poncz Mortimer 
Published: September 2022

AbstractHeterozygous defects in runt-related transcription factor-1 (RUNX1) are causative of a familial platelet disorder with associated myeloid malignancy (FPDMM). Since RUNX1-deficient animal models do not mimic FPDMM’s bleeding disorder or leukemic risk, establishment of a proper model system is critical to understand the underlying mechanisms of the observed phenotype and to identify therapeutic interventions. We previously reported an in vitro-megakaryopoiesis system using human CD34+-hematopoietic stem and progenitor cells that recapitulated the FPDMM quantitative megakaryocyte defect by decreasing RUNX1 expression using a lentiviral short-hairpin RNA (shRNA for RUNX1 or shRX) strategy. We now show that shRX-megakaryocytes have a marked reduction in agonist responsiveness. We then infused shRX-megakaryocytes into immunocompromised NOD-SCID gamma (NSG) mice and demonstrated that these megakaryocytes released fewer platelets than megakaryocytes transfected with a non-targeting shRNA, and these platelets had a diminished half-life. The platelets were also poorly responsive to agonists, unable to correct thrombus formation in NSG mice homozygous for a R1326H mutation in von Willebrand Factor (VWFR1326H), which switches species-binding specificity of the VWF from mouse to human glycoprotein Ibα. A small-molecule inhibitor RepSox, which blocks the transforming-growth factor beta pathway, and which rescued defective megakaryopoiesis in vitro, corrected the thrombopoietic defect, platelet half-life and agonist response, and thrombus formation in NSG/VWFR1326H mice. Thus, this model recapitulates the defect in FPDMM megakaryocytes and platelets, identifies previously unrecognized defects in thrombopoiesis and platelet half-life, and demonstrates, for the first time, reversal of RUNX1 deficiency’s hemostatic defects by a drug.Key PointsRUNX1-deficient megakaryocytes exhibit thrombopoietic and platelet defects in NSG/VWFR1326H mice.Pre-exposure of RUNX1-deficient megakaryocytes to a TGFβ1-pathway inhibitor ameliorated both defects, correcting hemostasis.
Differential contributions of nuclear lamina association and genome compartmentalization to gene regulation
Authors: Das Priyojit , San Martin Rebeca , McCord Rachel Patton 
Published: September 2022

ABSTRACTInteractions of chromatin with the nuclear lamina play a significant role in properly organizing the genome in 3D space and in regulating gene expression. Genome wide studies have inferred the global association between the lamina, heterochromatin, gene repression and the B genomic compartment, and repositioning genes to the lamina can result in their repression. However, there are scenarios in which these features are discordant and, in those cases, the relative contribution to gene regulation of genomic compartment, chromatin, and lamin association status can be examined. Here we compared datasets from cell lines representing different states of differentiation across different cell type lineages to examine the relationships between changes in genomic compartmentalization, lamin association, and gene expression. With these data, we could examine, for example, what gene expression changes occur when a B compartment region is moved from the nuclear interior to the nuclear lamina and what differences exist between lamin associated and internal A compartment regions. In general, we observed an additive rather than redundant effect in which lamin association and compartment status both contribute to gene expression state. However, we found that cell type lineages differed in whether compartment status or lamin association had a dominant influence on gene expression. Finally, we identified conserved trends of how compartment and lamin association status influence the likelihood that gene expression will be induced or repressed in response to a physiochemical treatment.