bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dissecting the Genetic Architecture of Intracranial Aneurysms
Authors: Adkar Shaunak S. , Lynch Julie , Choi Ryan B. , Roychowdhury Tanmoy , Judy Renae L. , Paruchuri Kaavya , Go Dong-Chuan , Bamezai Sharika , Cabot John , Sorondo Sabina , Levin Michael G. , Milewicz Dianna M. , Willer Cristen J. , Natarajan Pradeep , Pyarajan Saiju , Chang Kyong-Mi , Damrauer Scott , Tsao Phil , Skirboll Stephen , Leeper Nicholas J. , Klarin Derek 
Published: August 2023

ABSTRACTBackgroundThe genetic risk of intracranial aneurysm (IA) development has been ascribed largely to the genetic risk of smoking exposure and hypertension. However, the relationship of IA to other cardiovascular traits and the contribution of IA risk loci to aberrant gene programs within cerebrovascular cell types remains unclear.MethodsWe performed a genome-wide association study in the Million Veteran Program testing association of roughly 25 million DNA variants with unruptured IA (3,165 cases and 592,927 controls) in veterans of European, African, and Hispanic ancestries. This was meta-analyzed with publicly available summary statistics to yield a final cohort of 15,438 cases and 1,183,973 controls. Candidate causal genes were prioritized through expression quantitative trait loci colocalization, fine-mapping transcriptome wide association studies, and multi-trait colocalization. We constructed a cerebrovascular single nucleus RNA sequencing (snRNA-seq) dataset and integrated IA summary statistics to prioritize candidate causal cell types. We then constructed a polygenic risk score to identify patients at greater risk of developing IA.ResultsWe identified five novel loci association with IA, increasing the number of known susceptibility loci to 22. At these susceptibility loci, we prioritized 16 candidate causal genes. Amongst other cardiovascular traits, we found a significant positive genetic correlation of IA with coronary artery disease and abdominal aortic aneurysm, and we identified 13 IA risk loci that colocalize with aneurysmal, atherosclerotic, and blood pressure traits. Integration of an IA gene set with human cerebrovascular snRNA-seq data revealed significant association with matrix-producing pericytes, smooth muscle cells (SMCs), and other mural subtypes. In addition, gene expression analysis revealed enrichment of several candidate genes within SMCs and pericytes. Finally, a high polygenic risk score (PRS) was significantly associated with IA across European (OR: 1.87, CI: 1.61-2.17, P = 8.8 × 10−17), African (OR: 1.62, CI: 1.19-2.15, P = 1.2 × 10−3), and Hispanic (OR: 2.28, CI: 1.47-3.38, P = 1.0 × 10−4) ancestries.ConclusionHere, we identify five novel loci associated with IA. Integration of summary statistics with cerebrovascular snRNA-seq reveals association of cell-types involved in matrix production. We constructed and validated a PRS that predicts IA, while controlling for demographic variables including smoking status, sex, and blood pressure. Taken together, our findings suggest that an intrinsic deficit in matrix production and vascular integrity may drive IA pathogenesis independent of systemic hypertension and smoking exposure.
Pharmacotherapy for Children and adolescents with overweight and obesity: a systematic review and network meta-analysis of randomized controlled trials
Authors: Luo Li , Huang Tingting , Wang Hui , Zhao Jianglin , Qi Yunyun , Yan Zijing , Zhu Chunmei , Wang Chufeng , Su Na , Xu Ting , Zhang Shengzhao 
Published: August 2023

AbstractBackgroundOverweight and obesity are widespread among children and adolescents. We aimed to summarize the evidence for the pharmacotherapy as an adjunct to lifestyle interventions in overweight or obese children and adolescents by comparing the benefits and harms.MethodsRCTs (randomized controlled trials) were sourced from PubMed, Embase (using the OVID platform), the Cochrane Library (CENTRAL), as well as the trial registers ICTRP (WHO) and ClinicalTrials.gov. Searches were undertaken from inception to April 25, 2023. A network meta-analysis was performed using the frequentists framework based on random-effects model. We used GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach to evaluate the overall certainty of evidence and categorized the interventions.ResultsIn total, 42 RCTs (n=3883) comparing 8 different pharmacotherapy strategies were included in this study. Evidence strongly suggested that phentermine-topiramate reduced BMI the most (the mean difference (MD) -4.83 [95% CI, -7.46 to -2.20] kg/m2) and weight (MD, -14.59 [95% CI, -19.37, -9.81] kg) in children and adolescents with overweight or obesity. Compared to lifestyle intervention alone, phentermine-topiramate was associated with an additional 557 events per 1000 person-years in terms of the proportion of participants achieving a BMI reduction of ≥5%, but there was no increased harm in total gastrointestinal adverse effects and discontinuation due to adverse events.ConclusionsPhentermine-topiramate was closely related to weight loss and showed a good tolerability, proving to be the optimal treatment strategy for overweight or obese children and adolescents.RegistrationPROSPERO registry number: CRD42022329226
Small-molecule functional rescue of PIEZO1 channel variants associated with generalised lymphatic dysplasia
Authors: Ludlow Melanie J , Povstyan Oleksandr V , Linley Deborah M , Martin-Almedina Silvia , Revill Charlotte , Cuthbertson Kevin , Smith Katie A , Fay Emily , Fotiou Elisavet , Bush Andrew , Hogg Claire , Linden Tobias , Tan Natalie B , White Susan M , Dempsey Esther , Mansour Sahar , Parsonage Gregory , Kalli Antreas C , Foster Richard , Ostergaard Pia , Beech David J 
Published: August 2023

ABSTRACTGeneralised Lymphatic Dysplasia (GLD) is characterised by widespread lymphoedema, with at least one of the following: fetal hydrops, intestinal or pulmonary lymphangiectasia, pleural effusions, pericardial effusions and ascites. Satisfactory medical therapies are lacking. A genetic association has been identified that prevents expression or surface trafficking of PIEZO1, a subunit of mechanically activated calcium-permeable channels. However,PIEZO1is a large and highly polymorphic gene and interpretation of variants identified in this gene can be challenging.PIEZO1-related GLD with non-immune fetal hydrops is autosomal recessive, however, heterozygous variants inPIEZO1(often gain-of-function) causing Dehydrated Hereditary Stomatocytosis (DHS) (a relative mild anaemia), may also present with perinatal non-immune hydrops (not caused by anaemia).Here we sought to develop methods to confirm pathogenicity of missense variants of uncertain significance inPIEZO1, to gain deeper understanding and pharmacological solutions. Four novel GLD-associated missense variants inPIEZO1are identified that express and surface localise as full-length protein but with reduced or abolished mechanically activated channel function. Yoda1, a small-molecule agonist, functionally rescues the channels and their physiological regulation by mechanical force and hypo-osmolality. The GLD-associated variants mediate intracellular calcium release as well as calcium entry, suggesting two pools of channels and opportunity for increased rescue through access to the intracellular pool. New Yoda1 analogues are also identified that improve rescue.The functional assays have assisted the interpretation of the variants of uncertain significance as the data suggest loss of PIEZO1 force sensing as a cause of the GLD observed in the patients. The potential to pharmacologically overcome the loss of force sensing was demonstrated and supports the concept of stimulation of PIEZO1 with an agonist to address wide-ranging problems of lymphatic insufficiency.GRAPHICAL ABSTRACTHIGHLIGHTSPreviously unrecognised variants inPIEZO1that associate with GLD are identified and characterised and pathogenicity confirmedThe variants encode single amino acid changes that inhibit PIEZO1 channel activation by physiological mechanical forcesA small-molecule agonist rescues the channels and their physiological regulationVariants are partly intracellular, suggesting an opportunity for improved rescue through the use of intracellular-acting agonistsNew agonists are identified that improve rescue, suggesting routes to medical therapies for GLD and potentially other disorders of lymphatic insufficiency
A neuroimaging measure to capture heterogeneous patterns of atrophy in Parkinson’s disease and dementia with Lewy bodies
Authors: Bhome R , Verdi S , Martin SA , Hannaway N , Dobreva I , Oxtoby NP , Leal G Castro , Rutherford S , Marquand AF , Weil RS , Cole JH 
Published: August 2023

AbstractINTRODUCTIONParkinson’s disease (PD) and Dementia with Lewy bodies (DLB) show heterogeneous brain atrophy patterns and common group-average analyses are limited in capturing individual differences. Neuroanatomical normative modelling overcomes this by comparing individuals to a large reference cohort.METHODSWe generated z-scores from T1w-MRI scans for each participant (108 PD; 61 DLB) relative to normative regional cortical thickness and subcortical volumes, modelled in a reference cohort (n=58,836). Outliers (z<-1.96) were aggregated across 169 brain regions per participant. We examined total outlier counts between high versus low visual performance in PD; and PD versus DLB; and tested associations between these and cognition.RESULTSWe found greater total outlier counts in PD poor visual performers, compared to high; and in DLB versus PD. Outlier counts were associated with global cognition in DLB, and visuoperception in PD.DISCUSSIONNeuroanatomical normative modelling shows promise as a clinically informative technique in PD and DLB.
Adaptive health technology assessments to inform oncology based priority setting in India
Authors: Ghosh Srobana , Pramesh C S , Sengar Manju , Ranganathan Priya , Nemzoff Cassandra , Ruiz Francis , Wadasadawala Tabassum , Nayak Prakash , Thorat Jayashree , Ashok Apurva , Singh Malkeet , Mehndiratta Abha , Shah Hiral Anil 
Published: August 2023

AbstractBackgroundHealth technology assessment (HTA) is a valuable tool for informing the most efficient allocation of resources, yet is highly resource intensive limiting its applicability in practice. Adapting the HTA process by leveraging available international evidence offers a pragmatic solution to such challenges, saving time whilst still generating useful insight for decision making.ObjectiveTo develop an adaptive HTA (aHTA) framework that could be used to assess the likely cost-effectiveness of cancer treatments to inform the available entitlements under the Indian national health insurance scheme.MethodsThe International Decision Support Initiative worked with the National Cancer Grid in India to develop an aHTA framework which included topic selection, scoping, evidence review and appraisal to estimate the likely cost-effectiveness of cancer interventions. The evidence included international data on cost effectiveness (HTA reports and economic evaluations), price benchmarking and treatment cost estimates. Ten interventions were assessed with the newly developed framework by a working group of clinicians and health economists from both institutions.ResultsOf 10 interventions assessed, 9 had sufficient evidence to decide cost-effectiveness; 3 were cost-effective (1 only after a discount, 1 using the generic price), 5 were not and 1 was not cost-effective for all but was in a subgroup. A full HTA was recommended for one intervention due to uncertainty. Information on the likely cost-effectiveness, clinical benefits and treatment costs was consistently available through publicly available evidence. India on average paid almost 4 times the list price of other countries.ConclusionaHTA provides an alternative to using no economic evidence at all if a full HTA cannot be conducted. It is well-suited to cancer drugs for which there is ample available international information on cost-effectiveness. Our framework quickly generated consistent, transparent evidence to inform guidelines. The approach may be replicable in other settings in supplement to full HTA.Key messagesWhat is already known on this topicThere is an enormous need for more evidence informed priority setting, however there are often significant challenges to doing so such as insufficient data, capacity and resources available. Some countries are exploring the use of rapid or adaptive methods of health technology assessment (HTA) but there is no clear guidance on the methodology that should be used.What this study addsExperience of the results of an adaptive HTA framework in practice, based on 10 oncology problems.How this study might affect research, practice or policyOther countries or institutions with limited capacity for HTA could potentially use the framework to perform their own adaptive HTA assessments.
Estimating the effect of circulating vitamin D on body mass index: a Mendelian randomization study
Authors: Chadha Minal , Bell Joshua A. , Sanderson Eleanor 
Published: August 2023

AbstractBackgroundNumerous observational studies have shown an association between higher circulating 25 hydroxyvitamin D (vitamin D) and lower body mass index (BMI). Whether this represents a causal effect remains unclear. Mendelian randomization (MR) is an approach to causal inference that uses genetic variants as instrumental variables to estimate the effect of exposures on outcomes of interest. MR estimates are not biased by confounding, reverse causation and other biases in the same way as conventional observational estimates. In this study, we used MR with new data on genetic variants associated with vitamin D to estimate the effect of vitamin D on BMI.MethodsWe selected single nucleotide polymorphisms (SNPs) which were associated with vitamin D in a recent large genome-wide association study (GWAS) at genome-wide significance as instruments for vitamin D. We used inverse variance weighted models and further assessed individual SNPs that showed evidence of an effect, and biologically informed SNPs located in genetic regions previously associated with vitamin D, for associations with other traits at genome-wide significance, using Wald ratio estimation.ResultOur main results showed no evidence of an effect of vitamin D on BMI (estimated standard deviation change in BMI per standard deviation change in vitamin D: -0.003, 95% confidence interval [-0.06, 0.06]). This was also supported by pleiotropy robust sensitivity analyses. Individual SNPs that showed evidence of an effect of vitamin D on either lower or higher BMI were strongly associated with numerous other traits suggesting high levels of horizontal pleiotropy. Biologically informed SNPs showed no evidence of a causal effect of vitamin D on BMI and showed substantially less evidence of pleiotropic effects.ConclusionThe observed association between vitamin D and BMI is unlikely to be due to a causal effect of vitamin D on BMI. We also show how additional evidence can be incorporated into an MR study to interrogate individual SNPs for potential pleiotropy and improve interpretation of results.
Patient-Reported Reasons for Antihypertensive Medication Change: A Quantitative Study Using Social Media
Authors: Micale Cristina , Golder Su , O’Connor Karen , Weissenbacher Davy , Gross Robert , Hennessy Sean , Gonzalez-Hernandez Graciela 
Published: August 2023

AbstractIntroductionHypertension is the leading cause of heart disease in the world, and discontinuation or nonadherence of antihypertensive medication constitutes a significant global health concern. Patients with hypertension have high rates of medication nonadherence [13–15]. Studies of reasons for nonadherence using traditional surveys are limited, can be expensive, and suffer from response, white-coat, and recall biases. Mining relevant posts by patients on social media is inexpensive and less impacted by the pressures and biases of formal surveys, which may provide direct insights into factors that lead to non-compliance with antihypertensive medication.MethodsThis study examined medication ratings posted to WebMD, an online health forum that allows patients to post medication reviews. We used a previously developed natural language processing classifier to extract indications and reasons for changes in angiotensin receptor II blocker (ARBs) and angiotensin-converting enzyme inhibitor (ACEIs) treatments. After extraction, ratings were manually annotated and compared to data from the FAERS public database.ResultsFrom a collection of 343,459 WebMD reviews, we automatically extracted 1,867 posts mentioning changes in ACEIs or ARBs, and manually reviewed the 300 most recent posts regarding ACEI treatments and the 300 most recent posts regarding ARB treatments. After excluding posts that only mentioned a dose change or were a false positive mention, 142 posts in the ARBs dataset and 187 posts in the ACEIs dataset remained. The majority of posts (97% ARBs, 91% ACEIs) indicated experiencing an adverse event as the reason for medication change. The most common adverse events reported mapped to the Medical Dictionary for Regulatory Activities were “musculoskeletal and connective tissue disorders” like muscle and joint pain for ARBs, and “respiratory, thoracic, and mediastinal disorders” like cough and shortness of breath for ACEIs. These categories also had the largest differences in percentage points, appearing more frequently on WebMD data than FDA data (p=0.000).ConclusionMusculoskeletal and respiratory symptoms were the most commonly reported adverse effects in social media postings associated with drug discontinuation. Managing such symptoms is a potential target of interventions seeking to improve medication persistence.Key PointsThe major reason for the discontinuation of ARBs and ACEIs expressed through WebMD was the experience of adverse events.Musculoskeletal and respiratory symptoms were the most commonly reported adverse effects in social media postings associated with drug discontinuation.This study shows the promise of WebMD mining as an effective tool in medication nonadherence and adverse event research.
A multi-database based ceRNA regulatory network for gastric cancer prognosis
Authors: Yin Long-Kuan , Li Qian 
Published: August 2023

AbstractObjectiveCircular RNA(circRNA) is a kind of endogenous non-coding RNA, which may be related to the occurrence and development of cancer. Based on the GEO database, this paper constructs a circRNA as a competitive endogenous RNAs(ceRNAs) that binds with microRNAs (miRNAs) to affect and regulate the expression of target genes. The ceRNA regulatory network based on circRNA-miRNA-mRNA model plays an important role in tumor prognosis and treatment. This paper explores the mechanism of circRNA-related ceRNA regulatory network in gastric cancer.MethodCircRNA, miRNA and mRNA data sets related to gastric cancer were downloaded from The Gene Expression Omnibus (GEO), and the limma package of R software (R 4.2.1 version) was used to identify the differences between gastric cancer tissues and adjacent normal tissues of gastric cancer. DEcircRNA, DEmiRNAs, and DEmRNAs. Based on circBase database, we explored the interactions among circRNA, miRNA and mRNA, and constructed the circRNA-miRNA-mRNA ceRNA network by using Cytoscape_v3.8.0. Then KEGG, GO and survival analysis of ceRNA-related genes were performed. Then, the prognostic data of gastric cancer were extracted from the TCGA database to construct the prognostic subnetwork of gastric cancer.ResultsKEGG analysis of ceRNA’s mRNA showed that the pathway was mainly enriched in IL-17 signaling pathway, TNF signaling pathway and so on, which affected the prognosis of gastric cancer. hsa_circ_0055521/hsa-miR-204-5p/FAP, (hsa_circ_0005051, hsa_circ_0007613, hsa_circ_0045602, hsa_circ_0034398, hsa_circ_0006089) /hsa-miR-32-3p/FNDC1 were the ceRNA networks related to the prognosis of gastric cancer collaterals.ConclusionThis study found that IL-17 signaling pathway and TNF signaling pathway may affect the occurrence, development and prognosis of gastric cancer. And hsa_circ_0055521/hsa-miR-204-5p/FAP, (hsa_circ_0005051, hsa_circ_0007613, hsa_circ_0045602, hsa_circ_0034398, hsa_circ_0006089) /hsa-miR-32-3p/FNDC1 two circrNa-based stomachs The cancer ceRNA prognostic network is a new prognostic related ceRNA network for gastric cancer. FNDC1 and FAP may be potential therapeutic targets for gastric cancer.
Linear age-course association between non-alcoholic fatty liver disease, components of metabolic syndrome, and mortality
Authors: Zhao Xinyu , Chen Shuohua , Wang Xiao mo , Wang Zhenyu , Sun Yuanyuan , Yang Chenlu , Zheng Mengyi , Wang Yanhong , Liao Wei , Wu Shouling , Wang Li 
Published: August 2023

AbstractBackgroundThe study aimed to explore the relationship between non-alcoholic fatty liver disease (NAFLD) and mortality by age and metabolic syndrome (MetS) components.MethodWe enrolled 104,173 participants in the Kailuan cohort from June 2006 through October 2013. Cox regression models were used to evaluate the hazard ratio (HR) and 95% confidence interval (CI). Population-attributable fractions (PAFs) of metabolic components were also calculated.ResultsCompared with non-NAFLD, the excess risk of all-cause and cardiovascular disease (CVD)-related mortality in NAFLD increased with the number of MetS components but decreased with age. The highest all-cause and CVD-related death risks were observed in NAFLD aged 18-39 with 4-5 MetS (HR=2.81, 95% CI:1.55-5.08) and those aged 40-49 years with 3 MetS (HR=2.25, 95% CI:1.55-5.08), respectively. However, there was no significant extra risk of liver-related death in NAFLD patients of any age. For PAF, 28.5% of all-cause and 43.4% of CVD-related mortality among NAFLD patients was preventable by controlling MetS components < 2, with the highest PAF in those aged 50-69 and 18-49, respectively. Elevated blood pressure (PAF of 24.7% for all-cause; 38.6% for CVD-related), elevated fasting glucose (PAF of 13.4% all-cause; 9.2% CVD-related), and elevated triglycerides (PAF of 3.9% all-cause; 14.0% CVD-related) were the essential mortality contributors in NAFLD participants.ConclusionThe excess risk of all-cause and CVD-related mortality in NAFLD patients decreases with age. A substantial proportion of risks could be averted if NAFLD patients are controlled under two MetS components, especially managing blood pressure, fasting glucose, and triglycerides for the young.