bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biallelic loss of function variants inWBP4, encoding a spliceosome protein, result in a variable neurodevelopmental delay syndrome
Authors: Engal Eden , Oja Kaisa Teele , Maroofian Reza , Geminder Ophir , Le Thuy-Linh , Mor Evyatar , Tzvi Naama , Elefant Naama , Zaki Maha S. , Gleeson Joseph G. , Muru Kai , Pajusalu Sander , Wojcik Monica H. , Pachat Divya , Elmaksoud Marwa Abd , Jeong Won Chan , Lee Hane , Bauer Peter , Zifarelli Giovanni , Houlden Henry , Elpeleg Orly , Gordon Chris , Harel Tamar , Õunap Katrin , Salton Maayan , Mor-Shaked Hagar 
Published: June 2023

ABSTRACTOver two dozen spliceosome proteins are involved in human diseases, also referred to as spliceosomopathies. WBP4 (WW Domain Binding Protein 4) is part of the early spliceosomal complex, and was not described before in the context of human pathologies. Ascertained through GeneMatcher we identified eleven patients from eight families, with a severe neurodevelopmental syndrome with variable manifestations. Clinical manifestations included hypotonia, global developmental delay, severe intellectual disability, brain abnormalities, musculoskeletal and gastrointestinal abnormalities. Genetic analysis revealed overall five different homozygous loss-of-function variants inWBP4. Immunoblotting on fibroblasts from two affected individuals with different genetic variants demonstrated complete loss of protein, and RNA sequencing analysis uncovered shared abnormal splicing patterns, including enrichment for abnormalities of the nervous system and musculoskeletal system genes, suggesting that the overlapping differentially spliced genes are related to the common phenotypes of the probands. We conclude that biallelic variants inWBP4cause a spliceosomopathy. Further functional studies are called for better understanding of the mechanism of pathogenicity.
The dynamically neurodiverse human brain: Measuring excitatory-inhibitory dynamics and identifying homeostatic differences in autistic and non-autistic people
Authors: Ellis C. L. , Ahmad J. , Zoumpoulaki A. , Dimitrov M. , Velthuis H. E. , Pereira A. C. , Wong N. M. L. , Ponteduro M. F. , Kowalewski L. , Leonard A. , Garces P. , Huang Q. , Daly E. , Murphy D. , McAlonan G. 
Published: June 2023

AbstractBrain function is the dynamic output of coordinated excitatory and inhibitory (E-I) activity. E-I alterations, arising from differences in excitatory glutamate and inhibitory GABA pathways, are implicated in the development and heterogeneity of multiple neurodevelopmental conditions, such as autism; and are consequently targets for pharmacological support options. Yet, E-I measures of neurotransmitter levels or receptors in the living human brain (such as Magnetic Resonance Spectroscopy or Positron Emission Tomography) are expensive and/or invasive and do not capture dynamics. The determine if a candidate metric captures a neurosignalling system, the system must be challenged and changes observed objectively. This is basis of animal study designs. The aperiodic 1/f exponent of the EEG power spectrum is sensitive to E-I perturbations in animals but, more work is needed to translate to humans. Therefore, we tested the hypotheses that i) the aperiodic 1/f exponent of resting-state EEG in humans changes following a pharmacological E-I challenge with arbaclofen, a GABABreceptor agonist; and ii) dynamic responsivity to GABAergic challenge is different in a neurodevelopmental condition associated with E-I differences, namely autism. As predicted, in both groups the aperiodic 1/f exponent significantly increased following a high (30mg) dose of arbaclofen. However, an aperiodic exponent increase was also elicited at a lower (15mg) dose of arbaclofen in autistic but not non-autistic individuals. Hence, in humans, the aperiodic 1/f exponent captures E-I dynamics and autistic brains are dynamically different compared to non-autistic brains. We suggest that our results can be explained by homeostatic differences E-I regulation between groups.
PanelCAT: an Open-Source Comparative Analysis Tool for Next-Generation Sequencing Panel Target Regions
Authors: Oszwald André , Zisser Lucia , Compérat Eva , Müllauer Leonhard 
Published: June 2023

AbstractMulti-gene next-generation sequencing (NGS) panels have become a routine diagnostic method in the contemporary practice of personalised medicine. To avoid inadequate test choice or interpretation, a detailed understanding of the precise panel target regions is required. However, the necessary bioinformatic expertise is not always available, and publicly accessible and easily interpretable analyses of target regions are scarce. To address this critical knowledge gap, we present the Panel Comparative Analysis Tool (PanelCAT) an open-source application to analyze, visualize and compare NGS panel DNA target regions. PanelCat uses RefSeq, ClinVar and COSMIC cancer mutation census databases to quantify the exon and mutation coverage of target regions and provides interactive graphical representations and search functions to inspect the results. We demonstrate the utility of PanelCAT by analyzing two large NGS panels (Illumina TSO500 and Qiagen pan-cancer panel) to validate the advertized target genes, quantify targeted exons and mutations, and identify differences between panels. PanelCat will enable institutions and researchers to catalogue and visualize NGS panel target regions independent of the manufacturer, promote transparency of panel limitations, and share this information with employees and requisitioners.
Status of Magnetic Resonance Imaging Systems and Quality Control Programs in Nigeria
Authors: Adewole Maruf , Ige Taofeeq A. , Irurhe Nicholas , Adewole Philip , Akpochafor Michael , Ibitoye Ayo , Adeneye Samuel 
Published: June 2023

AbstractMagnetic Resonance Imaging (MRI) employs the use of magnetic field and radio waves to produce images of the body. Quality Control (QC) is essential for ensuring optimal performance of MRI systems, as recommended by American College of Radiology (ACR), American Association of Physicists in Medicine (AAPM), and the International Society of Magnetic Resonance in Medicine (ISMRM). This survey examines the status of MRI systems and QC in Nigeria. Questionnaires were administered through google form to Radiologists, Radiographers, Medical Physicists, and biomedical engineers working in various MRI centers across the country, with a total of 44 responses received from 24 centers. The professional bodies of the professionals involved facilitated the questionnaire administration. The survey results indicate that 1.5T is the most common field strength of MRI systems in the country. 83% of the imaging centers rely solely on the service engineer to keep the MRI operational. Although 71% of the centers have Radiation Safety Advisors (RSA), their services do not include MRI. Moreover, 45% of the centers lack an understanding of the composition and importance of MRI QC. This is due to factors such as the absence of regulatory requirements, high patient workload, no trained personnel, and the unavailability of QC equipment. The findings of this survey highlight the need for improved QC programs in the country to improve image quality and longevity of MRI systems. It also underscores the need for the establishment of a regulatory framework and national policy to ensure the safe use of MRI in Nigeria.
History of tuberculosis disease is associated with genetic regulatory variation in Peruvians
Authors: Suliman Sara , Nieto-Caballero Victor E. , Asgari Samira , Lopez Kattya , Iwany Sarah K. , Luo Yang , Nathan Aparna , Fernandez-Salinas Daniela , Chiñas Marcos , Huang Chuan-Chin , Zhang Zibiao , León Segundo R , Calderon Roger I , Lecca Leonid , Murray Megan , Van Rhijn Ildiko , Raychaudhuri Soumya , Moody D. Branch , Gutierrez-Arcelus Maria 
Published: June 2023

AbstractA quarter of humanity is estimated to be latently infected withMycobacterium tuberculosis(Mtb) with a 5-10% risk of developing tuberculosis (TB) disease. Variability in responses toMtbinfection could be due to host or pathogen heterogeneity. Here, we focused on host genetic variation in a Peruvian population and its associations with gene regulation in monocyte-derived macrophages and dendritic cells (DCs). We recruited former household contacts of TB patients who previously progressed to TB (cases, n=63) or did not progress to TB (controls, n=63). Transcriptomic profiling of monocyte-derived dendritic cells (DCs) and macrophages measured the impact of genetic variants on gene expression by identifying expression quantitative trait loci (eQTL). We identified 330 and 257 eQTL genes in DCs and macrophages (False Discovery Rate (FDR) < 0.05), respectively. Five genes in DCs showed interaction between eQTL variants and TB progression status. The top eQTL interaction for a protein-coding gene was withFAH, the gene encoding fumarylacetoacetate hydrolase, which mediates the last step in mammalian tyrosine catabolism.FAHexpression was associated with genetic regulatory variation in cases but not controls. Using public transcriptomic and epigenomic data ofMtb-infected monocyte-derived dendritic cells, we found thatMtbinfection results inFAHdownregulation and DNA methylation changes in the locus. Overall, this study demonstrates effects of genetic variation on gene expression levels that are dependent on history of infectious disease and highlights a candidate pathogenic mechanism through pathogen-response genes. Furthermore, our results point to tyrosine metabolism and related candidate TB progression pathways for further investigation.
The Finger Dexterity Test: validation study of a smartphone-based manual dexterity assessment
Authors: Van Laethem Delphine , Denissen Stijn , Costers Lars , Descamps Annabel , Baijot Johan , Van Remoortel Ann , Van Merhaegen-Wieleman Annick , D’hooghe Marie B , D’Haeseleer Miguel , Smeets Dirk , Sima Diana M , Van Schependom Jeroen , Nagels Guy 
Published: June 2023

AbstractBackgroundThe Nine-Hole Peg Test (9HPT) is the golden standard in clinical practice to measure manual dexterity in people with multiple sclerosis (MS). However, administration requires trained personnel and dedicated time during a clinical visit.ObjectiveTo validate a smartphone-based test for remote manual dexterity assessment, the icompanion Finger Dexterity Test (FDT), to be included into the icompanion application.Methods65 MS and 81 healthy subjects performed a first testing session, and 21 healthy subjects performed a second session approximately two weeks later.ResultsThe FDT significantly correlated with the 9HPT (dominant: Spearman’s ρ=0.62, p<0.001; non-dominant: ρ=0.52, p<0.001). FDT scores showed a significant difference between the MS and healthy subjects (dominant: Cohen’s d=0.24, p=0.015; non-dominant: Cohen’s d=0.18, p=0.013), which was not the case for the 9HPT. A significant correlation with age (dominant: ρ=0.46, p<.001; non-dominant: ρ=0.40, p=0.002), Expanded Disability Status Scale (EDSS, dominant: ρ=0.37, p=0.004; non-dominant: ρ=0.33, p=0.017), and disease duration for the non-dominant hand (ρ=0.31, p=0.016) was observed.ConclusionThe icompanion Finger Dexterity Test shows a moderate-to-good concurrent validity, ecological validity and test-retest reliability, and differentiates between the MS subjects and healthy controls. This test can be implemented into routine MS care for remote follow-up of manual dexterity.
SR-TWAS: Leveraging Multiple Reference Panels to Improve TWAS Power by Ensemble Machine Learning
Authors: Parrish Randy L. , Buchman Aron S. , Tasaki Shinya , Wang Yanling , Avey Denis , Xu Jishu , De Jager Philip L. , Bennett David A. , Epstein Michael P. , Yang Jingjing 
Published: June 2023

AbstractMultiple reference panels of a given tissue or multiple tissues often exist, and multiple regression methods could be used for training gene expression imputation models for TWAS. To leverage expression imputation models (i.e., base models) trained with multiple reference panels, regression methods, and tissues, we develop a Stacked Regression based TWAS (SR-TWAS) tool which can obtain optimal linear combinations of base models for a given validation transcriptomic dataset. Both simulation and real studies showed that SR-TWAS improved power, due to increased effective training sample sizes and borrowed strength across multiple regression methods and tissues. Leveraging base models across multiple reference panels, tissues, and regression methods, our real application studies identified 6 independent significant risk genes for Alzheimer’s disease (AD) dementia for supplementary motor area tissue and 9 independent significant risk genes for Parkinson’s disease (PD) for substantia nigra tissue. Relevant biological interpretations were found for these significant risk genes.
Restrictions on top speed and nighttime usage substantially decrease the incidence of electric scooter injuries
Authors: Pakarinen Oskari , Kobylin Arja , Harjola Veli-Pekka , Castrén Maaret , Vasara Henri 
Published: June 2023

AbstractObjectiveTo investigate the effectiveness of restrictions on top speed and nighttime usage on the incidence of e-scooter-related injuries.DesignA retrospective comparative study. We compared shared e-scooter injuries from two periods: Unrestricted period (1.1-31.8.2021), and Restricted period (1.1.-31.8.2022).SettingGeneral population of Helsinki, Finland. We collected the data from the electric patient database from three trauma hospitals representing all public hospitals treating acute trauma patients in Helsinki.ParticipantsAll patients with an injury related to shared e-scooter riding sustained in HelsinkiInterventionsThe restrictions established for shared e-scooters during the restricted period were: 1) The daytime top speed of 20km/h, as opposed to the previous 25km/h, 2) the use of shared e-scooters was prohibited on Friday and Saturday nights between 12 p.m. and 5 a.m, and 3) the nighttime top speed was lowered to 15 km/h from Sunday to Thursday between 12 p.m. and 5 a.m., as opposed to 25 km/h.Main outcome measureProportional incidence of e-scooter injuries compared to the total trips made by e-scooters.ResultsThere were 528 e-scooter injuries requiring hospital care during the unrestricted period (1.1.-31.8.2021) and 318 injuries during the restricted period of similar length (1.1.-31.8.2022). The proportional incidence of e-scooter injuries was 19 (95% CI 17-20) for every 100 000 rides during the unrestricted period and 9 (95% 8-10) per 100 000 rides during the restricted period. In the risk analysis, the odds ratio (OR) for shared e-scooter accidents was 0.5 (95% CI 0.4-0.6) for the restricted period when adjusted for hourly temperature, rain amount, wind speed, and visibility. After introducing the restrictions, the number of e-scooter injuries decreased significantly between 11 p.m. and 5 a.m.ConclusionsRestrictions on the top speed and nighttime usage of e-scooters decreased the amount of e-scooter injuries. We recommend similar restrictions in cities with shared e-scooter services.
Surveying Argentine healthcare providers’ knowledge, attitude, and practice about diagnosis and management of sports-related concussions
Authors: Russo María Julieta , Salvat Fernando , Kañevsky Agostina , Saco Marcelo , Hidalgo Ignacio Alonso , Vedova Franco Della , Allegri Ricardo Francisco , Sevlever Gustavo 
Published: June 2023

ABSTRACTBackgroundA better understanding of the healthcare providers’ knowledge, attitude, and practice (KAP) level would help athletes, trainers, and athletic administrators, implement more effective concussion-management recommendations and guidelines. This survey aims to understand healthcare providers’ KAP dimensions regarding the diagnosis and management of sports-related concussions.MethodsCross-sectional study. An online-based KAP survey was carried out on a convenience sample of healthcare providers, coaches, parents, and athletes (n=626) in partnership with sports concussion clinics, rugby union, and rugby league in Argentina. The questionnaire incorporated 25 questions. Descriptive analysis was estimated as means, SD, and proportion. Chi-square tests, two-sample t-tests, and regression analysis were utilized for the response analysis.ResultsSeventy-four percent of the respondents reported having concussion training. Respondents correctly answered on average 6.23 ± 2.16 (out of 10) knowledge questions. The largest gaps were related to the clinical interpretation of symptom severity and neuroimaging. The smallest gaps were identified in young athletes’ management. There was a significant difference in mean survey respondents’ knowledge scores [F (1,622) =109.479, p<0.001] between those who had received formal concussion training and those who had not.ConclusionsThis study reveals that healthcare providers have appropriate knowledge and attitude regarding sport-related concussions but there are important knowledge gaps and practices that are often wanting. Our findings confirm the need for training and education on sport-related concussions. It would be advisable to implement educational campaigns specifically focused on the diagnosis and management of sports concussions, to raise awareness about this topic in schools, leagues, and sports associations.
Exposome Epidemiology for Suspect Environmental Chemical Exposures during Pregnancy Linked to Subsequent Breast Cancer Diagnosis
Authors: Go Young-Mi , Weinberg Jaclyn , Teeny Sami , Cirillo Piera , Krigbaum Nickilou , Singer Grant , Ly ViLinh , Cohn Barbara , Jones Dean P. 
Published: June 2023

ABSTRACTBreast cancer is now the most common cancer globally, accounting for 12% of all new annual cancer cases worldwide. Despite epidemiologic studies having established a number of risk factors, knowledge of chemical exposure risks is limited to a relatively small number of chemicals. In this exposome research study, we used non-targeted, high-resolution mass spectrometry (HRMS) of pregnancy cohort biospecimens in the Child Health and Development Studies (CHDS) to test for associations with breast cancer identified via the California Cancer Registry. Second (T2) and third (T3) trimester archival samples were analyzed from 182 women who subsequently developed breast cancer and 384 randomly selected women who did not develop breast cancer. Environmental chemicals were annotated with the Toxin and Toxin-Target Database (T3DB) for chemical signals that were higher in breast cancer cases and used with an exposome epidemiology analytic framework to identify suspect chemicals and associated metabolic networks. Network and pathway enrichment analyses showed consistent linkage in both T2 and T3 to inflammation pathways, including linoleate, arachidonic acid and prostaglandins, and identified new suspect environmental chemicals associated with breast cancer, i.e., an N-substituted piperidine insecticide and a common commercial product, 2,4-dinitrophenol (DNP), linked to variations in amino acid and nucleotide pathways in T2 and benzo[a]carbazole and a benzoate derivative linked to glycan and amino sugar metabolism in T3. The results identify new suspect environmental chemical risk factors for breast cancer and provide an exposome epidemiology framework for discovery of suspect environmental chemicals and potential mechanistic associations with breast cancer.
Trajectories of atherosclerotic cardiovascular disease risk scores as a predictor for incident chronic kidney disease
Authors: Lee Hye Sun , Lim Hong Il , Moon Tae Ju , Lee So Young , Lee Jun-Hyuk 
Published: June 2023

AbstractBackgroundThe relationship between atherosclerosis and renal function is well established. Atherosclerotic cardiovascular disease (ASCVD) risk scores reflect atherosclerotic burden, which changes over time. We investigated the association between ASCVD risk trajectories and incident chronic kidney disease (CKD) using data from a large community-based Korean cohort with up to 16 years of follow-up.MethodsWe analyzed data from 5032 participants without CKD from the baseline survey of the Korean Genome and Epidemiology Study Ansan-Ansung cohort. Participants were categorized into stable or increasing ASCVD risk groups based on the revised ASCVD risk pooled cohort equation over a median period of exposure of 5.8 years. Incident CKD was defined as two consecutive events of an estimated glomerular filtration rate <60 mL/min/1.73 m2.ResultsDuring a median 9.9 years of event accrual period, 449 (8.92%) new-onset CKD cases were identified. Multiple Cox proportional regression analyses showed that the hazard ratio (95% confidence interval) for incident CKD in the increasing group, compared to the stable group, was 2.13 (1.74–2.62) in the unadjusted model and 1.35 (1.02–1.78) in the fully-adjusted model. Significant relationships were maintained in subgroups of individuals in their 50s, without diabetes mellitus or hypertension. The prevalence of proteinuria was consistently higher in the increasing group than that in the stable group.ConclusionsAn increasing trend in ASCVD risk scores independently predicted adverse renal outcomes. Continuous monitoring of ASCVD risk is not only important for predicting cardiovascular disease but also for predicting CKD.
Integrative metabolomics differentiate coronary artery disease, peripheral artery disease, and venous thromboembolism risks
Authors: Lee Jiwoo , Gilliland Thomas , Koyama Satoshi , Nakao Tetsushi , Dron Jacqueline , Lannery Kim , Wong Megan , Peloso Gina M. , Hornsby Whitney , Natarajan Pradeep 
Published: June 2023

AbstractRationaleArterial and venous cardiovascular conditions, such as coronary artery disease (CAD), peripheral artery disease (PAD), and venous thromboembolism (VTE), are genetically correlated. Interrogating distinct and overlapping mechanisms may shed new light on disease mechanisms.ObjectiveIn this study, we aimed to: identify and compare (1) epidemiologic and (2) causal, genetic relationships between metabolites and CAD, PAD, and VTE.MethodsWe used metabolomic data from 95,402 individuals in the UK Biobank, excluding individuals with prevalent cardiovascular disease. Logistic regression models adjusted for age, sex, genotyping array, first five principal components of ancestry, and statin use estimated the epidemiologic associations of 249 metabolites with incident CAD, PAD, or VTE. Bidirectional two-sample Mendelian randomization (MR) estimated the causal effects between metabolites and cardiovascular phenotypes using genome-wide association summary statistics for metabolites (N = 118,466 from UK Biobank), CAD (N = 184,305 from CARDIoGRAMplusC4D 2015), PAD (N = 243,060 from Million Veterans Project) and VTE (N = 650,119 from Million Veterans Project). Multivariable MR (MVMR) was performed in subsequent analyses.ResultsWe found that 194, 111, and 69 metabolites were epidemiologically associated (P < 0.001) with CAD, PAD, and VTE, respectively. Metabolomic profiles exhibited variable similarity between disease pairs: CAD and PAD (N = 100 shared associations, R2= 0.499), CAD and VTE (N = 68, R2= 0.455), and PAD and VTE (N = 54, R2= 0.752). MR revealed 28 metabolites that increased risk for both CAD and PAD and 2 metabolites that increased risk for CAD but decreased risk for VTE. Despite strong epidemiologic overlap, no metabolites had a shared genetic relationship between PAD and VTE. MVMR revealed several metabolites with shared causal effects on CAD and PAD related to cholesterol content within very-low-density lipoprotein particles.ConclusionsWhile common arterial and venous conditions are associated with overlapping metabolomic profiles, MR prioritized the role of remnant cholesterol in arterial diseases but not venous thrombosis.