bluuebunny/crossref_metadata_2025_split huggingface dataset:
FOG2 coding variant Ser657Gly is associated with Coronary Microvascular Disease through altered hypoxia-mediated gene transcription
Authors: Guerraty M.A. , Verma Shefali , Ko Y.A. , McQuillan M.A. , Conlon D. , Tobias J.W. , Levin M.G. , Haury W. , Zhang C. , Judy R. ,   Regeneron Genomics Center,   PennMedicine Biobank, Tishkoff S. , Damrauer S.M. , Arany Z. , Rader D.J. 
Published: May 2023

AbstractRationaleThe coronary microvasculature is crucial for proper cardiac function, and coronary microvascular disease (CMVD) has emerged as an underdiagnosed and undertreated cause of ischemic heart disease. Friend of GATA 2 (FOG2) is a transcriptional co-regulator crucial for coronary development and the maintenance of the coronary microvasculature in adult mice.Little is known about the role of FOG2 in humans or its role in CMVD.ObjectiveHere, we report a genotype-first approach to determine the role of FOG2 in human coronary microvascular disease.FindingsWe performed Phenome-Wide association studies and deep cardiac phenotyping through the Electronic Health record in patients with FOG2 coding variants and identified an association between rs28374544 (A1969G, S657G) and CMVD. Patients with S657G had increased chest pain, smaller burden of obstructive coronary artery disease, and altered coronary blood flow. Differential gene and pathway analysis using several genomic datasets showed that carriers of S657G have increased expression of genes involved in angiogenesis, glycolysis, and the hypoxia-inducible factor (HIF) pathway. In vitro functional studies show that FOG2 S657G promotes angiogenic gene expression and angiogenesis while decreasing oxygen consumption rate. FOG2 also regulates HIF1a occupancy of angiogenic genes.ConclusionsWe identified a human missense variant which is associated with CMVD and established a potential mechanism by which the variant may altered angiogenic gene expression.
Inferring Multi-Organ Genetic Causal Connections using Imaging and Clinical Data through Mendelian Randomization
Authors: Shu Juan , Zheng Rong , Chirinos Julio , Copana Carlos , Li Bingxuan , Fan Zirui , Yang Xiaochen , Yang Yilin , Wang Xiyao , Li Yujue , Xi Bowei , Li Tengfei , Zhu Hongtu , Zhao Bingxin 
Published: May 2023

AbstractUnderstanding the complex causal relationships among major clinical outcomes and the causal interplay among multiple organs remains a significant challenge. By using imaging phenotypes, we can characterize the functional and structural architecture of major human organs. Mendelian randomization (MR) provides a valuable framework for inferring causality by leveraging genetic variants as instrumental variables. In this study, we conducted a systematic multi-organ MR analysis involving 402 imaging traits and 372 clinical outcomes. Our analysis revealed 184 genetic causal links for 58 diseases and 56 imaging traits across various organs, tissues, and systems, including the brain, heart, liver, kidney, lung, pancreas, spleen, adipose tissue, and skeletal system. We identified intra-organ causal connections, such as the bidirectional genetic links between Alzheimer’s disease and brain function, as well as inter-organ causal effects, such as the impact of heart diseases on brain health. Metabolic disorders, such as diabetes, exhibited causal effects across multiple organs. These findings shed light on the genetic causal links spanning multiple organs, providing insights into the intricate relationships between organ functions and clinical outcomes.
Brain development mutations in the β-tubulin TUBB result in defective ciliogenesis
Authors: Mollica Antonio , Omer Safia , Evagelou Sonia L. , Naumenko Serhiy , Li Lu Yi , Teeling Aideen , Lindsay Kyle , Erwood Steven , Vernon Robert M. , Forman-Kay Julie D. , Shroff Manohar , Harrison Rene E. , Cohn Ronald D. , Ivakine Evgueni A. 
Published: May 2023

ABSTRACTTubulinopathies and neurodevelopmental ciliopathies are two groups of genetic disorders characterized by abnormal brain development resulting in structural brain malformations. Tubulinopathies are caused by dominant missense mutations in genes encoding for tubulins, the building blocks of microtubules. Neurodevelopmental ciliopathies are mostly recessive disorders caused by defects in the function of the primary cilium, a sensory organelle that modulates signaling pathways important for brain development. Though more than 40 genes have been associated with neurodevelopmental ciliopathies, many patients still do not have an identified genetic etiology. Herein, we present a novelde novoheterozygous missense variant in Tubulin Beta Class I (TUBB) identified through whole-genome sequencing analysis in a patient with both ciliopathy and tubulinopathy brain features. While microtubules are fundamental to primary cilia formation and function, no association between mutations in tubulin genes and neurodevelopmental ciliopathies has been found to date. Using patient-derived cells and gene-edited isogenic cell lines, we show that the identified variant impairs the early stages of cilia formation by altering microtubule dynamics and structure. Furthermore, we demonstrate that the disease mechanism is not haploinsufficiency and that other patient mutations inTUBBaffect cilia formationin vitro, putting forward defective ciliogenesis as a contributing pathogenic factor in a subset of tubulinopathy patients.
Environmental Sustainability in England’s NHS Respiratory Prescribing; A grounded theory analysis to define a methodology for estimation of inhaler carbon footprint
Authors: Nettleton Helena R.P. , Masters Gillian A. , Mason Monica M. 
Published: May 2023

BackgroundThe impact of climate change on health is increasing, as global warming continues to rise.1Within the health and social care sector, pressurised metered dose inhalers (pMDIs) and breath-actuated pMDIs (BA-pMDIs) have been identified as a significant contributing factor to England’s National Health Service carbon footprint.2MethodsA grounded theory study design was applied to formulate a process map and methodology for Inhaler carbon footprint estimation, utilising established inhaler carbon footprint values and pharmaceutical principles.ResultsA methodology has been developed to support estimation of inhaler carbon footprint values for those inhalers and refills, that do not have a manufacturer’s independently verified carbon footprint certificate.ConclusionDefinitive Inhaler carbon footprint values, such as those reported here, are required to enable analysis and monitoring of prescribing against Net Zero targets. Further application can also support sustainability assessment and formulary decision making.
Neurophysiological correlates of gait initiation in individuals with Huntington’s and Parkinson’s disease
Authors: Desai Radhika , Quinn Lori 
Published: May 2023

AbstractBackgroundHuntington’s disease (HD) and Parkinson’s disease (PD) are neurodegenerative diseases resulting in motor impairments of gait initiation (GI). However, the neurophysiological underpinnings of GI in HD and PD are not well understood. The aims of this study were to 1) evaluate the feasibility of a wireless EEG system to identify EEG-derived movement-related potentials (MRPs) in individuals with HD and PD during GI, and to 2) determine the tolerance of a high repetition GI protocol.New Method3 participants with HD and 3 participants with PD performed 3 blocks of 15 trials of GI. EEG-derived MRPs of readiness potential (RPs) and contingent negative variation (CNV) were identified during GI, using a wireless EEG system synced with kinetic measures of GI. Tolerance of the protocol was determined from changes in COP across GI blocks.ResultsThere were no differences between HD and PD for CNV and RP amplitudes and latencies, although they were within acceptable ranges of MRP values in HD and PD. There were no differences of COP values between GI blocks.Comparison with old methodA wireless EEG system elicits naturalistic GI biomechanical responses as opposed to previous methods employing tethered systems. In contrast to single-trial EEG studies, this study implemented a larger number of GI trials, which produces greater MRP resolution.ConclusionsThis study validated the use of a wireless EEG headset in determining MRP values during GI in HD and PD. Participants within these populations were able to tolerate a high repetition GI protocol. Future work will explore MRPs in larger cross-sectional studies for the development of clinical outcome measures.
The effect of level of injury on diabetes incidence and mortality after spinal cord injury – a longitudinal cohort study
Authors: Hoekstra Sven , Trbovich Michelle , Koek Wouter , Mader Michael , Salehi Marzieh 
Published: May 2023

AbstractObjectivePersons with spinal cord injury (SCI) are at increased risk to develop diabetes mellitus (DM) compared to their able-bodied counterparts, likely due to body composition alterations and autonomic nervous system dysfunction. These factors are more pronounced in persons with tetraplegia (TP) versus paraplegia (PP), however, the effect of level of injury (LOI) on DM incidence is largely unknown. Therefore, the objective is to examine the effect of LOI on DM incidence in persons with SCI.DesignRetrospective longitudinal cohort study of veterans with SCI.MethodsWe obtained electronic record data on age, sex, race/ethnicity, LOI and HbA1c concentration from January 1st2001 through December 31st2021. Cox proportional hazard regression analyses were used to assess the association between LOI, DM and all-cause mortality.ResultsAmong 728 non-diabetic veterans with SCI (350 TP/ 378 PP, 52±15 years, 690 male/38 female) 243 developed DM, of which 116 with TP and 127 with PP. Despite chronological variations between TP and PP, DM risk over the entire follow-up did not differ among the groups (hazard ratio (HR): 1.06, 95% CI: 0.82 - 1.38). Mortality was higher in TP versus PP (HR: 1.40, 95% CI: 1.09 – 1.78). However, developing DM did not increase the risk of death, regardless of LOI (HR: 1.07, 95% CI: 0.83 – 1.37).ConclusionsIn this cohort of veterans with SCI, the level of injury had minimal effect on long-term DM development but increased mortality as previously reported.Significance statementPersons with spinal cord injury are at increased risk for developing diabetes mellitus (DM); however, the effect of level of injury is unclear. In the current study using an electronic health record system we found that the incidence of DM is similar between persons with a high (i.e., tetraplegia) versus low (i.e., paraplegia) lesion level, and that developing DM does not affect the risk for mortality. Additionally, our findings suggest that baseline glycemic level (such as HbA1c), unlike baseline body mass index, is a strong predictor of DM development in this population. Further studies are warranted to explore pathophysiological factors responsible for DM development among patients with higher and lower LOI to develop targeted preventive and therapeutic strategies.
The Brazilian vaccine divide: how some municipalities are being left behind in the Covid-19 vaccine coverage
Authors: Boing Antonio Fernando , Boing Alexandra Crispim , Barberia Lorena , Borges Marcelo Eduardo , Subramanian SV 
Published: May 2023

AbstractObjectivesThis study aims to assess the progress of geographic, socioeconomic, and demographic disparities in Covid-19 vaccination coverage in Brazil over the first two years of the vaccination campaign.Study designEcologic study.MethodsData from the National Immunization Program Information System were used to estimate covid-19 vaccine coverage. Brazilian municipalities were divided into two groups based on their vaccine coverage for the booster dose. The first group comprised 20% of municipalities with the lowest coverage, while the second group (80% of municipalities) had higher coverage. The analysis was conducted separately for four age groups: 5-11, 12-17, 18-59, and 60+. Exploratory variables included socioeconomic and health services indicators. Crude and adjusted logistic regression models were used to estimate the probability of a municipality being among those with the worst vaccination coverage according to the categories of exploratory variables.ResultsBetween January/2021 and December/2022, Brazil administered 448.2 million doses of the covid-19 vaccine. The booster vaccination coverage varied from 24.8% among adolescents to 79.7% among the elderly. The difference between the group with the highest and lowest coverage increased during the national vaccination campaign. Municipalities with lower education levels, higher proportion of Black population, higher Gini index, and worse health service indicators had a greater likelihood of having lower vaccination coverage.ConclusionsHigh and increasing levels of inequality in Covid-19 vaccination were observed in Brazil across all age groups during the vaccination campaign in 2021-2022.
Identification of targets for drug repurposing to treat COVID-19 using a Deep Learning Neural Network
Authors: Wang Si-Han , Tang Yu-Hsuan , Hsu Hao , Yu Chu-Nien , Leea Oscar Kuang-Sheng 
Published: May 2023

AbstractThe COVID-19 pandemic has resulted in a global public health crisis requiring immediate acute therapeutic solutions. To address this challenge, we developed a useful tool deep learning model using the graph-embedding convolution network (GECN) algorithm. Our approach identified COVID-19-related genes and potential druggable targets, including tyrosine kinase ABL1/2, pro-inflammatory cytokine CSF2, and pro-fibrotic cytokines IL-4 and IL-13. These target genes are implicated in critical processes related to COVID-19 pathogenesis, including endosomal membrane fusion, cytokine storm, and tissue fibrosis. Our analysis revealed that ABL kinase inhibitors, lenzilumab (anti-CSF2), and dupilumab (anti-IL4Rα) represent promising therapeutic solutions that can effectively block virus-host membrane fusion or attenuate hyperinflammation in COVID-19 patients. Compared to the traditional drug screening process, our GECN algorithm enables rapid analysis of disease-related human protein interaction networks and prediction of candidate drug targets from a large-scale knowledge graph in a cost-effective and efficient manner. Overall, Overall, our results suggest that the model has the potential to facilitate drug repurposing and aid in the fight against COVID-19.
GPR161 structure uncovers the redundant role of sterol-regulated ciliary cAMP signaling in the Hedgehog pathway
Authors: Hoppe Nicholas , Harrison Simone , Hwang Sun-Hee , Chen Ziwei , Karelina Masha , Deshpande Ishan , Suomivuori Carl-Mikael , Palicharla Vivek R. , Berry Samuel P. , Tschaikner Philipp , Regele Dominik , Covey Douglas F. , Stefan Eduard , Marks Debora S. , Reiter Jeremy , Dror Ron O. , Evers Alex S. , Mukhopadhyay Saikat , Manglik Aashish 
Published: May 2023

AbstractThe orphan G protein-coupled receptor (GPCR) GPR161 is enriched in primary cilia, where it plays a central role in suppressing Hedgehog signaling1. GPR161 mutations lead to developmental defects and cancers2,3,4. The fundamental basis of how GPR161 is activated, including potential endogenous activators and pathway-relevant signal transducers, remains unclear. To elucidate GPR161 function, we determined a cryogenic-electron microscopy structure of active GPR161 bound to the heterotrimeric G protein complex Gs. This structure revealed an extracellular loop 2 that occupies the canonical GPCR orthosteric ligand pocket. Furthermore, we identify a sterol that binds to a conserved extrahelical site adjacent to transmembrane helices 6 and 7 and stabilizes a GPR161 conformation required for Gscoupling. Mutations that prevent sterol binding to GPR161 suppress cAMP pathway activation. Surprisingly, these mutants retain the ability to suppress GLI2 transcription factor accumulation in cilia, a key function of ciliary GPR161 in Hedgehog pathway suppression. By contrast, a protein kinase A-binding site in the GPR161 C-terminus is critical in suppressing GLI2 ciliary accumulation. Our work highlights how unique structural features of GPR161 interface with the Hedgehog pathway and sets a foundation to understand the broader role of GPR161 function in other signaling pathways.
Towards course of disease based epidemiological modelling: motivation and computational optimization
Authors: Wu Yu-Heng , Nordling Torbjörn E. M. 
Published: May 2023

AbstractThe ongoing COVID-19 pandemic has demonstrated the shortcoming of epidemiological modelling for guiding policy decisions. Due to the lack of public data on infection spread in contact networks and individual courses of disease, current forecasting models rely heavily on unreliable population statistics andad hocparameters, resulting in forecasts with high uncertainty. To tackle the problem of insufficient public individual data, we develop an agent-based model to generate a synthetic Taiwanese COVID-19 dataset. We collected COVID-19 data from Taiwanese public databases for the period when the original SARS-CoV-2 virus was most prevalent (Jan.-Oct., 2020) and fit our model to it. We used the Firefly algorithm to optimize the 194 epidemiological parameters and validated the synthetic dataset by comparing it to Taiwanese public data. Here we study the difference between population statistics and individual course of disease data, and computational optimization of our code to reduce run time. The discrepancy between serum prevalence and reported cases, as well as excess deaths and reported deaths, show that population statistics are unreliable. Monte Carlo simulations further exemplify the discrepancy between actual and reported infections. By using Python CProfiler and Snakeviz packages, we iteratively optimize our algorithm and has so far decreased the computation time of the core code from 0.11s to 0.07s. The large computation time implies that we need to further optimize the algorithm.
Trends in Prevalence of Cannabis Use Disorders among U.S. Veterans with and without Psychiatric Disorders Between 2005 and 2019
Authors: Livne Ofir , Malte Carol A. , Olfson Mark , Wall Melanie M. , Keyes Katherine M. , Maynard Charles , Gradus Jaimie L. , Saxon Andrew J. , Martins Silvia S. , Keyhani Salomeh , McDowell Yoanna , Fink David S. , Mannes Zachary L. , Gutkind Sarah , Hasin Deborah S. 
Published: May 2023

ABSTRACTObjectiveCannabis use disorders (CUD) are increasing among U.S. adults and are more prevalent among cannabis users with comorbid psychiatric disorders. Changing cannabis laws, increasing cannabis availability, and higher potency cannabis may have recently placed cannabis users with psychiatric disorders at disproportionately increasing risk for CUD. The authors used Veterans Health Administration (VHA) data to examine whether trends in CUD prevalence among VHA patients differ by whether they have psychiatric disorders.MethodsVHA electronic health records from 2005 to 2019 (n range=4,332,165-5,657,277) were used to identify overall and age-specific (<35, 35-64, ≥65 years) trends in prevalence of CUD diagnoses among patients with depressive, anxiety, PTSD, bipolar, or psychotic-spectrum disorders, and to compare these to corresponding trends among patients without any of these disorders. Given transitions in ICD coding, differences in trends were tested within two periods: 2005–2014 (ICD-9-CM) and 2016–2019 (ICD-10-CM).ResultsGreater increases in prevalence of CUD diagnoses were observed in veterans with, compared to without, psychiatric disorders (2005-2014: difference in prevalence change=1.91%, 95% CI=1.87%-1.96%; 2016-2019: 0.34%, 95% CI=0.29%-0.38%). Disproportionate increases in CUD prevalence among those with psychiatric disorders were greatest in veterans ages <35 between 2005-2014, and in those ages ≥65 between 2016-2019. Among patients with psychiatric disorders, greatest increases in CUD prevalences were observed in those with bipolar and psychotic-spectrum disorders.ConclusionsResults highlight disproportionately increasing disparities in risk of CUD among VA patients with common psychiatric disorders. Greater public health and clinical efforts are needed to monitor, prevent and treat CUD among this population.
Missing data and missed infections: Investigating racial and ethnic disparities in SARS-CoV-2 testing and infection rates in Holyoke, Massachusetts
Authors: Sauer Sara M. , Fulcher Isabel R. , Matias Wilfredo R. , Paxton Ryan , Elnaiem Ahmed , Gonsalves Sean , Zhu Jack , Guillaume Yodeline , Franke Molly , Ivers Louise C. 
Published: May 2023

AbstractRoutinely collected testing data has been a vital resource for public health response during the COVID-19 pandemic and has revealed the extent to which Black and Hispanic persons have borne a disproportionate burden of SARS-CoV-2 infections and hospitalizations in the United States. However, missing race and ethnicity data and missed infections due to testing disparities limit the interpretation of testing data and obscure the true toll of the pandemic. We investigated potential bias arising from these two types of missing data through a case study in Holyoke, Massachusetts during the pre-vaccination phase of the pandemic. First, we estimated SARS-CoV-2 testing and case rates by race/ethnicity, imputing missing data using a joint modelling approach. We then investigated disparities in SARS-CoV-2 reported case rates and missed infections by comparing case rate estimates to estimates derived from a COVID-19 seroprevalence survey. Compared to the non-Hispanic white population, we found that the Hispanic population had similar testing rates (476 vs. 480 tested per 1,000) but twice the case rate (8.1% vs. 3.7%). We found evidence of inequitable testing, with a higher rate of missed infections in the Hispanic population compared to the non-Hispanic white population (77 vs. 58 infections missed per 1,000).
Bacterial genome wide association study substantiatespapGIIofEscherichia colias a patient independent driver of urosepsis
Authors: Cuénod Aline , Agnetti Jessica , Seth-Smith Helena , Roloff Tim , Wälchli Denise , Scherbakov Dimitri , Akbergenov Rashid , Tschudin-Sutter Sarah , Bassetti Stefano , Siegemund Martin , Nickel Christian H. , Moran-Gilad Jacob , Keys Timothy G. , Pflüger Valentin , Thomson Nicholas R. , Egli Adrian 
Published: May 2023

AbstractUrinary tract infections are extremely common and often caused byEscherichia coli. Bacterial virulence factors and patient characteristics have been linked separately to progressive, invasive infection. The interaction of these factors has however rarely been considered. We whole genome sequenced 1076E. coliisolates recovered from urine-or blood culture samples from 825 clinical cases. The majority of isolates belonged to the phylogroups B2 and D and encoded polysaccharide capsules. In line with previous studies, our bGWAS identifiedpapGIIto be associated with bacteraemia. In a generalised linear model correcting for patient characteristics,papGIIwas substantiated as a major contributor to invasive infection. Further, an independent cohort of 1,657 urine samples was PCR screened forpapGIIcarryingE. coli, confirming the increased relative frequency ofpapGII+ strains to cause invasive infection. This study builds on previous work linkingpapGIIwith invasive infection by showing that it is a patient-independent risk factor that has diagnostic potential.