bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimation of Direct and Indirect Polygenic Effects and Gene-Environment Interactions using Polygenic Scores in Case-Parent Trio Studies
Authors: Wang Ziqiao , Grosvenor Luke , Ray Debashree , Ruczinski Ingo , Beaty Terri H. , Volk Heather , Ladd-Acosta Christine , Chatterjee Nilanjan 
Published: October 2024

AbstractFamily-based studies provide a unique opportunity to characterize genetic risks of diseases in the presence of population structure, assortative mating, and indirect genetic effects. We propose a novel framework, PGS-TRI, for the analysis of polygenic scores (PGS) in case-parent trio studies for estimation of the risk of an index condition associated with direct effects of inherited PGS, indirect effects of parental PGS, and gene-environment interactions. Extensive simulation studies demonstrate the robustness of PGS-TRI in the presence of complex population structure and assortative mating compared to alternative methods. We apply PGS-TRI to multi-ancestry trio studies of autism spectrum disorders (Ntrio= 1,517) and orofacial clefts (Ntrio= 1,904) to establish the first transmission-based estimates of risk associated with pre-defined PGS for these conditions and other related traits. For both conditions, we further explored offspring risk associated with polygenic gene-environment interactions, and direct and indirect effects of genetically predicted levels of gene expression and metabolite traits.
A Decade of Progress in HIV, Malaria, and Tuberculosis Initiatives in Malawi
Authors: Mangal Tara Danielle , Molaro Margherita , Nkhoma Dominic , Colbourn Timothy , Collins Joseph H. , Janoušková Eva , Graham Matthew M. , Lin Ines Li , Mnjowe Emmanuel , Mwenyenkulu Tisungane E. , Mohan Sakshi , She Bingling , Tamuri Asif U. , Twea Pakwanja D. , Winskill Peter , Phillips Andrew , Mfutso-Bengo Joseph , Hallett Timothy B. 
Published: October 2024

AbstractObjectiveHuge investments in HIV, TB, and malaria (HTM) control in Malawi have greatly reduced disease burden. However, the joint impact of these services across multiple health domains and the health system resources required to deliver them are not fully understood.MethodsAn integrated epidemiological and health system model was used to assess the impact of HTM programmes in Malawi from 2010 to 2019, incorporating interacting disease dynamics, intervention effects, and health system usage. Four scenarios were examined, comparing actual programme delivery with hypothetical scenarios excluding programmes individually and collectively.FindingsFrom 2010-2019, HTM programmes were estimated to have prevented 1.08 million deaths and 74.89 million DALYs. An additional 15,600 deaths from other causes were also prevented. Life expectancy increased by 13.0 years for males and 16.9 years for females.The HTM programmes accounted for 24.2% of all health system interactions, including 157.0 million screening/diagnostic tests and 23.2 million treatment appointments. Accounting for the anticipated health deterioration without HTM services, only 41.55 million additional healthcare worker hours were required (17.1% of total healthcare worker time) to achieve these gains. The HTM programme eliminated the need for 123 million primary care appointments, offset by a net increase in inpatient care demand (9.4 million bed-days) that would have been necessary in its absence.ConclusionsHTM programmes have greatly increased life expectancy, providing direct and spillover effects on health. These investments have alleviated the burden on inpatient and emergency care, which requires more intensive healthcare provider involvement.
Exploring the Relationship Between Education and Academic Ability in Childhood with Healthcare Utilisation in Adulthood: Findings from the Aberdeen Children of the 1950’s (ACONF)
Authors: Stannard S , Fraser SDS , Owen R , Berrington A , Paranjothy S , Alwan NA 
Published: October 2024

AbstractBackgroundInteractions with secondary care, including multiple outpatient appointments and hospital admissions, represents a common and often burdensome aspect of healthcare utilisation for people living with multiple long-term conditions. Lifecourse factors such as education and academic ability may play a role in shaping the risk of healthcare utilisation later in adulthood. We explored the association between education and academic ability in childhood and both outpatient appointments and hospital admissions in adulthood, accounting for the mediating role of adult factors, including long-term conditions.MethodThe analytical sample consisted of 7183 participants in the Aberdeen Children of the 1950’s. Three outcomes were measured using routine healthcare records (SMR00/SMR001/SMR004) over a five-year period (2004-2008) using the ‘burden’ cut-offs of: (1) ≥5 outpatient appointments, (2) ≥2 hospital admissions, or (3) ≥3 outpatient appointments plus ≥1 hospital admission. We constructed a childhood (age 6-11) education and academic ability domain and calculated predicted risk scores of the three outcomes for each cohort member. Nested logistic regression models investigate the association between domain predicted risk scores and odds of each of the three outcomes accounting for childhood confounders (maternal age, Rutter behaviour, physical grade at birth, birthweight, sex mother’s pre-marital occupation, and father’s social class) and self-reported adult mediators, including body mass index, smoking, employment status, housing tenure, having long-term conditions, and age left school.ResultAdjusting for childhood confounders, lower childhood education and academic ability was associated with ≥ 5 outpatient appointments (OR1.03 95%CI 1.01-1.05), ≥ 2 hospital admissions (OR1.04 95%CI 1.03-1.6) and combined ≥3 outpatient appointments plus ≥ 1 hospital admissions (OR1.04 95%CI 1.02-1.06). Accounting for adult mediators (including long-term conditions), associations remained statistically significant, but their effect sizes were slightly reduced. When age left school was included in the final model, the association between the exposure and the combined outpatient appointments and hospital admissions (OR1.02 95%CI 1.00-1.04), ≥ 2 hospital admissions (OR1.02 95%CI 0.99-1.05) and ≥ 5 outpatient appointments (OR1.01 95%CI 0.99-1.03) were attenuated.ConclusionsEducation and academic ability in early life may be related to the burden of multiple hospital admissions and outpatient appointments later in life. This relationship was not fully explained by accounting for multiple long-term conditions and other potential mediating factors in adulthood. However, the age at which the participant left school seems to substantially mediate this relationship underscoring the positive impact of time spent in formal education on health during the lifecourse.
The Double Burden of TB/HIV co-infection: Evidence from Central Region of Ghana
Authors: Lugutuah Martin Badagda , Boateng Daniel , Konadu Phenehance Effah , Okoh-Owusu Marion , Nakua Emmanuel Kwaku 
Published: October 2024

AbstractThe synergistic burden of Tuberculosis (TB) and Human Immunodeficiency Virus (HIV) is a significant health risk in low and middle-income economies. This study estimated the prevalence and predictors of TB/HIV co-infection in the Central region of Ghana. Using a cross-sectional study, we randomly selected five districts and employed a retrospective records review of TB cases registered between 2019 and 2022. A stepwise multivariate logistic regression was used to identify important predictors of TB/HIV co-infection. The overall prevalence of TB/HIV co-infection in the study period was 10.92%. This was highest at 55 (15.54%) among the age group 25 – 40 years. The burden of TB/HIV co-infection was highest at 36 (19.25%) in the Gomoa East district and lowest at 30 (8.38%) in Mfantseman municipal. In the adjusted model, TB patients 60 years and above had 78% lower odds of being HIV infected (AOR: 0.22; 95% CI: 0.08 – 0.66). Males were 37% less likely to be co-infected (AOR: 0.63; 95% CI: 0.42 – 0.96). Also, pulmonary-positive TB patients were 5 times more likely to be co-infected (AOR: 5.04; 95% CI: 1.71 – 14.85). Furthermore, TB patients who died in the course of treatment were 2 times more likely to be infected with HIV (AOR:2.15; 95% CI: 1.05 – 4.40). TB patients treated in the Gomoa East district were 2.7 times more likely to be HIV-infected (AOR: 2.67; 95% CI: 1.34 – 5.35). The burden of TB/HIV co-infection was moderate in the study sites and significantly associated with age, sex, bacteriological confirmation, type of TB, treatment outcome, treatment district, and year of treatment. There is a need for targeted interventions such as community awareness creation that is specific to sexually active female groups. Efforts to improve TB case detection such as health facility-based screening of patients with Respiratory Tract Infections (RTI) and contact tracing should be intensified.
Genetic architecture of cardiac structure and function
Authors: Lu Chang , McGurk Kathryn A , Zheng Sean L , de Marvao Antonio , Inglese Paolo , Bai Wenjia , Ware James S , O’Regan Declan P 
Published: October 2024

AbstractThe heart is the first organ to develop in the mammalian embryo and its architecture is dependent on the spatial organisation of diverse cell types and morphogenetic transformations shaped by biophysical forces. Cardiac remodelling occurs in the mature heart and is a cascade of adaptations in response to stress that are primed in early life. A key question remains as to the processes that regulate the geometry and motion of the heart, and how it adapts to stress. Here we performed a spatially-resolved genome-wide association study of three-dimensional cardiac traits in 47,549 participants of UK Biobank. We found 42 loci associated with cardiac structure and contractility many of which reveal patterns of spatial organisation in the heart. Newly discovered loci relate to pathways implicated in cardiomyocyte differentiation and chamber development as well as those linked to cardiomyopathies. These findings provide a comprehensive description of the pathways that orchestrate heart development and mechanisms that regulate adaptation in health and disease.
A Large-Scale, International Cross-Sectional Survey of Published Pediatrics Authors: Perceptions of Complementary, Alternative, and Integrative Medicine
Authors: Ng Jeremy Y. , Deol Gursimran , Anheyer Dennis , Cramer Holger 
Published: October 2024

AbstractBackgroundThe use of complementary, alternative, and integrative medicine (CAIM) is commonly used among pediatric patients for various conditions. Pediatrics clinicians and researchers’ perceptions towards the incorporation of CAIM therapies have varied. This study aims to investigate the perceptions of both pediatrics researchers and clinicians regarding CAIM.MethodsWe conducted a large-scale, international cross-sectional online survey with published pediatrics authors who have published their work in pediatrics medical journals that are indexed in MEDLINE. In total, 34 494 researchers and clinicians were invited to complete the survey. The survey recorded respondents’ perceptions on various CAIM therapies. Descriptive statistics were generated from the quantitative survey results. A thematic analysis was conducted for responses to open ended questions.ResultsIn total, 731 pediatrics clinicians and/or researchers responded to the survey, with about half of the respondents being faculty members/principal investigators (56.10%) and/or clinicians (43.45%) and from the Americas (46.56%) or Europe (30.53%). Over half of the respondents viewed mind-body therapies favourably (62.01%) and the fewest respondents held favourable perceptions of biofield therapies (6.98%). Respondents agreed or strongly agreed that there is value in conducting further research on CAIM therapies (85.52%) and disagreed or strongly disagreed that they felt comfortable recommending most CAIM therapies to patients (64.83%). A thematic analysis of our findings demonstrates that many pediatrics clinicians and/or researchers support further research on CAIM.ConclusionThe findings from this study demonstrate that pediatrics clinicians and researchers have varying perceptions towards CAIM therapies. Respondents had the most positive perceptions of mind-body therapies and felt they did not have adequate training on CAIM. Further research is needed to establish more evidence-based educational resources on CAIM.
Epigenetic and Genetic Profiling of Comorbidity Patterns among Substance Dependence Diagnoses
Authors: Pathak Gita A. , Pietrzak Robert H. , Lacobelle AnnMarie , Overstreet Cassie , Wendt Frank R. , Deak Joseph D. , Friligkou Eleni , Nunez Yaira , Montalvo-Ortiz Janitza L. , Levey Daniel F. , Kranzler Henry R. , Gelernter Joel , Polimanti Renato 
Published: October 2024

ABSTRACTObjectiveThis study investigated the genetic and epigenetic mechanisms underlying the comorbidity patterns of five substance dependence diagnoses (SDs; alcohol, AD; cannabis, CaD; cocaine, CoD; opioid, OD; tobacco, TD).MethodsA latent class analysis (LCA) was performed on 31,197 individuals (average age 42±11 years; 49% females) from six cohorts to identify comorbid DSM-IV SD patterns. In subsets of this sample, we tested SD-latent classes with respect to polygenic burden of psychiatric and behavioral traits and epigenome-wide changes in three population groups.ResultsAn LCA identified four latent classes related to SD comorbidities: AD+TD, CoD+TD, AD+CoD+OD+TD (i.e., polysubstance use, PSU), and TD. In the epigenome-wide association analysis,SPATA4cg02833127 was associated with CoD+TD, AD+TD, and PSU latent classes. AD+TD latent class was also associated with CpG sites located onARID1B,NOTCH1,SERTAD4,andSIN3B, while additional epigenome-wide significant associations with CoD+TD latent class were observed inANO6andMOV10genes. PSU-latent class was also associated with a differentially methylated region inLDB1. We also observed shared polygenic score (PGS) associations for PSU, AD+TD, and CoD+TD latent classes (i.e., attention-deficit hyperactivity disorder, anxiety, educational attainment, and schizophrenia PGS). In contrast, TD-latent class was exclusively associated with posttraumatic stress disorder-PGS. Other specific associations were observed for PSU-latent class (subjective wellbeing-PGS and neuroticism-PGS) and AD+TD-latent class (bipolar disorder-PGS).ConclusionsWe identified shared and unique genetic and epigenetic mechanisms underlying SD comorbidity patterns. These findings highlight the importance of modeling the co-occurrence of SD diagnoses when investigating the molecular basis of addiction-related traits.
Incidence of Right Ventricular Dysfunction in an Echocardiographic Referral Cohort
Authors: Garry Jonah D. , Huang Shi , Annis Jeffrey , Kundu Suman , Hemnes Anna , Freiberg Matthew , Brittain Evan L. 
Published: October 2024

AbstractIntroductionIncidence rates (IRs) of RV dysfunction (RVD) are unknown. We examined the rates, risk factors, and heart failure (HF) hospitalization hazard associated with incident RVD in patients referred for Transthoracic Echocardiogram (TTE).MethodsIn this retrospective cohort study, we extracted tricuspid regurgitant velocity (TRV) and tricuspid annular systolic plane excursion (TAPSE) from TTEs at Vanderbilt (2010-2023). We followed patients from their earliest TTE with normal RV function (TAPSE≥17mm) and a reported TRV. The primary outcome was new RVD (TAPSE<17mm), and the secondary outcome was HF hospitalization after second TTE. Poisson regression and multivariable cox models estimated IRs and hazard ratios, adjusted for demographics, comorbidities, and TTE measures.ResultsAmong 45,753 patients (63 years [IQR 50-72], 45% Male, 13% Black) meeting inclusion criteria, 13,735 (30.1%) underwent a follow up TTE and 4,198 (9.2%) developed RVD. The IR of RVD in the full cohort was 3.2/100 person/years (95%CI 3.1-3.3) and 8.2 (95%CI 8.0-8.5) in the repeat TTE cohort. IRs increased with rising RVSP. Risk factors for incident RVD were most prominently HF (HR 1.88; 95%CI 1.75–2.03), left-sided valvular disease (HR 1.68; 95%CI 1.53–1.85), and other cardiovascular comorbidities. Baseline RVSP >35 mmHg associated with TAPSE decline over time. Incident RVD increased hazard of HF hospitalization (HR 2.02; 95%CI 1.85-2.21). Hazard of HF hospitalization increased when TAPSE declined by ≥5mm.ConclusionsRVD incidence is substantial among patients referred for TTE. Clinical monitoring is warranted if RVSP >35mmHg. Cardiovascular comorbidities drive RVD in this population. Incident RVD associates with increased hazard of HF hospitalization.
A novel approach for the quantification of single-cell adhesion dynamics from microscopy images
Authors: Cortesi Marilisa , Li Jingjing , Liu Dongli , Guo Tianruo , Dokos Socrates , Warton Kristina , Ford Caroline E. 
Published: October 2024

ABSTRACTBackgroundCell adhesion, that is the ability to attach to a given substrate, is a key property of cancer cells, as it relates to their potential for dissemination and metastasis. Thein vitroassays used to measure it, however, are characterized by several drawbacks, including low temporal resolution and limited procedural standardisation which reduce their usefulness and accuracy.ResultsIn this work, we propose an alternative analytical approach, based on live-cell imaging data, that yields comprehensive information on cell adhesion dynamics at the single-cell level. It relies on a segmentation routine, to identify the pixels belonging to each cell from time-lapse microscopy images acquired during the adhesion process. A tracking algorithm then enables the study of individual cell adhesion dynamics over time. The increased resolution afforded by this method was instrumental for the identification of cell division prior to attachment and the co-existence of markedly different proliferation rates across the culture, previously unidentified patterns of behaviour in the adhesion process. Finally, we generalize our method by substituting the segmentation algorithm of the instrument used to acquire the images, with a custom-made one, showing that this approach can be integrated within routine laboratory analytical procedures and does not necessarily require high-performance microscopy and imaging setups.ConclusionsOur new analytical approach improves thein vitroquantification of cell adhesion, enabling the study of this process with high temporal resolution and increased level of detail. The extension of the analysis to the single-cell level, additionally, uncovered the role of population variability and proliferation in this process. The simple and cost-effective procedure here described enables the accurate characterisation of cell adhesion. Beside improving our understanding of adhesion dynamics, its results could support the development of treatments targeting the ability of cancer cells to adhere to surrounding tissues.
The molecular chronology of mammary epithelial cell fate switching
Authors: Vallmajo-Martin Queralt , Ma Zhibo , Srinivasan Sumana , Murali Divya , Dravis Christopher , Mukund Kavitha , Subramaniam Shankar , Wahl Geoffrey M. , Lytle Nikki K. 
Published: October 2024

SummaryThe adult mammary gland is maintained by lineage-restricted progenitor cells through pregnancy, lactation, involution, and menopause. Injury resolution, transplantation-associated mammary gland reconstitution, and tumorigenesis are unique exceptions, wherein mammary basal cells gain the ability to reprogram to a luminal state. Here, we leverage newly developed cell-identity reporter mouse strains, and time-resolved single-cell epigenetic and transcriptomic analyses to decipher the molecular programs underlying basal-to-luminal fate switchingin vivo. We demonstrate that basal cells rapidly reprogram toward plastic cycling intermediates that appear to hijack molecular programs we find in bipotent fetal mammary stem cells and puberty-associatiated cap cells. Loss of basal-cell specifiers early in dedifferentiation coincides with activation of Notch and BMP, among others. Pharmacologic blockade of each pathway disrupts basal-to-luminal transdifferentiation. Our studies provide a comprehensive map and resource for understanding the coordinated molecular changes enabling terminally differentiated epithelial cells to transition between cell lineages and highlights the stunning rapidity by which epigenetic reprogramming can occur in response to disruption of tissue structure.
Perinatal Reduction of Genetically Aberrant Neurons from Human Cerebral Cortex
Authors: Shao Diane D. , Zhao Yifan , Ghosh Urmi , Brew Joseph , Zhao Sijing , Qian Xuyu , Tran Julie , Taketomi Takumi , Tsuruta Fuminori , Park Peter J. , Walsh Christopher A. 
Published: October 2024

AbstractSince human neurons are postmitotic and long-lived, the regulation of their genomic content is crucial. Normal neuronal function is uniquely dependent on gene dosage, with diverse genome copy number alterations (CNA) associated with neurodevelopmental and neuropsychiatric conditions1–3. In this study, we evaluated the landscape of CNA arising in normal human brains, focusing on prenatal and perinatal ages. We surveyed ∼5,897 CNA in >1,200 single neurons from human postmortem brain of individuals without a neurological diagnosis, ranging in age from gestational week (GW) 14 to 90 years old. Using Tn5-based single-cell whole-genome amplification (scWGA) and informatic advances to validate CNAs in single neurons, we determined that a striking proportion of neurons (up to 45%) in human prenatal cortex showed aberrant genomes, characterized by large-scale CNAs in multiple chromosomes, which reduces significantly during the perinatal period (p<0.1). Furthermore, we identified micronuclei in the developing cortex, reflecting genetic instability reminiscent of that described in early embryonic development4–6. The scale of CNA appeared to alter the trajectory of neuronal elimination, as subchromosomal CNAs were more slowly eliminated, over the course of a lifetime. CNAs were depleted for dosage-sensitive genes and genes involved in neurodevelopmental disorders (p<.05), and thus represent genomic quality control mechanisms that eliminate selectively those neurons with CNA involving critical genes. Perinatal elimination of defective neuronal genomes may in turn reflect a developmental landmark essential for normal cognitive function.
Bio-informatics: Integrate negative controls to get the good data
Authors: van Nues Rob 
Published: October 2024

ABSTRACTHigh-throughput datasets, like any experimental output, can be full of noise. Negative controls, i.e. mock experiments not providing information concerning the biological system under study, visualize background. Overlooking this ‘training set’ of wrong examples in publicly available datasets can seriously undermine validity of bioinformatics analyses. We present a program, COALISPR, for explicit and transparent application of negative control data in the comparison of high-throughput sequencing results. This yields mapping coordinates that guide fast counting of reads, bypassing the need for a reference file, and is especially relevant when small RNA sequencing libraries contaminated with breakdown products are analysed for poorly annotated organisms.We have re-analysed small RNA datasets for mouse and fungusCryptococcus neoformans, leading to consistent identification of miRNAs and of fungal transcripts targeted by siRNAs. Cryptococcal Argonautes are directed to spliced transcripts indicating that RNAi must be triggered by events downstream of intron removal. Negative control datasets contain large amounts of ribosomal RNA (rRNA) fragments (rRFs). These differ from small RNAs associated with RNAi, making a biological role for rRFs in association with Argonautes unlikely. Background signals enabled identification of cryptococcal genes for RNase P, U1 snRNA, 37 H/ACA and 63 Box C/D snoRNAs, including U3 and U14 essential for pre-rRNA processing. To gain meaning, high-throughput RNA-Seq analyses need to incorporate negative data.GRAPHICAL ABSTRACT