Citations

Introduction: Greater religiosity, or degree of involvement in religious activities, associates with better CV health profiles. Yet, studies of the association between religiosity and incident CV events have yielded mixed results. The southeastern US is characterized by strong religious practice but has among the highest rates of incident heart failure (HF). The relationship between religiosity and incident HF is not well characterized, particularly among low-income populations. Methods: We studied 23,893 Black or White Southern Community Cohort Study participants (median age 53 years, 70% Black, 64% women, 70% annual household income <$15k) without prevalent HF or CAD at enrollment (2002-2009). Religiosity, defined by religious service attendance, was ascertained at enrollment via a single item adapted from the Duke University Religion Index. Incident HF was determined using Centers for Medicare and Medicaid Services Research Identifiable Files (ICD-9/-10 codes 428.x or I50, I110) through December 31, 2016. We quantified the association of religious attendance with incident HF via Cox models adjusted for demographics, HF risk factors (HTN, HLD, DM, BMI, CVA), health behaviors (smoking, alcohol, physical activity, DASH diet), socioeconomic (income, education, employment, neighborhood deprivation, rurality) and psychosocial factors (marital status, social support, depressive symptoms, anti-depressant use). Results: Religious service attendance was common: >1/week (24%), 1/week (27%), <1/week (33%), and never (15%). Participants attending >1/week were more likely to be older and female, had relatively higher SES and more comorbidities, but better health behaviors and psychosocial support. HF developed in 6081 participants (25%; median 10-yr follow-up). Adjusting for demographics and HF risk factors, attendance >1/week associated with lower HF risk (HR 0.88 [0.82,0.94] and HR 0.92 [0.84,1.00] compared to <1/week or never, respectively). Attendance 1/week compared to <1/week showed similar association (HR 0.91 [0.85, 0.97]). Further adjustment for health behaviors, socioeconomic and psychosocial factors attenuated the association to non-significance. There was no interaction between religiosity and race. Conclusion: Greater frequency of religious service attendance associated with lower incident HF risk adjusting for demographics and HF risk factors; however, this association attenuated with adjustment for health behaviors, socioeconomic and psychosocial factors.

Autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the development of disease-causing B cells and autoantibodies. Convention suggests that such autoreactivities are generated during germinal center reactions. Here, we explore earlier immune checkpoints, focusing on patients with contactin-associated protein-like 2 (CASPR2)–autoantibody encephalitis. In both disease and health, high (~0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with pathogenic effects in neuronal cultures and mice. The unmutated, precursor memory B cell receptors showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results identify permissive central tolerance, defective peripheral tolerance, and autoantigen-specific tolerance thresholds in humans as sequential steps that license CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches, with an experimental paradigm applicable across autoimmunity.

Spatial heterogeneity of liver viscoelasticity, measured at three-dimensional vector MR elastography, positively correlated with metabolic dysfunction–associated steatotic liver disease progression.

Abstract Introduction: Low-dose computed tomography (CT) has been increasingly utilized in FAI due to its improved ability to characterize the complex and variable hip morphologies of FAI patients, compared to plain radiographs. This study defined FAI morphology between females and males as well as across adolescents, young adults, and older adults. Methods: A multi-center, prospective cohort of FAI patients undergoing primary arthroscopy was performed. Patients 14-45 years of age with idiopathic FAI were included. Low-dose CT was used for preoperative planning. Analysis focused on acetabular and femoral morphology and the differences between females/males and adolescents (A,14-18.9)/young adults (Y,19-24.9)/older adults (O,25+). Adolescents were the reference group during analysis. Results: There were 604 patients with CT data. Mean age was 24.9 years with 55.9% female. Males had more anterosuperior coverage (i.e. 64.2% vs 62.5% at 1:00), lower version (14.1° vs 18.0°), smaller femoral neck-shaft angles (130.9° vs 133.4°), and larger alpha angles (i.e. 72.1° vs 58.6° at 1:00) compared to females. Multivariable analysis demonstrated that females had associations with more femoral anteversion (OR: 1.05,CI: 1.03-1.07) and larger femoral neck-shaft angles (OR: 1.11,CI: 1.06-1.16). Males has associations with larger alpha angles at 1:00 (OR: 1.05,CI: 1.02-1.07) and 1:30 (OR: 1.03,CI: 1.00-1.06) as well as radial coverage at 1:00 (OR: 1.18,CI: 1.11-1.26). For females, adolescents had slightly less radial coverage at 2:00 (49.9%) compared to young (51.2%) and older adults (51.4%). Femoral neck-shaft angle decreased across age groups (A: 134.4°,Y: 133.0°,O: 132.7°). Alpha angles increased at 2:00 with age (A:54.6°,Y:55.3°,O:58.7°). Multivariable analysis had femoral neck-shaft angle decreasing for young (OR: 0.932,CI: 0.87) and older adults (OR:0.92,CI: 0.86-0.98) and it also had alpha angle at 1:15 increasing for young adults (OR: 1.03,CI: 1.00-1.06) and older adults (OR: 1.03,CI: 1.01-1.06). Males did not have any appreciable differences alpha angles, femoral version, or acetabular coverage across age groups. Conclusion: Differences in morphology identified on CT exist between females and males as well as across age groups for females. These differences may offer insight into disease pathomechanics between these patient populations. Further studies should confirm these findings and look at how they affect patient outcomes after treatment.

Background and Aims: Screening for diseases can have psychological impacts, such as anxiety, and requires acceptability from the population to be effective. This study examined the perspectives on the benefits and harms of screening for metabolic dysfunction–associated steatotic liver disease (MASLD) among the general population to optimize screening practices. Approach and Results: A survey was sent to participants enrolled between 2020 and 2024 in a prospective MASLD screening study in Olmsted County, MN. The survey assessed participants' perceived anxiety, stigma, quality of life, preferred screening methods, financial concerns, and lifestyle impacts following screening and diagnosis. Of the 461 participants, 342 (74%) completed the survey. Overall, 14% of participants reported screening-related anxiety, and 14% were concerned about disclosing a potential MASLD diagnosis to others. Among those without a MASLD diagnosis, 99% felt reassured about their liver health, 48% reported an improved quality of life, and 25% made lifestyle changes pertaining to their diet, alcohol use, and physical activity. Of the 77 participants diagnosed with MASLD, 52% experienced some anxiety about their new diagnosis; however, 95% and 97% considered it important to receive an early MASLD diagnosis to mitigate the risk for cirrhosis and cardiovascular disease, respectively. Notably, 79% of diagnosed participants found the diagnosis beneficial in adopting healthier habits, with 30% achieving a >10% weight loss after screening. Conclusion: This population-based survey demonstrates that the perceived benefits of proactive MASLD screening, such as increased awareness, lifestyle changes, and early diagnosis, outweigh the harms. These findings highlight the importance of early screening through patient-centered protocols to improve health outcomes.

Abstract Purpose To evaluate the test–retest repeatability of a rapid, free‐breathing two‐dimensional (2D) MR elastography (MRE) technique and to assess the reliability of the liver‐stiffness measurements compared with conventional breath‐hold MREs. Methods Fifteen and 115 participants were enrolled in the technical repeatability and measurement equivalence assessment cohorts, respectively. All participants underwent rapid free‐breathing and conventional breath‐hold 2D MRE (twice in repeatability cohort) on 1.5T scanners. Both methods have four phase offsets over one harmonic motion cycle at 60 Hz; one and 10 cycles were collected and processed in breath‐hold and free‐breathing MREs, respectively. The liver stiffness measurements of free‐breathing (LS F ) and breath‐hold MRE (LS B ) were calculated from manually drawn regions of interest. The repeatability coefficients and Spearman correlation were used to assess technical repeatability and measurement agreement between LS F and LS B . Univariable and multivariable linear regressions were performed to identify potential influencing factors, including age, sex, body mass index, and fat fraction, in the measurement agreement between LS B and LS F . Results The repeatability coefficient of free‐breathing 2D MRE is comparable to breath‐hold MRE (LS F : 20.8%, LS B : 20.4%). LS F showed a strong agreement and significant correlation with LS B (LS F = 1.01 × LS B , ρ = 0.94, p < 0.001). The measurement agreement between LS F and LS B was only significantly affected by sex ( p = 0.047) after adjusting for confounding factors of age, body mass index, and fat fraction. Conclusions The nongated, free‐breathing, multislice 2D MRE technique can provide reliable liver stiffness measurements compared with conventional breath‐hold 2D MRE. It could provide a comfortable alternative method with reliable liver stiffness measurements for patients who have difficulty in suspending respiration.

Abstract The aging process is universal, and it is characterized by a progressive deterioration and decrease in physiological function leading to decline on the organismal level. Nevertheless, a number of genetic and nongenetic interventions have been described, which successfully extend healthspan and lifespan in different species. Furthermore, a number of clinical trials have been evaluating the feasibility of different interventions to promote human health. The goal of the annual Biological Sciences Section of the Gerontological Society of America meeting was to share current knowledge of different topics in aging research and provide a vision of the future of aging research. The meeting gathered international experts in diverse areas of aging research including basic biology, demography, and clinical and translational studies. Specific topics included metabolism, inflammaging, epigenetic clocks, frailty, senescence, neuroscience, stem cells, reproductive aging, inter-organelle crosstalk, comparative transcriptomics of longevity, circadian clock, metabolomics, and biodemography.

Background Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with a 5-year survival rate of 12%. It has two major molecular subtypes: classical and basal, regulated by the master transcription factors (MTFs) GATA6 and ΔNp63, respectively. Objective This study sought to uncover the transcriptional regulatory mechanisms controlling PDAC subtype identity. Design We integrated primary tumour single-cell RNA-seq, patient-derived xenograft RNA-seq and multispectral imaging to identify MTF-dependent, subtype-specific markers. We created subtype-specific fluorescent reporter systems and conducted drug screenings to find actionable targets. We analysed chromatin accessibility (ATAC-seq), genome-wide occupancy (ChIP-seq) for epigenetic status (H3K27ac), MTFs (GATA6, ΔNp63), RNA polymerase II (Pol II), H3K4me3-anchored chromatin topology (HiChIP) and nascent RNA capture sequencing (PRO-seq). Additionally, we used nuclease-dead Cas9 (dCas9) to manipulate transcriptional regulatory mechanisms. Results Our approach identified glucocorticoid receptor (GR) agonists as agents that suppress the classical transcriptional programme by interacting with GATA6. GATA6 regulates classical-specific transcription through promoter-proximal pause release. Depletion of GATA6 increased Pol II occupancy at GATA6-bound enhancers and transcriptional start sites, stabilising enhancer–promoter interactions. Artificially inducing pausing at GATA6-bound enhancers with dCas9 abrogated target gene expression and induced pausing at both the enhancer and target gene promoter. Conversely, in basal PDAC ΔNp63 promotes Pol II recruitment and stabilises enhancer–promoter interactions. Conclusion This study provides new insights into the transcriptional control and role of GR agonists in controlling PDAC molecular subtype identity.

Abstract Autoimmunity affects 10% of the population. Within this umbrella, autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the developmental pathway of disease-causing B cells and autoantibodies. While such autoreactivities are believed to be generated during germinal centre reactions, the roles of earlier immune checkpoints in autoantigen-specific B cell tolerance are poorly understood. We address this concept in patients with CASPR2-autoantibody encephalitis and healthy controls. In both groups, comparable and high (∼0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with heterogenous binding kinetics. These effector molecules possessed epitope-dependent pathogenic effects in vitro neuronal cultures and in vivo. The unmutated common ancestors of these memory B cells showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results are the first to propose mechanisms underlying autoantigen-specific tolerance in humans. We identify permissive central tolerance, defective peripheral tolerance and heterogenous autoantibody binding properties as sequential pathogenic steps which licence CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches in CASPR2-antibody diseases. This paradigm is applicable across autoimmune conditions.