VA Salt Lake City Healthcare System

Nocturia (i.e., waking to void during the primary sleep period) of two or more times per night affects nearly one-third of older adults and can have a severe impact on sleep, contributing to insomnia symptoms. Current treatment approaches for nocturia often overlook non-lower urinary tract factors that may contribute to nighttime awakenings. Nocturia management, for example, may benefit from more effective integration of cognitive behavioral therapy for insomnia (CBT-I) principles that address other factors underlying insomnia symptoms, and early evidence suggests it also reduces nocturia and the bother it causes. Because nocturia treatment crosses specialties, coordinated delivery of urological and sleep therapies is a treatment barrier. The overall purpose of this trial is to determine whether a promising coordinated, integrated behavioral, non-pharmacological, non-surgical treatment that simultaneously addresses both the urological and insomnia factors contributing to nocturia is efficacious for improving nocturia, sleep, and daytime function. This multicenter parallel-group randomized, efficacy trial compares a 5-week integrated behavioral treatment program delivered by a single interventionist (psychologist, nurse practitioner, or physician assistant) to a health education control program in adults aged 60years or older (proposed n = 192) recruited from sites in Atlanta and Los Angeles, who report typically getting up to urinate two or more times per night (International Consultation on Incontinence Questionnaire-Overactive bladder [ICIQ-OAB] nocturia item) and insomnia symptoms (Insomnia Severity Index > 7). The integrated program includes components of CBT-I and pelvic floor muscle exercise-based behavioral therapy for nocturia. The primary outcome is ICIQ-OAB-measured nocturia frequency 4months after randomization. Secondary outcomes are sleep diary-measured wake after sleep onset (mean minutes) and Insomnia Severity Index total score. The interdisciplinary trial team has developed a program aimed at improving nocturia symptoms and overall sleep of older adults in an efficient and safe manner. The integrated behavioral program has the potential to address nocturia, which is a challenging symptom because it has many etiologies that cross multiple specialties. Findings will provide rigorous evidence of the efficacy of the integrated behavioral treatment program to reduce nocturia frequency as well as sleep disturbance in older adults. Clinicaltrials.gov NCT06110091, registered 10/25/2023.

BACKGROUNDMetabolic dysfunction-associated steatotic liver disease (MASLD) has a substantial inherited component. Rare variants in apolipoprotein B gene (APOB) have been implicated in susceptibility to liver steatosis, but their role in disease progression and outcomes is unclear.METHODSWe investigated APOB rare variants in a case-control cohort of people with advanced MASLD versus healthy controls (n = 510 and 261, respectively), a family-based study (n = 43 and literature meta-analysis), the Million Veteran Program (MVP) cohort (n = 94,885), and the UK Biobank (UKBB) (n = 417,657).RESULTSIn the clinical cohort, APOB variants were enriched in people with advanced MASLD (OR 13.8, 95% CI: 2.7-70.7, P = 0.002) and associated with lower circulating lipids, but higher MASLD activity and fibrosis (P < 0.05). In the family study, APOB variants segregated with hepatic steatosis and fibrosis (P < 0.05). Cross-ancestry meta-analysis of the study cohorts yielded pooled ORs for cirrhosis and hepatocellular carcinoma (HCC) of 1.82, 95% CI: 1.33-2.49 and 3.53, 95% CI: 2.09-5.98, respectively. Variants affecting specifically ApoB100 had a 3-fold greater effect on hepatic lipid metabolism compared with those impairing also ApoB48 and were specifically protective against coronary artery disease (P < 0.05). The variants affected cirrhosis risk similarly, but ApoB48/100 had a larger effect on HCC (P < 0.05).CONCLUSIONSRare APOB variants predispose individuals to advanced MASLD and HCC, with distinct contributions from disrupted VLDL and chylomicrons secretion. These findings highlight the interplay between hepatic and intestinal lipid handling, suggesting that APOB genotyping may enhance MASLD risk stratification and patient identification.FUNDINGEuropean Union, Italian Ministry of Health, Swedish Research Council, Veterans Health Administration, NIH.

Sex chromosome trisomies (SCTs), caused by the presence of an extra X or Y chromosome, are among the most common chromosomal abnormalities but remain substantially underrecognized. Klinefelter syndrome (47,XXY) is the most frequently diagnosed SCT and, as a result, has been the primary focus of research on associated comorbidities, while individuals with 47,XYY and 47,XXX are typically undiagnosed and understudied. This reliance on clinically identified cases introduces bias and limits understanding of the full spectrum of SCT-associated disease, particularly for physical health outcomes. Large-scale biobanks that link genetic data with medical records offer a unique opportunity to study both diagnosed and undiagnosed SCTs across subtypes. This retrospective cohort study uses biobank data to examine the risk of physical comorbidities across all three SCTs, including both diagnosed and undiagnosed individuals. Data were compiled from three large population-based biobanks: the Million Veteran Program (MVP), FinnGen, and the UK Biobank, each of which includes genotyped blood-derived DNA linked to detailed electronic health records. The MVP cohort was started in 2011 and includes ~650,000 veterans in the VA health care system, while FinnGen includes 500,000 Finns across varied national health registries, with records beginning at or before 1969. The UK Biobank is a prospective cohort of ~500,000 volunteers in the United Kingdom aged 40 to 70 that began recruitment in 2006. To determine the presence of an SCT, the researchers analyzed SNP array data for the relative signal strength of X and Y chromosomes present, from which the copy number was inferred. The number of these patients who were officially diagnosed was abstracted from ICD-9 or ICD-10 codes. Disease outcome rates were captured using phecodes, which are clinically meaningful groups of International Classification of Diseases (ICD) codes, and were grouped into system-based categories. Associations between SCT subtypes and lifetime disease risk were evaluated using a matched case-control design, with each SCT carrier matched to five control individuals by genetic sex, birth year, and genetic ancestry. Among the 1.5 million individuals included, 2769 (0.19%) were found to have an SCT, the large majority of which (86.2%) were undiagnosed. Diagnosis rates differed by subtype, with 26.2% of 47,XXY patients, 1.4% of those with 47,XYY and 6.4% of those with 47,XXX carrying a clinical diagnosis. Phenome-wide association analyses identified hundreds of disease associations spanning nearly all organ systems, with 43 conditions shared across all three SCTs, most of which were categorized as cardiovascular, respiratory, and metabolic diseases. Vascular conditions, including venous thromboembolism, atherosclerosis, and cerebrovascular disease, showed strong associations across SCT subtypes. Metabolic and respiratory conditions, such as obesity, type 2 diabetes, asthma, and sleep apnea, were also more prevalent across SCT subtypes. Subtype-specific associations were also identified, with reproductive and bone disorders concentrated in 47,XXY, select renal and infectious conditions concentrated in 47,XXX, and no distinct phenotype unique to 47,XYY. The findings show that most individuals with SCTs remain undiagnosed into adulthood and experience an increase in a wide range of chronic diseases that are shared across SCT subtypes. Despite the historical attribution of many of these phenotypes to hypogonadism, particularly in cases of 47,XXY, the commonalities found across karyotypes, genetic sexes, and cohorts suggests that increased sex chromosome gene dosage plays a central role in SCT pathophysiology. The vascular phenotypes that were frequently observed across all three SCTs, including venous thromboembolism and chronic venous disease, are consistent with previous studies, and future research should investigate possible underlying etiologies. Limitations of the study include reliance on EHR-based phenotyping, potential homogeneity between biobanks, and limited power to assess phenotype severity or differences across ancestral groups. (Abstracted from Am J Hum Genet. 2025;112:2088–2101. doi:10.1016/j.ajhg.2025.07.017)

BackgroundGermline pathogenic variants can inform targeted therapy for metastatic prostate cancer (mPC), and improve cancer early detection and risk reduction for family members. Guidelines recommend germline genetic testing be offered to all men with mPC, yet uptake of testing is only 10%–12%.MethodsThis prospective study enrolled veterans participating in the VA Million Veteran Program (MVP) with a diagnosis of mPC. Veterans were contacted by mail with option to opt‐out of future contact. Eligible veterans who did not opt‐out were mailed study information and received a follow‐up phone call to establish interest in germline testing. Participants provided verbal consent and were mailed a saliva collection kit for a CLIA‐level multigene cancer predisposition gene panel test. Results were disclosed to the patient and oncology provider. All steps were performed with genetic counseling support.ResultsOf 2104 eligible patients, 1952 veterans with mPC did not opt out. Of these, 681 (35%) provided consent and 459 (24%) completed testing. Of those who were approached 63% were White and 25% were Black. Fifty‐nine (13%) of those completing testing carried a germline pathogenic variant in a cancer risk gene. Of the 37 eligible for targeted therapy, 14 received targeted therapy, 18 did not yet have an indication for that therapy, and five were deceased without having received targeted therapy.ConclusionsParticipant completion of remote germline testing was facilitated at rates higher than the 10% previously reported. Remote genetic testing can augment uptake of testing in large, integrated health care systems.

Caregivers' self-perceived preparedness for caregiving influences care recipients' and caregivers' emotional health, and care recipients' aging in place. Dementia's unique, long, and progressive nature compared to other age-related illnesses, along with associated behavioral symptoms and personality changes, may cause caregivers' preparedness to vary significantly from that of those caring for patients with other chronic conditions. This study aimed to describe and compare specific domains and tasks in which family caregivers of veterans with and without dementia reported wanting to be better prepared. Using the Veterans Affairs' HERO CARE (Home Excellence Resource Outcome Center to Advance, Redefine, and Evaluate Non-Institutional Care) Survey data, we analyzed caregivers' responses to one open-ended question: "Out of all the tasks that you help the veteran with, is there anything specific you would like to be better prepared for?" Response themes were deductively coded into 9 domains, and differences in reported domains between caregivers of care recipients with and without dementia were compared. A total of 732 caregivers were included: 301 (41.1%) caregivers of veterans with dementia and 431 (58.9%) without. Caregivers of veterans with and without dementia, respectively, were similar except in age, being spousal caregivers, working at least part-time, hours of care provision per week, and proportion with a high burden. Veterans with dementia, versus without, were older and had higher frailty and risk scores. Preparedness concerns among caregivers (N=732) included care coordination (n=164, 22.4%), emotional and social support (n=145, 19.8%), advance planning (n=116, 15.8%), nursing and health monitoring (n=94, 12.8%), personal care (n=65, 8.9%), mobility (n=79, 10.8%), household (n=58, 7.9%), caregiver self-care (n=36, 4.9%), and emergent situations (n=28, 3.8%). The commonest tasks caregivers expressed needs for included managing emotional and behavioral symptoms (n=74, 10.1%), recognizing and responding to significant changes in the veterans' condition (n=66, 9.0%), seeking medical information relevant to the veterans' needs (n=54, 7.4%), handling financial and legal matters (n=52, 7.1%), and advocating for services (n=49, 6.7%). Similar proportions of caregivers of veterans with and without dementia reported preparedness needs in all domains and tasks. The preparedness needs of caregivers of veterans with and without dementia were mostly similar in most domains and tasks. The commonest preparedness gaps were in the domains of care coordination, emotional and social support, and advance planning. The findings can inform interventions to prepare all caregivers to support aging in place.

ABSTRACTIntroductionLearning health systems leverage clinical data and knowledge to advance healthcare quality. Effective training in informatics concepts and tools is essential for medical trainees to become health system experts and contributors to positive organizational change. The objective of this study is to summarize characteristics of existing clinical informatics training programs and map these to recommended Learning Health System informatics competencies. We aim to answer the following research questions: (1) How are academic medical institutions implementing informatics education initiatives for medical trainees? (2) Are these initiatives implementing recommended informatics competencies? and (3) How effective are these initiatives according to established health professions education evaluation frameworks?MethodsWe searched for literature in the databases Embase, Ovid Medline, and Web of Science. Three researchers independently screened study titles and abstracts. Inclusion criteria were (a) studies with medical students and/or postgraduate medical professionals in the study sample, (b) in an academic medical setting, and (c) describing a clinical informatics curriculum initiative.ResultsWe included a total of 27 studies for analysis. Most curricula (n = 16) had the objective of basic informatics knowledge acquisition. Instruction delivery for most (n = 17) included a combination of didactic and practical components. The most common evaluation tool was student self‐reported confidence and self‐efficacy. All but three of the studies integrated the recommended informatics competency of demonstrating knowledge of clinical information systems such as Electronic Health Records. Most studies (n = 12) reported outcomes related to the Kirkpatrick Level II of Learning.ConclusionGaps remain in the context of leveraging education to pursue Learning Health System endeavors of clinical research, quality improvement, and achieving organizational‐level results. Further research on recent education initiatives targeting undergraduate and graduate medical trainees is needed to elevate the rate of clinical informatics education implementation, while simultaneously advocating for standardization in the design and evaluation of these initiatives.

Black individuals have higher incidence and mortality rates of prostate cancer than White individuals, and existing literature on treatment sequencing strategies in metastatic castration-resistant prostate cancer (mCRPC) is limited and conflicting. Understanding the interplay between race and treatment could optimize care and improve overall survival (OS). This retrospective observational cohort study assessed survival outcomes based on race and initial androgen receptor pathway inhibitor (ARPI) treatment among veterans with mCRPC. Participants included White or Black veterans diagnosed with mCRPC between January 1, 2011, and March 12, 2024, initially treated with either abiraterone or enzalutamide. The primary outcome was OS measured from the date of diagnosis and from the start of initial therapy. Kaplan-Meier estimates and Cox proportional hazards models were used to evaluate outcome differences by race and treatment. A total of 12,355 patients met eligibility criteria. The mean age of the cohort was 74.57 years, with Black patients diagnosed approximately 4 years younger than White patients (71.77 vs 75.60, respectively; P<.001). Median prostate-specific antigen and mean Charlson comorbidity index scores were higher among Black patients. Median OS was higher in Black patients compared with White patients (36.3 months [95% CI, 35-38] vs 31 months [95% CI, 30.3-31.7], respectively; inverse probability of treatment weighting hazard ratio [IPTW HR], 0.80; P<.0001) Median OS was also longer among patients prescribed enzalutamide compared with those prescribed abiraterone (28 months [95% CI, 27.0-28.9] vs 23.7 months [95% CI, 23.1-24.2], respectively; IPTW HR, 1.14; P<.0001). No significant race-by-treatment interaction was observed. Black veterans with prostate cancer treated with ARPIs lived approximately 6 months longer after developing mCRPC but had a shorter lifespan-by about 3 years-compared with White patients. Differences in tumor biology may help explain why Black individuals develop prostate cancer at a younger age and exhibit better responses to cancer therapy.

Genome-wide association studies (GWAS) have identified nearly 100 loci associated with metabolic dysfunction-associated steatotic liver disease (MASLD), but the molecular functions of these variant alleles remain elusive, particularly when they occur in non-coding regions. Here we profiled the chromatin accessibility landscape of liver nuclei from MASLD individuals, and demonstrated these accessible genomic sites were bound by cell type-specific transcription factors (TFs) and enriched for MASLD risk variants, highlighting lineage- and disease state-specific regulation. Using a massively parallel reporter assay (MPRA), we identified hundreds of differential activity variants (DAVs) that operate in a cell type-specific manner or in a stimulus-dependent context by disrupting liver pathogenesis-associated transcriptional regulatory network. Integrative analyses combining liver eQTLs, chromatin looping, and single-cell CRISPRi screening linked these DAVs to functional target genes. Notably, we demonstrated that DAVs located near SLC22A3 and core regulators of triglyceride metabolism (APOA5, ANGPTL3, and LPL) loci modulate their gene expression and contribute to altered lipid metabolism and hepatic stellate cell activation. Furthermore, these DAVs exhibit predictive power in distinguishing MASLD disease risk. Together, these multimodal integration analyses provide insights into the regulatory mechanisms of MASLD progression driven by noncoding genetic risks.

The primary aim of this study was to evaluate the feasibility, safety, and preliminary outcomes of the Equine Assisted Growth and Learning Association (Eagala) model of equine-assisted psychotherapy for active-duty military and veteran trauma survivors. This was a retrospective multi-site observational study. Study participants completed four psychological instruments pre- and post-intervention. These were the PTSD Checklist for DSM-5, the Patient Health Questionnaire, the Satisfaction with Life Scale and the Sheehan Disability Scale. The Client Satisfaction Questionnaire-8 was also completed post-intervention. Paired-sample t-tests were conducted to assess for changes in the primary outcome variables pre- and post-intervention. The RAPID qualitative approach was used to analyze the qualitative data and develop subthemes. Subjects were 107 participants at 12 sites. Participants ranged in age from 22 to 78 and were predominately male. Findings revealed that the Eagala model intervention can be implemented for this population across multiple sites. Further, treatment engagement may be better than found with conventional psychotherapy interventions for this population. Pre-to-post-intervention changes in scores on the psychological instruments revealed significant decreases in PTSD symptoms, depression, and disability as well as increases in satisfaction with life. Future randomized controlled trails of this intervention are warranted.

BackgroundFamily caregivers are integral to the care of patients and possess important perspectives regarding improving healthcare delivery. Yet, caregivers are seldom engaged in research in part because of challenges recruiting and retaining them. We sought to identify best practices for recruiting and retaining caregivers in health services research, drawing from researcher experiences in the Department of Veterans Affairs (VA).MethodsWe identified VA Health Systems Research (HSR) funded studies that focused on caregivers of Veterans by reviewing ongoing and completed projects from 2017 through 2024. “Caregiver” was defined as family members and/or friends who helped Veterans manage their health issues. We interviewed principal investigators and study team members to characterize their recruitment and retention practices. We further examined their studies’ published methods and results to summarize the breadth of strategies used, and to identify those that were most effective based on informants’ impressions of what worked.ResultsSeventeen research team members from 11 studies at six sites participated. Studies were observational (8 studies, n = 4183), experimental (2 studies, n = 237), and implementation-focused (1 study, n = 435), and included 4855 caregivers. All studies utilized multiple recruitment approaches, most commonly directly approaching potential participants, utilizing administrative data, and advertising. The most successful practices were: (1) directly approaching Veterans and caregivers; (2) recruiting through clinics; (3) reviewing registries of prior study participants; and (4) using administrative data to identify potential candidates. Flexible, virtual scheduling and individualized participant activities utilizing multiple participation modalities were helpful for caregiver retention.ConclusionsSuccessfully recruiting and retaining caregivers requires multiple strategies, and researcher flexibility. Health services researchers should prioritize direct outreach, outreach through trusted clinicians, and establishing registries to optimize efforts. Researchers should also use methods that allow for flexible, individualized participation to maximize retention. Enhancing caregiver-focused research through optimizing caregiver engagement will ultimately improve the evidence base necessary to inform care delivery and policy.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12913-025-13368-3.