Iowa City VA Health Care System

Chronic pain represents heritable conditions linked to suicide death. It has been suggested that a shared genetic predisposition may contribute to this relationship, but there has not yet been a comprehensive assessment of genetic and clinical overlaps of different types of chronic pain with suicide death. Here, we integrated whole-genome sequencing and electronic health records from 986 unrelated individuals of European ancestry who died by suicide in the Utah Suicide Mortality Research Study and 415 ancestrally-matched population controls selected for absence of disease. Polygenic scores (PGSs) for seven distinct types of chronic pain were calculated and tested in the suicide cohort. We observed significant positive associations of PGSs for multisite chronic pain (PGSMCP) and chronic widespread pain (PGSCWP) with suicide mortality. Sex-stratified analyses showed elevations in both males and females. Pain diagnosis-stratified analyses revealed associations with suicide death regardless of chronic pain diagnoses. Follow-up tests of PGSs for more specific pain conditions showed additional associations with suicide death for: 1) monoarticular arthritis, 2) back pain, and 3) chronic inflammatory demyelinating polyneuropathy across all suicide death individuals, and 4) irritable bowel syndrome within males only. In a multiple logistic regression test of all chronic pain PGSs associating suicide death status, four types of pain remained uniquely associated with suicide death, highlighting distinct subgroups within suicide death: some attributed to MCP and CWP, and others associated with monoarticular arthritis or chronic inflammatory demyelinating polyneuropathy. This cohort study reports associations between suicide death and PGSs from various pain conditions, regardless of sex or chronic pain diagnosis, suggesting that combining genetic and clinical risk factors may better identify genetic overlap, causal directions, and/or specific gene pathways.

The autonomic networks of the central nervous system tightly coordinate metabolic and cardiovascular functions. The frequent coexistence of metabolic and cardiovascular disorders suggests cross talk between neural circuits governing energy balance and cardiovascular regulation. In this study, we used trans-neuronal tracing to define the higher-order neurons involved in the coordination of cardiometabolic regulation in mice. We identified several nuclei that contain neurons associated with a cardiovascular organ (kidney) and metabolic tissues (brown adipose tissue [BAT] or liver), with substantial overlap across regions. Co-projecting neurons (kidney-BAT or kidney-liver) were observed in areas including the cortical, hypothalamic, midbrain, and brainstem regions. Analysis of soma size revealed regional and organ-specific differences, with some nuclei exhibiting multiple morphological phenotypes. Notably, soma size distributions differed significantly between kidney- and BAT-projecting neurons in the motor cortex and locus coeruleus, but not in the paraventricular nucleus or lateral hypothalamus. These findings indicate that while cardiometabolic control involves overlapping neuronal populations, morphological specialization may distinguish neurons regulating cardiovascular versus metabolic functions. Together, this work provides anatomical evidence supporting the integrative organization of autonomic networks that coordinate cardiovascular and metabolic regulation.

BackgroundInpatient antibiotic stewardship programs (ASP) promote avoiding unnecessary initiation, excessively long duration, and overly broad-spectrum selection of antibiotics to optimize usage. Commonly used metrics, such as Days of Therapy (DOT) per Days Present (DP) or Standardized Antimicrobial Administration Ratio (SAAR), reflect the overall usage but do not incorporate spectrum, nor provide specific information for components (initiation, duration, and spectrum). We aimed to create a novel framework to reflect all three components while providing information specific to each, based on Days of Antimicrobial Spectrum Coverage (DASC).Figure 1.Mathematical Framework for Three-Component Evaluation of Antimicrobial UsageFigure 2.Hospital Benchmarking by Overall Antibiotics UsageMethodsWe developed a mathematical framework to extract hospital-level variability with risk adjustment for three components (Figure 1), using DASC and length of therapy (LOT). This was applied to data from all 118 Veterans Health Administration (VHA) acute care hospitals, with models built on 2022–2023 data and validated with 2024 data. Patient demographics, intensive care status, specialty, 86 comorbidities, and 225 procedure categories were considered as candidate variables for risk-adjustments. Overall hospital performances were evaluated by composite metrics (predicted/expected [P/E] ratio), integrating three components (Figure 2), and three components in each hospital were visualized in a radar chart (Figure 3).Figure 3.Visualization of Hospital-Specific Antibiotics Usage CharacteristicsFigure 4.Examples of Hospital-Specific Antibiotics Usage CharacteristicsResultsThe cohort included 727,958 unique patients with 9,363,922 days present (DP: 2022-2023: 6,257,368; 2024: 3,106,554). Hospital-level usage density ranged widely (DASC per 1,000 DP: 1,311-5,275 [interquartile range (IQR): 2,738-3,563]; LOT per 1,000 DP: 132.2-517.6 [IQR: 301.0-367.5]). Risk-adjustment models included 115 variables for initiation, 125 for duration, and 128 for spectrum components. P/E ratios ranged from 0.713 to 1.533 [IQR: 0.912-1.077] (Figure 2). Three-component evaluation could offer more specific information for each hospital about its usage pattern (Figure 4).ConclusionWe propose a novel framework to assess ASP practices in initiation, duration, and spectrum separately while providing overall composite benchmarking. Further studies are needed to assess whether this framework reflects the appropriateness of antibiotic therapies or outcomes.DisclosuresAll Authors: No reported disclosures

Abstract Background During lytic infection, cytomegalovirus (CMV), like other Herpesviruses, follows a cascade of gene expression that is classically modeled by categorizing genes as Immediate Early (IE, involved in triggering Early gene expression), Early (E, involved in viral DNA replication), and Late (L, involved in virion assembly). Historically, this cascade is characterized by measuring levels of mRNA and protein products of viral genes. However, mRNA and protein levels are a function of multiple different processes. Without isolating a specific step in gene expression, identifying mechanisms that coordinate the expression of IE, E, and L genes is challenging. Here we aim to characterize the cascade of gene expression specifically at the level of transcription, the process by which DNA is expressed as RNA. By isolating transcriptional activity, we may be able to better identify the mechanisms that coordinate expression, which may serve as therapeutic targets. Methods We conducted a novel analysis of a previously published Precision Run-On Sequencing (PRO-seq) dataset. PRO-seq allows for genome-wide measurement of transcriptional activity at single-nucleotide resolution. This dataset was produced by infecting cultured human foreskin fibroblasts (HFFs) with CMV and performing PRO-seq at 4-, 12-, 24-, 48-, and 72-hours post-infection (covering the entire CMV life cycle). Results Hierarchical clustering was used to cluster both coding and non-coding genes into groups with similar temporal patterns of transcription. Some groups of genes are transcriptionally active at defined time-periods, consistent with the classic cascade model. Additionally, we find evidence of genes with transcriptional activity inconsistent with the classic cascade model – specifically, genes with transcriptional activity persistent throughout viral life cycle and genes with intermittent transcriptional activity. Conclusion Preliminary analysis of CMV transcription activity suggests coordinated transcription as well as inconsistencies with the classic cascade model of Herpesvirus gene expression. Next steps include: (1) test results through separate assays of transcriptional activity; (2) identify mechanisms of coordinated transcription; and (3) assess cell-type differences. Disclosures All Authors: No reported disclosures

Migraine is a disabling neurovascular disorder with limited therapeutic options, especially for patients unresponsive to current treatments targeting calcitonin gene-related peptide (CGRP) signaling. The endocannabinoid system (ECS) has emerged as a promising alternative for migraine modulation, offering analgesic, anti-inflammatory, and neuroimmune-regulatory effects through its main ligands, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their degrading enzymes. This review provides an updated map of endocannabinoid components in central and peripheral migraine-relevant regions, highlighting their spatial distribution and functional regulation in animal models. We summarize the available preclinical evidence supporting the anti-nociceptive effects of endocannabinoid-degrading enzyme inhibitors and cannabinoid receptor agonists/antagonists, with particular emphasis on the therapeutic potential of multi-target compounds. Moreover, we explore non-canonical ECS pathways, including TRPV1, D2 dopamine receptors, serotonergic and ion channel interactions, and their roles in modulating CGRP release and trigeminovascular signaling to treat migraine pathophysiology. Finally, we propose two sleep-related directions for treatments involving ECS modulation of circadian rhythms and glymphatic clearance. Although human translational data are limited, the ECS offers a multifaceted framework for developing next-generation therapeutics targeting migraine pathophysiology.

Women experiencing mental health disorders (MHD) have shown lower preventive mammography screening rates. Studies in veterans have shown inconsistent results and been limited to single facilities, failed to separate substance use and MHD into individual categories, and have had limited analyses on systems level covariates. The study examined the individual associations between MHD in univariate and multivariate analyses and included adjustments for factors previously shown to impact on the rate of receipt of recommended preventive breast cancer screening. Women veterans ages 50 through 54 receiving primary care in the Veterans Health Administration (VHA) in 2021 and 2022. The design was an observational cohort study using health data including patient level factors and system factors. Women veterans were studied over a 2-year period and generalized liner mixed regression models examined for the association between MHD (e.g., depression, PTSD, anxiety, opioid, cannabis) on mammography. A total of 36,720 eligible women veterans were identified in the 2-year evaluation period, of which 79.2% received preventive breast cancer screening. Depression was the most common MHD (17,798; 48.5%). In univariate analyses, depression, PTSD, and anxiety disorders were not associated with mammography receipt. For individual substance use disorders, univariate analyses revealed opioid, cocaine, cannabis, and alcohol were all significantly associated with lower mammogram rates. In multivariate models including any significant univariate person or system factors, decreased rates of mammography were associated with bipolar (OR 0.76, p < .001), schizophrenia (OR 0.62, p < .001), opioid use (OR 0.50, p < .001), and cannabis use (OR 0.77, p < .001). Multivariate regression revealed that bipolar disorder, schizophrenia, opioid and cannabis use disorders are significantly associated with lower mammography rates while depression, anxiety, PTSD and alcohol use disorder are not.

We assessed whether circulating adipokines are associated with incident fractures in patients with rheumatoid arthritis (RA). Three adipokines (adiponectin, leptin, and fibroblast growth factor [FGF]-21) were measured using banked enrollment serum from participants in a longitudinal RA cohort. Adipokine levels were dichotomized as high/low using median values. Incident osteoporotic fracture was defined based on published algorithms using diagnostic codes and confirmed by chart review. Cox proportional hazard models evaluated adipokines and incident fracture risk adjusting for age, sex, race, smoking status, body mass index (BMI), prednisone use, disease activity, comorbidity score, calendar year, osteoporosis history, and previous fracture. A total of 2,527 participants were included (89% male, mean age 72 years). There were 228 incident fractures over 27,540 person-years of follow-up (8.3 fractures per 1,000 person-years). After adjustment, the risk of incident fracture was increased for high levels of leptin (hazard ratio [HR] = 1.47; 95% confidence interval [CI] 1.15-1.90; P = 0.003), FGF-21 [HR = 1.39; 95% CI 1.16-1.67; P < 0.001), and adiponectin (HR = 1.21; 95% CI 0.94-1.55), with the latter not achieving significance (P = 0.13). Participants who had elevated levels of all three adipokines experienced twice the risk of fracture compared with those in whom none was elevated (HR = 2.17; 95% CI 1.27-3.70; P = 0.005). Elevations in adipokines are associated with an increased risk of fracture in patients with RA, independent of other established risk factors including BMI, smoking, and prednisone use. This supports further investigation to understand whether this association is related to altered body composition or disrupted metabolic pathways.