Citations

Background Traumatic injury is the fourth leading cause of death nationally; rural residents are twice as likely to die from injury as urban counterparts. On-scene mortality coverage gaps across regional trauma systems remain poorly characterized. Objective To identify geographic blind spots and time-critical, spatially advantageous on-scene deaths (2019-2023) that fall outside modeled 10-minute drive-time service areas across seven North Central state trauma regions. Methods This retrospective analysis geocoded death certificate records to ZIP Code Tabulation Areas and modeled 10-minute drive-time service areas in ArcGIS Online. EMS agency headquarters and staffing classification (volunteer, mixed, paid) were obtained from the DHS EMS Service Map. Candidate sites were identified by maximizing coverage of weighted, uncovered death centroids per region. Results Of 11,868 decedents (60.7% male; mean age 64.4 years [SD 25.6]; 49.9% fall, 26.4% firearm), 7815 had geocodable addresses. Coverage ranged from 53.5% (Western) to 87.0% (North Central); 5492 (70.3%) fell within a 10-minute service area. One candidate site per region could extend modeled coverage to 4-321 additional death locations (480 combined). Volunteer-dominant regions, where 63% of agencies reported scheduling gaps, had the lowest coverage, suggesting headquarters presence overstates availability. Conclusion Geospatial analysis identified actionable blind spots where one additional EMS resource per region could extend modeled coverage to hundreds of death locations. Because these are modeled coverage gains, not demonstrated mortality reductions, and depend in volunteer-dominant regions on staffing reliability that placement alone cannot resolve, the identified locations warrant further evaluation, not presumed survival benefit.

PURPOSE Bone metastases (BM) occur in approximately 30% of patients with metastatic renal cell carcinoma (mRCC) and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, and cabozantinib, a tyrosine kinase inhibitor, have demonstrated activity in BM. RADICAL (Alliance A031801; ClinicalTrials.gov identifier: NCT04071223 ) evaluated cabozantinib ± radium-223 in mRCC with BM. METHODS This phase II trial enrolled patients with mRCC of any histology with ≥1 BM. Patients were randomly assigned 1:1 to cabozantinib ± radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, opioid use, and International mRCC Database Consortium (IMDC) risk. The primary end point was SSE-free survival (SSE-FS). Secondary end points included safety, objective response rate (ORR), progression-free survival, and overall survival (OS). A target of 124 evaluable patients was planned, with a prespecified interim futility analysis at 50% of expected SSE-FS events; the trial would stop if the stratified hazard ratio (sHR) > 1.0. RESULTS The prespecified interim futility analysis was conducted after 90 patients were enrolled and crossed the futility boundary, leading to closure at 98 patients. The final analysis included all 98 patients. Median age was 63 years, 82.7% had clear cell histology, and 79.6% were using an OTT. IMDC risk was favorable (18.4%), intermediate (67.3%), and poor (14.3%). Median follow-up was 13.1 months. Median SSE-FS for cabozantinib with radium-223 versus cabozantinib was 16.7 versus 17.6 months (sHR, 1.46 [90% CI, 0.86 to 2.51]). Median OS was 28.3 versus 19.7 months (sHR, 1.40 [95% CI, 0.70 to 2.79]). ORR was 19.4% versus 25.0% ( P = .78). Grade ≥3 adverse events were similar across arms (69.6% v 75.5%). CONCLUSION Radium-223 did not improve SSE-FS when added to cabozantinib. The combination demonstrated a manageable safety profile.

Acanthosis nigricans (AN) is a common dermatologic condition characterized by hyperpigmented, velvety plaques that most frequently affect intertriginous areas. Although often associated with insulin resistance and obesity, AN may also serve as a cutaneous marker of underlying endocrinologic disorders, medication effects, genetic syndromes, or internal malignancy. Recognition of AN provides an important opportunity for early identification of systemic disease and implementation of targeted management strategies. This review summarizes the pathogenesis and etiologic subtypes of AN, highlights key clinical features and differential diagnoses, and outlines an evidence-based diagnostic approach. Management strategies are discussed with emphasis on lifestyle modification, pharmacologic therapies, topical treatments, procedural interventions, and the strength of supporting evidence. Practical considerations relevant to physician assistants are emphasized throughout, including interdisciplinary care and patient education. Early recognition and appropriate management of AN can improve both dermatologic outcomes and overall patient health.

The accurate diagnosis of disorders of gut-brain interaction (DGBI), such as functional dyspepsia and irritable bowel syndrome, is crucial for improving patient symptoms, outcomes and ultimately, quality of life. However, busy clinicians often face challenges in diagnosing and managing these conditions, particularly when patients present with non-specific gastrointestinal symptoms together with psychosocial distress and/or social issues. DGBI are among the most common reasons for gastroenterology referral, with a global prevalence of approximately 40% in adults based on large-scale epidemiologic studies. While diagnostic algorithms aid in positively identifying DGBI, they often overlook key factors influencing treatment decisions. The Rome V Multidimensional Clinical Profile (MDCP) offers a comprehensive, patient-centered framework that extends beyond diagnosis alone. It integrates five core domains: (1) the primary diagnosis, (2) clinical modifiers, (3) impact on daily activities and quality of life, (4) psychosocial modifiers, and (5) physiological features and biomarkers. By considering comorbidities, illness severity, psychosocial contributors, and potential biomarkers, the MDCP enables clinicians to develop a holistic understanding of the patient's condition. This multidimensional approach facilitates tailored, evidence-based treatment plans that address the biopsychosocial aspects of DGBI, ultimately enhancing symptom management and patient well-being. Furthermore, it highlights gaps in knowledge and stimulates targeted research into these highly prevalent disorders. This case-oriented educational review will evaluate three DGBIs – functional dyspepsia, irritable bowel syndrome, and chronic abdominal pain – using the MDCP approach.

Abstract Physical activity (PA) is a modifiable lifestyle behaviour associated with lower dementia risk; however, molecular pathways bridging PA-related dementia prevention are poorly understood. We leveraged large-scale plasma proteomics to identify biological signatures of objectively monitored PA and cognitive ageing in functionally intact older adults, cross-validated these signatures in independent exercise cohorts and tested associations with both symptomatic and presymptomatic stages of neurodegeneration across multiple Alzheimer’s disease and related dementias (ADRD) cohorts. We analysed large-scale plasma proteomics data (SomaScan 7k) across three cohorts including naturalistic, objective PA monitoring (University of California, San Francisco Brain Aging Network for Cognitive Health cohort, n = 65), self-reported PA (Atherosclerosis Risk In Communities study, n = 10 644) and PA intervention (Health Risk Factors, Exercise Training and Genetics study, n = 654). Differential regression models examined individual protein correlates of PA, adjusting for age and sex. Weighted gene co-expression network analysis assembled proteins into unbiased modules of protein co-expression, which were annotated for gene ontology and cell-type enrichment. To test clinical relevance to ADRD, we examined PA-related protein levels across-cohorts of symptomatic Alzheimer’s disease and Parkinson’s disease (Stanford Alzheimer’s Disease Research Center), as well as frontotemporal dementia-spectrum disorders (ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium). PA-related plasma proteins were also tested as predictors of antemortem cognitive change and post-mortem brain tissue mass spectrometry proteomic signatures in brain donors from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) cohort. Differential regression and network analyses identified PA plasma proteomic signatures linked to cell adhesion/extracellular matrix (ECM), immune response and lipid metabolism. Protein co-expression module M12 ECM/neurodevelopment harboured growth factor, cell adhesion and vascular remodelling proteins that (i) were positively associated with PA across exercise cohorts, (ii) positively associated with cognitive function and (iii) negatively associated with Alzheimer’s disease, Parkinson’s disease and frontotemporal dementia. Furthermore, M12 was enriched for proteins from Alzheimer’s disease risk genes and antemortem plasma abundance of anthrax toxin receptor cell adhesion molecule 2 (ANTXR2), an M12 ‘hub’ protein and top PA hit across-cohorts, forecasted longitudinal global cognitive decline and post-mortem brain tissue signatures of synaptic function and proteolysis in ROSMAP. Collectively, our integrated systems biology analysis of six independent plasma proteomic datasets facilitated discovery and validation of blood-detectable molecular signatures of PA and neurodegenerative disease, including PA-related proteins with clinical and biological relevance to early stages of disease. Circulating levels of PA-related proteins reflecting ECM biology (e.g. ANTXR2) may represent key molecular targets for dementia prevention.

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Objectives To understand the trade-offs between different statistical modeling approaches, using real world data with small sub-populations, with rare exposures and increasingly rare outcomes. In particular, to compare adjusted regression, inverse probability weighting, and matching. Methods Data for these analyses came from the RADAR (N=1,134) and combined CNICS/JHHCC (N=14,434) cohorts. We estimated prevalence ratios (PRs) for self-reported use of specific substances comparing subpopulations (SP), SP-1 vs SP-3 and SP-2 vs SP-3, where SP-1 was the largest proportion (92% in RADAR, 81% in CNICS/JHHCC), SP2 was moderate proportion (18% in CNICS/JHHCC) and SP-3 was the smallest proportion (8% in RADAR, 1% in CNICS/JHHCC) of the population. We calculated PRs using 1) unadjusted relative risk regression (RR); and adjusted estimates controlling for age, race/ethnicity, study site, and year of interview using: 2) standard adjustment in RR; 3) stabilized inverse probability of treatment weighting (IPTW); and 4) matching with up to 3 matches from SP-1 or SP-2 per SP-3 participant. Results For most substances, all methods yielded consistent estimates. There were large weights in some of the IPTW analyses and in three cases these resulted in substantially divergent estimates. For the comparison between SP-1 and SP-3, the estimate for smoking was 1.3-fold greater in the matched analysis (PR=1.33, 95% CI: 1.02-1.75) than in IPTW (PR=1.03, 95% CI: 0.78-1.37 ATE and PR=1.05, 95% CI: 0.88-1.26 ATT). Even more extreme divergence in estimates was observed for differences between SP-2 and SP-3 with respect to methamphetamine/amphetamine, (IPTW-ATE: PR=1.51, 95% CI: 0.79-2.89; IPTW-ATT: PR=2.36, 95% CI: 1.36-4.12); vs Matching: PR=2.71, 95%CI: 1.47-4.99) and cocaine (IPTW-ATE: PR=1.15, 95% CI: 0.55-2.38; IPTW-ATT: PR=1.81, 95% CI: 1.03-3.18); vs Matching: PR=1.38, 95%CI: 0.76-2.53). Conclusion The combination of a rare exposure and a rare outcome can produce challenges for commonly used confounding adjustment strategies, and it is often best to compare different modeling approaches to gain greater insight.