Citations

Abstract Endothelial specialization is increasingly recognized as a fundamental regulator of tissue homeostasis, yet the cellular diversity of the skeletal vasculature remains incompletely resolved. Here, we integrate large-scale single-cell transcriptomics, cross-tissue comparisons, and imaging to comprehensively define endothelial heterogeneity across the skeleton. Our analyses demonstrate that the proposed post- arterial “type R” endothelial population is not a distinct endothelial subtype but instead comprises canonical venous endothelial cells and fatty acid-handling endothelial state. RNA velocity supports a venous continuum, while the proposed type R markers FMO2, and AQP7 lack both endothelial and skeletal specificity. The fatty acid-handling endothelial state, characterized by Lpl and Cd36 is conserved across multiple skeletal sites and non-skeletal tissues, indicating a general endothelial metabolic programme. Within bone, this endothelial state expands following high-fat diet and is suppressed during injury. Together, these findings redefine skeletal endothelial heterogeneity and establish the proposed type R population as part of a venous continuum.

Objectives: Psychological health changes are known to occur during perimenopause, but the extent to which these differ from premenopause remains unclear. This study aimed to assess psychological symptoms during perimenopause compared with premenopause and evaluate differences by country. Methods: Flo app users aged 35 years or above not taking hormonal contraception or hormone therapy were included. The psychological domain of the Menopause Rating Scale (range 0-16) and symptoms within this domain of depressive mood, irritability, anxiety, and exhaustion (range 0-4 each) were evaluated. Participants in perimenopause were compared with those in premenopause (self-reported not in perimenopause or postmenopause). Results: A total of 7,975 women were included, with 2,353 in perimenopause (mean age 45 years [SD±4.5]) and 5,622 in premenopause (39 y [SD±4.0]). Psychological Menopause Rating Scale scores in the perimenopause group were significantly higher (7.3 [SD±3.56]) than in the premenopause group (4.8 [SD±3.56]; P <0.001). The individual symptoms of depressive mood, irritability, anxiety, and exhaustion were also higher in the perimenopause group ( P <0.001, for all respectively), with the largest difference being exhaustion. These findings remained after adjusting for known confounders, including an existing diagnosis of anxiety or depression. Geographic analysis included 20 countries across 6 continents, with significant differences identified between countries for the overall psychological symptom domain score and all individual symptoms. Conclusion: Significantly greater psychological symptom burden was identified in the perimenopause group compared with the premenopause group, with the greatest difference noted for the individual symptom of exhaustion. Differences in symptom burden were also identified by country.

Background: Shared Decision Making in palliative care encompassing patient-clinician collaboration has shown potential for improved patient outcomes. However, the impact of decision aids intended to support palliative care decision making discussions across clinical care settings remains uncertain. Aim: To assess the impact of shared of decision aids on decision making, clinical outcomes, and quality of life for patients with palliative care needs and their caregivers. Design: Systematic review and meta-analysis of randomized controlled trials, reported according to PRISMA, with overall evidence quality assessed using GRADE. Data sources: Ovid MEDLINE (all segments), EMBASE, Cochrane CENTRAL, Cochrane Database of Systematic Reviews, and Scopus, from inception through September 20, 2024, without restrictions on publication date, sample size, or language. Eligible studies were randomized controlled trials that included adult patients with palliative care needs or their caregivers, using any form of decision aids. Outcomes encompassed decision-related, clinical, and quality of life measures. Results: Sixteen randomized controlled trials were included. Participant ages ranged from 44 to 85 years. Predominant decision aids were videos or printed materials addressing goals of care and treatment options, with aims that included improving understanding of prognosis and supporting values clarification. Decision aids significantly improved decision-related knowledge (SMD: 0.40, 95% CI: 0.14–0.67, p = 0.003) and lowered preference for cardiopulmonary resuscitation (OR: 0.28, 95% CI: 0.20–0.40, p < 0.001). They showed no significant impact on decisional conflict, satisfaction, or regret. Conclusion: Evidence regarding the effectiveness of decision aids in palliative care decision making is limited and of low overall quality, with observed improvements primarily in patient knowledge and changes in stated treatment preferences rather than established improvements in decision quality or values-concordant care. Future research should prioritize integration into comprehensive shared decision making frameworks, cultural adaptations, and larger-scale studies to enhance patient-centered outcomes.

Abstract Epigenetic inheritance relies on the precise recycling of parental histones during DNA replication. The N-terminal region of Pol1, the catalytic subunit of DNA polymerase α, has previously been implicated in chaperoning parental histone recycling. In this study, we identify a single amino acid mutation in the C-terminal region of Saccharomyces cerevisiae Pol1 (pol1-F1396S) that destabilizes the protein and disrupts the transfer of parental histones to the lagging strand during DNA replication. As a primary consequence, pol1-F1396S cells exhibit decreased chromatin stability. Furthermore, we demonstrate that the cellular abundance—or dosage—of all three DNA polymerases (Pol α, Pol δ, and Pol ε) influences the distribution of parental histones between the leading and lagging strands, revealing a dosage-sensitive mechanism of epigenetic regulation during DNA replication.

Importance and Objective: Sexual health is a multidimensional aspect of women’s well-being. It is particularly vulnerable during midlife, when the physiological and psychosocial changes of the menopause transition intersect with the growing burden of obesity. Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as highly effective pharmacologic treatments for obesity, yet their effects on female sexual function remain largely uncharacterized. This review aims to discuss the interplay among obesity, midlife, obesity treatments, and female sexual health, with a focused synthesis of available evidence on GLP-1–based therapies and sexual outcomes in women. Methods: This narrative review synthesizes preclinical studies, case reports, observational data, and clinical trials identified through PubMed searches from inception through March 2026, examining female sexual function in the context of obesity, the menopause transition, obesity treatments, and GLP-1 receptor agonist therapy. Discussion and Conclusion: Obesity impairs female sexual function through hormonal, vascular, and psychosocial mechanisms. Accordingly, lifestyle interventions and bariatric surgery have demonstrated meaningful improvements in sexual function. In contrast, GLP-1 receptor agonists, despite conferring substantial weight loss and favorable metabolic effects, may paradoxically suppress sexual desire and arousal through central neuroendocrine mechanisms, including the modulation of dopaminergic reward and serotonergic signaling. While emerging case reports and preclinical data support this concern, systematic clinical evidence remains limited, highlighting the need for prospective studies with longitudinal sexual function endpoints. In this context, clinicians should proactively assess sexual function before and during GLP-1 therapy using validated instruments and integrate sexual health into comprehensive obesity care for midlife women.

Background: Ketamine and esketamine are increasingly used for treatment-resistant depression (TRD), yet their hepatic safety profile with repeated or long-term use remains poorly characterized. Chronic recreational ketamine abuse has been linked to cholestasis and cholangiopathy, raising concern that therapeutic use may carry similar risks. No systematic data exist on liver enzyme trajectories or biliary injury at subanesthetic doses used for depression. Methods: This historical cohort study included adults with TRD receiving IV ketamine or intranasal (IN) esketamine at the Mayo Clinic Ketamine Clinic (2017 to 2024). Patients were eligible if they had at least one liver enzyme value (AST, ALT, ALP, or bilirubin) within 12 months before through 3 months after treatment. Longitudinal enzyme trajectories were modeled using generalized linear-mixed models with a Gamma distribution. Clinically significant elevation was defined as ≥2× the upper limit of normal (ULN). Wilcoxon signed-rank tests compared pretreatment and post-treatment paired values. Results: Of 104 enrolled patients, 74 had liver enzyme data available; 51 had post-initiation data. Median age was 51.5 years; 72% were female. Most (78.4%) received IV ketamine. No clinically meaningful changes in enzyme trajectories were observed. Three patients (5.9%) had elevations ≥2× ULN, all attributable to alcohol use, myalgias, or pre-existing hepatic steatosis rather than (es)ketamine. Conclusions: Subanesthetic IV ketamine (0.5 mg/kg) and FDA-approved IN esketamine doses were not associated with clinically significant liver enzyme elevations in this real-world TRD cohort. Current evidence does not support routine hepatic monitoring for asymptomatic patients, although prospective, larger-scale studies are needed to confirm these findings.

Although structured reporting of adverse events related to medical therapies is a critical aspect of clinical trials, the current practice fails to capture postoperative complications accurately or systematically, which precludes our ability to fully assess the impact of the risks of surgical interventions on oncologic outcomes. The incorporation of standardized, procedure‐specific definitions and severity classifications for postoperative complications into adverse event reporting in trials conducted through the National Clinical Trials Network is proposed.

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.