Citations

ABSTRACT The FDA Modernization Act 3.0 represents a pivotal shift in biomedical research by formally removing the requirement for animal testing and enabling regulatory acceptance of New Approach Methodologies (NAMs). This transition creates an urgent need for robust, human‐relevant biomarkers that can anchor NAM‐generated data within regulatory decision‐making, particularly for first‐in‐human studies. Extracellular vesicles (EVs), owing to their biological stability, accessibility and rich molecular cargo, may be well positioned to fulfil this role. EVs reflect dynamic cellular states and intercellular communication, making them mechanistically informative readouts of pharmacology, toxicity, immune modulation and disease biology across human‐derived model systems. This Perspective outlines how EV‐based biomarkers can support the qualification, standardization, and regulatory acceptance of NAMs, with particular emphasis on ex vivo platforms such as organoids, microtissue systems, organ‐on‐chip devices and perfused tissue slices. We highlight the advantages of EVs for longitudinal, non‐destructive sampling, representation of human variability, and integration with quantitative systems pharmacology and physiologically based pharmacokinetic models. Finally, we discuss the scientific, operational and regulatory challenges that must be addressed and argue that coordinated leadership from the International Society for Extracellular Vesicles (ISEV) is essential. The convergence of regulatory reform and EV science presents a timely call to action to establish EVs as foundational biomarkers in next‐generation, human‐centric drug development.

ABSTRACT Biological aging greatly impacts the body’s ability to handle glucose, and represents a major risk factor the development and progression of type 2 diabetes (T2D). Nonetheless, despite advances in cellular senescence research and the development of new senolytic therapies, the heterogeneity of cellular senescence in the human endocrine pancreas, as well as its roles in normal aging, remains to be elucidated at the single-cell level. Here, we performed single-cell–resolved spatial proteomics and transcriptomics on intact pancreas from 26 donors (ages 20–80) and multiplexed single-cell RNA sequencing and functional assays on dispersed islets from 14 donors (ages 34–69). We identify two discrete SnC subpopulations distinguished by relative expression of CDKN1A and CDKN2A. CDKN1A ⁺ senescent cells (SnCs) exhibit loss of β-cell identity, impaired insulin secretion, and a proinflammatory SASP associated with increased islet immune infiltration. In contrast, CDKN2A ⁺ SnCs retain transcriptional identity and functional competence, with lower inflammatory signaling. Together, these findings identify heterogeneous and functionally divergent senotypes in the human pancreas, distinguishing an adaptive ( CDKN2A ⁺) from a maladaptive ( CDKN1A ⁺) senescence program, thus providing a mechanism-guided framework for senescence-targeted therapies in T2D.

Post–liver transplant (LT) weight gain and metabolic dysfunction predispose to cardiovascular (CV) morbidity, allograft steatosis, and reduced long-term survival. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) promote weight loss and improve cardiometabolic health, yet evidence in liver transplant recipients (LTRs) is limited. We aimed to evaluate the safety, tolerability, and efficacy of GLP-1 RAs in post-LT weight management. We performed a multicenter retrospective cohort study of adult LTRs treated with GLP-1 RAs across 4 international centers (January 1, 2010–June 30, 2025). Regular GLP-1 RA users were compared with matched non-users by age, sex, obesity, and diabetes status, transplant year, and center. The primary outcome was the change in body weight 1-year post-exposure. Secondary outcomes included glycemic and lipid profiles, kidney and allograft function, immunosuppression effects, major adverse cardiovascular events (MACE), and adverse effects. Longitudinal analyses used linear mixed models with multiple imputation. Among 104 GLP-1 RA users, 68.3% initiated therapy for diabetes; subcutaneous semaglutide was most used at a median dose of 0.82±0.46 mg weekly. Treatment led to significant reductions in body weight (−3.8 kg; −3.9%, p <0.001), body mass index (BMI) (−1.6 kg/m 2 ; −5.0%, p <0.001), and glycated hemoglobin (HbA1c) (−0.48%, p =0.002), with modest lipid improvement. Liver function tests and immunosuppression trough levels remained stable, and no treatment-limiting adverse events occurred. In matched analyses (80 GLP-1 RA users vs. 116 non-users), GLP-1 RAs facilitated greater weight loss (−3.4 kg difference, p =0.009) and HbA1c reduction (−0.43% difference in HbA1c, p =0.042) without increased risk of allograft dysfunction, T-cell–mediated rejection (TCMR), or MACE. This multicenter, international study demonstrates GLP-1 RAs are safe and moderately effective in reducing weight and improving metabolic parameters post-LT, without adverse effects on allograft function or immunosuppression, despite limitations of low dosing. Prospective, randomized trials of GLP-1 RAs in LTRs are thus warranted.

BACKGROUND AND OBJECTIVES: Stroke has the largest proportion of the global burden of neurological disorders with projected mortality rates to increase more rapidly in low- and middle-income countries than in high-income countries, and people of African descent are at greater risk. To better understand the burden, risk factors, and care pathways, this study aimed to review the risk factors, clinical presentation, and outcomes of patients presenting with stroke or stroke-like symptoms in a tertiary hospital in Sierra Leone. METHODS: A retrospective chart review was conducted of all patients presenting with neurological or neurosurgical conditions from January 2019 through December 2023 and those with stroke or stroke-like symptoms were included in this study. RESULTS: One thousand two hundred ninety-seven patients were diagnosed with stroke. Of these, a small majority were male (712, 54.9%), and the mean age was 57.8 years. About a third (38.1%) of the stroke patients were aged 60 years and above, and 562 (43.3%) were between 41 and 60 years. A majority of stroke patients (68.6%) had a prior diagnosis of hypertension, while significantly fewer had a documented diagnosis of diabetes (8.8%) and 4.6% of patients had a known prior stroke. Only half (50.8%) with ordered computed tomography scan were able to complete the ordered imaging. From these imaging findings, 123 patients (9.6%) were diagnosed with hemorrhagic stroke, while the remainder were diagnosed with ischemic stroke or transient ischemic attack vs hypertensive urgency. 32.9% experienced in-hospital mortality, while only 6.5% followed up. CONCLUSION: This study documents the significant stroke burden in Sierra Leone, much of which is unaddressed due to lack of specialty resources including inadequate community engagement to raise awareness of risk factors and preventative measures. Poor health-seeking behavior and access to medical services also contribute to this burden. These data are imperative to identify systems gaps and help support ongoing capacity building efforts.

Due to increasingly nuanced Crohn disease therapy selection and disease evaluation, radiologic assessment of transmural healing, although aspirational, may be more complete than endoscopic assessment of mucosal healing, which is the current treatment target.

Idiopathic pulmonary fibrosis (IPF) is a fatal, aging-related disease characterized by persistent lung fibroblast activation, progressive lung scarring, and several vascular abnormalities. We have previously demonstrated that aging-associated vascular dysfunction drives maladaptive endothelial responses to injury and exacerbates lung fibrosis via secretion of profibrotic endothelial cell–derived factors. However, regulatory mechanisms governing endothelial dysfunction during progressive lung fibrosis remain poorly understood. Here, using preclinical mouse models of progressive lung fibrosis as well as human IPF lungs, we demonstrate that miR-205-5p was overexpressed in lung endothelial cells (ECs) from fibrotic lungs and coordinated gene expression programs implicated in endothelial dysfunction and progressive fibrosis. Mechanistically, miR-205-5p induced senescence in lung ECs, mirroring the senescent phenotype of IPF lung ECs. Consistently, conditioned medium derived from lung ECs overexpressing miR-205-5p promoted lung fibroblast activation. Importantly, miR-205-5p inhibition in IPF lung ECs attenuated endothelial senescence and limited paracrine fibroblast activation. Finally, inhibition of miR-205-5p in vivo preserved the pulmonary vascular network and attenuated lung fibrosis progression in aged mice challenged with bleomycin. Collectively, our findings support what we believe to be a novel connection among lung endothelial miR-205-5p, endothelial senescence, and profibrotic alteration of the endothelial secretome and highlight miR-205-5p inhibition as a potential therapeutic intervention for pulmonary fibrosis.

Pulmonary embolism (PE) is a leading cause of cardiovascular morbidity and mortality. Systemic thrombolysis is recommended for high-risk PE, but risk of major bleeding limits its use despite its efficacy. While mechanical thrombectomy (MT) has emerged as an alternative reperfusion strategy, real-world safety data remains limited. The objective of this single-center retrospective observational cohort study was to characterize the safety profile and procedural complications of MT. Methods Adult patients with intermediate-risk and high-risk PE who underwent MT at a quaternary academic medical center between January 1, 2017, and December 31, 2024, were included. Demographic, clinical, laboratory, imaging, procedural, outcome, and mortality data were collected. Major adverse events and bleeding were defined according to established criteria. Results From a total of 103 screened patients, 65 were included. Of these, 22 (34%) were classified as high-risk and 43 (66%) as intermediate-risk. Baseline demographics were similar between groups. High-risk patients demonstrated greater clinical disease severity, with higher mean Pulmonary Embolism Severity Index (PESI) scores (188.5 vs 122.4). Clinical deterioration prior to MT occurred in 35% of intermediate-risk patients. Extracorporeal membrane oxygenation (ECMO) consultation rate (32% vs 7%), peri-procedural ECMO use (18% vs 2.3%), major bleeding (27% vs 4.7%), and in-hospital mortality (36% vs 11.6%) were higher in the high-risk group. Thrombus removal was achieved in 77% and 88% of high- and intermediate-risk patients, respectively. High-risk patients had longer ICU (mean 4 vs 1.3 days) and hospital stays (mean 21.5 vs 6.4 days), higher thirty-day mortality (36% vs 14%), and lower 90-day survival (59% vs 79%). Conclusions MT achieved high rates of thrombus removal in both groups. In this retrospective cohort, high-risk patients had greater baseline clinical severity and was associated with higher bleeding rates, greater resource utilization, including ECMO consultation and peri-procedural use, prolonged ICU and hospital stays, as well as increased mortality.