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Introduction Recent transcriptome analysis has demonstrated increased expression of Vascular Endothelial Growth Factor receptor-1 (VEGFR-1/FLT1) and in AD brain. Increased expression of VEGFR1 and its ligand VEGFB were associated with a more rapid rate of cognitive decline, providing evidence of a potential link between increased VEGFR-1 expression in AD pathogenesis. In this study, we explored the potential role of VEGFR-1 expression in neurons on AD pathology. Methods To confirm VEGFR1 expression in AD brains, we first performed immunostaining in AD brain sections (AD - Braak stage V-VI, and normal controls - Braak 0-II). And to determine a potential detrimental role of neuronal VEGFR1 expression on AD associated pathologies, we exposed SH-SY5Y human neuroblastoma cells and mouse primary neurons to either hypoxia conditions (1%O 2 ) or 5 μ Aβ1-42 oligomers or fibrils for 24, 28 and 72hrs. Results In this study, we found preferential staining of VEGFR-1 in the neuropil and neuronal cell bodies both in AD and Control hippocampus and increased VEGFR-1 immunoreactivity in dystrophic neuritic processes in the vicinity of Thio-S positive amyloid plaques in AD brains. And treatment of SH-SY5Y human neuroblastoma cell line and mouse primary neurons, with either hypoxia conditions or Aβ1-42 oligomers, resulted in increased VEGFR-1 expression and cleaved caspase 3 activation, leading to neuronal toxicities/cell death. Similarly, treatment with Aβ1-42 fibrils also increased VEGFR-1 and cleaved caspase 3 protein levels in the SH-SY5Y cells whereas treatment with Aβ1-42 monomers had no effect on VEGFR-1 expression. In addition, we show that over-expression of VEGFR-1 intracellular domains in SH-SY5Y cells directly induced neuronal toxicities and importantly, siRNA-mediated knockdown of VEGFR-1 in neurons prevented the hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril-induced toxicities and cell death phenotypes. Treatment with either hypoxia or Aβ1-42 oligomers also reduced expression of cell survival genes including VEGFR-2 and Hippo pathway YAP1 and siRNA-mediated VEGFR-1 knockdown in the neurons normalized expression of both VEGFR-2 and YAP1. Using differential gene expression analysis, we demonstrated upregulation of several inflammatory/interferon-stimulated genes (ISGs) as well as increased expression of genes involved in activation of oxidative stress and cell death pathways in response to Aβ1-42 oligomers treatment in mouse primary neurons. And siRNA-mediated VEGFR-1 knockdown in the mouse primary neurons, reduced gene expression of both the ISGs and oxidative stress/cell death pathways in response to Aβ1-42 oligomer treatment. Discussion In summary, these results show that siRNA-mediated knockdown of VEGFR-1 in neurons significantly prevented hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril-induced cellular toxicities and cell death phenotypes, indicating a potential detrimental role of aberrant VEGFR-1 expression and signaling in response to AD associated pathologies.

Donation after circulatory death (DCD) livers increasingly use machine perfusion (MP). This study evaluates MP’s impact on older DCD livers based on data from the United Network for Data Sharing, covering all first adult DCD liver transplants (2016–2025). The cohort, divided into pre-MP and MP eras (separated by the FDA approval of the first normothermic MP platform in 2021), showed accelerated growth in DCD liver transplants during the MP era. Donors ≥60 rose 7.8-fold, including donors ≥70 (a USA first). By 2025, DCD livers accounted for 43.2%, with 61.35% from donors ≥50. Normothermic regional perfusion (NRP) (3.0%–21.7%), NMP (2.3%–35.6%), and sequential NRP-NMP (0.1%–19.2%) increased significantly (p < 0.001). The MP era was associated with a decrease in median waitlist time from 112 to 62 days (p < 0.001). Early graft survival was similar across ages. For ages 50–59, 1- and 3-year survivals were 87.9%/78.4% pre-MP and 90.1%/78.8% in the MP era. For 60–69, survival was 85.0%/80.6% pre-MP and 90.0%/71.3% in the MP era. DCD LTs for ≥70 were limited to the MP era with 87.8% 1-year survival. Multivariable Cox regression showed that static cold storage (HR = 1.19), donor age 50–69 versus 18–49, and recipient age (HR = 1.04) increased the risk of graft loss after adjustment. MP is associated with an increased number of older DCD liver transplants and acceptable early graft survival.

Background Intermittent fasting (IF) represents a dietary strategy with known metabolic benefits, however its safety and applicability in patients with chronic kidney disease (CKD) remains poorly understood. AI chatbots’ reliability for clinical and dietary guidance in clinically complex areas remains underexplored. No study has examined AI performance on IF in patients with CKD. This study evaluated the accuracy, consistency, readability, and quality of responses generated by ChatGPT-5 and Claude 4.5 Sonnet regarding IF in CKD. Methods Twenty-five patient-centered questions spanning seven clinical domains were developed by two board-certified nephrologists and submitted independently to ChatGPT-5 and Claude 4.5 Sonnet twice per model. Prompts were submitted under standard and unmodified user conditions without customized system instructions to represent a zero-shot evaluation that is illustrative of typical patient use. Responses were evaluated for accuracy, consistency (comparatively between responses), and appropriateness by the evaluators. Response readability and quality were assessed using the Flesch-Kincaid Grade Level (FKGL) formula and the DISCERN instrument respectively. Results Both ChatGPT-5 and Claude 4.5 Sonnet demonstrated identical accuracy scores during the first question prompts with notable improvement upon re-prompting after 24-hours. Both models demonstrated an identical internal consistency at 90%. ChatGPT-5 produced responses at the middle school level, better aligned with the US adult health literacy benchmark, while Claude 4.5 Sonnet generated responses at the high school level. DISCERN scoring was comparable between chatbots indicative of good response quality. Both chatbots had similar performance regarding individual subdomains. Conclusions Both chatbots illustrated clinically accurate and cautious responses to questions regarding IF in CKD. ChatGPT-5 responses were better suited to the average health literacy of the general United States adult population. Despite our findings, we do not recommend either chatbot be used as the primary source for clinical counseling regarding IF in CKD. It is important for clinicians to help to guide patients toward evidence-based clinical information.

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.