OBJECTIVE:Ischemic tissue perfusion remains a major clinical challenge despite VEGF's central role in angiogenesis. Limited success of VEGF-based therapies underscores the need to understand endothelial heterogeneity, as distinct subsets exhibit differential responsiveness. This study explores conserved endothelial states that govern VEGF-driven angiogenesis across human organs and evaluates their functional significance. APPROACH:We performed single-cell and single-nucleus RNA-sequencing (scRNA-seq/snRNA-seq) analysis of endothelial cells (ECs) from eight human tissues using GTEx data, validated findings in independent skin and heart datasets, and conducted CRISPR-mediated PLCγ2 knockout in cultured ECs followed by scRNA-seq. RESULTS:Analysis of 209,126 nuclei revealed a universal arterial-like endothelial subset (cluster 2) enriched across all organs, characterized by high expression of PLCγ2, a critical VEGF signaling effector. PLCγ2high cells exhibited robust angiogenic and lymphangiogenic programs, including upregulation of VEGFC, NOTCH4, and JAG1, and enrichment of pathways for vasculature development and endothelial differentiation. Cell-cell communication analysis demonstrated exclusive BMP6, IGF2, and CXCL12 signaling from PLCγ2high cells to fibroblasts, pericytes, and immune cells, positioning this subset as a central angiogenic hub. Functional validation showed that PLCγ2 knockout depleted PLCγ2high clusters, suppressed VEGF signaling, and diminished BMP6 ligand secretion, confirming its role in maintaining proangiogenic endothelial states. INNOVATION:Ineffective targeting of the appropriate EC state may limit current therapeutic VEGF strategies, positioning PLCγ2high ECs as a clinically relevant target. CONCLUSION:We identify PLCγ2high arterial ECs as a conserved pan-organ population critical for VEGF responsiveness and vascular regeneration. These findings reimagine VEGF therapy by highlighting PLCγ2 as a critical regulator of a proangiogenic arterial-like endothelial state and a promising combinatorial target to overcome limitations of current angiogenic strategies.
OBJECTIVE:To benchmark zero-shot generative pre-trained transformer (GPT)-based multimodal large language models (MLLMs) for pressure injury (PI) staging from photographs and quantify the effects of prompt strategy, structured outputs, and clinically meaningful label granularity. APPROACH:We performed a retrospective observational benchmark using 1,091 public, de-identified PI photographs labeled Stage I-IV. In the standardized analysis, all 10 model/prompt conditions were evaluated using a standardized, resume-safe application programming interface pipeline with per-image logging. We evaluated exact four-class staging, three-class staging (I/II/III-IV), skin-break screening (I vs. II-IV), and an advanced-intervention threshold (I-II vs. III-IV). Reporting followed Strengthening the Reporting of Observational Studies in Epidemiology and artificial intelligence/machine learning guidance; metrics included accuracy, Wilson 95% confidence intervals, F1 scores, weighted kappa, and threshold sensitivity/specificity. RESULTS:All conditions yielded parsed predictions for all 1,091 images. The best accuracy was 93.77% for skin-break screening (GPT-5.2 structured JavaScript Object Notation [JSON]), 90.28% for the advanced-intervention threshold (GPT-5.1 full prompt, low reasoning), 83.78% for three-class staging (GPT-5.1 full prompt, low reasoning), and 65.08% for exact four-class staging (GPT-5.2 structured JSON). The best advanced-intervention condition achieved sensitivity 96.72%, specificity 83.79%, and negative predictive value 96.19%. Stage IV undercalling remained safety-relevant; GPT-5.2-pro had Stage IV recall 8.79% and false-negative rate 91.21%. INNOVATION:This prompt-transparent benchmark shows how outcome granularity, prompting, and structured outputs affect GPT-based PI staging and adds ordinal, threshold-based, and safety metrics. CONCLUSION:GPT-based MLLMs may support clinician-supervised triage and prioritization, but image-only autonomous exact staging is not clinically ready.[Figure: see text].
OBJECTIVE:Dressing changes after digit replantation can trigger pain, anxiety, and local wound cooling, yet the clinical impact of cleansing solution temperature remains unclear. This study evaluated whether warmed saline irrigation improves patient experience and physiological stability during wound care after digit replantation. APPROACH:In this single-center, parallel-group randomized controlled trial, 149 patients undergoing digit replantation were randomized to receive warmed or room-temperature saline irrigation during postoperative dressing changes. Primary outcomes were pain and digit temperature assessed before, during, and after dressing changes. Secondary outcomes included anxiety, comfort, complications, and digit survival. Analyses followed the intention-to-treat principle using linear mixed-effects models. Reporting adhered to CONSORT guidelines. RESULTS:Compared with room-temperature saline, warmed saline significantly reduced pain and anxiety and improved patient comfort over time (all p < 0.001). Warmed saline maintained peri-wound temperature during dressing changes, whereas room-temperature saline induced transient cooling. No between-group differences were observed in complication rates, C-reactive protein, or digit survival. Clinically meaningful improvements in pain, anxiety, and comfort were more frequent in the warmed-saline group. Exploratory analyses suggested greater benefit in younger patients and during colder seasons. INNOVATION:This trial provides preliminary randomized evidence in a microsurgical population demonstrating that warmed saline irrigation, a simple and low-cost modification, can improve patient-reported outcomes without compromising safety. CONCLUSION:Warmed saline irrigation offers a safe and practical strategy to enhance comfort and reduce distress during wound care after digit replantation. These findings highlight thermal management as an underutilized, patient-centered component of postoperative care and support its integration into routine practice.
OBJECTIVE:Burn injuries affect millions globally, with increasing survival rates due to advances in acute care. However, long-term cardiovascular outcomes including major adverse cardiovascular events (MACE), venous thromboembolism (VTE), and mortality in burn survivors remain under-investigated. APPROACH:We conducted a retrospective propensity score-matched cohort study using the TriNetX US Collaborative Network. Individuals aged 18 years or older who had an emergency department visit or hospitalization with a diagnosis of burn injuries occurring between January 1, 2014, and January 1, 2019, were identified and matched 1:1 to nonburn controls who were selected based on similar demographics, comorbidities, and medications. The primary outcomes were the hazard ratios (HRs) and absolute risk differences (ARDs) of MACE, VTE, and mortality occurring between 3 months and 5 years after the index date. Secondary cardiovascular and thromboembolic endpoints included the HRs and ARDs of coronary artery disease (CAD), cerebrovascular disease (CVD), pulmonary embolism (PE), and deep vein thrombosis (DVT). RESULTS:A total of 71,426 propensity score-matched pairs of burn survivors and nonburn controls were included. Burn survivors had significantly elevated risks of MACE (HR 1.95, 95% confidence intervals [CI] 1.84-2.07; ARD 0.9%), VTE (HR 1.99, 95% CI 1.80-2.19; ARD 0.4%), and all-cause mortality (HR 2.29, 95% CI 2.10-2.49; ARD 0.7%) compared with controls. Increased risks were also observed for CAD (HR 1.85, 95% CI 1.72-1.98; ARD 0.5%), CVD (HR 2.05, 95% CI 1.88-2.24; ARD 0.5%), PE (HR 2.09, 95% CI 1.77-2.47; ARD 0.1%), and DVT (HR 1.96, 95% CI 1.69-2.27; ARD 0.1%). INNOVATION:We demonstrate that burn injury is associated with sustained long-term cardiovascular and thromboembolic risks up to 5 years after injury. CONCLUSIONS:These findings establish burn injury as a chronic condition, requiring routine cardiovascular screening and targeted prevention in long-term care.
