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BACKGROUND AND OBJECTIVES: Medical management options for nontraumatic subdural hematoma (SDH) remain limited, with only atorvastatin demonstrating benefit in a single phase 2 randomized clinical trial and mixed evidence for dexamethasone. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may benefit SDH outcomes. The objective of this study was to evaluate the association between GLP-1 RA use and rescue surgery rates and mortality in patients with medically managed nontraumatic SDH. METHODS: We conducted a retrospective cohort study using the TriNetX database from 2016 to 2025, including adults with SDH who were managed conservatively without surgical evacuation or middle meningeal artery embolization. Patients prescribed GLP-1 RAs were compared with nonusers. After propensity matching, rescue surgical evacuation, all-cause mortality at 1 year, and GLP-1 RA–associated adverse events were analyzed. RESULTS: A total of 134 901 patients with conservatively managed nontraumatic SDH were identified, of whom 1470 (1.1%) were GLP-1 RA users. After propensity score matching, 2922 patients remained, with 1461 in each group. At 1 year, GLP-1 RA users experienced significantly lower rates of rescue surgery (2.23% vs 3.51%; P = .046), culminating in an overall 38% reduction in relative hazard. All-cause mortality was also significantly lower for GLP-1 RA users at 1 year (16.1% vs 23.7%, P < .001), reflecting a 33% reduction in hazards. GLP-1 RA users did not experience different rates of adverse events, such as pancreatitis, gallbladder disease, or ileus/bowel obstruction (all P > .05). CONCLUSION: Among patients with medically managed nontraumatic SDH, GLP-1 RA use was associated with significantly lower rates of rescue surgery and all-cause mortality without significantly increased risk of common GLP-1 RA–related complications.

Summary Background Body composition is recognized as a major determinant of health outcomes, but its multidimensional nature makes clinical adoption challenging. We sought to develop and validate a body composition index (BCI) for all-cause mortality risk assessment, integrating variables of six body composition tissues. Methods We analyzed 28509 consecutive patients undergoing myocardial perfusion imaging with routine low-dose chest CT attenuation correction (CTAC) scans acquired during myocardial perfusion imaging (MPI) at 12 centers across four countries. An artificial intelligence-based BCI was developed in a cohort of 15037 patients’ CTACs by integrating the CT-derived metrics of bone, skeletal muscle, and four adipose tissue compartments, coronary artery calcium score, and basic demographic variables (age, sex, BMI). The performance of BCI for mortality prediction was validated in an internal cohort of 6444 patients and an external cohort of 7028 patients by prognosis, calibration, net benefit, and explainability. Model-based simulation of tissue metrics modification was performed to evaluate estimated mortality risk reduction. Findings During a median of 3.5 (IQR [1.9, 5.1]) years, 4697 (16%) patients died. In the external testing cohort, the BCI demonstrated excellent discrimination for mortality (area under receiver operating characteristic curve 0.78 (95% CI [0.76, 0.79]) and Harrell’s concordance index 0.75 [0.73, 0.76]), calibration, and net benefit overall and across pre-specified subgroups stratified by patient characteristics and imaging protocols. Visceral adipose tissue attenuation was the most influential body composition measure, followed by skeletal muscle volume. Simulated improvement in body composition was associated with significant mortality risk reduction. Interpretation An index combining six body composition measures obtained opportunistically from routine chest CT provides robust mortality risk stratification. By converting complex body composition information into a single interpretable score, the BCI can facilitate clinical implementation of opportunistic CT biomarkers and guide individualized preventive strategies. Funding National Institute of Health Research in context Evidence before this study We searched PubMed and Google Scholar on July 7, 2026 for English language studies using the terms (“mortality prediction” OR “death prediction”) AND (“integrated body composition analysis” OR “body composition metrics integration”) AND (“predictive model” OR “model development”), and identified 41 publications describing predictive models incorporating body composition metrics. Recent advances in artificial intelligence (AI) have enabled increasingly granular quantification of body composition from CT, with multiple tissues and tissue-specific metrics showing independent prognostic value for all-cause mortality (ACM) prediction. However, reported associations of body composition metrics with mortality risk were highly inconsistent or even contradictory across studies. This heterogeneity likely reflected the differences in study design or the inherent complexity of body composition analysis, such as the interaction among variables derived from multiple tissues. Thus, it is difficult to interpret body composition results reliably in clinical practice. We hypothesized that integrating multiple body composition metrics could achieve comprehensive and reliable prediction of mortality across patient populations. Added value of this study In this large international, multicenter longitudinal cohort study of 28509 consecutive patients with suspected or known coronary artery disease (CAD) undergoing myocardial perfusion imaging across 12 sites in four countries, we developed and externally validated an artificial intelligence-based body composition index (BCI) for all-cause mortality prediction. The BCI integrated chest CT-derived metrics of six body composition tissue compartments – bone, skeletal muscle (SM), subcutaneous adipose tissue (SAT), intramuscular adipose tissue (IMAT), visceral adipose tissue (VAT), and epicardial adipose tissue (EAT), together with demographics (age, sex, BMI) and CT-derived coronary artery calcium (CAC) score, all derived automatically from routine low-dose attenuation correction CT scans without additional imaging or laboratory tests. In an external validation cohort of 7028 patients, the BCI achieved robust discrimination for mortality prediction, substantially outperforming a baseline model using demographics and calcium score alone, and exceeded the discriminative performance of prior body composition models. Performance was consistent across subgroups defined by sex, age, body mass index, cardiometabolic risk factors, imaging modality, and acquisition protocol, supporting generalizability across clinical settings. The BCI demonstrated excellent calibration and net clinical benefit. Explainability analysis identified visceral adipose tissue attenuation and skeletal muscle volume as the dominant contributors to mortality risk, offering tissue-specific therapeutic targets that complement generic weight-based metrics. Model-based simulations suggested that improvements in these specific compartments could reduce estimated mortality risk more effectively than equivalent changes in BMI alone, pointing toward precision therapeutic targets beyond weight reduction. Our study improved over previous literatures on body composition-based predictive models in one or more of the following ways: (1) we considered six types of body composition tissues while existing studies considered only three or less tissues, thus significantly higher granularity and improved ability to capture refined tissue interactions; (2) our model was rigorously validated in external sites, showing cross-site generalizability while most previous work lacked external validation; (3) our model achieved significant prediction performance improvement over previous body composition predictive models, offering better clinical outcomes prediction and facilitating the suitability for widespread clinical adoption; (4) our study was conducted with a large multi-center cohort across multiple countries, achieving statistical power and demonstrating reliability towards patients characteristics and imaging acquisition protocols while previous studies involved small single-center cohorts; (5) our model required only CT scans and basic demographics which were widely available in clinical routine while the existing models required dedicated laboratory tests or specialized imaging modalities, enhancing the applicability in routine clinical practice. Implications of all the available evidence BCI offers an explainable and clinically deployable tool for improved prediction of mortality risk from existing chest CT scans. Its use could inform updates to existing risk models, guide precision preventive strategies, and support development of therapeutics targeting specific body composition phenotypes.

TRAIL is a TNF family ligand that trimerizes TRAIL-R1 (DR4) or TRAIL-R2 (DR5) to induce apoptosis, necroptosis, and/or NF-κB activation in receptor-bearing cells. We previously identified TRAILshort as a splice variant of TRAIL that lacks cysteine 230, cannot trimerize, and acts as a dominant-negative ligand that blocks TRAIL-mediated apoptosis. TRAILshort is expressed on cell surfaces and within extracellular vesicles, enabling it to confer TRAIL resistance to both producing and bystander cells. In this study, we showed that elevated TRAILshort levels were associated with chronic viral infections, cancer, and autoimmune diseases, suggesting a link to impaired immune regulation. Using unbiased phosphoproteomics and mechanistic studies, we demonstrated that TRAILshort binding to DR5 recruited and activated the phosphatase Src homology region 2 domain–containing phosphatase 1 (SHP-1), leading to zeta-chain-associated protein kinase 70 (ZAP-70) dephosphorylation, disruption of ZAP-70–CD3ζ interactions, and impaired T cell receptor signaling, thereby reducing T cell activation, proliferation, and cytokine production in response to antigen or CD3/CD28 ligation. Genetic or pharmacologic SHP-1 inhibition reverses these effects. In humanized mouse models, TRAILshort promoted the persistence of transformed mouse embryonic fibroblasts (MEFs) and L428 and antagonized CD19-directed CAR T cell activity, revealing TRAILshort as an immunomodulator of T cell function with therapeutic implications, including blocking TRAILshort to restore T cell immunity or delivering TRAILshort to enforce tolerance. TRAILshort, a variant of TRAIL, suppresses T cell function and immune responses in cancer and infectious diseases, highlighting its potential as a therapeutic target.

Aim: Despite advances with immune checkpoint inhibitor (ICI)-based regimens in the past decade, patients with metastatic urothelial cancer (mUC) face a poor prognosis with few approved options. Platinum-based chemotherapy with paclitaxel and carboplatin (TC) +/– ICI may be a feasible choice. Methods: We generated an IRB-approved, HIPAA-compliant retrospective database of patients at Mayo Clinic Cancer Center with mUC who started TC +/– ICI after disease progression on ICI from January 2018 through December 2024. Baseline demographics, clinicopathologic features, and treatment outcomes were extracted from the electronic health record. Kaplan-Meier method was used to calculate median duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: There were 32 patients who fit inclusion criteria, including 31 patients who had disease progression on ICI in the metastatic setting and 1 patient who developed metastatic disease on adjuvant nivolumab. Patients received a median of 4 cycles (range 1–14) of TC over median 12 weeks (range 3–53). Overall, 81% of patients received TC concurrently with an ICI, and 28% continued maintenance ICI after TC discontinuation (at the treating oncologist’s discretion due to adequate response or toxicity). The best objective response rate was 41% and disease control rate was 75%, with median DOR of 4.8 months (IQR 2.7–10.4), median PFS of 4.6 months (IQR 3.3–10.2), and median OS of 9.4 months (IQR 6.3–15.9). Some patients in this series had very durable responses with PFS > 12 months and OS > 24 months. TC +/– ICI was overall well tolerated with expected type and severity of adverse events. Conclusions: Strategies to overcome ICI resistance are needed, and TC +/– ICI after disease progression on an ICI shows promising tolerability and efficacy in this setting for patients with mUC. Our series was notable for some patients having a durable response. Validation in larger cohorts is warranted.

Abstract Introduction Glioblastoma (GBM), the most aggressive primary brain tumor in adults, is marked by profound immune suppression. Tumor-derived extracellular vesicles (TEVs) are increasingly recognized as key mediators of this immunosuppressive environment. Methods In this study, we examined the tumor-immune microenvironment using ultrasonic aspirate samples from GBM patients (n = 14). Results Several immune checkpoint molecules, including PDL1, B7-H3, and VISTA, were notably elevated. TIGIT, a receptor typically associated with T cells, was widely expressed across multiple myeloid subsets, including monocytic myeloid-derived suppressor cells (mMDSCs; 64.27±7.99%) and non-classical monocytes (NCM; 39.8±4.37%). Co-culture of healthy donor CD11b+ cells (n = 10) with TEVs replicated similar effects (mMDSCs; control 11.691.87 vs EV treated 23.322.0). We found CD155, a primary TIGIT ligand, to be heavily enriched in TEVs and co-localized with TIGIT in co-culture, suggesting the TIGIT/CD155 axis may be involved in promoting immune suppression. induced MDSCs markedly suppressed T cell proliferation (30.65 ± 5.97% vs. control 86.47 ± 2.94, p = 0.0001), accompanied by elevated Th2 cytokine production and increased NLRP3 and IL-1β expression. Interestingly, TIGIT knockdown did not affect NLRP3 expression, but did restore T cell proliferation (64.13±1.33%; p = 0.02) and pro-inflammatory cytokine production. However, this effect was lost upon NLRP3 knockdown, indicating its essential role in mediating immune rescue. Furthermore, IL-13 (a Th2 cytokine) blockade, in this model, enhanced pro-inflammatory response by suppressing phosphorylation of STAT-6 protein. Conclusion Overall, our findings highlight a crucial role for the TIGIT/CD155 axis in driving myeloid-mediated immune suppression in GBM. Furthermore, TIGIT inhibition may unmask NLRP3 function, potentially contributing to immune rescue. Funding Source Neurosurgery Research & Education Foundation through the B*CURED & NREF Young Clinician Investigator Award, as well as intramural K12 funding through the Institute for Clinical and Translational Research and the NCI Paul Calabresi Career Development Award (1K12CA279871). Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Background Randomized trials have shown equivocal outcomes between a direct aspiration as first-pass technique (ADAPT) and stent retriever (SR) stroke thrombectomy, yet whether specific patient subgroups benefit differentially from one technique over the other remains unknown. Methods In this retrospective multicenter cohort study, patients with large vessel occlusion were included, and those who underwent ADAPT versus SR first-pass thrombectomy (either as standalone or combined with aspiration) were compared. The primary outcome was a composite of first-pass effect (FPE, modified Thrombolysis In Cerebral Infarction (mTICI) 2c or better with one attempt) with no symptomatic intracranial hemorrhage (sICH). A causal forest model was used to estimate the conditional average treatment effect (CATE) for each patient, with larger CATEs indicating that ADAPT is expected to be more advantageous. Patients were stratified by CATEs, and outcomes were compared between treatment groups. Results Among 6700 included patients, ADAPT (n=3695, 55%) was associated with a higher rate of FPE with no sICH (39.9% vs 26.9%; adjusted OR (aOR) 2.07, 95% CI 1.77 to 2.41, P<0.001). The causal forest identified significant treatment effect heterogeneity (interaction P<0.001), where ADAPT was more advantageous in more recent years and among patients with M1 occlusions presenting in earlier time windows. Low-CATE patients showed no statistically significant difference between techniques (aOR 0.91, 95% CI 0.57 to 1.45, P=0.70), while medium- and high-CATE patients demonstrated progressively larger ADAPT advantages (aOR 2.06, 95% CI 1.67 to 2.55, and aOR 2.99, 95% CI 2.24 to 3.98, respectively, both P<0.001). Conclusions ADAPT may be superior to SR for a majority of patients, particularly in recent years, and among patients with M1 occlusions presenting in earlier time windows.

Background The management of osteochondral lesions of the talus (OLT) is challenging, with 2 main options being conservative and surgical management. Orthobiologic therapies come to bridge the gap between these 2 options; however, inconsistencies in indication, composition, and heterogeneous evidence limit clinical decision-making. To address these challenges, 3 International Congress Meetings on Cartilage Repair of the Ankle were convened in Pittsburgh, USA (2017), Dublin, Ireland (2019), and New York, USA (2025) to establish agreement on the role of conservative management and injectable orthobiologic strategies in the treatment of OLT. Methods Seventy-five multidisciplinary experts from over 25 countries and 1 territory participated in a structured Delphi-based consensus process. Blinded surveys, structured questionnaires, and in-person discussions were used to develop and refine statements, supported by literature review and graded evidence (A1–E). Consensus strength was defined as consensus (51%-74%), strong consensus (75%-99%), or unanimous (100%) Results In total, 29 consensus statements were achieved across the 3 meetings. Strong agreement was reached regarding indications and expected outcomes of conservative management, including the role of immobilization and appropriate timing for surgical intervention. Orthobiologic injections, including platelet-rich plasma, concentrated bone marrow aspirate, and hyaluronic acid, were considered appropriate in select patients with persistent symptoms, although no superiority was demonstrated among formulations, preparation methods, or injection strategies. When used as adjuncts to surgical procedures, orthobiologics may improve radiological outcomes, with limited evidence for improvement in clinical outcomes. Technical considerations, including preferred harvest sites and a lack of standardized preparation protocols, were identified, along with key principles for patient counseling Conclusion These international consensus statements establish a standardized framework for the conservative management and use of injectable orthobiologic therapies in OLT. By clarifying indications, technical considerations, and current limitations, this work aims to improve consistency in clinical practice, guide treatment decision-making, and inform future research.