Citations

SUMMARY B cells can control inflammation, but the factors governing B cell-mediated immune regulatory network remain unclear. We report that IL-2/CD40L enable class-switched memory (CSM) B cells to acquire an immunosuppressive phenotype characterized by the expression of surface TIGIT as well as multiple other inhibitory receptors (PD-1, LAG-3, GITR, CD39, and CTLA-4) and soluble molecules (IL-10, granzyme B, and IL-35). TIGIT + CSM B cells expressing functional CCR9 exhibit significant defects in total immunoglobulin secretion, while preserving IgA2 secretion. Furthermore, IL-2/CD40L-induced ex vivo -generated TIGIT + CSM B cells suppress human T cell-mediated inflammation in a xenogeneic mouse model of acute graft-versus-host disease, while promoting IL-10-producing regulatory T cell (Treg) response. These findings identify IL-2/CD40L as key drivers of a B cell-mediated immune regulatory network, especially by generating TIGIT + CSM B cells that can further promote Treg response. This study supports the development of TIGIT + B cell-based therapy models for inflammatory diseases. Graphical Abstract Highlights IL-2/CD40L can generate and maintain immunosuppressive TIGIT + B cells in humans. TIGIT + B cells expressing CCR9 have defects in antibody secretion, but not IgA2. TIGIT + B cells suppress inflammation, while promoting Treg response in vivo . IL-2/CD40L can thus build a robust B cell-mediated immune regulatory network.

Abstract Patients with cancer and their caregivers face challenges accessing clinical trials because trial information, eligibility criteria, search, and referral pathways are complex and fragmented. These barriers can contribute to unequal access across racial, ethnic, and language groups. ALEX (Agents Leveraging Empathy for eXams) is a web-based portal that uses AI-enabled virtual health educators with synthesized voices and lip-synced facial animation to deliver trial education and a large language model to simplify trial information for search and referral. AI-generated content and virtual humans require human and community evaluation for accuracy, authenticity, and trust. This study examined how community feedback informed the iterative design and refinement of ALEX. The dataset included 34 English- and Spanish-language transcripts (about 44 hours) from focus groups and usability interviews using think-aloud procedures to evaluate the portal. The sessions were conducted from 2023 to 2025 at Mayo Clinic, UF-Gainesville, UF-Jacksonville, and the University of Miami. They examined 136 participants’ responses to the virtual health educators and their use of the portal for trial education, search, and referral. Participants reported their race as White (48.5%), Black or African American (47.1%), Native American or Alaska Native (0.7%), or other (3.7%). Separately, 50.7% identified as Hispanic or Latino, and nearly 25% reported Spanish as their primary language. Throughout data collection, feedback was reviewed and translated into design requirements for successive portal updates. We used deductive and inductive qualitative analysis to identify feedback patterns and user needs and reviewed version history to document portal changes. Three of the six themes derived from 1,653 coded excerpts were Trust Before Trial Search (“Who is Alex?”), Layered and Controllable Education (“If it was more in short bullets, maybe better”), and Motivation, Burden, and Research Trust (“There has to be some trust, some transparency or at least some acknowledgement”). Feedback informed portal refinements, including clearer language and institutional branding and content that was easier to scan. The virtual health educators were evaluated on representation, voice authenticity, lip-sync, warmth, and human likeness. Words like “sponsored study,” “diagnosis,” and “symptoms” guided language refinement. Suggested improvements included sample search terms, easy-to-read study cards, the ability to save results, a question guide, and direct coordinator contact. Research trust, privacy, security, and participation burden remained key priorities. To create an AI-enabled clinical trial portal that meets user needs, we used community feedback to identify modifiable barriers to communication, search, and referral. The goal of this formative process is to transparently incorporate that feedback into trial tools that are more credible, usable, acceptable, and equitable. Future work should evaluate whether these revisions improve referral outcomes. Citation Format: Fan Wang, Rashi Ghosh, Christopher You, Trevor Kauer, Andrew H. Maxim, Courtny Franco, Stephen Anton, Elizabeth Flood-Grady, Trudy Gaillard, Thomas J. George, Benjamin Lok, Carolyn Tucker, Melissa Vilaro, Tuo Lin, Fern Webb, Diana Wilkie, Danyell Wilson-Howard, Olveen Carrasquillo, Janice L. Krieger. Can artificial intelligence amplify community voice? Evidence from a multisite formative evaluation of the AI-Powered ALEX Portal to enhance equity in clinical trial access [abstract]. In: Proceedings of the 19th AACR Conference on the Science of Cancer Health Disparities; 2026 Oct 18-21; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2026;35(10 Suppl):Abstract nr B034.

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.

Background:The development of symptoms or left ventricular dysfunction in severe aortic stenosis (AS) is associated with high morbidity and mortality. While elective transcatheter aortic valve replacement (TAVR) is supported by robust randomized evidence, data on TAVR performed in non-elective settings (urgent, emergent, or salvage) remain limited and heterogeneous. In these settings, outcomes may be influenced more by baseline clinical severity than by procedural factors. This study aimed to systematically evaluate the safety and effectiveness of non-elective TAVR and to compare the associated outcomes with those of elective TAVR.Methods:This systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and registered with PROSPERO. The PubMed, Embase, and Scopus databases were searched for studies published after 2002 evaluating urgent, emergent, or salvage TAVR in adult patients with severe AS. Eligible studies were required to include elective TAVR as a comparator. Outcomes included mortality and major procedural complications. Prespecified era-based analyses and sensitivity analyses excluding studies at critical risk of bias were performed. Risk of bias was assessed using the ROBINS-I tool.Results:A total of 17 observational studies published between 2015 and 2025 were included, comprising 215,141 patients. Compared with elective patients, those undergoing non-elective TAVR had more advanced heart failure, higher NYHA class, greater comorbidity burden, and higher surgical risk scores, whereas baseline echocardiographic severity of AS was similar. Pooled outcomes for non-elective TAVR showed in-hospital, 30-day, and 1-year mortality rates of 5.1%, 12.4%, and 26.7%, respectively. Non-elective TAVR was associated with higher mortality at all time points compared with elective procedures; meanwhile, rates of stroke, vascular complications, and permanent pacemaker implantation were similar, while major bleeding and acute kidney injury were more frequent. Era-based analyses showed a stable relative mortality risk over time.Conclusions:Although non-elective TAVR is associated with worse outcomes than elective procedures, these differences appear to be largely driven by baseline clinical severity rather than by the transcatheter intervention. In unstable patients with severe AS, non-elective TAVR remains the most effective definitive treatment option compared with balloon aortic valvuloplasty or conservative management.The PROSPERO Registration:CRD420251239620, https://www.crd.york.ac.uk/PROSPERO/view/CRD420251239620.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

ABSTRACT Training in electrodiagnostic (EDX) medicine is highly variable globally, with trainees receiving widely different levels of didactic education, skills training, and hands‐on experience. Global standardization of EDX training has the potential to improve diagnostic accuracy, promote equitable care, and strengthen international collaboration. Major barriers include limited resources, faculty shortages, and a lack of standardized curricula. To address these disparities, opportunities and strategies for international collaboration are proposed, including developing a uniform content curriculum, competency‐based evaluation frameworks, and integration of online and simulation‐based learning tools.

Pre-hospital use of whole blood is becoming increasingly prevalent in EMS and military medicine. Technologies to store, transport, warm up, and transfuse the blood are now available, and the outcome of whole blood transfusion seems to be superior to infusion of crystalloid solutions or plasma and at least equivalent to packed cells with plasma. The auto-transfusion tourniquet (A-TT®, Oneg HaKarmel Ltd., Tirat Carmel, Israel) is a non-invasive device that shifts the patient’s own blood from the legs to the core and blocks its reentry. The A-TT consists of an elastic ring made of a stainless-steel coil, wrapped by an elastic sleeve and pulling straps. When rolled up the leg(s), it squeezes the soft-tissues’ blood into the central circulation, and the ring stops the return of blood to the leg. The application time of the A-TT is less than 20 s per leg, and the A-TT transfers more than 500 mL of blood from each leg to the core. The auto-transfused blood is of the patient’s own type, has full oxygen carrying capacity, is normothermic, and is not anticoagulated. The device can be applied by a trained first responder, even during transport, and its use can be titrated to avoid overshooting the patient’s blood pressure. The device can be kept on the leg for up to 2 h, and as such, can serve as a bridge to blood or a bridge to definitive care. This paper is a hypothesis-generating review that defines the potential role of the A-TT in settings where blood is not available and is a call for others to help generate more data.

Background: Patients with spina bifida are living longer and more productive lives; however, many continue to experience functional limitations in adulthood. This study evaluated long-term functional progression and ambulatory status using the combined Myelomeningocele Functional Classification (MMFC) and Functional Mobility Scale (FMS), and examined factors associated with long-term changes. Methods: A retrospective review at a tertiary care rehabilitation center identified 168 patients with spina bifida. MMFC and FMS classifications were recorded at initial and final visits. A subgroup of ambulatory patients who underwent 3D-gait analysis was analyzed to assess the relationship between MMFC, body mass index (BMI), and functional speed (FS) using multiple linear regression. Results: The average follow-up was 15±10.31 years. The mean age at final follow-up was 20 years (range, 5 to 52), with 52% of patients being male. Fifty-two percent of patients were ≥18 years of age at final follow-up. Within the MMFC1 cohort, 48% used wheelchair mobility (FMS 1,1,1) at initial presentation; this increased to 80% at final follow-up. Eighty percent of the MMFC2 patients were able to complete the 50-yard walk test at initial classification, whereas only 60% were able to complete it at final follow-up. Within the MMFC3 cohort, there was a decline in patients requiring no external support (FMS 6,6,6) from 90% to 78%. All MMFC4 patients maintained an FMS of 6,6,6. A statistically significant relationship was found between functional speed (FS) and MMFC (with MMFC4 faster than MMFC3 and MMFC2) ( P =0.01414). Conclusions: Long-term follow-up demonstrates that functional classification may decline over time in MMFC1 to 3 cohorts, whereas MMFC4 remains stable. In addition, within individual cohorts (MMFC1 to 3), there was also a decline in FMS and functional walk testing. A positive and statistically significant relationship was observed between gait analysis FS and MMFC, and a negative and statistically significant relationship was observed between BMI and MMFC. The combined use of MMFC and FMS provides a structured framework for longitudinal functional assessment in patients with spina bifida. Level of evidence: Level III.