Citations

Abstract Introduction The anatomical locations of generating adaptive immune responses to neurotropic viruses are still being investigated. Skull bone marrow (BM) has recently been identified as a pivotal immune site that can sense and respond to a local insult in the brain. Yet, there is a lack of understanding of the role of skull BM during viral encephalitis. We hypothesized that the skull BM is an important niche for antiviral CD8 T cells priming, expansion, and maintenance during Theiler’s murine encephalomyelitis virus infection. Methods Using peptide:MHC tetramer analysis, we determined that antiviral CD8 T cells are primed in the skull BM in early infection, at time points comparable to cervical lymph nodes. Employing MHC class I conditional knockout mice generated by our research group, we inactivated H-2Kb and H-2Db class I molecules on discrete antigen-presenting cell types. Results We determined using these transgenic mice that viral antigen presentation on dendritic cells (DCs) and endothelial cells is essential for the generation of virus-specific T cells in skull BM during acute viral encephalitis. However, antigen presentation by DCs is not required for long-lived antiviral CD8 T cells that reside in skull BM. Moreover, the use of FTY720 to block lymphocyte migration diminished skull antiviral CD8 T cell numbers, suggesting that peripheral trafficking is required for generating skull antiviral CD8 T cells. Conclusion We present compelling evidence for the importance of skull BM as a responsive site that is highly suitable for rapid generation of antiviral CD8 T cells during acute viral encephalitis. Skull BM also serves as a reservoir for memory T cells, long after the resolution of a neurotropic virus infection. This work sheds light on the skull as a potential target for further modulation of the immune response to viral infections in the brain. Funding Source NIH grants R01 NS5103212 and RF1 NS122174 Topic Categories Viral Immunology (VIR)

Introduction: Co-stimulatory proteins are master regulators of the immune system. We identified the co-stimulatory CD40-CD40L dyad as a key driver of inflammation during atherosclerosis and have shown that CD40 and CD40L exert cell-type divergent functions. Hypothesis: CD40 is abundantly expressed on endothelial cells (EC) undergoing endothelial mesenchymal transition (EndMT). We hypothesize that EC CD40 drives atherosclerosis via EndMT. Methods: We analyzed scRNAseq data from human carotid plaques, performed multiplex IHC, and used human aortic endothelial cells (HAECs) for in vitro studies. A tamoxifen-inducible EC specific CD40 deficient atherosclerotic mouse model (cadherin5 (cdh5)ERT2-CD40 flfl -ApoE -/- ) was generated. Results: Besides its presence on immune cells, CD40 is expressed on endothelial cells in both human and mouse atherosclerotic plaques. Analysis of scRNAseq data of human carotid atherosclerotic plaques showed that CD40 is highly expressed in COL1A2/FN1 expressing endothelial cells (ECs), a subset undergoing EndMT. Multiplex staining revealed that CD40 colocalized with the EndMT markers αSMA, NOTCH3, TWIST and VCAM1 in human plaques. In vitro , stimulation of human arterial endothelial cells (HAECs) with CD40L resulted in an increase in the EndMT markers markers fibronectin, vimentin, sm22α, FSP1 and snail. Using phosphoproteomics, CD40L was found to decrease phosphorylation of the junctional integrity proteins CTNNA1 [S652; S655] and ARHGAP21 [S1383]. To investigate the endothelial-specific effects of CD40 in atherosclerosis, 8-week-old cdh5ERT2-CD40 flfl -ApoE -/- mice and their CD40 flfl -ApoE -/- littermate controls were treated with tamoxifen and fed a high cholesterol diet for 10 wks. Deletion of EC-CD40 resulted in a significant reduction in plaque size. This reduction was accompanied by a shift from fibrous cap atheromas (FCA) towards intimal xanthoma (IX) and pathological intimal thickening (PIT). Flow cytometry analysis of the spleen showed that CD40 deletion in ECs results in a significant decrease in CD8 and CD4 effector T cells. This decrease in CD8 and CD4 effector T cells was accompanied by a diminished activation status, shown by a decrease in CD69 + CD8 + CD62 - CD44 + T cells, CD40L + CD8 + CD62 - CD44 + T cells and CD40L + CD4 + CD62 - CD44 + T cells. These findings demonstrate that endothelial CD40 drives atherosclerosis by inducing EndMT-driven plaque inflammation.

Introduction: V-domain Immunoglobulin Suppressor of T-cell Activation (VISTA), a co-inhibitory immune checkpoint protein, is known for regulating adaptive immune responses. Here, we investigated the role of VISTA in atherosclerosis. Hypothesis: VISTA is constitutively expressed on hematopoietic cells, particularly T cells. VISTA functions as both a ligand and receptor to maintain T cell quiescence. We hypothesize that VISTA expression is protective against plaque formation by inhibiting CD4 + T cell activation. Methods: Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) was performed on aortic CD45 + cells of HCD fed ApoE-/- mice. Spatial transcriptomics (VISIUM) was performed on carotid plaques from patients with either asymptomatic or symptomatic cerebrovascular disease. Plaque burden, characterization, and flow cytometry of blood and lymphoid organs were performed on VISTA -/- ApoE -/- (VISTA KO) and VISTA +/+ ApoE -/- (WT) mice that were fed a HCD for 10 weeks. ApoE -/- mice treated with VISTA agonist 8G8 or IgG control (200ug, intra-peritoneal, 3 times per week for the last 6/10 weeks of HCD feeding). In vitro proliferation, migration, and functional T cell assays were performed. Results: We found that VISTA is expressed on plaque T cell populations, particularly regulatory T cells, gamma-delta T cells, and naïve T cells. In humans, individuals with symptomatic CVD have significantly reduced VISTA gene expression in carotid plaques. VISTA KO mice have increased total plaque area and necrotic core area compared to littermate WT controls. VISTA KO mice have increased peripheral CD4 + and CD8 + effector memory T (T EM ) cells with a corresponding decrease in CD4 + and CD8 + naïve T (T N ) cells and CD4 + regulatory T (T reg ) cells. Further, VISTA KO mice have a higher frequency of CD4 + T H 1 (T-bet + IFNy + ) cells and lower frequencies of IL-10 + CD4 + T cells and CD4 + T H 2 (GATA-3 + IL-13 + ) cells. In vitro assays showed that VISTA suppresses CD4 + T cell proliferation, IFNγ production, and migration. Finally, VISTA agonist treatment significantly decreased plaque and necrotic core areas in atherosclerotic mice. Conclusion: Our data reveals a novel role for VISTA in reducing plaque development and in suppressing T cell activation, proliferation, and migration. Further characterization of T-cell specific VISTA-deficient mouse models and mechanistic insights into how VISTA modulates T cells are currently being investigated.

Abstract In response to a Cochrane review (published in April 2026) on the clinical trials of monoclonal antibodies targeting beta amyloid, this perspective outlines a number of critiques. The scientists, methodologists, subject‐matter experts, and clinicians on this perspective strongly recommend that the Cochrane editorial board consider a call for editorial response, correction of press materials, or commissioned reply to this review for four overarching reasons: (1) decision to pool antibodies that do and do not clear beta amyloid, (2) decision to include studies from a time when biomarkers of Alzheimer's disease were not available, (3) analytical and methodological limitations of the approach used, (4) conflating the distinct roles and methodological processes of systematic review and guideline methodologies, (5) contextualizing the present critique within the existing evidence‐synthesis literature, and (6) mechanistic inference beyond the scope of the presented analyses. Conclusions that may not accurately reflect treatment‐specific effects could cause significant downstream clinical and psychosocial harm to those currently undergoing treatment and their family members as well as individuals considering participation in Alzheimer's clinical trials.

PURPOSE Bone metastases (BM) occur in approximately 30% of patients with metastatic renal cell carcinoma (mRCC) and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, and cabozantinib, a tyrosine kinase inhibitor, have demonstrated activity in BM. RADICAL (Alliance A031801; ClinicalTrials.gov identifier: NCT04071223 ) evaluated cabozantinib ± radium-223 in mRCC with BM. METHODS This phase II trial enrolled patients with mRCC of any histology with ≥1 BM. Patients were randomly assigned 1:1 to cabozantinib ± radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, opioid use, and International mRCC Database Consortium (IMDC) risk. The primary end point was SSE-free survival (SSE-FS). Secondary end points included safety, objective response rate (ORR), progression-free survival, and overall survival (OS). A target of 124 evaluable patients was planned, with a prespecified interim futility analysis at 50% of expected SSE-FS events; the trial would stop if the stratified hazard ratio (sHR) > 1.0. RESULTS The prespecified interim futility analysis was conducted after 90 patients were enrolled and crossed the futility boundary, leading to closure at 98 patients. The final analysis included all 98 patients. Median age was 63 years, 82.7% had clear cell histology, and 79.6% were using an OTT. IMDC risk was favorable (18.4%), intermediate (67.3%), and poor (14.3%). Median follow-up was 13.1 months. Median SSE-FS for cabozantinib with radium-223 versus cabozantinib was 16.7 versus 17.6 months (sHR, 1.46 [90% CI, 0.86 to 2.51]). Median OS was 28.3 versus 19.7 months (sHR, 1.40 [95% CI, 0.70 to 2.79]). ORR was 19.4% versus 25.0% ( P = .78). Grade ≥3 adverse events were similar across arms (69.6% v 75.5%). CONCLUSION Radium-223 did not improve SSE-FS when added to cabozantinib. The combination demonstrated a manageable safety profile.

Abstract Cancer outcomes vary widely between individual patients, each accumulating an irregular record of treatments, diagnoses, measurements, and complications. Current prognostic models reduce this complexity into a single snapshot, focus on narrow clinical settings, and rarely generalize across hospitals. Here we introduce Chronicle , an explainable transformer that learns from entire patient trajectories to predict diverse clinical outcomes throughout the disease course while capturing both short- and long-term temporal dependencies. Trained on 53.7 million longitudinal data points from 51,711 patients spanning 67 cancer types, Chronicle operates natively on irregular data without imputation and jointly predicts eight endpoints within a flexible framework adaptable to additional outcomes. Chronicle outperformed cross-sectional models for overall survival prediction (C-index 0.84 vs 0.76-0.79), stratified patients more accurately than established prognostic systems, including TNM stage, and predicted seven adverse event and transfusion endpoints (AUC 0.80-0.92). Applied without retraining to 69,341 patients in Germany, Switzerland, and the United States, Chronicle generalized across healthcare systems and improved further with local fine-tuning. Integrated explainability traced each risk update to patient-specific clinical factors, revealing distinct temporal persistence of prognostic information, with relevance half-lives ranging from weeks for therapies to nearly one year for baseline characteristics. These findings demonstrate that learning from hospital-wide patient trajectories enables interpretable and continuously updated predictions, providing a scalable framework to support individualized treatment decisions.

Background: Rural communities face worsening surgical access because of hospital closures and workforce shortages. Although osteopathic physicians have historically practiced in rural settings, their contribution to the contemporary rural surgical workforce remains poorly defined. Study Design: Cross-sectional analysis of 74,404 US attending surgeons across seven specialties using the 2023 Centers for Medicare & Medicaid Services Doctors and Clinicians database. Practice addresses were linked to 2020 Rural-Urban Commuting Area codes, Area Deprivation Index quintiles, and census tract population density. Rural practice (mean Rural-Urban Commuting Area score ≥4) was modeled using multivariable logistic regression adjusted for specialty, graduation cohort, sex, Census division, and state urbanization, with state-clustered standard errors. Results: Rural practice was more common among DO than MD surgeons (18.3% vs 9.7%; risk difference, 8.6 percentage points; 95% CI, 7.6–9.6). Across all specialties, DO surgeons practiced in more socioeconomically deprived communities. After adjustment, DO surgeons had twice the odds of rural practice compared with MD surgeons (OR, 2.05; 95% CI, 1.85–2.28). Rural areas had 13.8 surgeons per 100,000 residents versus 23.6 per 100,000 in metropolitan areas. Surgeons graduating in 2010 or later had approximately half the odds of rural practice compared with those graduating in 1979 or earlier (adjusted OR, 0.48; 95% CI, 0.42–0.56). Conclusions: Osteopathic surgeons disproportionately practice in rural and socioeconomically disadvantaged communities, identifying an important workforce component for maintaining rural surgical access. The declining likelihood of rural practice among more recent training cohorts raises concerns regarding the future rural surgical workforce.

Objectives Long-term symptoms following infection with acute respiratory syndrome coronavirus-2 (SARS-CoV-2), termed post-acute sequelae of SARS-CoV-2 infection (PASC) or Long COVID (LC), persist beyond 90 days and may impact at least 10% of patients with acute infection. The exact cause of LC remains unknown, but several theories include persistent viral particles, immune dysfunction, and autonomic nervous system (ANS) imbalance, particularly involving the vagus nerve. Given the role of the vagus nerve in inflammation regulation, vagal nerve stimulation (VNS) is being explored as a treatment option. The present study aimed to evaluate the feasibility, safety, and exploratory effects of a handheld external transcutaneous cervical non-invasive VNS (tcVNS) on the primary endpoint of Post-COVID Functional Status (PCFS) grade, alongside secondary outcomes such as LC-related fatigue and other symptoms. Methods Participants from our Post COVID Care Clinic were randomized into treatment (tcVNS treatments two minutes, three times a day) and control (no VNS) groups for a study period of 12 weeks. Participants completed validated questionnaires, PET-CT scans, and inflammatory cytokines at baseline and 12 weeks. Results All randomized patients (8 tcVNS, 10 control) completed the 12-week study. Participants randomized to tcVNS were observed to have improvements in PHQ-9, PROMIS-F, and COMPASS-31 when compared to controls, but these differences were not statistically significant. Cortisol and DHEA were also observed to increase less in the tcVNS group when compared to the control group, but these changes were also not statistically significant. Conclusions tcVNS was well tolerated and may be a promising therapeutic approach for LC, a chronic disease with no approved treatments and very low rates of complete recovery.

Abstract Black/African American populations, globally, bear the greatest prostate cancer (CaP) burden compared to other racial/ethnic groups. Addressing CaP disparities in Black men is complex, requiring a patient-centered, community-centric and comprehensive approach. This study integrates iCCaRE Consortium findings and broader literature to address unmet needs in survivorship care. The iCCaRE Consortium implemented five complementary pilot studies using mixed-methods designs, including feasibility trials, qualitative research, and observational analyses across the United States and sub-Saharan Africa. Descriptive statistics, subgroup analyses, and qualitative thematic analyses were performed across these studies. Collectively, projects addressed multilevel determinants including social, behavioral, and biological drivers of disparities. Project 1 implemented a Virtual Reality Assistant (ViRA) across clinical and community settings, with ongoing evaluation in pragmatic trials. Project 2 showed strong patient preference for home-based cancer care. Project 3 enrolled demonstrated trends toward improved health-related quality of life. Project 4 identified key themes influencing survivorship experiences. Project 5 identified biological mechanisms linking stress, immune modulation, and symptom burden. The iCCaRE pilot projects demonstrate the feasibility and early impact of a consortium-based, transdisciplinary approach to addressing CaP disparities in Black men. These findings highlight the importance of integrating patient-centered interventions, community engagement, and biological insights to inform scalable strategies aimed at improving survivorship outcomes and advancing health equity. The iCCaRE Consortium demonstrates that a transatlantic, patient-centered, and multidisciplinary approach integrating social, clinical, and biological factors can generate scalable strategies to improve survivorship outcomes and advance equity in CaP care for Black men.