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BACKGROUND: Publicly reported 30-day acute myocardial infarction (AMI) mortality rates are widely used to benchmark hospital performance. However, these measures may lack validity when they include deaths among patients with do-not-resuscitate (DNR) orders or those receiving palliative care—groups for whom mortality may be expected and goal-concordant. METHODS: We analyzed the national 100% Medicare Inpatient Standard Analytic File and Medicare Beneficiary Summary file to assess 30-day AMI mortality rates stratified by DNR status (absent, present-on-admission, and postadmission) and palliative care involvement. We then conducted a retrospective chart review of all 30-day AMI mortalities at a single academic medical center (2019–2025), applying Global Registry of Acute Coronary Events and a Palliative Performance Scale scores to identify unpreventable deaths, which we defined as a Global Registry of Acute Coronary Events >190.5 or Palliative Performance Scale ≤40%. Global Registry of Acute Coronary Events is a risk-stratification tool using clinical and laboratory variables whereas the Palliative Performance Scale is a bedside functional status and palliative care assessment quantifying patient’s self-care ability. RESULTS: Across n=467 259 total AMI encounters, mean (SD) age was 75.1 (10.5), and the population was 44% female. Thirty-day mortality was 10.4% (39 112/376 062) among patients without DNRs, 43.1% (26 181/60 719) in those with present-on-admission DNR, and 72.1% (21 984/30 478) in those with postadmission DNR. Among 9.2% (43 090/467 259) of encounters with palliative care, there was a 76.9% mortality rate (33 151/43 090). Hazard ratios for mortality were 5.25 (95% CI, 5.17–5.33) for present-on-admission DNR and 10.73 (95% CI, 10.55–10.91) for postadmission DNR as compared with encounters without DNRs. Among n=24 AMI mortalities at our institution, 71% (17/24) had DNRs, and 33% (8/24) met the unpreventable death criteria. CONCLUSIONS: The validity of 30-day AMI mortality metrics may be undermined by their inclusion of high-acuity, end-of-life patients, which may disincentivize hospitals from delivering appropriate, patient-centered care. Removal of DNR or palliative cases from performance measures should be explored to better identify opportunities for reducing preventable deaths.

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 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)

Abstract Introduction We have shown that combining CAR T cells with oncolytic viruses (OVs) generates a subpopulation of highly cytotoxic CAR T cells that can mediate long-term solid tumor therapy. Methods To profile these CAR T cells, we used C57BL/6 mice bearing B16F10 tumors expressing EGFRviii, treated with anti-EGFRviii CAR T cells and the OV vesicular stomatitis virus (VSV). TCR signaling in CAR T cells was investigated using the novel Tocky transgenic mouse model, which reports T cell activation over time using an unstable fluorescent protein reporter of Nr4a3. We further investigated CAR T phenotypes using CyTOF and scRNA-Seq. Results Using an MHC I tetramer for the dominant VSV epitope VSV N52-59, we found that 20-50% of transfused CAR T adopted TCR specificity against VSV N (referred to as TCR-primed), indicating significant in vivo expansion. Ex vivo, these TCR-primed CAR T produced increased levels of granzyme B and IFNγ over tetramer-negative CAR T against either TCR or CAR targets. However, TCR-primed CAR T cells were notably less activated via Nr4a3 as compared to non-TCR-primed CAR T. CyTOF and scRNA-Seq analyses demonstrated a hypereffector phenotype among TCR-primed CAR, with increased expression of T-bet, CD44, granzyme B, IFNγ, and perforin. TCR sequencing revealed hyperexpansion of VSV N-specific CAR T cells and little overlap in clonotypes between CAR T co-treated with PBS versus VSV. These TCR-primed CAR T cells exhibited a CD4-helped phenotype with increased expression of chemotactic and migratory transcripts. When CAR T and OV were administered with antibody-mediated CD4 depletion, the TCR-primed CAR population was significantly diminished, emphasizing the importance of the immune triad for CAR T expansion. Conclusion Overall, CAR T cells that undergo endogenous anti-viral TCR priming and signaling adopt a unique phenotype that promotes their expansion and cytotoxic function. Interactions with CD4 T cells appear to be integral for the generation of this subpopulation of CD8 CAR T cells. Funding Source NIH Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

Polycystic kidney disease (PKD) arises from mutations in cilia-associated genes, such as PKD1 and PKD2 , expressed in renal epithelial cells, leading to progressive kidney dysfunction and end-stage kidney disease (ESKD). PKD patients exhibit significant heterogeneity in disease progression, largely due to genetic and environmental modifiers. Like patients, mouse models of PKD also exhibit significant heterogeneity with regards to the gene mutated, age of disease onset, and rate of disease progression. To elucidate the cellular and molecular consequences of these variables, we constructed an integrated single-cell RNA sequencing atlas across mouse models of PKD, mapping changes in cell type composition, gene expression, and intercellular signaling networks across the whole atlas and within individual models. Across models, single cell RNA sequencing (scRNAseq) data revealed increased Spp1 (osteopontin) expression and signaling from PKD-enriched clusters. Global deletion of Spp1 in Pkd1 RC/RC mice resulted in a modest reduction in cyst severity and improved kidney function. From these studies, we created a freely available, searchable website (https://bmblx.bmi.osumc.edu/scPKD/) that can be used to identify cross- and intra-model changes in gene expression, guiding researchers to new therapeutic targets for treating PKD.

Purpose of review To review the clinical, educational, academic, and institutional value of a dedicated neuroanesthesiology division beyond its practical role in scheduling neurosurgical and neurointerventional cases. Recent findings Neuroanesthesiology has matured into a recognized subspecialty with dedicated societies, journals, fellowship pathways, educational milestones, and defined research priorities. Recent observational studies suggest that dedicated neuroanesthetic care, formal fellowship training, and surgeon–anesthesiologist dyad familiarity may be associated with fewer neurologic complications, lower in-hospital morbidity, shorter length of stay, and reduced admission costs in high-acuity neurosurgical populations. Concurrently, quality improvement reports identify recurring challenges in medication management, communication, documentation, and equipment readiness that a focused division is well positioned to address. For instance, division-led initiatives at select institutions have successfully integrated The SNACC Neuroanesthetic Emergencies Critical Event Treatment Guides and Cognitive Aids into clinical and educational workflows. Cultivating this subspecialty identity may be a protective factor against clinician burnout. However, current evidence remains largely retrospective and context-dependent. Summary: A neuroanesthesiology division can provide infrastructure for clinical expertise, care pathways, simulation-based education, mentorship, research, quality improvement, and collaboration with neuroscience programs. Its core value lies in creating a reliable structure that supports both neuroanesthesiologists and general anesthesiologists caring for neurologically vulnerable patients.

This article introduces a novel, single‐operator stress ultrasound technique for evaluating medial ulnar collateral ligament (MUCL) integrity by assessing medial ulnohumeral joint (MUHJ) widening under valgus stress. Unlike prior methods requiring dual operators, specialized equipment, or the use of hand/wrist weights, this approach was designed for clinical efficiency, reproducibility, and patient comfort. By positioning the patient comfortably in a side‐lying position with the elbow flexed to 50°, MUHJ width is measured at baseline (maximally apposed) and manually stressed positions, in a manner that may reduce muscular compensation, avoid viscoelastic creep, and facilitate consistency. While additional research is needed to evaluate clinical feasibility, assess reliability, and compare our technique with previously published methods of dynamic MUCL assessment, the aim of this manuscript is to describe our technique and provide a rationale for its potential utility in musculoskeletal ultrasound practice and research.

Heart rate variability (HRV) is a widely utilized approach for investigating cardiovascular health and human performance. Methodological approaches, analyses, and interpretations of HRV can vary extensively, and scientific debates on HRV reliability and utility remain. These debates have been amplified in recent years by the rapid growth and ubiquity of wearable devices, and their incorporation into scientific research studies. The present guidelines paper takes an evidence-based approach to propose more consistent and rigorous measurement and interpretation of HRV within human cardiovascular research and application. First, HRV has some utility as a cardiovascular risk stratification tool, but is not appropriate to employ as a specific marker of cardiac sympathetic outflow or sympathovagal balance. While time-domain and spectral analysis can more accurately reflect respiratory modulation of cardiac vagal (parasympathetic) activity, caution is necessary to avoid overinterpretation, particularly with respect to the concept of “vagal tone”. Numerous experimental, demographic, and environmental factors influence HRV assessment, interpretation, and reliability. Specifically, it is critical to account for non-modifiable (age, sex, race/ethnicity, etc.) and modifiable (i.e., exercise, physical fitness, etc.) factors within participant samples. Furthermore, technical approaches such as the HRV input signal (e.g., electrocardiography vs. photoplethysmography), length of recording, location of recordings (i.e., laboratory vs. field), respiratory rate and depth, and analytical approaches (i.e., time vs. frequency domain) can all impact rigor, reliability, and study interpretations. Finally, with respect to the rapid advancements of HRV assessment using wearable technology, investigators should interpret and contextualize findings within the limitations outlined in this guideline review.

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.

PURPOSE Systematic integration of tobacco cessation treatment within cancer centers is needed to improve smoking cessation outcomes among cancer patients and survivors. The current study characterizes baseline rates of tobacco use, use of cessation support, and changes in tobacco use over time among 756 participants diagnosed with cancer and enrolled in 9 ECOG-ACRIN Cancer Research Group trials. MATERIALS AND METHODS Participants completed surveys at trial enrollment and at 3- and 6-month follow-ups. Descriptive statistics were used to characterize patient characteristics and selected items from the Cancer Patient Tobacco Use Questionnaire (C-TUQ). Generalized estimating equations were used to examine the time point effect on tobacco product use. RESULTS At baseline, 11% of participants (n = 740) currently smoked cigarettes. Among participants with data available at all time points (n = 443), prevalence of current smoking was stable over time, with 7.2% of participants (n = 32) reporting current smoking at baseline, 7.0% (n = 31) at the 3-month follow-up assessment, and 6.8% (n = 30) at the 6-month follow-up assessment. Most participants (n = 77/104) who smoked cigarettes within the year prior to their cancer diagnosis continued smoking after their diagnosis, and during (n = 44/72) and following completion (n = 30/46) of their treatment. Sixty-two percent of participants (n = 81) who were currently smoking at baseline reported using smoking cessation medication and 32.1% reported use of nonpharmacologic smoking cessation support since their cancer diagnosis. In longitudinal analyses, the odds of using cigarettes since their cancer diagnosis, 3-month follow-up, and 6-month follow-up was higher than the odds of using cigarettes for the past 30 days at baseline (odds ratio [OR] = 1.97, OR = 1.62, and OR = 1.50, respectively; all p s < .01). CONCLUSION Smoking persists over time among patients with cancer enrolled in therapeutic cancer trials. Findings highlight the importance of increasing access to integrated and longitudinal smoking cessation support.