Citations

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.

Abstract Background: Glioma diagnosed during pregnancy and pregnancy following glioma treatment present complex management challenges. The safety of glioma treatment during pregnancy is not well established. The ability to counsel patients on timing of conception after treatment remains limited. The aim of this study was to review our institution’s experience with glioma during and before pregnancy. Methods: In this single-institution study, we retrospectively identified patients diagnosed with glioma during or prior to pregnancy and reviewed treatment course and maternal and neonatal outcomes. Results: Twenty-one female patients were included in our study. Glioma diagnoses included 12 high-grade tumors and 9 low-grade tumors. Cohort A consisted of 8 patients who presented with glioma during pregnancy, of which, 7 underwent glioma treatment during pregnancy. All pregnancies in cohort A were without significant maternal complications and resulted in delivery of a healthy neonate. Cohort B consisted of 13 patients who experienced pregnancy after a prior diagnosis of glioma, totaling 23 pregnancies. Antepartum course was complicated by seizure in three pregnancies. Functionally inconsequential anatomic abnormalities in childhood offspring of cohort B occurred in 5 (27.8%) of the pregnancies. Four of the offspring with anatomic abnormalities had exposure to TMZ prior to conception. Conclusions: In this retrospective series, diagnosis of glioma before or during pregnancy was associated with generally favorable maternal, fetal and childhood outcomes. We observed a higher-than-expected rate of anatomic abnormalities in the post-diagnosis cohort, though none carried meaningful functional consequences. These findings add to the limited literature exploring maternal and fetal outcomes in patients with glioma.

Abstract Objectives This study used both researcher and patient perspectives to identify high-priority research questions related to clinical reasoning. Methods This study integrates findings from two previously published research prioritization exercises aimed at advancing the science of diagnostic safety, focusing on questions relevant to clinical reasoning. In Study 1 (April 2019), 97 researchers submitted 177 unique research questions that could be useful “to reduce patient harm in the diagnosis process”. In Study 2 (November 2019), 41 patients/caregivers/advocates submitted 84 unique research questions on the same topic. In an in-person meeting, a subset of these participants identified 81 of these questions as high-priority (51 from Study 1; 30 from Study 2). For the current study, five investigators identified questions that focused on clinical reasoning, first independently and then by consensus. They then categorized the clinical reasoning questions into inductively identified themes. Results Twenty-nine of the 81 high-priority research questions addressed clinical reasoning and were categorized into 5 themes: understanding clinical reasoning and cognition (12 questions), decision support/technology (6 questions), team-based decision making (5 questions), how to learn from cases/scenarios (3 questions), and patient engagement (3 questions). Questions addressed a range of basic/foundational science and clinical applications, and involved individuals, teams, and/or systems. Conclusions Identification of high-priority clinical reasoning research questions can help medical educators, clinicians, researchers, and funders catalyze research and discovery of interventions to improve clinical reasoning and ultimately improve patient outcomes.

Background:Aortic valve replacement is the primary treatment for aortic valve disease and can be performed using either transcatheter (TAVR) or surgical (SAVR) approaches. The risk of aortic dissection (AD) with TAVR compared with SAVR remains unclear. We aimed to compare AD risk between TAVR and SAVR using a large, real-world cohort. Methods:We conducted a retrospective cohort analysis using the TriNetX research network. Patients with a diagnosis of aortic stenosis, aortic insufficiency, mixed aortic valve disease (AVD), or unspecified AVDwho underwent either TAVR or SAVR were included. A 1:1 propensity score-matching (PSM) based on baseline characteristics was performed to adjust for potential confounding. Logistic regression and Cox proportional hazards models were used to estimate odds ratios (ORs) and hazard ratios (HRs), with 95% confidence intervals (CIs).Results:Among 95,043 patients undergoing isolated aortic valve replacement, 20,237 matched pairs were analyzed after 1:1 PSM. Baseline characteristics were well balanced, with a mean age of 73.3 ± 9.3 years in the TAVR group and 73.2 ± 8.5 years in the SAVR group; 60.8% and 60.7% were male, respectively. TAVR was associated with significantly lower odds of composite AD than SAVR at all time points (1-year OR 0.60; 95% CI 0.44–0.82; 3-year OR 0.64; 95% CI 0.48–0.83; 5-year OR 0.66; 95% CI 0.51–0.85; p < 0.01 for all). Stratified analyses demonstrated lower odds of both Stanford type A and type B AD at all time points. Kaplan–Meier analysis demonstrated a separation in composite AD-free survival between the two groups (HR 0.66; 95% CI 0.51–0.86; p = 0.002).Conclusion:In this large, real-world cohort, despite a low event rate, TAVR was associated with a significantly lower likelihood of composite AD than SAVR.

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 Objectives Embedded pragmatic clinical trials (ePCTs) are conducted as part of routine clinical care and therefore use data collected from real-world data sources, such as electronic health record systems and administrative claims. A common approach for using these types of data across all phases of trial conduct is to create a computable phenotype (an explicitly defined data query data, including specified data types, data codes, and logical parameters) to capture patients with a clinical condition, exposure, symptom, characteristic, treatment, or outcome of interest. Materials and Methods The Electronic Health Record (EHR) Core Working Group of the NIH Pragmatic Trials Collaboratory captured the experiences of investigators in developing, adapting, and applying computable phenotype definitions in their studies. Results Four case studies describe different approaches to developing and using computable phenotypes in pragmatic trials. Discussion We recommend: (1) developing computable phenotypes as part of a team with multiple areas of expertise; (2) appropriate validation; (3) dissemination of salient details regarding phenotype creation; and (4) capturing and reporting any modifications made to phenotypes during the conduct of the trial. Conclusion A range of issues and decisions influence how computable phenotypes are developed and used in pragmatic clinical trials. Multidisciplinary teams that understand the context of the data, including the reason the data are collected and potential sources of bias, are best suited for the development and validation of phenotypes for ePCTs.

Abstract Introduction Alzheimer’s disease (AD) is characterized by pathologies including amyloid, tau, neurodegeneration reflected in established blood biomarkers and track with clinical changes. However, the association between peripheral cell-specific signatures and AD-related phenotypes remain poorly characterized. Methods We analyzed bulk blood transcriptome data from the Mayo Clinic Study of Aging (MCSA) and Emory University Vascular study. We used BayesPrism, CIBERSORTx, and an in-house pipeline CNNreg to deconvolute these data and obtain peripheral cell proportions. Cell type specific transcripts were estimated with BayesPrism. We compared cell proportions between cases (AD/MCI) and controls. Association analysis was performed between cell type specific transcripts and AD-related phenotypes including diagnosis and cognition. Meta-analysis of transcripts associations and gene ontology analysis were conducted to assess the enriched pathways for significant genes. Results In MCSA, B and CD4+ T cells proportions are significantly lower while that of myeloid cells higher in cases. The Emory cohort had similar trends. We identified transcripts associated with AD-related phenotypes in CD4+ T and CD8+ T cells. In CD4+ T cells, transcripts downregulated in case are enriched in response to stimulus pathway, whereas those upregulated in negative regulation of immune response. Downregulation of CD4+ T genes enriched in extracellular matrix disassembly and epigenetic regulation and upregulation of those in protein localization associate with better cognition. In CD8+T cells, genes pertinent to vascular development were downregulated while those to metabolic processes were upregulated in cases. Downregulation of CD8+T genes involved in lipid transportation and upregulation of those in mitochondria associate with better cognition. Conclusion We identified peripheral cellular transcriptional changes associated with AD/MCI phenotypes and involved in important biological pathways, revealing potential disease mechanisms in AD. Funding Source RF1 AG051504 Topic Categories Neuroimmunology (NEUR)

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.

Purpose: The purpose of the current study was to cross-validate previously developed RMR prediction equations using laboratory measurements of RMR as a criterion. Methods: National Collegiate Athletic Association (NCAA) Division I (n = 60) and III (n = 113) male wrestlers participated in the current study (n = 173; Age: 19.6 ± 1.5 yrs.; Height: 176.3 ± 6.3 cm; Weight: 76.6 ± 10.9 kg; Body Fat: 11.4 ± 3.0%). Indirect calorimetry was used to measure RMR and Skinfold thickness was used to estimate body fat percentage (BF%) during the preseason period under standardized dress (underwear only), fasting, and resting conditions. Results: Mean measured RMR was 2102±341 kcal·d −1 . All body mass-based RMR prediction equations significantly underestimated the measured RMR, with the exception of the Jagim and Schofield equations. The Tinsley fat-free mass (FFM) equation and the Cunningham equation had the lowest constant error (CE) values when compared to measured RMR (mean bias ± standard error: 80 ± 20 kcal and 126 ± 20 kcal·d −1 , respectively). Linear regression indicated the Tinsley FFM (R 2 = 0.422, RMSE = 279 kcals, %RMSE = 13.3%), and Cunningham FFM equations had the closest agreement to measured RMR (R 2 = 0.422, RMSE = 301 kcals, %RMSE = 14.3%), along with the Jagim equation for a body mass-based prediction equation (R 2 = 0.377, RMSE = 338 kcals, %RMSE = 16.1%). The standard error of the estimate (SEE) ranged from 260 to 272 kcal·day −1 across equations. Coefficients of determination (R 2 ) ranged from 37% to 42%. The new body mass and FFM-based equations exhibited good agreement based on the CE (26 and -13 kcal·day −1 ), RMSE (274 and 252 kcal·day −1 ), respectively. Conclusions: The newly developed equations demonstrated mean bias <2% of measured RMR.

Acute cholecystitis affects ∼200,000 individuals annually in the United States, with laparoscopic cholecystectomy as the gold standard treatment. However, in high-risk surgical candidates, alternative drainage methods are necessary. Percutaneous transhepatic gallbladder drainage (PT-GBD) has traditionally served as the primary alternative intervention, offering rapid decompression, but is limited by a negative impact on the patient’s quality of life, the risk of long-term or even permanent tube placement, adverse events, and high recurrence rates. Endoscopic approaches, such as endoscopic transpapillary gallbladder drainage (ET-GBD) and, more recently, endoscopic ultrasound-guided gallbladder drainage (EUS-GBD), have emerged as viable alternatives to PT-GBD. EUS-GBD, first introduced in 2007, offers technical and clinical outcomes comparable to PT-GBD with fewer adverse events, shorter hospital stays, and lower rates of recurrence. The introduction of lumen-apposing metal stents (LAMS) has revolutionized EUS-GBD, simplifying deployment and enabling subsequent internal gallbladder access, which allows additional interventions such as cholecystoscopy and stone removal. EUS-GBD is now supported by international guidelines, and 1 device has achieved FDA approval for the management of acute cholecystitis in nonsurgical candidates. Proper patient selection is essential, guided by multidisciplinary evaluation, with EUS-GBD contraindicated in specific scenarios such as gallbladder perforation, coagulopathy, and large-volume ascites. Technical considerations include choice of access site (transgastric versus transduodenal), stent type, and procedural route [direct (freehand) or wire-guided]. Postprocedural care and stent management remain variable and nonstandardized. Emerging data suggest that interval cholecystectomy can still be performed safely after EUS-GBD. As adoption of EUS-GBD with LAMS expands, structured training and standardization of practice are crucial to optimizing outcomes.