Citations

Abstract Polygenic risk scores (PRSs), which quantify inherited susceptibility to complex traits and diseases, have emerged as valuable tools for risk stratification and precision medicine. Despite their promise, PRS developed on European cohorts often demonstrate substantially reduced predictive accuracy in non-European populations, due to differences in genetic architecture. The disproportionate representation of European ancestry cohorts in genome-wide association studies (GWAS) leads to inequitable deployment of PRS technologies across diverse populations. Here, we introduce PRANA (Polygenic Risk Adaptation via Neural-network Architecture), a deep learning framework that adapts an existing PRS developed on one population to other ancestries. Unlike methods that require large-scale GWAS in the target population, PRANA leverages pre-trained PRS models derived from European cohorts and adapts them using modestly sized cohorts from the target population. We evaluated PRANA on seven complex traits in South Asian, East Asian and Ashkenazi Jewish populations, as well as in selected smaller East Asian subpopulations where the scarcity of training data poses a particular challenge. PRANA mostly improved predictive performance of the baseline PRS models by 5%-20% in terms of effect size (β) and Nagelkerke’s R², and, in most cases, outperformed existing cross-ancestry multi-PRS approaches. These results highlight PRANA as a scalable and practical strategy to reduce disparities in genomic risk prediction and advance the equitable application of PRS in diverse populations.

Importance As the use of robotic cholecystectomy increases, its value remains poorly defined for complex elective cholecystectomy (CEC), where complex gallbladder pathology results in increased technical difficulty. Objective To determine whether a robotic approach is associated with improved clinical outcomes and altered total hospital cost as compared with a laparoscopic approach for patients undergoing CEC. Design, Setting, and Participants This cohort study analyzed data from an academic hepatobiliary referral center for patients who underwent cholecystectomy from August 2018 to August 2024. CEC was defined by preoperative criteria: prior aborted or partial cholecystectomy, presence of a cholecystostomy tube, and/or history of gallbladder perforation or fistula. Exposure Robotic-assisted vs laparoscopic cholecystectomy. Main Outcomes and Measures The primary outcome was a composite of an unplanned postoperative endoscopic retrograde cholangiopancreatography or interventional radiology procedure. Secondary outcomes included operative time, postoperative complications, and operative and total hospital costs. Results A total of 863 patients underwent cholecystectomy and met inclusion criteria; 525 (60.8%) were female and 338 (39.2%) were male, and their median (IQR) age was 61 (45-71) years. Among patients undergoing CEC, the laparoscopic approach was independently associated with an increased need for unplanned endoscopic or percutaneous intervention compared with the robotic group (odds ratio, 4.24; 95% CI, 1.24-14.52; P = .02). There were no significant differences in postoperative outcomes between the laparoscopic and robotic groups in patients undergoing non-CEC. Patients undergoing the laparoscopic approach had significantly reduced operating room costs when compared with patients undergoing a robotic approach in both the CEC ($7720 vs $8936, respectively) and non-CEC groups ($6368 vs $ 8351, respectively). However, there was no difference in the overall total cost of care between laparoscopic CEC and robotic CEC groups ($14 309 vs $14 476, respectively). The overall total cost of care was significantly higher for patients undergoing robotic non-CEC as compared with laparoscopic non-CEC ($11 416 vs $9925, respectively). Conclusions and Relevance This study found that for complex gallbladder disease, robotic cholecystectomy offers a clinical advantage, reducing complications and downstream interventions without increasing the overall costs of care. These findings suggest strategic application of the robotic platform may offer clinical advantages in high-complexity gallbladder surgery, maximizing patient benefit and resource efficiency.

Abstract Glioblastoma (GBM) remains a deadly cancer driven in part by invasion of tumor cells into the brain. Transcriptomic analyses have identified distinct molecular subtypes, but mechanistic differences that account for clinical differences are not clear. In this study, we show that, as predicted by the motor-clutch model of cell migration, mesenchymal glioma cells are more spread, generate larger traction forces, and migrate faster in brain tissue compared with proneural cells. Despite their rapid migration and comparable proliferation rates in vitro, mice with mesenchymal tumors survive longer than those with proneural tumors. This improved survival correlated with an immune response in mesenchymal tumors, including T cell–mediated. Consistently, inducing mesenchymal tumors in immunodeficient mice resulted in shorter survival, supporting a protective immune role in mesenchymal tumors. Thus, mesenchymal tumors have aggressive migration but are immunologically “hot,” which suppresses net proliferation. These two features counteract each other and may explain the lack of a strong survival difference between subtypes clinically, while also opening up new opportunities for subtype-specific therapies. Significance: This study highlights new mechanical and immunologic insights into GBM molecular subtypes using an integrated modeling–genome engineering strategy, which can potentially facilitate GBM subtype-specific therapeutic strategies.

ABSTRACT Background Strongyloides stercoralis is an intestinal parasitic nematode that can infect humans with a 2%–7% prevalence in the United States. Immunosuppression is a crucial risk factor for disseminated infection. Diagnosis is often delayed and targeted treatment is frequently initiated late. We therefore sought to review the prevalence of positive Strongyloides antibody results and undertook a descriptive analysis of such patients. Methods We retrospectively reviewed patients with positive Strongyloides IgG serology from August 2012 to April 2023 across geographically distinct academic medical centers. Study period pre‐dated universal donor and recipient Strongyloides screening recommendation by the Organ Procurement and transplantation network (OPTN). Clinical presentation was classified into three categories: chronic infection (positive Strongyloides IgG serology without additional clinical manifestations), hyperinfection syndrome (positive serology with involvement of the skin, gastrointestinal tract, or lungs), and disseminated infection (positive serology with involvement beyond those typically involved in hyperinfection). Results A total of 412 patients were identified; median age was 59 years and 66% (272) were male. The primary indication for testing was pretransplant evaluation in 230 (56%), eosinophilia workup in 84 (20%), suspicion of symptomatic infection in 74 (18%), testing based on travel history in 27 (7%), and pre‐immunosuppression screening in 27 (7%). Furthermore, 401 patients (97.3%) were categorized as having chronic infection, 10 patients (2.42%) had hyperinfection, and one patient (0.24%) had disseminated infection, presenting with Escherichia coli bacteremia and meningitis. Symptomatic infection was more common at the Mayo Clinic in Rochester and Mayo Clinic Health Sciences than at the Arizona and Florida Mayo Clinic sites (6% vs. 2%, p = 0.079). Treatment was administered to 366/412 (89%) patients. Conclusion Most patients with positive Strongyloides serology were asymptomatic, and treatment regimens were not uniform. Patients who tested positive should be treated prior to immunosuppression initiation, though this was not systematically assessed in this cohort. The observed variability in treatment regimens highlights the need for standardized protocols.

Importance In vivo biomarkers for detecting neuropathologies from repetitive head impacts (RHI), including chronic traumatic encephalopathy (CTE), are needed. Objective To evaluate the utility of plasma phosphorylated tau 217 (p-tau217), assess its performance as a beta-amyloid (Aβ) biomarker in participants with RHI exposure at risk for CTE, and explore concordance with CTE neuropathology in a postmortem subsample. Design, Setting, and Participants This longitudinal, multicenter, case-control study used data from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of CTE (DIAGNOSE CTE) Research Project, collected from September 2016 to October 2023. Participants were former American football players (case participants) and asymptomatic men unexposed to RHI (control participants). A subsample had available neuropathologic data. Exposures RHI, traumatic encephalopathy syndrome (TES) diagnoses, and levels of CTE certainty. Main Outcomes and Measures Plasma p-tau217 (classified as positive [≥0.63 pg/mL], intermediate [0.40-0.62 pg/mL], and negative [<0.40 pg/mL]), Aβ–positron emission tomography (PET; 18 F-florbetapir; with Aβ-positive defined as a standardized uptake value ratio [SUVR] ≥1.10), and tau-PET ( 18 F-flortaucipir). TES diagnoses were assigned by multidisciplinary consensus conference. Analyses of postmortem brains controlled for age, race, and APOE ε4 status. Results Among 231 participants (mean [SD] age, 57.75 [8.25] years), 177 were former football players (117 professional and 60 college) and 54 were unexposed participants. Former football players had higher baseline mean (SD) p-tau217 concentrations than unexposed participants (0.35 [0.26] pg/mL vs 0.27 [0.14] pg/mL; P = .008), although this was driven by a higher proportion of Aβ-PET–positive participants among former players. Plasma p-tau217 increased over time across the sample (B = 0.207 [95% CI, 0.117-0.298]; P < .001), with no significant time × exposure group interactions. Among football players, p-tau217 showed no time × group interactions with TES diagnosis, TES-CTE certainty, or RHI metrics. Higher p-tau217 concentration correlated with higher global Aβ-PET SUVR (B = 0.058 [95% CI, 0.053-3.501; P = .01), with a few discordant cases (5 participants were p-tau217–negative and Aβ-PET–positive; 7 participants were p-tau217–positive and Aβ-PET–negative). P-tau217 had similar areas under the curve for projecting Aβ-PET positivity as cerebrospinal fluid (CSF) p-tau181/Aβ42 and CSF Aβ40/42 measures (p-tau217: AUC, 0.88 [95% CI, 0.80-0.96]; CSF p-tau181/Aβ42: AUC, 0.89 [95% CI, 0.79-1.00]; CSF Aβ40/42: AUC, 0.85 [95% CI, 0.72-0.98]). Among 9 brain donors, 6 had CTE (stages II-IV; none with Alzheimer disease). Seven had negative or intermediate p-tau217, concordant with Aβ-PET. Two p-tau217 outliers with stage III CTE had normal concentrations upon additional testing. Conclusions and Relevance The findings of this study suggest that plasma p-tau217 concentration is unlikely to be useful for the detection of CTE, but it does show utility for ruling out Aβ pathology in participants at risk for CTE.

Background/Objectives: Mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BD), along with obstructive sleep apnea (OSA), are prevalent conditions that have serious effects on affected individuals and public health. These issues have received more attention recently, as research shows there are similar risk factors and they can influence each other by worsening symptoms and treatment response. However, there is still no clear understanding of the extent of this co-occurrence and the factors that influence it. Methods: A systematic review of comorbid OSA and mood disorders was conducted from EMBASE, Ovid MEDLINE, Global Health, and APA PsycINFO (1 January 2013–25 July 2025), with meta-analyses applying random-effects models in R (metafor). Heterogeneity, publication bias, subgroup effects, and meta-regression analyses were performed by assessing demographic, clinical, and study quality variables. Results: Out of 6221 screened studies, 23 articles met eligibility criteria, yielding 2,380,986 OSA patients, with 446,495 comorbid mood disorders (MDD = 446,290; BD = 205), and 5724 mood disorder patients (MDD = 1987; BD = 3737) with 450 comorbid OSA. All meta-analyses demonstrated a significant prevalence of comorbidity, accompanied by substantial heterogeneity. Meta-regression analyses identified mean age (β = 0.18, 95% CI 0.03–0.33, p = 0.02) and mean body mass index (β = −0.18, 95% CI −0.32 to −0.04, p = 0.01) as significant moderators of OSA prevalence. Conclusions: This meta-analysis indicates a high prevalence of comorbidity between OSA and mood disorders, including MDD and BD, with significant heterogeneity. Age and body mass index emerged as significant moderators of OSA prevalence, emphasizing the need for systematic screening and tailored approaches in both clinical practice and research.

Background Radionuclide SPECT/computed tomography (CT) is standard for diagnosing transthyretin cardiac amyloidosis (ATTR-CM), but the prognostic value of quantitative metrics remains incompletely defined. We investigated their prognostic utility and additive value beyond existing staging systems. Methods Retrospective study of patients undergoing technetium-99m-pyrophosphate (PYP) SPECT/CT, including consecutive clinically referred patients (October 2023 to 2024) and trial participants with positive scans from January 2022. Myocardial PYP was quantified using standardized uptake values (SUV mean and SUV max ) and volumetric measures [percent injected dose (%ID), cardiac amyloid activity (CAA)]. Major adverse cardiovascular events (MACEs) comprised heart failure hospitalization or death. Cox and Kaplan–Meier analyses assessed associations; likelihood ratio testing and change in area under the curve (AUC) evaluated the additive prognostic value to existing staging systems. Results Among 43 patients with ATTR-CM, 16 experienced MACE over a median 518 days. AUCs ranged from 0.74 to 0.88 at 3 months and 0.56–0.62 at 12 months. All variables trended toward association with MACE: SUV mean ( P = 0.02), SUV max ( P = 0.03), %ID ( P = 0.06), and CAA ( P = 0.06). After age adjustment, cut-points for SUV max (5.8) and SUV mean (3.5) remained associated with MACE. Adding imaging variables to the National Amyloidosis Centre and Columbia staging systems did not significantly improve prognostic accuracy (Δ χ 2 : 0.40–2.48, P = 0.11–0.53). Interobserver reproducibility was high (intraclass correlation coefficients = 0.89–0.99). Conclusion Quantitative Tc-99m–PYP SPECT/CT metrics were associated with short-term outcomes in ATTR-CM, but did not improve established staging systems. Findings are hypothesis-generating and require validation in larger cohorts.

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.

ABSTRACT Ischemic events after contemporary percutaneous coronary intervention (PCI) are uncommon but carry high morbidity/mortality. Identifying patients at highest risk is critical to guide dual antiplatelet therapy (DAPT) intensity while minimizing bleeding. Current machine learning (ML) model‐developed risk scores do not incorporate pharmacogenetic data. To develop and externally validate ML models that integrate clinical, demographic, and CYP2C19 genetic information to predict 1‐year ischemic outcomes post‐PCI to refine clinical decision making. We analyzed 8317 patients from TAILOR‐PCI trial ( n = 4572) and the Precision PCI registry ( n = 3745). The outcome was a composite of cardiovascular death, myocardial infarction, stroke, and stent thrombosis at 1 year. Boruta feature selection identified 11 predictors. Multiple ML algorithms were trained in TAILOR‐PCI and validated in Precision PCI using cross‐validation and synthetic minority oversampling (SMOTE). Model performance was assessed by area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. The best external performance was achieved with a support vector machine (SVM, polynomial kernel) (AUC 0.667; sensitivity 0.871; specificity 0.282), while XGBoost provided a more balanced profile (AUC 0.619; sensitivity 0.442; specificity 0.688). Variable importance for the SVM polynomial model demonstrated that all 11 included Boruta feature selected predictors had relatively high importance (> 75). ML models trained on large clinical trial and real‐world registry datasets can help identify the small subset of patients at high ischemic risk after PCI. This distinction is of relevance because ischemic events are rare, and most patients may safely de‐escalate DAPT to reduce bleeding risk while maintaining ischemic protection through a multimodal approach to risk stratification. Trial Registration: TAILOR‐PCI URL: https://clinicaltrials.gov/ct2/show/NCT01742117

Abstract Immune checkpoint inhibitors (ICIs) which target immune checkpoint proteins like programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have revolutionized cancer therapy. Skeletal toxicities are emerging immune-related adverse events for patients treated with ICIs, and PD-1 blockade in pre-clinical mouse models significantly reduces bone mass. However, the effect of PD-L1 inhibition on the bone throughout development is not well understood. We investigated the role of PD-L1 loss on bone microarchitecture with genetic PD-L1 knockout in myeloid cells using LysM-Cre;PD-L1Flox/Flox mice and pharmacologic inhibition with a PD-L1 neutralizing antibody in adult and aged mice. We report that neither PD-L1 deletion in myeloid cells nor inhibition with α-PD-L1 significantly impacts femoral trabecular bone microarchitecture; however, α-PD-L1 treatment increases vertebral trabecular bone volume. Additionally, PD-L1 blockade influences T cell expansion by decreasing naïve T cells and increasing effector memory T cells in the bone marrow, consistent with previous studies on the effects of PD-1 inhibition. The trabecular bone-sparing effect of PD-L1 inhibition is strikingly different from the bone loss observed with PD-1 blockade. Clinical studies are necessary and justified to determine if PD-L1 may be a less bone destructive alternative for cancer patients treated with ICIs who are at high risk of fracture.