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Introduction The World Health Organization (WHO) endorses male circumcision as an effective human immunodeficiency virus (HIV) prevention intervention in settings where the expected impact is greatest, including Sub-Saharan Africa. Data on cost implications of early infant male circumcision (EIMC) are limited. The ShangRing (SR) is a WHO pre-qualified device for circumcision. We sought to perform a comprehensive cost assessment alongside a randomized controlled trial (RCT) of the SR versus the standard of care Mogen clamp (MoC) for EIMC to enable future scale-up towards a cost-effective HIV prevention strategy. Methods We collected resource utilization and economic data as part of an RCT of infants aged 0–60 days old undergoing EIMC in Kenya, Tanzania, and Uganda. Cost data for both the SR and MoC included baseline facility costs, direct costs, and indirect costs. The Decision Makers Program Planning Tool v1.0 was used to perform a direct cost comparison of these two devices. The Goals model was used to compare the costs of EIMC in 2023 using the present value of money to circumcise an adolescent male 15 years from now. Results A total of 1,378 infant males underwent circumcision, 689 via SR and 689 via MoC. The overall cost of a single EIMC in Kenya, Tanzania, and Uganda were 61.30 United States Dollars ($), $47.14, and $64.59 respectively for the SR, and $56.38, $50.43, and $58.57 respectively for the MoC. In Kenya, EIMC would be less expensive based on nominal present costs in 2023 compared to waiting for adolescent circumcision at age 15 years in 2038. This finding is reversed in Tanzania and Uganda. Conclusions The overall cost of EIMC via SR versus MoC is comparable in an RCT. With scale-up utilizing lower level personnel, the cost of SR may be further reduced. The SR is an attractive alternative for future EIMC initiatives in Sub-Saharan Africa to further reduce HIV burden.

Abstract Background and Objective Management of von Hippel–Lindau (VHL) disease is challenging due to multisystem involvement and limited systemic treatment options. Belzutifan has shown promising efficacy in clinical trials; however, real-world data remain limited. We aimed to evaluate its effectiveness and safety in a real-world cohort. Methods We conducted a retrospective study of 59 patients with VHL disease treated with belzutifan between August 2021 and January 2026. Objective response rates (ORR) for renal cell carcinoma (RCC), central nervous system hemangioblastomas (CNS HB), and pancreatic neuroendocrine tumors (pNET) were assessed by an independent radiologist. Retinal hemangioblastoma outcomes were evaluated through ophthalmology records by chart review. Results Median follow-up was 29 months. ORR was 27.6%, 39.6%, and 85.7% for RCC, CNS HB, and pNET, respectively. Among 13 patients with retinal hemangioblastomas (20 eyes), 17 eyes (85%) showed improvement. At data cutoff, 47 patients (79.6%) remained on treatment, while 12 (20.3%) discontinued (7 due to adverse events, 3 to disease progression, and 2 to other reasons). The most common adverse event was anemia (86.4%). Grade ≥3 events occurred in 10 patients (16.9%). The procedure rate per patient-year decreased from 0.35 in the 3 years prior to treatment to 0.08 during follow-up (Incidence Rate Ratio, 0.23; 95% CI, 0.12–0.47; P < 0.001) Conclusions Belzutifan demonstrated efficacy across VHL-associated lesions, with favorable safety profile. Most adverse events were grade 1–2. A reduction in procedure rate was observed after treatment initiation.

BACKGROUND: Cardiac computed tomography (CT) acquired during the acute stroke imaging protocol is an emerging modality to detect cardiac thrombi. We determined its yield in patients with acute ischemic stroke. METHODS: We performed a 1-stage individual patient data meta-analysis of 4 prospective observational cohorts (AIS of HEARTS [Acute Ischemic Stroke of Heart-Related Embolic Sources Detected on Acute Cardiac CT Scans]), including patients with acute ischemic stroke who underwent ECG-gated or non–ECG-gated cardiac CT between May 2018 and June 2024. We excluded patients with transient ischemic attack or stroke mimics. The primary outcome was the proportion of patients with a thrombus on cardiac CT. Secondary outcomes were additional scan time, radiation dose, comparison with echocardiography, and 90-day outcomes. We performed logistic regression analyses to compare 90-day outcomes between patients with and without thrombus, adjusting for age, sex, history of atrial fibrillation, ischemic heart disease, chronic heart failure, stroke or transient ischemic attack, anticoagulant use, prestroke modified Rankin Scale score, National Institutes of Health Stroke Scale score, large vessel occlusions, and intravenous thrombolysis, as appropriate for each outcome. RESULTS: We included 3919 patients (median age, 74 [interquartile range (IQR), 63–82], 58% male, median National Institutes of Health Stroke Scale score 6 [IQR, 3–12]). Cardiac CT detected a thrombus in 243 (6.2%) patients. Among 1323 patients that underwent both cardiac CT and transthoracic echocardiography, cardiac CT had a higher yield than transthoracic echocardiography (odds ratio, 7.4 [95% CI, 4.0–15.1]; P <0.001). Median additional scan time was 6 minutes (IQR, 5–7) for ECG-gated and 13 seconds (IQR, 12–61) for non–ECG-gated cardiac CT. Median additional radiation dose was 2.9 mSv (IQR, 1.6–4.1). Patients with thrombi had higher 90-day mortality (33% versus 15%, adjusted odds ratio, 1.6 [95% CI, 1.1–2.3]) and worse modified Rankin Scale scores (median modified Rankin Scale score 3 versus 2, adjusted odds ratio, 1.6 [95% CI, 1.2–2.0]), but similar recurrent stroke rates (5% versus 4%, adjusted odds ratio, 1.4 [95% CI, 0.7–2.5]). CONCLUSIONS: Implementing cardiac CT into the acute stroke imaging protocol is feasible, detects thrombi in ≈6% of patients, and has a higher yield than transthoracic echocardiography. Cardiac thrombi were associated with higher mortality, but not higher stroke recurrence. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT07165093.

ABSTRACT Truncating mutations in the tumor suppressor STAG2 , which encodes a component of the cohesin complex, are prevalent across diverse human cancers. Here, we report that acute reconstitution of physiological STAG2 levels in STAG2 -mutant human glioblastoma multiforme cancer cells triggers a rapid reduction in the size of chromatin loops genome-wide. Despite this global change in chromatin loop size, early transcriptional responses to STAG2 restoration are limited to a small number of genes, most of which are induced by STAG2 reconstitution. Notably, the growth-suppressor EFEMP1 (Fibulin-3), a secreted glycoprotein that functions as an extracellular matrix-associated inhibitor of glioblastoma growth and invasion, was the only gene consistently induced across all experimental models. The most robust and conserved STAG2-induced genes all reside within intense chromatin loops whose anchors and overall intensity did not appear to change in response to STAG2 reconstitution. These findings suggest that inactivating mutations of STAG2 promote neoplastic transformation by alleviating a restriction on chromatin loop size, allowing for an expanded range of chromatin interactions that disrupts the maintenance of a tumor-suppressive transcriptome.

Background: Asymptomatic intracranial atherosclerotic arterial stenosis (ICAS) is an underrecognized entity for which vascular risk-factor optimization is the primary management strategy, with no current indication for routine antiplatelet therapy or endovascular intervention for primary stroke prevention. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce major adverse cardiovascular events, including stroke, in high-risk cardiometabolic populations, but their association with outcomes in asymptomatic ICAS is yet to be evaluated. The present study aims to evaluate the association between GLP-1RA use and cerebrovascular outcomes in adults with asymptomatic ICAS. Materials and Methods: We used the TriNetX US Collaborative Network (71 healthcare organizations) to identify adults (≥18 years) with ICAS between 1 January 2016 and 31 December 2025, and excluded patients with prior cerebral infarction, intracranial hemorrhage, or cerebrovascular ischemic syndromes. Exposure was defined as initiation of any GLP-1 receptor agonist (lixisenatide, semaglutide, liraglutide, tirzepatide, dulaglutide) during the 6 months before or on the date of index ICAS diagnosis. Outcomes were assessed at 1 year, and included ischemic stroke, all-cause mortality, and a composite of ischemic stroke or mortality. Propensity-score matching (1:1) was performed, including demographics, vascular risk factors, comorbidities, antithrombotics, lipid/diabetes therapies, and cardiometabolic laboratory/physiologic measures. Results: Before matching, 1746 GLP-1RA users and 71,792 non-users met inclusion criteria; after matching, 1728 patients remained in each cohort. GLP-1RA use was associated with lower 1-year risk of ischemic stroke (4.40% vs. 6.10%; hazard ratio [HR] 0.70, 95% CI 0.52–0.95; p = 0.044), lower all-cause mortality (3.40% vs. 9.40%; HR 0.35, 95% CI 0.26–0.47; p < 0.001), and lower composite outcome risk (7.50% vs. 15.00%; HR 0.48, 95% CI 0.39–0.59; p < 0.001). Notably, these associations were observed despite matching for HbA1c, LDL cholesterol, BMI, and systolic blood pressure, suggesting potential effects beyond measured cardiometabolic risk profiles. Conclusions: In this large, propensity-matched cohort of adults with a-ICAS, GLP-1RA use was associated with lower ischemic stroke, all-cause mortality, and composite outcome at 1 year. These findings are hypothesis-generating and require further prospective studies to confirm this observation.

Background: Although donor and recipient characteristics are used to estimate graft failure risk, they remain limited in predicting early acute rejection. We developed and validated a next-generation sequencing (NGS) assay targeting the pre-transplant immunologic profile to predict early acute rejection following kidney transplantation. Methods: This prospective, international study enrolled 321 kidney transplant participants across 13 sites, forming discovery and validation cohorts. Peripheral blood was collected prior to transplant and at 1, 3, 6, 12, and 24 months post-transplant, with protocol biopsies performed at 3 and 12 months, as well as any indication biopsies. Biopsies were assessed by a blinded central pathologist according to the 2019 Banff criteria. The pre-transplant risk assessment (PTRA™) test to evaluate RNA expression of a 29-gene signature algorithm designed to predict early acute rejection risk was clinically validated utilizing 122 deceased donor kidney transplant recipients. Results: PTRA classified 31 of 122 participants (25%) as high-risk and 91 (75%) as low-risk. There were 9 early acute rejection events in the first 60 days post-transplant: 6/31 (19%) in the high-risk group and 3/91 (3%) in the low-risk group. PTRA discrimination for early acute rejection at 60 days post-transplant yielded an AUC of 0.78 (95% confidence interval [CI]: 64.4 to 91.5), p<0.001. A cut-off of ≤45 was defined as low-risk and >45 as high-risk for early acute rejection within 60 days post-transplant. Sensitivity 0.67 (95% CI: 0.36 to 0.97), specificity 0.78 (95% CI: 0.70 to 0.86), positive predictive value 0.19 (95% CI: 0.05 to 0.33), and negative predictive value 0.97 (95% CI: 0.93 to 1.00). The odds ratio comparing patients identified as high- vs low-risk by PTRA was 7.04 (95% CI: 1.64 to 30.2), p=0.009. Conclusions: This study validates the ability of PTRA to stratify kidney transplant recipients as high- or low-risk for early acute rejection using a pre-transplant transcriptomic profile, with implications for graft health and personalized treatment management.

Abstract Context Prior reports of plasma estradiol concentrations and their reference ranges in postmenopausal women identified marked variation, in part due to assay method and body mass index (BMI). Objective To develop an international reference range for plasma estradiol in postmenopausal women, support accurate assessment of concentrations during systemic and local (eg, vaginal) estradiol therapy, and improve risk prediction for diseases, including osteoporosis, breast, and endometrial cancers. Methodology Estradiol concentrations were measured using primarily liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays in 5 international cohorts of community-dwelling, postmenopausal women of primarily European ancestry aged 38-100 years who were not using exogenous estrogens (n = 7206). Measurements were harmonized to the Centers for Disease Control and Prevention (CDC) reference measurement procedure (RMP) by re-assaying a subset of samples for each cohort and generating recalibration equations. Reference intervals were determined for all women, non-obese women, and specific BMI categories. Results Estradiol concentrations from separate LC-MS/MS assays correlated closely with the CDC RMP, and harmonization minimized inter-assay variability. Estradiol concentrations correlated with BMI but not with chronological age. The reference range (2.5th-97.5th percentile) was 1.1-18.2 pg/mL (4.0-66.8 pmol/L) with median of 4.9 pg/mL (18.0 pmol/L) for all postmenopausal women and 1.1-12.5 pg/mL (4.0-45.9 pmol/L) with median of 4.1 pg/mL (15.1 pmol/L) for non-obese women (BMI &lt; 30). Reference ranges increased progressively with higher BMI categories. Conclusion Cross-calibration of estradiol measurements with the CDC RP enabled the development of harmonized plasma estradiol reference ranges for postmenopausal women who were not using exogenous estrogens, suitable for future studies to establish clinical utility. Increasing obesity in postmenopausal women was associated with increasing estradiol concentration and BMI category-specific reference ranges.

Abstract Purpose The aim was to evaluate the ability of four large language models (LLMs) (OpenAI's ChatGPT‐3.5, Microsoft 365 Copilot, DeepSeek‐R1, and Google Gemini 2.5 Pro) to develop treatment options when presented with clinical cases published in the maxillofacial prosthodontics literature. Materials and Methods Six maxillofacial case reports were fed to the LLMs following a prompt that requested prosthodontic treatment options from the perspective of a prosthodontist. Expert evaluators scored the relevance, clarity, depth, focus, and coherence of the responses. Statistical analyses, including descriptive statistics, two‐way analysis of variance (ANOVA), post hoc Tukey tests, Pearson correlation analyses, and intraclass correlation coefficients (ICCs), were performed ( α < 0.05). Results There were significant differences among the total mean relevance ( p = 0.003), clarity ( p = 0.006), depth ( p < 0.001), focus ( p < 0.001), and coherence ( p < 0.001) scores of chatbots. Copilot consistently scored the lowest, and Gemini or DeepSeek scored the highest for all five factors. Depth ( p = 0.006), focus ( p = 0.024), and coherence ( p = 0.013) scores of senior prosthodontists were slightly higher than those of junior prosthodontists. Pearson correlation analysis revealed positive correlations between the total mean scores for all five factors ( p < 0.001). Conclusions The study demonstrates the ability of LLMs to develop maxillofacial prosthetic treatment plans tailored to specific clinical scenarios. There were significant differences between the abilities of the LLMs evaluated in this study. Copilot scored the lowest for all factors evaluated, and Gemini and/or DeepSeek scored the highest.

We searched for oncogenes activated by copy number increases using whole-genome sequencing data of 535 pancreatic ductal adenocarcinomas (PDACs). We found that gains of 1q were the second most common gain, occurring in 213 (39.8%) of PDACs. Single-cell analysis via fluorescence in situ hybridization on 33 cancers confirmed these results. A portion of 1q, rather than the entire 1q arm, was gained in 75 (14.0%) PDACs, allowing us to pinpoint two ~3-megabase regions of 1q that were nearly always gained. These two regions contained NCSTN and PSEN2 , genes that code two subunits of the γ-secretase complex. Evaluation of 267 precancerous lesions revealed that extra copies of NCSTN and PSEN2 were common (49%) in noninvasive neoplasms (high-grade pancreatic intraepithelial neoplasms), which are at relatively high risk for progression to PDACs, but uncommon (6%) in low-grade pancreatic intraepithelial neoplasia lesions, which have low malignant potential. We hypothesize that γ-secretase genes are genetically activated oncogenes in the early phases of pancreatic neoplasia.

Background: Cardiac CT acquired during the acute stroke imaging protocol is an emerging diagnostic modality to detect cardiac thrombi. We aimed to determine its diagnostic yield in a large, international, multicenter study. Methods: We performed an individual patient data meta-analysis by pooling prospective and retrospective observational data of patients with acute ischemic stroke (AIS) who underwent cardiac CT (ECG-gated or non-ECG-gated) as part of the acute imaging protocol between May 2018 and June 2024. We excluded patients with a TIA or stroke mimic. The primary outcome was the proportion of patients with a cardiac thrombus detected on cardiac CT. Secondary outcomes were additional scan time and radiation dose, comparison of yield with echocardiography, and 90-day mortality and recurrent ischemic stroke rates. Results: We included 3940 patients from 4 hospitals (median age 74 [IQR 63-82], 58.0% male, median NIHSS 6 [IQR 3-12], median time onset to hospital arrival 100 minutes [IQR 62-185]). Atrial fibrillation at baseline was present in 23.1% patients, and 29.6% had a large vessel occlusion. Cardiac CT was non-diagnostic in 17 (0.4%) patients. In total, cardiac CT detected 254 cardiac thrombi in 243/3923 (6.2%) patients. Thrombi were located in the left atrial appendage (n=193), left atrium (n=19), and left ventricle (n=42). Of 95/243 (39.1%) patients with a cardiac thrombus that underwent echocardiography (median interval cardiac CT-echocardiography: 2 days), transthoracic echocardiography detected a thrombus in 18/92 (19.6%) patients and transesophageal echocardiography in 2/5 (40.0%) patients. The diagnostic yield in patients that underwent both modalities was higher for cardiac CT (OR 7.5 [CI 4.0-15.3], p<0.001). Median additional scan time was 6 minutes (IQR 5-7) for ECG-gated and 17 seconds (IQR 15-63) for non-ECG-gated cardiac CT. Median additional radiation dose was 5.4mSv (IQR 3.0-7.6). Patients with a cardiac thrombus on cardiac CT had higher 90-day mortality than those without a thrombus (33.3% vs 14.6%, p<0.001). We found no difference in 90-day recurrent stroke rate (5.4% vs 4.4%, p=0.50). Conclusion: Routine cardiac CT performed during the acute stroke imaging protocol detects a cardiac thrombus in 1 out of 16 patients with AIS, with a 7-times higher yield than routine echocardiography. Mortality rate was doubled in patients with a cardiac thrombus, but 90-day stroke recurrence risk did not differ.