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Abstract Aims SCN5A-E1784K (c.5350G>A) is the most common variant associated with the long QT (LQTS) and Brugada syndromes (BrS). It can manifest variably as LQTS, BrS, and/or conduction disorders. This presents a challenge for risk stratification. We aimed to describe clinical and ECG characteristics and identify risk markers that associate with arrhythmic events. Methods and results We undertook a retrospective observational multicentre study of a large cohort of 231 subjects with SCN5A-E1784K from Europe, USA, and Japan. Comprehensive demographic and clinical data, including initial presentation ECG and follow-up, were collected. ‘Lethal events’ were defined as sudden death, non-fatal cardiac arrest, and documented sustained VT or VF. ‘Cardiac events’ were defined as arrhythmic syncope plus any lethal events. Clinical characteristics and ECG parameters corrected for age were investigated for association with lethal and/or cardiac events. Fourteen (6%) subjects experienced a lethal event and 45 (19%) a cardiac event. PR interval and QRS duration were associated with lethal and cardiac events. In multivariable models, both PR interval and QRS duration were associated with lethal events, but only QRS duration was associated with cardiac events. Only age-corrected QRS (rQRS) was associated with lethal and cardiac event-free survival from birth after correction for multiple testing. Conclusion Ventricular myocardial conduction appears likely to play a role in the risk of arrhythmic events in patients with SCN5A-E1784K. This provides an important opportunity for the personalization of management and has the potential to guide preventative therapies.

Background: Objective performance assessment is essential in surgical skill training, yet current methods are labor-intensive and focus on observing the trainee rather than the end-product of the procedure. Machine learning (ML) methods offer reproducible feedback but have mainly relied on kinematic or video data, often reducing assessment to binary or ternary classification. Our objective was to compare ML regression models predicting expert-assigned scores of vascular anastomoses from computational fluid dynamics (CFD) features of the final product. Additionally, we aimed to assess biomechanical plausibility of predictions. Methods: A total of 146 participants performed 419 end-to-side anastomoses on case-specific three-dimensional (3D) printed simulators. Anastomoses were digitized via 3D scanning, ranked by experts, and characterized using CFD-derived hemodynamic features. These served as input for linear models (Ridge, Partial Least Squares), support vector machines, and tree-based ensembles (Random Forest, Extremely Randomized Trees, and Extreme Gradient Boosting [XGBoost]), evaluated using 10-fold nested cross-validation with genetic hyperparameter optimization. Results: Inter-rater reliability of expert indicated strong agreement (intraclass correlation coefficient ICC3k = 0.846). XGBoost achieved the lowest mean root mean squared error of 0.758 (95% bootstrap CI: 0.722–0.799) and a coefficient of determination (R2) of 0.673 (0.617–0.725), with the most stable performance across folds. Shapley additive explanations (SHAP) identified the wall shear stress gradient, transverse wall shear stress, and maximum pressure as the most influential features—variables associated with intimal hyperplasia and atherosclerotic remodeling. Conclusions: Tree-based ensemble methods, particularly XGBoost, effectively modeled biomechanical properties against expert scores. Combining CFD and ML can provide reproducible, mechanistically relevant feedback in vascular surgical skill training.

Background The middle meningeal artery (MMA) has emerged as an endovascular route for treating chronic subdural hematoma (CSDH), meningioma, and refractory headaches. The third ARISE roundtable convened experts from neurology, neurosurgery, neuroradiology, industry, and regulatory agencies to develop consensus guidance on current evidence for MMA-based therapies Methods Over 50 experts participated in a multi-stakeholder discussion. Evidence from randomized and observational studies, early-phase interventional series, and preclinical work was reviewed. Breakout groups focused on four domains: (1) MMA embolization (MMAE) for CSDH, (2) preoperative embolization of meningiomas, (3) MMA-targeted therapies for headache, and (4) transvascular access for endovascular drainage of subdural hematomas. Consensus recommendations were developed by a writing committee Results Randomized trials support MMAE as an adjunct to surgery or medical management for selected patients with non-acute, symptomatic CSDH to reduce recurrence, progression, and reoperation. Evidence remains insufficient to support MMAE for acute or asymptomatic subdural hematomas. For meningioma, observational data suggest that preoperative embolization in experienced centers can reduce blood loss and operative time and may delay recurrence in large, hypervascular tumors with predominant dural or external carotid supply; primary embolization and intra-arterial oncologic therapies remain investigational. Early series of MMA-directed lidocaine infusion for refractory migraine, status migrainosus, and post-subarachnoid hemorrhage headache show short-term benefit, highlighting the need for controlled trials. Preclinical and first-in-human studies of combined MMAE and transvascular drainage for CSDH demonstrate high technical success, rapid radiographic and clinical improvement, and no early recurrences Conclusion The MMA represents a vascular pathway for an expanding spectrum of neurointerventional therapies.

Background: Considering the pathophysiological importance of the intestine-passing microbiota, we hypothesized that the mutational and microbial profiles of colorectal cancer might gradually change along detailed anatomical locations and that these trends might differ by the age of diagnosis and the microsatellite instability (MSI) status. Methods: We assessed somatic mutations and selected bacterial species in colorectal carcinomas along the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum, utilizing targeted sequencing data ( N = 5685) from the Genetics and Epidemiology of Colorectal Cancer Consortium and tissue microbial data ( N = 1389) from the Health Professionals Follow-up Study and Nurses’ Health Study. Results: There were decreasing trends from the cecum to rectum in the prevalence of gene mutations in the IGF/PI3K, receptor tyrosine kinase (RTK)/RAS, TGFB, and WNT signaling pathways (all P trend < 0.0001), as well as high levels of Bacteroides fragilis ( P trend < 0.0001) and high levels of Fusobacterium nucleatum ( P trend = 0.0029) (but not enterotoxigenic Bacteroides fragilis or pks+ Escherichia coli ). Conversely, TP53 pathway mutations showed an increasing cecum-to-rectum trend ( P trend < 0.0001). Similar to later-onset cases diagnosed at ages 50 years and older, in early-onset cases diagnosed under the age of 50 years, we found generally decreasing cecum-to-rectum trends of IGF/PI3K, RTK/RAS, TGFB, and WNT pathway mutations and an increasing cecum-to-rectum trend in TP53 pathway mutations. By contrast, the cecum-to-rectum prevalence-changing trends in IGF/PI3K, RTK/RAS, TGFB, and TP53 pathway mutations were present in non–MSI-high tumors but not in MSI-high tumors (all P interaction < 0.0052). Conclusion: Non–MSI-high colorectal cancers exhibited decreasing cecum-to-rectum trends of IGF/PI3K, RTK/RAS, and TGFB pathway mutations (and an increasing trend of TP53 pathway mutations), in contrast to MSI-high tumors that demonstrated no such trends. Our study highlights the importance of detailed colorectal subsite information combined with tumor molecular and microbial characteristics in colorectal cancer research.

Background: Several special tests for detecting medial ulnar collateral ligament (MUCL) injuries of the elbow have been described, but data on the clinical utility of these tests are limited. Purpose: To determine the clinical utility of selected elbow special tests to detect MUCL injuries in an athletic population. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 84 consecutive patients with sports-related elbow pain underwent a standardized clinical examination. Overall, 6 special tests (moving valgus stress test, static valgus stress test, modified valgus stress test, milking maneuver, pronation flexion resistance test, and temple/cheek press test) were performed. Sensitivity, specificity, accuracy, positive/negative predictive value, and positive/negative likelihood ratio (LR+ and LR–, respectively) were calculated for individual tests and combinations of tests to detect MUCL injuries. Higher values for the LR+ and lower values for the LR– represent stronger clinical utility. Results: For detecting MUCL injuries, the moving valgus stress test resulted in the highest sensitivity (98%) and accuracy (93%) with the lowest LR– (2%). The milking maneuver had the highest LR+ (5.1) with the second highest sensitivity (77%) and accuracy (79%). The pronation flexion resistance test and the temple/cheek press test had the lowest LR+ (1.5 and 1.8, respectively) and highest LR– (94% and 95%, respectively) in addition to the lowest sensitivity (16% and 9%, respectively) and accuracy (33% and 30%, respectively). No combination of tests resulted in increased clinical utility. Conclusion: The moving valgus stress test and milking maneuver demonstrated acceptable clinical utility in which the moving valgus stress test was better for ruling out MUCL injuries and the milking maneuver was better at ruling in MUCL injuries. There was no added value when combining the 2 tests together or with other maneuvers.

Abstract Chronic low‐grade inflammation characterizes type 2 diabetes mellitus (T2DM) and underlies the development of peripheral neuropathy, symptoms of which include mechanical allodynia and an exaggerated exercise pressor reflex. The purpose of this study was to determine whether mechanical allodynia and/or specific concentrations of inflammatory mediators coincide with the presence of an exaggerated exercise pressor reflex. Haemoglobin A1c was assessed to detect diabetes onset (threshold ≥5.6%) in male University of California Davis (UCD)‐T2DM rats ( n = 18). Age‐matched, healthy Sprague–Dawley rats ( n = 18) served as controls. Monthly measurements assessed mechanical allodynia (via paw withdrawal threshold), insulin and inflammatory mediators (via ELISA and multiplex kits). Paw withdrawal threshold was not different between groups prior to diabetes onset. However, by 8 weeks post‐onset, T2DM rats demonstrated a significant decrease in pain threshold compared to that before diabetes onset, which persisted for 8 weeks. This is the same period in diabetes progression as when the exercise pressor reflex is exaggerated. Prior to diabetes onset, UCD‑T2DM rats had significantly higher circulating levels of IL‑6 and IL‑1β, and these elevations persisted throughout disease progression, with only CRP showing a significant increase at 8 weeks post‑onset. These findings offer a useful foundation for further exploration into the assessments of mechanical allodynia and inflammation to determine when those with T2DM are at an increased risk for experiencing adverse cardiovascular events.

This multicenter, single-arm, phase 1/2 study evaluated the safety and efficacy of CD19-directed allogeneic chimeric-antigen-receptor (CAR) immunotherapy CTX110 in adult patients with relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (NHL). Patients received 1 or 2 treatment courses: standard lymphodepletion, followed by 1 CTX110 infusion at dose levels (DLs) 1-4 (3-60 × 107 CAR T-cells; dose escalation, N=32), or 2 infusions at DL4 on days 1 and 35 (cohort expansion, N=31). Primary endpoints in dose escalation and cohort expansion were incidence of dose-limiting toxicities and objective response rate, respectively. CTX110 was administered to 63 heavily pretreated patients: 59% primary refractory, 43% with ≥3 prior treatment lines. Among 57 patients whose first infusion was DL≥3, rates of objective and complete response (CR) were 65% and 39%, respectively. Among 22 patients achieving CR, 5 (23%) had ongoing CR at data cutoff, with 15-50 (median 34) months follow-up. The 2-infusion regimen appeared to prolong response duration compared to 1 infusion (hazard ratio 0.65). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were reported in 54% and 13% of treated patients, respectively, including 2 grade ≥3 cases each. The most common grade ≥3 adverse events were neutropenia (59%), and anemia and thrombocytopenia (35% each). Serious adverse events occurred in 32% of treated patients, including CRS (14%), ICANS (8%), and febrile neutropenia (6%). In this r/r NHL population, CTX110 was well-tolerated, resulting in clinically meaningful responses at DL≥3, with a second infusion demonstrating evidence of further clinical benefit. This trial (NCT04035434) was registered at www.clinicaltrials.gov.

Background Grade group 5 (GG5) prostate cancer (PCa) carries a less favorable prognosis after standard-of-care (SOC) therapy, necessitating novel therapeutic approaches. High-dose rate brachytherapy (HDRBT) and androgen deprivation therapy (ADT) may modulate immune response in GG5 PCa, particularly in tumors with increased immune content. This study evaluated whether the addition of nivolumab to SOC was associated with improved disease control in patients with high-volume GG5 PCa, including those with oligometastatic disease. Methods In this non-randomized phase II trial, 31 patients with localized or oligometastatic GG5 PCa and >30% positive biopsy cores were evaluated between September 2018 and April 2021. Patients received four doses of nivolumab (240 mg every 2 weeks) beginning 4 weeks prior to HDRBT, alongside ADT, HDRBT, and external beam radiation. The primary endpoint was to evaluate whether the 2-year freedom from biochemical recurrence (FFBR) rate would exceed a prespecified historical control rate of 75%. Results Among the 31 patients, the median follow-up was 38.8 months (IQR 31.0–46.5 months). The addition of nivolumab to SOC RT with ADT was associated with a 2-year FFBR rate of 90.3% (95% CI 74.3% to 98.0%) (median FFBR not reached), exceeding the prespecified historical control rate of 75% (one-sided p value from binomial test=0.024). Definitive and probable nivolumab-related toxicity included 6.3% acute grade 2 and 6.3% acute grade 3 adverse events (AEs), with no grade 4+ AEs observed. A higher Decipher immunosuppression score at diagnosis correlated with early pathologic response (p=0.005) and was independently associated with time to metastatic failure (p=0.044). Conclusions Nivolumab combined with SOC was associated with encouraging FFBR in this high-risk GG5 PCa population and may represent a promising therapeutic intensification strategy. The Decipher immunosuppression score may serve as a predictive biomarker for response. These findings warrant further investigation in randomized trials.

RELA-related disease is a rare, autosomal-dominant condition presenting with immune dysregulation and immunodeficiency. RELA encodes the p65 subunit, a component of the canonical NFκB pathway. The underlying pathogenesis, at least in part, involves impaired NFκB activation, increased susceptibility to TNFα-induced apoptosis, and hyperinflammation. To date, only a modest number of cases have been documented worldwide, and the full clinical and functional spectrum of disease remains incompletely defined. This study represents a large global cohort identified with RELA variants, comprising 40 patients from 30 institutions, expanding our previous report of a single large kindred (1). The clinical spectrum includes arthritis, mucocutaneous ulcers, uveitis, dermatitis, irritable bowel disease, recurrent infections, lymphopenia, hypogammaglobulinemia, recurrent fevers, and susceptibility to neoplasia. The patients represent 36 kindreds with 28 unique RELA variants, of which 15 are missense, 7 nonsense, and 6 frameshift variants. Fifteen are in the Rel homology domain, 7 in the transcriptional activation domain, and 6 in the C-terminal region proximal to TAD (Fig. 1). Functional studies assessed the canonical NFκB pathway in 27% of the cohort (n = 11; healthy controls = 40). Patient peripheral blood mononuclear cells (PBMCs) were used to quantify total and phosphorylated p65 (ph-p65, Ser529) by flow cytometry after stimulation with PMA (100 ng/ml) and ionomycin (1 uM). In 8 patients, we assessed the kinetics of IκBα degradation, required for p65 phosphorylation and nuclear translocation of p65/p50. All patients tested had decreased total p65, while 64% had decreased ph-p65 with altered phosphorylation kinetics. Nearly 45% had impaired IκBα degradation. One patient (P4) demonstrated increased IκBα degradation and ph-p65, while a related proband (P1) had decreased ph-p65. Additionally, P4 did not have the same mucocutaneous clinical phenotype as P1 despite sharing the same RELA variant. This could reflect the effect of other genetic modifiers, epigenetic, environmental, or stochastic variations, which could lead to variable expressivity and/or incomplete penetrance. All patients appeared to have haploinsufficiency, as none had normal levels of p65. This study expands the clinical and genetic spectrum of RELA-related disease and provides mechanistic insights into the impact of these variants on p65 phosphorylation and downstream function, resulting in variable expressivity. Figure 1. RelA protein structure. Represents unique variant locations and categories, key domains, and phosphorylation sites. Source: UniProt. Adapted from (2). BioRender.

Background: Contemporary data on trends in survival after incident atrial fibrillation (AF) are limited. Methods: Residents of a 27-county area in southern Minnesota and western Wisconsin with new-onset atrial fibrillation or atrial flutter between 2013 and 2023 were identified. An electronic algorithm requiring 1 inpatient code or 2 outpatient codes separated by >7 days but within 1 year was used to define AF. Patients were followed for all-cause mortality through March 31, 2025. Standardized mortality ratios of observed versus expected survival were calculated, and time trends in survival were examined using Cox regression adjusting for demographics, cardiovascular risk factors, comorbid conditions, and area-level measures of socioeconomic status and rurality. Results: There were 44,930 individuals identified with incident AF from 2013-2023 (56.4% male; mean (SD) age 72.8 (13.5) years; 95.8% were non-Hispanic white). Within the first 90 days, the risk of all-cause mortality was greatly elevated compared with individuals of a similar age and sex distribution in the general population (standardized mortality ratios 12.6, 95% CI, 12.1-13.0 and 3.8, 95% CI, 3.6-4.0 for the first 30 days and 31 to 90 days after diagnosis, respectively). This excess risk was observed for all age groups but was greatest in the youngest age group (standardized mortality ratios among 18-64 year olds for the first 30 days: 49.9, 95% CI, 44.6-55.7 and 31 to 90 days: 11.1, 95% CI: 9.4-13.1; Figure ). In the youngest age group, the excess risk persists through 5 years post AF, however, in the oldest age group the excess risk only persisted through 1 year. Survival within the first 90 days improved over the study period (adjusted hazard ratio [aHR], 0.88; 95% CI, 0.79-0.99 for 2023 vs 2013); likewise, among 90-day survivors, survival improved between 2013 and 2023 (aHR,0.82; 95% CI, 0.76-0.88). These trends were driven by improvements in the younger age groups, particularly for death among 90-day survivors (aHR for 18-64 years, 0.66, 95% CI, 0.52-0.83; 65-74 years: 0.77, 95% CI: 0.65-0.90; 75-84 years, 0.84, 95% CI: 0.75-0.95; 85+ years, 0.99, 95% CI: 0.98-1.01). Conclusion: In a Midwestern community, the excess risk of death is high within the first 90 days after incident AF. Furthermore, survival after AF has improved between 2013 and 2023, with the improvement greatest in younger age groups.