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Abstract Backgrounds Isolated REM sleep behaviour disorder (iRBD) is a prodromal marker of α-synucleinopathies. Although cognitive impairment is consistently reported in iRBD, its assessment varies considerably across studies. This study characterized mild cognitive impairment (MCI) patterns in iRBD using machine learning and identified the minimal neuropsychological test battery needed for accurate diagnosis. Methods Comprehensive neuropsychological data from 216 assessments (162 with MCI, 54 without) in 110 iRBD patients were analysed. Four supervised classifiers (logistic regression, support vector machine, random forest, gradient boosting) were trained across three frameworks (raw scores, raw scores plus demographics, binarized scores) to distinguish MCI status. A multi-objective hyperparameter optimization approach then identified the minimal test subset preserving diagnostic accuracy. Results Of MCI cases, 30% were single-domain and 70% multi-domain, with attention/executive functions and memory most frequently impaired. Binarized neuropsychological scores yielded the best classification performance, with support vector machine achieving 94.7% accuracy. Feature importance analyses consistently highlighted episodic memory, executive, and visuospatial measures. The optimization framework identified a mean of 8 informative tests spanning these domains, achieving comparable diagnostic accuracy to the full battery. Conclusions Cognitive impairment is common in iRBD and predominantly multidomain. Machine learning approaches applied to neuropsychological data can accurately classify MCI status and identify a concise, clinically feasible set of tests with high diagnostic value. These findings support comprehensive, multidomain neuropsychological assessment in iRBD and may inform optimized risk stratification in prodromal α-synucleinopathies.

PURPOSE Age ≥40 years is regarded as a high-risk feature and an indication for adjuvant chemoradiotherapy for patients with lower-grade glioma in clinical practice guidelines. It is unclear whether age remains a relevant prognostic factor for contemporary definitions of lower-grade gliomas in the molecular era. METHODS The Prospective Gliomas Research (PROGRES) database contains individual patient-level data from 11 prospective clinical trials or observational registries of histologically defined lower-grade 2-3 oligodendroglioma or astrocytoma. We determined the association of age (18-39 years v ≥40 years) with progression-free survival (PFS) stratified by isocitrate dehydrogenase 1 or 2 ( IDH1/2 ) status, using log-rank tests and Cox regression models. We validated our findings in a separate multi-institutional retrospective cohort (Retrospective Glioma Research [REGRES] database). RESULTS We identified 1,619 and 1,292 eligible patients in the PROGRES and REGRES cohorts, respectively. IDH -wildtype tumors were more common in patients 40 years and older (38% v 5%, odds ratio: 11.3 [95% CI, 6.5 to 19.7]). Age was associated with PFS in IDH -wildtype (5-year PFS for ≥40 v 18-39 years: 6% v 24%, hazard ratio [HR], 1.74 [95% CI, 1.21 to 2.50]) but not in IDH -mutant glioma (60% v 59%, HR, 0.89 [95% CI, 0.76 to 1.05], P interaction < .001). In IDH -wildtype tumors, older age predicted aggressive molecular features, including TERT promoter mutation (65% v 28%), EGFR amplification (41% v 15%), and chromosome +7/–10 alteration (57% v 25%). In a pooled analysis of four clinical trials, age was not predictive of a benefit from chemoradiotherapy versus radiotherapy alone for IDH -mutant glioma. CONCLUSION In the absence of additional clinical or molecular risk factors, age alone should not be considered an indication for administration or deferral of adjuvant treatment. Practice guidelines should be revised to reflect contemporary prognostic factors in the molecular era.

ABSTRACT Many real‐world patients with advanced biliary tract cancer (BTC) are excluded by TOPAZ‐1 criteria; this study assessed cisplatin and gemcitabine plus durvalumab (CGD) efficacy and safety in these patients. Data from 1358 patients with advanced BTC treated with first‐line CGD across 55 international centers were retrospectively analyzed. Patients were classified as TOPAZ‐1‐in (meeting all inclusion criteria) or TOPAZ‐1‐out (meeting ≥ 1 exclusion criterion). Primary endpoints were overall survival (OS) and progression‐free survival (PFS); secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. Furthermore, OS and PFS of the TOPAZ‐1‐out cohort were compared with reconstructed survival data from the phase III trial. 912 (67.1%) patients were classified as TOPAZ‐1‐in , and 446 (32.9%) as TOPAZ‐1‐out . After a median follow‐up of 14.5 months (95% CI: 13.7–36.5), OS was 16.1 months in TOPAZ‐1‐in and 12.5 months in TOPAZ‐1‐out (HR 0.69, 95% CI: 14.6–16.5, p = 0.0001); PFS was 8.2 versus 6.5 months (HR 0.73, 95% CI: 7.1–8.1, p < 0.0001). Median OS in the TOPAZ‐1‐out cohort (12.5 months) was nearly identical to the phase III trial experimental arm (12.9 months; HR 1.15, p = 0.13); for PFS the HR was 1.12 (95% CI 0.93–1.42; p = 0.09). Among TOPAZ‐1‐out patients, active infection, elevated bilirubin, and ECOG PS > 1 were linked to poorer OS, while no detrimental impact emerged for ALT/AST abnormalities, corticosteroid use, renal or hematologic parameters, or prior surgery within 6 months, suggesting treatment effectiveness was broadly maintained across clinical subgroups. Furthermore, TOPAZ‐1‐out patients experienced no significant increase in adverse events compared with the TOPAZ‐1‐in group. Real‐world data suggest CGD may be effective in TOPAZ‐1‐out patients, with no evident increase in toxicity, supporting the potential expanded use of the regimen in clinical practice.

ABSTRACT Anti‐Spike monoclonal antibodies (mAbs) progressively lost efficacy during the COVID‐19 pandemic due to the emergence and predominance of resistant SARS‐CoV‐2 variants. By contrast, high‐titre COVID‐19 convalescent plasma (CCP) collected from vaccinated donors recently recovered from infection provides a polyclonal source of antibodies that remains effective in clearing SARS‐CoV‐2 in immunosuppressed patients, unable to mount an adequate immune response against the virus. We conducted a systematic review and individual participant data meta‐analysis to examine the effect of CCP in immunocompromised patients persistently positive for SARS‐CoV‐2 viraemia following mAb therapy, and to evaluate possible biological factors associated with a favourable outcome. Electronic databases were searched for studies published from January 2020 to January 2026. All studies including eligible cases were considered in the systematic review. Unpublished cases were also collected from investigators of the selected studies. The protocol was registered at PROSPERO (CRD420251142891). Forty‐seven cases (30 cases from 12 published studies and 17 unpublished cases) were included. In 33 out of 47 patients (70.2%) with a mAb‐resistant infection, SARS‐CoV‐2 clearance occurred following CCP transfusion, with a mean of 2.7 CCP units administered. In logistic regression, total CCP volume transfused was positively associated with SARS‐CoV‐2 clearance. In conclusion, CCP transfusion was associated with SARS‐CoV‐2 clearance in persistently positive immunocompromised patients following failure of anti‐Spike mAb therapy.

This Viewpoint reflects on a decay in surgical skill related to falling laparoscopic case volumes and describes strategies to preserve laparoscopic proficiency amid the rapid adoption of robotic platforms.

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 Surgery after response to first‐line chemoimmunotherapy may offer a potential curative option for patients with locally advanced biliary tract cancer (BTC) initially considered unresectable. However, robust real‐world evidence in this setting remains limited. We retrospectively analyzed patients with locally advanced BTC treated with first‐line cisplatin, gemcitabine, and durvalumab (CGD) across 55 centers in 12 countries. Endpoints included overall survival (OS), progression‐free survival (PFS), disease‐free survival (DFS) among resected patients, objective response rate (ORR), and the prognostic impact of surgery. A multivariable logistic regression model was developed to predict surgical conversion using baseline clinical and laboratory variables. Among 1358 screened patients, 219 had locally advanced disease and were included in the analysis. Median follow‐up was 14.5 months. ORR was 34.6%, with median PFS and OS of 10.0 and 20.7 months, respectively. Twenty‐four patients (10.9%) underwent surgical resection after systemic therapy. Median OS was 22.5 months in resected patients versus 19.9 months in those who did not undergo surgery. Median DFS after resection was 15.8 months. Pathological lymph node involvement was independently associated with shorter DFS. Larger baseline tumor size correlated with higher odds of radiological response but not with OS. An exploratory elastic‐net model retained four baseline variables and showed moderate discriminative ability for surgical conversion, with an apparent AUC of 0.72 and an optimism‐corrected AUC of 0.65. First‐line CGD enabled secondary resection in approximately 11% of patients with locally advanced BTC. A simple baseline model may support patient selection for conversion surgery, although prospective validation is needed.