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Importance Cerebral hemodynamic impairment in patients with asymptomatic internal carotid artery (ICA) stenosis is associated with reduced cognition. It is uncertain whether revascularization might be an effective treatment for cognitive impairment in these patients. Objective To test whether any cognitive benefit from revascularization of high-grade, asymptomatic ICA stenosis varies based on the degree of baseline cerebral hemodynamic impairment. Design, Setting, and Participants This substudy was conducted within a multicenter phase 3 randomized clinical trial. Adults (aged 35-86 years) without dementia with eighth-grade education or higher and unilateral asymptomatic ICA stenosis greater than or equal to 70% were enrolled from January 2018 to July 2024 at 61 sites in North America (last follow-up in July 2025). Of 607 participants screened from 2485 in CREST-2, 392 were enrolled. Magnetic resonance or computed tomographic perfusion imaging tested for baseline hemodynamic impairment defined by delayed time-to-peak (TTP) arrival of intravenous contrast in the hemisphere ipsilateral minus contralateral to the stenotic artery. Intervention Carotid revascularization (endarterectomy or stenting) plus intensive medical management (IMM) vs IMM alone. Main Outcomes and Measures The primary outcome was the difference in composite cognitive z score over 1 year based on 5 cognitive tests. The primary analysis tested for an interaction between treatment group (revascularization vs IMM alone) and degree of baseline hemodynamic impairment among those with reduced baseline cognition (cognitive z score ≤−1.0 SD). Results Of 392 participants enrolled (mean age, 71 years; 125 [32%] females), 61 were excluded for missing baseline imaging and 40 for missing cognitive examinations or other covariates, leaving 291 with complete data. Fifty-one had reduced cognition at baseline (25 in the revascularization group and 26 in the IMM alone group). TTP ranged from no interhemispheric TTP delay to a more-than-2-second delay. Mean (SD) cognitive z scores were −1.36 (0.51) at baseline and −1.17 (0.47) at 1 year in the revascularization group and −1.34 (0.83) at baseline and −1.01 (0.97) at 1 year in the IMM alone group. The primary analysis showed no difference in cognition by treatment group over 1 year, adjusting for treatment group × hemodynamic status interaction and other covariates (adjusted difference in cognitive z score, −0.15 SD [95% CI, −0.54 to 0.24]). The interaction was not significant (β estimate = 0.018 [95% CI, −0.025 to 0.061]; P = .40). Conclusions and Relevance In this substudy of a randomized clinical trial, there was no differential effect of revascularization vs IMM alone on cognition over 1 year by cerebral hemodynamic status among those with baseline reduced cognition, suggesting that revascularization does not improve cognitive dysfunction by restoring flow to the brain in chronic asymptomatic carotid stenosis. Trial Registration ClinicalTrials.gov Identifier: NCT03121209

ABSTRACT Objective To compare outcomes of phenobarbital‐based versus benzodiazepine‐based pathways for alcohol withdrawal syndrome (AWS) in critically ill adults and evaluate whether pathway design and timing of phenobarbital use affect treatment outcomes. Data Sources A librarian‐led search of MEDLINE, Embase, Cochrane Central, CINAHL, Web of Science, Scopus, ClinicalTrials.gov , and the World Health Organization International Clinical Trials Registry Platform was conducted through July 2024, with updates in December 2024, August 2025, and December 2025. Search concepts included phenobarbital, benzodiazepines, and alcohol withdrawal. Study Selection and Data Extraction Comparative studies of adults admitted or transferred to an intensive care unit (ICU) with AWS and treated with phenobarbital‐based versus benzodiazepine‐based pathways were included. Sixteen nonrandomized studies were included in the qualitative synthesis, and 12 treatment‐oriented studies were included in the primary meta‐analysis. Multiple reviewers independently screened studies, extracted data, and assessed risk of bias using Risk Of Bias In Non‐randomized Studies—of Interventions (ROBINS‐I). Data Synthesis Phenobarbital‐based pathways were not associated with significantly different intubation (11 studies; odds ratio (OR), 0.62; 95% confidence interval (CI), 0.20–1.87; I 2 = 73%) or hospital length of stay (five studies; mean differences [MD], −1.75 days; 95% CI, −5.07 to 1.56; I 2 = 63%) compared with benzodiazepine‐based pathways. ICU length of stay was shorter with phenobarbital‐based pathways (eight studies; MD, −0.60 days; 95% CI, −0.79 to −0.41; I 2 = 0%). In exploratory subgroup analyses, front‐loaded, protocolized phenobarbital‐first pathways were associated with lower intubation and shorter hospital length of stay, but certainty of evidence was very low. Relevance to Patient Care and Clinical Practice This review distinguishes phenobarbital‐first, protocolized ICU pathways from adjunctive or mixed phenobarbital strategies, suggesting that implementation design may influence outcomes. Conclusions Although evidence remains very low certainty, these findings suggest that phenobarbital's role in ICU AWS may be pathway dependent. Front‐loaded, protocolized phenobarbital‐first pathways may be associated with favorable outcomes in exploratory analyses, but these findings should be considered hypothesis‐generating and require confirmation in prospective randomized trials. Trial Registration: CRD42024595819

Abstract Purpose Validate the semiquantitative (SQ)-MRI score for chronic pancreatitis (CP) diagnosis in an independent, multicenter cohort. Methods We analyzed MRIs performed at baseline in 337 participants with acute (AP) or recurrent AP (RAP) and 67 with non-calcific chronic pancreatitis (NCCP) enrolled in the PROCEED study from 6/2017 to 3/2023. MRIs were performed at multiple clinical centers using site-specific clinical protocols and a variety of MRI vendors to evaluate the SQ-MRI score in a real-world setting. The SQ-MRI score was calculated using the T1 signal intensity ratio of the pancreas to the spleen (T1 score), arteriovenous enhancement ratio (AVR), and pancreatic body diameter (PBD). We adjusted for confounding by participant characteristics via propensity score weighting. Results Median AVR was higher in AP/RAP (1.18, IQR: 0.97–1.44) than in the NCCP group (1.03, IQR: 0.78–1.22, p = 0.007). Pancreatic body diameters were larger in AP/RAP than in the NCCP group − 7–14 mm (10% vs 25%), 14–20 mm (40% vs 54%), and > 20 mm (50% vs 21%), respectively ( p < 0.01). Median T1 score was higher in AP/RAP (1.18, IQR: 0.96–1.40) than in the NCCP group (1.04, IQR: 0.86–1.32, p = 0.10). Median SQ-MRI score in the AP/RAP group was significantly lower, 1.91 (IQR: 0.97, 2.95), than in the NCCP group, 2.74 (IQR: 2.04–4.03) ( p < 0.001). The propensity score-adjusted AUC for SQ-MRI to distinguish AP/RAP from NCCP was 0.64, which was higher than for individual parameters. Conclusion We have validated the SQ-MRI score in a multicenter cohort using an independent, real-world MRI dataset.

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 Background Opportunistic bilateral salpingectomy (OBS), the removal of fallopian tubes during hysterectomy or instead of tubal ligation, is recommended to reduce ovarian cancer risk. However, data on the effectiveness of prophylactic OBS is limited. Methods This population-based retrospective cohort included individuals aged 18–80 in Ontario, Canada, who underwent OBS or comparator surgeries (hysterectomy with ovarian and tubal conservation or tubal ligation) from 2011 to 2023. Individuals with gynecologic cancer before or within six months of surgery were excluded. Hazard ratios and 95% confidence intervals were estimated using Cox proportional hazards regression. Sensitivity analyses varied the time between surgery and cancer diagnosis to account for pre-existing serous tubal intraepithelial carcinomas. Results Among 196,839 individuals, 57,941 underwent OBS and 138,898 underwent comparator surgeries. 142 epithelial ovarian cancers were diagnosed (19 in the OBS group and 123 in the comparator surgery group). OBS was associated with reduced risk of any ovarian carcinoma, with an adjusted hazard ratio (aHR) of 0.60 (95% CI, 0.36 to 0.98). For serous ovarian carcinoma (high- and low-grade combined due to missing grade data), the aHR was 0.47 (95% CI, 0.22 to 0.99). Sensitivity analyses with 12- and 18-month intervals showed aHRs of 0.59 (95% CI, 0.35 to 0.99) and 0.60 (95% CI, 0.35 to 1.01) for all ovarian carcinomas, and 0.49 (95% CI, 0.23 to 1.01) and 0.47 (95% CI, 0.22 to 0.99) for serous ovarian carcinoma, respectively. Conclusions OBS was associated with reduced risk of ovarian carcinoma, supporting its role as a primary prevention strategy.

Abstract Improved understanding of how chimeric antigen receptor (CAR) and endogenous T‐cell phenotypes associate with progression‐free survival (PFS) is needed to individualize and improve immunotherapy outcomes in multiple myeloma (MM). We characterized and investigated the prognostic value of immune dynamics defined with multidimensional and computational flow cytometry in 258 bone marrow aspirates from 107 MM patients treated with idecabtagene vicleucel in the KarMMa trial. At screening, there was an association between longer PFS and increased percentages of PD1 + cytotoxic T cells and ICOS − TIGIT + Tregs. At Month 1 after infusion, the presence of >1% CAR‐T cells, a CD4/CD8 CAR‐T‐cell ratio >0.09, and greater abundance of non‐activated non‐cytolytic CAR‐T cells identified patients with longer PFS. Notably, 47 of the 115 endogenous T‐cell clusters were prognostic at the latest assessment performed after CAR‐T infusion. Lower percentages of ICOS + TIGIT − Tregs showed the strongest association with longer PFS. Altogether, this large dataset of dynamic immune profiling throughout treatment with anti‐B‐cell maturation antigen (anti‐BCMA) CAR‐T cells uncovered that the T‐cell composition prior to apheresis as well as CAR‐T and endogenous T‐cell phenotypes after infusion associates with PFS. These findings have potential for translation into routine laboratory practice for improved understanding of response and resistance to CAR‐T cells in relapsed/refractory MM.

Importance The NRG Oncology research organization and NSABP B-35 randomized clinical trial prospectively collected margin width data on postmenopausal women with hormone receptor (HR)–positive ductal carcinoma in situ (DCIS) who underwent lumpectomy, whole-breast irradiation (WBI), and randomly assigned adjuvant anastrozole or tamoxifen therapy. This permitted analysis of outcomes per margin width. Objective To analyze the effect of margin width on ipsilateral breast tumor recurrence (IBTR). Design, Setting, and Participants NSABP B-35 was a phase 3, double-blind, randomized clinical trial in which patients were randomized to either 5 years of tamoxifen or anastrozole. Postmenopausal women with HR-positive DCIS and tumor-free margins were eligible. Enrollment was from January 6, 2003, to June 15, 2006, in academic and community hospital members of the NSABP. Study data were analyzed from July 2024 to April 2025. Interventions There were no specific interventions based on lumpectomy margin width. Main Outcomes and Measures Lumpectomy margin width data were prospectively collected within 3 months of randomization. A pathology form classified margins as positive (ink on tumor), close (&amp;lt;1 mm), or negative (≥1 mm). For the negative margin subgroup, closest margin width was stated separately. Thus, an ancillary analysis using 1-mm and 2-mm margin width partitions was performed. Results A total of 3104 postmenopausal women (mean [SD] age, 61 [7.8] years) were enrolled in NSABP B-35. In an ancillary analysis, 2707 patients were included in the 1-mm margin width partition group, and 2546 patients were included in the 2-mm margin width partition group. IBTR was the most common first event, occurring in 90 of 2707 patients (3.3%): 24 of 502 patients (4.8%) with a margin width less than 1 mm and 66 of 2205 patients (3.0%) with a margin width greater than or equal to 1 mm. Ten-year unadjusted cumulative incidence of IBTR events was 5.6% vs 4.0% for margins less than 1 mm vs margins greater than or equal to 1 mm ( P = .04). Using 2 mm as the discriminant threshold for margin width, 39 of 879 patients (4.4%) with margins less than 2 mm and 49 of 1667 patients (2.9%) with margins greater than or equal to 2 mm experienced an IBTR first. Ten-year unadjusted cumulative incidence of IBTR events with margins less than or equal to 2 mm was 5.3% vs 3.8% for those with margins greater than 2 mm ( P = .05). In models adjusting for other patient and tumor factors, margin width was not a significant predictor of IBTR risk (2-mm threshold hazard ratio, 1.33; 95% CI, 0.86-2.06). Conclusions and Relevance Results of this ancillary analysis of the NSABP B-35 trial show that absolute differences in IBTR rates using margin width groupings of less than 1 mm or greater than or equal to 1 mm and margin width groupings of less than 2 mm or greater than or equal to 2 mm in postmenopausal women with HR-positive DCIS receiving lumpectomy, WBI, and adjuvant endocrine therapy were small. Omission of reexcision lumpectomies based on margin widths of less than 1 mm or less than 2 mm can be reconsidered in appropriate patients. Trial Registration ClinicalTrials.gov Identifier: NCT00053898

Aims Reverse shoulder arthroplasty (RSA) after prior rotator cuff repair (RCR) is commonly performed for recurrence of pain and arthritic progression; however, the influence of prior RCR timing and technique on outcomes of RSA has not been adequately explored. Our primary aim was to evaluate the relationship between the postoperative American Shoulder and Elbow Surgeons (ASES) score, whether prior RCR was performed open or arthroscopic, and the time interval between RSA and prior RCR. Secondary outcomes were forward elevation (FE) and external rotation (ER). Methods A prospectively collected single-institution shoulder arthroplasty database was queried to identify patients undergoing primary RSA after prior RCR between 2004 and 2022 for non-tumour and non-fracture indications with minimum two-year follow-up. We evaluated the relationship between the postoperative ASES score, FE, and ER stratified by prior RCR approach (open vs arthroscopic) and time between RSA and RCR. Multivariable analysis was used to adjust for potential confounders. Results We included 104 RSAs (99 patients) with a mean 8.8 years (SD 7.3) after RCR and a mean age of 68 years (SD 8.3). Prior RCR was performed arthroscopically in 40 RSAs (38%). Mean follow-up was 4.8 years (SD 2.8). On multivariable analysis, arthroscopic RCR was independently associated with a 13-point greater postoperative ASES score (p = 0.008), 14° greater forward elevation (p = 0.011), and 8° greater external rotation (p = 0.018) compared with open RCR. A ten-year increase in time between RCR and RSA was associated with a seven-point greater postoperative ASES score (p = 0.029) and 5° greater external rotation (p = 0.015). Conclusion A greater time interval between prior RCR and RSA, as well as arthroscopic techniques, is associated with improved outcomes after primary RSA in patients with prior RCR. Cite this article: Bone Joint J 2026;108-B(7):928–935.

Abstract Background Breast cancer chemoprevention is underutilized among high-risk women. We examined whether decision support could increase informed decision making. Methods We conducted a cluster randomized controlled trial to evaluate the effect of a patient-facing decision aid (RealRisks) and provider tool (BNAV) compared with standard education on the number of women with high-risk breast lesions making informed choices. Questionnaires were administered at baseline and 6 and 12 months. The primary outcome was chemoprevention informed choice (defined as adequate knowledge and attitudes congruent with decision) at 6 months. Secondary endpoints included breast cancer risk perceptions, worry, chemoprevention knowledge, decision conflict, and chemoprevention decision. Results Across 31 randomized sites, we enrolled 210 providers, who were primarily breast health specialists. Of these, 24 sites (14 intervention, 10 control) enrolled 412 patients. Among 287 patients evaluable for the primary outcome, there were no statistically significant differences in informed choice between the intervention and control arms at 6 months (35% vs 27%, respectively; P = .20) and 12 months (37% vs 25%, respectively; P = .05). At 6 months, women in the intervention compared with control arm were more likely to have accurate breast cancer risk perceptions (31% vs 21%, respectively; P = .03) and adequate chemoprevention knowledge (33% vs 23%, respectively; P = .04). At 12 months, 52% of women in the control and 50% in the intervention arm self-reported initiating chemoprevention. Conclusion Decision support led to modest improvements in accurate risk perceptions and chemoprevention knowledge but not informed choice. Relatively high chemoprevention uptake was achieved among women with high-risk breast lesions managed mainly by breast health specialists. Trial Registration NCT04496739, https://clinicaltrials.gov/study/NCT04496739?cond=NCT04496739&viewType=Card&rank=1