Citations

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.

White matter hyperintensities (WMHs) are common MRI findings and established markers of cerebral small-vessel disease associated with stroke, cognitive decline, and vascular risk factors. Several studies have suggested that individuals with migraine, particularly migraine with aura (MA), may have an increased burden of WMHs compared with individuals without migraine. Early population-based studies and meta-analyses reported a higher prevalence of WMHs in migraine, whereas more recent large neuroimaging cohorts have reported conflicting findings or no association. Differences in study design, migraine ascertainment, MRI acquisition parameters, WMH quantification methods, and adjustment for vascular risk factors complicate interpretation of the existing literature. An updated systematic review focusing on methodologically comparable population-based cohorts is therefore warranted. The primary objective of this systematic review and meta-analysis is to determine whether adults with migraine have a higher prevalence or burden of WMHs on MRI than non-migraine controls. Secondary objectives include evaluating associations according to migraine subtype (MA vs. migraine without aura and episodic vs. chronic migraine), sex, WMH location, age, and MRI acquisition or WMH quantification methods, as well as examining longitudinal WMH progression where available. We will include population-based cross-sectional or longitudinal cohort studies of adults undergoing brain MRI with sequences suitable for WMH detection. Migraine exposure may be defined using International Classification of Headache Disorders criteria, structured interviews, validated questionnaires, physician diagnosis, or ICD codes. Controls must originate from the same source population. Searches will be conducted in PubMed/MEDLINE, EMBASE, Web of Science, and Scopus. Study selection, data extraction, and risk-of-bias assessment will be performed independently by two reviewers using Covidence, and risk of bias will be evaluated using the ROBINS-E tool. Because WMH burden is reported using heterogeneous metrics across studies, the primary synthesis will use a precision-weighted direction-of-effect approach, in which each study contributes the direction of the association, weighted by statistical precision. Where sufficiently comparable outcomes are available, random-effects meta-analysis will be performed. Sensitivity analyses will explore the influence of diagnostic criteria, MRI field strength, and confounder adjustment. This review will provide an updated and methodologically rigorous synthesis of the evidence on the association between migraine and WMHs.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) TPMT/NUDT15 Pharmacogene Curation Expert Panel (PCEP) conducted a comprehensive review of clinical, laboratory, and computational evidence to determine the clinical function assignments for TPMT and NUDT15 star alleles. These genes are critical for the metabolism of thiopurines, which are widely used in the treatment of cancer and autoimmune disorders. Standardized allele function assignment is essential for predicting metabolizer phenotypes and pharmacogenetics‐guided thiopurine dosing. The work presented here includes the first designation of decreased function alleles for both TPMT and NUDT15 , reflecting new clinical data that demonstrate partial loss of enzymatic activity and reduced dose tolerance. The panel also reclassified several alleles previously assigned uncertain or unknown function. The functional assignments were informed by a standardized framework incorporating clinical data, such as thiopurine tolerance and toxicity, as well as in vitro protein activity, ex vivo enzymatic measurements, and in silico variant effect prediction tools. These updates enhance the precision of genotype‐to‐phenotype mapping and support more personalized thiopurine therapy across diverse patient populations.

Background: Acute otitis media (AOM) is among the most common pediatric infections and a leading indication for antibiotic prescribing. Although current guidelines recommend 5 to 7 days of therapy for children 2 to 5 years of age with uncomplicated AOM, variation in antibiotic duration remains common. We evaluated whether a 5-day antibiotic course was associated with similar short-term outcomes compared with a 7-day course. Methods: We conducted a retrospective multicenter cohort study using electronic health record data from 44 pediatric emergency departments, urgent care centers, and primary care practices within an integrated health care system. Children 2 to 5 years of age with uncomplicated AOM treated with a single oral antibiotic during 2022 were included. The primary analysis compared children prescribed 5 versus 7 days of therapy. Treatment failure was defined as an AOM-related return encounter requiring a new systemic antibiotic prescription within 7 days after completion of therapy (EOT+7). Secondary analyses evaluated outcomes by antibiotic class and prespecified sensitivity analyses. Results: The final analytic cohort included 7528 children; 906 received 5-day therapy, and 1799 received 7-day therapy. Treatment failure occurred in 0.44% and 0.61%, respectively (absolute risk difference: −0.17%; 95% CI: −0.73 to 0.39; risk ratio: 0.72; 95% CI: 0.23-2.26). Findings were consistent across antibiotic-specific and sensitivity analyses. Conclusions: Among children 2 to 5 years of age with uncomplicated AOM, a 5-day antibiotic course was not associated with an increased risk of short-term treatment failure compared with a 7-day course, supporting guideline-concordant prescribing and outpatient antimicrobial stewardship.

ABSTRACT Genetic counselors describe their professional identity as who they are (personal characteristics and attributes), what they do (actions and skills), and what they possess (training and knowledge). A shared multidimensional perspective highlights the transferability of their skills across diverse roles and settings. This qualitative study aimed to identify factors that influence genetic counselors' perceptions and formation of their professional identities. Using Social Identity Theory as a theoretical framework, semi‐structured recorded interviews were conducted with 50 genetic counselors who were purposefully sampled to ensure diversity of personal demographics (gender, race/ethnicity, sexual orientation, disability, and caregiver status), as well as years, settings, and roles in genetic counseling practice. Transcripts were coded and subjected to codebook thematic analysis using NVivo. Professional identity was influenced by internal validation (sense of purpose in work, pride, and confidence), external validation (from other colleagues, work system, degree of autonomy, and patients), one's personal identities (demographics, life experiences, and persona), and connections with others (professional network, peer support, role models, and giving back). Alignment and misalignment of these factors and the perceived collective identity of the profession impacted genetic counselors' sense of belonging to the profession both positively and negatively, respectively. Continued efforts to diversify the profession, as well as expanded opportunities for genetic counselors to work in new settings and roles, require critical reflection and discussion about the collective identity of the genetic counseling profession. The findings of this study can inform the recruitment, training, credentialing, continuing education, and retention of genetic counselors to ensure that genetic counselors, regardless of their personal identities or their work roles or settings, develop and maintain a sense of belonging and commitment to the profession and its values. In turn, the support of professional identity formation can positively impact genetic counselors' job satisfaction, competency, and delivery of healthcare to their patients and the populations they serve.

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.

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.

Introduction: Inclusive hair and skin care are essential for culturally congruent health care; however, hospitalized patients with textured hair and skin of color experience limited access to appropriate products. Nursing staff also report gaps in knowledge related to culturally responsive care of hair and skin. This initiative aimed to improve care through product access and education. Methods: A quality improvement project was conducted at a Midwestern academic medical center. Surveys of nurses, patient care assistants, and employee resource groups informed product selection and education design. Interventions included stocking products and providing education supported by a webpage and video library. Results: Post-education evaluations showed increased knowledge of hair and skin care, along with improved confidence and ability to provide culturally sensitive care. Discussion: Addressing hair and skin care through access to products and education enhances patient care. This model offers a replicable framework to improve inclusive hair and skin care practices.

Importance Limited granular data exist on breast cancer in transgender, nonbinary, and/or gender-diverse (TGD) individuals. Objective To describe patient demographic and tumor clinicopathological variables, clinically relevant risk factors, method of breast cancer detection, treatment characteristics, and locoregional outcomes and to estimate a 5-year breast cancer–specific survival (BCSS). Design, Setting, and Participants This cohort study obtained data on patients treated from 1990 to 2023 from 22 US academic medical centers using institutional databases, electronic medical records, and tumor registries. Included participants were TGD individuals 18 years or older with stage 0 to IV breast cancer. A comparative breast cancer cohort was selected from the 2016 to 2021 Surveillance, Epidemiology, and End Results Program (SEER) breast cancer dataset. Data were analyzed from January to October 2025. Exposure Breast cancer. Main Outcomes and Measures Estimated 5-year BCSS and locoregional recurrence rates. Wilcoxon rank sum and χ 2 tests were used to compare continuous and categorical variables. Kaplan-Meier analysis was used to estimate 5-year BCSS. Results A total of 112 TGD persons (median [IQR] age at diagnosis, 42.5 [36.5-51.0] years; 104 individuals [92.9%] were assigned female at birth) with breast cancer and 1 with bilateral disease were included in the analysis. Forty-three patients (38.4%) used gender-affirming hormone therapy before diagnosis. Among the entire cohort, 58 patients (51.8%) detected their own breast cancer, 68 (60.7%) had a familial breast cancer history, and 16 (14.3%) had a pathogenic germline variant. Tumors were predominantly hormone receptor positive (96 [85.7%]) and early stage (29 [25.7%] ductal carcinoma in situ [DCIS]; 51 [45.1%] stage I). The TGD cohort, compared with patients with breast cancer in the SEER dataset (N = 480 915), was younger (median [IQR] age, 42.5 [36.5-51.0] years vs 62.0 [52.0-72.0] years), had a higher proportion of persons assigned male at birth (8 [7.1%] vs 3522 [0.7%]), more often had progesterone receptor–positive disease (89 [79.5%] vs 335 491 [69.8%]), and presented with earlier-stage disease (eg, DCIS: 29 [25.9%] vs 79 604 [16.6%]). With a median (IQR) follow-up time for the TGD cohort of 38 (24-74) months, 5-year BCSS was favorable at 96.2% (95% CI, 85.3%-99.0%). Conclusions and Relevance This cohort study of TGD patients with breast cancer found that this population was young and often detected their own tumors via self-examination, suggesting opportunities to improve early detection through screening for individuals at elevated risk. Although short-term BCSS appeared favorable, prospective research is essential to define evidence-based guidelines and elucidate long-term outcomes.

Introduction: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease without approved medical therapies. We examined the efficacy and safety of oral vancomycin (OV) in those with PSC. Methods: In this phase 3, 18-month, double-blind, placebo-controlled trial, we randomly assigned adults with PSC and a serum alkaline phosphatase (SAP) greater than 1.5 times the upper limit of normal to placebo or oral vancomycin (OV) with dosages ranging from 125-375 mg four times daily pending biochemical response. The primary endpoint was normalization of SAP. Results: Of the 82 patients who underwent randomization, 73 individuals had at least one outcome assessment. Individuals who withdrew early were less likely to rate their baseline health as excellent or very good (23.4% vs 54.5%, p<0.01) despite having similar PSC prognostic features to those who completed the study. SAP normalization rates were similar (5% placebo, 6.7% OV, p=1.00) after 18 months. Those who received OV had greater reduction in SAP (+1.2% placebo, -21.9% OV, p=0.03). There were no differences in the changes in either the Mayo PSC risk score (-0.1 placebo, -0.1 OV, p=0.88) or liver stiffness values (+0.1 kPa placebo, -4.0 kPa OV, p=0.15). Discoloration of the teeth and tongue was the most common side effect of OV (17.5%). Conclusions: OV was not associated with clinically significant reductions in markers of PSC disease severity. Impairments in quality of life may influence patient retention in clinical trials.