Citations

ABSTRACT The limited efficacy of current therapies against cholangiocarcinoma (CCA) necessitates the development of novel treatment strategies. Src family kinases (SFKs) contribute significantly to tumor progression and resistance in CCA. Therefore, we investigated the novel, first-in-class SFK ‘OFF’ inhibitor NXP900 in diverse preclinical CCA models, including those with acquired resistance. This study evaluated the therapeutic effects of NXP900 and detailed adaptive molecular responses to SFK inhibitor therapy. We also aimed to identify biomarkers predictive of drug sensitivity using integrated multiomic profiling and develop strategies to overcome resistance. NXP900 inhibited YAP activity through direct inhibition of tyrosine phosphorylation and indirect activation of the Hippo pathway via LATS. These effects were associated with decreased tumor cell viability in CCA cell lines and several in vivo models. Notably, IDH -mutant patient-derived xenograft CCA models were particularly sensitive to NXP900. NXP900 also synergized with gemcitabine/cisplatin chemotherapy, enhancing antitumor efficacy in both in vitro and in vivo models. Multiomic analyses combining transcriptomics, global proteomics, and phosphoproteomics identified molecular features associated with primary response and acquired resistance. IL13RA-AKT signaling was upregulated in resistant models; NXP900 sensitivity could be restored with AKT or IL13RA2 inhibition. Together, these findings demonstrate the therapeutic potential of NXP900 as a novel YAP inhibitor in CCA and support further investigation in a clinical trial. Graphical Abstract

Abstract Despite advances in endoscopic techniques, many colorectal surgeries in the United States are still performed for non-malignant colorectal polyps (NMCRPs). This study evaluated trends, demographic variations, and outcomes of surgeries for NMCRPs among all colorectal surgeries over the past decade. Using the TriNetX nationwide database, we identified adults (≥ 18 years of age) who underwent colectomy or proctectomy for NMCRPs or colorectal cancer between 2013 and 2023. We evaluated the proportion of surgeries performed for NMCRPs, stratified by demographic factors, and compared postoperative adverse events (AEs) between NMCRP and colorectal cancer surgeries. Among 136,721 surgeries, 52,480 (38.4%) were for NMCRPs. The proportion of NMCRP surgeries decreased from 59% in 2013 to 33% in 2023, with the most significant decline between 2013 and 2016. Black individuals showed the highest decrease. Compared with colorectal cancer surgeries, NMCRP surgeries were associated with significantly lower risks of wound, infectious, urinary, pulmonary, gastrointestinal, and cardiac AEs. Although the proportion of NMCRP surgeries has declined, ongoing efforts in education and training are needed to further reduce unnecessary surgeries and improve patient outcomes.

PURPOSE There is growing scientific interest in incorporating patient-reported outcomes (PROs) in early phase dose-finding oncology trials (DFOTs) to assess tolerability, inform dose selection, and guide later stage trial design. However, research indicates that PRO objectives in DFOTs are often unclear. The Incorporating Patient-Reported Outcomes in Dose-Finding Trials-Research Objectives Recommendations (OPTIMISE-ROR) project was established to support trialists to effectively incorporate PROs into DFOTs. METHODS Using the Enhancing Quality and Transparency of Health Research (EQUATOR) Network's methodological framework, guideline development included the following: (1) a methodological review of published DFOTs incorporating PROs; (2) candidate item generation, refined through expert consultation; (3) a two-round international multistakeholder Delphi survey (N = 109 in Round 1 [October 2024]; N = 96 in Round 2 [December 2024]); and (4) an independently chaired virtual consensus meeting (N = 31; January 2025) where multidisciplinary, international experts reviewed and voted to finalize items for inclusion. RESULTS Consensus was reached on six recommendations emphasizing three core PRO tolerability concepts: overall side effect impact, symptomatic adverse events, and overall health-related quality of life. The integration of PROs to inform final dose recommendations in dose escalation and optimization trials should be considered, regardless of trial design. The recommendations highlight the importance of PRO data analysis over time and across dose levels, defining PRO research objectives as descriptive or statistically powered, and assessing PRO-related end points to guide end point selection for subsequent studies. CONCLUSION This foundational guidance outlines key PRO research objectives in DFOTs. By facilitating the systematic integration of PROs, this guidance supports the utilization of patient-centered evidence for the tolerability and efficacy assessment of therapies to inform dose escalation, optimization, and regulatory evaluation—ultimately contributing to the development of safer, more effective therapies.

What was done? A review of artificial intelligence (AI) applications for the imaging of uterine fibroids, endometriosis, and adenomyosis. What was found? AI models can assist with the recognition, segmentation, and localization of uterine fibroids, and the differentiation of benign fibroids and sarcomas. Models can aid in the diagnosis of adenomyosis and endometriosis, and the prediction of the impact of endometriosis on fertility. What the findings mean? Deployed thoughtfully, AI tools could reduce variability, shorten read times, and add objective measurements to routine care. Studies evaluating these models are limited by single-institution designs and continued reliance on expert sonologists and radiologists.

Variability and persistent gaps in reporting have been consistently observed across studies evaluating adverse events in healthcare, dating back to the early days of the patient safety movement. Incomplete descriptions—particularly missing details regarding study design, conduct, methodologies and applied definitions—impede interpretation, hinder critical appraisal and limit reproducibility. These deficiencies not only obstruct a shared understanding of findings but also diminish the overall impact such studies may have on patient safety initiatives and policy development. To address these challenges and enhance the quality of reporting, we developed the SESAME (Standard Elements in Studies of Adverse Events and Medical Error) reporting guideline. SESAME is a 44-item checklist designed to support comprehensive and standardised reporting in studies evaluating potential patient harm. The guideline was developed over a 2-year period by an international, multidisciplinary panel through a consensus-driven process aligned with Enhancing the QUAlity and Transparency Of Health Research Network standards.

Introduction: Glutamic acid decarboxylase 65 (GAD65) antibody-associated temporal lobe epilepsy (GAD65-TLE) is a rare form of autoimmune-associated epilepsy characterized by medically refractory seizures and cognitive decline. Diagnosis typically requires antibody testing and clinical correlation, and treatment options include immunotherapy and antiseizure medications (ASMs). However, many patients experience persistent or worsening symptoms despite ongoing treatment. Case Report: A 20-year-old woman presented with mild cognitive impairment and focal aware seizures that gradually progressed in frequency and severity. A diagnostic workup revealed GAD65-TLE, and the patient began treatment with intravenous methylprednisolone infusions and antiseizure medications within 6 months of her presentation. After 20 months of treatment, the patient was on stable doses of levetiracetam and lamotrigine and finished tapering immunosuppressive therapy with methylprednisolone. The frequency of her focal aware seizures significantly decreased, whereas the focal impaired aware and focal bilateral tonic-clonic seizures resolved. The patient was able to return to all of her previous daily activities. Conclusions: In patients presenting with new-onset seizures characterized by unusual semiology and frequent focal aware seizures, it is crucial to consider GAD65-TLE in the list of potential diagnoses. Delayed diagnosis may lead to resistance to both ASMs and immunotherapy. This case report emphasizes how prompt identification and early initiation of immunotherapy can significantly impact the course of the disease.

Importance Youth mental health crises have been increasing over the last decade, and there is an urgent need for clinicians to be more knowledgeable about patients with high emergency department (ED) utilization. Several disparities in ED utilization and outcomes have already been identified; however, little data exist on disparities affecting youths with histories of out-of-home placement (OOHP). Objective To explore whether history of OOHP is associated with increased length of stay among child and adolescent patients who present to the emergency department with psychiatric symptoms. Design, Setting, and Participants This retrospective, electronic health record (EHR)–based, cross-sectional study included patients aged 17 years or younger with a child and adolescent psychiatric consultation placed in the Mayo Clinic Rochester ED between January 1, 2021, and June 30, 2024. The Mayo Clinic Rochester is a tertiary referral center that serves as a regional hub for both primary and specialized psychiatric care. Main Outcomes and Measures The primary outcome was the length of stay in the ED. Secondary outcomes were use of physical and pharmacological restraint. Associations between OOHP and length of stay were examined via linear mixed-effects regression models with length of stay log transformed. Results Of the 1572 care encounters (median [IQR] age, 14,9 [13.3-16.3] years) among 1119 unique patients, there were 1244 with no history of OOHP and 328 with history of OOHP. Among the OOHP group, 158 (48%) were male and 170 (52%) female; 11 (4%) American Indian or Alaska Native, 7 (2%) Asian, 49 (16%) Black, 43 (14%) Hispanic, and 222 (71%) White. Among the 1244 encounters without OOHP, 820 (66%) were among female patients and 423 (34%) male; 21 (2%) American Indian or Alaska Native, 47 (4%) Asian, 121 (10%) Black, 125 (10%) Hispanic, and 971 (80%) White. Children and adolescents with history of OOHP were observed to spend 24% (95% CI, 12%-36%) more time in the ED even when adjusting for age at admission, sex, insurance, number of prior diagnoses, presenting concerns, and reasons for prolonged boarding ( P = .004). Children and adolescents with history of OOHP had 2.05 (95% CI, 1.69-2.48) higher odds of being physically restrained ( P < .001) and 2.15 (95% CI, 1.79-2.58) higher odds of receiving pharmacologic restraints ( P < .001) while in the ED. Conclusions and Relevance In this cross-sectional study of 1572 care encounters among 1119 patients, history of OOHP was associated with longer lengths of stay in the emergency department for children and adolescents who presented for mental health concerns. The findings highlight the need for further research on ways to mitigate the risk of extended emergency department stays for children with OOHP.

Background: Running often elicits stress urinary incontinence (SUI) in parous athletes. While cadence retraining improves running biomechanics, its impact on incontinence is unclear. This feasibility study assessed the implementation and preliminary effects of a 6-week cadence retraining program in parous female runners with SUI. Methods: A total of 8 participants with self-reported SUI and a preferred running cadence ≤ 170 steps/minute underwent treadmill testing before and after the intervention. The program involved a 6-week cadence retraining program using a Garmin Forerunner 55 watch. Feasibility was assessed across 6 domains. Running outcome measures included cadence and vertical oscillation. SUI outcome measures included the Questionnaire for Urinary Incontinence Diagnosis and Urinary Distress Inventory-6 scores. Paired t-tests were conducted (α = .05). Results: Following the 6-week program, feasibility outcomes supported the viability of study procedures and high adherence. Statistically significant increases in cadence ( P = .016) and decreases in vertical oscillation ( P = .019) and concomitant decreases in Questionnaire for Urinary Incontinence Diagnosis ( P = .013) and Urinary Distress Inventory-6 ( P = .042) scores were observed. Discussion: This study demonstrated the feasibility and acceptability of a 6-week cadence retraining program for parous runners with SUI. Given the growing movement to foster athleticism after pregnancy, these findings will appeal to physical therapists searching for acceptable treatment options for SUI in parous runners. Preliminary running mechanics and SUI symptoms warrant a larger randomized controlled trial. A power analysis estimated a sample size of 66 participants for a future full-scale efficacy study.

BACKGROUND AND OBJECTIVES: Surgeon-team familiarity is a critical factor that affects surgical outcomes. The relationships between familiarity and surgical outcomes are varied, and an operational definition of this measure remains underdeveloped. This study creates an effective time-based measure of surgeon-team familiarity and assesses its association with clinical and operational outcomes for neurosurgery. METHODS: Retrospective analysis of 9049 neurosurgery cases performed at 2 campuses of a tertiary academic medical center over a 3-year timeframe was conducted. This study measures normalized case duration as a proxy for operational performance and 30-day postoperative complications for clinical outcomes. Multivariate linear regression and logistic regression were used to analyze relationships between surgeon-team familiarity and surgical outcomes, with risk factors as control variables for case mix. RESULTS: For normalized case duration, the coefficient of surgeon-team familiarity is negative (β = −0.015, P = .03), but the squared term exhibits a positive relationship (β = 0.049, P = .003). The overall regression is statistically significant ( R 2 = 0.046, adjusted R 2 = 0.045, P < .001). The logistic regression shows that surgeon-team familiarity scores are negatively correlated (odds ratio = 0.356, 95% CI [0.126, 0.987]) with the risks of postoperative complications. It is statistically significant and explains between 2.4% (Cox & Snell R Square) and 6.0% (Nagelkerke R Square) of the variance for postoperative complications. CONCLUSION: This study found that surgeon-team familiarity is positively associated with neurosurgery outcomes. Teams familiar with the surgeons will likely improve operational performance and reduce the risk of postoperative complications, whereas too much familiarity may lengthen the case duration. Surgical practice leaders can use electronic health record data to define appropriate familiarity scores and incorporate key metrics when developing surgical team assignments for optimal operating room performance.