Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis

Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNT Dysregulation

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of beta-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis

Exploring Wearables to Focus on the “Sweet Spot” of Physical Activity and Sleep After Hospitalization: Secondary Analysis

BackgroundInadequate sleep and physical activity are common during and after hospitalization, but their impact on patient-reported functional outcomes after discharge is poorly understood. Wearable devices that measure sleep and activity can provide patient-generated data to explore ideal levels of sleep and activity to promote recovery after hospital discharge. ObjectiveThis study aimed to examine the relationship between daily sleep and physical activity with 6 patient-reported functional outcomes (symptom burden, sleep quality, physical health, life space mobility, activities of daily living, and instrumental activities of daily living) at 13 weeks after hospital discharge. MethodsThis secondary analysis sought to examine the relationship between daily sleep, physical activity, and patient-reported outcomes at 13 weeks after hospital discharge. We utilized wearable sleep and activity trackers (Withings Activité wristwatch) to collect data on sleep and activity. We performed descriptive analysis of device-recorded sleep (minutes/night) with patient-reported sleep and device-recorded activity (steps/day) for the entire sample with full data to explore trends. Based on these trends, we performed additional analyses for a subgroup of patients who slept 7-9 hours/night on average. Differences in patient-reported functional outcomes at 13 weeks following hospital discharge were examined using a multivariate linear regression model for this subgroup. ResultsFor the full sample of 120 participants, we observed a “T-shaped” distribution between device-reported physical activity (steps/day) and sleep (patient-reported quality or device-recorded minutes/night) with lowest physical activity among those who slept 9 hours/night. We also performed a subgroup analysis (n=60) of participants that averaged the recommended 7-9 hours of sleep/night over the 13-week study period. Our key finding was that participants who had both adequate sleep (7-9 hours/night) and activity (>5000 steps/day) had better functional outcomes at 13 weeks after hospital discharge. Participants with adequate sleep but less activity (<5000 steps/day) had significantly worse symptom burden (z-score 0.93, 95% CI 0.3 to 1.5; P=.02), community mobility (z-score –0.77, 95% CI –1.3 to –0.15; P=.02), and perceived physical health (z-score –0.73, 95% CI –1.3 to –0.13; P=.003), compared with those who were more physically active (≥5000 steps/day). ConclusionsParticipants within the “sweet spot” that balances recommended sleep (7-9 hours/night) and physical activity (>5000 steps/day) reported better functional outcomes after 13 weeks compared with participants outside the “sweet spot.” Wearable sleep and activity trackers may provide opportunities to hone postdischarge monitoring and target a “sweet spot” of recommended levels for both sleep and activity needed for optimal recovery. Trial RegistrationClinicalTrials.gov NCT03321279; https://clinicaltrials.gov/ct2/show/NCT0332127

Deploying Digital Health Technologies for Remote Physical Activity Monitoring of Rural Populations With Chronic Neurologic Disease

Objective: The objective of this pilot study was to examine the feasibility of a remote physical activity monitoring program, quantify baseline activity levels, and examine predictors of activity among rurally residing adults with Parkinson disease (PD) or stroke. Design: Thirty-day observational study. Participants completed standardized assessments, connected a wearable device, and synced daily step counts via a remote monitoring platform. Setting: Community-based remote monitoring. Participants: Rurally residing adults with PD or stroke enrolled in the Veterans Health Administration. Intervention: N/A. Main outcome measures: Feasibility was evaluated using recruitment data (response rates), study completion (completed assessments and connected the wearable device), and device adherence (days recording ≥100 steps). Daily step counts were examined descriptively. Predictors of daily steps were explored across the full sample, then by diagnosis, using linear mixed-effects regression analyses. Results: Forty participants (n=20 PD; n=20 stroke) were included in the analysis with a mean (SD) age of 72.9 (7.6) years. Participants resided 252.6 (105.6) miles from the coordinating site. Recruitment response rates were 11% (PD) and 6% (stroke). Study completion rates were 71% (PD) and 80% (stroke). Device adherence rates were 97.0% (PD) and 95.2% (stroke). Participants with PD achieved a median [interquartile range] of 2618 [3896] steps per day and participants with stroke achieved 4832 [7383] steps. Age was the only significant predictor of daily steps for the full sample (-265 steps, 95% confidence interval [-407, -123]) and by diagnosis (PD, -175 steps, [-335, -15]; stroke, -357 steps [-603, -112]). Conclusions: A remote physical activity monitoring program for rurally residing individuals with PD or stroke was feasible. This study establishes a model for a scalable physical activity program for rural, older populations with neurologic conditions from a central coordinating site

Behavioural economics to improve and motivate vaccination in primary care using nudges through the electronic health record: rationale and design of the BE IMMUNE randomised clinical trial

Introduction Annual influenza vaccination reduces disease burden but vaccination rates are suboptimal, with persistent disparities among subpopulations. The purpose of this trial is to evaluate multicomponent behavioural economic nudge interventions to clinicians and patients to increase influenza vaccination. This trial also includes an intensification nudge to reduce disparities in vaccination among older adult, primary care patients.Methods This is a two-part, multisite cluster randomised, pragmatic clinical trial. In the first part, a multicomponent nudge intervention will be tested over approximately 6 months (September 2023–February 2024). The second part consists of a replication trial conducted at an additional site during the following influenza season (September 2024–February 2025). Primary care clinics will be randomised to the nudge intervention or usual care. Eligible clinicians and patients at intervention clinics will receive the intervention, and patients deemed high risk for not receiving a vaccine will be further randomised to receive an intensification nudge. The primary outcome is vaccine completion during the eligible visit and the secondary outcome is vaccine completion within 3 months of the eligible visit.Analysis The effect of the clinic-level nudge intervention on the primary and secondary outcomes will be evaluated using generalised estimating equations (GEEs) with a clinic-level exchangeable working correlation to account for clustering of observations within the clinic. GEE models with an independent working correlation will be used to evaluate the impact of the additional intensification nudge on the primary and secondary outcomes.Ethics and dissemination The University of Pennsylvania Institutional Review Board (IRB) approved this trial and serves as the single IRB of record (IRB #851838). Results will be disseminated via peer-reviewed publication and conference presentations.Trial registration number NCT06057727

A novel mutation expands the genetic and clinical spectrum of MYH7-related myopathies

MYH7 mutations are an established cause of Laing distal myopathy, myosin storage myopathy, and cardiomyopathy, as well as additional myopathy subtypes. We report a novel MYH7 mutation (p.Leu1597Arg) that arose de novo in two unrelated probands. Proband 1 has a myopathy characterized by distal weakness and prominent contractures and histopathology typical of multi-minicore disease. Proband 2 has an axial myopathy and histopathology consistent with congenital fiber type disproportion. These cases highlight the broad spectrum of clinical and histological patterns associated with MYH7 mutations, and provide further evidence that MYH7 is likely responsible for a greater proportion of congenital myopathies than currently appreciated