Trials

Background Simon two-stage designs for binary endpoints and their time-to-event analogues, including the Kwak and Jung method, rely on a fixed null benchmark. Their Type I error control is valid only when that benchmark is correctly specified. In practice, historical benchmarks are often inconsistent due to small samples, population heterogeneity, changing eligibility criteria, and evolving standards of care. Even modest misspecifications can substantially inflate the Type I error rate, leading to costly advancement of ineffective treatments. Methods We propose the Interval-Null Robust (INR) two-stage design framework that accounts for uncertainty in the historical null benchmark. We define the null hypothesis as a plausible range of clinically uninteresting values: p[isin][p0L, p0U] for binary endpoints and {lambda}[isin][{lambda}0L, {lambda}0U] (or equivalent survival probabilities) for time-to-event endpoints. Type I error is controlled uniformly over the full null interval: sup{theta}[isin]{theta}0 Pr{theta}(Go) [≤] . Under the monotonicity of the Go probability, the supremum occurs at the least favorable null configuration - p0U and {lambda}0L - but the design is not reduced to a point-null formulation. The interval defines the uncertainty set for error control and is used in selecting among feasible designs through robust criteria such as worst-case regret or minimal average expected sample size. Results Across representative planning scenarios for both endpoint types, classic designs calibrated to a single benchmark exhibit substantial Type I error inflation when the true null parameter exceeds the assumed planning value. INR designs maintain the nominal Type I error rate across the full null interval, directly addressing this vulnerability to benchmark misspecification. The robustness-efficiency trade-off can be managed through design constraints and robust optimization criteria while preserving uniform Type I error control. Conclusions INR two-stage designs offer a transparent framework for addressing historical control uncertainty in single-arm Phase II trials. By replacing reliance on a fixed benchmark assumption with a more realistic interval of clinically plausible null values, INR design reduces the risk of false-positive Go-decisions caused by benchmark misspecification. INR applies to both binary and time-to-event endpoints and is implemented in the open-source INRDesign R package and accompanying interactive Shiny app.

BackgroundLarge-scale estimates of animal-to-human drug translation and the study characteristics associated with successful translation remain limited. The expanding preclinical literature also challenges manual evidence synthesis. We developed a natural language processing (NLP) pipeline to structure and link preclinical and clinical evidence at scale. MethodsIn this retrospective meta-research study, we analysed more than 500,000 neuroscience-related animal drug studies from PubMed and linked them to clinical trial and regulatory approval data. NLP methods extracted drug, disease, and experimental design characteristics from abstracts and full texts. Translation was defined as progression to completed phase III/IV trials or regulatory approval. Logistic regression assessed associations between preclinical study characteristics and successful translation. FindingsAmong 291,624 drug entities identified in animal studies, 6{middle dot}7% entered clinical development and 3{middle dot}1% reached phase III/IV trials or regulatory approval. At the drug-disease level, 4{middle dot}4% entered clinical development and 1{middle dot}9% achieved translation. Restricting analyses to successfully linked ontology entities increased estimates to 11{middle dot}3% and 4{middle dot}1%, respectively. Male-only animal studies predominated, whereas reporting of randomisation, blinding, and sample size calculations remained limited. Testing across multiple species and reporting blinding were associated with higher odds of successful translation. InterpretationOnly a minority of interventions tested in animals progress to advanced clinical development or regulatory approval. Greater species diversity and blinding were associated with improved translational success. NLP-based evidence synthesis may support scalable evaluation of translational research and identification of potentially modifiable research practices. FundingSwiss National Science Foundation, UZH Digital Entrepreneurship Fellowship, Universities Federation for Animal Welfare. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched the literature for studies quantifying large-scale animal-to-human translation and factors associated with successful translation. Existing work was mainly limited to specific diseases, interventions, or manually curated datasets, and large-scale linkage of animal and clinical evidence remained limited. Added value of this studyWe developed a natural language processing pipeline linking more than 500,000 animal studies to clinical trial and regulatory approval data. The study provides large-scale estimates of translation and identifies experimental characteristics associated with successful translation. Implications of all the available evidenceThe findings suggest that only a minority of interventions tested in animals progress to advanced clinical development or regulatory approval. Greater species diversity and reporting of blinding were associated with improved translation. Automated evidence synthesis may support more systematic evaluation of translational research practices.

Introduction: Osteoarthritis (OA) is a chronic joint disease, often leading to pain, joint stiffness and impaired function. The first metatarsophalangeal (MTP-1) joint is the most frequently affected joint in foot OA. Footwear interventions might have potential to reduce pain for people with MTP-1 joint OA. The aim of this study is to determine the effectiveness and cost-effectiveness of orthopaedic modifications to off-the-shelf footwear in addition to usual care, compared to usual care alone, for people with MTP-1 joint OA. Methods and analyses: We perform a pragmatic, non-blinded, two-armed, parallel-group, randomised controlled trial (RCT). A total of 136 people with MTP-1 joint OA and presence of foot pain are recruited. Participants are randomised to orthopaedic modifications to off-the-shelf footwear in addition to usual care or to usual care alone. The footwear modifications comprise a combination of sole-stiffening, rocker sole adjustments and custom-made insoles. During a 12-month follow-up period, participants receive monthly questionnaires. Primary outcomes include walking pain at 6-month follow-up and quality-adjusted life years and societal costs at 12-month follow-up. Secondary outcomes include walking pain at 12-month follow-up and foot health, physical activity level, patient acceptability and self-reported recovery at 6- and 12-month follow-up. Intention-to-treat and per-protocol analyses will be performed using (generalised) linear mixed models. Ethics and dissemination: The study is approved by the local Medical Ethics Committee of the Erasmus MC University Medical Center Rotterdam, The Netherlands (MEC-2024-0615). Prior to study participation, participants provide informed consent. Results will be disseminated amongst researchers through peer-reviewed scientific articles and presentations at conferences; and amongst people with MTP-1 joint OA and healthcare professionals through layman articles in newsletters, on websites and on social media. Discussion: This is the first RCT to investigate the effectiveness and cost-effectiveness of orthopaedic modifications to off-the-shelf footwear in addition to usual care, compared to usual care alone for people with MTP-1 joint OA. Study findings will support healthcare professionals in making substantiated decisions in the treatment of people with MTP-1 joint OA.

Introduction: A prominent symptom of post-acute sequelae of SARS-CoV-2 infection (i.e., Long COVID) is exercise intolerance with or without post-exertional malaise (PEM). PEM is characterized by the worsening of both symptoms and function following even minor physical or mental exertion, with symptoms typically worsening 12 to 48 hours after activity and lasting for days or even weeks. Individualized, supervised cardiopulmonary rehabilitation is considered a safe and effective intervention for many cardiac and pulmonary conditions, and has been effective in gradually improving function in previously hospitalized and nonhospitalized patients with severe COVID-19. While traditional cardiopulmonary rehabilitation approaches appear helpful in some situations, the exercise intolerance symptoms experienced by many individuals with Long COVID may require a different approach, especially when attempts to increase physical activity result in PEM. No clear consensus exists on the optimal treatment of PEM, and no major studies have evaluated the efficacy in individuals with Long COVID of either carefully supervised, individualized cardiopulmonary rehabilitation programs for exercise intolerance without significant PEM or activity pacing interventions designed to treat or prevent PEM. Methods and Analysis: The Researching COVID to Enhance Recovery Clinical Trials (RECOVER-CT) initiative funded by the National Institutes of Health (NIH) included a prospective, multicenter, randomized controlled platform trial (RECOVER-ENERGIZE) designed to assess two interventions in patients with Long COVID and exercise intolerance: (1) cardiopulmonary rehabilitation for patients without significant PEM and (2) structured activity pacing to prevent or reduce PEM in participants who experience the symptom. The intervention duration will be 12 weeks. The primary endpoints for the trial include the Endurance Shuttle Walk Test as a measure of endurance capacity for the cardiopulmonary rehabilitation intervention and a modified version of the DePaul Symptom Questionnaire - Post-Exertional Malaise for the pacing intervention. Assessments will be completed at baseline, middle of intervention, end of intervention, and 12 weeks after completion of the intervention, and include physical performance measures and patient-reported surveys. Ethics and Dissemination: The RECOVER-ENERGIZE trial protocol has been approved by an institutional review board (Advarra), and written informed consent will be obtained from all participants prior to enrollment. The trial is registered on ClinicalTrials.gov (NCT06404047). Formally assessing PEM and developing a structured activity pacing intervention delivered by local pacing coaches are novel features of this trial. Results will be disseminated through peer-reviewed publications, presentations at scientific conferences, and communication with participants, patient advocacy organizations, and the broader Long COVID community. De-identified participant data will be made available through the NIH RECOVER data repository in accordance with NIH data-sharing policies. If successful, this protocol will provide accessible tools that clinicians can use to address exercise intolerance and PEM in patients with Long COVID.

Introduction: While growing evidence suggests that music training supports child development, few long-term randomized controlled trials (RCTs) have rigorously tested these claims. Moreover, it remains unclear whether the benefits are confined to music-specific domains or extend to higher-order cognitive functions such as inhibitory control (IC), a core executive function associated with long-term outcomes in academic achievement, career success, socio-emotional health, and physical well-being. This paper presents the protocol for the Extracurricular Activity and Child Early Learning and Development (EXCEL) trial, an RCT designed to assess the feasibility of a long-term music training program focusing on the brain and behavioral correlates of IC. Methods: A total of 126 children, aged 6 to 8 years and residing in neighborhoods with limited resources in Los Angeles, were individually randomized to either a music (intervention) or theatre (active control) after-school program. Both programs were delivered over 24 months by established community arts organizations. Eligibility criteria included: average intellectual functioning, no major medical or psychiatric conditions, and MRI eligibility. Children with prior formal music training exceeding six months or severe hearing impairment were excluded. Before the intervention began, all participants completed baseline behavioral and neuroimaging assessments. The primary trial aim was to assess the effects of extended music training, relative to theatre training, on changes in measures of IC (i.e., Go/No-Go task and delayed gratification) and related neural functional activation. A secondary interim aim of the trial was to evaluate the feasibility of conducting a long-term RCT of music education in a first cohort, measured by participant retention, adherence to the program, willingness to continue at the 12-month mark, and fidelity. Progress: Recruitment, screening, baseline testing, randomization, and program enrollment began in August 2022, and after-school programming began in October 2022. The randomized interventions and all data for the first cohort (N = 42) have been collected. Intervention and active control programs for a second cohort are ongoing and will end in Fall 2026. Discussion: This paper reports the EXCEL trial protocol and provides feasibility estimates for implementing a long-term randomized controlled trial of music training in real-world, community-based settings with children. While similar neuroimaging RCTs are currently underway in Europe, the EXCEL trial is among the first in the United States to integrate longitudinal neuroimaging with arts intervention. Findings will inform the viability of scaling such programs and contribute to our understanding of how sustained music engagement may influence the development of inhibitory control circuitry in childhood.

ImportanceChildren with Down syndrome (DS), a genetic condition associated with neuromotor impairments, walk [~]1 year later than typically developing peers. Treadmill training is the most successful known intervention for accelerating walking onset in DS. Overground stepping with mobility devices better mimics critical properties of real-world walking, but it is unknown how overground stepping develops in pre-walking infants with DS. ObjectiveWe aimed to characterize the developmental trajectory of stepping quantity and quality in supported overground stepping compared to supported treadmill stepping. We also measured infants ability to self-propel in the walker. Finally, we assessed caregivers perspectives on both devices. DesignWe tested infants at 10, 13, 16, and/or 19 months of age. SettingThis study occurred in a university laboratory in the United States. ParticipantsWe tested 31 pre-walking infants with Down syndrome across 69 sessions. ExposureAt each session, infants completed four trials per task (treadmill and walker) and a test of self-propulsion in the walker. Main Outcomes and MeasuresWe measured step quantity (overall step rate and alternating step rate), step quality (percentage of steps that were alternating, forward, and flat-landing), the ability to self-propel the walker, and caregiver perspectives on both devices. ResultsStep quantity increased with age and varied by task--infants took more steps per minute in the walker compared to the treadmill. Moreover, steps were of equal or higher quality in the walker. By 16 months, about half of infants could self-propel. Caregivers viewed both devices favorably, though the majority preferred the walker for home and/or community use. ConclusionsOverground walkers promote more stepping than a treadmill in pre-walking infants with DS, with stepping of similar or higher quality. Caregivers feel positively about overground walkers. RelevanceOverground stepping using a suspension walker shows promise as an intervention for pre-walking infants with Down syndrome.

Purpose: To identify, through iterative user-centered design, the auditory biofeedback requirements and sound preferences supporting gait training in children with cerebral palsy (CP), and to determine which feedback variables, sound mappings, and sound types yield clinically viable and movement-interpretable paradigms. Methods: The iterative process spanned two prototype phases. Prototype A comprised seven paradigms demonstrated to two experienced physiotherapists (Workshop 1A). Two of these were subsequently discarded owing to poor sound-movement interpretability and two were modified. Six paradigms were added to Prototype B, demonstrated to four children, five parents, and one therapist (Workshop 1B) and two therapists (Workshop 2B). Data were analyzed using systematic text condensation. Results: Within-child sound preferences varied with energy level and sensory state on a given day. Sound-movement interpretability tended to suffer for paradigms with greater acoustic complexity (e.g. computer-generated music). Therapists endorsed a repertoire spanning both movement quality and movement quantity targets. Participants independently proposed paradigms rewarding restrained and controlled movement, a feedback category absent from the current prototype. Conclusions: Session-level calibration is preferable to fixed sound profiles, requiring real-time interface support for paradigm adjustment. Acoustic complexity must remain subordinate to movement-sound interpretability. Paradigms targeting movement restraint are a development priority unaddressed in the literature.

Abstract Background: Management of high sagittal split fractures of the mandibular condyle remains a formidable surgical chal-lenge due to limited visualization, technical difficulties in direct in-situ fixation, and the high risk of secondary avascular necrosis or temporomandibular joint (TMJ) ankylosis. Objectives: To evaluate the clinical outcomes and technical efficacy of the "Motamed Technique, "a standardized protocol involving extracorporeal rigid internal fixation followed by anatomical re-implantation for complex high condylar split fractures. Methods: A retrospective evaluation was conducted on a clinical series of 11 consecutive patients (9 males, 2 females) presenting with severe, displaced high sagittal split condylar fractures secondary to high velocity trauma. In all cases, the fragmented condylar segments were completely retrieved, stabilized ex vivo on a back table using a titanium X-shaped 3D mini-plate system (1.5 mm), and meticulously reimplanted into the glenoid fossa. Total cold ischemia time was strictly maintained between 10 to 20 minutes. The postoperative longitudinal follow-up period ranged from 6 to 11 months (mean duration: 8.6 months). Comprehensive post-operative tracking included clinical parameter checking, 3D Computed Tomography (3D-CT), and high-resolution dynamic Magnetic Resonance Imaging (MRI) to analyze ony union, vertical ramus height restoration, and articular disc kinetics. Results: All 11 patients achieved predictable and stable functional outcomes. At the definitive milestones, the mean maximum mouth opening (MMO) was 37.3 mm (range, 33-45 mm), demonstrating excellent vertical clearance and stable lateral/protrusive excursions. Pre-traumatic stable centric occlusion was perfectly restored and maintained in 100% of cases (n=11), with zero incidence of postoperative open bite or crossbite. Facial nerve motor function was entirely pre-served across the cohort (100% House-Brackmann Grade I at final follow-up). Longitudinal 3D-CT scans confirmed complete osseous union and anatomical alignment in all cases by the 4th postoperative month, with no radiographic evidence of condylar head resorption or hardware failure. Follow-up MRI findings demonstrated the preservation of TMJ dynamics, functional articular disc movement (with stable reduction in 3 cases), and a total absence of avascular necrosis or intra-articular effusion. No cases of TMJ ankylosis were reported. Conclusion: The Motamed Technique provides a reliable, reproducible, and biologically sound approach for managing intricate high condylar split fractures. By utilizing systematic extracorporeal mini-fixation, this protocol effectively overcomes intraoperative spatial limitations while ensuring excellent long-term anatomical stability, stable occlusion, and functional joint mobility without compromising facial nerve integrity.

Abstract Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular benefit in type 2 diabetes and obesity, with recent observational data suggesting favorable associations after transcatheter aortic valve replacement. Whether similar associations exist after surgical aortic valve replacement (SAVR) is unknown. Methods: Retrospective propensity-matched cohort analysis using the TriNetX U.S. Collaborative Network. Adults with type 2 diabetes or obesity (BMI [≥]30 kg/m2) undergoing SAVR were categorized by GLP-1 RA exposure (any use within 3 months before through 1 year after SAVR) versus no use. One-to-one matching was performed on 44 covariates. Primary outcomes were 1-year all-cause mortality, heart failure, acute kidney injury, acute myocardial infarction, cerebral infarction, and atrial fibrillation. Sensitivity analyses included 30-day landmark restriction and falsification outcomes. Results: After matching, 1,984 patients were retained per cohort. GLP-1 RA use was associated with lower 1-year risks of all-cause mortality (4.8% vs 10.4%; HR, 0.44; 95% CI, 0.34-0.56), acute kidney injury (6.9% vs 10.1%; HR, 0.65; 95% CI, 0.49-0.85), myocardial infarction (3.0% vs 5.1%; HR, 0.57; 95% CI, (0.40-0.82), heart failure (11.3% vs 15.7%; HR, 0.68; 95% CI, (0.51-0.90), and atrial fibrillation or flutter (10.1% vs 13.9%; HR, 0.69; 95% CI, 0.54-0.90; all P[≤]006). Cerebral infarction did not differ. In landmark analysis, mortality, heart failure, and acute kidney injury associations persisted; myocardial infarction and atrial fibrillation associations were attenuated. Falsification outcomes were null. Conclusions: Perioperative GLP-1 RA use was associated with lower 1-year cardiovascular event rates after SAVR. These hypothesis-generating findings support prospective randomized investigation.

Background: The global SARS-CoV-2 pandemic disrupted healthcare systems worldwide, raising concerns about its impact on clinical research. Early reports suggested reductions in participant enrollment, interruptions to ongoing trials, and challenges to protocol adherence, yet the magnitude and duration of these operational disruptions remain unclear. Methods: We conducted a registry-based analysis comparing clinical trials during the COVID-19 pandemic (December 2019 to November 2022) with a matched pre-pandemic cohort (December 2016 to November 2019). Studies were included if they reported any modifications to trial status, enrollment, or protocols during the study periods. Key variables included trial stoppage, enrollment changes, and adoption of remote or hybrid procedures. Results: The global SARS-CoV-2 pandemic resulted in widespread disruptions to trial operations with 13,323 clinical trials terminated, suspended or withdrawn over the course of the pandemic, a 38% increase compared to the 9,665 trials that stopped in the 3 years prior to the pandemic. Registries indicated a sharp decline in new participant enrollment across geographic regions and therapeutic areas, with partial recovery in later months. Review findings highlighted barriers including patient inaccessibility, staff redeployment, and supply chain interruptions. Conclusions: The pandemic caused system-wide operational shocks that compromised trial timelines and may have downstream methodological consequences. Recovery in enrollment does not imply restoration of pre-pandemic protocol fidelity or outcome ascertainment. Standardized reporting of disruptions, proactive contingency planning, and resilient trial designs are needed to maintain data integrity during large-scale disruptions and to support reliable evidence generation.

Background: Pretest genetic counseling (GC) is recommended in conjunction with genetic testing (GT) for cardiovascular (CV) indications, yet access to CVGC is limited leading to delayed GT. Posttest GC could increase GC and GT access but requires efficient pretest education that supports both informed GT decision-making and robust GT uptake. Methods: We developed four indication-tailored online CV genetics education videos and deployed them in a 3-arm randomized trial comparing pretest vs. posttest outpatient CVGC (RESEQUENCE-GC, NCT05422573). Participants were 1:1:1 randomized to pretest video education plus an optional (efficiency arm) or required (flipped arm) phone call with a genetic counselor and planned posttest CVGC or to standard pretest CVGC (SOC arm). Questionnaires administered at baseline and post-education included the CV Multidimensional Model of Informed Choice [MMIC] to quantify GT knowledge and informed GT choice. Results: 389/767 (50.7%) adults aged 18-80 (mean 51.2{+/-}14.9 years) scheduling a first CVGC appointment consented to RESEQUENCE-GC and completed the baseline questionnaire. Efficiency arm participants (video education + optional phone call) were most likely to complete pretest education (134, 97.4% efficiency; 107, 85.6% flipped; 111, 87.4% SOC, p=0.0012) and elect GT (131, 95.6% efficiency; 105, 84.0% flipped; 107, 84.2% SOC, p=0.0036). Few (4, 2.9%) efficiency arm participants requested an optional pretest phone call. Most flipped arm participants (90, 84.1%) had no post-video questions, consistent with the 97 second [IQR: 65s-145s] median call duration. CV genetics knowledge was high post-education (median 8 [IQR 7,8]/8 MMIC items correct). Only video-based pretest education was associated with a significant increase in knowledge (p<0.0001). Nearly all participants made an informed GT choice with no difference between intervention (95.6%) and SOC (90.4%) arms (p=0.074). Conclusions: Tailored, online video pretest education can enhance CV GT uptake, support informed GT decision-making, and be integrated into efficient pretest workflows, suggesting utility in scalable posttest CVGC.

Introduction Spinal muscular atrophy (SMA) is a monogenic neuromuscular disease caused by mutations in the survival motor neuron 1 (SMN1) gene. Onasemnogene abeparvovec is a U.S. FDA-approved single-dose gene therapy for SMA. Both its intravenous formulation (Zolgensma, approximately USD 2.13 million per patient) and intrathecal formulation (Itvisma, around USD 2.59 million per patient) are prohibitively expensive, substantially limiting accessibility in low- and middle-income countries (LMICs). We conducted a clinical study of vesemnogene lantuparvovec, an alternative to onasemnogene abeparvovec developed for use in LMIC settings. Methods Sixteen patients with SMA, including 8 with type 1 SMA and 8 with type 2 SMA, received a single intrathecal administration of vesemnogene lantuparvovec. Eleven patients were treated with a low dose (1.5 * 10^14 vg) and five with a high dose (3.0 * 10^14 vg). The primary endpoints were safety and efficacy, assessed by changes from baseline in developmental gross motor milestones according to the World Health Organization criteria. Overall survival was primarily evaluated in type 1 SMA patients. This trial was registered with ClinicalTrials.gov NCT06288230. Results As of the March 2026 cutoff date, 15 of 16 treated patients had completed at least 12 months of follow-up after treatment, while the remaining one type 1 SMA patient died of disease progression at month 6 post-treatment. At 12 months post-treatment, among the surviving 7 patient with type 1 SMA, the median age was 21.6 months (range, 16.1 to 32.3 months). Among the 16 treated patients, the median age at diagnosis was 4.4 months (range, 0.0 to 18.0 months), and the median age at dosing was 10.7 months (range, 2.8 to 22.5 months). All patients experienced at least one AE. Thirty-one AESIs were reported in 13 patients, including hepatotoxicity, thrombocypenia-related events and cardiac events. No patient required prolonged prednisolone prophylaxis. SAEs, including pneumonia, lower respiratory tract infection, upper respiratory tract infection, and haemorrhagic diarrhoea, occurred in 5 of 8 (63%) patients with type 1 SMA and 2 of 8 (25%) patients with type 2 SMA. Two patients with type 1 SMA required invasive ventilation, and one of whom subsequently died. At 12 months post-treatment, 11 of 16 treated patients (69%) gained at least one new WHO motor milestone versus baseline, including 3 type 1 and 8 type 2 SMA patients; one type 2 patient gained six WHO motor milestones and achieved independent walking. Conclusions In patients younger than 24 months of age with type 1 or type 2 SMA, a single intrathecal dose of vesemnogene lantuparvovec was safe and generally well tolerated and was associated with improvements in developmental gross motor milestones compared with outcomes observed among referred but untreated patients. Additional studies are required to further evaluate the long-term safety and efficacy of this gene therapy.

Objective: To assess the feasibility and acceptability of VISON-ACT, a standalone, mobile app psychosocial intervention for psychological distress in individuals with primary open-angle glaucoma (POAG). Design: Single-arm pilot. Participants: Patients (N=28) with a diagnosis of POAG, self-reporting at least mild (>3) distress on the 4-item Patient Health Questionnaire, were recruited from the Duke Eye Center between April 2025-December 2025. Methods: Patients (n=28) were consented and completed a baseline (A1) self-report assessment. VISION-ACT was comprised of 6 weekly modules. Follow-up self-report assessments occurred at post- (A2) and 1-month post-intervention (A3) and included measures of psychological distress, vision and health-related quality of life, psychological flexibility, disease acceptance, self-efficacy for symptom management, mindfulness, and social support. Participants were invited to complete an exit interview at 1-month post-intervention to gather qualitative feedback on the VISION-ACT protocol. Descriptive statistics were used to assess feasibility and acceptability metrics and patterns of pre-post change on patient reported outcomes were explored with linear mixed mdels using R Statistical Software. Main Outcome Measures: Feasibility (target accrual (n=25) in 12 months, <20% attrition at post-intervention); Acceptability (>75% reporting use of VISION-ACT skills or ideas at post-intervention, >80% reporting M>3.00/4.00 at post-intervention on the Client Satisfaction Questionnaire); Psychological Distress (Hospital Anxiety and Depression Scale [HADS], Subjective Units of Distress Scale [SUDS]). Results: VISION-ACT was highly feasible; accrual target was surpassed (N=28) in 6 months, and attrition was low (3.85%) at post-intervention (A2). Acceptability was strong with 100% of participants reporting use of VISION-ACT skills or ideas at A2 and M=3.27/4.00 intervention satisfaction. Adherence was remarkable with 88.5% of participants completing all six VISION-ACT modules. Pre-post change patterns were in the expected direction for psychological distress (HADS A1 M=13.88, A2 M=11.21; SUDS A1 M=35.54, A2 M=26.46) and all other patient-reported outcomes across baseline, post- and 1-month post-intervention assessments. Data on participant perspectives highlighted valuable aspects of VISION-ACT, and areas for refinement. Conclusions: Robust feasibility and acceptability data seen here provide support a fully-powered, randomized trial to evaluate the efficacy of VISION-ACT for reducing psychological distress and improving related patient-reported and clinical outcomes.

Purpose: Unilateral breast cancer (BC) patients scheduled for mastectomy often choose to undergo contralateral prophylactic mastectomy (CPM), despite substantial declines in contralateral breast cancer (CBC) risk in recent decades. Models predicting absolute risk of future CBC can aid informed decision-making about CPM. CBCRisk is an existing CBC absolute risk prediction model trained on unilateral BC patients regardless of whether they had mastectomy. Here we developed CBCRisk-Mastectomy, tailored specifically to BC patients scheduled for mastectomy and considering CPM. Patients and Methods: We used data on BC patients who underwent mastectomy to treat their first BC from two nationally representative sources: Breast Cancer Surveillance Consortium (BCSC) and Surveillance, Epidemiology, and End Results (SEER) cancer registry. We imputed missing data in the BCSC sample and used conditional logistic regression models, trained on 2,660 BC patients (665 CBC cases) from BCSC, to identify predictors and estimate relative risks (RRs). These were combined with attributable risks and CBC incidence rates estimated from SEER to obtain absolute risk. Cross-validation was used to internally validate CBCRisk-Mastectomy and compare with CBCRisk. Results: CBCRisk-Mastectomy has nine predictors: first BC type, lobular carcinoma in situ status, estrogen receptor status, tumor stage, breast density, age at BC diagnosis, family history of BC, age at first birth, and body mass index. The areas under the curve and their 95% confidence intervals for 5-year predictions for CBCRisk-Mastectomy and CBCRisk were 0.62 (0.59, 0.65) and 0.58 (0.55, 0.61), respectively. Conclusions: CBCRisk-Mastectomy may aid clinicians in counseling BC patients scheduled for mastectomy, enabling improved decision-making regarding CPM.

Background: High school students may be able to communicate health topics to peers and adults. Yet, few studies have evaluated the role of high school students in community health initiatives, making them an underutilized group for disseminating health information. We pilot tested stroke education across five high schools using varied delivery approaches as a preliminary step toward evaluating youth stroke education to improve community health. Methods: In April-May 2025, five high schools in Connecticut and New York participated in stroke education. The format was designed to fit the needs of each school and included an 8-session classroom curriculum (Derby, CT), after-school club meetings (New Haven, CT; Long Island, NY), and one large assembly (Bridgeport, CT). Developed by teachers and neurology providers, the curriculum covered stroke risk factors, symptoms, and emergency response. Students completed a 15-point assessment adapted from the validated Stroke Action Test before, immediately after, and 4-6 weeks post-intervention; data were collected between April and July 2025. Results: Of 112 students completing the pre-test, 99 (88%) completed the immediate post-test and 51 (46%) the delayed follow-up. Average scores rose from 47% pre-intervention to 75% post and 70% at 4-6 weeks. All schools scored <50% on pre-tests suggesting poor baseline stroke knowledge. Conclusion: This pilot suggests that stroke education can be delivered to high school students across varied settings and may support knowledge gains up to 6 weeks. Limitations included small sample sizes and missing follow-up data. If validated in larger studies, this adaptable, teacher-supported approach could offer a scalable public health strategy for improving community stroke preparedness.

BackgroundThe pivot shift (PS) test is the most specific clinical examination for anterolateral rotational instability in ACL-deficient knees, yet grading remains subjective, as evidenced by poor inter-observer reliability, particularly for Grade 2. Since low-grade (Grade 1) versus high-grade (Grades 2/3) PS is the threshold for recommending lateral extra-articular augmentation, performing the test in awake clinic patients limits grading reproducibility and introduces variability in surgical decision-making. Existing methods to quantify the pivot shift usually require examiner-performed testing under general anaesthesia. No prior approach has ascertained PS grading from a separate patient-performed functional movement. PurposeTo evaluate the feasibility of a machine learning (ML) classifier, trained on kinematic ultrasound bone-tracking signals acquired during a patients sit-stand-sit (SSS) knee movement, to predict their PS grade, and to clinically validate its ability to differentiate low versus high-grade PS. MethodsUltrasound bone-tracking kinematic data were collected during SSS manoeuvres in 23 ACL-injured patients using the GATOR device, and ground truth PS grades (0-3) were assigned under general anaesthesia by fellowship-trained orthopaedic sports surgeons. From the data collected, Leave-one-out cross-validation (LOOCV) was used to train the ML classifier. Clinical SSS data from 6 ACL-deficient patients was used for independent held-out validation of their low-grade (Grade 1) versus high-grade (Grade 2/3) PS. Multiple deep learning architectures (XceptionTime, InceptionTime, FCN, ResNet, ResCNN) and training strategies (including mixup augmentation and supervised contrastive learning) were tested. Performance was measured by one-versus-rest (OVR) AUC under LOOCV and by AUC (low vs high grade PS) from the held-out patient sessions. ResultsThe ML classifier achieved a maximum OVR AUC of 0.928 {+/-} 0.084 under LOOCV. Classifier performance increased with pivot-shift severity: Grade 3 was identified most reliably (AUC ~0.81; sensitivity 0.70-0.80), whereas Grade 2 remained the most challenging boundary (sensitivity 0.20-0.75 across configurations). For the clinically relevant binary classification of low-versus high-grade pivot shift, the classifier generalised well to a completely unseen patient cohort (AUC 0.889; accuracy 0.860; sensitivity 0.850; minimum-class sensitivity 0.767). ConclusionThe study demonstrates that kinematic ultrasound bone-tracking during sit-stand-sit contains transferable information about rotational instability severity in ACL-deficient patients, and represents the first reported approach to predict pivot shift grade from a patient-performed functional movement. The strong cross-validation performance confirms that the signals contain meaningful PS grade-discriminative information, but larger datasets targeting 50-100 sessions per grade will be required to achieve patient-level generalisation and advance this novel rotational instability assessment tool toward full clinical adoption. Level of EvidenceLevel IV, diagnostic feasibility study.

Abstract: Background: Acute war-related traumatic wounds present significant challenges due to significant soft-tissue damage/loss, risk of contamination, limited access to antimicrobial therapy, need for delayed closure, and limited access to surgical and wound care. Negative Pressure Wound Therapy (NPWT) has been used effectively to reduce the volume of soft-tissue defects, edema, and infection in traumatic wounds, and to promote growth of healthy granulation tissue. However, conventional NPWT devices are costly and electricity-dependent, limiting their utility in conflict settings. Methods: This retrospective cohort study evaluated the use of PragmaVAC, a manually operated, electricity-independent NPWT device, in patients across three hospitals in Gaza with conflict-related wounds that were deemed by the treating surgeon to be unsuitable for primary closure. Secondary analysis was performed of clinical records of patients treated with the PragmaVac NPWT device to assess ability to achieve a primary outcome of wound bed with healthy granulation tissue, time to primary outcome, and rates of adverse effects. Secondary outcome of wound closure and closure method was also assessed. Results: Treatment with PragmaVAC manual NPWT was prescribed to 88 patients. Of those, 27 (31%) had incomplete documentation of their wound healing or were lost to follow up. The remaining 61 (69%) had complete documentation of their wound healing, complications, and final outcome with 59 (67%) successful closure and 2(2%) failure. Conclusion: The use of the PragmaVAC NPWT device provided a safe, effective wound care option to achieve wound closure for large conflict-related traumatic wounds in resource-limited settings. Future studies may further evaluate such use through prospective trials, evalutions of patients' experiences with manual NPWT, and evaluating outcomes beyond primary wound closure to include medium- and long-term complications, cosmesis, and cost of therapy.

Background Virtual Hospital (VH) pathways enable early discharge and are promoted across the NHS. However, evidence supporting their safety, effectiveness, equity, and patient acceptability in elective colorectal surgery remains limited. Objective To evaluate implementation of a VH pathway following elective colorectal surgery and its impact on clinical outcomes, patient-centred recovery, and equality, diversity and inclusion (EDI). Design Retrospective service evaluation with a historical comparator. A 1:1 propensity-matched analysis was performed in colorectal cancer patients using age, sex, body mass index, ASA grade, Charlson Comorbidity Index, procedure type, tumour site, and anastomosis. Setting West Hertfordshire Teaching Hospitals NHS Trust. Patients Patients undergoing elective colorectal surgery between November 2023 and March 2025 managed via a VH pathway, compared with a non-VH cohort. Main outcome measures Primary outcomes were inpatient length of stay (IPLOS), VH length of stay (VHLOS), and days alive and at home within 30 days (DAH30). Secondary outcomes were patient-reported experience and EDI characteristics. Results Eighty-one patients were managed via VH. Median [Q1 - Q3] IPLOS was 2 [1 - 2] days and VHLOS was 2 [2 - 3] days, with no deaths. Forty-two colorectal cancer patients were propensity matched 1:1 to a pre-VH cohort. IPLOS was shorter in the VH cohort (2 [1 - 2] vs 4 [3 - 5] days; p<0.001), and DAH30 was higher (28 [28 - 29] vs 25.5 [24 - 27] days; p<0.0001). Patient experience was positive, with mean satisfaction >8.5/10 and over 90% preferring VH-supported recovery. Sex and ethnicity distributions were similar, although VH patients were younger (p=0.028). Limitations This single-centre retrospective evaluation had a modest sample size and non-randomised design. VH patients were carefully selected, limiting generalisability. Conclusions A VH pathway following elective colorectal surgery is feasible, safe, and acceptable. Compared with a pre-VH cohort, VH care reduced inpatient stay and improved patient-centred recovery without compromising safety.

Background: Freezing of gait (FOG) in Parkinson's disease (PD) is provoked by turning, doorways and dual-task walking. We evaluated WALK, a cadence-linked vibration neuromodulation combined with motor-learning training. Methods: Single-centre, sham-controlled pilot randomised trial. Adults with PD (Hoehn and Yahr 2 to 4) and neurologist-verified FOG were randomised 1:1 to intervention (WALK; vibration enabled) or sham (WALK; vibration disabled), alongside identical supervised home-based training for 6 weeks (3 sessions per week). OFF-medication assessments were performed at S0, S8 and S16. At S8 and S16, assessments were completed without a device and then with a device (fixed order). The primary endpoint was the mZ-FOG total (0 to 36). Results: Forty participants completed follow-up assessments (intervention n=24; sham n=16) with 100% session adherence and no serious device-related adverse events. In the intervention group, mZ-FOG total improved when assessed with the device at S8 ({Delta}=8.08) and S16 ({Delta}=9.21) relative to S0, with partial retention when assessed without the device at S16 ({Delta}=5.54). Conclusions: Cadence-linked, localised vibration neuromodulation plus motor-learning training was feasible and was associated with clinically meaningful within-intervention-group reductions in FOG. Taken together, the effect sizes and task-specific pattern support progression to a multicentre, assessor-blinded trial with an active sham, powered for between-group comparisons and durability and/or adherence endpoints.

Background: In 2024, the BMJ updated its data-sharing policy for clinical trials, requiring deidentified individual patient data (IPD) to be openly deposited prior to publication. Our objective was to discover if data-sharing increased after introduction of the new policy. Method: All data-sharing statements were downloaded from BMJ trials published in 2023 (submitted pre-updated policy) and 2025 (submitted post-updated policy). Data for 2025 were gathered for trials in five comparison medical journals. Data-sharing statements were coded to specify whether IPD were immediately available, and if not, the reason why. Where a statement gave a link to a repository, we checked whether data were available. Results: Openly available IPD for BMJ trials increased from 0/32 prior to the new policy to 19/33 (58%) after the updated policy; seven articles gave repository links that did not yield any data. In the five comparison journals, rates of open IPD varied from 0% to 5.6%. Conclusions: There was a substantial increase in open sharing of IPD after introduction of the new policy compared to a prior period. Open sharing of IPD is possible, but it is unpopular with authors and is unlikely to be achieved without firm editorial enforcement