Trials

BackgroundThis randomized controlled trial was conducted to evaluate the impact of posterior pericardiotomy on the prevention of postoperative atrial fibrillation (POAF) in patients who underwent off-pump coronary artery bypass grafting (CABG). MethodsAdult patients who were scheduled to undergo isolated off-pump CABG were assessed for eligibility, and eligible patients were randomly assigned in a 1:1 manner to pericardiotomy or no intervention. Patients and postoperative caregivers were blinded to treatment assignment. The primary endpoint was the occurrence rate of POAF, and the secondary endpoints were the cumulative time spent in POAF and early outcomes, including operative mortality. ResultsA total of 403 patients were screened for eligibility, and 270 patients were randomly assigned to the posterior pericardiotomy group (n=136) or control group (n=134). The mean age was 67.8{+/-}10.3 years, and 20.4% (55 of 270 patients) were female. There was no intergroup difference in baseline characteristics or surgical data. Off-pump CABG was performed as planned in all patients except one. All patients received the assigned treatment regarding pericardiotomy, and no intergroup crossover occurred. POAF occurred in 27.8% (75 of 270 patients) of patients at a median of 2 days (interquartile range 1-3 days) after surgery. There was no significant difference in the occurrence rate of POAF between the two groups (30.1% and 25.4% in the pericardiotomy and control groups, P =.38). There were no significant differences in the secondary endpoints between the two groups. ConclusionsPosterior pericardiotomy does not reduce the occurrence rate of POAF in patients undergoing off-pump CABG. (NCT06159985)

BackgroundRandomized controlled trials (RCTs) often have incomplete methods reporting despite widespread adoption of the CONSORT guideline. The editorial process is supposed to detect these shortcomings and request clarifications from authors, which is time-consuming. We developed an LLM-based CONSORT Rohe Nordberg Report that highlights which CONSORT items appear fully or partially reported and checks page references claimed by authors, and then creates follow up questions for authors to more easily correct missing information. MethodsThis parallel-arm, superiority RCT will randomize eligible RCT submissions (after desk screening) 1:1 into intervention (editorial team and authors receive the Rohe Nordberg Report) or control (standard editorial review only). The primary outcome is whether manuscripts improve their reporting of CONSORT items in the Methods and Results sections between the original submission and first revision. This will be assessed by blinded human reviewers who evaluate the textual changes for improvements between the original and revised manuscripts for each relevant CONSORT item. Secondary outcomes include time to editorial decisions, rejection and non-resubmission rates, if authors can correctly identify where CONSORT items are reported, and extent of revisions. Human evaluators will be blinded to whether the manuscript was in the intervention or control group. DiscussionBy providing authors and the editorial team with specific follow up questions for each underreported CONSORT item, we hypothesize that basic underreporting will be more efficiently detected and corrected. Using blinded human reviewers as the primary outcome assessors ensures a rigorous, unbiased evaluation. If successful, this approach may help align manuscripts more closely with CONSORT standards, ultimately benefiting evidence synthesis. Trial Registration[To be registered prior to enrollment; e.g., ClinicalTrials.gov or ISRCTN] 1. Administrative Information1.1 TitleLLM-Generated CONSORT Rohe Nordberg Report for Increased Reporting: Protocol for a Parallel-Arm Randomized Controlled Trial. IRB registered name: LLM-Generated CONSORT Report Phase III Trial 1.2 Trial RegistrationThis trial will be registered before enrollment commences in a publicly accessible registry (e.g., ClinicalTrials.gov or ISRCTN). The trial identifier will be inserted here upon registration. All items from the World Health Organization Trial Registration Data Set will be provided at the time of registration, including: primary registry and trial ID, date of registration, secondary IDs, source of funding, contact for public and scientific queries, title, research ethics review, study design, study setting, interventions, eligibility criteria, primary outcome, key secondary outcomes, target sample size, recruitment status, and results dissemination plan. 1.3 Protocol VersionVersion 1.0 26 March 2026 [Subsequent amendments will be tracked by version number, date, and a summary of changes.] 1.4 FundingOpen Philanthropy, grant title "From Manual to Machine: Validating and Scaling LLM-Based CONSORT Compliance Assessment for Evidence-Based Medicine Publishing" Participating journals provide in-kind editorial resources (staff time, system access) to facilitate trial conduct. 1.5 Roles and ResponsibilitiesO_ST_ABSProtocol contributorsC_ST_ABSAuden Nordberg Krauska (University of Wisconsin-Madison; krauska@wisc.edu): conceived the study design, wrote the initial protocol draft Karl Rohe (University of Wisconsin-Madison): primary investigator, co-developed the LLM-based CONSORT and RoB 2 systems Gary Collins (University of Birmingham): senior methodologist, contributed to trial design and statistical analysis plan Sara Schroter (British Medical Journal): research editor, contributed to trial design and implementation plans Hyunseung Kang (University of Wisconsin-Madison): aided in statistical analysis plan Trial sponsorUniversity of Wisconsin-Madison, Department of Statistics, 1300 University Avenue, Madison, WI 53706. Role of sponsor and fundersThe research team leads trial design, data collection, analysis, interpretation, and reporting. The sponsor and funders have no role in data collection, management, analysis, interpretation of data, writing of the report, or the decision to submit the report for publication. The funder provides financial support only. Participating journal editorial teams are consulted for feasibility and operational feedback but do not have authority over data analysis or reporting. Trial oversight groupsThe trial will be coordinated by Karl Rohe and Auden Nordberg Krauska (University of Wisconsin-Madison), with methodological input from Gary Collins (University of Birmingham). Day-to-day operations, including manuscript tracking, diff file preparation, and data management will be carried out by Auden Nordberg Krauska and trained undergraduate research assistants at UW-Madison. Sara Schroter, Research Editor at The BMJ, will facilitate integration with the journals editorial workflow and monitor recruitment progress. This group will meet as needed to review trial progress and resolve operational issues.

Background and objectiveIn cluster-randomised trials (CRTs), different estimands can be targeted, such as the individual-or cluster-average effect. These two estimands can differ in magnitude when outcomes or treatment effects vary with cluster size (termed informative cluster size). When informative cluster size is present, commonly used estimators for CRTs, such as mixed-effects model and generalised estimating equations with an exchangeable correlation structure (termed GEEs(exch)), can be biased for both these estimands. With little documented evaluation of When informative cluster size, it is currently unknown how commonly it occurs in practice. The aim of this work was to explore whether informative cluster size is present in a published CRT and to investigate its impact on trial results. MethodsWe re-analysed the RESTORE CRT, which compared protocolised sedation with usual care for critically ill children. For each outcome, we first modelled the association between cluster size and outcome/treatment effect; next, we assessed the impact of informative cluster size by comparing differences between (i) individual-vs. cluster-average estimates and (ii) estimates from mixed-effects models and GEEs(exch) (which can be affected by informative cluster size) to those from IEEs (which are robust to informative cluster size). ResultsWe found evidence of an association between cluster size and either outcomes or treatment effects for 16/33 outcomes (48%). This led to statistically significant differences between the individual- and cluster-average treatment effects for 5 of 33 outcomes (15%). There were >10% differences between (i) individual- and cluster-average treatment effect estimates for 17 outcomes (52%) and (ii) estimates from mixed-effects models/GEEs(exch) and estimates from unweighted IEEs for 13 outcomes (39%). For some outcomes, differences in the choice of estimator or estimand led to differences in the interpretation of results. For example, for the outcome postextubation stridor, the individual-average estimate showed a significant harmful effect (OR=1.65, 95% CI 1.02 to 2.67), unlike the cluster-average (OR=1.38, 95% CI 0.87 to 2.19) or GEEs(exch) estimate (OR=1.57, 95% CI 0.98, 2.50). Discussioninformative cluster size can occur in CRTs, and the use of estimators that are not clearly aligned to the target estimand can affect the interpretation of some results. What is new?O_ST_ABSKey findingsC_ST_ABSO_LIThis re-analysis of the RESTORE cluster randomised trial found that choice of estimand and estimator could affect the interpretation of results for some outcomes C_LI What this adds to what is knownO_LIThis work provides empirical evidence that informative cluster size can occur in cluster randomised trials, and can affect results based on the choice of estimand or estimator C_LI What is the implication and what should we change nowO_LITrialists should clearly define their target estimand and choose an estimator that is aligned to that estimand C_LIO_LICareful consideration of the plausibility of assumptions underpinning each estimator, including the likelihood of informative cluster size, can help ensure appropriate analysis methods are used C_LIO_LIWhen mixed-effects models or GEEs with an exchangeable correlation structure are used, sensitivity analyses using independence estimating equations or other appropriate methods should be used to evaluate the robustness of results to informative cluster size C_LI

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.

Background: Clinical trials are essential for therapeutic development but increasingly face challenges due to imprecise inclusion criteria, leading to low event rates and the need for large sample sizes. This inefficiency makes modern trials costly and time-consuming. Despite the availability of extensive clinical, genomic, and biological data, current trial enrollment strategies do not fully leverage this information. Incorporating genomic information into trial design could enable risk-based participant enrichment by preferentially enrolling individuals with higher disease risk, thereby increasing event rates and improving trial efficiency. Methods: In this study, we developed an in silico framework for evaluating prognostic enrichment guided by polygenic risk scores (PRS) in clinical trial design using genomic and electronic health record data from large-scale biobanks. Naturally occurring protective genetic variants were used as analogs of therapeutic interventions, with variant carriers treated as 'treatment' arms and non-carriers as 'control' arms. We compared unenriched designs, in which carriers and non-carriers were drawn from the full population, against PRS-enriched designs in which both arms were restricted to participants in the upper 75%, 50%, or 25% of the PRS distribution, respectively. Across these four designs, we quantified disease prevalence, statistical power, sample size requirements, and time-to-event accrual. Results: We applied this approach to the UK Biobank using three model gene-disease pairs: the protective variant p.Arg46Leu in PCSK9 for coronary artery disease (CAD), p.Gln175His in ANGPTL7 for glaucoma, and p.Arg381Gln in IL23R for inflammatory bowel disease (IBD). Across all three disease contexts, PRS-enriched designs increased disease prevalence, improved empirical power, and accelerated event accrual relative to unenriched cohorts. At 80% power, restricting enrollment to the upper 25% of the PRS distribution reduced required per-arm sample sizes by approximately 60% for CAD-PCSK9 and 78% for IBD-IL23R. Consistent reductions in time-to-event were also observed across enriched strata, suggesting that PRS-enriched trials could achieve target event counts with both smaller sample sizes and shorter follow-up. However, for glaucoma-ANGPTL7, the most restrictive threshold did not yield additional gains over moderate enrichment, as reduced sample size attenuated the detectable difference between arms. These results highlight the need to balance enrichment for higher-risk participants against retaining a sufficient eligible population, and underscore that optimal PRS thresholds are disease-context dependent. Conclusions: These findings establish a generalizable, data-driven framework for prospectively evaluating PRS-guided prognostic enrichment prior to trial initiation. In general, PRS-guided study designs lead to improved empirical power, lower required sample sizes, and faster trials. As population-scale genomic data become increasingly available within healthcare systems and biobanks, this framework provides a scalable foundation for integrating genetic risk information into clinical trial design.

Objectives: To assess the availability of key clinical trial registration data and compliance with legal reporting requirements for all Phase 2-4 drug trials registered on the new European Clinical Trial Information System (CTIS) registry. This study is the first ever assessment of data quality and legal compliance with reporting requirements on CTIS. Design: Cross-sectional observational study of CTIS registry data combined with manual review of results documents. Setting: Cohort of all 7,547 Phase II-IV clinical trials registered on CTIS as of November 2025. Main outcome measures: Number and proportion of missing data points in CTIS registration data. Proportion of completed clinical trials that are compliant with regulatory reporting requirements. Results: Trial registration data quality was high overall with more than 99% of expected data present. Of 234 clinical trials legally required to report results, fewer than half (49.6%) fully reported results within the required timeframe, 20 trials (8.5%) fully reported results late, and 98 trials (41.9%) failed to fully report results. Legal compliance was similar for adult trials (79/158) and paediatric trials (37/76). Conclusions: Sponsor compliance with legal reporting requirements is weak. Current efforts by European regulators to monitor and enforce compliance appear to be insufficient. New results reporting functions currently being set up by trial registries worldwide will require quality assurance processes. Trial registration: Study protocol prospectively registered on OSF: https://osf.io/sn4j2/overview

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.

BackgroundPatients with type 2 intestinal failure (T2IF) due to double enterostomy or enterocutaneous fistula (DES/ECF) require parenteral nutrition (PN), carrying risks of catheter sepsis, venous thrombosis, and liver disease. Chyme reinfusion therapy (CRT) may reduce PN dependence but has not been evaluated in a randomised controlled trial (RCT). This study assessed whether device-assisted CRT using The Insides System reduces PN requirements. MethodsThis multicentre, open-label RCT enrolled PN-dependent adults with T2IF due to DES/ECF across 12 centres in the UK and USA. Patients with insufficient distal limb length, proximal bowel obstruction, active sepsis, or severe hepatorenal failure were excluded. Participants were block randomised 2:1 to device-assisted CRT plus standard care (active) or standard care (control). The primary endpoint was 50% or greater reduction in PN caloric intake at 30 days, using an intention-to-treat analysis, for a comparison between randomised groups using a two tailed p-value of 0.025 to allow for a single interim analysis. Secondary outcomes were rate of PN cessation at 30 and 60 days, quality of life, and adverse events. ResultsThe population comprised 39 (26 active, 13 control) participants. At Day 30, 8/26 (31%) active participants achieved the primary endpoint versus no controls (p=0.035). By Day 60, 10/23 (43%) active participants had completely ceased PN versus no controls (p=0.008), with median intestinal losses reduced by 1,344 mL/day at Day 30 (p=0.005) and 1,450 mL/day at Day 60 (p=0.026 between group). Device-related adverse events were predominantly mild; one death unrelated to the device occurred. ConclusionCRT with the Insides System demonstrated substantial therapeutic advantages in patients with T2IF from DES/ECF, with 31% of participants reducing PN calories by 50% at 30 days and >40% of participants achieving complete PN cessation by 60 days, and an acceptable safety profile. Trial registrationClinicalTrials.gov NCT04577456 FundingThis trial was sponsored by The Insides Company Ltd. Surgical RelevanceWhat is already known: Patients with type 2 intestinal failure due to double enterostomy or enterocutaneous fistula depend on parenteral nutrition, which carries significant risks including central venous catheter (CVC) sepsis, venous thrombosis, and intestinal failure-associated liver disease. Chyme reinfusion therapy restores distal gut function but has only been evaluated in non-randomised cohort studies. What is new: This first randomised controlled trial of device-assisted chyme reinfusion demonstrates that 43 per cent of participants can completely cease parenteral nutrition by 60 days, with a 70 per cent reduction in intestinal losses, high participant satisfaction and an acceptable risk profile. Potential impact on future practice: Early initiation of device-assisted chyme reinfusion in suitable patients with double enterostomy or enterocutaneous fistula reduces parenteral nutrition dependence, avoids associated complications and costs, and facilitates rehabilitation before reconstructive surgery.

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.

BackgroundSocial prescribing (SP) connects individuals with sources of support within their local communities and has been shown to improve loneliness. However, uptake from young people (YP) has been lower than for adults, in part due to them not accessing SP in primary care where it has been predominantly based. The INACT (INcreasing AdolesCent social and community support) programme is a novel, co-produced, SP pathway via schools for YP to access community assets and support. MethodsThis trial utilises a two-group (intervention vs. active control) parallel randomised design, with YP as the unit of randomisation. A minimum of 215 YP will be recruited across approximately 30 mainstream schools (primary and secondary) in England. YP reporting high levels of loneliness (7 or above on the Good Childhood index) will be randomly allocated to receive either SP or signposting. SP will consist of 6-12 sessions with a Link Worker who will work with individuals, on a one-to-one basis, to understand what matters to them and connect them with local sources of support, whilst pupils in the signposting arm will receive a leaflet from a school staff member detailing the same sources of support. YP will be followed up at 3, 6, and 12 months after treatment allocation. Secondary outcome measures include wellbeing, emotional difficulties, service use, health related quality of life, stress, emotional regulation, as well as intervention feasibility, acceptability and appropriateness. Data about health-related quality of life and service use will be used to investigate the cost-effectiveness of the INACT programme. DiscussionThis trial will provide robust evidence about the effectiveness and cost-effectiveness of the INACT programme and whether it can be recommended for use in practice. The trial is due to finish 30 June 2027.

BackgroundPhenome-wide association studies (PheWAS) can reveal novel associations between variants in drug-target genes and disease and, as such, can be used to predict new drug-indication pairs for repurposing drugs with a known mechanism of action. A platelet-derived growth factor receptor beta (PDGFR{beta}) PheWAS demonstrated that patients with a single nucleotide variant that reduces PDGFR{beta} expression exhibit a higher prevalence of chronic skin ulcers, skin grafts, and reconstructive surgeries. Recombinant human platelet derived growth factor BB (rhPDGF) is a therapeutic that binds to and activates PDGFR{beta} and has received FDA approval for multiple indications, including improving healing of lower extremity diabetic neuropathic ulcers, augmenting periodontal bone and soft tissue reconstruction, and stimulating orthopedic bone regeneration. Leveraging a drug-repurposing methodology informed by PheWAS, we hypothesize that rhPDGF will provide therapeutic benefit in the treatment of other complex wounds, like full-thickness surgical wounds of the head or neck that cannot heal by primary intention following skin cancer excision. MethodsThis prospective, double-blinded, single-site study aims to enroll 40 participants, randomized at a ratio of 1:1, comparing the efficacy of an advanced wound matrix saturated with rhPDGF or saline. Comparisons will be stratified by anatomical location (scalp/forehead versus face/neck) and maximum surgical defect dimensions (< 3cm versus > 3cm). The primary outcome of this study will evaluate the time in days to 81-100% granulation of the wound bed by expert clinical assessment of daily photographs. Secondary outcomes will assess the superiority of the rhPDGF-enhanced wound matrix relative to control with respect to wound granulation rate, epithelialization, complete wound healing, and patient reported outcomes (PROMs). DiscussionAlthough reconstructive techniques are available for healing complex head and neck wounds following skin cancer excision, these procedures are invasive, and older, frail patients are often suboptimal candidates. There remains a need for less invasive therapeutic approaches that reduce the healing time and mitigate the morbidity associated with chronic wounds. A PheWAS analysis identified complex wounds requiring reconstructive surgery as a novel drug-indication pair for repurposing rhPDGF. This protocol is designed to evaluate the efficacy of an rhPDGF-enhanced advanced wound matrix for healing complex head and neck wounds post skin cancer excision that cannot heal by primary intention. Clinical trial registrationThis trial is registered at ClinicalTrials.gov (NCT06634030).

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.

BackgroundChronic stroke-related gait impairment remains a major source of disability. InTandem is an autonomous neurorehabilitation system delivering individualized, progressive rhythmic auditory stimulation for home-based gait rehabilitation. ObjectivesTo evaluate: (1) engagement during a 12-week autonomous, home-based intervention, (2) changes in walking endurance and functional mobility, and (3) outcome differences across pre-defined engagement and baseline speed subgroups. MethodsThis pragmatic, decentralized trial enrolled adults [&ge;]6 months post-stroke with residual gait deficits. Participants were asked to complete 30-minute sessions 3x/week for up to 12 weeks. Engagement was primarily assessed as the proportion achieving moderate-to-high weekly usage (> 4 weeks; benchmark p1 = 0.60). Changes in 6-Minute Walk Test (6MWT) distances and Timed Up and Go (TUG) times were analyzed using linear mixed-effects models. ResultsOf the 204 who initiated the intervention, 81.9% (95% CI [0.76-0.87]) engaged at least 4 weeks, meeting the primary endpoint (p < 0.001). Overall, 58.1% achieved high engagement (> 9 weeks), 23.9% moderate engagement (4-8 weeks), and 18.1% low engagement ([&le;]3 weeks). Significant improvements in 6MWT distance (+ 26.1 {+/-}5.6 m; 95% CI [14.99, 37.22]) and TUG times (-1.45{+/-}0.31 s; 95% CI [-2.06, -0.84]) (p < 0.001) were observed. Engagement influenced effectiveness: each additional week engaged predicted a 5.82 m greater gain in the 6MWT (SE = 2.05; 95% CI [1.77, 9.87], p < 0.005). ConclusionsAutonomous home-based delivery of music-based rhythmic auditory stimulation achieved moderate-to-high engagement and improved walking endurance and functional mobility, supporting InTandem as a scalable approach to chronic stroke gait rehabilitation. Trial registrationTrial registration: Clinicaltrials.gov NCT06051539. Registered on 20 September 2023. https://clinicaltrials.gov/study/NCT06051539

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.

Background: Lumbar spinal stenosis (LSS) can cause pain and severe walking limitation. Although surgery aims to improve walking, many patients do not achieve clinically meaningful gains. Rehabilitation can improve outcomes, yet existing programmes lack robust evidence and theoretical underpinning. This study aimed to (1) co-design a theory-informed rehabilitation programme to improve walking after LSS surgery, and (2) evaluate feasibility of conducting a future trial and acceptability of the intervention. Methods: A multi-methods study included intervention co-design followed by a single-arm feasibility study. Co-design used an adapted Experience-Based Co-Design approach with patients, carers, and healthcare professionals (n=39), integrating the Behaviour Change Wheel. This resulted in STructured Rehabilitation and InDividualised Exercise and Education (STRIDE), delivered over 12-week pre- and 12-weeks post-surgery, targeting knowledge, expectations, perceived control, physical capability, and fears. Adults aged [&ge;]50 years awaiting LSS surgery were recruited to a before-after feasibility study. Feasibility outcomes included recruitment and retention. Acceptability was assessed using the Theoretical Framework of Acceptability questionnaire (0-5 (high acceptability)) and focus groups. Clinical outcomes measured at baseline, post-prehabilitation, and post-rehabilitation included 6-minute walk distance (6MWD) and mean daily step count over 7 days. Results: Fifteen of 31 eligible participants were recruited (48%; mean age 70 years), with 80% retained to study end (2 decided against surgery, 1 unable to complete final assessment). Acceptability was high (median 5/5, IQR 0). Participants valued the personalised, supportive approach and reported improved motivation and preparation for surgery, though travel was burdensome. Small pre-operative and moderate-to-large post-operative improvements were observed in 6MWD (+49.9 m and +81.6 m) and daily step count (+868 and +1405 steps/day). Conclusions: This co-designed, physiotherapy-led, behaviour-change rehabilitation programme was acceptable to participants, with encouraging recruitment, retention, and signals of improved walking following LSS surgery. The findings support progression to a future trial.

ObjectiveTo investigate the long-term (defined as [&ge;]12 months) prognosis of knee pain and knee function in adults and adolescents with patellofemoral pain (PFP). DesignSystematic review with meta-analysis and meta-regressions. Data sourcesMEDLINE, OVID, CENTRAL, Web of Science, OpenGrey, and International Patellofemoral Research Retreat abstract books. Eligibility criteria for selecting studiesProspective studies of patients clinically diagnosed with PFP, aged <40 years, with a long-term follow-up (minimum of 12 months). Primary outcomes were self-reported pain intensity (worst, during activity, and usual) and function. Meta-analyses and meta-regressions were performed where appropriate. Narrative synthesis was performed for those not included in the metanalysis. Risk of bias was assessed using the Quality In Prognosis Studies (QUIPS) tool, and certainty of evidence using GRADE. ResultsA total of 42 studies (n = 3,230) were included. At 12 months, meta-analysis indicated reduction in worst pain (SMD 1.36; 95% CI 0.85-1.86), pain during activity (SMD 1.36; 95% CI 0.61-2.11), and resting pain (SMD 0.91; 95% CI: 0.75- 1.08). No significant reduction was found for usual pain. We found improvement in self-reported function (investigated using the Anterior Knee Pain Scale (AKPS) MD 14.60; 95% CI 11.60-17.61), FIQ (MD 3.33; 95% CI: 2.46- 4.20) and the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) (MD -7.73; 95% CI: -10.36 to - 5.10). Extended follow-up ([&ge;]60 months) suggested more variable improvements. Meta-regression showed no association between age and 12-month function, while older age was modestly associated with greater improvement in activity-related pain at extended follow-up. Overall, a considerable proportion of participants continued to report persistent symptoms, and heterogeneity across studies was substantial. Certainty of evidence ranged from very low to moderate across outcomes investigated. ConclusionPain and self-reported function generally improve over time, particularly within the first 12 months. However, substantial heterogeneity and persistent symptoms in a considerable proportion of patients at extended follow-up indicate that recovery is not universal and trajectories are highly variable. What is already knownO_LIPatellofemoral Pain (PFP) is a very common condition in both adolescents and adults. C_LIO_LIMultiple treatments modalities exist, including patient education and exercise therapy. C_LIO_LIPeople suffering from PFP request more knowledge on the long-term prognosis. C_LI What are the new findings?O_LIThis systematic review and meta-analysis provide the most comprehensive synthesis to date of long-term outcomes ([&ge;]12 months) in adolescents and adults with patellofemoral pain. C_LIO_LIPain and self-reported knee function generally improve at the group level over time, particularly within the first 12 months. C_LIO_LIDespite group-level improvement, a substantial proportion of individuals continue to report persistent symptoms, indicating that patellofemoral pain is often not fully self-limiting. C_LIO_LILong-term outcomes are highly heterogeneous, with different pain constructs demonstrating distinct trajectories across follow-up periods. C_LIO_LIMeta-regression identified no consistent prognostic associations, suggesting that current study-level variables explain little of the variability in long-term outcomes. C_LI How might this study affect research, practice or policy?O_LIClinicians should communicate that while improvement is common in patellofemoral pain, persistent symptoms are frequent, highlighting the need for realistic prognostic expectations and long-term management strategies. C_LIO_LIFuture research should prioritise harmonised outcome measures and long-term follow-up to better understand recovery trajectories and identify subgroups at risk of persistent symptoms. C_LI

Background and purposeIn the QUADX-1 trial, we randomized 140 patients with severe knee osteoarthritis (OA) eligible for a knee arthroplasty to home-based exercise for 12 weeks. Seventy-nine (68%) of the 117 patients, who completed the exercise intervention, postponed surgery. Here, we report how many patients, who completed the 12-week exercise intervention, had received a knee arthroplasty at 2 years and describe their initial exercise response. MethodsFrom the QUADX-1 trial, we had the following: isometric knee-extensor strength, Oxford Knee Score (OKS), Knee Osteoarthritis Outcome Score (KOOS), average knee pain last week (0-10 numeric rating scale [NRS]), 6-minute walk test, stair climbing test, and self-reported exercise behaviour. ResultsAt the 2-year follow-up, 50 (43%) of the 117 patients had received a knee arthroplasty (KA group) and 67 (57%) had not (NO-KA group). Compared with the KA group, the NO-KA group had less severe radiographic OA at baseline (KL grade 4: 38% vs 55%) and showed greater-- and often clinically relevant--improvements after the 12-week exercise intervention, including knee pain (-2.1 vs -0.1 NRS points), OKS (+6.9 vs +0.5 points), and KOOS ADL (+13.9 vs +1.3 points). ConclusionTwo years after completing the initial 12-week QUADX-1 exercise intervention, more than half the cohort had not received a knee arthroplasty despite initially being considered eligible. Those who had not received a knee arthroplasty at two years had less severe radiographic OA at baseline and generally responded better to 12-week exercise two years earlier, compared to those who had. ClinicalTrials.gov-IDNCT02931058.

Background. Recent meta-analyses of randomized controlled trials (RCTs) claimed efficacy of higher-dose fluvoxamine (2 x 100 mg/day, as opposed to 2 x 50 mg/day) in prevention of disease deterioration in adults with mild - moderate COVID-19 disease. Objectives. Investigate whether such claims are supported by the data. Methods. Systematic review and meta-analysis of RCTs evaluating higher-dose fluvoxamine in this indication. Results. Seven studies declared as RCTs were identified, one of which was severely biased (open-label, non-standardized and unreported standard of care as a control), and eventually ended as non-randomized (huge attrition). Composite endpoints of deterioration in the 6 included placebo-controlled trials contained elements susceptible to error and bias. Three trials were small (<100 patients/arm), three were larger (270 - 750 patients/arm). Deaths and need for mechanical ventilation were sporadic and observed in only one trial. Hospitalizations were also sporadic in 5/6 trials. Frequentist methods generally appropriate for random-effects analysis of low number of trials with rare outcomes (generalized linear mixed models, beta-binomial or binomial-normal) greatly underestimated heterogeneity, but still did not document benefits regarding the composite endpoints or hospitalizations. Bayesian hierarchical models revealed huge heterogeneity and indicated no benefit regarding: (i) composites of deterioration, large trials OR = 0.78 (95% CrI 0.55 - 1.21); multiplicity corrected OR = 0.87 (0.64 - 1.21); (ii) hospitalizations, small trials OR = 0.88 (0.45 - 1.72); large trials OR = 0.94 (0.52 - 1.75); all trials OR = 0.81 (0.47 - 1.43). Heterogeneity was unlikely due to clinical particulars (vaccination status, treatment duration, time horizon), and more likely due to unidentified bias. Conclusions. RCTs do not support efficacy of higher-dose fluvoxamine in prevention of disease deterioration in adults with mild - moderate COVID-19 disease.

BackgroundPostoperative pancreatic fistula (POPF) is a major cause of morbidity after pancreatoduodenectomy, particularly in patients with high-risk pancreatic remnants. Preventive strategies based solely on surgical technique have yielded inconsistent results, and thus there has been growing interest in strategies aiming to modify the biological behavior of the pancreatic remnant. This preclinical study evaluated the biological and histopathological effects of preoperative endoluminal radiofrequency ablation (ERFA) of the main pancreatic duct (MPD) performed 4 weeks before pancreatic transection in a porcine model. MethodsAnimals underwent laparoscopic MPD occlusion followed by pancreatic transection at 4 weeks and necropsy 15 days thereafter. Feasibility, safety, histological atrophy, and macroscopic findings associated with POPF risk were assessed. As a secondary objective, outcomes were compared with a that underwent MPD occlusion using cyanoacrylate glue. ResultsPreoperative ERFA was technically feasible and safe. At 4 weeks, ERFA induced marked and homogeneous acinar atrophy that was significantly greater than that observed after glue occlusion (p = 0.018), indicating effective biological conditioning of the pancreatic remnant. At necropsy, pseudocyst formation and intra-abdominal adhesions, known surrogate markers of pancreatic fistula in pigs, were significantly more frequent in the glue group and absent in ERFA-treated animals. Serum amylase levels, postoperative weight gain, complication rates, and preservation of endocrine architecture were comparable between groups. ConclusionsDuctal ablation of the MPD via ERFA induced stable, progressive exocrine pancreatic atrophy, effectively preconditioning the gland prior to pancreatic transection. Experimental evidence suggests that its biological effects stabilize approximately 4 weeks after treatment. Compared to cyanoacrylate occlusion, ERFA achieved more homogeneous early biological effects and fewer fistula-related macroscopic complications. These findings support the further investigation of preoperative pancreatic conditioning as a potential adjunct strategy for POPF risk reduction, although clinical studies are needed to clarify its role alongside established reconstructive approaches.

BackgroundModerate- to high-intensity walking training (M-HIT) is an established intervention for improving walking capacity in chronic stroke. Musculoskeletal (MSK) adverse events commonly occur during M-HIT, yet tools to identify individuals at higher risk are limited. Baseline clinical characteristics may provide insight into susceptibility to training-related MSK adverse events during M-HIT. Thus, this study aimed to develop and internally validate a model for predicting MSK adverse events during a 12-week M-HIT program in chronic stroke using baseline clinical characteristics. MethodsParticipants (n=100) from HIT-Stroke Trials 1 and 2 were included. Baseline clinical characteristics included measures of orthopedic history, pre-existing pain, motor function, recent exercise history, demographics and health characteristics, stroke chronicity, and psychological health. Logistic regression models evaluated all possible combinations of baseline characteristics with up to three predictors. Leave-one-out cross-validation was used for internal validation to mitigate overfitting. Predictive performance was quantified using the C-statistic, and the candidate model with the highest cross-validated C-statistic was selected as the final model. ResultsMSK adverse events occurred in 32.0% of participants. The optimal three-variable model included prior orthopedic condition (Odds ratio [OR] 3.02 [95% CI 1.14-8.64]), Fugl-Meyer lower extremity motor score (OR 1.14 [95% CI 1.02-1.28]), and self-reported participation in regular walking exercise (OR 0.17 [95% CI 0.05-0.49]) at baseline. This model demonstrated moderate discrimination (cross-validated C-statistic = 0.74; apparent C-statistic = 0.78). ConclusionsParticipants reporting at least one pre-existing lower extremity or lumbar spine orthopedic condition and those with better lower-extremity motor function exhibited greater odds of experiencing MSK adverse events during M-HIT, while participants reporting participation in regular walking exercise had lower odds. These findings suggest that baseline clinical characteristics may help identify individuals at elevated risk for MSK adverse events during M-HIT who may warrant closer monitoring or risk-reduction strategies. Future studies are needed for external validation. Clinical Trial Registrationhttps://ClinicalTrials.gov; Unique identifiers: NCT03760016, NCT06268041