Trials

Background: Stepped-wedge cluster randomized trials (SW-CRTs) are increasingly used when interventions need to be implemented sequentially across clusters. Despite extensive developments in the design and analysis of superiority SW-CRTs, methods for planning noninferiority SW-CRTs remain limited. Methods: We propose swNIsim, a simulation-based framework for power calculation in noninferiority SW-CRTs using generalized linear mixed-effects models (GLMMs). The proposed approach accommodates both continuous and binary outcomes and supports practical design features, including unequal numbers of clusters across sequences, varying cluster-period sizes, delayed intervention effects, and analyses with or without adjustment for secular time effects. Noninferiority margins can be specified using several commonly applied strategies. Results: Through extensive simulation studies, we examined the impact of key design parameters on statistical power, including the number of periods, the number of clusters per sequence, the number of individuals per cluster-period, and the degree of between-cluster variability. For a fixed total sample size, designs with more time periods consistently achieved higher power. Increasing the number of clusters per sequence produced modest gains in power, whereas greater between-cluster variability reduced power. Type I error rates were well controlled across the scenarios examined. Balanced allocation of clusters across sequences was more efficient than unbalanced allocation schemes. Two real-world SW-CRT examples were used to illustrate application of the method. Conclusions: The proposed swNIsim provides a flexible and practical approach for power calculation in noninferiority SW-CRTs. By accommodating a wide range of design configurations and outcome types, and through implementation as a freely available R package, swNIsim may facilitate the planning and design of noninferiority stepped-wedge trials.

Background Traditional participant information and consent forms (PICFs) have changed little over time and are often lengthy and complex. A novel consent process incorporating plain language, an infographic brochure and a short explanatory video was developed to improve communication of clinical trial information. The SImPLE study was designed to evaluate whether this novel consent process improves comprehension of clinical trial information, participant engagement and the consent experience compared with a traditional PICF. Design and Setting SImPLE is a randomised two-period crossover study involving adults receiving cancer treatment who are potentially eligible for clinical trial participation. Study materials were developed for the ANZadapt (ANZUP2101) prostate cancer clinical trial; however, participants are not being recruited to ANZadapt itself. Participants are randomised to receive either a standard 17-page NHMRC-style PICF followed by a novel consent process, or the reverse sequence, with a washout period of at least 7 days between study periods. The novel consent process comprises a simplified 4-page PICF, infographic brochure and short explanatory video. Twenty-four hours following each PICF review, participants complete a comprehension assessment and structured interview. Outcomes and Endpoints The primary endpoint is comprehension of clinical trial information, measured using a study-specific 22-item questionnaire comprising 10 true/false and 12 multiple-choice questions. Secondary endpoints include acceptability, assessed through participant preference for communication format, and engagement, assessed through confidence in explaining the trial and likelihood of agreeing to participate. Planned Analyses The primary analysis will compare comprehension scores between the novel and standard consent approaches using a paired t-test among participants completing both study periods. Secondary outcomes relating to acceptability and engagement will be summarised descriptively and compared between consent approaches as appropriate. Sensitivity analyses will be performed to assess the robustness of the primary findings and the potential impact of crossover design effects.

Introduction: Clinical deterioration in patients admitted to hospital wards is a major cause of preventable morbidity and mortality and is frequently preceded by abnormalities in vital signs that occur hours before serious adverse events occur. Early identification of patients at risk provides an opportunity for timely intervention before irreversible organ dysfunction develops. The objective of this trial is to evaluate whether implementing a wireless patient monitoring system reduces mortality and cardiopulmonary failure in patients admitted to hospital wards. Methods and analysis: The i-PROTECT trial is designed as a stepped-wedge cluster randomized controlled trial. Hospital wards (total of 28 wards, constituting clusters in this design) are randomized to have wireless monitoring for selected high-risk patients, 7 wards at a time, with every 7 wards constituting a sequence. In the first period, all wards will have no wireless monitoring. After a baseline period of 2 (+1 transition) months, the intervention is implemented in a randomly selected new sequence every 3-month period until the intervention is implemented in all sequences. The control group will receive usual care with standard intermittent monitoring and no wireless monitoring. The calculated sample size is 13160 patients. The primary endpoint is cardiopulmonary failure; a composite endpoint of 30-day in-hospital mortality, cardiac arrest, and need for vasopressor or intubation. The trial started on Feb 1, 2026, and is expected to complete patient follow-up by the end of May 2027. Ethics and dissemination: The trial was approved by the Institutional review board (IRB) of Ministry of National Guard Health Affairs (IRB/2623/23). The results will be presented at relevant national and international critical care conferences and published in international peer-reviewed journals.

South Asian communities in the UK experience disproportionate maternal and child health inequalities linked to non-recommended infant feeding practices, limited health literacy, and socioeconomic constraints. Participatory learning and action (PLA) is effective in low- and middle-income countries, but high-income evidence is scarce. This pilot assessed the feasibility of a community facilitator-led PLA intervention to improve infant feeding among South Asian families in East London. A three-arm pilot feasibility cluster randomised controlled trial (ISRCTN10234623) was conducted in Tower Hamlets and Newham, East London (May-September 2022), with 12 wards randomised 1:1:1 to face-to-face PLA, online PLA, or usual care. Multilingual community facilitators delivered eight biweekly sessions over 14 weeks. Feasibility outcomes were assessed against prespecified Go/Stop criteria; exploratory outcomes included child feeding behaviours (Children's Eating Behaviour Questionnaire, CEBQ), parental feeding style (Parental Feeding Style Questionnaire, PFSQ), and child BMI Z-scores. Of 263 enrolled participants, 261 had a recorded trial arm allocation; consent to the pilot feasibility study was 70.7% (186/263; 95% CI 65.0-75.9%) meeting the [≥]50% Go criterion. Attendance was 37% (Tower Hamlets 59%, Newham 29%), below the [≥]80% Go threshold. Six-month retention was 54.8% (Tower Hamlets 78%, Newham 48.5%; 95% CI 41.8-55.3%), triggering the Definite Stop criterion. Significant baseline imbalances included BMI Z-score (p = 0.005), ethnicity, borough, and education; no between-arm BMI differences were observed at follow-up (p = 0.249). CEBQ and PFSQ baseline completion was 24.5% and 23.0%, with no usable follow-up data. PLA Phases 3 and 4 were not completed by any group; all participants providing feedback reported it acceptable. Recruitment was feasible and the intervention acceptable, but a Definite Stop criterion was triggered in Newham, no group completed the full PLA cycle, and outcome data were insufficient for evaluation. A definitive trial requires stratified randomisation, digitised multilingual data collection, participant reimbursement, and explicit PLA phase-completion criteria.

Background: Digital reminders reduce outpatient no-shows, but the optimal timing and frequency of messages remain unclear, particularly in Latin American public health systems. We emulated a target trial to evaluate the comparative effectiveness of four WhatsApp reminder strategies on appointment absenteeism and patient-initiated cancellations. Methods: We analyzed administrative and electronic health-record data from the public health system of the Autonomous City of Buenos Aires, Argentina (June 2023-May 2024). Eligible individuals had scheduled an in-person outpatient appointment in one of 15 prioritized specialties at least 75 hours in advance and had a mobile phone on record. We compared four strategies: (1) dual reminders at ~72 and ~24 hours before the appointment; (2) a single reminder at ~72 hours; (3) a single reminder at ~24 hours; and (4) no reminders. The primary outcome was the proportion of no-shows by the end of follow-up. Secondary outcomes were the cumulative incidence of patient-initiated cancellations overall, within 12 hours of the appointment, and followed by rebooking. We emulated the target trial using a cloning-censoring-weighting approach to estimate per-protocol controlled direct effects, with inverse-probability weights to address time-varying confounding and selection bias. Cumulative incidence of secondary outcomes was estimated using weighted Kaplan-Meier curves. Three pre-specified sensitivity analyses and standardized mean differences assessed robustness and covariate balance. Results: A total of 475,214 first eligible person-appointments were included; baseline no-show risk in the control arm was 34.6%. All three active strategies reduced no-shows compared with no reminders. The single 24-hour reminder produced the largest reduction (Risk Ratio [RR] 0.76, 95% CI 0.72, 0.81; Risk Difference [RD] -8.21 percentage points [pp], 95% CI -9.68, -6.54), followed by the dual-reminder strategy (RR 0.80, 95% CI 0.79,0.81; RD -7.05 pp, 95% CI -7.41, -6.71) and the single 72-hour reminder (RR 0.91, 95% CI 0.84,0.99; RD -3.16 pp, 95% CI -5.69, -0.49). All active strategies increased patient-initiated cancellations relative to control, with the dual-reminder strategy producing the largest increase. Sensitivity analyses preserved the qualitative ranking of strategies across all specifications. Conclusions: In this large target trial emulation, a single just-in-time WhatsApp reminder sent ~24 hours before the appointment was as effective as a dual-reminder schedule in preventing no-shows and superior to a distal 72-hour reminder alone. Adding a second, distal reminder provided no measurable benefit for attendance but substantially increased patient-initiated cancellations, which may be operationally valuable when active slot reallocation is a goal. These findings support timing, rather than frequency, as the primary lever of digital-reminder effectiveness, and favor the deployment of a single proximal reminder as the default strategy in resource-constrained outpatient settings.

Objectives: To develop consensus on core domains and items to inform a reporting guideline for intervention fidelity in non-drug, non-surgical trials (ReFiND). Design: International, online three-round Delphi process. Methods: We invited researchers with expertise in intervention fidelity, non-drug, non-surgical trials, trial reporting, and process evaluation methods to take part in a three-round Delphi study. They rated the importance of 7 intervention fidelity domains and 79 items using a 9-point scale (1 to 3= not important, 4 to 6= important but not essential, 7 to 9= very important). A comment box was provided along with each domain and item for panellists to provide the rationale for their ratings. Consensus was defined as more than 70% of panellists rating 1-3 (exclusion) or 7-9 (inclusion) after two voting rounds. A summary of ratings and panellists rationale from Rounds One and Two were provided to panellists in Round Two and Three, respectively. We conducted a thematic analysis to synthesise qualitative data. Results: Sixty-one panellists completed Round One, 55 completed Round Two and 56 completed Round Three. Panellists had diverse backgrounds and were from 21 countries, including six low- and middle-income countries. After three rounds, five domains (Intervention Design, Intervention Fidelity Measurement Methods, Provider Training, Intervention Delivery by Providers, Intervention Receipt by Participants) and 20 items reached consensus for inclusion in the reporting guideline. Panellists rationale for their ratings was based on how specifically each domain and item related to intervention fidelity, how feasible it would be to implement in practice, and how broadly it could be applied across different contexts. Conclusions: Using systematic methods, this study reached consensus on a core set of domains and items for inclusion in ReFiND. This core set provides a foundation for consistent and transparent reporting of intervention fidelity and helps researchers and clinicians better interpret and replicate interventions tested in non-drug, non-surgical trials.

Background: Large language models (LLMs) configured as virtual patients may expand structured practice of clinical reasoning in health professions education. Before testing effectiveness, it must be established whether students engage with them and whether the resulting scores are complete, reliable, and related to performance with real patients. Our earlier pilot randomized trial found very low engagement with a less structured LLM-based approach. Objective: This study aimed to assess the feasibility (adherence, acceptability, and data completeness) of a revised, structured LLM-based clinical reasoning laboratory (Laboratorio de Inteligencia Artificial [LIA]) in undergraduate physical therapy education and to explore its measurement properties, including its association with clinical judgment with a real patient assessed with the Lasater Clinical Judgment Rubric (LCJR). Methods: In this single-arm pilot feasibility study, 27 third-year physical therapy students at a Spanish university completed, in 2024-2025, 3 virtual patient cases (lumbar, cervical, and thoracic spine pain) simulated by ChatGPT (GPT-4) over 4 weeks, each twice. ChatGPT scored each attempt from 0 to 4 on the same 10 dimensions of the Lasater Clinical Judgment Rubric (LCJR; 0-40 points) that human assessors applied (1-4 per dimension; 10-40 points) during a real patient encounter. Feasibility outcomes were case completion, data completeness, and satisfaction (0-10). Measurement outcomes were internal consistency and convergent validity (Spearman correlations between model-generated and human LCJR scores). Variability estimates informed the sample size of a future trial. Results: All 27 students were assessed with the LCJR; 22 (81%) completed at least 1 LIA case. Both attempts of the lumbar, cervical, and thoracic cases were completed by 78%, 63%, and 74% of students, respectively. Satisfaction data were available for 15 students (56%; mean 6.0, SD 1.3), and missing secondary data clustered in the third rotation. Internal consistency was excellent for the LCJR (alpha=.96) and ranged from .43 to .90 for model-generated ratings. Model-generated LIA scores clustered near the maximum (mean 36.0, SD 1.4). Among completers, LIA scores correlated weakly with the LCJR (rho=0.25, 95% CI -0.20 to 0.61; rho=0.44, 95% CI 0.05-0.71, when noncompleted attempts were scored as 0). Grade point average correlated almost perfectly with the LCJR (rho=0.96; n=22); after adjustment for it, the LIA-LCJR association disappeared (partial rho=-0.10). A future trial would require approximately 39 students per group (80% power, conservative variance). Conclusions: Delivering the LIA within the curriculum was feasible, but clinical judgment ratings generated by ChatGPT did not reflect those of human assessors with a real patient: they clustered near the maximum and showed no convergent validity once noncompletion was separated from performance. LLM-generated ratings should not be used as outcome or assessment measures without validation against human raters. Case calibration, completion tracking, and clarification of the GPA-LCJR relationship are also needed before a definitive trial. Trial Registration: ClinicalTrials.gov NCT06809634; https://clinicaltrials.gov/study/NCT06809634

Importance Non-inferiority trials are becoming increasingly popular in abdominal surgery. The non- inferiority margin is critical in the interpretation and conclusion of these trials. Objective This systematic review aims to assess the methodological and reporting quality of non- inferiority randomized controlled trials in abdominal surgery. Evidence Review Non-inferiority trials were systematically identified by searching Ovid Medline, Embase and the CENTRAL databases from 2006 until December 2025. Randomized controlled trials in adult patients with any type of abdominal surgical intervention in at least one trial arm and a sample size greater than or equal to 100 were eligible for inclusion. The primary outcome was the definition of the non- inferiority margin. Secondary outcomes were the reporting of the non-inferiority margin, the robustness of its estimation, the uncertainty of the point estimate and the adequacy of conclusions. Findings A total of 11 045 trials were identified, of which 101 were eligible, enrolling 44 370 patients. Most trials provided a rationale for the non-inferiority design, while six (5.9%) trials did not. Previous literature was commonly used (n=56; 55.4%), but the non-inferiority margin was most often based on a clinical fixed margin or on historical comparison of the treatment and the active comparator. Based on the margin, investigators tolerated substantially worse outcomes of the treatment compared to the comparator. Conclusions were appropriate based on the confidence interval and the predefined non- inferiority margin in 88 (87.1%) of trials. The clinical judgement of the conclusion was overall adequate. Confidence interval estimations were reported in 16 (15.8%) of trials. Simulation studies were limited by the reporting quality. Conclusions and Relevance Clinical fixed margins are commonly used in abdominal surgery non-inferiority randomized controlled trials, however, substantial shortcomings in reporting limit the interpretability and reproduction of study findings. Based on the findings of this study, guidance on surgical- specific non-inferiority margin definitions is needed.

Background: Uncontrolled hypertension frequently persists after emergency department (ED) discharge because of limited education, poor adherence, and fragmented follow-up. This quality improvement initiative evaluated whether structured discharge education plus telephone follow-up could improve blood pressure (BP) and continuity of care. Methods: A prospective, single-center initiative enrolled 50 consecutive adults with uncontrolled hypertension presenting to an ED in Lahore, Pakistan, from May to July 2026. Participants received standardized counseling on medication adherence, lifestyle modification, BP monitoring, warning symptoms, and primary care follow-up, followed by a structured telephone assessment approximately 2 weeks after discharge. We compared pre- and post-intervention BP values among follow-up completers using a paired-samples t-test; we summarized categorical outcomes as frequencies and percentages. Results: Of 50 enrolled patients, 38 (76%) completed follow-up, and 12 (24%) were lost to follow-up. Among completers, mean systolic BP decreased from 165.64 +/- 19.26 to 143.75 +/- 18.52 mmHg and mean diastolic BP decreased from 94.92 +/- 7.86 to 84.88 +/- 7.47 mmHg (P<0.001). Thirty-seven of 38 completers (97.4%; 74% of all enrolled) demonstrated BP improvement, and 19 of 38 (50%; 38% of all enrolled) achieved BP below 140/90 mmHg. Using the conservative all-enrolled denominator, 58% reported medication adherence, 64% reported lifestyle modification, 48% reported primary care follow-up, and 60% reported symptom improvement. Conclusion: Structured discharge education with short-term telephone follow-up was associated with clinically and statistically significant BP reductions and improved self-reported care behaviors. This low-cost approach may strengthen transitions from emergency to primary care in resource-limited settings, although loss to follow-up and the absence of a concurrent control group limit causal inference.

Reliable extraction of trial characteristics and outcomes is essential for systematic reviews, yet incorrect values can alter evidence synthesis and are difficult to detect without clear source evidence. We evaluate EviSearch, a clinical evidence-curation system that links extracted values to source passages, independently verifies cited evidence, and prioritizes higher-risk cells for review. Using ten trial publications, a 133-column schema, reference annotations, and consistent scoring across model families, we assess answer quality, inter-reading agreement, evidence reproduction, targeted review, and evidence modality. In the Qwen evaluation, EviSearch achieved 91.70% accuracy, cited 100.0% of admitted values, and reproduced 98.9% independently. Reviewing 15.6% of cells increased accuracy to 95.22%.

Abstract Background Community-based exercise may support physical and cognitive recovery after stroke, but the preferences of stakeholders involved in receiving, supporting and delivering these programmes are poorly understood. This study piloted a discrete choice experiment (DCE) that aimed to evaluate stroke survivors, carers, clinicians, and fitness instructors preferences for community-based exercise programmes for stroke survivors. The pilot aimed to assess the feasibility of conducting and analysing data for a larger-scale study and inform the sample size for a definitive DCE. Methods A DCE design was developed using literature reviews, stakeholder consultations, and evaluations of current services. Six attributes were included in the design: location, price, session frequency, individualisation, carer involvement, and recovery. Sixteen Bayesian D-optimal choice sets were developed, then blocked into two sets of eight to reduce cognitive burden. Main-effects were analysed using a mixed logit model, and stakeholder differences were explored using a conditional logit interaction model. Willingness to pay was also calculated. Results Overall, 161 respondents started the survey and 106 (66%) fully completed it. Stakeholders significantly preferred programmes that were delivered at a leisure centre, lower priced, individualised, had carer-specific sessions and offered greater chances of recovery. The largest willingness-to-pay estimates were {pound}49.41/ month for 80% chance of meaningful recovery vs 20%, and {pound}18.61/ month for leisure centre delivery vs online. Significant preference heterogeneity was identified in the main-effects model. Exploratory stakeholder interactions suggested clinicians were more price sensitive and placed greater importance on recovery and carer-specific sessions than stroke survivors, while fitness instructors placed greater importance on programme location and recovery. Carer interaction estimates were unstable due to the small subgroup sample. Conclusions The pilot supported the feasibility of the DCE design and analytical approach but identified limitations in the recruitment methods and survey completion. Addition of face-to-face recruitment methods are recommended for a larger-scale study. A larger sample size is required to investigate differences in preferences between stakeholder groups.

Background: Prolonged mechanical ventilation is associated with inspiratory muscle weakness and difficulty weaning from respiratory support. While decades of research have demonstrated that inspiratory strength training (IST) is beneficial in adult critical care populations, the literature on its use in pediatric cardiac critical care remains limited. We sought to evaluate the feasibility, safety, and physiologic response to IST in children in the pediatric cardiac intensive care unit (PCICU). Methods and Results: We performed a single-center retrospective cohort study of children with congenital heart disease referred for IST between January 2015 and August 2021. Feasibility was defined as completion of [&ge;]1 IST session following referral. Safety outcomes included physiologic events documented during IST sessions. Changes in maximal inspiratory pressure (MIP) were assessed in patients who completed [&ge;]2 IST sessions. Of 105 eligible patients, 93 (89%) successfully completed at least 1 IST session. Monitoring events were reviewed across 389 IST sessions and included pre-oxygenation (62%), desaturations (13%), bradycardia (7%), and hypertension (2%). All events were transient and did not require escalation of care. 84% of patients were successfully liberated from mechanical ventilation and required a median of 2 (IQR 1-4) sessions of IST. Among patients completing [&ge;]2 IST sessions, MIP improved signicantly over time (p>0.0001). Improvements were observed in both patients who did and did not wean from mechanical ventilation. Patients who failed to wean from mechanical ventilation had longer ventilator exposure prior to IST initiation and were more sedated at the outset of IST. Conclusions: IST was feasible and well tolerated in this medically complex PCICU cohort. High completion rates and improvements in MIP support the use of IST as a clinically deliverable intervention that can produce measurable improvements in inspiratory muscle strength during critical illness.

Panvascular intervention research requires evidence workflows that preserve source identity, outcome definitions and observation windows. We developed PanVasc Research, an executable research framework, and evaluated a fixed local Qwen3-4B model using two complementary tasks. Fifty ClinicalTrials.gov records from five vascular query strata generated 200 source-fidelity tests with intact evidence or controlled removal of the requested source, primary outcome or timeframe, plus 50 clean controls. A separate 100-statement sample from the official NLI4CT test set assessed clinical-trial entailment and evidence selection against existing expert labels. Generic and checklist prompts used identical evidence and maximum generation budgets; each output was also evaluated with an input-only deterministic contract. Registry exact accuracy was 51/200 (25.5%) with the generic prompt and 77/200 (38.5%) with the checklist; intact-case agreement was 50/50 and 48/50. The rule baseline recovered 200/200 tuples. NLI label accuracy was 48/100 (48.0%) and 50/100 (50.0%), respectively. The source contract retained 35 and 31 incorrect NLI labels in the two arms. Registry references establish fidelity to a registration snapshot, while NLI4CT concerns breast-cancer trials and does not validate vascular expertise. The framework also retains provenance-recorded literature retrieval, structured research planning and local numerical analysis. These experiments support a bounded assessment of source handling and semantic failure, rather than a new foundation model or autonomous scientific discovery. A proposed endpoint representation identifies the additional domain annotation and independent validation required for a panvascular research model.

LLMs are increasingly used to mediate patient communication, yet scalable evaluation of their safety, accuracy, and communication quality remains an open problem. LLM judges have emerged as automated evaluators, but whether they can holistically replicate human expert judgment is unvalidated. Informed consent for clinical trials presents a demanding case for such validation because it requires conveying complex information to lay audiences under ethical and safety constraints. We developed a stakeholder-informed seven-criterion evaluation rubric spanning safety, reliability, and communication quality. Clinician reference ratings showed strong interrater reliability across all criteria. We validated the rubric on the Informed CONsent Benchmark (ICON-Bench) and benchmarked 19 LLM judges across multiple implementation strategies. LLM judges achieved strong clinician agreement for safety screening and factual verification (Spearman {rho} > 0.80) but weaker agreement for communication quality ({rho} < 0.60). Safety-specialized guard models underperformed general-purpose models. Patient advocates rated communication quality lower than both clinicians and LLM judges. These findings support LLM judges for scalable patient communication oversight while demonstrating the need for recalibration to patient-centered evaluation standards.

Gaps remain in the evidence base for postoperative management following forefoot surgery. A recent randomized controlled trial (ClinicalTrials.gov NCT04927234) demonstrated improved outcomes with intermittent one Hertz (Hz) neuromuscular electrical stimulation (NMES) of the common peroneal nerve. This sub-analysis evaluates its effect in patients undergoing forefoot surgery. Forty-two patients undergoing forefoot procedures were included; 26 received NMES plus standard of care (SOC) and 16 received SOC alone. Wound healing was assessed at 14 days. Edema was measured using the figure-of-eight (FO8) method. Patient-reported outcomes were assessed using the Manchester-Oxford Foot Questionnaire (MOXFQ). At 14 days, complete wound healing occurred in 77% of patients receiving NMES plus SOC compared with 40% in the SOC group (p<0.05). Edema reduction was significantly greater in the NMES group, with a 74% relative reduction compared with SOC (p=0.02). Intermittent one Hz NMES of the common peroneal nerve was associated with improved wound healing and reduced postoperative edema following forefoot surgery.

Background: As musculoskeletal physiotherapy evolves toward advanced practice and direct access, evaluating high levels of clinical competence has become pressing. Quality indicators underpin large-scale audit systems, but indicators discriminating advanced competence remain insufficiently defined. Objective: To identify and characterize indicators capable of discriminating high levels of clinical competence in musculoskeletal physiotherapy. Methods: A modified Delphi comprised an exploratory pre-round and two consensus rounds. Experienced French-speaking musculoskeletal physiotherapists were recruited using an expertise scoring grid. Candidate indicators, generated from open-ended responses and existing quality indicators, were rated on 6-point Likert scales for relevance, formulation, and tool adequacy. Consensus was predefined as [&ge;]75% of ratings [&ge;]5. Results: Thirty-two experts completed the pre-round, 29 the first round, and 27 the second (84% retention), generating 49 candidate indicators. Thirteen reached consensus for relevance, and 10 also for formulation. Retained indicators primarily reflected advanced clinical reasoning: real-time adaptation, hypothesis prioritization, decision-making under uncertainty, and error management. Only one outcome indicator reached consensus: clinical performance weighted by case complexity. Conclusion: High levels of clinical competence in musculoskeletal physiotherapy appear characterized less by standardized outcome attainment than by managing complexity, uncertainty, and error through advanced clinical reasoning. These findings may inform competence-oriented audit and feedback systems. Trials registration: Not applicable.

As internet and mobile phone access increases, digital health interventions are increasingly used to support remote and low-resource populations. In many settings, the health impact of digital interventions is constrained by limited or short-lived engagement. We tested if conditional mobile data credit incentives increase digital intervention engagement within a digital intervention trial. This nested cluster randomized controlled trial was conducted with caregivers of children 3-9 months at baseline. Of 72 neighborhood clusters from the treatment arm of the parent trial (evaluating a digital early childhood development intervention), 20 were randomly assigned to treatment and 52 as controls. Eligible participants had a phone provider through which mobile data credits could be most affordably administered. Treated participants received around 250 MB mobile data credits every two weeks, conditional upon using the digital intervention at least once in the same period. Credits were digitally administered via a third-party service. Digital intervention engagement (primary outcome) was monitored continuously until endline data collection approximately 2 years after assignment. Secondary outcomes included caregivers views, behaviors, and early childhood development. We used intent-to-treat analyses to assess all outcomes. This trial was registered as NCT05202106 at clinicaltrials.gov and was completed in 2025. Participants were recruited between September 2021 and March 2023 (N Treatment = 147; N Control = 333). Conditional mobile data credits extended engagement with the digital early childhood development intervention by 6.50 weeks on average (treatment mean = 26.19 weeks, control mean = 19.69; p=0.011). No significant impacts were identified on secondary outcomes. As such, mobile data credits may be a cost-effective way for increasing caregiver engagement with digital health intervention in low resource settings.

Objective: To examine changes in function and pain interference among patients utilizing a digital exercise therapy application (DETA) for knee and shoulder pain. Methods: We conducted a retrospective analysis of data from patients utilizing a DETA for non-operative knee and shoulder pain. Primary outcomes for the study were 8-week changes in physical function, measured using the PROMIS-Physical Function (knee pain) and PROMIS-Upper Extremity Function (shoulder pain); and pain interference, measured using the PROMIS-Pain Interference. Data on patient characteristics was used to examine outcomes among specific patient subgroups. Results: We observed a 3.5 point (SD: 7.8) increase in function and a 3.9 point (SD: 7.5) decrease in pain interference overall (p<0.001), with changes in function and pain interference surpassing the minimal clinically important difference for patients with knee and shoulder pain. Patients with knee pain experienced greater improvements in function than those with shoulder pain (p=0.02), as did patients who report moderate-high levels of exertion during exercise compared to those reporting low levels of exertion (p=0.05). We saw greater reductions in pain interference among those with higher education (p=0.03), those with more acute symptoms (p=0.01) and those reporting moderate-high levels of exercise exertion (p=0.02). Conclusion: We observed a clinically meaningful improvement in pain interference and function among patients utilizing a DETA for knee and shoulder pain. Patients with knee pain, higher levels of education, more acute symptoms, and those who reported higher levels of exertion with exercise experienced the greatest changes in function and pain. Impact Statement: This study indicates that self-guided interventions, such as those delivered through a DETA, may be beneficial for patients with knee and shoulder pain. These results may also inform the development of patient profiles that can be used to identify patients most appropriate to receive care through a mobile application.

Bayesian borrowing of external information can improve trial efficiency, particularly in pediatric and rare disease settings where patient populations are limited, but may introduce bias and inflate the Type~I error rate when the trial differs from external studies. Recent U.S. Food and Drug Administration (FDA) draft Bayesian guidance emphasizes careful evaluation of external information, prior specification, and assessment of operating characteristics. This paper compares three meta-analytic-predictive (MAP)-based methods for Bayesian borrowing: the MAP prior, robust MAP (RMAP) prior, and self-adapting mixture (SAM) prior. An adaptive platform trial design in Rett syndrome is used as a case study. Simulation studies evaluate frequentist operating characteristics under varying prior--data conflict, between-study heterogeneity, treatment effects, and clinically significant differences (CSDs) for the SAM prior. The MAP prior achieved the greatest efficiency when external and current data were compatible but exhibited the largest bias under substantial prior--data conflict. The RMAP priors improved robustness through fixed robust-component weights, whereas the SAM prior adaptively adjusted borrowing and was less sensitive to prior--data conflict while retaining efficiency gains when the data were compatible. Although the CSD influenced the degree of adaptive borrowing, as reflected by effective sample size, it had only a modest impact on frequentist operating characteristics. Sensitivity analyses using a skeptical robust component yielded similar qualitative conclusions, while accentuating the differences between the MAP and RMAP priors. These findings provide guidance for evaluating and selecting MAP-based borrowing strategies before trial implementation, particularly in rare disease settings, consistent with current FDA recommendations.

Background. Long COVID affects an estimated 400 million people worldwide, and is associated with low quality of life. Nearly all completed Long COVID clinical trials reported no benefit, and most required participants to travel to study sites. This requirement systematically excludes severely affected patients. Because there are numerous candidate therapeutics with established safety profiles and regulatory approvals for other indications, scaled, efficient evaluation of therapeutics is needed. Methods. We designed and are conducting a double-blind, placebo-controlled, phase two trial of tirzepatide for Long COVID fatigue, using an entirely remote infrastructure. Design elements included electronic consent, identity and diagnosis verification through document upload, cold-chain delivery of an injectable study drug through a central pharmacy, shared decision-making for dose titration, repeated at-home capillary blood collection in a biospecimen subcohort, weekly participant touch points through study application, wrist-worn wearable monitoring, and clinical support. The trial is operating under FDA Investigational New Drug authorization. Results. This trial enrolled 1,058 participants in 73 days, at least double the rate of any other Long COVID trial. Mean baseline metrics include mean Fatigue Severity Scale of 59.3 (standard deviation [SD] 4.9), daily step count of 3,611 (SD 2,706, general population reference mean 7,731), EQ-5D-5L of 0.6 (SD 0.2), and FUNCAP27 4.0 (SD 1.0), which was a more severely affected population than other clinical trials that collected comparable data. Study processes are working as designed. Participants use existing advocacy and support channels to gather and communicate. Conclusions. A direct-to-participant, siteless infrastructure can support a double-blind placebo-controlled trial of an injectable drug at scale, accelerate accrual, and reach severely affected participants who are routinely excluded by site-based designs. Modernizing drug distribution and regulatory pathways is needed to realize the full potential of decentralized infrastructure for drug repurposing clinical trials.