Contemporary Clinical Trials Communications

Background: Large language models (LLMs) offer promise for systematic review data extraction, but performance in complex multidisciplinary domains and utility for clinical statement generation remain insufficiently described. Objectives: To evaluate Google NotebookLM for AI-assisted data extraction and RAND/UCLA consensus statement generation in a systematic review of IBD, obesity, and cardiometabolic comorbidities. Methods: Studies were organized into domain-specific notebooks; structured prompts generated standardized evidence tables. Two independent reviewers validated outputs against full-text articles using a four-category error classification. Cell-level accuracy and critical accuracy (cells free of major factual errors) were the primary metrics; workflow time was compared against a published conventional extraction benchmark. Concordance between AI-generated and expert-finalized statements was assessed. Results: Across 57 articles, 1,710 data cells were extracted; 151 (8.83%) were flagged, yielding 91.17% cell-level accuracy. Major factual errors occurred in only 4 cells (0.23%), for a critical accuracy of 99.77%. Most errors were minor omissions (59.6%) or incomplete extractions (30.5%); domain error rates ranged from 7.08% to 11.33%. The pipeline required 17.7 versus a projected 165.1 person-hours (89.3% reduction). PICO-structured prompting generated 70 candidate statements; 58 of 112 finalized panel statements (51.8%) were AI-derived, and 85.7% were retained in the finalized set. Conclusion: Google NotebookLM demonstrates feasibility as a primary extraction and synthesis tool in a multidisciplinary systematic review, with extractive incompleteness as the principal limitation and substantial time savings over conventional approaches. Its novel application to RAND/UCLA consensus statement generation extends AI-assisted evidence synthesis to clinical consensus generation workflow.

Background: The Cilostazol Albumin Treatment in Subarachnoid Hemorrhage (CATS) trial evaluates eight active cilostazol-human albumin regimens plus control in patients with aneurysmal subarachnoid hemorrhage. We summarized the rationale for the primary statistical design, compared alternative Phase II methodologies, and evaluated reduced-arm sensitivity scenarios. Methods: The binary primary endpoint is Common Data Elements-defined delayed cerebral ischemia within 14 days after randomization. The selected design is Bayesian adaptive, with a burn-in phase, response-adaptive randomization among active arms while maintaining fixed control allocation, four interim analyses, early stopping for expected success or futility, and a two-dimensional normal dynamic linear model. Primary operating characteristics were obtained from 1,000 virtual trials per scenario using Fixed and Adaptive Clinical Trial Simulator version 7.0.0. Exploratory simulations evaluated six-, four-, and two-active-arm configurations and simplified alternative designs. Results: Compared with fixed equal allocation, the Bayesian adaptive design preserved an approximately 10% false-success probability under the global null while improving probability of success and efficiency in clinically relevant scenarios. Under the Realistic scenario, probability of success increased from 0.61 to 0.86, expected sample size decreased from 400 to 308, and expected duration decreased from 235 to 187 weeks. Under common thresholds, null probability of success was 0.098 for the full anchor and 0.073 for Reduced-6; Reduced-6 probabilities of success were 0.774 and 0.765 in the Realistic and Realistic2 scenarios. However, Reduced-6 omitted two monotherapy anchors and was less robust in Backwards2. In the comparator simulation, the selected design had probability of success of 0.858 and expected sample size of 308.3 under the Realistic scenario, compared with 0.624 to 0.845 and approximately 352 to 400 for simplified comparators. Conclusions: For identifying the most promising cilostazol-human albumin regimen for Phase III rather than confirming efficacy, the Bayesian response-adaptive design with two-dimensional normal dynamic linear model borrowing is more efficient and better aligned than simplified comparators. The full nine-arm design remains preferable because it preserves the complete therapeutic discovery space and is more robust to misspecified or non-smooth response surfaces.

Background Optimal timing for resuming direct oral anticoagulants (DOACs) after high-risk endoscopic procedures remains uncertain, and existing recommendations derive largely from expert opinion. The objective of this study was to characterize practice patterns and perceptions among endoscopists and outcome prioritization among patients with atrial fibrillation, in order to inform the design of the planned RESUME randomized trial. Methods We conducted parallel, cross-sectional surveys of practicing endoscopists and patients with atrial fibrillation using electronic questionnaires administered via Qualtrics. The endoscopist survey, distributed through the American Society for Gastrointestinal Endoscopy, assessed practice patterns, acceptability of early (postoperative day [POD] +1), intermediate (POD +3), and late (POD +5) resumption strategies, and perceptions of clinical equipoise. The patient survey, distributed through two advocacy organizations, assessed perceived confidence in existing guidance and prioritization of bleeding versus thromboembolic risk. Results A total of 201 endoscopists and 477 patients (92.5% taking a DOAC) provided evaluable responses. Endoscopists demonstrated wide variability in preferred timing of DOAC resumption after a standardized high-risk mucosal resection vignette, ranging from same-day resumption to delays beyond five days. POD +2 was the most commonly selected strategy, and most respondents rated more than one proposed RESUME trial arm as acceptable. Nearly all endoscopists (98.9%) rated a randomized trial to determine optimal timing as important. Patient preferences regarding bleeding versus stroke risk were heterogeneous and symmetrically distributed around the neutral response on a five-point ordinal scale. Preferences did not differ by prior stroke or transient ischemic attack, prior major bleeding, age, sex, or geographic region. More than half of patients (54.6%) reported being very or somewhat confident that clear guidance exists regarding DOAC resumption, despite the absence of high-quality randomized evidence informing this question. Conclusions Endoscopists demonstrate substantial practice variability and clinical equipoise, and patients demonstrate heterogeneous and balanced outcome preferences, regarding the timing of DOAC resumption after high-risk endoscopy. These findings support the ethical justification and relevance of the planned RESUME trial.

Background: Functional dyspepsia (FD) is among the most common gastrointestinal disorders worldwide and is characterized by symptoms including epigastric pain, early satiety, postprandial fullness, bloating, and upper abdominal discomfort. Itopride hydrochloride is commonly administered as 50 mg three times daily (TID). To improve convenience and potentially enhance adherence, a once-daily (OD) 150 mg extended-release formulation was developed. Phase 1 studies demonstrated bioequivalent overall exposure between the OD and TID regimens, with sustained-release characteristics and no evidence of dose dumping, supporting advancement to Phase 3. This pivotal clinical study evaluated whether itopride hydrochloride 150 mg OD is non-inferior to the established 50 mg TID regimen in improving FD symptoms over 8 weeks. Methods: This Phase 3, randomized, open-label, multicenter, active-controlled study enrolled 564 participants with FD (or chronic gastritis) to compare the efficacy and safety of itopride hydrochloride 150 mg OD versus 50 mg TID over 8 weeks. The primary endpoint was change in overall FD severity from baseline to Week 8, assessed using the Leeds Dyspepsia Questionnaire (LDQ) severity score. Secondary endpoints included symptom-specific severity, disease-specific quality of life, responder rates, treatment acceptance, and safety. Results: Clinical non-inferiority in terms of overall FD severity was demonstrated with OD treatment compared to TID. LDQ severity improved by -9.60 (95% CI -10.15, -9.05) with TID and -9.76 (95% CI -10.32, -9.19) with OD, with a between-group difference of 0.16 (95% CI -0.42, 0.74). Improvements across symptom domains and quality of life measures were comparable. Treatment acceptance favored OD (mean 4.22 vs 3.83; p < 0.001). Both regimens were well tolerated, with predominantly mild adverse events. This clinical evaluation of OD was supported by the Phase 1 results confirming that both single-dose and multiple-dose administration of itopride hydrochloride 150 mg OD provided a comparable extent of exposure to the 50 mg TID regimen, demonstrated by area under the curve (AUC) values within the 80 to125% bioequivalence range and stable pharmacokinetic profiles across fed and fasted conditions. Conclusion: The study confirmed that itopride hydrochloride 150 mg OD is non-inferior to the TID regimen for improving FD (or chronic gastritis) symptoms. The OD regimen demonstrated comparable efficacy, favorable treatment acceptance, and a positive benefit-risk profile, offering a more convenient therapeutic option for patients.

Background: Despite ample evidence of the benefits of cardiac rehabilitation (CR), few transcatheter aortic valve replacement (TAVR) patients participate. Commercially available mobile health offers an opportunity to deliver activity-promotion content to populations that are challenged to participate in CR. This study aims to test the efficacy of clinically controlled, commercially available fitness programming for improving physical activity and cardiovascular health outcomes designed to be initiated while patients are on waitlists for traditional CR. Methods: The Cardio Heart Connect study is a hybrid type I effectiveness-implementation trial aiming to enroll N=200 patients who have been placed on a cardiac rehab waitlist following a TAVR procedure from the University of Colorado Hospital Heart and Vascular Center. Participants will be randomized 1:1 to the Cardio Heart Connect intervention with commercially available fitness or attention control, designed to control for technology access. At baseline, post-intervention (8 weeks), and follow-up (12 months), we will assess the primary outcome of participants? daily steps as measured by smartwatch accelerometer and secondary outcomes of interest including functional capacity (Duke Activity Status Index; VO2max), quality of life (Kansas City Cardiomyopathy Questionnaire), and cardiovascular health status (Life Essential 8). In addition, we will use mixed methodologies to evaluate the implementation of intervention using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) Framework. Conclusions: Commercially available fitness programs have the potential to provide more accessible opportunities for patients recovering from TAVR to engage in physical activity and may be preferred due to their customizability, convenience, and ease of scheduling. Overall, this study will provide insight into the use of commercial mHealth to promote activity following TAVR.

Importance: The ASPREE randomized trial found no overall benefit of low-dose aspirin for disability-free survival among older adults. However, individual estimates in pre-specified subgroups indicated potential benefit among racial and ethnic minoritized participants in the United States (US). Objective: To evaluate whether the effect of low-dose aspirin vs placebo on disability-free survival differed across US Black and Hispanic ASPREE participants using individualized treatment-effect estimation. Design, Setting, and Participants: Post hoc clinical trial analysis of ASPREE, a randomized, double-blind, placebo-controlled clinical trial of daily low-dose aspirin vs placebo. This analysis included US ASPREE participants who self-identified as non-Hispanic Black or Hispanic, were aged 65 years or older, and had complete baseline predictor and outcome data. Interventions: Randomization to daily 100-mg aspirin or placebo. Main Outcomes and Measures: The primary outcome was loss of disability-free survival, defined as death, persistent physical disability, or dementia. Individualized treatment effects were estimated post hoc using a Random Survival Forest X-learner. Heterogeneity was evaluated on the relative scale with Cox proportional hazards models and on the absolute scale with 5-year risk differences. Results: Among 2411 US ASPREE participants, 1270 were included in the Black and Hispanic analytic cohort (897 non-Hispanic Black and 373 Hispanic participants; mean age, 71.8 years). Aspirin was associated with lower risk of disability-free survival loss compared with placebo (hazard ratio [HR], 0.65; 95% CI, 0.45-0.93). In model-derived tertiles, aspirin was associated with lower risk in the greatest predicted-benefit group (HR, 0.36; 95% CI, 0.19-0.71; 5-year absolute risk difference [ARD], -11.1 percentage points; 95% CI, -22.0 to -0.1) but not in the lowest predicted-benefit group (HR, 1.26; 95% CI, 0.70-2.27; ARD, +3.9 percentage points; 95% CI, -5.9 to 13.6). Conclusions and Relevance: In these analyses of US Black and Hispanic ASPREE participants, aspirin effects on disability-free survival appear to be heterogeneous, with benefit concentrated in a subset of participants. Because these findings are from post-hoc models, they should be externally validated before being incorporated into clinical decision-making. Trial Registration: ClinicalTrials.gov Identifier: NCT01038583; https://clinicaltrials.gov/study/NCT01038583

Background: Recruitment of diverse participants remains a challenge in cardiovascular clinical trials. Little is known about how recruitment efficiency and advertising costs with web-based tools vary across US communities. We evaluated an online recruitment platform and examined the cost of acquiring both all-comers and diverse participants in relation to community-level income. Methods: The Heartbeat Study evaluated a digital recruitment strategy to identify US participants for the ongoing Phase 3 LIBREXIA-AF trial. Online advertisements directed individuals with atrial fibrillation to a pre-screening website, where demographic and health data were collected. Advertising impressions, clicks, and costs were recorded. Participant ZIP codes were linked to Core Based Statistical Areas (CBSAs) and CBSA-level income. We measured recruits from underrepresented groups (women, African Americans, Latinos) completing online registration per $100,000 in advertising expenses. Click-weighted linear regression evaluated associations between CBSA income and advertising efficiency. Results: A total of 1,406 recruits completed online registration, with 1,319 participants from 260 CBSAs included in the geographic analysis. Participants were 73 years old on average; 547 (41.5%) were women, 59 (4.5%) African American, and 44 (3.3%) Latino. A total of $163,949.13 was spent on 82,681,711 impressions and 454,750 clicks. Recruits per $100,000 in advertising spend were 334 for women, 36 for African Americans, and 27 for Latinos. CBSA-level income was modestly inversely associated with cost per impression (R2=0.058; p<0.001) and cost per click (R2=0.038; p=0.005), but not recruitment yield for African Americans (p=0.99), Latinos (p=0.37), or women (p=0.21) (R2 range, 0.000-0.13). Conclusions: In this national analysis, online advertising enabled broad engagement across diverse US communities, but income was not associated with recruitment yield among women, African American, or Latino participants. Minority representation remained limited, suggesting digital recruitment alone may be insufficient to improve trial diversity. Targeted, culturally and linguistically tailored strategies may be needed to enhance diverse recruitment.

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.

Objective: Breast milk is the optimal source of nutrition for preterm infants, however, low breast milk production is common following a preterm birth. This study aimed to determine if taking brewers yeast' or beta-glucan improves daily expressed breast milk volume. Design: Randomised, blinded, parallel, placebo-controlled trial. Setting: Three Australian tertiary level neonatal units. Patients: Mothers with a singleton or twin pregnancy who gave birth at less than 34 weeks' gestation. Interventions: Mothers were randomised within 72 hours of birth into three parallel groups in 1:1:1 ratio to receive either brewers' yeast, beta-glucan or placebo capsules for seven days. Main outcome measure: Total expressed breast milk volume over a 24-hour period on day seven of intervention. Results: A total of 105 mothers underwent randomisation between August 2022 and April 2024 (36 brewers' yeast, 35 beta-glucan, and 34 placebo). The adjusted mean difference in daily expressed breast milk volume was 94 mL/day (95% CI -51 to 239 mL/day) between the brewers' yeast and placebo groups, and -25 mL/day (95% CI -173 to 123 mL/day) between the beta-glucan and placebo groups. Maternal side effects were similar across groups. Conclusion: We found no clear effect of short-term administration of brewers' yeast or beta-glucan on breast-milk production following preterm birth; both interventions were well tolerated. Given the small sample size, these findings do not rule out the possibility of a clinically meaningful benefit of brewers' yeast and suggest further research with a larger sample size may be warranted to clarify the potential clinical impact. Trial registration number ACTRN12622000968774.

Background: Chronic knee pain, primarily due to knee osteoarthritis, significantly impairs quality of life of the elderly by restricting mobility, reducing physical activity, and contributing to psychological distress such as depression and anxiety. The standard of care include pharmacological treatments (e.g., NSAIDs, analgesics), physical therapy, lifestyle modifications, and, in severe cases, surgical interventions, most of which often do not provide sustained relief, may carry adverse effects, and lead to poly-pharmacy, particularly in elderly patients with comorbidities. Ashwagandha is known to have Balya (strengthening) and Rasayana (adaptogenic/ rejuvenating) properties, pacifies Vata and thus may be helpful in mitigating chronic musculoskeletal pain. Objective: To evaluate the efficacy of oral Ashwagandha & Til Taila Abhyanga for six weeks on chronic knee pain, functionality, mobility, quality of life, general wellbeing, sleep quality of the older adults with knee osteoarthritis. Materials & Methods: Patients of any gender, above 60 years age and having pain in one or both knee joints since more than 3 months and average severity rated [&ge;]4 on the Wong-Baker Faces, due to knee osteoarthritis diagnosed as per the American College of Rheumatology Criteria are being included in the study. Medically unstable and non-ambulatory patients with severity Grade>4 of Kellgren and Lawrence scale for OA, BMI[&ge;]30 kg/m2, those on recent treatment with intra-articular injections or Ayurveda medications, having knee implant or fixed flexion deformity in knees, history of acute trauma, or with severe systemic/infectious ailments or other chronic conditions affecting the knee joint are excluded. Total 72 participants are enrolled and allocated randomly to either group. Participants are given either Ahwagandha Churna or Boswellia extract as oral medication for 45 days. Til Taila and standard operating procedure of Abhyanga (external oleation through massage) at the affected knee are given in both groups. The severity of pain is assessed by the numeric pain rating scale after every 15 days. Other outcomes are change in Knee Injury and Osteoarthritis Outcome Score, score of WHO Wellbeing Index -5, Global Sleep Assessment Questionnaire, Five Times Sit and Stand test and Time to Up and Go, after the intervention period. The need for conventional analgesics through the study duration is also observed and will be compared in both groups. Discussion: The outcomes of this double-blind randomized controlled trial will inform about the efficacy of Ashwagandha which is generally considered as Balya in alleviating chronic pain of knee osteoarthritis among elderly. This study can generate evidence and lead to larger effectiveness studies on role of adding Ashwagandha to the standard care for management of chronic musculoskeletal pain in older adults.

In February 2026, the FDA announced that a single pivotal phase 3 (P3) trial would become the new default standard for drug approval - a regulatory direction that had been legally enabled since the FDA Modernization Act of 1997. This announcement has strategic, scientific, and economic implications for drug developers, contract research organizations (CROs), and biotech investors. We argue that the expansion of this framework, originally reserved for various niche submissions, represents a paradigm change, dramatically increasing the value of rigorous early phase (P1 and P2) trial design, requiring sponsors to establish both statistical efficacy signals and mechanistic biological understanding before entering phase 3. Using a CNS indication cost model, we show that single P3 approval can reduce total development expenditure from approximately $447 million over 14 years to $297 million over 12 years - a savings of $150 million and providing two years of additional commercial runway for a modeled CNS drug. Case examples including lecanemab, omaveloxolone, and tofersen illustrate how biomarker-informed early phase strategies can establish the confirmatory evidence necessary for single-trial approval. We provide practical guidance for maximizing the value of P1 and P2 under this evolving framework.

Post-stroke depression affects approximately 30% of patients after stroke and is associated with delayed recovery in activities of daily living, reduced rehabilitation effectiveness, and poorer quality of life. Attentional bias modification may provide a low-burden, nonpharmacological approach for patients in the acute phase of stroke. However, before such an intervention can be implemented in clinical practice, it is necessary to clarify whether attentional bias is present in patients with acute stroke and depressive symptoms, whether cognitive function influences the manifestation of this bias, and which task and stimulus formats are most appropriate for assessment. This multicenter, cross-sectional observational study will enroll patients with acute stroke between 7-30 days after stroke onset. Depressive symptoms will be assessed using the depression subscale of the Hospital Anxiety and Depression Scale. Attentional bias will be measured under four task conditions based on the dot-probe task and the cue-target task, using face and word stimuli. Secondary assessments will include cognitive function, anxiety symptoms, activities of daily living, health-related quality of life, and clinical background variables. The aims of this study are to investigate the association between depressive symptoms and attentional bias in patients with acute stroke, compare attentional bias characteristics across task and stimulus types, and examine the potential influence of cognitive function on this association. The findings are expected to provide an empirical basis for designing future attentional bias modification protocols targeting post-stroke depression in the acute phase. This study has been registered with the UMIN Clinical Trials Registry (UMIN000059166).

Background. Depression affects an estimated 332 million people worldwide and is a leading cause of disability, with up to 80% of major depressive episodes preceded by an identifiable adverse life event [17,18]. First-line treatments target symptoms rather than the precipitating event and are resource-intensive: standard CBT averages roughly 12 sessions, and antidepressant discontinuation carries relapse rates near 35% at six months [8]. These limitations create a clear rationale for brief, structured interventions that address the cognitive and somatic sequelae of adverse life events directly. Painhunting therapy is one such intervention, in which each session targets a discrete adverse event through a structured incident-processing procedure. Methods. We conducted a two-arm, parallel-group, single-site randomised controlled trial comparing Painhunting therapy (Arm A, immediate; n=42) with a waitlist control (Arm B, delayed; n=42) in adults with PHQ-9 >= 9 and active psychological distress related to an adverse life event. After the primary endpoint at T2 (approximately two weeks post-randomisation), Arm B crossed over to active treatment, with T3 as the post-crossover endpoint at approximately four weeks. The primary outcome was PHQ-9 at T2 (between-arm contrast); secondary outcomes were ICG, GAD-7, WHO-DAS 2.0 (12-item), and the Global Impression of Change (GIC). Pre-specified analyses included intention-to-treat, per-protocol, and single-exclusion sensitivity populations. Results. Eighty-four participants were randomised (198 applications, 134 completed screening questionnaire, 119 passed psychometric screening). At T2, mean PHQ-9 was 2.32 (SD 2.59) in Arm A and 16.56 (SD 6.76) in Arm B, yielding an ITT between-arm Cohen d = 2.78 (95% CI 2.19-3.76, p < 0.001). Within-arm paired reductions during each arm's active-treatment window reproduced this magnitude (Arm A T0 to T2 change 14.71, Morris d = 2.80; Arm B T2 to T3 change 14.19, Morris d = 2.77, eligible n=26). Treatment gains were durable at the T4 follow-up (week 8). Aligning each arm to its own end-of-treatment timepoint, the off-treatment drift to week 8 was almost identical between arms: Arm A rose 0.78 points from T2 to T4 (2.19 to 2.97, n=37) and Arm B rose 1.59 points from T3 to T4 (4.74 to 6.33, n=27), the latter falling to 0.77 points once a single documented relapse case (R59) is excluded (4.81 to 5.58, n=26). This small off-treatment rebound then stabilised rather than continuing: Arm A was essentially unchanged from T3 to T4 (change +0.05), with concordant maintenance on ICG, GAD-7, and WHO-DAS. At T4, 68% of Arm A and 41% of Arm B remained in remission (PHQ-9 < 5). Secondary measures (ICG, GAD-7, WHO-DAS) moved in the same direction and to comparable magnitude at every timepoint. The waitlist window in Arm B showed essentially no change on any measure (PHQ-9 change 0.22, p = 0.81). Sensitivity analyses excluding six sub-threshold T2 cases, the single treated-in-error case (R82), the R59 relapse case, and one late T2 submitter left all conclusions unchanged. Conclusions. Painhunting therapy produced large and statistically robust reductions in depression, complicated grief, anxiety, and functional disability over a brief course of three to four sessions, with effect sizes substantially exceeding benchmarks reported for established first-line psychotherapies including CBT and EMDR. Critically, these gains persisted at the week-8 follow-up: depression scores in the immediate-treatment arm were essentially unchanged from four weeks to eight weeks post-randomisation, indicating that the benefit reflects durable change rather than a transient post-session dip. Treatment-window concordance between arms, durability of gains at one month off-treatment, and the flat waitlist trajectory together strengthen the evidence for genuine efficacy rather than spontaneous remission. Baseline covariates including therapeutic alliance, treatment expectancy, self-efficacy, age, and sex showed near-zero associations with outcome, reducing the plausibility of allegiance bias or expectancy effects as primary drivers. The differential retention between arms (88% vs 64% at T3) is attributable to the waitlist design and is discussed as a limitation. These findings support proceeding to a confirmatory active-comparator trial against manualized CBT. Trial registration: ClinicalTrials.gov NCT07490691, prospectively registered.

Background Delirium is common among hospitalized older adults on many clinical services and associated with poor outcomes. Given delirium's fluctuations, wearable devices are promising continuous monitors. While recruiting for a wearable electroencephalography (EEG) delirium study, we initially experienced low enrollment rates among older adults and patients on non-neurologic services. Our aim was to understand patient and community perspectives on inpatient, wearable research to adapt recruitment protocols and increase enrollment. Methods We approached patients admitted to an academic medical center to participate in an observational, wearable EEG delirium study and recorded reasons for enrolling or declining. To gain insight into recruitment protocols, we held a community panel with patients, family members, and caregivers. Recruitment protocols were refined in two phases: 1) personalizing the recruitment approach to emphasize symptoms that were personally relevant to individual patients and 2) sharing educational materials about the study in addition to delirium. We compared enrollment rates before and after these protocol adaptations. Results Initially, 18.5% of approached patients enrolled (68/367). Despite antecedent concerns that wearable devices would be the primary deterrent to participation, only a small proportion of people who did not participate did so because of wearable EEG (8.8%, 26/299). Community panel members (n=7) suggested that personal relevance and understanding of the clinical conditions being studied, such as delirium, would have a greater impact on decisions to participate than study procedures. Adapting recruitment protocols to highlight personally relevant delirium-related symptoms, such as sleep disturbance, significantly increased enrollment rates (30.1%, 58/188, p<0.001), including for patients over 65 years old (p<0.001) and patients on non-neurologic services (p<0.001). The addition of educational materials focused on clinical delirium did not further impact enrollment (p=0.61). Conclusions Recruitment of older, hospitalized patients for inpatient research can be challenging, but can be significantly improved by highlighting familiar symptoms of personal relevance.

Background/Objectives Tooth loss may impair masticatory function, potentially affecting gastrointestinal health. This study examined the association between clinically examined tooth loss and abnormal bowel habits among US adults. Methods This cross-sectional study used NHANES 2005-2010 data. Adults aged [&ge;]20 with clinical oral examination (OHX) and Bristol Stool Scale (BSS) data were included. Missing teeth (0-28) were categorized as 0, 1-5, 6-10, 11-27, and 28. The primary outcome was abnormal bowel habits (BSS 1-2 or 6-7 vs. 3-5); secondary outcomes included constipation, diarrhea, and fecal incontinence symptoms. Survey-weighted logistic regression with progressive covariate adjustment was used, with Benjamini-Hochberg FDR correction for secondary outcomes. Results Among 9,988 participants (14.5% prevalence), the P-for-trend for abnormal bowel habits was significant (OR = 1.015, 95% CI: 1.006-1.024, P = 0.001), corroborated by omnibus Wald (P = 0.006) and restricted cubic spline analyses (P = 0.019). Complete edentulism was associated with 1.5-fold higher odds (OR = 1.545, P = 0.006). Constipation survived FDR correction (FDR-adjusted P = 0.032). Results were robust across most of five sensitivity analyses, with modest attenuation noted after denture use adjustment in a restricted subset. Conclusions Tooth loss was significantly associated with abnormal bowel habits, with constipation surviving FDR correction. These findings support the oral-gut axis hypothesis and highlight the importance of maintaining natural dentition for gastrointestinal health.

Introduction Chronic musculoskeletal pain (CMSKP) in adolescence is associated with physical, psychological, social, and academic impairment and increased risk for chronic pain in adulthood. Although physical activity interventions are an evidence-based approach for managing pediatric chronic pain, many adolescents with CMSKP avoid physical activity due to fear of increased pain, low confidence in physical functioning, and other pain-avoidance behaviors. Resilience-focused interventions targeting self-efficacy, motivation, and mental flexibility may improve engagement in valued activities despite pain. This study describes the design and protocol of the Pain REsilience Promotion for Youth (PREP-Y) intervention, a resilience-focused physical activity intervention for adolescents with CMSKP. Methods and analysis This single-site, pilot phase 2, single-group, non-randomized clinical trial will enroll 40 adolescents aged 12-17 years with CMSKP from Nationwide Childrens Hospital in Columbus, Ohio, USA. Participants complete questionnaires, objective physical functioning assessments, and physical activity monitoring using activPAL devices as baseline measures. Participants then complete 4 virtual resilience-focused intervention sessions targeting pain resilience, self-efficacy, motivation, and adaptive coping related to physical activity. Garmin watches are used to track activity during the intervention period. Follow-up assessments occur post-intervention and at 3 months post-intervention. Primary outcomes include feasibility and acceptability, assessed through recruitment, retention, attendance, intervention fidelity, and completion of study measures. Exploratory outcomes include physical activity, sedentary behavior, pain-related functioning, pain catastrophizing, kinesiophobia, self-efficacy, and resilience-related constructs. Ethics and dissemination The study was approved by the Nationwide Childrens Hospital Institutional Review Board. Findings will inform a future randomized clinical trial. This manuscript reflects protocol version 5.0 dated 23 March 2026. Trial registration ClinicalTrials.gov: NCT06923891.

Background: Although the acute phase of the COVID-19 pandemic has passed, SARS-CoV-2 continues to cause outpatient morbidity. Antioxidant micronutrients support immune regulation and may offer a low-cost, scalable adjunctive treatment in early infection. Objective: To evaluate a pilot combination antioxidant therapy within CanTreatCOVID. Methods: This pilot sub-protocol enrolled non-hospitalized adults across five Canadian provinces (September 5th, 2024-March 31st, 2025) with mild-to-moderate SARS-CoV-2 infection within five days of symptom onset. Participants were randomized to usual care plus a 10-day antioxidant regimen (selenium 300 g, zinc 40 mg, lycopene 45 mg, vitamin C 1.5 g) or usual care alone. Pilot objectives assessed feasibility, retention, adherence, and safety. The primary outcome was hospitalization or death within 28 days; exploratory outcomes included recovery and symptom measures by day 14. Results: Eighty-one participants were randomized (41 antioxidant; 40 usual care). Retention was high 85.4% antioxidant; 82.5% usual care), and 90.2% of antioxidant participants completed the intervention course. Adverse events were infrequent (9.8% vs 2.5%), with no serious adverse events reported. No deaths occurred in either group; no hospitalizations occurred in the antioxidant arm versus 2/40 (5%) in usual care. By day 14, recovery was reported in 32/40 (80.0%) participants receiving antioxidants versus 23/36 (63.9%) in usual care (OR 2.128; 95% CI 0.7474.871). Sustained alleviation of all symptoms occurred in 38/40 (95.0%) versus 29/36 (80.6%), respectively (OR 3.498; 95% CI 0.872 --10.017). Return to usual activity by day 14 occurred in 38/40 (95.0%) versus 30/36 (83.3%) (OR 3.113; 95% CI 0.762--9.022). Adjusted between-group differences in dietary intake were not statistically significant. Conclusions: Combination antioxidant therapy was feasible to deliver in a decentralized outpatient setting, with high adherence and tolerability. While the trial was not powered for definitive efficacy conclusions, consistent directional improvements across symptom outcomes support evaluation of this host-directed antioxidant strategy in larger trials. Keywords: Adaptive Platform Trial; Antioxidant Therapy; SARS-CoV-2 ; Outpatient Therapeutics; Micronutrient Supplementation Trial registration number: https://clinicaltrials.gov/study/NCT05614349

Importance. Systematic reviews and meta-analyses inform suicide-prevention policy and practice, but broad database searches are difficult to screen manually. This limits capture of upstream interventions, such as economic policies, with indirect effects on suicide. Reliable automated screening could make broader and more comprehensive evidence syntheses feasible. Objective. To develop and validate ScreenAgent, a large language model (LLM) agent for title and abstract screening, and a review-specific method for prospectively estimating screening performance. Design, Setting, and Participants. ScreenAgent was validated internally on a prospective meta-analysis, and externally on two published systematic reviews. The correct include and exclude decisions followed standard systematic-review screening methodology. Exposures. ScreenAgent, an LLM agent returning structured include-or-exclude decisions. Records it marked for inclusion were re-checked by a second, cascade pass using a higher-effort LLM. For the external reviews, the agent's prompt was tuned automatically on a small set of labeled examples. Main Outcomes and Measures. We calculated sensitivity, specificity, workload reduction (the percentage of records removed from human review), and agent-versus-human reliability via Cohen kappa. Sensitivity was estimated by direct comparison (internal) and 5-fold cross-validation (external). Results. In the internal validation, ScreenAgent identified 43 of 44 eligible studies (sensitivity 97.7%; 95% CI, 88.2%-99.6%) with a generic prompt applied without any review-specific optimization, specificity 98.0%, and a measured full-corpus workload reduction of 99.4%. The cost was $855.91 for the full 201,064-record corpus (0.43 US cents per record). Agent-versus-human-consensus agreement exceeded human-versus-human agreement (Cohen kappa 0.75 vs 0.64; percent agreement 97.3% vs 95.4%). For two external validation studies, automatic tuning resulted in a cross-validated sensitivity of 95.9% (95% CI, 90.0%-98.4%) and 97.4% (90.9%-99.3%), with workload reductions of 97.4% and 98.4%. Conclusions and Relevance. Suicide prevention efforts often require rapid consolidation of evidence because of the inherent challenges of single studies trying to prevent rare outcomes. On both internal and external validation sets, ScreenAgent identified nearly all eligible studies with human-level reliability for a fraction of a US cent per record while keeping human reviewers as the final arbiters. By making broad searches feasible and screening performance measurable beforehand, this approach can serve as a transparent methodology to strengthen the speed at which we can inform and advance suicide prevention efforts.

Background: Blood-based colorectal cancer (CRC) screening is a novel, less invasive screening that has the potential to improve CRC screening adherence, particularly among Black American populations, which has historically lower screening rates. We evaluated factors associated with preference for blood-based CRC screening among Black adults in church-based community settings. Methods: From October 2023 to January 2024, a cross-sectional survey was conducted over 101 adults aged 45 to 75 years at three Black churches in metropolitan Atlanta, Georgia. Demographics, CRC screening history, healthcare access, and attitudes toward blood-based CRC screening were assessed. Results: Overall, 72 participants (71.3%) preferred blood-based CRC screening. Preference was not associated with demographic or socioeconomic characteristics, screening history, or healthcare access. The most commonly reported reasons for ease of testing (83.3%), avoidance of stool collection (38.9%), avoidance of bowel preparation (36.1%), perceived fewer side effects (34.7%), and perceived lower risk (33.3%). Needle concerns were the only factor significantly associated with non-preference (p=0.034). Conclusion: Blood-based colorectal cancer screening was preferred by most Black adults and may improve CRC screening participation through greater convenience.

Stroboscopic light stimulation (SLS) is a candidate non-pharmacological intervention that induces transient visual and affective experiences, with potential application in depression. Before efficacy testing, clinical development requires safety, tolerability and feasibility data. We report a staged, single-site programme in adults reporting depressive symptoms. Work Package (WP) 1 tested 11 SLS parameter sets for safety and tolerability. An interim bridge study assessed whether a low-phenomenology SLS control reduced subjective visual effects while preserving session context. WP2 randomised 84 participants to four weekly supervised 31-minute sessions of the intervention or a low-phenomenology control. In WP1, 31 participants were analysed; no severe adverse reactions occurred, mean discomfort was low (0.49/10), and the highest session-level upper 80% confidence limit was 1.13/10, well below the prespecified threshold. The interim study supported experiential separation between intervention and control. In WP2, endpoint data were available for 70/84 participants (83.3%): 39/42 in the intervention arm and 31/42 in the control arm. Overall retention met the criterion, but lower control-arm retention remains a design issue; protocol adherence was high, discomfort remained low, and no serious SLS-attributable adverse events occurred. Exploratory depressive-symptom changes suggested a possible BDI-II signal, but do not establish efficacy. Supervised SLS met key safety, tolerability, and feasibility criteria, and a lower visual-phenomenology active control can be carried forward, while masking and comparator credibility remain to be established. The next step is a diagnostically defined, CTU-governed Phase 2a feasibility trial that pre-registers a locked protocol and tests masking, credibility, retention and endpoint precision.