Intervention Trial Research Articles

Occupational future time perspective and mental health problems across adolescence: Random-intercept cross-lagged panel analysis and alternative variations.

Adolescence is a crucial developmental stage characterized by escalating mental health issues as well as an increasing awareness of future career possibilities. Occupational future time perspective has been shown to be a promotive factor for social functioning and mental health, and a component in evidence-based clinical practices and randomized controlled trial intervention studies. However, it requires more rigorous and ecological corroboration from longitudinal analysis at the within-person level. Random intercept cross-lagged panel models with several adjustments and sensitivity analyses were applied to the longitudinal data from the Zurich Project on the Social Development from Childhood to Adulthood (Zurich, Switzerland), to analyze how occupational future time perspective and psychological/neurodevelopmental outcomes (attention deficit hyperactivity disorder symptoms/externalizing/internalizing problems) covaried across ages 13 (N = 1365), 15 (N = 1446), and 17 (N = 1305) in the years 2016, 2018, and 2020, after controlling for sex (52% male), SES, and school type. A small effect was found in a random intercept cross-lagged panel model whereby occupational future time perspective at age 15 predicted externalizing problems at age 17 (β = .146, p = .05, [95% CI = 0.000, 0.292]), and in a random intercept (contemporaneous) reciprocal panel model specification attention deficit hyperactivity disorder symptoms at age 17 were contemporaneously associated with occupational future time perspective at age 17 (β = -.310, p < .05, [95% CI = -0.580, -0.041]). No cross-lagged associations were found to be robust across different model specifications/adjustments. These findings suggest that improving occupational future time perspective may have limited impact on enhancing mental health, offering valuable insights for school-based interventions. Further research and replication are necessary to confirm these results.

Supplemental Material for Safety Behavior Reduction for Appearance Concerns: A Randomized Controlled Trial of a Smartphone-Based Intervention

Supplemental Material for Safety Behavior Reduction for Appearance Concerns: A Randomized Controlled Trial of a Smartphone-Based Intervention

Communities That HEAL Intervention and Mortality Including Polysubstance Overdose Deaths

The HEALing Communities Study (HCS) evaluated the effectiveness of the Communities That HEAL (CTH) intervention in preventing fatal overdoses amidst the US opioid epidemic. To evaluate the impact of the CTH intervention on total drug overdose deaths and overdose deaths involving combinations of opioids with psychostimulants or benzodiazepines. This randomized clinical trial was a parallel-arm, multisite, community-randomized, open, and waitlisted controlled comparison trial of communities in 4 US states between 2020 and 2023. Eligible communities were those reporting high opioid overdose fatality rates in Kentucky, Massachusetts, New York, and Ohio. Covariate constrained randomization stratified by state allocated communities to the intervention or control group. Trial groups were balanced by urban or rural classification, 2016-2017 fatal opioid overdose rate, and community population. Data analysis was completed by December 2023. Increased overdose education and naloxone distribution, treatment with medications for opioid use disorder, safer opioid prescribing practices, and communication campaigns to mitigate stigma and drive demand for evidence-based interventions. The primary outcome was the number of drug overdose deaths among adults (aged 18 years or older), with secondary outcomes of overdose deaths involving specific opioid-involved drug combinations from death certificates. Rates of overdose deaths per 100 000 adult community residents in intervention and control communities from July 2021 to June 2022 were compared with analyses performed in 2023. In 67 participating communities (34 in the intervention group, 33 in the control group) and including 8 211 506 participants (4 251 903 female [51.8%]; 1 273 394 Black [15.5%], 603 983 Hispanic [7.4%], 5 979 602 White [72.8%], 354 527 other [4.3%]), the average rate of overdose deaths involving all substances was 57.6 per 100 000 population in the intervention group and 61.2 per 100 000 population in the control group. This was not a statistically significant difference (adjusted rate ratio [aRR], 0.92; 95% CI, 0.78-1.07; P = .26). There was a statistically significant 37% reduction (aRR, 0.63; 95% CI, 0.44-0.91; P = .02) in death rates involving an opioid and psychostimulants (other than cocaine), and nonsignificant reductions in overdose deaths for an opioid with cocaine (6%) and an opioid with benzodiazepine (1%). In this clinical trial of the CTH intervention, death rates involving an opioid and noncocaine psychostimulant were reduced; total deaths did not differ statistically. Community-focused data-driven interventions that scale up evidence-based practices with communications campaigns may effectively reduce some opioid-involved polysubstance overdose deaths. ClinicalTrials.gov Identifier: NCT04111939.

In Vitro Sonodynamic Therapy Using a High Throughput 3D Glioblastoma Spheroid Model with 5-ALA and TMZ Sonosensitizers.

Sonodynamic therapy (SDT) administered using low-intensity pulsed ultrasound and sonosensitizers is an emerging, minimally invasive, targeted deep-tissue therapy for solid tumors such as glioblastoma multiforme (GBM). Initial clinical trials show promising outcomes for SDT treatments of GBM. A crucial aspect of SDT is the sonosensitizer that interacts with ultrasound, facilitating energy transfer to the tumor, thus inducing therapeutic efficacy. Current in vitro methods for determining the therapeutic efficacies of sonosensitizers are time-consuming and expensive. A novel high-throughput magnetically printed 3D GBM model is used to overcome this challenge. The hypothesis is that the use of two sonosensitizers, one a chemotherapeutic drug, enhances SDT efficacy through their additive chemical interactions. The GBM model is used to evaluate the effectiveness of two sonosensitizer molecules, 5-aminolevulinic acid (5-ALA) and theU.S. Food and Drug Administration (FDA)-approved chemotherapeutic drug Temozolomide (TMZ). It is confirmed that implement high-throughput GBM models to evaluate sonosensitizer combinations and their efficacies is feasible and, for the first time, show that the combined effect of both sensitizers, 5-ALA and TMZ, is superior for preventing spheroid growth than employing each molecule separately. This finding is relevant for future clinical trials of GBM treatment with SDT.

Little disease but lots of bites: social, urbanistic, and entomological risk factors of human exposure to Aedes aegypti in South Texas, U.S.

Aedes aegypti presence, human-vector contact rates, and Aedes-borne virus transmission are highly variable through time and space. The Lower Rio Grande Valley (LRGV), Texas, is one of the few regions in the U.S. where local transmission of Aedes-borne viruses occurs, presenting an opportunity to evaluate social, urbanistic, entomological, and mobility-based factors that modulate human exposure to Ae. aegypti. Mosquitoes were collected using BG-Sentinel 2 traps during November 2021 as part of an intervention trial, with knowledge, attitudes, and practices (KAP) and housing quality surveys to gather environmental and demographic data. Human blood samples were taken from individuals and a Bitemark Assay (ELISA) was conducted to quantify human antibodies to the Ae. aegypti Nterm-34kDa salivary peptide as a measure of human exposure to bites. In total, 64 houses were surveyed with 142 blood samples collected. More than 80% of participants had knowledge of mosquito-borne diseases and believed mosquitoes to be a health risk in their community. Our best fit generalized linear mixed effects model found four fixed effects contributed significantly to explaining the variation in exposure to Ae. aegypti bites: higher annual household income, younger age, larger lot area, and higher female Ae. aegypti abundance per trap night averaged over 5 weeks prior to human blood sampling. Most surveyed residents recognized mosquitoes and the threat they pose to individual and public health. Urbanistic (i.e., lot size), social (i.e., income within a low-income community and age), and entomological (i.e., adult female Ae. aegypti abundance) factors modulate the risk of human exposure to Ae. aegypti bites. The use of serological biomarker assays, such as the Bitemark Assay, are valuable tools for surveillance and risk assessment of mosquito-borne disease, especially in areas like the LRGV where the transmission of target pathogens is low or intermittent.

Cardiovascular Precision Medicine and Remote Intervention Trial Rationale and Design

Background: It has recently been shown that excessive fluctuation in blood pressure readings for an individual over time is closely associated with poor outcomes, including increased risk of cardiovascular mortality, coronary heart disease and stroke. Fluctuations may be associated with inconsistent adherence to medical recommendations. This new marker of risk has not yet been incorporated into a monitoring and intervention strategy that seeks to reduce cardiovascular risk by identifying patients through an algorithm tied to their electronic health record (EHR). Methods: We describe the methods used in an innovative “proof of concept” trial using CP&amp;R (Cardiovascular Precision Medicine and Remote Intervention). A blood pressure variability index is calculated for clinic patients via an EHR review. Consenting patients with excessive variability are offered a remote intervention aimed at improving adherence to medical recommendations. The outcomes include the ability to identify and engage the identified patients and the effects of the intervention on blood pressure variability using a pre–post comparison design without parallel controls. Conclusions: Our innovative approach uses a recently identified marker based on reviewing and manipulating EHR data tied to a remote intervention. This design reduces patient burden and supports equitable and targeted resource allocation, utilizing an objective criterion for behavioral risk. This study is registered under ClinicalTrials.gov Identifier: NCT05814562.

Second‐degree burns treatment: Preclinical in vivo approaches using natural latex rubber containing Aloe vera extract

AbstractNatural rubber latex (NRL) obtained from Hevea brasiliensis is emerging as a viable and economical alternative for biomedical treatments, particularly for dermal injuries. Its effectiveness is enhanced when combined with bioactive molecules, such as those found in Aloe vera (AV), known for their healing properties and are commonly used in low‐cost wound healing therapies. Thus, this study evaluated the physicochemical and biological properties of NRL incorporated with 25%, 35%, and 50% AV, both in vitro and in vivo. FTIR analyses revealed only physical interactions between NRL and AV, facilitating their release, as evidenced by the release profile. In vitro assays indicated improved biocompatibility in samples composed of 25% and 35% AV, while complete cell death occurred at 50% AV. Histological evaluations of second‐degree burn models in rats showed greater re‐epithelialization of the epidermis with 35% AV after 14 days of treatment. However, 50% AV highlighted the importance of avoiding overdosing to prevent tissue necrosis. Despite the differences observed between in vitro and in vivo results, NRL membranes containing AV are a promising approach for future clinical trials in skin wounds treatment, offering an effective and affordable solutions for skin regeneration in clinical settings.

Combined machine learning models, docking analysis, ADMET studies and molecular dynamics simulations for the design of novel FAK inhibitors against glioblastoma

Gliomas, particularly glioblastoma (GBM), are highly aggressive brain tumors with poor prognosis and high recurrence rates. This underscores the urgent need for novel therapeutic approaches. One promising target is Focal adhesion kinase (FAK), a key regulator of tumor progression currently in clinical trials for glioma treatment. Drug development, however, is both challenging and costly, necessitating efficient strategies. Computer-Aided Drug Design (CADD), especially when combined with machine learning (ML), streamlines the processes of virtual screening and optimization, significantly enhancing the efficiency and accuracy of drug discovery. Our study integrates ML, docking analysis, ADMET (absorption, distribution, metabolism, elimination, and toxicity) studies to identify novel FAK inhibitors specific to GBM. Predictive models showed strong performance, with an R2 of 0.892, MAE of 0.331, and RMSE of 0.467 using protein-level IC50 data in combined CDK, CDK extended fingerprints, and substructure fingerprint counts derived from 1280 FAK inhibitors. Another model, based on IC50 data from 2608 compounds tested on U87-MG cells, achieved an R2 of 0.789, MAE of 0.395, and RMSE of 0.536. Using these models, we efficiently identified 275 potentially active compounds out of 5107 candidates. Subsequent ADMET analysis narrowed this down to 16 potential FAK inhibitors that meet the established drug-likeness criteria. Moreover, molecular dynamics (MD) simulations validated the stable binding interactions between the selected compounds and the FAK protein. This study highlights the effectiveness of combining ML, docking analysis, and ADMET studies to rapidly identify potential FAK inhibitors from large databases, providing valuable insights for the systematic design of FAK inhibitors.

Antihypertensive therapy and unplanned maternal postpartum healthcare utilization in patients with mild chronic hypertension

ObjectiveTo test whether treatment of mild chronic hypertension (CHTN) in pregnancy is associated with lower rates of unplanned maternal healthcare utilization postpartum. MethodsThis was a secondary analysis of the CHTN and pregnancy study, a prospective, open-label, pragmatic, multicenter, randomized treatment trial of pregnant people with mild CHTN. All patients with a postpartum follow-up assessment were included. The primary outcome was unplanned healthcare utilization, defined as unplanned postpartum clinic visits, Emergency Department (ED) or triage visits, or unplanned hospital admissions within 6 weeks postpartum. Differences in outcomes were compared between study groups (Active Group: blood pressure goal of<140/90 mm Hg, and Control Group: blood pressure goal of <160/105 mm Hg), and factors associated with outcomes were examined using logistic regression. ResultsA total of 2293 patients were included with 1157 (50.5%) in the active group and 1136 (49.5%) in the control group. Rates of unplanned maternal postpartum healthcare utilization did not differ between treatment and control groups, (20.2% vs 23.3%, P=.07, aOR 0.84, 95% CI 0.69–1.03). However, ED or triage/maternity evaluation unit visits were significantly lower in the Active group (10.2% vs 13.2%, P=.03, aOR 0.76, 95% 0.58–0.99). Higher BMI at enrollment and cesarean delivery were associated with higher odds of unplanned postpartum healthcare utilization. ConclusionWhile treatment of mild CHTN during pregnancy and postpartum was not significantly associated with overall unplanned healthcare resource utilization, it was associated with lower rates of postpartum ED and triage visits.

Alzheimer's Disease and (Phyto) Estrogen Treatment: Modification of Effects by Age, Type of Treatment, and Duration of Use.

There is a continued debate on whether menopausal hormone therapy (MHT) protects women against Alzheimer's disease (AD). It is also unclear whether phytoestrogen could be an alternative treatment for AD. To investigate whether mixed study findings may be due to differences in age at initiation of MHT and duration of prescription of different types of MHT using meta-analyses. After a systematic literature search, meta-analyses were carried out using Cochrane Revman 5.4.1.software including data from large nationwide studies of registered medically diagnosed AD and prescribed MHT. These analyses were stratified for duration and type of treatment, by age at start of prescription of therapy. Insufficient quality data were available for phytoestrogen treatment and AD meta-analyses. A total of 912,157 women were included from five registries, of whom 278,495 had developed AD during follow-up. Meta-analyses suggested a small increased AD risk after 5-10 years prescription of combination MHT regardless of age, and over 10 years only in women younger than 60 years of age. No association was seen for estrogen alone for women younger than 60 years of age, but AD risk did increase for women over 60 years of age for up to 5 years of MHT prescriptions. Combination MHT should probably be prescribed for less than 5 years after menopause to reduce risk for AD, while estrogen alone should not be prescribed to women over 60. For phytoestrogen, small treatment trials suggested some benefit of tempeh (fermented soy), which should be investigated further.

Effectiveness of gamification-based teaching in approach to eye trauma: a randomized educational intervention trial

IntroductionOphthalmology education is evolving with the use of new teaching approaches. Teaching based on gamification is one of the new developments in health professions education. This study was conducted to investigate the effect of gamification-based virtual reality on the learning outcome of students regarding the highly important topic of approach to eye trauma.Materials and methodsThis randomized educational intervention trial with a control group was conducted at Kermanshah University of Medical Sciences (KUMS). A total of 10 ophthalmology residents and 60 medical students were recruited in this study (each group comprised 5 residents and 30 medical students). Individuals were randomly divided into two teaching groups gamification method (intervention group) and lecture-based method (Control group). Data were collected through questionnaires and tests and analyzed by SPSS-26 software using descriptive and analytical statistics.ResultsResidents and medical students evaluated the usability of this method to be favorable (132.72 ± 10.17). In resident students (16.80 ± 2.58, 13.60 ± 1.14, P ≤ 0.05) and medicine students (17.27 ± 4.50, 15.20 ± 0.71, P ≤ 0.05), the mean score of learning outcome score in the intervention group was higher than the control group.ConclusionGamification-based teaching is an effective educational strategy that can be used as a complementary educational tool for teaching ophthalmology residents and medical students.

P13.01.A 11C-METHIONIN PET FOR RADIOTHERAPY TREATMENT PLANNING IN PATIENTS WITH RAPID EARLY PROGRESSION AFTER GLIOBLASTOMA SURGERY: PROSPECTIVE PHASE II TRIAL

Abstract BACKGROUND Radiotherapy (RT) is a standard treatment for nearly all glioblastoma patients following initial surgery. Few retrospective studies indicate negative prognostic instances of progression during the planning magnetic resonance (MR) (up to 1 week before initiating RT), termed Rapid Early Progression (REP). The optimal RT management for REP patients remains uncertain. The objective of this prospective phase II trial (NCT05608395) is to assess impact of 11C-Methionine PET used for RT planning in REP glioblastoma patients. It is one of the first prospective clinical interventional trials focused on this specific cohort of patients. MATERIAL AND METHODS We enrolled glioblastoma, IDHwt, or Astrocytoma, IDHmt, WHO grade IV patients, who developed REP characterized by 1) increase in postoperative residuum by ≥ 25%, 2) appearance of new contras enhancing lesion, 3) unequivocal progression of the unresected satelite. Patients received treatment based on the Stupp or Perry protocol. Treatment response was evaluated using RANO criteria. RT target volumes were delineated as follows: Gross tumor volume included tumor cavity, enhancing lesion and 11C-MET PET (1.3 tumor-to-background ratio). The clinical target volume was GTV plus a modified 2cm margin reflecting surrounding organs at risk. Volumetric analyses of different radiotherapy target volume were performed using EclipseTM software including patterns of failure. RESULTS During 12/2020 - 12/2023, total of 31 patients were enrolled (16 treated via abbreviated RT course); median age 60 years, ECOG 0-1 in 28 patients, median follow up 20 months. No effect of 11C-MET PET - based radiotherapy treatment planning of GBM patients with REP was observed on PFS (median 3.4 months comparing to 4.9 in historical control cohort) and OS (12.3 months comparing to 15.7 months). Median MET volume was 7.3cm3 (43% of MRI volume), MET avidity was presented in 7 patients et least 1cm beyond MRI volume. Central recurrence was presented in 87% patients. CONCLUSION The optimal treatment of patients with REP is unknown and needs to be studied in more details including dose escalation studies with reduced target margins potentialy directed also by aminoacid PET examination. Adjustment of target radiotherapy volumes using 11C-MET PET did not lead to improved PFS or OS. Supported by NU20-03-00148.

OA17.05 A Randomized Controlled Trial of a Digital Lung Health Intervention to Facilitate Smoking Cessation and Lung Cancer Screening

OA17.05 A Randomized Controlled Trial of a Digital Lung Health Intervention to Facilitate Smoking Cessation and Lung Cancer Screening

Reducing Learning and Psychosocial Disparities in Latino Children with Cancer: A Randomized Intervention Trial.

We developed a high-intensity parenting intervention (HIP) to help parents support the academic success of childhood cancer survivors (CCSs), who often face post-treatment challenges affecting their school-related functioning. This randomized controlled trial (NCT03178617) evaluated HIP's efficacy compared to lower-intensity, single-session, treatment-as-usual services (LIP) in Latino families. Primary outcomes were parenting efficacy and CCSs' school functioning; secondary outcomes included parenting knowledge and measures of CCSs' academic performance, attention, and functioning outside of school. 106 Latino survivors of childhood leukemia and lymphoblastic lymphoma (aged 6-12 years) and their parents were randomly assigned to HIP (n = 54) or LIP (n = 52). Linear mixed-effects models evaluated group differences across baseline, 6-month (T2), and 12-month (T3) assessments. Parenting efficacy and knowledge improved significantly in the HIP arm, resulting in higher scores vs LIP at T2 and T3 (P ≤ .01). No significant between-group differences were found in child school functioning; however, HIP children showed significantly better social functioning and performance on one measure of attention (CPT-3 commissions) at T3 (P < .05). While HIP adherence challenges were observed, with only 33 (61%) completing the intervention, exploratory analyses suggest that benefits were most evident among those who fully engaged. Satisfaction and perceived benefit were greater for HIP vs LIP at both time points (P < .05). Our results suggest the potential value of parent-directed behavioral interventions like HIP for CCSs and their families. Further studies are needed to address participation barriers and enhance engagement to maximize and sustain benefits.

What is the carbon footprint of academic clinical trials? A study of hotspots in 10 trials

BackgroundClinical trials are fundamental to healthcare, however, they also contribute to anthropogenic climate change. Following previous work to develop and test a method and guidance to calculate the carbon footprint...

Pathways through which water, sanitation, hygiene, and nutrition interventions reduce antibiotic use in young children: a mediation analysis of a cluster-randomized trial.

Low-cost, household-level water, sanitation, and hygiene (WASH) and nutrition interventions can reduce pediatric antibiotic use, but the mechanism through which interventions reduce antibiotic use has not been investigated. We conducted a causal mediation analysis using data from the WASH Benefits Bangladesh cluster-randomized trial ( NCT01590095 ). Among a subsample of children within the WSH, nutrition, nutrition+WSH, and controls arms (N=1,409), we recorded caregiver-reported antibiotic use at ages 14 and 28 months and collected stool at age 14 months. Mediators included caregiver-reported child diarrhea, acute respiratory infection (ARI), and fever; and enteric pathogen carriage in stool measured by qPCR. Models controlled for mediator-outcome confounders. The receipt of any WSH or nutrition intervention reduced antibiotic use in the past month by 5.5 percentage points (95% CI 1.2, 9.9) through all pathways, from 49.5% (95% CI 45.9%, 53.0%) in the control group to 45.0 % (95% CI 42.7%, 47.2%) in the pooled intervention group. Interventions reduced antibiotic use by 0.6 percentage points (95% CI 0.1, 1.3) through reduced diarrhea, 0.7 percentage points (95% CI 0.1, 1.5) through reduced ARI with fever, and 1.8 percentage points (95% CI 0.5, 3.5) through reduced prevalence of enteric viruses. Interventions reduced antibiotic use through any mediator by 2.5 percentage points (95% CI 0.2, 5.3). Our findings bolster a causal interpretation that WASH and nutrition interventions reduced pediatric antibiotic use through reduced infections in a rural, low-income population. Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases. Evidence before this study: We searched for primary studies and systematic reviews that investigated mediation of antibiotic use by water, sanitation and hygiene interventions in Scopus using (TITLE-ABS-KEY(("WASH" OR "sanitation" OR "water" OR "hygiene" OR "nutrition") AND ("antibiot*") AND ("interven*") AND ("mediat*" OR "indirect effect*" OR "pathway" OR "mechanism") AND ("use" OR "practice*")). We included all publications until September 4, 2024. We restricted results to studies in English, focused on humans, and within medicine, agricultural and biological sciences, immunology or microbiology, or environmental science. Our search yielded 115 studies. We found no relevant research studies. Four review studies discussed the need for improved sanitation and drinking water as an AMR control strategy in LMICs. Two study protocols described longitudinal observational studies in LMICs that will explore the relationship between WASH and antibiotic resistance.Added value of this study: We used causal mediation analysis to investigate mechanisms through which WASH and nutrition interventions reduced antibiotic use in young children in a community setting in rural Bangladesh. This study is rigorous because it leverages a randomized trial with high intervention adherence and includes objectively measured mediators. We found that WASH and nutrition interventions reduced antibiotic use via reduced diarrhea, ARI with fever, and enteric virus carriage. This study improves on previous studies by identifying a specific mechanism through which WASH and nutrition interventions reduced pediatric antibiotic use in an understudied setting and population.Implications of all the available evidence: In a previous analysis of a randomized trial of WASH and nutrition interventions, we found that pediatric antibiotic use was lower in the intervention arms compared to control. Here, using causal mediation analysis, we identified several biologically plausible pathways through which interventions likely reduced antibiotic use. This analysis bolsters a causal interpretation that low-cost, household-level WASH and nutrition interventions can reduce pediatric antibiotic use in settings with similar infectious disease dynamics and antimicrobial access.

The CO-produced Psychosocial INtervention delivered by GPs to young people after self-harm (COPING): protocol for a feasibility study.

Self-harm in young people is a growing concern and reducing rates a global priority. Rates of self-harm documented in general practice have been increasing for young people in the UK in the last two decades, especially in 13-16-year-olds. General practitioners (GPs) can intervene early after self-harm but there are no effective treatments presently available. We developed the GP-led COPING intervention, in partnership with young people with lived experience and GPs, to be delivered to young people 16-25 years across two consultations. This study aims to examine the feasibility and acceptability of conducting a fully powered effectiveness trial of the COPING intervention in NHS general practice. This will be a mixed-methods external non-randomised before-after single arm feasibility study in NHS general practices in the West Midlands, England. Patients aged 16-25 years who have self-harmed in the last 12 months will be eligible to receive COPING. Feasibility outcomes will be recruitment rates, intervention delivery, retention rates, and completion of follow-up outcome measures. All participants will receive COPING with a target sample of 31 with final follow-up data collection at six months from baseline. Clinical data such as self-harm repetition will be collected. A nested qualitative study and national survey of GPs will explore COPING acceptability, deliverability, implementation, and likelihood of contamination. Brief GP-led interventions for young people after self-harm are needed to address national guideline and policy recommendations. This study of the COPING intervention will assess whether a main trial is feasible. ISRCTN (ISRCTN16572400; 28.11.2023).

Successful completion of large, low-cost randomized cancer trials at an academic cancer center.

Concerns about low accrual have long been a standard part of the discourse on cancer clinical trials, reaching even as far as the news media. Indeed, so many trials are closed before completing accrual that a cottage industry has recently developed creating statistical models to predict trial failure. We previously proposed four methodologic fixes for the current crisis in clinical trials: (1) dramatically reducing the number of eligibility criteria, (2) using data routinely collected in clinical practice for trial endpoints; then lowering barriers to accrual by (3) cluster randomization or (4) staged consent. We report our practical experience of applying these fixes to randomized trials at Memorial Sloan Kettering Cancer Center. We have completed seven single-center randomized trials, with several more underway and accruing rapidly, with a total accrual approaching 10,000. Many of the trials have compared surgical interventions, an area where trials have traditionally been hard to complete. Only one of these trials was externally funded. While low costs were possible due to the existing research infrastructure at our institution, such infrastructure is common at major cancer centers. Further research on innovative clinical trial designs is warranted, particularly in higher-stakes settings, and in trials of medical and radiotherapy interventions.

A randomized-controlled trial of parent-administered interventions to improve short-term motor outcomes in hospitalized very low birthweight infants.

Premature infants are at increased risk for cerebral palsy (CP). Early interventions with a motor focus and administered by parents may improve motor outcomes. Secondary study evaluating the short-term motor outcomes and risk for CP in very low birthweight (VLBW) infants randomized to multimodal interventions with a motor focus provided by parents versus usual care. Randomized controlled trial (intervention vs. usual care (control group)). Infants (<32 weeks' gestational age (GA) and/or <1500 grams birthweight) born between March 2019 and October 2020. Short-term motor outcomes and risk for CP was evaluated using the Hammersmith Infant Neurological Evaluation (HINE, primary motor outcome), the General Movement Assessment (GMA) and the Test of Infant Motor Performance (TIMP) at 3 months' postmenstrual age (PMA). 70 participants were enrolled (GA 28.3±2.7 weeks, birthweight 1139.2±376.6 grams, 64.3% male). The in-person follow-up rate was 73%, lower than expected, in part due to COVID-19 restrictions, resulting in 25 infants (intervention) and 26 infants (control) with outcome data available for analysis. There was not a significant difference in the HINE, GMA or TIMP at 3 months' PMA between groups. Multimodal interventions with a motor focus and provided by parents need further investigation to determine if they can improve short-term motor outcomes in VLBW infants. These interventions are evidence-based and the evaluation of broader implementation into routine care is also needed.

Variability in Causal Effects and Noncompliance in a Multisite Trial: A Bivariate Hierarchical Generalized Random Coefficients Model for a Binary Outcome.

Within each of 170 physicians, patients were randomized to access e-assist, an online program that aimed to increase colorectal cancer screening (CRCS), or control. Compliance was partial: of the experimental patients accessed e-assist while no controls were provided the access. Of interest are the average causal effect of assignment to treatment and the complier average causal effect as well as the variation of these causal effects across physicians. Each physician generates probabilities of screening for experimental compliers (experimental patients who accessed e-assist), control compliers (controls who would have accessed e-assist had they been assigned to e-assist), and never takers (patients who would have avoided e-assist no matter what). Estimating physician-specific probabilities jointly over physicians poses novel challenges. We address these challenges by maximum likelihood, factoring a "complete-data likelihood" uniquely into the conditional distribution of screening and partially observed compliance given random effects and the distribution of random effects. We marginalize this likelihood using adaptive Gauss-Hermite quadrature. The approach is doubly iterative in that the conditional distribution defies analytic evaluation. Because the small sample size per physician constrains estimability of multiple random effects, we reduce their dimensionality using a shared random effects model having a factor analytic structure. We assess estimators and recommend sample sizes to produce reasonably accurate and precise estimates by simulation, and analyze data from a trial of a CRCS intervention.