Intervention Trial Research Articles

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.

Discrimination of primary and chronic cytomegalovirus infection based on humoral immune profiles in pregnancy.

BACKGROUNDMost humans have been infected with cytomegalovirus (CMV) by midlife without clinical signs of disease. However, in settings in which the immune system is undeveloped or compromised, the virus is not adequately controlled and consequently presents a major infectious cause of both congenital disease during pregnancy as well as opportunistic infection in children and adults. With clear evidence that risk to the fetus varies with gestational age at the time of primary maternal infection, further research on humoral responses to primary CMV infection during pregnancy is needed.METHODSHere, systems serology tools were applied to characterize antibody responses to CMV infection in pregnant and nonpregnant women experiencing either primary or chronic infection.RESULTSWhereas strikingly different antibody profiles were observed depending on infection status, limited differences were associated with pregnancy status. Beyond known differences in IgM responses used clinically for identification of primary infection, distinctions observed in IgA and FcγR-binding antibodies and among antigen specificities accurately predicted infection status. Machine learning was used to define the transition from primary to chronic states and predict time since infection with high accuracy. Humoral responses diverged over time in an antigen-specific manner, with IgG3 responses toward tegument decreasing over time as typical of viral infections, while those directed to pentamer and glycoprotein B were lower during acute and greatest during chronic infection.CONCLUSIONIn sum, this work provides insights into the antibody response associated with CMV infection status in the context of pregnancy, revealing aspects of humoral immunity that have the potential to improve CMV diagnostics.FUNDINGCYMAF consortium and NIH NIAID.

StratosPHere 2: study protocol for a response-adaptive randomised placebo-controlled phase II trial to evaluate hydroxychloroquine and phenylbutyrate in pulmonary arterial hypertension caused by mutations in BMPR2

BackgroundPulmonary arterial hypertension is a life-threatening progressive disorder characterised by high blood pressure (hypertension) in the arteries of the lungs (pulmonary artery). Although treatable, there is no known cure for this rare disorder, and its exact cause is unknown. Mutations in the bone morphogenetic protein receptor type-2 (BMPR2) are the most common genetic cause of familial pulmonary arterial hypertension. This study represents the first-ever trial of treatments aimed at directly rescuing the BMPR2 pathway, repurposing two drugs that have shown promise at restoring levels of BMPR2 signalling: hydroxychloroquine and phenylbutyrate.MethodsThis three-armed phase II precision medicine study will investigate BMPR2 target engagement and explore the efficacy of two repurposed therapies in pulmonary arterial hypertension patients with BMPR2 mutations. Patients will be stratified based on two BMPR2 mutation classes: missense and haploinsufficient mutations. Eligible subjects will be randomised to one of the three arms (two active therapy arms and a placebo arm, all plus standard of care) following a Bayesian response-adaptive design implemented independently in each stratum and updated in response to a novel panel of primary biomarkers designed to assess biological modification of the disease.DiscussionThe results of this trial will provide the first randomised evidence of the efficacy of these therapies to rescue BMPR2 function and will efficiently explore the potential for a differential response of these therapies per mutation class to address causes rather than consequences of this rare disease.Trial registrationThe study has been registered with ISRCTN (ISRCTN10304915, 22/09/2023).

A prediction model for the walking and balance milestone in Parkinson's disease

BackgroundWalking and balance impairments, represented by freezing of gait and falls, are significant contributors to disability in advanced Parkinson's disease (PD) patients. However, the composite measure of the Walking and Balance Milestone (WBMS) has not been thoroughly investigated. MethodsThis study included 606 early-stage PD patients from the Parkinson's Progression Markers Initiative (PPMI) database, with a disease duration of less than 2 years and no WBMS at baseline. Patients were divided into a model development cohort (70 %) and a validation cohort (30 %) according to the enrollment site. Longitudinal follow-up data over a period of 12 years were analyzed. ResultsAmong all 606 patients, the estimated probability of being WBMS-free at the 5th and 10th year was 88 % and 60 %, respectively. Five clinical variables (Age, Symbol Digit Modalities Test (SDMT), postural instability and gait difficulty (PIGD) score, Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part I (MDS-UPDRS-I) score, and REM Sleep Behavior Disorder (RBD) were used to construct the Cox predictive model. The C-index of the model was 0.75 in the development cohort and 0.76 in the validation cohort. By optimizing the PIGD and MDS-UPDRS-I variables, an easy-to-use model was achieved with comparable predictive performance. ConclusionA predictive model based on five baseline clinical measures (Age, SDMT, PIGD score, MDS-UPDRS-I score, RBD) could effectively estimate the risk of the WBMS in early PD patients. This model is valuable for prognostic counseling and clinical intervention trials for gait and balance impairment.

Longitudinal Analysis of Natural History Progression of Rare and Ultra-Rare Cerebellar Ataxias Using Item Response Theory.

Degenerative cerebellar ataxias comprise a heterogeneous group of rare and ultra-rare genetic diseases. While disease-modifying treatments are now on the horizon for many ataxias, robust trial designs and analysis methods are lacking. To better inform trial designs, we applied item response theory (IRT) modeling to evaluate the natural history progression of several ataxias, assessed with the widely used scale for assessment and rating of ataxia (SARA). A longitudinal IRT model was built utilizing real-world data from the large autosomal recessive cerebellar ataxia (ARCA) registry. Disease progression was evaluated for the overall cohort as well as for the 10 most common ARCA genotypes. Sample sizes were calculated for simulated trials with autosomal recessive spastic ataxia Charlevoix-Saguenay (ARSACS) and polymerase gamma (POLG) ataxia, as showcased, across multiple design and analysis scenarios. Longitudinal IRT models were able to describe the changes in the latent variable underlying SARA as a function of time since ataxia onset for both the overall ARCA cohort and the common genotypes. The typical progression rates varied across genotypes between relatively high in POLG (~ 0.98 SARA points/year at SARA = 20) and very low in COQ8A ataxia (~ 0.003 SARA points/year at SARA = 20). Smaller trial sizes were required in case of faster progression, longer trials (~ 75-90% less with 5 years vs. 2 years), and larger drug effects (~ 70-80% less with 100% vs. 50% inhibition). Simulating under the developed IRT model, the longitudinal IRT model had the highest power, with a well-controlled type I error, compared to total score models or end-of-treatment analyses. The established longitudinal IRT framework allows efficient utilization of natural history data and ultimately facilitates the design and analysis of treatment trials in rare and ultra-rare genetic ataxias.

Outcomes of an adapted prolonged exposure psychotherapy for people with early phase psychosis, substance misuse, and a history of adversity: the PE + trial

BackgroundSeveral adversity-focused treatment trials have reported improvements to adversity sequelae (e.g., PTSD symptoms) and decreases in psychotic symptoms among individuals with psychotic disorders. Yet, no trials have examined the impact of adversity-focused treatment on substance use or examined the outcomes among an early phase psychosis population. These gaps in both the research literature and clinical practice have resulted in less knowledge about the outcomes of adversity-focused treatment at this stage of illness, including the impact on substance use.MethodsThe outcomes of an adapted prolonged exposure protocol (PE+) among an early phase psychosis population were examined using a multiple-baseline design. Nineteen adults with a psychotic disorder, current substance misuse, and a history of adversity were recruited from an early psychosis program. Participants were randomized to treatment start time and participated in a 15-session course of PE + therapy. Ten assessments were completed focusing on primary outcomes (i.e., adversity sequelae, negative psychotic symptoms, substance misuse) and secondary outcomes (i.e., functioning, hopelessness, experiential avoidance). The Reliable Change Index (RCI) was used to establish whether there were clinically significant changes to primary or secondary outcomes.ResultsHalf or more of treatment completers experienced clinically significant changes to most domains of adversity sequelae, no participants experienced improvements in negative psychotic symptoms, and substance misuse increased for several participants. In terms of secondary outcomes, functioning and experiential avoidance were improved for a number of participants, while hopelessness decreased for only one participant. Participants reported high satisfaction with the PE + treatment, and exposure and coping skills were rated as the most helpful elements of treatment.ConclusionsReductions in adversity sequelae were observed following PE + treatment, suggesting that adversity-focused treatment may be beneficial for an early psychosis population. Yet, few positive changes to psychotic symptoms or substance use were observed. Further integrating treatment strategies for psychosis and substance use into PE + may be required to effectively treat the links between psychosis, adversity sequelae, and substance use. Future studies should make efforts to integrate substance use strategies into adversity treatment trials for people with psychotic disorders.Trial registrationClinicaltrials.gov, NCT04546178; registration posted 11/09/2020, https://clinicaltrials.gov/ct2/show/NCT04546178?term=NCT04546178&draw=2&rank=1.

A Systematic Review of Dental Antibiotic Stewardship Interventions.

Antimicrobial resistance is a significant threat to global health. Antimicrobial stewardship is reducing inappropriate antimicrobial prescribing to counter it. Dentists prescribe ~10% of all antibiotics worldwide, yet up to 90% of antibiotic prescriptions by dentists are inappropriate. The aim of this systematic review was to update a 2017 review evaluating the effects of antibiotic stewardship interventions in dental settings, using the international consensus on core outcomes for dental antibiotic stewardship. Systematic database searches were undertaken in April 2023, of the: Cochrane Oral Health Group Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE via OVID, EMBASE via OVID, Dentistry and Oral Sciences Source, the US National Institutes of Health Trials Register, the World Health Organisation International Clinical Trials Registry Platform and the ISRCTN registry databases. Randomised controlled trials (or non-randomised studies with clearly reported mechanism of group formation and inclusion criteria) of interventions to optimise and/or reduce dental antibiotic prescribing were eligible for inclusion. Two authors independently screened for eligible studies. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool, certainty of evidence assessed using GRADE. Meta-analysis was planned whether the results of studies reported similar outcomes, otherwise narrative synthesis was undertaken. Three eligible studies randomising 2148 participants were included. The interventions were combinations of education, audit and feedback and written behaviour change messages, guideline summary, practice visits and patient leaflets. None of the control groups received an intervention. All three included studies measured the quantity of antibiotics prescribed and two measured the appropriateness of prescribing. None measured patient-reported or adverse outcomes. Two included studies were assessed as 'high risk' and one with 'low risk' of bias. There was high-certainty evidence that audit and personalised feedback with individualised behaviour change messages can be effective. Evidence for in-person education was low-certainty. Guideline dissemination alone was ineffective at improving antibiotic prescribing. Due to different outcomes reported, meta-analysis was inappropriate. Although various dental antibiotic stewardship interventions have been reported in the literature, none provided high-certainty evidence of effectiveness and only three have been evaluated using a randomised design. To strengthen the body of evidence, well-powered, robust, randomised controlled trials are required, with adequate follow-up, reporting the internationally-agreed core outcomes and including a parallel process evaluation is recommended. PROSPERO (CRD42023411476).

Understanding menstrual factors associated with poor mental health among female secondary school students in Uganda: a cross-sectional analysis

BackgroundThere is growing global concern about poor mental health among adolescents in sub-Saharan Africa. In particular, adolescent girls face multiple challenges in managing menstruation which can impact both their health and wellbeing. In this study we address an evidence gap on the association of a broad range of menstrual-related factors with mental health problems amongst secondary school female adolescents in Uganda.MethodsWe used baseline data from a cluster-randomised menstrual health intervention trial conducted in 60 secondary schools in two districts in Uganda. Baseline data were collected between March and July 2022, including socio-demographic characteristics, menstrual knowledge and attitudes, menstrual practices and self-efficacy, and mental health problems measured using the Strengths and Difficulties Questionnaire Total Difficulties score (SDQ-25). We used random-effects linear regression to estimate the adjusted mean difference (aMD) for the association between mental health problems (SDQ Total Difficulties Score) and menstrual-related factors, including the Menstrual Practice Needs Scale (MPNS) and the Self-Efficacy in Addressing Menstrual Needs scale (SAMNS)), accounting for school-level clustering and adjusting for prior confounders.ResultsAmong the 3841 female participants, there was strong and consistent evidence of associations between mental health problems and menstrual-related factors. Mental health problems were associated with poor knowledge about menstruation (aMD = 1.17, 95%CI 0.50, 1.84 <0.001), using disposable and reusable menstrual products compared to using just disposable products (aMD = 1.42, 95%CI 0.92, 1.92, p <0.001), and experiencing menstrual pain even when using an effective management method at last menstrual period (LMP) compared to those experiencing no pain (aMD = 1.60, 95%CI 1.19, 2.01, p <0.001). Mental health problems were also associated with greater unmet menstrual needs according to the MPNS (aMD = 4.40 95%CI 3.96, 4.84, p <0.001), and with lower menstrual self-efficacy measured by the SAMNS (aMD = 0.94 95% CI 0.51, 1.37, p <0.001).ConclusionThis study shows strong evidence that mental health problems reported by adolescent girls in Uganda are associated with poor menstrual health. The association between menstrual health and mental health provides evidence as to why menstrual health should be a public health priority.Trial registrationTrial registration: ISRCTN 45461276. Registered on 16 September 2021.

Reductions in recurrence in women with early breast cancer entering clinical trials between 1990 and 2009: a pooled analysis of 155 746 women in 151 trials

Distant recurrence in women with oestrogen receptor-positive early breast cancer persists at a constant rate for more than 20 years after diagnosis, with little equivalent data for oestrogen receptor-negative breast cancer. Using the database of the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) we investigated rates of distant breast-cancer recurrence in oestrogen receptor-positive and oestrogen receptor-negative tumours and trends in outcomes over time. In this pooled analysis of randomised controlled trial data, patients in the EBCTCG database of more than 650 000 women in trials of treatment for early-stage breast cancer were screened for eligibility. Women were eligible if they were enrolled between 1990 and 2009 and newly diagnosed with oestrogen receptor-positive breast cancer and scheduled for at least 5 years of endocrine therapy, or oestrogen receptor-negative disease, and if they were younger than 75 years at diagnosis, had a tumour diameter of 50 mm or less, and fewer than ten positive axillary lymph nodes, and no evidence of distant metastases at entry. Trial of neoadjuvant therapy, or those in which adjuvant therapy was unclear, and women with oestrogen receptor-negative, progesterone receptor-positive disease, or those for whom outcome or baseline data were missing were excluded. The primary outcome was time to first distant recurrence as defined by each trial, ignoring any locoregional recurrence or contralateral breast cancer. 10-year risks of distant recurrence by period of diagnosis were compared using Cox regression adjusted for patient and tumour characteristics, trial, and assigned treatment. Of the 652 258 women with early breast cancer in the EBCTCG database on Jan 17, 2023, patient-level data were available from 151 randomised trials that included 155 746 women. Rates of distant tumour recurrence improved similarly in women with oestrogen receptor-positive and oestrogen receptor-negative tumours. 80·5% of the improvement for oestrogen receptor-positive disease and 89·8% of the improvement for eostrogen receptor-negative disease was explained by changes in patient and tumour characteristics and improved treatments, but remained significant (p<0·0001). More recently diagnosed patients were more likely to have node-negative disease. 10-year distant recurrence risks during 1990-99 versus 2000-09 were as follows: for node-negative disease, 10·1% versus 7·3% for oestrogen receptor-positive disease and 18·3% versus 11·9% for oestrogen receptor-negative disease; for disease with one to three positive nodes, 19·9% versus 14·7% for oestrogen receptor-positive disease and 31·9% versus 22·1% for oestrogen receptor-negative disease; and for disease with four to nine positive nodes, 39·6% versus 28·5% for oestrogen receptor-positive disease and 47·8% versus 36·5% for oestrogen receptor-negative disease. After adjustment for therapy, rates were reduced by 25% (oestrogen receptor-positive disease) and 19% (oestrogen receptor-negative disease) after 2000 versus the 1990s, with similar improvements observed in oestrogen receptor-positive disease beyond 5 years. Most of the improvement in trial outcomes is explained by a greater proportion of women with lower-risk disease entering trials and improved adjuvant treatment. After adjustment, women diagnosed since 2000 have about a fifth lower rate of distant recurrence than the 1990s. Long-term risks of distant recurrence for oestrogen receptor-positive disease remain, but are about a tenth lower now than in our previous report. Cancer Research UK, UK Medical Research Council.

The impact of antidepressant discontinuation prior to treatment with psilocybin for treatment-resistant depression

It has been suggested that the recent use and discontinuation of antidepressant drugs compromises the action of psilocybin. As evidence is only available from small or uncontrolled samples, this post hoc analysis investigated this using data from the largest, phase II, randomized controlled trial of psilocybin treatment to date. Data from 233 participants with treatment-resistant depression (TRD) who received 25 mg, 10 mg, or 1 mg of investigational drug COMP360 psilocybin (a proprietary, pharmaceutical-grade synthetic psilocybin formulation, developed by the sponsor, Compass Pathfinder Ltd.), administered with psychological support, were compared for groups of participants who either discontinued one or more antidepressant drugs during screening or entered the trial antidepressant drug free. Measures of depression symptom severity change during the antidepressant drug discontinuation period, baseline suicidality, acute subjective psychedelic effects, and the study's primary endpoint (change in depression symptom severity between Baseline and Week 3) are described for both groups. Antidepressant drug discontinuation was not related to worsening of depression severity before Baseline. Suicidality was comparable between groups at Baseline. Psilocybin treatment efficacy and the subjective psychedelic experience did not appear to be compromised by antidepressant drug discontinuation. Thus, it does not limit the feasibility of psilocybin treatment for the future. These findings also support the overall homogeneity of our findings with psilocybin treatment as a monotherapy for TRD. The prior contradictory reports may come to appear misleading.

Barriers and facilitators to healthy eating during post-partum among non-Hispanic Black mothers.

Maternal diet is a key predictor of child diet, yet an in-depth inquiry into the barriers and facilitators for the adoption of healthy eating behaviours during the post-partum period is lacking, specifically for non-Hispanic Black mothers. This study used qualitative research methods to investigate healthy eating practices among a sample of non-Hispanic Black mothers participating in a family-based obesity prevention intervention. In-depth interviews were conducted with 22 mothers who participated in the Mothers and Others: Family-based Obesity Prevention for Infants and Toddlers intervention trial. Interviews were audio-recorded and transcribed verbatim. A deductive and inductive process was used to develop a consensus codebook; once the data were coded, matrices were developed to explore the data and identify similarities and differences between respondents. Relevant themes were identified, and salient quotes were used to illustrate each theme. Mothers believed that time and taste were significant barriers to eating healthy. Social influence and social support had both positive and negative influences on mothers' ability to adopt healthy eating behaviours. Despite their children often being a facilitator to healthy eating, many mothers struggled with finding the time, energy and desire to focus on themselves when it came to healthy eating. Many mothers were intent on preparing healthy meals and snacks for their children but did not prepare them for themselves. Future interventions should focus on the importance of role-modelling healthy eating behaviours for their children and include behaviour change strategies that incorporate skill-building activities emphasizing time-saving methods for planning and preparing healthy meals and snacks for the whole family to eat.

Impact of the Mediterranean Diet on Athletic Performance, Muscle Strength, Body Composition, and Antioxidant Markers in Both Athletes and Non-Professional Athletes: A Systematic Review of Intervention Trials.

Background: The Mediterranean Diet (MD) has gained attention for its potential benefits in enhancing athletic performance and overall health. This systematic review aims to evaluate the effects of the MD on athletic performance, strength, body composition, and metabolic markers in both athletes and non-professional athletes. Methods: The review included seven studies with a total of 116 participants, ranging from professional handball players to non-professional strength athletes. The studies assessed various aspects of athletic performance, including strength, power, endurance, and body composition. Results: The main key findings from the review showed that MD may improve muscle endurance and power, as well as anaerobic performance in CrossFit athletes, and MD was associated with enhanced strength performance, including increased vertical jump height, hand grip strength, and shuttle run performance. The results on the impact on body composition were mixed, with some studies showing improvements in fat-free mass and skeletal muscle mass, while others found no significant changes. The MD also demonstrated positive effects on several markers, such as increased plasma total antioxidant activity and decreased markers of oxidative stress and inflammation. Conclusions: In conclusion, while the MD seems to represent a viable dietary strategy for enhancing athletic performance and overall health, more rigorous studies are necessary to clarify its impact across diverse athletic populations.

A psychometric evaluation of the Opening Minds Scale for Workplace Attitudes (OMS-WA), a measure of public stigma towards mental illnesses in the workplace

The anti-stigma Opening Minds initiative (Mental Health Commission of Canada) identified the workplace as one of four critical areas for stigma evaluation and programming. Researchers found, however, that no validated tool to measure stigma in this context existed at the time. The purpose of the current research was to develop and assess the psychometric properties of a multi-component quantitative measure of public stigma towards mental illnesses in the workplace: Opening Minds Scale for Workplace Attitudes (OMS-WA). Three studies are discussed. Study 1 outlines the initial development of the OMS-WA, finding a five-factor structure with 23 items (EFA analysis; N = 207). Study 2 utilized employees from various businesses to further validate the OMS-WA, (N = 107), finding good internal consistency and good convergent/divergent validity. Study 3 utilized baseline data from two national large-scale stigma reduction and resiliency programs (first responders and general workplaces) to confirm the factor structure, finding good model fit and reliability with both samples (N = 5385; N = 1207). Together, these results provide strong evidence of the OMS-WA. Its use in measuring workplace stigma related to mental illness is recommended. Considerable future evaluation is warranted, and directions for generalizability studies, as well as suggestions for using the OMS-WA in intervention trials, are provided.

Interventional Pharmacoepidemiology: Origins, Current Status, and Future Possibilities.

Interventional pharmacoepidemiology applies quantitative analysis of patterns of medication use and outcomes to help design, guide and then evaluate programs to improve prescription drug use and outcomes. Surveillance of prescribing and drug-taking in large populations is increasingly practical because of the proliferation of detailed data on medication use decisions, often based on paid claims billing data. At the same time, increasingly granular clinical information is available on patient characteristics and outcomes. This can offer important opportunities to identify problematic use, focus interventions to address them, and measure their impact. Alexander et al (Am J Epidemiol. 0000;000(00):0000-0000) review the need for such research and provide methodological guidance for its performance. While randomized controlled trials of such interventions are ideal, real-world considerations often require other evaluation strategies, including stepped-wedge designs and interrupted time-series analysis. As drug therapy becomes more powerful and more costly, and the risks of poor medication choices as well as under-use of effective treatments become even better understood, the health care system will increasingly rely on such approaches to assess current patterns of prescribing and patient adherence, target programs to address problem areas, and measure the effectiveness of such interventions.

A Randomized Controlled Trial of a Digital Intervention to Improve the Sexual Health of Adolescent and Young Adult Male Emergency Department Patients

PurposeTo assess implementation outcomes and potential efficacy of a user-informed, theory-based digital health intervention developed to improve adolescent and young adult (AYA) male sexual health. MethodsWe conducted a pilot randomized controlled trial of sexually active male emergency department (ED) patients aged 14–21 years. Participants were randomized to the intervention (Dr. Eric, Emergency Room Interventions to improve Care) or usual care. Dr. Eric consists of an ED-based sexual health app followed by 3 months of interactive text messages. We assessed the feasibility, adoption, and fidelity among users. Condom use, defined as the number of sexual encounters with condoms divided by the total number of sexual encounters over the past 4 weeks, was the primary efficacy outcome. ResultsWe enrolled 119 patients; mean age was 17.9 years, 87% were Hispanic, and half used condoms at last intercourse. Dr. Eric demonstrated feasibility, with high rates of consent (86.2%) and follow-up (81.5%). Intervention participants found Dr. Eric acceptable, liking (86.2%) and recommending (87.9%) the program. 98% of intervention participants interacted with all five app modules; one-quarter opted out of text messaging. At 6-week follow-up, the intervention group more often used a condom compared to the control group [OR 3.57, 95% confidence interval (1.93, 6.60)], p < .001]; however, this significant difference did not sustain at 13 weeks. DiscussionDr. Eric was feasible to deliver and acceptable to male AYA patients. To our knowledge, Dr. Eric is the first intervention to demonstrate evidence of short-term efficacy for improving condom use among male AYA in the ED.

Plant protein, fibre and physical activity solutions to address poor appetite and prevent undernutrition in older adults: study protocol for the APPETITE randomised controlled trial.

Reduced appetite with ageing is a key factor that may increase risk of undernutrition. The objective of this study is to determine the impact of innovative plant protein fibre (PPF) products within a personalised optimised diet (PD), a physical activity (PA) programme, and their combination on appetite, and other nutritional, functional and clinical outcomes in community-dwelling older adults in a multi-country randomised controlled intervention trial. One hundred and eighty community-dwelling adults (approximately sixty per trial centre in Germany, Ireland and Italy) aged 65 years and over will be recruited to participate in a 12-week, parallel-group, controlled trial. Participants will be randomised into one of four groups: 1, PD (incorporating two PPF products): 2, PA; 3, PD + PA; and 4, no intervention (control). The primary outcome is appetite measured by visual analogue scales and energy intake from an ad libitum test meal. Secondary outcomes include fasting and postprandial appetite-related gut hormones, Simplified Nutritional Appetite Questionnaire score, body composition, cardiorespiratory fitness, muscle strength, physical function and PA. In addition, self-efficacy, cognitive status, dietary restraint, depressive symptoms and compliance and acceptability of the intervention will be assessed. Metabolomic profiles, RMR, muscle motor unit properties and gut microbiome will also be assessed to explore potential underlying mechanisms. This multi-centre randomised controlled trial will advance knowledge on how PD (incorporating PPF products), PA and their combination influence appetite, nutritional status and related health outcomes in community-dwelling older adults and contribute to the prevention of undernutrition. Trial registration: Clinical Trials.gov Registry NCT05608707 (registered on 2 November 2022). Protocol Version: NCT05608707 Version 4 (registered on 29 September 2023).