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Many individually randomized group treatment (IRGT) trials randomly assign individuals to study arms but deliver treatments via shared agents, such as therapists, surgeons, or trainers. Post-randomization interactions induce correlations in outcome measures between participants sharing the same agent. Agents can be nested in or crossed with trial arm, and participants may interact with a single agent or with multiple agents. These complications have led to ambiguity in choice of models but there have been no systematic efforts to identify appropriate analytic models for these study designs. To address this gap, we undertook a simulation study to examine the performance of candidate analytic models in the presence of complex clustering arising from multiple membership, single membership, and single agent settings, in both nested and crossed designs and for a continuous outcome. With nested designs, substantial type I error rate inflation was observed when analytic models did not account for multiple membership and when analytic model weights characterizing the association with multiple agents did not match the data generating mechanism. Conversely, analytic models for crossed designs generally maintained nominal type I error rates unless there was notable imbalance in the number of participants that interact with each agent., (© 2024 The Author(s). Statistics in Medicine published by John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Objective: Young people living with HIV (YPLWH) experience increased morbidity and mortality compared to all other age groups. Adolescence brings unique challenges related to sexual reproductive health, the elevated importance of peer groups, and often, emerging symptoms of emotional distress. Failure to address this unique life stage for YPLWH can lead to worse HIV and mental health outcomes. Herein lies the protocol for a hybrid-type-1 effectiveness-implementation trial designed to evaluate a mental health and life skills intervention that aims to address these needs for YPLWH in Tanzania., Methods: This is an individually randomized group-treatment trial designed to evaluate the effectiveness of Sauti ya Vijana (SYV: The Voice of Youth) toward improving viral suppression (HIV RNA <400 copies/mL) and mental health outcomes and to assess implementation including acceptability, feasibility, fidelity, and cost-effectiveness of the manualized intervention. The trial is being conducted across four geographically distinct regions of Tanzania. Peer group leaders (PGL) with lived HIV experience deliver the 10-session group-based intervention and two individual sessions during which participants describe their disclosure narrative (when they learned they live with HIV) and value-based goal setting. Caregiver or chosen supportive adults are encouraged to attend two specific group sessions with their youth. Participants are 10-24 years of age, prescribed antiretroviral therapy for at least 6 months, fully aware of their HIV status, able to commit to session attendance, and able to understand and meaningfully contribute to group sessions. Participant study visits occur at 5 time points for evaluation: baseline, 4-, 6-, 12-, and 18-months post baseline. A single booster session is conducted before the 12-month visit. Study visits evaluate mental health, adverse childhood events, interpersonal violence, resilience, stigma, HIV knowledge, substance use, sexual relationships, ART adherence, and HIV RNA. Implementation outcomes evaluate feasibility and acceptability through attendance, intervention session notes, focus discussion groups and qualitative interviews. Fidelity to the intervention is measured using fidelity checklists by a PGL observer at each group session. Cost effectiveness is calculated using an incremental cost-effectiveness ratio that utilizes a patient cost questionnaire and financial records of study costs., Significance: Few mental health interventions for YPLWH have demonstrated effectiveness. Results from this study will provide information about effectiveness and implementation of a peer-led intervention for delivering a mental health and life skills intervention in low-income settings., Trial Identifier: This trial is registered at clinicaltrials.gov NCT05374109., Competing Interests: All authors have declared that no competing interests exist., (Copyright: © 2024 Mollel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Malaria remains a major health priority in Nigeria. Among children with fever who seek care, less than a quarter gets tested for malaria, leading to inappropriate use of the recommended treatment for malaria; Artemisinin-based Combination Therapy (ACT). Here we test an innovative strategy to target ACT subsidies to clients seeking care in Nigeria's private retail health sector who have a confirmed malaria diagnosis. We supported point-of-care malaria testing (mRDTs) in 48 Private Medicine Retailers (PMRs) in the city of Lagos, Nigeria and randomized them to two study arms; a control arm offering subsidized mRDT testing for USD $0.66, and an intervention arm where, in addition to access to subsidized testing as in the control arm, clients who received a positive mRDT at the PMR were eligible for a free (fully subsidized) first-line ACT and PMRs received USD $0.2 for every mRDT performed. Our primary outcome was the proportion of ACTs dispensed to individuals with a positive diagnostic test. Secondary outcomes included proportion of clients who were tested at the PMR and adherence to diagnostic test results. Overall, 23% of clients chose to test at the PMR. Test results seemed to inform treatment decisions and resulted in enhanced targeting of ACTs to confirmed malaria cases with only 26% of test-negative clients purchasing an ACT compared to 58% of untested clients. However, the intervention did not offer further improvements, compared to the control arm, in testing rates or dispensing of ACTs to test-positive clients. We found that ACT subsidies were not passed on to clients testing positive in the intervention arm. We conclude that mRDTs could reduce ACT overconsumption in Nigeria's private retail health sector, but PMR-oriented incentive structures are difficult to implement and may need to be complemented with interventions targeting clients of PMRs to increase test uptake and adherence. Trials registration: Clinical Trials Registration Number: NCT04428307. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816435/ Correction: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9476591/., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Visser et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Maintaining healthy behaviors is challenging. Based upon previous reports that in North Carolina (NC), USA, overweight/obese clergy lost weight during a two-year religiously tailored health intervention, we described trajectories of diet, physical activity, and sleep. We investigated whether behavior changes were associated with weight and use of health-promoting theological messages. Improvements were observed in sleep, calorie-dense food intake, and physical activity, with the latter two associated with weight loss. While theological messages were well-retained, their relationship with behaviors depended on the specific message, behavior, and timing. Findings offer insights into weight loss mechanisms, including the role of theological messages in religiously tailored health interventions., (© 2023. The Author(s).)

Importance: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) reported no effect of prostate-specific antigen (PSA) screening on prostate cancer mortality at a median 10-year follow-up (primary outcome), but the long-term effects of PSA screening on prostate cancer mortality remain unclear., Objective: To evaluate the effect of a single invitation for PSA screening on prostate cancer-specific mortality at a median 15-year follow-up compared with no invitation for screening., Design, Setting, and Participants: This secondary analysis of the CAP randomized clinical trial included men aged 50 to 69 years identified at 573 primary care practices in England and Wales. Primary care practices were randomized between September 25, 2001, and August 24, 2007, and men were enrolled between January 8, 2002, and January 20, 2009. Follow-up was completed on March 31, 2021., Intervention: Men received a single invitation for a PSA screening test with subsequent diagnostic tests if the PSA level was 3.0 ng/mL or higher. The control group received standard practice (no invitation)., Main Outcomes and Measures: The primary outcome was reported previously. Of 8 prespecified secondary outcomes, results of 4 were reported previously. The 4 remaining prespecified secondary outcomes at 15-year follow-up were prostate cancer-specific mortality, all-cause mortality, and prostate cancer stage and Gleason grade at diagnosis., Results: Of 415 357 eligible men (mean [SD] age, 59.0 [5.6] years), 98% were included in these analyses. Overall, 12 013 and 12 958 men with a prostate cancer diagnosis were in the intervention and control groups, respectively (15-year cumulative risk, 7.08% [95% CI, 6.95%-7.21%] and 6.94% [95% CI, 6.82%-7.06%], respectively). At a median 15-year follow-up, 1199 men in the intervention group (0.69% [95% CI, 0.65%-0.73%]) and 1451 men in the control group (0.78% [95% CI, 0.73%-0.82%]) died of prostate cancer (rate ratio [RR], 0.92 [95% CI, 0.85-0.99]; P = .03). Compared with the control, the PSA screening intervention increased detection of low-grade (Gleason score [GS] ≤6: 2.2% vs 1.6%; P < .001) and localized (T1/T2: 3.6% vs 3.1%; P < .001) disease but not intermediate (GS of 7), high-grade (GS ≥8), locally advanced (T3), or distally advanced (T4/N1/M1) tumors. There were 45 084 all-cause deaths in the intervention group (23.2% [95% CI, 23.0%-23.4%]) and 50 336 deaths in the control group (23.3% [95% CI, 23.1%-23.5%]) (RR, 0.97 [95% CI, 0.94-1.01]; P = .11). Eight of the prostate cancer deaths in the intervention group (0.7%) and 7 deaths in the control group (0.5%) were related to a diagnostic biopsy or prostate cancer treatment., Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, a single invitation for PSA screening compared with standard practice without routine screening reduced prostate cancer deaths at a median follow-up of 15 years. However, the absolute reduction in deaths was small., Trial Registration: isrctn.org Identifier: ISRCTN92187251.

ACTs are responsible for a substantial proportion of the global reduction in malaria mortality over the last ten years, made possible by publicly-funded subsidies making these drugs accessible and affordable in the private sector. However, inexpensive ACTs available in retail outlets have contributed substantially to overconsumption. We test an innovative, scalable strategy to target ACT-subsidies to clients with a confirmatory diagnosis. We supported malaria testing(mRDTs) in 39 medicine outlets in western Kenya, randomized to three study arms; control arm offering subsidized mRDT testing (0.4USD), client-directed intervention where all clients who received a positive RDT at the outlet were eligible for a free (fully-subsidized) ACT, and a combined client and provider directed intervention where clients with a positive RDT were eligible for free ACT and outlets received 0.1USD for every RDT performed. Our primary outcome was the proportion of ACT dispensed to individuals with a positive diagnostic test. Secondary outcomes included proportion of clients tested at the outlet and adherence to diagnostic test results. 43% of clients chose to test at the outlet. Test results informed treatment decisions, resulting in targeting of ACTs to confirmed malaria cases- 25.3% of test-negative clients purchased an ACT compared to 75% of untested clients. Client-directed and client+provider-directed interventions did not offer further improvements, compared to the control arm, in testing rates(RD = 0.09, 95%CI:-0.08,0.26) or dispensing of ACTs to test-positive clients(RD = 0.01,95% CI:-0.14, 0.16). Clients were often unaware of the price they paid for the ACT leading to uncertainty in whether the ACT subsidy was passed on to the client. This uncertainty undermines our ability to definitively conclude that client-directed subsidies are not effective for improving testing and appropriate treatment. We conclude that mRDTs could reduce ACT overconsumption in the private retail sector, but incentive structures are difficult to scale and their value to private providers is uncertain. Trial registration: ClinicalTrials.gov NCT04428307., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Laktabai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In cluster randomized trials, individuals from the same cluster tend to have more similar outcomes than individuals from different clusters. This correlation must be taken into account in the analysis of every cluster trial to avoid incorrect inferences. In this paper, we describe the principles guiding the analysis of cluster trials including how to correctly account for intra-cluster correlations as well as how to analyze more advanced designs such as stepped-wedge and cluster cross-over trials. We then describe how to handle specific issues such as small sample sizes and missing data., Competing Interests: Declaration of competing interest The authors declare there is no conflict of interests., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Individually randomized group treatment (IRGT) trials, in which the clustering of outcome is induced by group-based treatment delivery, are increasingly popular in public health research. IRGT trials frequently incorporate longitudinal measurements, of which the proper sample size calculations should account for correlation structures reflecting both the treatment-induced clustering and repeated outcome measurements. Given the relatively sparse literature on designing longitudinal IRGT trials, we propose sample size procedures for continuous and binary outcomes based on the generalized estimating equations approach, employing the block exchangeable correlation structures with different correlation parameters for the treatment arm and for the control arm, and surveying five marginal mean models with different assumptions of time effect: no-time constant treatment effect, linear-time constant treatment effect, categorical-time constant treatment effect, linear time by treatment interaction, and categorical time by treatment interaction. Closed-form sample size formulas are derived for continuous outcomes, which depends on the eigenvalues of the correlation matrices; detailed numerical sample size procedures are proposed for binary outcomes. Through simulations, we demonstrate that the empirical power agrees well with the predicted power, for as few as eight groups formed in the treatment arm, when data are analyzed using the matrix-adjusted estimating equations for the correlation parameters with a bias-corrected sandwich variance estimator., (© 2023 John Wiley & Sons Ltd.)

Background: While early autism intervention can significantly improve outcomes, gaps in implementation exist globally. These gaps are clearest in Africa, where forty percent of the world's children will live by 2050. Task-sharing early intervention to non-specialists is a key implementation strategy, given the lack of specialists in Africa. Naturalistic Developmental Behavioral Interventions (NDBI) are a class of early autism intervention that can be delivered by caregivers. As a foundational step to address the early autism intervention gap, we adapted a non-specialist delivered caregiver coaching NDBI for the South African context, and pre-piloted this cascaded task-sharing approach in an existing system of care., Objectives: First, we will test the effectiveness of the caregiver coaching NDBI compared to usual care. Second, we will describe coaching implementation factors within the Western Cape Department of Education in South Africa., Methods: This is a type 1 effectiveness-implementation hybrid design; assessor-blinded, group randomized controlled trial. Participants include 150 autistic children (18-72 months) and their caregivers who live in Cape Town, South Africa, and those involved in intervention implementation. Early Childhood Development practitioners, employed by the Department of Education, will deliver 12, one hour, coaching sessions to the intervention group. The control group will receive usual care. Distal co-primary outcomes include the Communication Domain Standard Score (Vineland Adaptive Behavior Scales, Third Edition) and the Language and Communication Developmental Quotient (Griffiths Scales of Child Development, Third Edition). Proximal secondary outcome include caregiver strategies measured by the sum of five items from the Joint Engagement Rating Inventory. We will describe key implementation determinants., Results: Participant enrolment started in April 2023. Estimated primary completion date is March 2027., Conclusion: The ACACIA trial will determine whether a cascaded task-sharing intervention delivered in an educational setting leads to meaningful improvements in communication abilities of autistic children, and identify implementation barriers and facilitators., Trial Registration: NCT05551728 in Clinical Trial Registry (https://clinicaltrials.gov)., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests. Drs. Geraldine Dawson and Guillermo Sapiro, who are investigators on this project, have developed a technology that is being used in the study. If the technology is commercially successful in the future, the developers and Duke University may benefit financially., (Copyright: © 2024 Franz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Preschool programs provide essential preventive services, such as hearing screening, but in rural regions, limited access to specialists and loss to follow-up compound rural health disparities. We conducted a parallel-arm cluster-randomized controlled trial to evaluate telemedicine specialty referral for preschool hearing screening. The goal of this trial was to improve timely identification and treatment of early childhood infection-related hearing loss, a preventable condition with lifelong implications. We hypothesized that telemedicine specialty referral would improve time to follow-up and the number of children receiving follow-up compared with the standard primary care referral., Design: We conducted a cluster-randomized controlled trial in K-12 schools in 15 communities over two academic years. Community randomization occurred within four strata using location and school size. In the second academic year (2018-2019), an ancillary trial was performed in the 14 communities that had preschools to compare telemedicine specialty referral (intervention) to standard primary care referral (comparison) for preschool hearing screening. Randomization of communities from the main trial was used for this ancillary trial. All children enrolled in preschool were eligible. Masking was not possible because of timing in the second year of the main trial, but referral assignment was not openly disclosed. Study team members and school staff were masked throughout data collection, and statisticians were blinded to allocation during analysis. Preschool screening occurred once, and children who were referred for possible hearing loss or ear disease were monitored for follow-up for 9 months from the screening date. The primary outcome was time to ear/hearing-related follow-up from the date of screening. The secondary outcome was any ear/hearing follow-up from screening to 9 months. Analyses were conducted using an intention-to-treat approach., Results: A total of 153 children were screened between September 2018 and March 2019. Of the 14 communities, 8 were assigned to the telemedicine specialty referral pathway (90 children), and 6 to the standard primary care referral pathway (63 children). Seventy-one children (46.4%) were referred for follow-up: 39 (43.3%) in the telemedicine specialty referral communities and 32 (50.8%) in the standard primary care referral communities. Of children referred, 30 (76.9%) children in telemedicine specialty referral communities and 16 (50.0%) children in standard primary care referral communities received follow-up within 9 months (Risk Ratio = 1.57; 95% confidence interval [CI], 1.22 to 2.01). Among children who received follow-up, median time to follow-up was 28 days (interquartile range [IQR]: 15 to 71) in telemedicine specialty referral communities compared with 85 days (IQR: 26 to 129) in standard primary care referral communities. Mean time to follow-up for all referred children was 4.5 (event time ratio = 4.5; 95% CI, 1.8 to 11.4; p = 0.045) times faster in telemedicine specialty referral communities compared with standard primary care referral communities in the 9-month follow-up time frame., Conclusions: Telemedicine specialty referral significantly improved follow-up and reduced time to follow-up after preschool hearing screening in rural Alaska. Telemedicine referrals could extend to other preventive school-based services to improve access to specialty care for rural preschool children., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 The Authors. Ear & Hearing is published on behalf of the American Auditory Society, by Wolters Kluwer Health, Inc.)

Stepped wedge trials are increasingly adopted because practical constraints necessitate staggered roll-out. While a complete design requires clusters to collect data in all periods, resource and patient-centered considerations may call for an incomplete stepped wedge design to minimize data collection burden. To study incomplete designs, we expand the metric of information content to discrete outcomes. We operate under a marginal model with general link and variance functions, and derive information content expressions when data elements (cells, sequences, periods) are omitted. We show that the centrosymmetric patterns of information content can hold for discrete outcomes with the variance-stabilizing link function. We perform numerical studies under the canonical link function, and find that while the patterns of information content for cells are approximately centrosymmetric for all examined underlying secular trends, the patterns of information content for sequences or periods are more sensitive to the secular trend, and may be far from centrosymmetric.

Objective: Suicidal ideation is strikingly common among people living with HIV (PLWH) worldwide, leading to higher burden of disease, poor HIV care engagement, and loss of life. In low- and middle-income countries such as Tanzania, mental health resources are scarce, requiring innovative strategies for treatment. We describe the protocol for a clinical trial of a three-session telehealth counseling intervention to reduce suicidality and improve HIV care engagement in Tanzania., Methods: In a pilot randomized controlled trial, we will assess the feasibility, acceptability, and potential efficacy of a new telehealth intervention, termed "IDEAS for Hope". A total of 60 PLWH will be enrolled from two HIV clinics in the Kilimanjaro region and connected to telehealth counsellors based at a large regional hospital. Participants will be ≥18 years old and speak either Kiswahili or English. Patient screening will occur during routine HIV clinical care to identify PLWH experiencing suicidal ideation. Baseline surveys will be administered upon enrollment and participants will be randomized 1:1 to receive either IDEAS for Hope or the comparison condition, a brief safety planning session. All participants will receive an additional referral for psychiatric treatment. Follow-up assessment will occur at three months. IDEAS for Hope is informed by a Motivational Interviewing-enhanced safety planning intervention (MI-SafeCope) and our formative work in Tanzania. The model consists of Four Pillars: living healthy with HIV, managing HIV stigma, seeking social support, and meeting basic needs. Together, these mechanisms serve as a foundation for developing a sense of safety and hope for the future. Outcome measures will include intervention feasibility, acceptability, participant suicidality, and HIV care engagement., Significance: Innovative, telehealth-based counseling represents a promising treatment for suicidality among PLWH in low-resource settings. Results from this pilot trial will inform intervention refinement and parameter estimates for a future clinical trial powered to evaluate effectiveness., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Knettel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: This manuscript describes the Day-in-the-Life (DIL) method for assessing child caregiving activities, its implementation, and findings regarding family members' roles and associations with maternal depression symptoms., Background: Infant caregiving activities are most commonly performed by the mother, although there is increasing acknowledgement of others' contribution. Few methods exist to measure the diverse caregiving activities that mothers and others perform., Method: Method development occurred within the Bachpan Cohort Study in rural Pakistan ( N = 1,154 maternal-child dyads) when the child was 3 months old. The DIL was designed as a semi-structured interview in which the mother describes her child's day from their perspective. Regression analyses were then used to explore the correlation between the DIL and depression symptoms, using the Patient Health Questionnaire-9 (PHQ-9) measure., Results: The DIL method was easy to administer and displayed excellent interrater agreement. The findings indicated that instrumental caregiving was mostly provided by the mother alone, others in the household tended to contribute more to infant social interactions, and there was more support from others when the mother was less able to provide care (e.g., when ill). Depression symptoms were higher among women who experienced less contribution from family members when the mother was less able to provide care., Conclusions: The DIL can be deployed to measure infant caregiving activities and associations with maternal mental health., Implications: This method is promising for researchers interested in disentangling the contribution of multiple family members toward child caregiving and its impacts on maternal and child health.

Background and Objectives: Marginal models with generalized estimating equations (GEE) are usually recommended for analyzing correlated ordinal outcomes which are commonly seen in a longitudinal study or clustered randomized trial (CRT). Within-cluster association is often of interest in longitudinal studies or CRTs, and can be estimated with paired estimating equations. However, the estimators for within-cluster association parameters and variances may be subject to finite-sample biases when the number of clusters is small. The objective of this article is to introduce a newly developed R package ORTH.Ord for analyzing correlated ordinal outcomes using GEE models with finite-sample bias corrections., Methods: The R package ORTH.Ord implements a modified version of alternating logistic regressions with estimation based on orthogonalized residuals (ORTH), which use paired estimating equations to jointly estimate parameters in marginal mean and association models. The within-cluster association between ordinal responses is modeled by global pairwise odds ratios (POR). The R package also provides a finite-sample bias correction to POR parameter estimates based on matrix multiplicative adjusted orthogonalized residuals (MMORTH) for correcting estimating equations, and bias-corrected sandwich estimators with different options for covariance estimation., Results: A simulation study shows that MMORTH provides less biased global POR estimates and coverage of their 95% confidence intervals closer to the nominal level than uncorrected ORTH. An analysis of patient-reported outcomes from an orthognathic surgery clinical trial illustrates features of ORTH.Ord., Conclusions: This article provides an overview of the ORTH method with bias-correction on both estimating equations and sandwich estimators for analyzing correlated ordinal data, describes the features of the ORTH.Ord R package, evaluates the performance of the package using a simulation study, and finally illustrates its application in an analysis of a clinical trial., Competing Interests: Declaration of Competing Interest Authors have no other conflicts of interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Differences in activity limitations between stroke survivors and people with other chronic conditions and how their levels of activity limitation vary by sociodemographic characteristics have not been well quantified., Objective: To quantify activity limitations experienced by Chinese older adult stroke survivors and explore stroke effects in specific subgroups., Methods: We used Chinese Longitudinal Healthy Longevity Survey 2017-2018 data (N = 11,743) to produce population-weighted estimates of activity limitations using the Activities of Daily Living (ADL) and the Instrumental ADL (IADL) scales for older adults (age 65 and older) stroke survivors compared to those with non-stroke chronic conditions and those without chronic conditions. Multinomial logistic regressions were run with outcomes "no activity limitation," "IADL only limitation," and "ADL limitation.", Results: The weighted marginal prevalence of ADL limitation was higher in the stroke group (14.8%) than in those with non-stroke chronic condition (4.8%) or no chronic conditions (3.6%) (p < 0.01). The corresponding prevalence of IADL limitation for the three groups was 36.0%, 31.4%, and 22.2%, respectively (p < 0.01). Stroke survivors aged ≥ 80 years had a higher prevalence of ADL/IADL limitation than those aged 65-79 years (p < 0.01). Formal education was associated with a lower prevalence of ADL/IADL limitation in each chronic condition group (p < 0.01)., Conclusions: Prevalence and severity of activity limitation among Chinese older adult stroke survivors were several times higher than those without chronic conditions and those with non-stroke chronic conditions. Stroke survivors, particularly those aged ≥80 years and those without formal education, might be predisposed to more severe activity limitation and require more support to compensate., Competing Interests: Conflicts of interest The authors have no conflicts of interest to report for this study., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Screening men for prostate cancer using prostate-specific antigen (PSA) testing remains controversial. We aimed to estimate the likely budgetary impact on secondary care in England and Wales to inform screening decision makers., Methods: The Cluster randomised triAl of PSA testing for Prostate cancer study (CAP) compared a single invitation to men aged 50-69 for a PSA test with usual care (no screening). Routinely collected hospital care data were obtained for all men in CAP, and NHS reference costs were mapped to each event via Healthcare Resource Group (HRG) codes. Secondary-care costs per man per year were calculated, and cost differences (and population-level estimates) between arms were derived annually for the first five years following randomisation., Results: In the first year post-randomisation, secondary-care costs averaged across all men (irrespective of a prostate cancer diagnosis) in the intervention arm (n = 189279) were £44.80 (95% confidence interval: £18.30-£71.30) higher than for men in the control arm (n = 219357). Extrapolated to a population level, the introduction of a single PSA screening invitation could lead to additional secondary care costs of £314 million., Conclusions: Introducing a single PSA screening test for men aged 50-69 across England and Wales could lead to very high initial secondary-care costs., (© 2023. The Author(s).)

Background: Despite the high number of children living with neurodevelopmental disabilities in sub-Saharan Africa, access to early intervention is almost non-existent. It is therefore important to develop feasible, scalable early autism intervention that can be integrated into systems of care. While Naturalistic Developmental Behavioural Intervention (NDBI) has emerged as an evidence-based intervention approach, implementation gaps exist globally, and task-sharing approaches may address access gaps. In this South African proof-of-principle pilot study, we set out to answer two questions about a 12-session cascaded task-sharing NDBI-whether the approach could be delivered with fidelity, and whether we could identify signals of change in child and caregiver outcomes., Methods: We utilized a single-arm pre-post design. Fidelity (non-specialists, caregivers), caregiver outcomes (stress, sense of competence), and child outcomes (developmental, adaptive) were measured at baseline (T1) and follow-up (T2). Ten caregiver-child dyads and four non-specialists participated. Pre-to-post summary statistics were presented alongside individual trajectories. Non-parametric Wilcoxon signed rank test for paired samples was used to compare group medians between T1 and T2., Results: Caregiver implementation fidelity increased in 10/10 participants. Non-specialists demonstrated a significant increase in coaching fidelity (increases in 7/10 dyads). Significant gains were seen on two Griffiths-III subscales (Language/Communication-9/10 improved, Foundations of Learning-10/10 improved) and on the General Developmental Quotient (9/10 improved). Significant gains were also seen on two Vineland Adaptive Behaviour Scales (Third Edition) subscales (Communication-9/10 improved, Socialization-6/10 improved) and in the Adaptive Behaviour Standard Score (9/10 improved). Caregiver sense of competence improved in 7/10 caregivers and caregiver stress in 6/10 caregivers., Conclusions: This proof-of-principle pilot study of the first cascaded task-sharing NDBI in Sub-Saharan Africa provided fidelity and intervention outcome data which supported the potential of such approaches in low-resource contexts. Larger studies are needed to expand on the evidence-base and answer questions on intervention effectiveness and implementation outcomes., (© 2023. The Author(s).)

Background: Between 1999 and 2009 in the United Kingdom, 82,429 men between 50 and 69 years of age received a prostate-specific antigen (PSA) test. Localized prostate cancer was diagnosed in 2664 men. Of these men, 1643 were enrolled in a trial to evaluate the effectiveness of treatments, with 545 randomly assigned to receive active monitoring, 553 to undergo prostatectomy, and 545 to undergo radiotherapy., Methods: At a median follow-up of 15 years (range, 11 to 21), we compared the results in this population with respect to death from prostate cancer (the primary outcome) and death from any cause, metastases, disease progression, and initiation of long-term androgen-deprivation therapy (secondary outcomes)., Results: Follow-up was complete for 1610 patients (98%). A risk-stratification analysis showed that more than one third of the men had intermediate or high-risk disease at diagnosis. Death from prostate cancer occurred in 45 men (2.7%): 17 (3.1%) in the active-monitoring group, 12 (2.2%) in the prostatectomy group, and 16 (2.9%) in the radiotherapy group (P = 0.53 for the overall comparison). Death from any cause occurred in 356 men (21.7%), with similar numbers in all three groups. Metastases developed in 51 men (9.4%) in the active-monitoring group, in 26 (4.7%) in the prostatectomy group, and in 27 (5.0%) in the radiotherapy group. Long-term androgen-deprivation therapy was initiated in 69 men (12.7%), 40 (7.2%), and 42 (7.7%), respectively; clinical progression occurred in 141 men (25.9%), 58 (10.5%), and 60 (11.0%), respectively. In the active-monitoring group, 133 men (24.4%) were alive without any prostate cancer treatment at the end of follow-up. No differential effects on cancer-specific mortality were noted in relation to the baseline PSA level, tumor stage or grade, or risk-stratification score. No treatment complications were reported after the 10-year analysis., Conclusions: After 15 years of follow-up, prostate cancer-specific mortality was low regardless of the treatment assigned. Thus, the choice of therapy involves weighing trade-offs between benefits and harms associated with treatments for localized prostate cancer. (Funded by the National Institute for Health and Care Research; ProtecT Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.)., (Copyright © 2023 Massachusetts Medical Society.)

BACKGROUND: Long-term patient-reported outcomes are needed to inform treatment decisions for localized prostate cancer. METHODS: Patient-reported outcomes of 1643 randomly assigned participants in the ProtecT (Prostate Testing for Cancer and Treatment) trial were evaluated to assess the functional and quality-of-life impacts of prostatectomy, radiotherapy with neoadjuvant androgen deprivation, and active monitoring. This article focuses on the outcomes of the randomly assigned participants from 7 to 12 years using mixed effects linear and logistic models. RESULTS: Response rates exceeded 80% for most measures. Among the randomized groups over 7 to 12 years, generic quality-of-life scores were similar. Among those in the prostatectomy group, urinary leakage requiring pads occurred in 18 to 24% of patients over 7 to 12 years, compared with 9 to 11% in the active monitoring group and 3 to 8% in the radiotherapy group. In the prostatectomy group, 18% reported erections sufficient for intercourse at 7 years, compared with 30% in the active monitoring and 27% in the radiotherapy groups; all converged to low levels of potency by year 12. Nocturia (voiding at least twice per night) occurred in 34% in the prostatectomy group compared with 48% in the radiotherapy group and 47% in the active monitoring group at 12 years. Fecal leakage affected 12% in the radiotherapy group compared with 6% in the other groups by year 12. The active monitoring group experienced gradual age-related declines in sexual and urinary function, avoiding radical treatment effects unless they changed management. CONCLUSIONS: ProtecT provides robust evidence about continued impacts of treatments in the long term. These data allow patients newly diagnosed with localized prostate cancer and their clinicians to assess the trade-offs between treatment harms and benefits and enable better informed and prudent treatment decisions. (Funded by the UK National Institute for Health and Care Research Health Technology Assessment Programme projects 96/20/06 and 96/20/99; ISRCTN number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.)

Background and Objectives: Generalized estimating equations (GEE) are used to analyze correlated outcomes in marginal regression models with population-averaged interpretations of exposure effects. Limitations of popular software for GEE include: (i) user choice is restricted to a small set of within-cluster pairwise correlation (intra-class correlation; ICC) structures; and (ii) inference on ICC parameters is usually not possible because the precision of their estimates is not quantified. This is important because ICC values inform the design of cluster randomized trials. Beyond the standard GEE implementation, use of paired estimating equations (Prentice 1988) provides: (i) flexible specification of models for pairwise correlations and (ii) standard errors for ICC estimates. However, most GEEs give biased estimates of standard errors and correlations when the number of clusters is small (roughly, ≤40). Consequently, there is a need for software to provide GEE analysis with finite-sample bias-corrections., Methods: The SAS macro GEEMAEE implements paired estimating equations to simultaneously estimate parameters in marginal mean and ICC models. It provides bias-corrected standard errors and uses matrix-adjusted estimating equations (MAEE) for bias-corrected estimation of correlations. Several built-in correlation matrix options, rarely found in software, are offered for multi-period, cluster randomized trials and similarly structured longitudinal observational data structures. Additional options include user-specified correlation structures and deletion diagnostics, namely Cooks' Distance and DBETA statistics that estimate the influence of observations, cluster-periods (when applicable) and clusters., Results: GEEMAEE is illustrated for a binary and a count outcome in two stepped wedge cluster randomized trials and a binary outcome in a longitudinal study of disease surveillance. Use of MAEE resulted in larger values of correlation estimates compared to uncorrected estimating equations. Use of bias-corrected variance estimators resulted in (appropriately) larger values of standard errors compared to the usual sandwich estimators. Deletion diagnostics identified the clusters and cluster-periods having the most influence., Conclusions: The SAS macro GEEMAEE provides regression analysis for clustered or longitudinal responses, and is particularly useful when the number of clusters is small. Flexible specification and bias-corrected estimation of pairwise correlation parameters and standard errors are key features of the software to provide valid inference in real-world settings., Competing Interests: Declaration of Competing Interest We have no other conflicts of interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cluster randomized trials (CRTs) frequently recruit a small number of clusters, therefore necessitating the application of small-sample corrections for valid inference. A recent systematic review indicated that CRTs reporting right-censored, time-to-event outcomes are not uncommon and that the marginal Cox proportional hazards model is one of the common approaches used for primary analysis. While small-sample corrections have been studied under marginal models with continuous, binary, and count outcomes, no prior research has been devoted to the development and evaluation of bias-corrected sandwich variance estimators when clustered time-to-event outcomes are analyzed by the marginal Cox model. To improve current practice, we propose nine bias-corrected sandwich variance estimators for the analysis of CRTs using the marginal Cox model and report on a simulation study to evaluate their small-sample properties. Our results indicate that the optimal choice of bias-corrected sandwich variance estimator for CRTs with survival outcomes can depend on the variability of cluster sizes and can also slightly differ whether it is evaluated according to relative bias or type I error rate. Finally, we illustrate the new variance estimators in a real-world CRT where the conclusion about intervention effectiveness differs depending on the use of small-sample bias corrections. The proposed sandwich variance estimators are implemented in an R package CoxBcv., (© 2022 Wiley-VCH GmbH.)

Stepped wedge designs have uni-directional crossovers at randomly assigned time points (steps) where clusters switch from control to intervention condition. Incomplete stepped wedge designs are increasingly used in cluster randomized trials of health care interventions and have periods without data collection due to logistical, resource and patient-centered considerations. The development of sample size formulae for stepped wedge trials has primarily focused on complete designs and continuous responses. Addressing this gap, a general, fast, non-simulation based power procedure is proposed for generalized estimating equations analysis of complete and incomplete stepped wedge designs and its predicted power is compared to simulated power for binary and continuous responses. An extensive set of simulations for six and twelve clusters is based upon the Connect-Home trial with an incomplete stepped wedge design. Results show that empirical test size is well controlled using a t-test with bias-corrected sandwich variance estimator for as few as six clusters. Analytical power agrees well with a simulated power in scenarios with twelve clusters. For six clusters, analytical power is similar to simulated power with estimation using the correctly specified model-based variance estimator. To explore the impact of study design choice on power, the proposed fast GEE power method is applied to the Connect-Home trial design, four alternative incomplete stepped wedge designs and one complete design.

Objectives: To examine how drug shop clients' expenditures are affected by subsidies for malaria diagnostic testing and for malaria treatment, and also to examine how expenditures vary by clients' malaria test result and by the number of medications they purchased., Design: Secondary cross-sectional analysis of survey responses from a randomised controlled trial., Setting: The study was conducted in twelve private drug shops in Western Kenya., Participants: We surveyed 836 clients who visited the drug shops between March 2018 and October 2019 for a malaria-like illness. This included children >1 year of age if they were physically present and accompanied by a parent or legal guardian., Interventions: Subsidies for malaria diagnostic testing and for malaria treatment (conditional on a positive malaria test result)., Primary and Secondary Outcome Measures: Expenditures at the drug shop in Kenya shillings (Ksh)., Results: Clients who were randomised to a 50% subsidy for malaria rapid diagnostic tests (RDTs) spent approximately Ksh23 less than those who were randomised to no RDT subsidy (95% CI (-34.6 to -10.7), p=0.002), which corresponds approximately to the value of the subsidy (Ksh20). However, clients randomised to receive free treatment (artemisinin combination therapies (ACTs)) if they tested positive for malaria had similar spending levels as those randomised to a 67% ACT subsidy conditional on a positive test. Expenditures were also similar by test result, however, those who tested positive for malaria bought more medications than those who tested negative for malaria while spending approximately Ksh15 less per medication (95% CI (-34.7 to 3.6), p=0.102)., Conclusions: Our results suggest that subsidies for diagnostic health products may result in larger household savings than subsidies on curative health products. A better understanding of how people adjust their behaviours and expenditures in response to subsidies could improve the design and implementation of subsidies for health products., Trial Registration Number: NCT03810014., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objective: Most guidelines in the UK, Europe and North America do not recommend organised population-wide screening for prostate cancer. Prostate-specific antigen-based screening can reduce prostate cancer-specific mortality, but there are concerns about overdiagnosis, overtreatment and economic value. The aim was therefore to assess the cost effectiveness of eight potential screening strategies in the UK., Methods: We used a cost-utility analysis with an individual-based simulation model. The model was calibrated to data from the 10-year follow-up of the Cluster Randomised Trial of PSA Testing for Prostate Cancer (CAP). Treatment effects were modelled using data from the Prostate Testing for Cancer and Treatment (ProtecT) trial. The participants were a hypothetical population of 10 million men in the UK followed from age 30 years to death. The strategies were: no screening; five age-based screening strategies; adaptive screening, where men with an initial prostate-specific antigen level of < 1.5 ng/mL are screened every 6 years and those above this level are screened every 4 years; and two polygenic risk-stratified screening strategies. We assumed the use of pre-biopsy multi-parametric magnetic resonance imaging for men with prostate-specific antigen ≥ 3 ng/mL and combined transrectal ultrasound-guided and targeted biopsies. The main outcome measures were projected lifetime costs and quality-adjusted life-years from a National Health Service perspective., Results: All screening strategies increased costs compared with no screening, with the majority also increasing quality-adjusted life-years. At willingness-to-pay thresholds of £20,000 or £30,000 per quality-adjusted life-year gained, a once-off screening at age 50 years was optimal, although this was sensitive to the utility estimates used. Although the polygenic risk-stratified screening strategies were not on the cost-effectiveness frontier, there was evidence to suggest that they were less cost ineffective than the alternative age-based strategies., Conclusions: Of the prostate-specific antigen-based strategies compared, only a once-off screening at age 50 years was potentially cost effective at current UK willingness-to-pay thresholds. An additional follow-up of CAP to 15 years may reduce uncertainty about the cost effectiveness of the screening strategies., (© 2022. The Author(s).)

Stepped wedge cluster randomized trials are increasingly being used to evaluate interventions in medical, public health, educational, and social science contexts. With the longitudinal and crossover nature of a SW-CRT, complex analysis techniques are often needed which makes appropriately powering SW-CRTs challenging. In this paper, we introduce a newly-developed SW-CRT power calculator, embedded within the power command in Stata. The power calculator assumes a marginal model (i.e., generalized estimating equations [GEE]) for the primary analysis of SW-CRTs, for which other currently available SW-CRT power calculators may not be suitable. The program accommodates complete cross-sectional and closed-cohort designs, and includes multilevel correlation structures appropriate for such designs. We discuss the methods and formulae underlying our SW-CRT calculator, and provide illustrative examples of the use of power swgee. We provide suggestions about the choice of parameters in power swgee, and conclude by discussing areas of future research which may improve the program.

Background: The prevalence of opioid use disorder has increased across the United States, but the rural population of Appalachia has been disproportionately impacted. Concurrently, the slow, but steady progress in the legalization of marijuana may be affecting perception of marijuana use in pregnancy. However, marijuana use in pregnancy has been associated with adverse perinatal outcomes. Concomitant use of opioids and marijuana in pregnancy has not been evaluated., Objective: The primary aim of the study was to evaluate the association between confirmed marijuana use in late pregnancy and preterm birth in opioid-exposed pregnancies., Methodology: A retrospective chart review was conducted that included all births from July 2011 to June 2016 from 6 delivery hospitals in South-Central Appalachia. Out of 18,732 births, 2368 singleton pregnancies indicated opioid use and met remaining inclusion criteria, with 108 of these mothers testing positive for marijuana at delivery. Independent sample t -test and Chi-Square analyses compared marijuana and non-marijuana exposed groups on maternal and neonatal outcomes. Regression analyses controlled for confounding variables in predicting neonatal abstinence syndrome (NAS), NICU admission, preterm birth, small for gestational age, and low birth weight outcomes as shown in Table 1., Results: Neonates born to marijuana-positive women in opioid-exposed pregnancy were more likely to be born preterm, small for gestational age, have low birth weight, and be admitted to NICU. After statistically controlling for parity, marital status, tobacco and benzodiazepine use, preterm birth and low birth weight remained statistically significant with aOR of 2.35 (1.30-4.24) and 2.01 (1.18-3.44), respectively., Conclusions: Maternal use of marijuana in any opioid-exposed pregnancy may increase risk of preterm birth and low-birth weight infants. Prospective studies need to examine the dose and timing of marijuana and opioid use in pregnancy to better delineate perinatal effects. Nonetheless, pregnant women using opioids, including recommended medication assisted treatment for opioid use disorder, should be educated about the risks of concurrent marijuana use during pregnancy and may need to be counseled to abstain from marijuana use during pregnancy for an optimal outcome.

Objective: To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making., Patients and Methods: Men aged 50-69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores., Results: Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL., Conclusion: Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes., (© 2022 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Stepped wedge cluster randomized trials (SW-CRTs) with binary outcomes are increasingly used in prevention and implementation studies. Marginal models represent a flexible tool for analyzing SW-CRTs with population-averaged interpretations, but the joint estimation of the mean and intraclass correlation coefficients (ICCs) can be computationally intensive due to large cluster-period sizes. Motivated by the need for marginal inference in SW-CRTs, we propose a simple and efficient estimating equations approach to analyze cluster-period means. We show that the quasi-score for the marginal mean defined from individual-level observations can be reformulated as the quasi-score for the same marginal mean defined from the cluster-period means. An additional mapping of the individual-level ICCs into correlations for the cluster-period means further provides a rigorous justification for the cluster-period approach. The proposed approach addresses a long-recognized computational burden associated with estimating equations defined based on individual-level observations, and enables fast point and interval estimation of the intervention effect and correlations. We further propose matrix-adjusted estimating equations to improve the finite-sample inference for ICCs. By providing a valid approach to estimate ICCs within the class of generalized linear models for correlated binary outcomes, this article operationalizes key recommendations from the CONSORT extension to SW-CRTs, including the reporting of ICCs., (© The authors 2021. Published by Oxford University Press.)

Growing evidence suggests considerable variation in endemic typhoid fever incidence at some locations over time, yet few settings have multi-year incidence estimates to inform typhoid control measures. We sought to describe a decade of typhoid fever incidence in the Kilimanjaro Region of Tanzania. Cases of blood culture confirmed typhoid were identified among febrile patients at two sentinel hospitals during three study periods: 2007-08, 2011-14, and 2016-18. To account for under-ascertainment at sentinel facilities, we derived adjustment multipliers from healthcare utilization surveys done in the hospital catchment area. Incidence estimates and credible intervals (CrI) were derived using a Bayesian hierarchical incidence model that incorporated uncertainty of our observed typhoid fever prevalence, of healthcare seeking adjustment multipliers, and of blood culture diagnostic sensitivity. Among 3,556 total participants, 50 typhoid fever cases were identified. Of typhoid cases, 26 (52%) were male and the median (range) age was 22 (<1-60) years; 4 (8%) were aged <5 years and 10 (20%) were aged 5 to 14 years. Annual typhoid fever incidence was estimated as 61.5 (95% CrI 14.9-181.9), 6.5 (95% CrI 1.4-20.4), and 4.0 (95% CrI 0.6-13.9) per 100,000 persons in 2007-08, 2011-14, and 2016-18, respectively. There were no deaths among typhoid cases. We estimated moderate typhoid incidence (≥10 per 100 000) in 2007-08 and low (<10 per 100 000) incidence during later surveillance periods, but with overlapping credible intervals across study periods. Although consistent with falling typhoid incidence, we interpret this as showing substantial variation over the study periods. Given potential variation, multi-year surveillance may be warranted in locations making decisions about typhoid conjugate vaccine introduction and other control measures., Competing Interests: The authors have declared that no competing interests exist.

Background: School-based programmes, including hearing screening, provide essential preventive services for rural children. However, minimal evidence on screening methodologies, loss to follow-up, and scarcity of specialists for subsequent care compound rural health disparities. We hypothesised telemedicine specialty referral would improve time to follow-up for school hearing screening compared with standard primary care referral., Methods: In this cluster-randomised controlled trial conducted in 15 rural Alaskan communities, USA, we randomised communities to telemedicine specialty referral (intervention) or standard primary care referral (control) for school hearing screening. All children (K-12; aged 4-21 years) enrolled in Bering Straight School District were eligible. Community randomisation occurred within four strata using location and school size. Participants were masked to group allocation until screening day, and assessors were masked throughout data collection. Screening occurred annually, and children who screened positive for possible hearing loss or ear disease were monitored for 9 months from the screening date for follow-up. Primary outcome was the time to follow-up after a positive hearing screen; analysis was by intention to treat. The trial was registered with ClinicalTrials.gov, NCT03309553., Findings: We recruited participants between Oct 10, 2017, and March 28, 2019. 15 communities were randomised: eight (750 children) to telemedicine referral and seven (731 children) to primary care referral. 790 (53·3%) of 1481 children screened positive in at least one study year: 391 (52∤1%) in the telemedicine referral communities and 399 (50∤4%) in the primary care referral communities. Of children referred, 268 (68·5%) in the telemedicine referral communities and 128 (32·1%) in primary care referral communities received follow-up within 9 months. Among children who received follow-up, mean time to follow-up was 41·5 days (SD 55·7) in the telemedicine referral communities and 92·0 days (75·8) in the primary care referral communities (adjusted event-time ratio 17·6 [95% CI 6·8-45·3] for all referred children). There were no adverse events., Interpretation: Telemedicine specialty referral significantly improved the time to follow-up after hearing screening in Alaska. Telemedicine might apply to other preventive school-based services to improve access to specialty care for rural children., Funding: Patient-Centered Outcomes Research Institute., Competing Interests: Declaration of interests SKR has received payment for telehealth lectures by the American Academy of Audiology and Audiology Today. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: There are increasing efforts for the integration of mental health services into primary care settings in low- and middle-income countries. However, commonly used approaches to train primary care providers (PCPs) may not achieve the expected outcomes for improved service delivery, as evidenced by low detection rates of mental illnesses after training. One contributor to this shortcoming is the stigma among PCPs. Implementation strategies for training PCPs that reduce stigma have the potential to improve the quality of services., Design: In Nepal, a type 3 hybrid implementation-effectiveness cluster randomized controlled trial will evaluate the implementation-as-usual training for PCPs compared to an alternative implementation strategy to train PCPs, entitled Reducing Stigma among Healthcare Providers (RESHAPE). In implementation-as-usual, PCPs are trained on the World Health Organization Mental Health Gap Action Program Intervention Guide (mhGAP-IG) with trainings conducted by mental health specialists. In RESHAPE, mhGAP-IG training includes the added component of facilitation by people with lived experience of mental illness (PWLE) and their caregivers using PhotoVoice, as well as aspirational figures. The duration of PCP training is the same in both arms. Co-primary outcomes of the study are stigma among PCPs, as measured with the Social Distance Scale at 6 months post-training, and reach, a domain from the RE-AIM implementation science framework. Reach is operationalized as the accuracy of detection of mental illness in primary care facilities and will be determined by psychiatrists at 3 months after PCPs diagnose the patients. Stigma will be evaluated as a mediator of reach. Cost-effectiveness and other RE-AIM outcomes will be assessed. Twenty-four municipalities, the unit of clustering, will be randomized to either mhGAP-IG implementation-as-usual or RESHAPE arms, with approximately 76 health facilities and 216 PCPs divided equally between arms. An estimated 1100 patients will be enrolled for the evaluation of accurate diagnosis of depression, generalized anxiety disorder, psychosis, or alcohol use disorder. Masking will include PCPs, patients, and psychiatrists., Discussion: This study will advance the knowledge of stigma reduction for training PCPs in partnership with PWLE. This collaborative approach to training has the potential to improve diagnostic competencies. If successful, this implementation strategy could be scaled up throughout low-resource settings to reduce the global treatment gap for mental illness., Trial Registration: ClinicalTrials.gov, NCT04282915 . Date of registration: February 25, 2020., (© 2022. The Author(s).)

Sauti ya Vijana is a mental health and life skills intervention delivered by young adult group leaders for the improvement of HIV outcomes in young people living with HIV in Tanzania. This pilot randomized controlled trial estimated exploratory intervention effectiveness compared to standard of care. YPLWH (N = 105) were randomized to receive intervention or SOC. The mean age of participants was 18.1 years and 53% were female. Mean scores on mental health measures (Patient Health Questionnaire [PHQ-9], Strengths and Difficulties Questionnaire [SDQ], UCLA Trauma) were asymptomatic to mild in both study arms through 30-month follow-up with a non-significant fluctuation of 1-2 points. The mean self-reported adherence was higher in the intervention arm across all time points (but the confidence interval contained the null at all time points except 6 months). Risk ratio of virologic suppression (HIV RNA < 400 copies/mL) in the intervention arm compared to SOC was 1.15 [95% CI = 0.95, 1.39]) at 6-months, 1.17 [95% CI: 0.92, 1.48] at 12-months, and 0.99 [95% CI 0.76, 1.31] at 18-months. Though these findings were not powered for statistical significance, the trends in HIV outcomes suggest that SYV holds promise for improving antiretroviral therapy (ART) adherence and virologic suppression in YPLWH., (© 2021. The Author(s).)

Background: There is little evidence of the influence of dietary patterns on mortality risk among adults 80 years or older ("oldest-old"). We evaluated the association between the Simplified Healthy Eating index (SHE-index) and mortality among Chinese oldest-old., Methods: Population-based cohort study from the Chinese Longitudinal Healthy Longevity Survey (CLHLS 1998-2014, n = 35 927), conducted in 22 Chinese provinces, were pooled for analysis. The first seven waves of the CLHLS (1998, 2000, 2002, 2005, 2008-09, 2011-12, and 2013-2014) were utilized, with follow-up to the last wave (2018) (range 0-21 years). The SHE-index was collected in each wave, and was constructed from intake frequency of nine dietary variables, with a higher score indicating better diet quality. Cox proportional hazards model with dietary patterns as a time-varying exposure was employed to analyze the relationship between SHE-index and mortality., Results: At baseline, the median age of all participants was 92 years (25th percentile, 85 years; 75th percentile, 100 years). In multivariable models, the hazard ratios (95% confidence intervals) for SHE-index quartile 2, quartile 3 and quartile 4 versus quartile1 were 0.91 (0.88, 0.93), 0.89 (0.86, 0.92) and 0.82 (0.78, 0.85), respectively. Results were generally consistent for men and women and in a large number of sensitivity analyses., Conclusions: Healthier eating patterns were associated with a significant reduction in the risk of all-cause mortality among Chinese oldest-old, lending support to the importance of life-long adherence to healthy diet into advanced old age., (© 2022. The Author(s).)

A practical limitation of cluster randomized controlled trials (cRCTs) is that the number of available clusters may be small, resulting in an increased risk of baseline imbalance under simple randomization. Constrained randomization overcomes this issue by restricting the allocation to a subset of randomization schemes where sufficient overall covariate balance across comparison arms is achieved. However, for multi-arm cRCTs, several design and analysis issues pertaining to constrained randomization have not been fully investigated. Motivated by an ongoing multi-arm cRCT, we elaborate the method of constrained randomization and provide a comprehensive evaluation of the statistical properties of model-based and randomization-based tests under both simple and constrained randomization designs in multi-arm cRCTs, with varying combinations of design and analysis-based covariate adjustment strategies. In particular, as randomization-based tests have not been extensively studied in multi-arm cRCTs, we additionally develop most-powerful randomization tests under the linear mixed model framework for our comparisons. Our results indicate that under constrained randomization, both model-based and randomization-based analyses could gain power while preserving nominal type I error rate, given proper analysis-based adjustment for the baseline covariates. Randomization-based analyses, however, are more robust against violations of distributional assumptions. The choice of balance metrics and candidate set sizes and their implications on the testing of the pairwise and global hypotheses are also discussed. Finally, we caution against the design and analysis of multi-arm cRCTs with an extremely small number of clusters, due to insufficient degrees of freedom and the tendency to obtain an overly restricted randomization space., (© 2022 John Wiley & Sons Ltd.)

In this article, we develop methods for sample size and power calculations in four-level intervention studies when intervention assignment is carried out at any level, with a particular focus on cluster randomized trials (CRTs). CRTs involving four levels are becoming popular in healthcare research, where the effects are measured, for example, from evaluations (level 1) within participants (level 2) in divisions (level 3) that are nested in clusters (level 4). In such multilevel CRTs, we consider three types of intraclass correlations between different evaluations to account for such clustering: that of the same participant, that of different participants from the same division, and that of different participants from different divisions in the same cluster. Assuming arbitrary link and variance functions, with the proposed correlation structure as the true correlation structure, closed-form sample size formulas for randomization carried out at any level (including individually randomized trials within a four-level clustered structure) are derived based on the generalized estimating equations approach using the model-based variance and using the sandwich variance with an independence working correlation matrix. We demonstrate that empirical power corresponds well with that predicted by the proposed method for as few as eight clusters, when data are analyzed using the matrix-adjusted estimating equations for the correlation parameters with a bias-corrected sandwich variance estimator, under both balanced and unbalanced designs., (© 2021 Wiley-VCH GmbH.)