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Background The burden of stillbirth, neonatal and maternal deaths are unacceptably high in low- and middle-income countries, especially around the time of birth. There are scarce resources and/or support implementation of evidence-based training programs. SaferBirths Bundle of Care is a well-proven package of innovative tools coupled with data-driven on-the-job training aimed at reducing perinatal and maternal deaths. The aim of this project is to determine the effect of scaling up the bundle on improving quality of intrapartum care and perinatal survival. Methods The project will follow a stepped-wedge cluster implementation design with well-established infrastructures for data collection, management, and analysis in 30 public health facilities in regions in Tanzania. Healthcare workers from selected health facilities will be trained in basic neonatal resuscitation, essential newborn care and essential maternal care. Foetal heart rate monitors (Moyo), neonatal heart rate monitors (NeoBeat) and skills trainers (NeoNatalie Live) will be introduced in the health facilities to facilitate timely identification of foetal distress during labour and improve neonatal resuscitation, respectively. Heart rate signal-data will be automatically collected by Moyo and NeoBeat, and newborn resuscitation training by NeoNatalie Live. Given an average of 4000 baby-mother pairs per year per health facility giving an estimate of 240,000 baby-mother pairs for a 2-years duration, 25% reduction in perinatal mortality at a two-sided significance level of 5%, intracluster correlation coefficient (ICC) to be 0.0013, the study power stands at 0.99. Discussion Previous reports from small-scale Safer Births Bundle implementation studies show satisfactory uptake of interventions with significant improvements in quality of care and lives saved. Better equipped and trained birth attendants are more confident and skilled in providing care. Additionally, local data-driven feedback has shown to drive continuous quality of care improvement initiatives, which is essential to increase perinatal and maternal survival. Strengths of this research project include integration of innovative tools with existing national guidelines, local data-driven decision-making and training. Limitations include the stepwise cluster implementation design that may lead to contamination of the intervention, and/or inability to address the shortage of healthcare workers and medical supplies beyond the project scope. Trial registration Name of Trial Registry: ISRCTN Registry. Trial registration number: ISRCTN30541755 . Date of Registration: 12/10/2020. Type of registration: Prospectively Registered.

The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials (CRTs), published in 2012, is the first and remains the only international ethics guidance document specific to CRTs. However, the stepped-wedge CRT design raises complex ethical issues for which guidance may be lacking. The overarching objective of this review is to inform the forthcoming update of the Ottawa Statement; specific objectives are to characterize the types of interventions and data collection procedures in stepped-wedge CRTs (SW-CRTs), and to examine adherence to key ethical design, conduct, and reporting recommendations. Primary reports of SW-CRTs evaluating health interventions published 2016-2022 in English were reviewed. Two reviewers extracted data from each trial independently; discrepancies were resolved through consensus. Among 160 SW-CRTs, most evaluated multilevel interventions (78, 49%), and uncommonly involved therapeutic patient interventions (19, 12%). Few (10, 6%) exclusively used routinely collected data sources for outcome assessment. Sixty-four trials (40%) provided explicit justifications for using cluster randomization and the stepped-wedge design. Most (157, 98%) included a statement about research ethics committee (REC) review, of which 148 (94%) reported approval. A statement about consent was reported in 145 (91%), with 113 (78%) pertaining to patients only, 10 (7%) to health-care providers only, and 22 (15%) to both. Among 135 trials reporting on patient consent, consent was not obtained in 55 (41%). Justifications for not obtaining consent were provided in 42 (76%). The updated Ottawa Statement should provide guidance about when people should be considered research participants and when their consent is required, justifications for using a stepped-wedge design, the need for REC review, and the burden of data collection procedures in SW-CRTs. We reviewed 160 SW-CRTs published between 2016 and 2022. These trials often evaluate multifaceted interventions delivered at the cluster or professional level rather than individual level, and most had to rely on at least some form of primary data collection. Although almost all SW-CRTs reported ethics review, fewer than half explained why they used the SW-CRT design, and a substantial minority did not include a statement about whether participant informed consent was obtained. Rarely did consent statement pertain to health-care providers; most statements pertained to patients. Among the SW-CRTs that had consent statements pertaining to patients, almost half reported not obtaining or waiving consent from them, and many of these did not report clear reasons for this. Our findings highlight the need for clearer guidance in the forthcoming update to the Ottawa Statement on the Ethical Design and Conduct of CRTs. •Stepped-wedge cluster randomized trials (SW-CRTs) raise complex ethical issues.•We reviewed 160 SW-CRTs to identify gaps in and inform an update of ethics guidelines.•We found five ethical issues raised by SW-CRTs in need of additional guidance.

National health insurance schemes are generally impractical in lowincome countries due to limited resources and low organizational capacity. In response to such obstacles, community-based health insurance (CBHI) schemes have emerged over the past 20 years. CBHIs are designed to reduce the financial burden generated by unanticipated treatment cost among individuals falling sick, and thus are expected to make health care more affordable. In this paper, we investigate whether schemes effectively protect individuals against large financial shocks using a stepped-wedge clusterrandomized design on data from a CBHI program rolled out in rural Burkina Faso. We investigate statistical properties of the stepped-wedge design following the parametric mixed model approach proposed by Hussey and Hughes in 2007. We find that testing for the treatment effect is generally sensitive to specification of the parametric model. For instance, if we fail to account for cluster-by-time interactions present in the data, the Type I error rate is severely inflated. We develop a more robust and efficient strategy—randomization inference. We demonstrate how to apply randomization inference to test for constant treatment effects and discuss test statistics suitable for the stepped-wedge design. Randomization inference guarantees a valid Type I error rate; simulation studies show that randomization inference test statistics also have power that is comparable to the currently used procedures that do not guarantee a valid Type I error rate. Finally, we apply our proposed method to the Burkina Faso CBHI dataset. We conclude that the insurance had limited effects on reducing the likelihood of low to moderate levels of catastrophic health expenditure, but substantially reduced the likelihood of extremely high health expenditure that exceeds half of a person's monthly income.

Background Adherent pre-exposure prophylaxis (PrEP) uptake can prevent HIV infections. Despite the high HIV incidence, Chinese key populations have low PrEP uptake and adherence. New interventions are needed to increase PrEP adherence among key populations in China. Co-creation methods are helpful to solicit ideas from the community to solve public health problems. The study protocol aims to describe the design of a stepped-wedge trial and to evaluate the efficacy of co-created interventions to facilitate PrEP adherence among key populations in China. Methods The study will develop intervention packages to facilitate PrEP adherence among Chinese key populations using co-creation methods. The study will then evaluate the efficacy of the co-created intervention packages using a stepped-wedge randomized controlled trial. This four-phased closed cohort stepped-wedge design will have four clusters. Each cluster will start intervention at three-month intervals. Seven hundred participants who initiated PrEP will be recruited. Participants will be randomized to the clusters using block randomization. The intervention condition includes receiving co-created interventions in addition to standard of care. The control condition is the standard of care that includes routine clinical assessment every 3 months. All participants will also receive an online follow-up survey every 3 months to record medication adherence and will be encouraged to use a WeChat mini-app for sexual and mental health education throughout the study. The primary outcomes are PrEP adherence and retention in PrEP care throughout the study period. We will examine a hypothesis that a co-created intervention can facilitate PrEP adherence. Generalized linear mixed models will be used for the primary outcome analysis. Discussion Developing PrEP adherence interventions in China faces barriers including suboptimal PrEP uptake among key populations, the lack of effective PrEP service delivery models, and insufficient community engagement in PrEP initiatives. Our study design addresses these obstacles by using co-creation to generate social media-based intervention materials and embedding the study design in the local healthcare system. The study outcomes may have implications for policy and intervention practices among CBOs and the medical system to facilitate PrEP adherence among key populations. Trial registration The study is registered in Clinical Trial databases in China (ChiCTR2100048981, July 19, 2021) and the US (NCT04754139, February 11, 2021).

BackgroundShortening time between office visits for patients with uncontrolled hypertension represents a potential strategy for improving blood pressure (BP).ObjectiveWe evaluated the impact of multimodal strategies on time between visits and on improvement in systolic BP (SBP) among patients with uncontrolled hypertension.DesignWe used a stepped-wedge cluster randomized controlled trial with three wedges involving 12 federally qualified health centers with three study periods: pre-intervention, intervention, and post-intervention.ParticipantsAdult patients with diagnosed hypertension and two BPs ≥ 140/90 pre-randomization and at least one visit during post-randomization control period (N = 4277).InterventionThe core intervention included three, clinician hypertension group-based trainings, monthly clinician feedback reports, and monthly meetings with practice champions to facilitate implementation.Main MeasuresThe main measures were change in time between visits when BP was not controlled and change in SBP. A secondary planned outcome was changed in BP control among all hypertension patients in the practices.Key ResultsMedian follow-up times were 34, 32, and 32 days and the mean SBPs were 142.0, 139.5, and 139.8 mmHg, respectively. In adjusted analyses, the intervention did not improve time to the next visit compared with control periods, HR = 1.01 (95% CI: 0.98, 1.04). SBP was reduced by 1.13 mmHg (95% CI: −2.10, −0.16), but was not maintained during follow-up. Hypertension control (< 140/90) in the practices improved by 5% during intervention (95% CI: 2.6%, 7.3%) and was sustained post-intervention 5.4% (95% CI: 2.6%, 8.2%).ConclusionsThe intervention failed to shorten follow-up time for patients with uncontrolled BP and showed very small, statistically significant improvements in SBP that were not sustained. However, the intervention showed statistically and clinically relevant improvement in hypertension control suggesting that the intervention affected clinician decision-making regarding BP control apart from visit frequency. Future practice initiatives should consider hypertension control as a primary outcome.Clinical Trialwww.ClinicalTrials.gov Identifier: NCT02164331

Background Tuberculosis is among the top-10 causes of mortality in children with more than 1 million children suffering from TB disease annually worldwide. The main challenge in young children is the difficulty in establishing an accurate diagnosis of active TB. The INPUT study is a stepped-wedge cluster-randomized intervention study aiming to assess the effectiveness of integrating TB services into child healthcare services on TB diagnosis capacities in children under 5 years of age. Methods Two strategies will be compared: i) The standard of care, offering pediatric TB services based on national standard of care; ii) The intervention, with pediatric TB services integrated into child healthcare services: it consists of a package of training, supportive supervision, job aids, and logistical support to the integration of TB screening and diagnosis activities into pediatric services. The design is a cluster-randomized stepped-wedge of 12 study clusters in Cameroon and Kenya. The sites start enrolling participants under standard-of-care and will transition to the intervention at randomly assigned time points. We enroll children aged less than 5 years with a presumptive diagnosis of TB after obtaining caregiver written informed consent. The participants are followed through TB diagnosis and treatment, with clinical information prospectively abstracted from their medical records. The primary outcome is the proportion of TB cases diagnosed among children < 5 years old attending the child healthcare services. Secondary outcomes include: number of children screened for presumptive active TB; diagnosed; initiated on TB treatment; and completing treatment. We will also assess the cost-effectiveness of the intervention, its acceptability among health care providers and users, and fidelity of implementation. Discussion Study enrolments started in May 2019, enrolments will be completed in October 2020 and follow up will be completed by June 2021. The study findings will be disseminated to national, regional and international audiences and will inform innovative approaches to integration of TB screening, diagnosis, and treatment initiation into child health care services. Trial resistration NCT03862261, initial release 12 February 2019.

Background Recently, more and more men who have sex with men (MSM) look for casual partners through online dating platforms in China. However, most are unable to know their partners’ HIV and other sexually transmitted diseases (STD) statuses, leading to the rapid increase in HIV infection among Chinese MSM. Effective partner notification is urgently needed to increase the risk awareness of MSM and prevent HIV and other STDs transmission. However, the traditional intervention mainly targets to the HIV-positive MSM and the effect is not promising. Our study aims to provide Internet-based partner notification, along with a series of health services for HIV-negative MSM to protect them from HIV and other STDs. Methods A pragmatic stepped wedge cluster randomized controlled trial design is used to evaluate the effectiveness of a new intervention paradigm, which aims to reduce HIV and other STDs incidences among MSM in China. Through integrating a mobile health (mHealth) service application (app) to the current HIV and other STDs prevention and control methods, the new paradigm provides partner notification of HIV, syphilis, hepatitis B, and hepatitis C statuses. A total of 6172 MSM in 16 districts of Beijing, China will be recruited and randomized to sequentially receive partner notification intervention through the app at 6-month intervals. The primary outcomes are HIV incidence and the additional cost of the intervention. The secondary outcomes include incidences of syphilis, hepatitis B, and hepatitis C, disease transmission social networks, testing adherence, knowledge of HIV and STDs control, health self-responsibility awareness, changes of high risk behaviors and other related outcomes. The generalized linear mixed models (GLMM) will be used to analyze the differences of outcomes in the control period and in the intervention period. Discussion We expect that the HIV incidence will be significantly lower and the secondary outcomes will also be improved with providing health service of partner notification through mhealth intervention. The feasible and affordable public health intervention paradigm will have implications for HIV and STDs prevention and control among MSM and other key populations. Trial registration ClinicalTrials.gov, NCT04349748 . Registered on 16 April 2020.

Health researchers are familiar with the concept of trial power, a number that prior to the start of a trial is intended to describe the probability that the results of the trial will correctly conclude that the intervention has an effect. Trial power, as calculated using standard software, is an expected power that arises from averaging hypothetical trial results over all possible treatment allocations that could be generated by the randomization algorithm . However, in the trial that ultimately is conducted, only one treatment allocation will occur , and the corresponding attained power (conditional on the allocation that occurred) is not guaranteed to be equal to the expected power and may be substantially lower. We provide examples illustrating this issue, discuss some circumstances when this issue is a concern, define and advocate the examination of the pre-randomization power distribution for evaluating the risk of obtaining unacceptably low attained power, and suggest the use of randomization restrictions to reduce this risk. In trials that randomize only a modest number of units, we recommend that trial designers evaluate the risk of getting low attained power and, if warranted, modify the randomization algorithm to reduce this risk.

Background Low back pain (LBP) is one of the most prevalent and expensive health care problems in industrialised countries. LBP leads to high health care utility and productivity losses; leaving the individual, the employer, and society with substantial costs. To improve the care for LBP patients and reduce the high societal and financial burden of LBP, in 2010 the ‘Multidisciplinary care guideline for nonspecific low back pain’ was developed in the Netherlands. The current paper describes the design of a study aiming to evaluate the (cost-) effectiveness of a multifaceted strategy to implement this guideline. Methods In a cluster-randomised controlled trial, the (cost-) effectiveness of a multifaceted implementation strategy will be compared to passive guideline dissemination. Using a stepped-wedge approach, participating general practitioners, physiotherapists, and occupational physicians are allocated into clusters and will attend a multidisciplinary continuing medical education training session. The timing these clusters receive the training is the unit of randomisation. LBP patients visiting the participating health care providers are invited to participate in the trial and will receive access to a multimedia intervention aimed at improving beliefs, cognitions, and self-management. The primary outcome measure of this study is patient back beliefs. Secondary outcome measures on patient level include pain, functional status, quality of life, health care utility, and productivity losses. Outcome measures on professional level include knowledge and attitude towards the guideline, and guideline adherence. A process evaluation for the implementation strategy will be performed among the health care providers and the patients. Furthermore, a qualitative subgroup analysis among patients with various ethnic backgrounds will be performed. Discussion This study will give insight into the (cost-) effectiveness of a multifaceted implementation strategy for the Dutch multidisciplinary guideline for non-specific back pain to improve outcomes on patient and professional level. The valuable information gained with this study may prove useful for policy-makers, health care providers, and researchers who are in the process of reducing the burden of back pain on individuals and society. Trial Registration Netherlands Trial Register (NTR): NTR4329 . Registered December 20th, 2013.

Background Many interventions against infectious diseases have geographically diffuse effects. This leads to contamination between arms in cluster-randomized trials (CRTs). Pathogen elimination is the goal of many intervention programs against infectious agents, but contamination means that standard CRT designs and analyses do not provide inferences about the potential of interventions to interrupt pathogen transmission at maximum scale-up. Methods A generic model of disease transmission was used to simulate infections in stepped wedge cluster-randomized trials (SWCRTs) of a transmission-reducing intervention, where the intervention has spatially diffuse effects. Simulations of such trials were then used to examine the potential of such designs for providing generalizable causal inferences about the impact of such interventions, including measurements of the contamination effects. The simulations were applied to the geography of Rusinga Island, Lake Victoria, Kenya, the site of the SolarMal trial on the use of odor-baited mosquito traps to eliminate Plasmodium falciparum malaria. These were used to compare variants in the proposed SWCRT designs for the SolarMal trial. Results Measures of contamination effects were found that could be assessed in the simulated trials. Inspired by analyses of trials of insecticide-treated nets against malaria when applied to the geography of the SolarMal trial, these measures were found to be robust to different variants of SWCRT design. Analyses of the likely extent of contamination effects supported the choice of cluster size for the trial. Conclusions The SWCRT is an appropriate design for trials that assess the feasibility of local elimination of a pathogen. The effects of incomplete coverage can be estimated by analyzing the extent of contamination between arms in such trials, and the estimates also support inferences about causality. The SolarMal example illustrates how generic transmission models incorporating spatial smoothing can be used to simulate such trials for a power calculation and optimization of cluster size and randomization strategies. The approach is applicable to a range of infectious diseases transmitted via environmental reservoirs or via arthropod vectors.