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There is an urgent need to reduce the burden of depression among older adults in low-income and middle-income countries (LMICs). We aimed to evaluate the efficacy of a task-shared, collaborative care psychosocial intervention for improving recovery from depression in older adults in Brazil.PROACTIVE was a pragmatic, two-arm, parallel-group, cluster-randomised controlled trial conducted in Guarulhos, Brazil. Primary care clinics (clusters) were stratified by educational level and randomly allocated (1:1) to either enhanced usual care alone (control group) or to enhanced usual care plus the psychosocial intervention (intervention group), which involved a 17-week psychosocial programme based on psychoeducation and behavioural activation approaches. Individuals approached for the initial screening assessment were selected randomly from a list of individuals provided by the Health Secretariat of Guarulhos. Face-to-face baseline assessments were conducted among adults aged 60 years or older registered with one of the primary care clinics and identified with clinically significant depressive symptomatology (9-item Patient Health Questionnaire [PHQ-9] score ≥10). Community health workers delivered the programme through home sessions, supported by a dedicated tablet application. Masking of clinic staff and community health workers who delivered the intervention was not feasible; however, research assistants conducting recruitment and follow-up assessments were masked to trial allocation. The primary outcome was recovery from depression (PHQ-9 score10) at 8-month follow-up. All primary analyses were performed by intention to treat with imputed data. Adaptations to the protocol were made due to the COVID-19 pandemic; recruitment and intervention home sessions were stopped, and follow-up assessments were conducted by telephone. This trial is registered with the ISRCTN registry, ISRCTN57805470.We identified 24 primary care clinics in Guarulhos that were willing to participate, of which 20 were randomly allocated to either the control group (ten [50%] clusters) or to the intervention group (ten [50%] clusters). The four remaining eligible clusters were kept as reserves. Between May 23, 2019, and Feb 21, 2020, 8146 individuals were assessed for eligibility, of whom 715 (8·8%) participants were recruited: 355 (49·7%) in the control group and 360 (50·3%) in the intervention group. 284 (80·0%) participants in the control group and 253 (70·3%) in the intervention group completed follow-up at 8 months. At 8-month follow-up, 158 (62·5%) participants in the intervention group showed recovery from depression (PHQ-9 score10) compared with 125 (44·0%) in the control group (adjusted odds ratio 2·16 [95% CI 1·47-3·18]; p0·0001). These findings were maintained in the complete case analysis. No adverse events related to the intervention were observed.Although the COVID-19 pandemic altered delivery of the intervention, the low-intensity psychosocial intervention delivered mainly by non-mental health professionals was highly efficacious in improving recovery from depression in older adults in Brazil. Our results support a low-resource intervention that could be useful to reduce the treatment gap for depression among older people in other LMICs.São Paulo Research Foundation and Joint Global Health Trials (UK Department for International Development, Medical Research Council, and the Wellcome Trust).

BackgroundUnderstanding how and under what circumstances a highly effective psychological intervention, improved symptoms of depression is important to maximise its clinical effectiveness.AimsTo address this complexity, we estimate the indirect effects of potentially important mediators to improve symptoms of depression (measured with the Patient Health Questionnaire (PHQ-9)) in the Healthy Activity Program trial.MethodInterventional in(direct) effects were used to decompose the total effect of the intervention on PHQ-9 scores into the direct and indirect effects. The following indirect effects were considered: characteristics of sessions, represented by the number of sessions and homework completed; behavioural activation, according to an adapted version of the Behavioural Activation for Depression Scale – Short Form; and extra sessions offered to participants who did not respond to the intervention.ResultsOf the total effect of the intervention measured through the difference in PHQ-9 scores between treatment arms (mean difference: −2.1, bias-corrected 95% CI −3.2 to −1.5), 34% was mediated through improved levels of behavioural activation (mean difference: −0.7, bias-corrected 95% CI −1.2 to −0.4). There was no evidence to support the mediating role of characteristics of the sessions nor the extra sessions offered to participants who did not respond to the treatment.ConclusionsFindings from our robust mediation analyses confirmed the importance of targeting behavioural activation. Contrary to published literature, our findings suggest that neither the number of sessions nor proportion of homework completed improved outcomes. Moreover, in this context, alternative treatments other than extra sessions should be considered for patients who do not respond to the intervention.

BackgroundSubthreshold depression is a substantial risk factor for the development of major depression and is, for example, associated with poorer health in older adults, functional disabilities, and reduced quality of life. There is a paucity of cost-effective psychosocial interventions for this population in primary care worldwide, particularly in low- and middle-income countries.ObjectiveWe will evaluate the effectiveness and cost-effectiveness of the Viva Vida Programme, a 6-week digital psychosocial intervention for treating older adults with subthreshold depression in primary care.MethodsA two-arm, individually randomised controlled trial with a 1:1 allocation ratio with integrated economic and process evaluations. We will recruit 450 individuals 60 years of age and older with subthreshold depression (essentially, at least 5 and below 10 on the 9-item Patient Health Questionnaire (PHQ-9)) registered with one of the 46 primary care clinics in Guarulhos, Brazil. The intervention comprises a 6-week self-help digital psychosocial package delivered via automated WhatsApp messages (audio and visual), with psychoeducation and behavioural activation contents adapted from our previously-evaluated PROACTIVE intervention. It involves 48 messages, delivered twice-daily, four days a week. Participants in the control arm will receive a single message with general information about depression. The primary outcome is PHQ-9 at the three-month follow-up. The cost-effectiveness of the intervention will be assessed at five months. A detailed process evaluation will explore context and implementation outcomes.DiscussionThe Viva Vida Programme is an innovative digital psychosocial intervention delivered via WhatsApp messaging without the participation of health professionals. The results of this study will hopefully contribute to the development of simple and cost-effective models of remote self-help interventions for reducing depressive symptoms among older adults with subthreshold depression in primary care.Trial registrationThe protocol is registered with Registro Brasileiro de Ensaios Clinicos (ReBEC) (RBR-6c7ghfd).

BackgroundTwo CONEMO trials in Lima, Peru and São Paulo, Brazil evaluated a digital mental health intervention (DMHI) based on behavioural activation (BA) that demonstrated improvements in symptoms of depression between trial arms at three-months, but not at six-months. To understand how we can optimize CONEMO in the longer-term, we therefore aim to investigate mediators through which the DMHI improved symptoms of depression at six-months, separately for the two trials and then using a pooled dataset.MethodsWe used data that included adults with depression (Patient Health Questionnaire – 9 (PHQ-9) score ≥10) and comorbid hypertension and/or diabetes. Interventional effects were used to decompose the total effect of DMHI on symptoms of depression at six months into indirect effects via: understanding the content of the sessions without difficulty; number of activities completed that were self-selected to improve levels of BA; and levels of activation measured using the Behavioural Activation for Depression Short Form (BADS-SF).FindingsUsing the pooled dataset, understanding the content of the sessions without difficulty mediated a 10% [0.10: 95% CI: 0.03 to 0.15] improvement in PHQ-9 scores at six months; completing self-selected activities mediated a 12% improvement [0.12: 0.01 to 0.23]; and, lastly, BA mediated a 2% [0.02: 0.01, 0.05] improvement.ConclusionsOur findings suggest that targeting participants to complete activities they find enjoyable will help to improve levels of activation and maintain the effect of the CONEMO intervention in the longer-term. Improving the content of the sessions to facilitate understanding can also help to maintain improvements.

Introduction: Understanding how and under what circumstances complex psychological therapies work (or not) is important to bring evidence-informed intervention to scale, especially in resource poor settings. However, current methods do not apply methodology that account for the underlying complexity of these interventions including the interplay between implementation outcomes, implementation strategies and mechanisms. Here we apply a robust mediation analysis to address these issues to data from the Healthy Activity Program (HAP) trial –a psychological intervention for depression delivered using task-shifting with lay counsellors in Goa India.Methods: Interventional in(direct) effects were used to simultaneously decompose the total effect of the intervention on depression symptoms measured through the Patient Health Questionnaire (PHQ-9). The following indirect effects were considered: fidelity of receipt including number of sessions and homework completed; behavioural activation according to an adapted version of the Behavioural Activation for Depression Short Form (BADS-SF), and extra sessions offered to participants who did not respond to the intervention. Results: Of the total effect of the intervention measured through the difference in PHQ-9 scores between treatment arms (mean difference: -2.2, 95% bias-corrected CI: -3.2, -0.8), 45% was mediated through improved levels of behavioural activation (-1.0, -1.3, -0.6). There was little evidence to support the mediating role of characteristics of the sessions nor the extra sessions offered to participants who did not respond to the treatment. ConclusionsFindings from our analyses have demonstrated how interventional (in)direct effects can be applied to understand how implementation research programmes can be optimised for scale-up. Our results highlight the importance of sessions focusing on behavioural activation to improve symptoms of depression. Targeting non-responders with strategies other than extra therapy sessions has the potential to improve depression outcomes at a population level.

BackgroundUnderstanding how and under what circumstances a highly effective psychological intervention, improved symptoms of depression is important to bring this evidence-informed intervention to scale, particularly in resource-poor settings. We aim to estimate the indirect effects of potentially important mediators to improve symptoms of depression in the Healthy Activity Program (HAP) trial.MethodsInterventional in(direct) effects were used to simultaneously decompose the total effect of the intervention on depression symptoms measured through the Patient Health Questionnaire (PHQ-9). The following indirect effects were considered: characteristics of sessions including the number of sessions and homework completed; behavioural activation according to an adapted version of the Behavioural Activation for Depression Short Form (BADS-SF), and extra sessions offered to participants who did not respond to the intervention.ResultsOf the total effect of the intervention measured through the difference in PHQ-9 scores between treatment arms (mean difference: -2.2, 95% bias-corrected CI: -3.2, -0.8), 45% was mediated through improved levels of behavioural activation (−1.0, -1.3, -0.6). There was no evidence to support the mediating role of characteristics of the sessions nor the extra sessions offered to participants who did not respond to the treatment.ConclusionsFindings from our robust mediation analyses, confirmed the importance of behavioural activation in improving depression symptoms. Contrary to published literature, our findings suggest that neither the number of sessions nor proportion of homework completed, improved outcomes. Moreover, results indicate that the extra sessions were insufficient to improve symptoms of depression for participants who did not respond to the intervention.

Background During the perinatal period, common mental disorders (CMDs) such as depression and anxiety are highly prevalent, especially in low-resource settings, and are associated with domestic violence, poverty, and food insecurity. Perinatal CMDs have been associated with several adverse maternal and child outcomes. While the Department of Health in South Africa provides healthcare workers with the tools to detect psychological distress and experiences of domestic violence, few healthcare workers routinely screen pregnant women at clinic visits, citing discomfort with mental health issues and the lack of standardised referral pathways as the key barriers. The aim of this study is to select and evaluate a set of health systems strengthening (HSS) interventions aimed at improving the care and outcomes for perinatal women with CMDs and experiences of domestic violence, attending public healthcare facilities in Cape Town. Methods This study consists of a pre-implementation, development, and implementation phase. Contextual barriers identified during the pre-implementation phase included poor patient knowledge and health-seeking behaviour, high levels of stigma, and poor detection, referral, and treatment rates. Implementation science determinant frameworks were applied to findings from the pre-implementation phase to identify determinants and gaps in delivering high-quality evidence-informed care. A participatory Theory of Change workshop was used to design a HSS programme, consisting of awareness raising, detection, referral, and treatment. HSS interventions selected to support the delivery of the HSS programme includes training, health promotion, change to the healthcare environment, task-sharing, audit and feedback, and performance monitoring. The implementation phase will be used to assess several implementation and clinical outcomes associated with the delivery of the HSS programme, which will be piloted at three healthcare facilities. Qualitative and quantitative methods will be used to evaluate the implementation and clinical outcomes. Discussion This pilot implementation study will inform us about a range of implementation and clinical outcome measures that are relevant for assessing HSS interventions for perinatal women with depression, anxiety, or experiences of domestic violence in low-resource settings. Lessons learnt from the pilot study will be incorporated into the design of a cluster randomised control trial for which further funding will be sought.

ObjectivesASSET (Health System Strengthening in sub-Saharan Africa) is a health system strengthening (HSS) programme involving eight work-packages (ie, a research study that addresses a specific need for HSS) that aims to develop solutions that support high-quality care. Here we present the protocol for the implementation science (IS) theme within ASSET (ASSET-ImplmentER) that aims to understand what HSS interventions work, for whom and how, and how IS methodologies can be adapted to improve the HSS interventions within resource-poor contexts.SettingsPublicly funded health facilities in rural and urban areas in in Ethiopia, South Africa, Sierra Leone, and Zimbabwe.ParticipantsResearch staff including principal investigators, coinvestigators, field staff, PhD students, and research assistants.InterventionsWork-packages use a mixed-methods effectiveness–effectiveness hybrid designs. At the end of the pre-implementation phase, a workshop is held whereby the IS theme, jointly with ASSET work-packages apply IS determinant frameworks to research findings to identify factors that influence the effectiveness of delivering evidence-informed care. Determinants are used to select a set of HSS interventions for further evaluation, where work-packages also theorise selective mechanisms.In the piloting and rolling implementation phase, work-packages pilot the HSS interventions. An iterative process then begins involving evaluation, reflection and adaptation. Throughout this phase, IS determinant frameworks are applied to monitor and identify barriers/enablers to implementation. Selective mechanisms of action are also investigated. Implementation outcomes are evaluated using qualitative and quantitative methods. The psychometric properties of outcome measures including acceptability, appropriateness and feasibility are also evaluated. In a final workshop, work-packages come together, to reflect and explore the utility of the selected IS methods and provide suggestions for future use.Structured templates are used to organise and analyse common and heterogeneous patterns across work-packages. Qualitative data are analysed using thematic analysis and quantitative data are analysed using means and proportions.ConclusionsWe use a novel combination of IS methods at a programmatic level to facilitate comparisons of determinants and mechanisms that influence the effectiveness of HSS interventions in achieving implementation outcomes across different contexts. The study also contributes conceptual development and clarification at the underdeveloped interface of IS, HSS and global health.The ASSET-ImplementER theme is considered minimal risk as we only interview researchers involved in the different work-packages. To this effect we have received approval from King’s College London Ethics Committee for research that is considered minimal risk (Reference number: MRA-20/21-21772).

ObjectivesTo achieve universal health coverage, health systems need to be strengthened to support the consistent delivery of high-quality, evidence-informed care at scale. The aim of the National Institute for Health Research (NIHR) Global Research Unit on HeAlth System StrEngThening in Sub-Saharan Africa (ASSET) is to address this need in a four-year programme spanning three healthcare platforms (primary health care for the integrated treatment of chronic conditions in adults, maternal and newborn, surgical care) involving eight work packages. This paper describes the pre-implementation phase research protocols that assess: (1) barriers to accessing care; (2) health system bottlenecks in care process and pathways; (3) quality of care, and; (4) people centredness. Findings from this research are used to engage stakeholders and to inform the selection of a set of health system strengthening interventions (HSSIs) and subsequent methodology for evaluation. SettingsPublicly funded health systems in rural and urban areas in Ethiopia, Sierra Leone, South Africa, and Zimbabwe. PopulationStakeholders including patients and their caregivers, community representatives, clinicians, managers, administrators, and policymakers. Study methodologies and deliveryIn each work package, we apply a mixed-methods approach, including: literature reviews; situation analyses; cohort studies; cross-sectional surveys; ethnographic observations; semi-structured interviews, and; focus group discussions. At the end of the pre-implementation phase, findings are fed back to stakeholders in participatory theory of change workshops that are used to select/adapt an initial set of contextually relevant HSSIs. To ensure a theory-informed approach across ASSET, implementation science determinant frameworks are also applied, to help identify any additional contextual barriers and enablers and complementary HSSIs. Outputs from these activities are used to finalise underlying assumptions, potential unintended consequences, process indicators and implementation and clinical outcomes. ConclusionsASSET places a strong emphasis of the pre-implementation phase of the programme in order to provide an in-depth and systematic diagnosis of the existing heath system functioning, needs for strengthening and active stakeholder engagement. This approach will inform the design and evaluation of the HSSIs to increase effectiveness across work packages and contexts, to better understand what works, for whom, and how. Strengths and limitations of this studyO_LIThe National Health Institute of Research (NIHR) Global Research Unit on Health System Strengthening in sub-Saharan Africa (ASSET) is a four-year programme (2017-2021) that is closely aligned with the SDG goal of UHC, and the recommendations of the Lancet Commission for High Quality Health Systems. C_LIO_LIThe aim of ASSET is to develop and evaluate effective and sustainable HSSIs, promoting consistent delivery of high-quality, people-centred care. C_LIO_LIThe ASSET programme is being conducted in two phases including the diagnostic pre-implementation and piloting/rolling implementation phase. C_LIO_LIThe purpose of this paper is to describe the methodology for the pre-implementation phase, which has the core aim of mapping comprehensive care pathways of a patients journey though the health system including the community, different providers), and health facilities, documenting what care is provided at what level of the health system and the associated health system bottlenecks. C_LIO_LIAt the end of the pre-implementation phase of ASSET, it is hoped the common approach taken across different countries, care platforms and health conditions will facilitate cross platform learning and understanding of how differences in health systems and broader contextual influences shaped the development of the interventions. C_LIO_LIThe overarching expectation is that by using an in-depth participatory process to engage with the stakeholders and map care pathways to and through the health system, we develop a HSS programme that can be implemented at scale that meets the needs and priorities of the local community. C_LI

ObjectivesTo achieve universal health coverage, health systems need to be strengthened to support the consistent delivery of high-quality, evidence-informed care at scale. The aim of the National Institute for Health Research (NIHR) Global Research Unit on HeAlthSystemStrEngThening in Sub-Saharan Africa (ASSET) is to address this need in a four-year programme spanning three healthcare platforms (primary health care for the integrated treatment of chronic conditions in adults, maternal and newborn, surgical care) involving eight work packages. This paper describes the pre-implementation phase research protocols that assess: (1) barriers to accessing care; (2) health system bottlenecks in care process and pathways; (3) quality of care, and; (4) people centredness. Findings from this research are used to engage stakeholders and to inform the selection of a set of health system strengthening interventions (HSSIs) and subsequent methodology for evaluation.SettingsPublicly funded health systems in rural and urban areas in Ethiopia, Sierra Leone, South Africa, and Zimbabwe.PopulationStakeholders including patients and their caregivers, community representatives, clinicians, managers, administrators, and policymakers.Study methodologies and deliveryIn each work package, we apply a mixed-methods approach, including: literature reviews; situation analyses; cohort studies; cross-sectional surveys; ethnographic observations; semi-structured interviews, and; focus group discussions. At the end of the pre-implementation phase, findings are fed back to stakeholders in participatory theory of change workshops that are used to select/adapt an initial set of contextually relevant HSSIs. To ensure a theory-informed approach across ASSET, implementation science determinant frameworks are also applied, to help identify any additional contextual barriers and enablers and complementary HSSIs. Outputs from these activities are used to finalise underlying assumptions, potential unintended consequences, process indicators and implementation and clinical outcomes.ConclusionsASSET places a strong emphasis of the pre-implementation phase of the programme in order to provide an in-depth and systematic diagnosis of the existing heath system functioning, needs for strengthening and active stakeholder engagement. This approach will inform the design and evaluation of the HSSIs to increase effectiveness across work packages and contexts, to better understand what works, for whom, and how.Strengths and limitations of this studyThe National Health Institute of Research (NIHR) Global Research Unit on Health System Strengthening in sub-Saharan Africa (ASSET) is a four-year programme (2017-2021) that is closely aligned with the SDG goal of UHC, and the recommendations of the Lancet Commission for High Quality Health Systems.The aim of ASSET is to develop and evaluate effective and sustainable HSSIs, promoting consistent delivery of high-quality, people-centred care.The ASSET programme is being conducted in two phases including the diagnostic pre-implementation and piloting/rolling implementation phase.The purpose of this paper is to describe the methodology for the pre-implementation phase, which has the core aim of mapping comprehensive care pathways of a patient’s journey though the health system including the community, different providers), and health facilities, documenting what care is provided at what level of the health system and the associated health system bottlenecks.At the end of the pre-implementation phase of ASSET, it is hoped the common approach taken across different countries, care platforms and health conditions will facilitate cross platform learning and understanding of how differences in health systems and broader contextual influences shaped the development of the interventions.The overarching expectation is that by using an in-depth participatory process to engage with the stakeholders and map care pathways to and through the health system, we develop a HSS programme that can be implemented at scale that meets the needs and priorities of the local community.

BackgroundASSET (Health System Strengthening in Sub-Saharan Africa) is a health system strengthening (HSS) programme that aims to develop and evaluate effective and sustainable solutions that support high-quality care that involve eight work packages across four sub-Saharan African countries. Here we present the protocol for the implementation science (IS) theme within ASSET that aims to (1) understand what HSS interventions work, for whom and how; and (2) how implementation science methodologies can be adapted to improve the design and evaluation of HSS interventions within resource-poor contexts.MethodsPre-implementation phaseThe IS theme, jointly with ASSET work-packages, applies IS determinant frameworks to identify factors that influence the effectiveness of delivering evidence-informed care. Determinants are used to select a set of HSS interventions for further evaluation, where work packages also theorise selective mechanisms to achieve the expected outcomes.Piloting phase and rolling implementation phaseWork-packages pilot the HSS interventions. An iterative process then begins involving evaluation, refection and adaptation. Throughout this phase, IS determinant frameworks are applied to monitor and identify barriers and enablers to implementation in a series of workshops, surveys and interviews. Selective mechanisms of action are also investigated. In a final workshop, ASSET teams come together, to reflect and explore the utility of the selected IS methods and provide suggestions for future use.Structured templates are used to organise and analyse common and heterogeneous patterns across work-packages. Qualitative data are analysed using thematic analysis and quantitative data is analysed using means and proportions.ConclusionsWe use a novel combination of implementation science methods at a programmatic level to facilitate comparisons of determinants and mechanisms that influence the effectiveness of HSS interventions in achieving implementation outcomes across different contexts. The study will also contribute conceptual development and clarification at the underdeveloped interface of implementation science, HSS and global health.Strengths and limitations of this studyThe purpose of this protocol paper is to describe the methodology for the implementation science theme within ASSET (ASSET-ImplementER).The overall aim of the ASSET-ImplementER theme is to advance our understanding of how to design and evaluate HSS interventions using a systems level approach informed by implementation science, across different health systems and contexts.This is one of the first large-scale implementation research programmes for health system strengthening in Sub-Saharan Africa that spanning three care platforms (primary care for the integrated treatment of chronic conditions in adults, maternal and newborn care, surgical care), involving eight work packages in four sub-Saharan African countries that aims to apply robust, implementation science and other theory-informed approaches to understand what works for whom and how. Equally as important, we aim to improve implementation science methodologies to design and evaluate HSS interventions within LMIC settings.Although our programme is theory-informed through the use of ToC workshops andimplementation science determinant frameworks, we have not used implementation science theories or other middle-range theories to guide the design and evaluate of ASSET as a programme. This is a pragmatic approach given many of the work-packages teams were unfamiliar with implementation science methods at the time of ASSET set-up.To mitigate the effects of this approach to our research, we work with the different work packages throughout the different phases of research, to theorise and conceptualise how the selected determinants interact with mechanisms introduced by the selected HSS on implementation outcomes.Although there are limitations to our approach, we expect to begin advance our understanding of what HSS work for whom, and how. It is also hoped that we will start to address the issues in understanding the complexity surrounding how to effectively strengthen health systems in resource-poor contexts within LMICs.

Implementation research is a multidisciplinary field that addresses the complex phenomenon of how context influences our ability to deliver evidence-informed healthcare. There is increasing realisation of the importance of applying robust implementation research to scale-up life-saving interventions that meet health-related sustainable development goals. However, the lack of high-quality implementation research is impeding our ability to meet these targets, globally. Within implementation research, theory refers to the proposed hypothesis and/or explanation of how an intervention is expected to interact with the local context and actors to bring about change. Although there is increasing interest in applying theory to understand how and why implementation programmes work in real-world settings, global health actors still tend to favour impact evaluations conducted in controlled environments. This may, in part, be due to the relative novelty as well as methodological complexity of implementation research and the need to draw on divergent disciplines, including epidemiology, implementation science and social sciences. Because of this, implementation research is faced with a particular set of challenges about how to reconcile different ways of thinking and constructing knowledge about healthcare interventions. To help translate some of the ambiguity surrounding how divergent theoretical approaches and methods contribute to implementation research, we draw on our multidisciplinary expertise in the field, particularly in global health. We offer an overview of the different theoretical approaches and describe how they are applied to continuously select, monitor and evaluate implementation strategies throughout the different phases of implementation research. In doing so, we offer a relatively brief, user-focused guide to help global health actors implement and report on evaluation of evidence-based and scalable interventions, programmes and practices.

Objectives The Consolidated Standards of Reporting Trials extension for the stepped-wedge cluster randomized trial (SW-CRT) is a recently published reporting guideline for SW-CRTs. We assess the quality of reporting of a recent sample of SW-CRTs. Study Design and Setting Quality of reporting was asssessed according to the 26 items in the new guideline using a novel crowd sourcing methodology conducted independently and in duplicate, with random assignment, by 50 reviewers. We assessed reliability of the quality assessments, proposing this as a novel way to assess robustness of items in reporting guidelines. Results Several items were well reported. Some items were very poorly reported, including several items that have unique requirements for the SW-CRT, such as the rationale for use of the design, description of the design, identification and recruitment of participants within clusters, and concealment of cluster allocation (not reported in more than 50% of the reports). Agreement across items was moderate (median percentage agreement was 76% [IQR 64 to 86]). Agreement was low for several items including the description of the trial design and why trial ended or stopped for example. Conclusions When reporting SW-CRTs, authors should pay particular attention to ensure clear reporting on the exact format of the design with justification, as well as how clusters and individuals were identified for inclusion in the study, and whether this was done before or after randomization of the clusters, which are crucial for risk of bias assessments. Some items, including why the trial ended, might either not be relevant to SW-CRTs or might be unclearly described in the statement.

The call for universal health coverage requires the urgent implementation and scale-up of interventions that are known to be effective, in resource-poor settings. Achieving this objective requires high-quality implementation research (IR) that evaluates the complex phenomenon of the influence of context on the ability to effectively deliver evidence-based practice. Nevertheless, IR for global health is failing to apply a robust, theoretically driven approach, leading to ethical concerns associated with research that is not methodologically sound.Inappropriate methods are often used in IR to address and report on context. This may result in a lack in understanding of how to effectively adapt the intervention to the new setting and a lack of clarity in conceptualising whether there is sufficient evidence to generalise findings from previous IR to a new setting, or if a randomised controlled trial (RCT) is needed. Some of the ethical issues arising from this shortcoming include poor-quality research that may needlessly expose vulnerable participants to research that has not been adapted to suit local needs and priorities, and the inappropriate use of RCTs that denies participants in the control arm access to treatment that is effective within the local context.To address these concerns, we propose a complementary approach to clinical equipoise for IR, known as contextual equipoise. We discuss challenges in the evaluation of context and also with assessing the certainty of evidence to justify an RCT. Finally, we describe methods that can be applied to improve the evaluation and reporting of context and to help understand if contextual equipoise can be justified or if significant adaptations are required. We hope our analysis offers helpful insight to better understand and ensure that the ethical principle of beneficence is upheld in the real-world contexts of IR in low-resource settings.

OBJECTIVE: Understanding the causes of death is key to tackling the burden of three million annual neonatal deaths. Resource-poor settings lack effective vital registration systems for births, deaths and causes of death. We set out to describe cause-specific neonatal mortality in rural areas of Malawi, Bangladesh, Nepal and rural and urban India using verbal autopsy (VA) data. DESIGN: We prospectively recorded births, neonatal deaths and stillbirths in seven population surveillance sites. VAs were carried out to ascertain cause of death. We applied descriptive epidemiological techniques and the InterVA method to characterise the burden, timing and causes of neonatal mortality at each site. RESULTS: Analysis included 3772 neonatal deaths and 3256 stillbirths. Between 63% and 82% of neonatal deaths occurred in the first week of life, and males were more likely to die than females. Prematurity, birth asphyxia and infections accounted for most neonatal deaths, but important subnational and regional differences were observed. More than one-third of deaths in urban India were attributed to asphyxia, making it the leading cause of death in this setting. CONCLUSIONS: Population-based VA methods can fill information gaps on the burden and causes of neonatal mortality in resource-poor and data-poor settings. Local data should be used to inform and monitor the implementation of interventions to improve newborn health. High rates of home births demand a particular focus on community interventions to improve hygienic delivery and essential newborn care.

Background The World Health Organization recommends participatory learning and action (PLA) in women’s groups to improve maternal and newborn health, particularly in rural settings with low access to health services. There have been calls to understand the pathways through which this community intervention may affect neonatal mortality. We examined the effect of women’s groups on key antenatal, delivery, and postnatal behaviours in order to understand pathways to mortality reduction. Methods and findings We conducted a meta-analysis using data from 7 cluster-randomised controlled trials that took place between 2001 and 2012 in rural India (2 trials), urban India (1 trial), rural Bangladesh (2 trials), rural Nepal (1 trial), and rural Malawi (1 trial), with the number of participants ranging between 6,125 and 29,901 live births. Behavioural outcomes included appropriate antenatal care, facility delivery, use of a safe delivery kit, hand washing by the birth attendant prior to delivery, use of a sterilised instrument to cut the umbilical cord, immediate wrapping of the newborn after delivery, delayed bathing of the newborn, early initiation of breastfeeding, and exclusive breastfeeding. We used 2-stage meta-analysis techniques to estimate the effect of the women’s group intervention on behavioural outcomes. In the first stage, we used random effects models with individual patient data to assess the effect of groups on outcomes separately for the different trials. In the second stage of the meta-analysis, random effects models were applied using summary-level estimates calculated in the first stage of the analysis. To determine whether behaviour change was related to group attendance, we used random effects models to assess associations between outcomes and the following categories of group attendance and allocation: women attending a group and allocated to the intervention arm; women not attending a group but allocated to the intervention arm; and women allocated to the control arm. Overall, women’s groups practising PLA improved behaviours during and after home deliveries, including the use of safe delivery kits (odds ratio [OR] 2.92, 95% CI 2.02–4.22; I2 = 63.7%, 95% CI 4.4%–86.2%), use of a sterile blade to cut the umbilical cord (1.88, 1.25–2.82; 67.6%, 16.1%–87.5%), birth attendant washing hands prior to delivery (1.87, 1.19–2.95; 79%, 53.8%–90.4%), delayed bathing of the newborn for at least 24 hours (1.47, 1.09–1.99; 68.0%, 29.2%–85.6%), and wrapping the newborn within 10 minutes of delivery (1.27, 1.02–1.60; 0.0%, 0%–79.2%). Effects were partly dependent on the proportion of pregnant women attending groups. We did not find evidence of effects on uptake of antenatal care (OR 1.03, 95% CI 0.77–1.38; I2 = 86.3%, 95% CI 73.8%–92.8%), facility delivery (1.02, 0.93–1.12; 21.4%, 0%–65.8%), initiating breastfeeding within 1 hour (1.08, 0.85–1.39; 76.6%, 50.9%–88.8%), or exclusive breastfeeding for 6 weeks after delivery (1.18, 0.93–1.48; 72.9%, 37.8%–88.2%). The main limitation of our analysis is the high degree of heterogeneity for effects on most behaviours, possibly due to the limited number of trials involving women’s groups and context-specific effects. Conclusions This meta-analysis suggests that women’s groups practising PLA improve key behaviours on the pathway to neonatal mortality, with the strongest evidence for home care behaviours and practices during home deliveries. A lack of consistency in improved behaviours across all trials may reflect differences in local priorities, capabilities, and the responsiveness of health services. Future research could address the mechanisms behind how PLA improves survival, in order to adapt this method to improve maternal and newborn health in different contexts, as well as improve other outcomes across the continuum of care for women, children, and adolescents., In a meta-analysis of randomized controlled trials, Nadine Seward and colleagues find that in Asian and African settings with limited access to medical services, participatory learning women’s groups are associated with improved perinatal health behaviors., Author summary Why was this study done? A systematic review and meta-analysis of trials of participatory learning and action in women’s groups found a 25% reduction in neonatal mortality associated with these groups, but the pathways to improved survival have not been explored using available evidence from all trials. We used data from cluster-randomised trials of women’s groups to explore behaviours in the antenatal, delivery, and postnatal periods in order to better explain the reduction in neonatal mortality associated with these groups. We also examined whether women who were assigned to the intervention arm and attended group meetings were more likely to have improved care practices than women who were also in the intervention arm but did not attend group meetings. What did the researchers do and find? We conducted a meta-analysis using individual-level data to explore the relationship between women’s groups and key behaviours in the antenatal, delivery, and postnatal periods. Our findings suggest that women’s groups are able to improve key behaviours for home deliveries including clean delivery practices and thermal care practices. To determine whether women who attended group meetings were more likely to have improved behaviours compared with women who did not attend, we compared behaviours between these women separately for the different trials. Overall, we found that women who attended group meetings were more likely to have improved behaviours than women who did not attend. What do these findings mean? Our meta-analysis showed that women’s groups were associated with improvements in critical practices including clean deliveries and appropriate thermal care for home deliveries. Evidence suggests that these care practices are essential for reducing neonatal mortality because of the importance of sepsis and hypothermia in areas with high neonatal mortality and low rates of facility births. Although this finding explains how women’s groups improved survival in these contexts, we also found that women’s groups improved survival in areas with lower neonatal mortality, such as rural Bangladesh and rural Malawi. It is possible that women’s groups were able to help families make more timely, better informed decisions about care seeking. Women’s groups have demonstrated flexibility in adapting to a shifting environment to improve birth outcomes through important pathways. Key to the continued reduction in adverse birth outcomes will be sustained improvement in community-level practices, as well as ensuring that health facilities are equipped to support quality care.

BACKGROUND: Few studies have reported long-term data on mortality rates for children admitted to hospital with pneumonia in Africa. We examined trends in case fatality rates for all-cause clinical pneumonia and its risk factors in Malawian children between 2001 and 2012.METHODS: Individual patient data for children (FINDINGS: Between November, 2012, and May, 2013, we retrospectively collected all available hard copies of yellow forms from 40 of 41 participating hospitals. We examined 113 154 pneumonia cases, 104 932 (92·7%) of whom had mortality data and 6903 of whom died, and calculated an overall case fatality rate of 6·6% (95% CI 6·4-6·7). The case fatality rate significantly decreased between 2001 (15·2% [13·4-17·1]) and 2012 (4·5% [4·1-4·9]; ptrendINTERPRETATION: Pneumonia mortality and its risk factors have steadily improved in the past decade in Malawi; however, mortality remains high in specific subgroups. Improvements in hospital care may have reduced case fatality rates though a lack of sufficient data on quality of care indicators and the potential of socioeconomic and other improvements outside the hospital precludes adequate assessment of why case-fatality rates fell. Results from this study emphasise the importance of effective national systems for data collection. Further work combining this with data on trends in the incidence of pneumonia in the community are needed to estimate trends in the overall risk of mortality from pneumonia in children in Malawi.FUNDING: Bill & Melinda Gates Foundation.

Summary box Murray et al suggest, via sophisticated mathematical modelling, that a radio intervention saved thousands of lives in Burkina Faso because it increased care-seeking for childhood illnesses, and that it could save tens of thousands more if scaled up across sub-Saharan Africa.1 2 In this commentary, we examine Murray et al ’s methods, remind readers that the Burkina Faso trial found no effect on child mortality and argue that privileging modelled over actual empirical data is both questionable and unnecessary. We have five concerns about the methods used in Murray et al . First, the authors ignore empirically recorded mortality data from the trial’s control arm, and instead choose to use a modelled estimate of higher mortality relative to the intervention arm. Second, the models assume that all children seeking treatment for pneumonia received appropriate care and oral antibiotics. We know this is often not the case and is even less likely when a health system is strained by sudden increases in care-seeking.3 Third, there is no discussion of the significant increase in consultations for ‘other diagnoses’ in the trial’s control arm. This indicates that the …

BACKGROUND: Globally, puerperal sepsis accounts for an estimated 8-12% of maternal deaths, but evidence is lacking on the extent to which clean delivery practices could improve maternal survival. We used data from the control arms of four cluster-randomised controlled trials conducted in rural India, Bangladesh and Nepal, to examine associations between clean delivery kit use and hand washing by the birth attendant with maternal mortality among home deliveries. METHODS: We tested associations between clean delivery practices and maternal deaths, using a pooled dataset for 40,602 home births across sites in the three countries. Cross-sectional data were analysed by fitting logistic regression models with and without multiple imputation, and confounders were selected a priori using causal directed acyclic graphs. The robustness of estimates was investigated through sensitivity analyses. RESULTS: Hand washing was associated with a 49% reduction in the odds of maternal mortality after adjusting for confounding factors (adjusted odds ratio (AOR) 0.51, 95% CI 0.28-0.93). The sensitivity analysis testing the missing at random assumption for the multiple imputation, as well as the sensitivity analysis accounting for possible misclassification bias in the use of clean delivery practices, indicated that the association between hand washing and maternal death had been over estimated. Clean delivery kit use was not associated with a maternal death (AOR 1.26, 95% CI 0.62-2.56). CONCLUSIONS: Our evidence suggests that hand washing in delivery is critical for maternal survival among home deliveries in rural South Asia, although the exact magnitude of this effect is uncertain due to inherent biases associated with observational data from low resource settings. Our findings indicating kit use does not improve maternal survival, suggests that the soap is not being used in all instances that kit use is being reported.

Background Short birth intervals are known to have negative effects on pregnancy outcomes. We analysed data from a large population surveillance system in rural Bangladesh to identify predictors of short birth interval and determine consequences of short intervals on pregnancy outcomes. Methods The study was conducted in three districts of Bangladesh – Bogra, Moulavibazar and Faridpur (population 282,643, 54,668 women of reproductive age). We used data between January 2010 and June 2011 from a key informant surveillance system that recorded all births, deaths and stillbirths. Short birth interval was defined as an interval between consecutive births of less than 33 months. Initially, risk factors of a short birth interval were determined using a multivariate mixed effects logistic regression model. Independent risk factors were selected using a priori knowledge from literature review. An adjusted mixed effects logistic regression model was then used to determine the effect of up to 21-, 21-32-, 33-44- and 45-month and higher birth-to-birth intervals on pregnancy outcomes controlling for confounders selected through a directed acyclic graph. Results We analysed 5,571 second or higher order deliveries. Average birth interval was 55 months and 1368/5571 women (24.6%) had a short birth interval (

This is the first study to examine effective doses of controlled-release (CR) melatonin in children with chronic sleep wake cycle disorders. All 42 subjects had severe neurodevelopmental difficulties. Initially, a randomized double-blinded cross-over design was used in 16 children, comparing the effectiveness of fast-release (FR) and CR melatonin. In the remainder of the patients, the CR melatonin was studied on a clinical basis. The effectiveness of treatment was assessed by sleep charts and clinical follow-up. Emphasis was placed on the judgement of the parents, who had guidance from the physicians. The average final CR melatonin dose in the 42 patients was 5.7 mg (2-12 mg). The studies showed that the FR melatonin was most effective when there was only delayed sleep onset, but CR formulations were more useful for sleep maintenance. Children appeared to require higher doses than adults.

Background Approximately 1.2 million stillbirths occur in the intrapartum period, and a further 717,000 annual neonatal deaths are caused by intrapartum events, most of which occur in resource poor settings. We aim to test the ‘double-hit’ hypothesis that maternal infection in the perinatal period predisposes to neurodevelopmental sequelae from an intrapartum asphyxia insult, increasing the likelihood of an early neonatal death compared with asphyxia alone. This is an observational study of singleton newborn infants with signs of intrapartum asphyxia that uses data from three previously conducted cluster randomized controlled trials taking place in rural Bangladesh and India. Methods From a population of 81,778 births in 54 community clusters in rural Bangladesh and India, we applied mixed effects logistic regression to data on 3890 singleton infants who had signs of intrapartum asphyxia, of whom 769 (20%) died in the early neonatal period. Poor infant condition at five minutes post-delivery was our proxy measure of intrapartum asphyxia. We had data for two markers of maternal infection: fever up to three days prior to labour, and prolonged rupture of membranes (PROM). Cause-specific verbal autopsy data were used to validate our findings using previously mentioned mixed effect logistic regression methods and the outcome of a neonatal death due to intrapartum asphyxia. Results Signs of maternal infection as indicated by PROM, combined with intrapartum asphyxia, increased the risk of an early neonatal death relative to intrapartum asphyxia alone (adjusted odds ratio (AOR) 1.28, 95% CI 1.03 – 1.59). Results from cause-specific verbal autopsy data verified our findings where there was a significantly increased odds of a early neonatal death due to intrapartum asphyxia in newborns exposed to both PROM and intrapartum asphyxia (AOR: 1.52, 95% CI 1.15 – 2.02). Conclusions Our data support the double-hit hypothesis for signs of maternal infection as indicated by PROM. Interventions for pregnant women with signs of infection, to prevent early neonatal deaths and disability due to asphyxia, should be investigated further in resource-poor populations where the chances of maternal infection are high.

A pooled analysis of data from three studies in South Asia demonstrates an association between use of clean delivery kits during home births and reduced risk of neonatal mortality., Background Sepsis accounts for up to 15% of an estimated 3.3 million annual neonatal deaths globally. We used data collected from the control arms of three previously conducted cluster-randomised controlled trials in rural Bangladesh, India, and Nepal to examine the association between clean delivery kit use or clean delivery practices and neonatal mortality among home births. Methods and Findings Hierarchical, logistic regression models were used to explore the association between neonatal mortality and clean delivery kit use or clean delivery practices in 19,754 home births, controlling for confounders common to all study sites. We tested the association between kit use and neonatal mortality using a pooled dataset from all three sites and separately for each site. We then examined the association between individual clean delivery practices addressed in the contents of the kit (boiled blade and thread, plastic sheet, gloves, hand washing, and appropriate cord care) and neonatal mortality. Finally, we examined the combined association between mortality and four specific clean delivery practices (boiled blade and thread, hand washing, and plastic sheet). Using the pooled dataset, we found that kit use was associated with a relative reduction in neonatal mortality (adjusted odds ratio 0.52, 95% CI 0.39–0.68). While use of a clean delivery kit was not always accompanied by clean delivery practices, using a plastic sheet during delivery, a boiled blade to cut the cord, a boiled thread to tie the cord, and antiseptic to clean the umbilicus were each significantly associated with relative reductions in mortality, independently of kit use. Each additional clean delivery practice used was associated with a 16% relative reduction in neonatal mortality (odds ratio 0.84, 95% CI 0.77–0.92). Conclusions The appropriate use of a clean delivery kit or clean delivery practices is associated with relative reductions in neonatal mortality among home births in underserved, rural populations. Please see later in the article for the Editors' Summary, Editors' Summary Background Worldwide, around 3.3 million babies die in the first month of life, according to data for 2009 from the World Health Organization. Although the global neonatal mortality rate declined by 28% (from 33.2 deaths per 1,000 live births to 23.9) between 1990 and 2009, the proportion of child deaths that are now in the neonatal period has increased in all regions of the world, and currently stands at 41%. This figure is concerning and neonatal mortality remains a big obstacle to the international community in meeting the target of Millennium Development Goal 4—to reduce deaths in children under 5 years by two-thirds from 1990 levels by 2015. At least 15% of all neonatal deaths are due to sepsis (systematic bacterial infection) and an estimated 30%–40% of infections are transmitted at the time of birth. Therefore preventing infections through clean delivery practices is an important strategy to reduce sepsis-related deaths in newborns and can contribute to reducing the overall burden of neonatal deaths. Why Was This Study Done? In South Asia, around 65% of deliveries occur at home, without skilled birth attendants, making practices around clean delivery particularly challenging. To date, evidence on the impact of clean delivery kits and clean delivery practices on neonatal mortality or sepsis-related neonatal deaths from community-based studies is scarce. In this study the researchers explored the associations between neonatal mortality, the use of clean delivery kits, and individual clean delivery practices by using data from the control arms of three cluster-randomized controlled trials conducted among rural populations in South Asia. What Did the Researchers Do and Find? The researchers used data from almost 20,000 (19,754) home births available from the control arms of three community-based cluster-randomized trials conducted between 2000 and 2008 in India (n = 6,841, 18 clusters), Bangladesh (n = 7,041, five clusters), and Nepal (n = 5,872, five clusters). The researchers did not include data from other previously conducted trials on clean delivery practices because of the mix of designs used in these studies and limited their analysis to live-born singleton infants delivered at home in control areas, for whom data on birth kit use were available. The researchers conducted a separate analysis for each country on kit use and clean delivery practices and also analyzed the pooled dataset for all countries while controlling for factors about the mother, the pregnancy, the delivery, and the postnatal period. Using these methods, the researchers found that kits were used for 18.4% of home births in India, 18.4% in Bangladesh, and 5.7% in Nepal. Importantly, according to the pooled analysis, kit use was associated with a 48% relative reduction in neonatal mortality (odds ratio/chance 0.52), which was similar across all countries: 57% relative reduction in neonatal mortality in India, 32% in Bangladesh, and 49% in Nepal. Delivery practices were also important: in the pooled country analysis, the use of a boiled blade to cut the cord, antiseptic to clean the cord, a boiled thread to tie the cord, and a plastic sheet for a clean delivery surface were all associated with significant relative reductions in mortality after controlling for kit use and confounders common to all sites. The researchers found a 16% relative reduction in mortality with each additional clean delivery practice used. What Do These Findings Mean? These findings show that the appropriate use of a clean delivery kit and clean delivery practices could lead to substantial reductions in neonatal mortality among home births in poor rural communities with limited access to health care. The results also reinforce the importance of each clean delivery practice; hand washing and use of a sterilised blade, boiled thread, and plastic sheet were linearly associated with a reduction in neonatal deaths with each additional clean delivery practice used. Costs of such kits are low (US$0.44 in India, US$0.40 in Nepal, and US$0.27 in Bangladesh, although these costs may still be prohibitive for the poorest women), and given the impact of clean delivery kits and clean delivery practices in reducing neonatal practices, such strategies should be widely promoted by the international community. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001180. A recent PLoS Medicine study by Oestergaard et al. has the latest figures on neonatal mortality worldwide UNICEF has information about progress toward Millennium Development Goal 4 The United Nations Population Fund has more information about safe birth practices The EquiNam web site describes ongoing work on socioeconomic inequalities in newborn and maternal health in Asia and Africa by some of the study authors

Summary Background Maternal and neonatal mortality rates remain high in many low-income and middle-income countries. Different approaches for the improvement of birth outcomes have been used in community-based interventions, with heterogeneous effects on survival. We assessed the effects of women's groups practising participatory learning and action, compared with usual care, on birth outcomes in low-resource settings. Methods We did a systematic review and meta-analysis of randomised controlled trials undertaken in Bangladesh, India, Malawi, and Nepal in which the effects of women's groups practising participatory learning and action were assessed to identify population-level predictors of effect on maternal mortality, neonatal mortality, and stillbirths. We also reviewed the cost-effectiveness of the women's group intervention and estimated its potential effect at scale in Countdown countries. Findings Seven trials (119 428 births) met the inclusion criteria. Meta-analyses of all trials showed that exposure to women's groups was associated with a 23% non-significant reduction in maternal mortality (odds ratio 0·77, 95% CI 0·48–1·23), a 20% reduction in neonatal mortality (0·80, 0·67–0·96), and a 7% non-significant reduction in stillbirths (0·93, 0·82–1·05), with high heterogeneity for maternal ( I 2 =64·0%, p=0·011) and neonatal results ( I 2 =73·2%, p=0·001). In the meta-regression analyses, the proportion of pregnant women in groups was linearly associated with reduction in both maternal and neonatal mortality (p=0·019 and p=0·009, respectively). A subgroup analysis of the four studies in which at least 30% of pregnant women participated in groups showed a 49% reduction in maternal mortality (0·51, 0·29–0·89) and a 33% reduction in neonatal mortality (0·67, 0·60–0·75). The intervention was cost effective by WHO standards and could save an estimated 283 000 newborn infants and 36 600 mothers per year if implemented in rural areas of 74 Countdown countries. Interpretation With the participation of at least a third of pregnant women and adequate population coverage, women's groups practising participatory learning and action are a cost-effective strategy to improve maternal and neonatal survival in low-resource settings. Funding Wellcome Trust, Ammalife, and National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care for Birmingham and the Black Country programme.