Human resources and curricula content for early child development implementation: multicountry mixed methods evaluation.

OBJECTIVE: The WHO recommends responsive caregiving and early learning (RCEL) interventions to improve early child development (ECD), and to achieve the Sustainable Development Goals' vision of a world where all children thrive. Implementation of RCEL programmes in low and middle-income countries (LMIC) requires evidence to inform decisions about human resources and curricula content. We aimed to describe human resources and curricula content for implementation of RCEL projects across diverse LMICs, using data from the Grand Challenges Canada Saving Brains ECD portfolio. SETTING: We evaluated 32 RCEL projects across 17 LMICs on four continents. PARTICIPANTS: Overall, 2165 workers delivered ECD interventions to 25 909 families. INTERVENTION: Projects were either stand-alone RCEL or RCEL combined with health and nutrition, and/or safety and security. PRIMARY AND SECONDARY OUTCOMES: We undertook a mixed methods evaluation of RCEL projects within the Saving Brains portfolio. Quantitative data were collected through standardised reporting tools. Qualitative data were collected from ECD experts and stakeholders and analysed using thematic content analysis, informed by literature review. RESULTS: Major themes regarding human resources included: worker characteristics, incentivisation, retention, training and supervision, and regarding curricula content: flexible adaptation of content and delivery, fidelity, and intervention duration and dosage. Lack of an agreed standard ECD package contributed to project heterogeneity. Incorporation of ECD into existing services may facilitate scale-up but overburdened workers plus potential reductions in service quality remain challenging. Supportive training and supervision, inducement, worker retention, dosage and delivery modality emerged as key implementation decisions. CONCLUSIONS: This mixed methods evaluation of a multicountry ECD portfolio identified themes for consideration by policymakers and programme leaders relevant to RCEL implementation in diverse LMICs. Larger studies, which also examine impact, including high-quality process and costing evaluations with comparable data, are required to further inform decisions for implementation of RCEL projects at national and regional scales.

Contextual design choices and partnerships for scaling early child development programmes.

Translating the Nurturing Care Framework and unprecedented global policy support for early child development (ECD) into action requires evidence-informed guidance about how to implement ECD programmes at national and regional scale. We completed a literature review and participatory mixed-method evaluation of projects in Saving Brains®, Grand Challenges Canada® funded ECD portfolio across 23 low- and middle-income countries (LMIC). Using an adapted programme cycle, findings from evaluation related to partnerships and leadership, situational analyses, and design for scaling ECD were considered. 39 projects (5 'Transition to Scale' and 34 'Seed') were evaluated. 63% were delivered through health and 84% focused on Responsive Caregiving and Early Learning (RCEL). Multilevel partnerships, leadership and targeted situational analysis were crucial to design and adaptation. A theory of change approach to consider pathways to impact was useful for design, but practical situational analysis tools and local data to guide these processes were lacking. Several RCEL programmes, implemented within government services, had positive impacts on ECD outcomes and created more enabling caregiving environments. Engagement of informal and private sectors provided an alternative approach for reaching children where government services were sparse. Cost-effectiveness was infrequently measured. At small-scale RCEL interventions can be successfully adapted and implemented across diverse settings through processes which are responsive to situational analysis within a partnership model. Accelerating progress will require longitudinal evaluation of ECD interventions at much larger scale, including programmes targeting children with disabilities and humanitarian settings with further exploration of cost-effectiveness, critical content and human resources.

Scaling early child development: what are the barriers and enablers?

The Sustainable Development Goals, Global Strategy for Women's, Children's and Adolescents' Health (2016-2030) and Nurturing Care Framework all include targets to ensure children thrive However, many projects to support early childhood development (ECD) do not 'scale well' and leave large numbers of children unreached. This paper is the fifth in a series examining effective scaling of ECD programmes. This qualitative study explored experiences of scaling-up among purposively recruited implementers of ECD projects in low- and middle-income countries. Participants were sampled, by means of snowball sampling, from existing networks notably through Saving Brains®, Grand Challenges Canada®. Findings of a recent literature review on scaling-up frameworks, by the WHO, informed the development of a semistructured interview schedule. All interviews were conducted in English, via Skype, audio recorded and transcribed verbatim. Interviews were analysed using framework analysis. Framework analysis identified six major themes based on a standard programme cycle: planning and strategic choices, project design, human resources, financing and resource mobilisation, monitoring and evaluation, and leadership and partnerships. Key informants also identified an overarching theme regarding what scaling-up means. Stakeholders have not found existing literature and available frameworks helpful in guiding them to successful scale-up. Our research suggests that rather than proposing yet more theoretical guidelines or frameworks, it would be better to support stakeholders in developing organisational leadership capacity and partnership strategies to enable them to effectively apply a practical programme cycle or systematic process in their own contexts.

Practical considerations for transitioning early childhood interventions to scale: lessons from the Saving Brains portfolio.

Small pilot studies of young children have frequently shown promise, but very few have been successfully scaled to the regional or national levels. How can we ensure that these promising approaches move from a suite of pilots to full-scale implementation that can deliver sustainable impact for hundreds of millions of children? To elucidate concrete lessons learned and suggestions on accelerating the transition to impact at scale, we reviewed the Saving Brains portfolio to better understand three points: (1) the extent to which useful signals of impact could be extracted from data at the seed phase, (2) the ways in which innovators (project leaders) were approaching human resource challenges critical for scaling, and (3) the multisector diversity of the portfolio and the way innovators entered partnerships. The findings suggest key considerations for transitioning early childhood development interventions to scale and sustainability: strong entrepreneurial leadership, rigorous measurement and active use of data in support of adaptive learning, and champions acting at subnational levels. Together, these can enable flexible, iterative learning that can make the scaling process an opportunity to increase the level of benefit each child receives from an intervention.

Prioritizing research for integrated implementation of early childhood development and maternal, newborn, child and adolescent health and nutrition platforms.

BACKGROUND: Existing health and nutrition services present potential platforms for scaling up delivery of early childhood development (ECD) interventions within sensitive windows across the life course, especially in the first 1000 days from conception to age 2 years. However, there is insufficient knowledge on how to optimize implementation for such strategies in an integrated manner. In light of this knowledge gap, we aimed to systematically identify a set of integrated implementation research priorities for health, nutrition and early child development within the 2015 to 2030 timeframe of the Sustainable Development Goals (SDGs). METHODS: We applied the Child Health and Nutrition Research Initiative method, and consulted a diverse group of global health experts to develop and score 57 research questions against five criteria: answerability, effectiveness, deliverability, impact, and effect on equity. These questions were ranked using a research priority score, and the average expert agreement score was calculated for each question. FINDINGS: The research priority scores ranged from 61.01 to 93.52, with a median of 82.87. The average expert agreement scores ranged from 0.50 to 0.90, with a median of 0.75. The top-ranked research question were: i) "How can interventions and packages to reduce neonatal mortality be expanded to include ECD and stimulation interventions?"; ii) "How does the integration of ECD and MNCAH&N interventions affect human resource requirements and capacity development in resource-poor settings?"; and iii) "How can integrated interventions be tailored to vulnerable refugee and migrant populations to protect against poor ECD and MNCAH&N outcomes?". Most highly-ranked research priorities varied across the life course and highlighted key aspects of scaling up coverage of integrated interventions in resource-limited settings, including: workforce and capacity development, cost-effectiveness and strategies to reduce financial barriers, and quality assessment of programs. CONCLUSIONS: Investing in ECD is critical to achieving several of the SDGs, including SDG 2 on ending all forms of malnutrition, SDG 3 on ensuring health and well-being for all, and SDG 4 on ensuring inclusive and equitable quality education and promotion of life-long learning opportunities for all. The generated research agenda is expected to drive action and investment on priority approaches to integrating ECD interventions within existing health and nutrition services.

Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria.

Cerebral malaria is a leading cause of global morbidity and mortality. Interventions targeting the underlying pathophysiology of cerebral malaria may improve outcomes compared to treatment with antimalarials alone. Microvascular leak plays an important role in the pathogenesis of cerebral malaria. The angiopoietin (Ang)-Tie-2 system is a critical regulator of vascular function. We show that Ang-1 expression and soluble Tie-2 expression were associated with disease severity and outcome in a prospective study of Ugandan children with severe malaria and in a preclinical murine model of experimental cerebral malaria. Ang-1 was necessary for maintenance of vascular integrity and survival in a mouse model of cerebral malaria. Therapeutic administration of Ang-1 preserved blood-brain barrier integrity and, in combination with artesunate treatment, improved survival beyond that with artesunate alone. These data define a role for dysregulation of the Ang-Tie-2 axis in the pathogenesis of cerebral malaria and support the evaluation of Ang-Tie-2-based interventions as potential adjunctive therapies for treating severe malaria.

Experimental Malaria in Pregnancy Induces Neurocognitive Injury in Uninfected Offspring via a C5a-C5a Receptor Dependent Pathway.

The in utero environment profoundly impacts childhood neurodevelopment and behaviour. A substantial proportion of pregnancies in Africa are at risk of malaria in pregnancy (MIP) however the impact of in utero exposure to MIP on fetal neurodevelopment is unknown. Complement activation, in particular C5a, may contribute to neuropathology and adverse outcomes during MIP. We used an experimental model of MIP and standardized neurocognitive testing, MRI, micro-CT and HPLC analysis of neurotransmitter levels, to test the hypothesis that in utero exposure to malaria alters neurodevelopment through a C5a-C5aR dependent pathway. We show that malaria-exposed offspring have persistent neurocognitive deficits in memory and affective-like behaviour compared to unexposed controls. These deficits were associated with reduced regional brain levels of major biogenic amines and BDNF that were rescued by disruption of C5a-C5aR signaling using genetic and functional approaches. Our results demonstrate that experimental MIP induces neurocognitive deficits in offspring and suggest novel targets for intervention.

Next-generation sequencing to dissect hereditary nephrotic syndrome in mice identifies a hypomorphic mutation in Lamb2 and models Pierson's syndrome.

The study of mutations causing the steroid-resistant nephrotic syndrome in children has greatly advanced our understanding of the kidney filtration barrier. In particular, these genetic variants have illuminated the roles of the podocyte, glomerular basement membrane and endothelial cell in glomerular filtration. However, in a significant number of familial and early onset cases, an underlying mutation cannot be identified, indicating that there are likely to be multiple unknown genes with roles in glomerular permeability. We now show how the combination of N-ethyl-N-nitrosourea mutagenesis and next-generation sequencing could be used to identify the range of mutations affecting these pathways. Using this approach, we isolated a novel mouse strain with a viable nephrotic phenotype and used whole-genome sequencing to isolate a causative hypomorphic mutation in Lamb2. This discovery generated a model for one part of the spectrum of human Pierson's syndrome and provides a powerful proof of principle for accelerating gene discovery and improving our understanding of inherited forms of renal disease.

Complement activation and the resulting placental vascular insufficiency drives fetal growth restriction associated with placental malaria.

Placental malaria (PM) is a major cause of fetal growth restriction, yet the underlying mechanism is unclear. Complement C5a and C5a receptor levels are increased with PM. C5a is implicated in fetal growth restriction in non-infection-based animal models. In a case-control study of 492 pregnant Malawian women, we find that elevated C5a levels are associated with an increased risk of delivering a small-for-gestational-age infant. C5a was significantly increased in PM and was negatively correlated with the angiogenic factor angiopoietin-1 and positively correlated with angiopoietin-2, soluble endoglin, and vascular endothelial growth factor. Genetic or pharmacological blockade of C5a or its receptor in a mouse model of PM resulted in greater fetoplacental vessel development, reduced placental vascular resistance, and improved fetal growth and survival. These data suggest that C5a drives fetal growth restriction in PM through dysregulation of angiogenic factors essential for placental vascular remodeling resulting in placental vascular insufficiency.

Circulating soluble endoglin levels in pregnant women in Cameroon and Malawi--associations with placental malaria and fetal growth restriction.

Placental infections with Plasmodium falciparum are associated with fetal growth restriction resulting in low birth weight (LBW). The mechanisms that mediate these effects have yet to be completely described; however, they are likely to involve inflammatory processes and dysregulation of angiogenesis. Soluble endoglin (sEng), a soluble receptor of transforming growth factor (TGF)-ß previously associated with preeclampsia in pregnant women and with severe malaria in children, regulates the immune system and influences angiogenesis. We hypothesized that sEng may play a role in development of LBW associated with placental malaria (PM). Plasma levels of sEng were measured in women (i) followed prospectively throughout pregnancy in Cameroon (n = 52), and (ii) in a case-control study at delivery in Malawi (n = 479). The relationships between sEng levels and gravidity, peripheral and placental parasitemia, gestational age, and adverse outcomes of PM including maternal anemia and LBW were determined. In the longitudinal cohort from Cameroon, 28 of 52 women (54%) experienced at least one malaria infection during pregnancy. In Malawi we enrolled two aparasitemic gravidity-matched controls for every case with PM. sEng levels varied over the course of gestation and were significantly higher in early and late gestation as compared to delivery (P<0.006 and P<0.0001, respectively). Circulating sEng levels were higher in primigravidae than multigravidae from both Cameroon and Malawi, irrespective of malarial infection status (p<0.046 and p<0.001, respectively). Peripheral parasitemia in Cameroonian women and PM in Malawian women were each associated with elevated sEng levels following correction for gestational age and gravidity (p = 0.006 and p = 0.033, respectively). Increased sEng was also associated with the delivery of LBW infants in primigravid Malawian women (p = 0.017); the association was with fetal growth restriction (p = 0.003) but not pre-term delivery (p = 0.286). Increased circulating maternal sEng levels are associated with P. falciparum infection in pregnancy and with fetal growth restriction in primigravidae with PM.

Complement activation: a critical mediator of adverse fetal outcomes in placental malaria?

Malaria infection is a significant risk factor for low birth weight outcomes in pregnancy. Despite efforts to define the molecular mechanisms that cause low birth weight as a result of intrauterine growth restriction, the roles of inflammation and mononuclear cells in the process are incompletely understood. Data from adverse pregnancy outcomes in humans and from murine models of pathological pregnancies suggest that C5a could be an important upstream regulator of placental angiogenesis, and excessive C5a could lead to functional placental insufficiency by impairing adequate vascularization of the placenta. Based on recent evidence, we hypothesize that complement factor C5a is a central initiator of poor birth outcomes associated with placental malaria by promoting mononuclear cell migration, activation and dysregulated angiogenesis.

Complement driven innate immune response to malaria: fuelling severe malarial diseases.

Severe malaria remains a major cause of global mortality. The innate immune response to infection is a key determinant of malaria severity and outcome. The complement system plays a key role in initiating and augmenting innate immune responses, including inflammation, endothelial activation, opsonization and coagulation, processes which have been implicated in malaria pathogenesis. In this review, we discuss the evidence supporting a role for excessive complement activation in the pathogenesis of severe malaria.

Dysregulation of angiopoietins is associated with placental malaria and low birth weight.

BACKGROUND: Placental malaria (PM) is associated with adverse pregnancy outcomes including low birth weight (LBW). However, the precise mechanisms by which PM induces LBW are poorly defined. Based on the essential role of angiopoietin (ANG)-1 and -2 in normal placental vascular development, we hypothesized that PM may result in the dysregulation of angiopoietins and thereby contribute to LBW outcomes. METHODS AND FINDINGS: In a mouse model of PM, we show that Plasmodium berghei ANKA infection of pregnant mice resulted in dysregulated angiopoietin levels and fetal growth restriction. PM lead to decreased ANG-1, increased ANG-2, and an elevated ratio of ANG-2/ANG-1 in the placenta and the serum. These observations were extended to malaria-exposed pregnant women: In a study of primigravid women prospectively followed over the course of pregnancy, Plasmodium falciparum infection was associated with a decrease in maternal plasma ANG-1 levels (P = 0.031) and an increase in the ANG-2:ANG-1 ratio (P = 0.048). ANG-1 levels recovered with successful treatment of peripheral parasitemia (P = 0.010). In a cross-sectional study of primigravidae at delivery, angiopoietin dysregulation was associated with PM (P = 0.002) and LBW (P = 0.041). Women with PM who delivered LBW infants had increased ANG-2:ANG-1 ratios (P = 0.002) compared to uninfected women delivering normal birth weight infants. CONCLUSIONS: These data support the hypothesis that dysregulation of angiopoietins is associated with PM and LBW outcomes, and suggest that ANG-1 and ANG-2 levels may be clinically informative biomarkers to identify P. falciparum-infected mothers at risk of LBW deliveries.

MyD88-dependent autoimmune disease in Lyn-deficient mice.

Recent evidence suggests that systemic autoimmune disease depends on signals from TLR ligands, but little is known about how TLR-dependent pathways lead to the loss of self tolerance in vivo. To address this, we have examined the role of TLR signaling in Lyn-deficient mice, which develop an autoimmune disease similar to SLE. We found that absence of the TLR signaling adaptor molecule MyD88 suppresses plasma cell differentiation of switched and unswitched B cells, and prevents the generation of antinuclear IgG antibodies and glomerulonephritis. In mixed chimeras the increased IgM and IgG antibody secretion in Lyn-deficient mice is at least partially due to B cell-independent effects of Lyn. We now show that MyD88 deficiency blocks the expansion and activation of DC in which Lyn is also normally expressed, and prevents the hypersecretion of proinflammatory cytokines IL-6 and IL-12 by Lyn-deficient DC. These findings further highlight the important role of TLR-dependent signals in both lymphocyte activation and autoimmune pathogenesis.