Strep A: challenges, opportunities, vaccine-based solutions, and economics.

This collection of articles focuses on Streptococcus pyogenes (Strep A) vaccine research and innovation, with a focus on emerging efforts to understand and estimate the full societal value of Strep A vaccination.

Qualitative assessment of healthy volunteer experience receiving subcutaneous infusions of high-dose benzathine penicillin G (SCIP) provides insights into design of late phase clinical studies.

INTRODUCTION: Secondary prophylaxis to prevent rheumatic heart disease (RHD) progression, in the form of four-weekly intramuscular benzathine benzylpenicillin G (BPG) injections, has remained unchanged since 1955. Qualitative investigations into patient preference have highlighted the need for long-acting penicillins to be delivered less frequently, ideally with reduced pain. We describe the experience of healthy volunteers participating in a phase-I safety, tolerability and pharmacokinetic trial of subcutaneous infusions of high-dose benzathine penicillin G (BPG)-the SCIP study (Australian New Zealand Clinical Trials Registry ACTRN12622000916741). METHODS: Participants (n = 24) received between 6.9 mL to 20.7 mL (3-9 times the standard dose) of BPG as a single infusion into the abdominal subcutaneous tissues via a spring-driven syringe pump over approximately 20 minutes. Semi-structured interviews at four time points were recorded, transcribed verbatim and thematically analysed. Tolerability and specific descriptors of the experience were explored, alongside thoughts on how the intervention could be improved for future trials in children and young adults receiving monthly BPG intramuscular injections for RHD. RESULTS: Participants tolerated the infusion well and were able describe their experiences throughout. Most reported minimal pain, substantiated via quantitative pain scores. Abdominal bruising at the infusion site did not concern participants nor impair normal activities. Insight into how SCIP could be improved for children included the use of topical analgesia, distractions via television or personal devices, a drawn-out infusion time with reduced delivery speed, and alternative infusion sites. Trust in the trial team was high. CONCLUSION: Qualitative research is an important adjunct for early-phase clinical trials, particularly when adherence to the planned intervention is a key driver of success. These results will inform later-phase SCIP trials in people living with RHD and other indications.

A pilot study to develop assessment tools for Group A Streptococcus surveillance studies.

Introduction: Group A Streptococcus (GAS) causes pharyngitis (sore throat) and impetigo (skin sores) GAS pharyngitis triggers rheumatic fever (RF) with epidemiological evidence supporting that GAS impetigo may also trigger RF in Australian Aboriginal children. Understanding the concurrent burden of these superficial GAS infections is critical to RF prevention. This pilot study aimed to trial tools for concurrent surveillance of sore throats and skins sore for contemporary studies of RF pathogenesis including development of a sore throat checklist for Aboriginal families and pharynx photography. Methods: Yarning circle conversations and semi-structured interviews were performed with Aboriginal caregivers and used to develop the language and composition of a sore throat checklist. The sore throat story checklist was combined with established methods of GAS pharyngitis and impetigo surveillance (examination, bacteriological culture, rapid antigen detection and serological tests) and new technologies (photography) and used for a pilot cross-sectional surveillance study of Aboriginal children attending their health clinic for a routine appointment. Feasibility, acceptability, and study costs were compiled. Results: Ten Aboriginal caregivers participated in the sore-throat yarning circles; a checklist was derived from predominant symptoms and their common descriptors. Over two days, 21 Aboriginal children were approached for the pilot surveillance study, of whom 17 were recruited; median age was 9 years [IQR 5.5-13.5], 65% were female. One child declined throat swabbing and three declined finger pricks; all other surveillance elements were completed by each child indicating high acceptability of surveillance assessments. Mean time for screening assessment was 19 minutes per child. Transport of clinical specimens enabled gold standard microbiological and serological testing for GAS. Retrospective examination of sore throat photography concorded with assessments performed on the day. Conclusion: Yarning circle conversations were effective in deriving culturally appropriate sore throat questionnaires for GAS pharyngitis surveillance. New and established tools were feasible, practical and acceptable to participants and enable surveillance to determine the burden of superficial GAS infections in communities at high risk of RF. Surveillance of GAS pharyngitis and impetgio in remote Australia informs primary RF prevention with potential global translation.

A Systematic Framework for Prioritizing Burden of Disease Data Required for Vaccine Development and Implementation: The Case for Group A Streptococcal Diseases.

Vaccine development and implementation decisions need to be guided by accurate and robust burden of disease data. We developed an innovative systematic framework outlining the properties of such data that are needed to advance vaccine development and evaluation, and prioritize research and surveillance activities. We focus on 4 objectives-advocacy, regulatory oversight and licensure, policy and post-licensure evaluation, and post-licensure financing-and identify key stakeholders and specific requirements for burden of disease data aligned with each objective. We apply this framework to group A Streptococcus, a pathogen with an underrecognized global burden, and give specific examples pertinent to 8 clinical endpoints. This dynamic framework can be adapted for any disease with a vaccine in development and can be updated as vaccine candidates progress through clinical trials. This framework will also help with research and innovation priority setting of the Immunization Agenda 2030 (IA2030) and accelerate development of future vaccines.

Rheumatic heart disease in Indigenous young peoples.

Indigenous children and young peoples live with an inequitable burden of acute rheumatic fever and rheumatic heart disease. In this Review, we focus on the epidemiological burden and lived experience of these conditions for Indigenous young peoples in Australia, New Zealand, and Canada. We outline the direct and indirect drivers of rheumatic heart disease risk and their mitigation. Specifically, we identify the opportunities and limitations of predominantly biomedical approaches to the primary, secondary, and tertiary prevention of disease among Indigenous peoples. We explain why these biomedical approaches must be coupled with decolonising approaches to address the underlying cause of disease. Initiatives underway to reduce acute rheumatic fever and rheumatic heart disease in Australia, New Zealand, and Canada are reviewed to identify how an Indigenous rights-based approach could contribute to elimination of rheumatic heart disease and global disease control goals.

The economic and health burdens of diseases caused by group A Streptococcus in New Zealand.

OBJECTIVES: In preparation for the future arrival of a group A Streptococcus (GAS) vaccine, this study estimated the economic and health burdens of GAS diseases in New Zealand (NZ). METHODS: The annual incidence of GAS diseases was based on extrapolation of the average number of primary healthcare episodes managed each year in general practices (2014-2016) and on the average number of hospitalizations occurring each year (2005-2014). Disease incidence was multiplied by the average cost of diagnosing and managing an episode of disease at each level of care to estimate the annual economic burden. RESULTS: GAS affected 1.5% of the population each year, resulting in an economic burden of 29.2 million NZ dollars (2015 prices) and inflicting a health burden of 2373 disability-adjusted life years (DALYs). Children <5 years of age were the most likely age group to present for GAS-related healthcare. Presentations for superficial throat and skin infections (predominantly pharyngitis and impetigo) were more common than other GAS diseases. Cellulitis contributed the most to the total economic and health burdens. Invasive and immune-mediated diseases disproportionately contributed to the total economic and health burdens relative to their frequency of occurrence. CONCLUSION: Preventing GAS diseases would have substantial economic and health benefits in NZ and globally.

Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study.

Cardiovascular diseases (CVDs), principally ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and a major contributor to disability. This paper reviews the magnitude of total CVD burden, including 13 underlying causes of cardiovascular death and 9 related risk factors, using estimates from the Global Burden of Disease (GBD) Study 2019. GBD, an ongoing multinational collaboration to provide comparable and consistent estimates of population health over time, used all available population-level data sources on incidence, prevalence, case fatality, mortality, and health risks to produce estimates for 204 countries and territories from 1990 to 2019. Prevalent cases of total CVD nearly doubled from 271 million (95% uncertainty interval [UI]: 257 to 285 million) in 1990 to 523 million (95% UI: 497 to 550 million) in 2019, and the number of CVD deaths steadily increased from 12.1 million (95% UI:11.4 to 12.6 million) in 1990, reaching 18.6 million (95% UI: 17.1 to 19.7 million) in 2019. The global trends for disability-adjusted life years (DALYs) and years of life lost also increased significantly, and years lived with disability doubled from 17.7 million (95% UI: 12.9 to 22.5 million) to 34.4 million (95% UI:24.9 to 43.6 million) over that period. The total number of DALYs due to IHD has risen steadily since 1990, reaching 182 million (95% UI: 170 to 194 million) DALYs, 9.14 million (95% UI: 8.40 to 9.74 million) deaths in the year 2019, and 197 million (95% UI: 178 to 220 million) prevalent cases of IHD in 2019. The total number of DALYs due to stroke has risen steadily since 1990, reaching 143 million (95% UI: 133 to 153 million) DALYs, 6.55 million (95% UI: 6.00 to 7.02 million) deaths in the year 2019, and 101 million (95% UI: 93.2 to 111 million) prevalent cases of stroke in 2019. Cardiovascular diseases remain the leading cause of disease burden in the world. CVD burden continues its decades-long rise for almost all countries outside high-income countries, and alarmingly, the age-standardized rate of CVD has begun to rise in some locations where it was previously declining in high-income countries. There is an urgent need to focus on implementing existing cost-effective policies and interventions if the world is to meet the targets for Sustainable Development Goal 3 and achieve a 30% reduction in premature mortality due to noncommunicable diseases.

The American Heart Association's Call to Action for Reducing the Global Burden of Rheumatic Heart Disease: A Policy Statement From the American Heart Association.

Rheumatic heart disease (RHD) affects ≈40 million people and claims nearly 300 000 lives each year. The historic passing of a World Health Assembly resolution on RHD in 2018 now mandates a coordinated global response. The American Heart Association is committed to serving as a global champion and leader in RHD care and prevention. Here, we pledge support in 5 key areas: (1) professional healthcare worker education and training, (2) technical support for the implementation of evidence-based strategies for rheumatic fever/RHD prevention, (3) access to essential medications and technologies, (4) research, and (5) advocacy to increase global awareness, resources, and capacity for RHD control. In bolstering the efforts of the American Heart Association to combat RHD, we hope to inspire others to collaborate, communicate, and contribute.

Contemporary Incidence and Prevalence of Rheumatic Fever and Rheumatic Heart Disease in Australia Using Linked Data: The Case for Policy Change.

Background In 2018, the World Health Organization prioritized control of acute rheumatic fever (ARF) and rheumatic heart disease (RHD), including disease surveillance. We developed strategies for estimating contemporary ARF/RHD incidence and prevalence in Australia (2015-2017) by age group, sex, and region for Indigenous and non-Indigenous Australians based on innovative, direct methods. Methods and Results This population-based study used linked administrative data from 5 Australian jurisdictions. A cohort of ARF (age <45 years) and RHD cases (<55 years) were sourced from jurisdictional ARF/RHD registers, surgical registries, and inpatient data. We developed robust methods for epidemiologic case ascertainment for ARF/RHD. We calculated age-specific and age-standardized incidence and prevalence. Age-standardized rate and prevalence ratios compared disease burden between demographic subgroups. Of 1425 ARF episodes, 72.1% were first-ever, 88.8% in Indigenous people and 78.6% were aged <25 years. The age-standardized ARF first-ever rates were 71.9 and 0.60/100 000 for Indigenous and non-Indigenous populations, respectively (age-standardized rate ratio=124.1; 95% CI, 105.2-146.3). The 2017 Global Burden of Disease RHD prevalent counts for Australia (<55 years) underestimate the burden (1518 versus 6156 Australia-wide extrapolated from our study). The Indigenous age-standardized RHD prevalence (666.3/100 000) was 61.4 times higher (95% CI, 59.3-63.5) than non-Indigenous (10.9/100 000). Female RHD prevalence was double that in males. Regions in northern Australia had the highest rates. Conclusions This study provides the most accurate estimates to date of Australian ARF and RHD rates. The high Indigenous burden necessitates urgent government action. Findings suggest RHD may be underestimated in many high-resource settings. The linked data methods outlined here have potential for global applicability.

School-based intervention to address self-regulation and executive functioning in children attending primary schools in remote Australian Aboriginal communities.

Executive functioning and self-regulation influence a range of outcomes across the life course including physical and mental health, educational success, and employment. Children prenatally exposed to alcohol or early life trauma (ELT) are at higher risk of impairment of these skills and may require intervention to address self-regulation deficits. Researchers partnered with the local Aboriginal health organization and schools to develop and pilot a manualized version of the Alert Program® in the Fitzroy Valley, north Western Australia, a region with documented high rates of fetal alcohol spectrum disorder and ELT. This self-controlled cluster randomized trial evaluated the effect of an 8-week Alert Program® intervention on children's executive functioning and self-regulation skills. Following parent or caregiver consent (referred to hereafter as parent), 271 students were enrolled in the study. This reflects a 75% participation rate and indicates the strong community support that exists for the study. Teachers from 26 primary school classrooms across eight Fitzroy Valley schools received training to deliver eight, one-hour Alert Program® lessons over eight-weeks to students. Student outcomes were measured by parent and teacher ratings of children's behavioral, emotional, and cognitive regulation. The mean number of lessons attended by children was 4.2. Although no significant improvements to children's executive functioning skills or behavior were detected via the teacher-rated measures as hypothesized, statistically significant improvements were noted on parent-rated measures of executive functioning and behavior. The effectiveness of future self-regulation programs may be enhanced through multimodal delivery through home, school and community based settings to maximize children's exposure to the intervention. Despite mixed findings of effect, this study was an important first step in adapting and evaluating the Alert Program® for use in remote Australian Aboriginal community schools, where access to self-regulation interventions is limited.

SToP (See, Treat, Prevent) skin sores and scabies trial: study protocol for a cluster randomised, stepped-wedge trial for skin disease control in remote Western Australia.

INTRODUCTION: Skin is important in Australian Aboriginal culture informing kinship and identity. In many remote Aboriginal communities, scabies and impetigo are very common. Untreated skin infections are painful, itchy and frequently go untreated due to under-recognition and lack of awareness of their potential serious complications. We hypothesise that the skin infection burden in remote Aboriginal communities can be reduced by implementing streamlined training and treatment pathways integrated with environmental health and health promotion activities, tested in the See, Treat, Prevent (SToP skin sores and scabies) trial. METHODS AND ANALYSIS: SToP will evaluate a skin control programme using a stepped-wedge, cluster randomised trial design with three intervention components (the 'SToP activities'): (1) seeing skin infections (development of training resources implemented within a community dermatology model); (2) treating skin infections (employing the latest evidence for impetigo, and scabies treatment); and (3) preventing skin infections (embedded, culturally informed health promotion and environmental health activities). Four community clusters in the remote Kimberley region of Western Australia will participate. Following baseline data collection, two clusters will be randomly allocated to the SToP activities. At 12 months, the remaining two clusters will transition to the SToP activities. The primary outcome is the diagnosis of impetigo in children (5-9 years) at school-based surveillance. Secondary outcome measures include scabies diagnosis, other child health indicators, resistance to cotrimoxazole in circulating pathogenic bacteria, determining the economic burden of skin disease and evaluating the cost effectiveness of SToP activities. ETHICS AND DISSEMINATION: This study protocol was approved by the health ethics review committees at the Child and Adolescent Health Service (Approval number RGS0000000584), the Western Australian Aboriginal Health Ethics Committee (Reference number: 819) and the University of Western Australia (Reference RA/4/20/4123). Study findings will be shared with community members, academic and medical communities via publications and presentations, and in reports to funders. Authorship for all publications based on this study will be determined in line with the Uniform Requirements for Manuscripts Submitted to Biomedical Journals published by the International Committee of Medical Journal Editors. Sharing results with organisations and communities who contributed to the study is paramount. The results of the SToP trial will be shared with participants in a suitable format, such as a single summary page provided to participants or presentations to communities, the Kimberly Aboriginal Health Planning Forum Research Subcommittee and other stakeholders as appropriate and as requested. Communication and dissemination will require ongoing consultation with Aboriginal communities to determine appropriate formats. TRIAL REGISTRATION NUMBER: ACTRN12618000520235.

Talking skin: attitudes and practices around skin infections, treatment options, and their clinical management in a remote region in Western Australia.

INTRODUCTION: Skin infections including scabies and impetigo have a high burden and cause significant morbidity in remote Aboriginal communities in Australia. Nevertheless, there is limited knowledge about community, healthcare practitioner and service provider perspectives on skin infections and treatment preferences. An increased understanding of their respective knowledge, attitudes and practices will contribute to improving healthcare seeking behaviour, improved diagnosis, treatment acceptability and quality of care within remote Aboriginal communities. The aim of this study was to explore Aboriginal parent/carer, healthcare practitioner, and service provider attitudes and practices regarding skin infections in Aboriginal communities in remote communities in the Pilbara, Western Australia. The study documents their perspectives and preferences regarding treatments for skin infections, as well as the perceived barriers and enablers to treatment uptake for scabies and impetigo amongst Aboriginal families in this region. METHODS: A qualitative study consisting of semi-structured interviews and focus group discussions was conducted with parents/carers, healthcare practitioners and community service providers in four remote communities in Western Australia. All interviews and focus group discussions were voice recorded and data were analysed using NVivo software and thematic analysis. RESULTS: Despite the high burden, skin infections were considered normal in these communities, and their impact on child health was under-recognised. Common themes identified by all participants included the inadequacy of health services, the pain of the benzathine penicillin G injection, uncertainty regarding the use of oral antibiotics and topical creams, and the need for health practitioner training and improved communication and resources. CONCLUSION: Documenting carer, service provider and healthcare practitioner perspectives on skin infections provides a more informed understanding of the context in which treatment decisions are made. The ongoing need for culturally appropriate targeted, translational health education; improved treatment guidelines and feasible, painless treatments; and potential for the use of bush medicines for skin infections were themes that emerged.

The Path to Group A Streptococcus Vaccines: World Health Organization Research and Development Technology Roadmap and Preferred Product Characteristics.

Group A Streptococcus (GAS) infections result in a considerable underappreciated burden of acute and chronic disease globally. A 2018 World Health Assembly resolution calls for better control and prevention. Providing guidance on global health research needs is an important World Health Organization (WHO) activity, influencing prioritization of investments. Here, the role, status, and directions in GAS vaccines research are discussed. WHO preferred product characteristics and a research and development technology roadmap, briefly presented, offer an actionable framework for vaccine development to regulatory and policy decision making, availability, and use. GAS vaccines should be considered for global prevention of the range of clinical manifestations and associated antibiotic use. Impediments related to antigen diversity, safety concerns, and the difficulty to establish vaccine efficacy against rheumatic heart disease are discussed. Demonstration of vaccine efficacy against pharyngitis and skin infections constitutes a key near-term strategic goal. Investments and collaborative partnerships to diversify and advance vaccine candidates are needed.

An economic case for a vaccine to prevent group A streptococcus skin infections.

BACKGROUND: Group A streptococcus (GAS) causes an exceptionally diverse range of diseases, raising questions about the optimal product characteristics of a commercially viable vaccine. The objectives of this study were to (1) estimate the current health and economic burdens caused by 24 diseases attributable to GAS each year in Australia and (2) use these estimates to explore the value of a GAS vaccine for different clinical indications, age schedules, and population groups. METHODS: For objective 1, we estimated the population heath and economic burdens by synthesising data from administrative databases, nationally representative surveys, literature reviews, public reimbursement schedules, and expert opinion. For objective 2, we modelled the prospective lifetime burden of GAS for all infants from birth, for children from 5 years of age, and for adults from 65 years of age. A vaccine was assumed to reduce each GAS disease by 70% for a period of 10 years, and the difference in outcomes between vaccinated and non-vaccinated cohorts were used to calculate the cost-effective value of vaccination. RESULTS: The annual health and economic burdens of GAS diseases totalled 23,528 disability-adjusted life years and AU$185.1 million in healthcare costs respectively; approximately half of each measure was due to cellulitis, followed by other skin infections and throat infections. Reducing the incidence of throat infections, skin infections, and cellulitis in non-Indigenous cohorts resulted in 30%, 33%, and 28% of the total vaccine value for an infant schedule (cost-effective vaccine price AU$260 per course); 47%, 26%, and 22% of the value for a child schedule (AU$289); and 2%, 15% and 74% for an adult schedule (AU$489). CONCLUSIONS: A vaccine that prevents GAS cellulitis and other skin infections, in addition to throat infections, would maximise its value and commercial viability, with a cost-effective price in line with other recently-licensed and funded vaccines in Australia.

Primary prevention of rheumatic fever in the 21st century: evaluation of a national programme.

Background: Acute rheumatic fever (ARF) has largely disappeared from high-income countries. However, in New Zealand (NZ) rates remain high in indigenous (Maori) and Pacific populations. In 2011, NZ launched an intensive and unparalleled primary Rheumatic Fever Prevention Programme (RFPP). We evaluated the impact of the school-based sore throat service component of the RFPP. Methods: The evaluation used national trends of all-age first episode ARF hospitalisation rates before (2009-11) and after (2012-16) implementation of the RFPP. A retrospective cohort study compared first-episode ARF incidence during time-not-exposed (23 093 207 person-days) and time-exposed (68 465 350 person-days) with a school-based sore throat service among children aged 5-12 years from 2012 to 2016. Results: Following implementation of the RFPP, the national ARF incidence rate declined by 28% from 4.0 per 100 000 [95% confidence interval (CI) 3.5-4.6] at baseline (2009-11) to 2.9 per 100 000 by 2016 (95% CI 2.4-3.4, P <0.01). The school-based sore throat service effectiveness overall was 23% [95% CI -6%-44%; rate ratio (RR) 0.77, 95% CI 0.56-1.06]. Effectiveness was greater in one high-risk region with high coverage (46%, 95% CI 16%-66%; RR 0.54, 95% CI 0.34-0.84). Conclusions: Population-based primary prevention of ARF through sore throat management may be effective in well-resourced settings like NZ where high-risk populations are geographically concentrated. Where high-risk populations are dispersed, a school-based primary prevention approach appears ineffective and is expensive.

Rheumatic heart disease in pregnancy: How can health services adapt to the needs of Indigenous women? A qualitative study.

OBJECTIVES: To study rheumatic heart disease health literacy and its impact on pregnancy, and to identify how health services could more effectively meet the needs of pregnant women with rheumatic heart disease. MATERIALS AND METHODS: Researchers observed and interviewed a small number of Aboriginal women and their families during pregnancy, childbirth and postpartum as they interacted with the health system. An Aboriginal Yarning method of relationship building over time, participant observations and interviews with Aboriginal women were used in the study. The settings were urban, island and remote communities across the Northern Territory. Women were followed interstate if they were transferred during pregnancy. The participants were pregnant women and their families. We relied on participants' abilities to tell their own experiences so that researchers could interpret their understanding and perspective of rheumatic heart disease. RESULTS: Aboriginal women and their families rarely had rheumatic heart disease explained appropriately by health staff and therefore lacked understanding of the severity of their illness and its implications for childbearing. Health directives in written and spoken English with assumed biomedical knowledge were confusing and of limited use when delivered without interpreters or culturally appropriate health supports. CONCLUSIONS: Despite previous studies documenting poor communication and culturally inadequate care, health systems did not meet the needs of pregnant Aboriginal women with rheumatic heart disease. Language-appropriate health education that promotes a shared understanding should be relevant to the gender, life-stage and social context of women with rheumatic heart disease.

Global, Regional, and National Burden of Rheumatic Heart Disease, 1990-2015.

BACKGROUND: Rheumatic heart disease remains an important preventable cause of cardiovascular death and disability, particularly in low-income and middle-income countries. We estimated global, regional, and national trends in the prevalence of and mortality due to rheumatic heart disease as part of the 2015 Global Burden of Disease study. METHODS: We systematically reviewed data on fatal and nonfatal rheumatic heart disease for the period from 1990 through 2015. Two Global Burden of Disease analytic tools, the Cause of Death Ensemble model and DisMod-MR 2.1, were used to produce estimates of mortality and prevalence, including estimates of uncertainty. RESULTS: We estimated that there were 319,400 (95% uncertainty interval, 297,300 to 337,300) deaths due to rheumatic heart disease in 2015. Global age-standardized mortality due to rheumatic heart disease decreased by 47.8% (95% uncertainty interval, 44.7 to 50.9) from 1990 to 2015, but large differences were observed across regions. In 2015, the highest age-standardized mortality due to and prevalence of rheumatic heart disease were observed in Oceania, South Asia, and central sub-Saharan Africa. We estimated that in 2015 there were 33.4 million (95% uncertainty interval, 29.7 million to 43.1 million) cases of rheumatic heart disease and 10.5 million (95% uncertainty interval, 9.6 million to 11.5 million) disability-adjusted life-years due to rheumatic heart disease globally. CONCLUSIONS: We estimated the global disease prevalence of and mortality due to rheumatic heart disease over a 25-year period. The health-related burden of rheumatic heart disease has declined worldwide, but high rates of disease persist in some of the poorest regions in the world. (Funded by the Bill and Melinda Gates Foundation and the Medtronic Foundation.).