Mapping the global endemicity and clinical burden of Plasmodium vivax, 2000-17: a spatial and temporal modelling study.

BACKGROUND: Plasmodium vivax exacts a significant toll on health worldwide, yet few efforts to date have quantified the extent and temporal trends of its global distribution. Given the challenges associated with the proper diagnosis and treatment of P vivax, national malaria programmes-particularly those pursuing malaria elimination strategies-require up to date assessments of P vivax endemicity and disease impact. This study presents the first global maps of P vivax clinical burden from 2000 to 2017. METHODS: In this spatial and temporal modelling study, we adjusted routine malariometric surveillance data for known biases and used socioeconomic indicators to generate time series of the clinical burden of P vivax. These data informed Bayesian geospatial models, which produced fine-scale predictions of P vivax clinical incidence and infection prevalence over time. Within sub-Saharan Africa, where routine surveillance for P vivax is not standard practice, we combined predicted surfaces of Plasmodium falciparum with country-specific ratios of P vivax to P falciparum. These results were combined with surveillance-based outputs outside of Africa to generate global maps. FINDINGS: We present the first high-resolution maps of P vivax burden. These results are combined with those for P falciparum (published separately) to form the malaria estimates for the Global Burden of Disease 2017 study. The burden of P vivax malaria decreased by 41·6%, from 24·5 million cases (95% uncertainty interval 22·5-27·0) in 2000 to 14·3 million cases (13·7-15·0) in 2017. The Americas had a reduction of 56·8% (47·6-67·0) in total cases since 2000, while South-East Asia recorded declines of 50·5% (50·3-50·6) and the Western Pacific regions recorded declines of 51·3% (48·0-55·4). Europe achieved zero P vivax cases during the study period. Nonetheless, rates of decline have stalled in the past five years for many countries, with particular increases noted in regions affected by political and economic instability. INTERPRETATION: Our study highlights important spatial and temporal patterns in the clinical burden and prevalence of P vivax. Amid substantial progress worldwide, plateauing gains and areas of increased burden signal the potential for challenges that are greater than expected on the road to malaria elimination. These results support global monitoring systems and can inform the optimisation of diagnosis and treatment where P vivax has most impact. FUNDING: Bill & Melinda Gates Foundation and the Wellcome Trust.

Mapping the global prevalence, incidence, and mortality of Plasmodium falciparum, 2000-17: a spatial and temporal modelling study.

BACKGROUND: Since 2000, the scale-up of malaria control interventions has substantially reduced morbidity and mortality caused by the disease globally, fuelling bold aims for disease elimination. In tandem with increased availability of geospatially resolved data, malaria control programmes increasingly use high-resolution maps to characterise spatially heterogeneous patterns of disease risk and thus efficiently target areas of high burden. METHODS: We updated and refined the Plasmodium falciparum parasite rate and clinical incidence models for sub-Saharan Africa, which rely on cross-sectional survey data for parasite rate and intervention coverage. For malaria endemic countries outside of sub-Saharan Africa, we produced estimates of parasite rate and incidence by applying an ecological downscaling approach to malaria incidence data acquired via routine surveillance. Mortality estimates were derived by linking incidence to systematically derived vital registration and verbal autopsy data. Informed by high-resolution covariate surfaces, we estimated P falciparum parasite rate, clinical incidence, and mortality at national, subnational, and 5 × 5 km pixel scales with corresponding uncertainty metrics. FINDINGS: We present the first global, high-resolution map of P falciparum malaria mortality and the first global prevalence and incidence maps since 2010. These results are combined with those for Plasmodium vivax (published separately) to form the malaria estimates for the Global Burden of Disease 2017 study. The P falciparum estimates span the period 2000-17, and illustrate the rapid decline in burden between 2005 and 2017, with incidence declining by 27·9% and mortality declining by 42·5%. Despite a growing population in endemic regions, P falciparum cases declined between 2005 and 2017, from 232·3 million (95% uncertainty interval 198·8-277·7) to 193·9 million (156·6-240·2) and deaths declined from 925 800 (596 900-1 341 100) to 618 700 (368 600-952 200). Despite the declines in burden, 90·1% of people within sub-Saharan Africa continue to reside in endemic areas, and this region accounted for 79·4% of cases and 87·6% of deaths in 2017. INTERPRETATION: High-resolution maps of P falciparum provide a contemporary resource for informing global policy and malaria control planning, programme implementation, and monitoring initiatives. Amid progress in reducing global malaria burden, areas where incidence trends have plateaued or increased in the past 5 years underscore the fragility of hard-won gains against malaria. Efforts towards elimination should be strengthened in such areas, and those where burden remained high throughout the study period. FUNDING: Bill & Melinda Gates Foundation.

Global, Regional, and Country-Specific Lifetime Risks of Stroke, 1990 and 2016.

BACKGROUND: The lifetime risk of stroke has been calculated in a limited number of selected populations. We sought to estimate the lifetime risk of stroke at the regional, country, and global level using data from a comprehensive study of the prevalence of major diseases. METHODS: We used the Global Burden of Disease (GBD) Study 2016 estimates of stroke incidence and the competing risks of death from any cause other than stroke to calculate the cumulative lifetime risks of first stroke, ischemic stroke, or hemorrhagic stroke among adults 25 years of age or older. Estimates of the lifetime risks in the years 1990 and 2016 were compared. Countries were categorized into quintiles of the sociodemographic index (SDI) used in the GBD Study, and the risks were compared across quintiles. Comparisons were made with the use of point estimates and uncertainty intervals representing the 2.5th and 97.5th percentiles around the estimate. RESULTS: The estimated global lifetime risk of stroke from the age of 25 years onward was 24.9% (95% uncertainty interval, 23.5 to 26.2); the risk among men was 24.7% (95% uncertainty interval, 23.3 to 26.0), and the risk among women was 25.1% (95% uncertainty interval, 23.7 to 26.5). The risk of ischemic stroke was 18.3%, and the risk of hemorrhagic stroke was 8.2%. In high-SDI, high-middle-SDI, and low-SDI countries, the estimated lifetime risk of stroke was 23.5%, 31.1% (highest risk), and 13.2% (lowest risk), respectively; the 95% uncertainty intervals did not overlap between these categories. The highest estimated lifetime risks of stroke according to GBD region were in East Asia (38.8%), Central Europe (31.7%), and Eastern Europe (31.6%), and the lowest risk was in eastern sub-Saharan Africa (11.8%). The mean global lifetime risk of stroke increased from 22.8% in 1990 to 24.9% in 2016, a relative increase of 8.9% (95% uncertainty interval, 6.2 to 11.5); the competing risk of death from any cause other than stroke was considered in this calculation. CONCLUSIONS: In 2016, the global lifetime risk of stroke from the age of 25 years onward was approximately 25% among both men and women. There was geographic variation in the lifetime risk of stroke, with the highest risks in East Asia, Central Europe, and Eastern Europe. (Funded by the Bill and Melinda Gates Foundation.).

Mapping Plasmodium falciparum Mortality in Africa between 1990 and 2015.

BACKGROUND: Malaria control has not been routinely informed by the assessment of subnational variation in malaria deaths. We combined data from the Malaria Atlas Project and the Global Burden of Disease Study to estimate malaria mortality across sub-Saharan Africa on a grid of 5 km2 from 1990 through 2015. METHODS: We estimated malaria mortality using a spatiotemporal modeling framework of geolocated data (i.e., with known latitude and longitude) on the clinical incidence of malaria, coverage of antimalarial drug treatment, case fatality rate, and population distribution according to age. RESULTS: Across sub-Saharan Africa during the past 15 years, we estimated that there was an overall decrease of 57% (95% uncertainty interval, 46 to 65) in the rate of malaria deaths, from 12.5 (95% uncertainty interval, 8.3 to 17.0) per 10,000 population in 2000 to 5.4 (95% uncertainty interval, 3.4 to 7.9) in 2015. This led to an overall decrease of 37% (95% uncertainty interval, 36 to 39) in the number of malaria deaths annually, from 1,007,000 (95% uncertainty interval, 666,000 to 1,376,000) to 631,000 (95% uncertainty interval, 394,000 to 914,000). The share of malaria deaths among children younger than 5 years of age ranged from more than 80% at a rate of death of more than 25 per 10,000 to less than 40% at rates below 1 per 10,000. Areas with high malaria mortality (>10 per 10,000) and low coverage (<50%) of insecticide-treated bed nets and antimalarial drugs included much of Nigeria, Angola, and Cameroon and parts of the Central African Republic, Congo, Guinea, and Equatorial Guinea. CONCLUSIONS: We estimated that there was an overall decrease of 57% in the rate of death from malaria across sub-Saharan Africa over the past 15 years and identified several countries in which high rates of death were associated with low coverage of antimalarial treatment and prevention programs. (Funded by the Bill and Melinda Gates Foundation and others.).

Methods for Estimating the Global Burden of Cerebrovascular Diseases.

The Global Burden of Disease (GBD) study is a long-standing effort to report consistent and comprehensive measures of disease burden for the world. In this paper, we describe the methods used to estimate the global burden of stroke for the GBD 2013 study. Pathologic subtypes of stroke are modeled separately for two mutually exclusive and exhaustive categories: (1) ischemic stroke and (2) hemorrhagic and other non-ischemic strokes. Acute and chronic strokes are estimated separately. The GBD 2013 study has incorporated large amounts of new data on stroke death rates, incidence and case fatality. Disease modeling methods have been updated to better integrate mortality and incidence data. Future efforts will focus on incorporating data on the regional variation in severity of disability. Stroke remains a new area for disease modeling. A better understanding of stroke incidence, mortality and severity, and how it varies among countries, can help guide priority setting and improve health policy related to this important condition.

Stroke Prevalence, Mortality and Disability-Adjusted Life Years in Adults Aged 20-64 Years in 1990-2013: Data from the Global Burden of Disease 2013 Study.

BACKGROUND: Recent evidence suggests that stroke is increasing as a cause of morbidity and mortality in younger adults, where it carries particular significance for working individuals. Accurate and up-to-date estimates of stroke burden are important for planning stroke prevention and management in younger adults. OBJECTIVES: This study aims to estimate prevalence, mortality and disability-adjusted life years (DALYs) and their trends for total, ischemic stroke (IS) and hemorrhagic stroke (HS) in the world for 1990-2013 in adults aged 20-64 years. METHODOLOGY: Stroke prevalence, mortality and DALYs were estimated using the Global Burden of Disease (GBD) 2013 methods. All available data on rates of stroke incidence, excess mortality, prevalence and death were collected. Statistical models were used along with country-level covariates to estimate country-specific stroke burden. Stroke-specific disability weights were used to compute years lived with disability and DALYs. Means and 95% uncertainty intervals (UIs) were calculated for prevalence, mortality and DALYs. The median of the percent change and 95% UI were determined for the period from 1990 to 2013. RESULTS: In 2013, in younger adults aged 20-64 years, the global prevalence of HS was 3,725,085 cases (95% UI 3,548,098-3,871,018) and IS was 7,258,216 cases (95% UI 6,996,272-7,569,403). Globally, between 1990 and 2013, there were significant increases in absolute numbers and prevalence rates of both HS and IS for younger adults. There were 1,483,707 (95% UI 1,340,579-1,658,929) stroke deaths globally among younger adults but the number of deaths from HS (1,047,735 (95% UI 945,087-1,184,192)) was significantly higher than the number of deaths from IS (435,972 (95% UI 354,018-504,656)). There was a 20.1% (95% UI -23.6 to -10.3) decline in the number of total stroke deaths among younger adults in developed countries but a 36.7% (95% UI 26.3-48.5) increase in developing countries. Death rates for all strokes among younger adults declined significantly in developing countries from 47 (95% UI 42.6-51.7) in 1990 to 39 (95% UI 35.0-43.8) in 2013. Death rates for all strokes among younger adults also declined significantly in developed countries from 33.3 (95% UI 29.8-37.0) in 1990 to 23.5 (95% UI 21.1-26.9) in 2013. A significant decrease in HS death rates for younger adults was seen only in developed countries between 1990 and 2013 (19.8 (95% UI 16.9-22.6) and 13.7 (95% UI 12.1-15.9)) per 100,000). No significant change was detected in IS death rates among younger adults. The total DALYs from all strokes in those aged 20-64 years was 51,429,440 (95% UI 46,561,382-57,320,085). Globally, there was a 24.4% (95% UI 16.6-33.8) increase in total DALY numbers for this age group, with a 20% (95% UI 11.7-31.1) and 37.3% (95% UI 23.4-52.2) increase in HS and IS numbers, respectively. CONCLUSIONS: Between 1990 and 2013, there were significant increases in prevalent cases, total deaths and DALYs due to HS and IS in younger adults aged 20-64 years. Death and DALY rates declined in both developed and developing countries but a significant increase in absolute numbers of stroke deaths among younger adults was detected in developing countries. Most of the burden of stroke was in developing countries. In 2013, the greatest burden of stroke among younger adults was due to HS. While the trends in declining death and DALY rates in developing countries are encouraging, these regions still fall far behind those of developed regions of the world. A more aggressive approach toward primary prevention and increased access to adequate healthcare services for stroke is required to substantially narrow these disparities.

Stroke Prevalence, Mortality and Disability-Adjusted Life Years in Children and Youth Aged 0-19 Years: Data from the Global and Regional Burden of Stroke 2013.

BACKGROUND: There is increasing recognition of stroke as an important contributor to childhood morbidity and mortality. Current estimates of global childhood stroke burden and its temporal trends are sparse. Accurate and up-to-date estimates of childhood stroke burden are important for planning research and the resulting evidence-based strategies for stroke prevention and management. OBJECTIVES: To estimate the prevalence, mortality and disability-adjusted life years (DALYs) for ischemic stroke (IS), hemorrhagic stroke (HS) and all stroke types combined globally from 1990 to 2013. METHODOLOGY: Stroke prevalence, mortality and DALYs were estimated using the Global Burden of Disease 2013 methods. All available data on stroke-related incidence, prevalence, excess mortality and deaths were collected. Statistical models and country-level covariates were employed to produce comprehensive and consistent estimates of prevalence and mortality. Stroke-specific disability weights were used to estimate years lived with disability and DALYs. Means and 95% uncertainty intervals (UIs) were calculated for prevalence, mortality and DALYs. The median of the percent change and 95% UI were determined for the period from 1990 to 2013. RESULTS: In 2013, there were 97,792 (95% UI 90,564-106,016) prevalent cases of childhood IS and 67,621 (95% UI 62,899-72,214) prevalent cases of childhood HS, reflecting an increase of approximately 35% in the absolute numbers of prevalent childhood strokes since 1990. There were 33,069 (95% UI 28,627-38,998) deaths and 2,615,118 (95% UI 2,265,801-3,090,822) DALYs due to childhood stroke in 2013 globally, reflecting an approximately 200% decrease in the absolute numbers of death and DALYs in childhood stroke since 1990. Between 1990 and 2013, there were significant increases in the global prevalence rates of childhood IS, as well as significant decreases in the global death rate and DALYs rate of all strokes in those of age 0-19 years. While prevalence rates for childhood IS and HS decreased significantly in developed countries, a decline was seen only in HS, with no change in prevalence rates of IS, in developing countries. The childhood stroke DALY rates in 2013 were 13.3 (95% UI 10.6-17.1) for IS and 92.7 (95% UI 80.5-109.7) for HS per 100,000. While the prevalence of childhood IS compared to childhood HS was similar globally, the death rate and DALY rate of HS was 6- to 7-fold higher than that of IS. In 2013, the prevalence rate of both childhood IS and HS was significantly higher in developed countries than in developing countries. Conversely, both death and DALY rates for all stroke types were significantly lower in developed countries than in developing countries in 2013. Men showed a trend toward higher childhood stroke death rates (1.5 (1.3-1.8) per 100,000) than women (1.1 (0.9-1.5) per 100,000) and higher childhood stroke DALY rates (120.1 (100.8-143.4) per 100,000) than women (90.9 (74.6-122.4) per 100,000) globally in 2013. CONCLUSIONS: Globally, between 1990 and 2013, there was a significant increase in the absolute number of prevalent childhood strokes, while absolute numbers and rates of both deaths and DALYs declined significantly. The gap in childhood stroke burden between developed and developing countries is closing; however, in 2013, childhood stroke burden in terms of absolute numbers of prevalent strokes, deaths and DALYs remained much higher in developing countries. There is an urgent need to address these disparities with both global and country-level initiatives targeting prevention as well as improved access to acute and chronic stroke care.

Update on the Global Burden of Ischemic and Hemorrhagic Stroke in 1990-2013: The GBD 2013 Study.

BACKGROUND: Global stroke epidemiology is changing rapidly. Although age-standardized rates of stroke mortality have decreased worldwide in the past 2 decades, the absolute numbers of people who have a stroke every year, and live with the consequences of stroke or die from their stroke, are increasing. Regular updates on the current level of stroke burden are important for advancing our knowledge on stroke epidemiology and facilitate organization and planning of evidence-based stroke care. OBJECTIVES: This study aims to estimate incidence, prevalence, mortality, disability-adjusted life years (DALYs) and years lived with disability (YLDs) and their trends for ischemic stroke (IS) and hemorrhagic stroke (HS) for 188 countries from 1990 to 2013. METHODOLOGY: Stroke incidence, prevalence, mortality, DALYs and YLDs were estimated using all available data on mortality and stroke incidence, prevalence and excess mortality. Statistical models and country-level covariate data were employed, and all rates were age-standardized to a global population. All estimates were produced with 95% uncertainty intervals (UIs). RESULTS: In 2013, there were globally almost 25.7 million stroke survivors (71% with IS), 6.5 million deaths from stroke (51% died from IS), 113 million DALYs due to stroke (58% due to IS) and 10.3 million new strokes (67% IS). Over the 1990-2013 period, there was a significant increase in the absolute number of DALYs due to IS, and of deaths from IS and HS, survivors and incident events for both IS and HS. The preponderance of the burden of stroke continued to reside in developing countries, comprising 75.2% of deaths from stroke and 81.0% of stroke-related DALYs. Globally, the proportional contribution of stroke-related DALYs and deaths due to stroke compared to all diseases increased from 1990 (3.54% (95% UI 3.11-4.00) and 9.66% (95% UI 8.47-10.70), respectively) to 2013 (4.62% (95% UI 4.01-5.30) and 11.75% (95% UI 10.45-13.31), respectively), but there was a diverging trend in developed and developing countries with a significant increase in DALYs and deaths in developing countries, and no measurable change in the proportional contribution of DALYs and deaths from stroke in developed countries. CONCLUSION: Global stroke burden continues to increase globally. More efficient stroke prevention and management strategies are urgently needed to halt and eventually reverse the stroke pandemic, while universal access to organized stroke services should be a priority. © 2015 S. Karger AG, Basel.

Sex Differences in Stroke Incidence, Prevalence, Mortality and Disability-Adjusted Life Years: Results from the Global Burden of Disease Study 2013.

BACKGROUND: Accurate information on stroke burden in men and women are important for evidence-based healthcare planning and resource allocation. Previously, limited research suggested that the absolute number of deaths from stroke in women was greater than in men, but the incidence and mortality rates were greater in men. However, sex differences in various metrics of stroke burden on a global scale have not been a subject of comprehensive and comparable assessment for most regions of the world, nor have sex differences in stroke burden been examined for trends over time. METHODS: Stroke incidence, prevalence, mortality, disability-adjusted life years (DALYs) and healthy years lost due to disability were estimated as part of the Global Burden of Disease (GBD) 2013 Study. Data inputs included all available information on stroke incidence, prevalence and death and case fatality rates. Analysis was performed separately by sex and 5-year age categories for 188 countries. Statistical models were employed to produce globally comprehensive results over time. All rates were age-standardized to a global population and 95% uncertainty intervals (UIs) were computed. FINDINGS: In 2013, global ischemic stroke (IS) and hemorrhagic stroke (HS) incidence (per 100,000) in men (IS 132.77 (95% UI 125.34-142.77); HS 64.89 (95% UI 59.82-68.85)) exceeded those of women (IS 98.85 (95% UI 92.11-106.62); HS 45.48 (95% UI 42.43-48.53)). IS incidence rates were lower in 2013 compared with 1990 rates for both sexes (1990 male IS incidence 147.40 (95% UI 137.87-157.66); 1990 female IS incidence 113.31 (95% UI 103.52-123.40)), but the only significant change in IS incidence was among women. Changes in global HS incidence were not statistically significant for males (1990 = 65.31 (95% UI 61.63-69.0), 2013 = 64.89 (95% UI 59.82-68.85)), but was significant for females (1990 = 64.892 (95% UI 59.82-68.85), 2013 = 45.48 (95% UI 42.427-48.53)). The number of DALYs related to IS rose from 1990 (male = 16.62 (95% UI 13.27-19.62), female = 17.53 (95% UI 14.08-20.33)) to 2013 (male = 25.22 (95% UI 20.57-29.13), female = 22.21 (95% UI 17.71-25.50)). The number of DALYs associated with HS also rose steadily and was higher than DALYs for IS at each time point (male 1990 = 29.91 (95% UI 25.66-34.54), male 2013 = 37.27 (95% UI 32.29-45.12); female 1990 = 26.05 (95% UI 21.70-30.90), female 2013 = 28.18 (95% UI 23.68-33.80)). INTERPRETATION: Globally, men continue to have a higher incidence of IS than women while significant sex differences in the incidence of HS were not observed. The total health loss due to stroke as measured by DALYs was similar for men and women for both stroke subtypes in 2013, with HS higher than IS. Both IS and HS DALYs show an increasing trend for both men and women since 1990, which is statistically significant only for IS among men. Ongoing monitoring of sex differences in the burden of stroke will be needed to determine if disease rates among men and women continue to diverge. Sex disparities related to stroke will have important clinical and policy implications that can guide funding and resource allocation for national, regional and global health programs.

Estimates of global and regional premature cardiovascular mortality in 2025.

BACKGROUND: United Nations member states have agreed to reduce premature cardiovascular disease (CVD) mortality 25% by 2025. Global CVD risk factor targets have been recommended. We produced estimates to show how selected risk factor reduction would affect CVD mortality for different regions and countries. METHODS AND RESULTS: We used mortality, risk factor, and relative risk data from the Global Burden of Disease, Risk Factors, and Injuries (GBD) 2013 study to project CVD mortality for 188 countries up to the year 2025. We disaggregated observed CVD mortality in 1990 and 2013 into deaths attributable and unattributable to hypertension, tobacco smoking, diabetes mellitus, and obesity using an age- and sex-specific population-attributable fraction. Risk factors were projected to 2025 assuming that current trends continue. Counterfactual scenarios were then constructed reflecting CVD premature mortality if United Nations risk factor targets are achieved in the year 2025, adjusting for joint effects of risk factors. We estimate 7.8 million premature CVD deaths in 2025 if current risk factor trends continue. Premature CVD deaths would be reduced to 5.7 million if these risk factors targets are achieved as a result of a 26% reduction for men and a 23% reduction for women in the global risk of premature CVD death. Globally, decreasing the prevalence of hypertension accounted for the largest risk reduction, followed by a reduction in tobacco smoking for men and obesity for women, but these results varied by region. The impact of meeting all risk factor targets on CVD mortality varied widely by region and sex. CONCLUSIONS: The United Nations target of a 25% reduction in premature CVD mortality by the year 2025 appears achievable for some countries, but more aggressive risk factor targets may be required if all regions are to reach this goal. Without these reductions in CVD risk factors, many countries will see no change or even an increase in premature CVD mortality.

Demographic and epidemiologic drivers of global cardiovascular mortality.

BACKGROUND: Global deaths from cardiovascular disease are increasing as a result of population growth, the aging of populations, and epidemiologic changes in disease. Disentangling the effects of these three drivers on trends in mortality is important for planning the future of the health care system and benchmarking progress toward the reduction of cardiovascular disease. METHODS: We used mortality data from the Global Burden of Disease Study 2013, which includes data on 188 countries grouped into 21 world regions. We developed three counterfactual scenarios to represent the principal drivers of change in cardiovascular deaths (population growth alone, population growth and aging, and epidemiologic changes in disease) from 1990 to 2013. Secular trends and correlations with changes in national income were examined. RESULTS: Global deaths from cardiovascular disease increased by 41% between 1990 and 2013 despite a 39% decrease in age-specific death rates; this increase was driven by a 55% increase in mortality due to the aging of populations and a 25% increase due to population growth. The relative contributions of these drivers varied by region; only in Central Europe and Western Europe did the annual number of deaths from cardiovascular disease actually decline. Change in gross domestic product per capita was correlated with change in age-specific death rates only among upper-middle income countries, and this correlation was weak; there was no significant correlation elsewhere. CONCLUSIONS: The aging and growth of the population resulted in an increase in global cardiovascular deaths between 1990 and 2013, despite a decrease in age-specific death rates in most regions. Only Central and Western Europe had gains in cardiovascular health that were sufficient to offset these demographic forces. (Funded by the Bill and Melinda Gates Foundation and others.).