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Concept: Bill & Melinda Gates Foundation

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Background Although the rising pandemic of obesity has received major attention in many countries, the effects of this attention on trends and the disease burden of obesity remain uncertain. Methods We analyzed data from 68.5 million persons to assess the trends in the prevalence of overweight and obesity among children and adults between 1980 and 2015. Using the Global Burden of Disease study data and methods, we also quantified the burden of disease related to high body-mass index (BMI), according to age, sex, cause, and BMI in 195 countries between 1990 and 2015. Results In 2015, a total of 107.7 million children and 603.7 million adults were obese. Since 1980, the prevalence of obesity has doubled in more than 70 countries and has continuously increased in most other countries. Although the prevalence of obesity among children has been lower than that among adults, the rate of increase in childhood obesity in many countries has been greater than the rate of increase in adult obesity. High BMI accounted for 4.0 million deaths globally, nearly 40% of which occurred in persons who were not obese. More than two thirds of deaths related to high BMI were due to cardiovascular disease. The disease burden related to high BMI has increased since 1990; however, the rate of this increase has been attenuated owing to decreases in underlying rates of death from cardiovascular disease. Conclusions The rapid increase in the prevalence and disease burden of elevated BMI highlights the need for continued focus on surveillance of BMI and identification, implementation, and evaluation of evidence-based interventions to address this problem. (Funded by the Bill and Melinda Gates Foundation.).

Concepts: Cancer, Nutrition, Obesity, Overweight, Body mass index, Body shape, Bariatrics, Bill & Melinda Gates Foundation

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Background We hypothesized that mass distribution of a broad-spectrum antibiotic agent to preschool children would reduce mortality in areas of sub-Saharan Africa that are currently far from meeting the Sustainable Development Goals of the United Nations. Methods In this cluster-randomized trial, we assigned communities in Malawi, Niger, and Tanzania to four twice-yearly mass distributions of either oral azithromycin (approximately 20 mg per kilogram of body weight) or placebo. Children 1 to 59 months of age were identified in twice-yearly censuses and were offered participation in the trial. Vital status was determined at subsequent censuses. The primary outcome was aggregate all-cause mortality; country-specific rates were assessed in prespecified subgroup analyses. Results A total of 1533 communities underwent randomization, 190,238 children were identified in the census at baseline, and 323,302 person-years were monitored. The mean (±SD) azithromycin and placebo coverage over the four twice-yearly distributions was 90.4±10.4%. The overall annual mortality rate was 14.6 deaths per 1000 person-years in communities that received azithromycin (9.1 in Malawi, 22.5 in Niger, and 5.4 in Tanzania) and 16.5 deaths per 1000 person-years in communities that received placebo (9.6 in Malawi, 27.5 in Niger, and 5.5 in Tanzania). Mortality was 13.5% lower overall (95% confidence interval [CI], 6.7 to 19.8) in communities that received azithromycin than in communities that received placebo (P<0.001); the rate was 5.7% lower in Malawi (95% CI, -9.7 to 18.9), 18.1% lower in Niger (95% CI, 10.0 to 25.5), and 3.4% lower in Tanzania (95% CI, -21.2 to 23.0). Children in the age group of 1 to 5 months had the greatest effect from azithromycin (24.9% lower mortality than that with placebo; 95% CI, 10.6 to 37.0). Serious adverse events occurring within a week after administration of the trial drug or placebo were uncommon, and the rate did not differ significantly between the groups. Evaluation of selection for antibiotic resistance is ongoing. Conclusions Among postneonatal, preschool children in sub-Saharan Africa, childhood mortality was lower in communities randomly assigned to mass distribution of azithromycin than in those assigned to placebo, with the largest effect seen in Niger. Any implementation of a policy of mass distribution would need to strongly consider the potential effect of such a strategy on antibiotic resistance. (Funded by the Bill and Melinda Gates Foundation; MORDOR ClinicalTrials.gov number, NCT02047981 .).

Concepts: Africa, Sub-Saharan Africa, Sahara, Malawi, United Nations, Bill & Melinda Gates Foundation, Bill Gates, Melinda Gates

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BACKGROUND: Fast weight gain and linear growth in children in low-income and middle-income countries are associated with enhanced survival and improved cognitive development, but might increase risk of obesity and related adult cardiometabolic diseases. We investigated how linear growth and relative weight gain during infancy and childhood are related to health and human capital outcomes in young adults. METHODS: We used data from five prospective birth cohort studies from Brazil, Guatemala, India, the Philippines, and South Africa. We investigated body-mass index, systolic and diastolic blood pressure, plasma glucose concentration, height, years of attained schooling, and related categorical indicators of adverse outcomes in young adults. With linear and logistic regression models, we assessed how these outcomes relate to birthweight and to statistically independent measures representing linear growth and weight gain independent of linear growth (relative weight gain) in three age periods: 0-2 years, 2 years to mid-childhood, and mid-childhood to adulthood. FINDINGS: We obtained data for 8362 participants who had at least one adult outcome of interest. A higher birthweight was consistently associated with an adult body-mass index of greater than 25 kg/m(2) (odds ratio 1·28, 95% CI 1·21-1·35) and a reduced likelihood of short adult stature (0·49, 0·44-0·54) and of not completing secondary school (0·82, 0·78-0·87). Faster linear growth was strongly associated with a reduced risk of short adult stature (age 2 years: 0·23, 0·20-0·52; mid-childhood: 0·39, 0·36-0·43) and of not completing secondary school (age 2 years: 0·74, 0·67-0·78; mid-childhood: 0·87, 0·83-0·92), but did raise the likelihood of overweight (age 2 years: 1·24, 1·17-1·31; mid-childhood: 1·12, 1·06-1·18) and elevated blood pressure (age 2 years: 1·12, 1·06-1·19; mid-childhood: 1·07, 1·01-1·13). Faster relative weight gain was associated with an increased risk of adult overweight (age 2 years: 1·51, 1·43-1·60; mid-childhood: 1·76, 1·69-1·91) and elevated blood pressure (age 2 years: 1·07, 1·01-1·13; mid-childhood: 1·22, 1·15-1·30). Linear growth and relative weight gain were not associated with dysglycaemia, but a higher birthweight was associated with decreased risk of the disorder (0·89, 0·81-0·98). INTERPRETATION: Interventions in countries of low and middle income to increase birthweight and linear growth during the first 2 years of life are likely to result in substantial gains in height and schooling and give some protection from adult chronic disease risk factors, with few adverse trade-offs. FUNDING: Wellcome Trust and Bill & Melinda Gates Foundation.

Concepts: Cohort study, Epidemiology, Hypertension, Obesity, Blood pressure, Relative risk, High school, Bill & Melinda Gates Foundation

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Background The prevalence of facility-based childbirth in low-resource settings has increased dramatically during the past two decades, yet gaps in the quality of care persist and mortality remains high. The World Health Organization (WHO) Safe Childbirth Checklist, a quality-improvement tool, promotes systematic adherence to practices that have been associated with improved childbirth outcomes. Methods We conducted a matched-pair, cluster-randomized, controlled trial in 60 pairs of facilities across 24 districts of Uttar Pradesh, India, testing the effect of the BetterBirth program, an 8-month coaching-based implementation of the Safe Childbirth Checklist, on a composite outcome of perinatal death, maternal death, or maternal severe complications within 7 days after delivery. Outcomes - assessed 8 to 42 days after delivery - were compared between the intervention group and the control group with adjustment for clustering and matching. We also compared birth attendants' adherence to 18 essential birth practices in 15 matched pairs of facilities at 2 and 12 months after the initiation of the intervention. Results Of 161,107 eligible women, we enrolled 157,689 (97.9%) and determined 7-day outcomes for 157,145 (99.7%) mother-newborn dyads. Among 4888 observed births, birth attendants' mean practice adherence was significantly higher in the intervention group than in the control group (72.8% vs. 41.7% at 2 months; 61.7% vs. 43.9% at 12 months; P<0.001 for both comparisons). However, there was no significant difference between the trial groups either in the composite primary outcome (15.1% in the intervention group and 15.3% in the control group; relative risk, 0.99; 95% confidence interval, 0.83 to 1.18; P=0.90) or in secondary maternal or perinatal adverse outcomes. Conclusions Birth attendants' adherence to essential birth practices was higher in facilities that used the coaching-based WHO Safe Childbirth Checklist program than in those that did not, but maternal and perinatal mortality and maternal morbidity did not differ significantly between the two groups. (Funded by the Bill and Melinda Gates Foundation; Clinical Trials number, NCT02148952 .).

Concepts: Childbirth, Death, Medical statistics, Obstetrics, Maternal death, Perinatal mortality, Bill & Melinda Gates Foundation, Bill Gates

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Background Implementation of an ivermectin-based community treatment strategy for the elimination of onchocerciasis or lymphatic filariasis has been delayed in Central Africa because of the occurrence of serious adverse events, including death, in persons with high levels of circulating Loa loa microfilariae. The LoaScope, a field-friendly diagnostic tool to quantify L. loa microfilariae in peripheral blood, enables rapid, point-of-care identification of persons at risk for serious adverse events. Methods A test-and-not-treat strategy was used in the approach to ivermectin treatment in the Okola health district in Cameroon, where the distribution of ivermectin was halted in 1999 after the occurrence of fatal events related to L. loa infection. The LoaScope was used to identify persons with an L. loa microfilarial density greater than 20,000 microfilariae per milliliter of blood, who were considered to be at risk for serious adverse events, and exclude them from ivermectin distribution. Active surveillance for posttreatment adverse events was performed daily for 6 days. Results From August through October 2015, a total of 16,259 of 22,842 persons 5 years of age or older (71.2% of the target population) were tested for L. loa microfilaremia. Among the participants who underwent testing, a total of 15,522 (95.5%) received ivermectin, 340 (2.1%) were excluded from ivermectin distribution because of an L. loa microfilarial density above the risk threshold, and 397 (2.4%) were excluded because of pregnancy or illness. No serious adverse events were observed. Nonserious adverse events were recorded in 934 participants, most of whom (67.5%) had no detectable L. loa microfilariae. Conclusions The LoaScope-based test-and-not-treat strategy enabled the reimplementation of community-wide ivermectin distribution in a heretofore “off limits” health district in Cameroon and is a potentially practical approach to larger-scale ivermectin treatment for lymphatic filariasis and onchocerciasis in areas where L. loa infection is endemic. (Funded by the Bill and Melinda Gates Foundation and others.).

Concepts: Parasitic diseases, Filariasis, Neglected diseases, Ivermectin, Loa loa filariasis, Bill & Melinda Gates Foundation, Bill Gates, Melinda Gates

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BACKGROUND: As Chagas disease continues to expand beyond tropical and subtropical zones, a growing need exists to better understand its resulting economic burden to help guide stakeholders such as policy makers, funders, and product developers. We developed a Markov simulation model to estimate the global and regional health and economic burden of Chagas disease from the societal perspective. METHODS: Our Markov model structure had a 1 year cycle length and consisted of five states: acute disease, indeterminate disease, cardiomyopathy with or without congestive heart failure, megaviscera, and death. Major model parameter inputs, including the annual probabilities of transitioning from one state to another, and present case estimates for Chagas disease came from various sources, including WHO and other epidemiological and disease-surveillance-based reports. We calculated annual and lifetime health-care costs and disability-adjusted life-years (DALYs) for individuals, countries, and regions. We used a discount rate of 3% to adjust all costs and DALYs to present-day values. FINDINGS: On average, an infected individual incurs US$474 in health-care costs and 0·51 DALYs annually. Over his or her lifetime, an infected individual accrues an average net present value of $3456 and 3·57 DALYs. Globally, the annual burden is $627·46 million in health-care costs and 806 170 DALYs. The global net present value of currently infected individuals is $24·73 billion in health-care costs and 29 385 250 DALYs. Conversion of this burden into costs results in annual per-person costs of $4660 and lifetime per-person costs of $27 684. Global costs are $7·19 billion per year and $188·80 billion per lifetime. More than 10% of these costs emanate from the USA and Canada, where Chagas disease has not been traditionally endemic. A substantial proportion of the burden emerges from lost productivity from cardiovascular disease-induced early mortality. INTERPRETATION: The economic burden of Chagas disease is similar to or exceeds those of other prominent diseases globally (eg, rotavirus $2·0 billion, cervical cancer $4·7 billion) even in the USA (Lyme disease $2·5 billion), where Chagas disease has not been traditionally endemic, suggesting an economic argument for more attention and efforts towards control of Chagas disease. FUNDING: Bill & Melinda Gates Foundation, the National Institute of General Medical Sciences Models of Infectious Disease Agent Study.

Concepts: Medicine, Epidemiology, Infectious disease, Cardiomyopathy, Heart failure, Infection, Chagas disease, Bill & Melinda Gates Foundation

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BACKGROUND: Data for trends in contraceptive use and need are necessary to guide programme and policy decisions and to monitor progress towards Millennium Development Goal 5, which calls for universal access to contraceptive services. We therefore aimed to estimate trends in contraceptive use and unmet need in developing countries in 2003, 2008, and 2012 . METHODS: We obtained data from national surveys for married and unmarried women aged 15-49 years in regions and subregions of developing countries. We estimated trends in the numbers and proportions of women wanting to avoid pregnancy, according to whether they were using modern contraceptives, or had unmet need for modern methods (ie, using no methods or a traditional method). We used comparable data sources and methods for three reference years (2003, 2008, and 2012). National survey data were available for 81-98% of married women using and with unmet need for modern methods. FINDINGS: The number of women wanting to avoid pregnancy and therefore needing effective contraception increased substantially, from 716 million (54%) of 1321 million in 2003, to 827 million (57%) of 1448 million in 2008, to 867 million (57%) of 1520 million in 2012. Most of this increase (108 million) was attributable to population growth. Use of modern contraceptive methods also increased, and the overall proportion of women with unmet need for modern methods among those wanting to avoid pregnancy decreased from 29% (210 million) in 2003, to 26% (222 million) in 2012. However, unmet need for modern contraceptives was still very high in 2012, especially in sub-Saharan Africa (53 million [60%] of 89 million), south Asia (83 million [34%] of 246 million), and western Asia (14 million [50%] of 27 million). Moreover, a shift in the past decade away from sterilisation, the most effective method, towards injectable drugs and barrier methods, might have led to increases in unintended pregnancies in women using modern methods. INTERPRETATION: Achievement of the desired number and healthy timing of births has important benefits for women, families, and societies. To meet the unmet need for modern contraception, countries need to increase resources, improve access to contraceptive services and supplies, and provide high-quality services and large-scale public education interventions to reduce social barriers. Our findings confirm a substantial and unfinished agenda towards meeting of couples' reproductive needs. FUNDING: UK Department for International Development, the Bill & Melinda Gates Foundation, and the UN Population Fund (UNFPA).

Concepts: Pregnancy, Birth control, Emergency contraception, Marriage, Abortion, Condom, Need, Bill & Melinda Gates Foundation

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BACKGROUND: The efficacy of RTS,S/AS01 as a vaccine for malaria is being tested in a phase 3 clinical trial. Early results show significant, albeit partial, protection against clinical malaria and severe malaria. To ascertain variations in vaccine efficacy according to covariates such as transmission intensity, choice of adjuvant, age at vaccination, and bednet use, we did an individual-participant pooled analysis of phase 2 clinical data. METHODS: We analysed data from 11 different sites in Africa, including 4453 participants. We measured heterogeneity in vaccine efficacy by estimating the interactions between covariates and vaccination in pooled multivariable Cox regression and Poisson regression analyses. Endpoints for measurement of vaccine efficacy were infection, clinical malaria, severe malaria, and death. We defined transmission intensity levels according to the estimated local parasite prevalence in children aged 2-10 years (PrP2-10), ranging from 5% to 80%. Choice of adjuvant was either AS01 or AS02. FINDINGS: Vaccine efficacy against all episodes of clinical malaria varied by transmission intensity (p=0·001). At low transmission (PrP2-10 10%) vaccine efficacy was 60% (95% CI 54 to 67), at moderate transmission (PrP2-10 20%) it was 41% (21 to 57), and at high transmission (PrP2-10 70%) the efficacy was 4% (-10 to 22). Vaccine efficacy also varied by adjuvant choice (p<0·0001)-eg, at low transmission (PrP2-10 10%), efficacy varied from 60% (95% CI 54 to 67) for AS01 to 47% (14 to 75) for AS02. Variations in efficacy by age at vaccination were of borderline significance (p=0·038), and bednet use and sex were not significant covariates. Vaccine efficacy (pooled across adjuvant choice and transmission intensity) varied significantly (p<0·0001) according to time since vaccination, from 36% efficacy (95% CI 24 to 45) at time of vaccination to 0% (-38 to 38) after 3 years. INTERPRETATION: Vaccine efficacy against clinical disease was of limited duration and was not detectable 3 years after vaccination. Furthermore, efficacy fell with increasing transmission intensity. Outcomes after vaccination cannot be gauged accurately on the basis of one pooled efficacy figure. However, predictions of public-health outcomes of vaccination will need to take account of variations in efficacy by transmission intensity and by time since vaccination. FUNDING: Medical Research Council (UK); Bill & Melinda Gates Foundation Vaccine Modelling Initiative; Wellcome Trust.

Concepts: Immune system, Regression analysis, Clinical trial, Malaria, Vaccine, Vaccination, Clinical data acquisition, Bill & Melinda Gates Foundation

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Information generated from economic evaluation is increasingly being used to inform health resource allocation decisions globally, including in low- and middle- income countries. However, a crucial consideration for users of the information at a policy level, e.g. funding agencies, is whether the studies are comparable, provide sufficient detail to inform policy decision making, and incorporate inputs from data sources that are reliable and relevant to the context. This review was conducted to inform a methodological standardisation workstream at the Bill and Melinda Gates Foundation (BMGF) and assesses BMGF-funded cost-per-DALY economic evaluations in four programme areas (malaria, tuberculosis, HIV/AIDS and vaccines) in terms of variation in methodology, use of evidence, and quality of reporting. The findings suggest that there is room for improvement in the three areas of assessment, and support the case for the introduction of a standardised methodology or reference case by the BMGF. The findings are also instructive for all institutions that fund economic evaluations in LMICs and who have a desire to improve the ability of economic evaluations to inform resource allocation decisions.

Concepts: Decision making, Evaluation, Tuberculosis, World Health Organization, Resource allocation, Bill & Melinda Gates Foundation, Bill Gates, Melinda Gates

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Background Taeniasis and cysticercosis are major causes of seizures and epilepsy. Infection by the causative parasite Taenia solium requires transmission between humans and pigs. The disease is considered to be eradicable, but data on attempts at regional elimination are lacking. We conducted a three-phase control program in Tumbes, Peru, to determine whether regional elimination would be feasible. Methods We systematically tested and compared elimination strategies to show the feasibility of interrupting the transmission of T. solium infection in a region of highly endemic disease in Peru. In phase 1, we assessed the effectiveness and feasibility of six intervention strategies that involved screening of humans and pigs, antiparasitic treatment, prevention education, and pig replacement in 42 villages. In phase 2, we compared mass treatment with mass screening (each either with or without vaccination of pigs) in 17 villages. In phase 3, we implemented the final strategy of mass treatment of humans along with the mass treatment and vaccination of pigs in the entire rural region of Tumbes (107 villages comprising 81,170 people and 55,638 pigs). The effect of the intervention was measured after phases 2 and 3 with the use of detailed necropsy to detect pigs with live, nondegenerated cysts capable of causing new infection. The necropsy sampling was weighted in that we preferentially included more samples from seropositive pigs than from seronegative pigs. Results Only two of the strategies implemented in phase 1 resulted in limited control over the transmission of T. solium infection, which highlighted the need to intensify the subsequent strategies. After the strategies in phase 2 were implemented, no cyst that was capable of further transmission of T. solium infection was found among 658 sampled pigs. One year later, without further intervention, 7 of 310 sampled pigs had live, nondegenerated cysts, but no infected pig was found in 11 of 17 villages, including all the villages in which mass antiparasitic treatment plus vaccination was implemented. After the final strategy was implemented in phase 3, a total of 3 of 342 pigs had live, nondegenerated cysts, but no infected pig was found in 105 of 107 villages. Conclusions We showed that the transmission of T. solium infection was interrupted on a regional scale in a highly endemic region in Peru. (Funded by the Bill and Melinda Gates Foundation and others.).

Concepts: Epidemiology, Infectious disease, Taenia solium, Cysticercosis, Taenia, Bill & Melinda Gates Foundation, Bill Gates, Melinda Gates