Ministry of Health

BACKGROUND: The burden of cardiovascular diseases (CVDs) remains unclear in many regions of the world. OBJECTIVES: The GBD (Global Burden of Disease) 2015 study integrated data on disease incidence, prevalence, and mortality to produce consistent, up-to-date estimates for cardiovascular burden. METHODS: CVD mortality was estimated from vital registration and verbal autopsy data. CVD prevalence was estimated using modeling software and data from health surveys, prospective cohorts, health system administrative data, and registries. Years lived with disability (YLD) were estimated by multiplying prevalence by disability weights. Years of life lost (YLL) were estimated by multiplying age-specific CVD deaths by a reference life expectancy. A sociodemographic index (SDI) was created for each location based on income per capita, educational attainment, and fertility. RESULTS: In 2015, there were an estimated 422.7 million cases of CVD (95% uncertainty interval: 415.53 to 427.87 million cases) and 17.92 million CVD deaths (95% uncertainty interval: 17.59 to 18.28 million CVD deaths). Declines in the age-standardized CVD death rate occurred between 1990 and 2015 in all high-income and some middle-income countries. Ischemic heart disease was the leading cause of CVD health lost globally, as well as in each world region, followed by stroke. As SDI increased beyond 0.25, the highest CVD mortality shifted from women to men. CVD mortality decreased sharply for both sexes in countries with an SDI >0.75. CONCLUSIONS: CVDs remain a major cause of health loss for all regions of the world. Sociodemographic change over the past 25 years has been associated with dramatic declines in CVD in regions with very high SDI, but only a gradual decrease or no change in most regions. Future updates of the GBD study can be used to guide policymakers who are focused on reducing the overall burden of noncommunicable disease and achieving specific global health targets for CVD.

BACKGROUND: We have previously estimated that respiratory syncytial virus (RSV) was associated with 22% of all episodes of (severe) acute lower respiratory infection (ALRI) resulting in 55 000 to 199 000 deaths in children younger than 5 years in 2005. In the past 5 years, major research activity on RSV has yielded substantial new data from developing countries. With a considerably expanded dataset from a large international collaboration, we aimed to estimate the global incidence, hospital admission rate, and mortality from RSV-ALRI episodes in young children in 2015. METHODS: We estimated the incidence and hospital admission rate of RSV-associated ALRI (RSV-ALRI) in children younger than 5 years stratified by age and World Bank income regions from a systematic review of studies published between Jan 1, 1995, and Dec 31, 2016, and unpublished data from 76 high quality population-based studies. We estimated the RSV-ALRI incidence for 132 developing countries using a risk factor-based model and 2015 population estimates. We estimated the in-hospital RSV-ALRI mortality by combining in-hospital case fatality ratios with hospital admission estimates from hospital-based (published and unpublished) studies. We also estimated overall RSV-ALRI mortality by identifying studies reporting monthly data for ALRI mortality in the community and RSV activity. FINDINGS: We estimated that globally in 2015, 33·1 million (uncertainty range [UR] 21·6-50·3) episodes of RSV-ALRI, resulted in about 3·2 million (2·7-3·8) hospital admissions, and 59 600 (48 000-74 500) in-hospital deaths in children younger than 5 years. In children younger than 6 months, 1·4 million (UR 1·2-1·7) hospital admissions, and 27 300 (UR 20 700-36 200) in-hospital deaths were due to RSV-ALRI. We also estimated that the overall RSV-ALRI mortality could be as high as 118 200 (UR 94 600-149 400). Incidence and mortality varied substantially from year to year in any given population. INTERPRETATION: Globally, RSV is a common cause of childhood ALRI and a major cause of hospital admissions in young children, resulting in a substantial burden on health-care services. About 45% of hospital admissions and in-hospital deaths due to RSV-ALRI occur in children younger than 6 months. An effective maternal RSV vaccine or monoclonal antibody could have a substantial effect on disease burden in this age group. FUNDING: The Bill & Melinda Gates Foundation.

BACKGROUND: Remarkable financial and political efforts have been focused on the reduction of child mortality during the past few decades. Timely measurements of levels and trends in under-5 mortality are important to assess progress towards the Millennium Development Goal 4 (MDG 4) target of reduction of child mortality by two thirds from 1990 to 2015, and to identify models of success. METHODS: We generated updated estimates of child mortality in early neonatal (age 0-6 days), late neonatal (7-28 days), postneonatal (29-364 days), childhood (1-4 years), and under-5 (0-4 years) age groups for 188 countries from 1970 to 2013, with more than 29,000 survey, census, vital registration, and sample registration datapoints. We used Gaussian process regression with adjustments for bias and non-sampling error to synthesise the data for under-5 mortality for each country, and a separate model to estimate mortality for more detailed age groups. We used explanatory mixed effects regression models to assess the association between under-5 mortality and income per person, maternal education, HIV child death rates, secular shifts, and other factors. To quantify the contribution of these different factors and birth numbers to the change in numbers of deaths in under-5 age groups from 1990 to 2013, we used Shapley decomposition. We used estimated rates of change between 2000 and 2013 to construct under-5 mortality rate scenarios out to 2030. FINDINGS: We estimated that 6·3 million (95% UI 6·0-6·6) children under-5 died in 2013, a 64% reduction from 17·6 million (17·1-18·1) in 1970. In 2013, child mortality rates ranged from 152·5 per 1000 livebirths (130·6-177·4) in Guinea-Bissau to 2·3 (1·8-2·9) per 1000 in Singapore. The annualised rates of change from 1990 to 2013 ranged from -6·8% to 0·1%. 99 of 188 countries, including 43 of 48 countries in sub-Saharan Africa, had faster decreases in child mortality during 2000-13 than during 1990-2000. In 2013, neonatal deaths accounted for 41·6% of under-5 deaths compared with 37·4% in 1990. Compared with 1990, in 2013, rising numbers of births, especially in sub-Saharan Africa, led to 1·4 million more child deaths, and rising income per person and maternal education led to 0·9 million and 2·2 million fewer deaths, respectively. Changes in secular trends led to 4·2 million fewer deaths. Unexplained factors accounted for only -1% of the change in child deaths. In 30 developing countries, decreases since 2000 have been faster than predicted attributable to income, education, and secular shift alone. INTERPRETATION: Only 27 developing countries are expected to achieve MDG 4. Decreases since 2000 in under-5 mortality rates are accelerating in many developing countries, especially in sub-Saharan Africa. The Millennium Declaration and increased development assistance for health might have been a factor in faster decreases in some developing countries. Without further accelerated progress, many countries in west and central Africa will still have high levels of under-5 mortality in 2030. FUNDING: Bill & Melinda Gates Foundation, US Agency for International Development.

Abstract Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities 1,2 . This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity 3–6 . Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017—and more than 80% in some low- and middle-income regions—was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing—and in some countries reversal—of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.

Child stunting reduction is the first of 6 goals in the Global Nutrition Targets for 2025 and a key indicator in the second Sustainable Development Goal of Zero Hunger. The prevalence of child stunting in Indonesia has remained high over the past decade, and at the national level is approximately 37%. It is unclear whether current approaches to reduce child stunting align with the scientific evidence in Indonesia. We use the World Health Organization conceptual framework on child stunting to review the available literature and identify what has been studied and can be concluded about the determinants of child stunting in Indonesia and where data gaps remain. Consistent evidence suggests nonexclusive breastfeeding for the first 6 months, low household socio-economic status, premature birth, short birth length, and low maternal height and education are particularly important child stunting determinants in Indonesia. Children from households with both unimproved latrines and untreated drinking water are also at increased risk. Community and societal factors-particularly, poor access to health care and living in rural areas-have been repeatedly associated with child stunting. Published studies are lacking on how education; society and culture; agriculture and food systems; and water, sanitation, and the environment contribute to child stunting. This comprehensive synthesis of the available evidence on child stunting determinants in Indonesia outlines who are the most vulnerable to stunting, which interventions have been most successful, and what new research is needed to fill knowledge gaps.

BACKGROUND: Multidrug-resistant Plasmodium vivax (Pv) is widespread in eastern Indonesia, and emerging elsewhere in Asia-Pacific and South America, but is generally regarded as a benign disease. The aim of the study was to review the spectrum of disease associated with malaria due to Pv and P. falciparum (Pf) in patients presenting to a hospital in Timika, southern Papua, Indonesia. METHODS AND FINDINGS: Data were prospectively collected from all patients attending the outpatient and inpatient departments of the only hospital in the region using systematic data forms and hospital computerised records. Between January 2004 and December 2007, clinical malaria was present in 16% (60,226/373,450) of hospital outpatients and 32% (12,171/37,800) of inpatients. Among patients admitted with slide-confirmed malaria, 64% of patients had Pf, 24% Pv, and 10.5% mixed infections. The proportion of malarial admissions attributable to Pv rose to 47% (415/887) in children under 1 y of age. Severe disease was present in 2,634 (22%) inpatients with malaria, with the risk greater among Pv (23% [675/2,937]) infections compared to Pf (20% [1,570/7,817]; odds ratio [OR] = 1.19 [95% confidence interval (CI) 1.08-1.32], p = 0.001), and greatest in patients with mixed infections (31% [389/1,273]); overall p < 0.0001. Severe anaemia (haemoglobin < 5 g/dl) was the major complication associated with Pv, accounting for 87% (589/675) of severe disease compared to 73% (1,144/1,570) of severe manifestations with Pf (p < 0.001). Pure Pv infection was also present in 78 patients with respiratory distress and 42 patients with coma. In total 242 (2.0%) patients with malaria died during admission: 2.2% (167/7,722) with Pf, 1.6% (46/2,916) with Pv, and 2.3% (29/1260) with mixed infections (p = 0.126). CONCLUSIONS: In this region with established high-grade chloroquine resistance to both Pv and Pf, Pv is associated with severe and fatal malaria particularly in young children. The epidemiology of P. vivax needs to be re-examined elsewhere where chloroquine resistance is increasing.

BACKGROUND: The burden of shigellosis is greatest in resource-poor countries. Although this diarrheal disease has been thought to cause considerable morbidity and mortality in excess of 1,000,000 deaths globally per year, little recent data are available to guide intervention strategies in Asia. We conducted a prospective, population-based study in six Asian countries to gain a better understanding of the current disease burden, clinical manifestations, and microbiology of shigellosis in Asia. METHODS AND FINDINGS: Over 600,000 persons of all ages residing in Bangladesh, China, Pakistan, Indonesia, Vietnam, and Thailand were included in the surveillance. Shigella was isolated from 2,927 (5%) of 56,958 diarrhoea episodes detected between 2000 and 2004. The overall incidence of treated shigellosis was 2.1 episodes per 1,000 residents per year in all ages and 13.2/1,000/y in children under 60 months old. Shigellosis incidence increased after age 40 years. S. flexneri was the most frequently isolated Shigella species (1,976/2,927 [68%]) in all sites except in Thailand, where S. sonnei was most frequently detected (124/146 [85%]). S. flexneri serotypes were highly heterogeneous in their distribution from site to site, and even from year to year. PCR detected ipaH, the gene encoding invasion plasmid antigen H in 33% of a sample of culture-negative stool specimens. The majority of S. flexneri isolates in each site were resistant to amoxicillin and cotrimoxazole. Ciprofloxacin-resistant S. flexneri isolates were identified in China (18/305 [6%]), Pakistan (8/242 [3%]), and Vietnam (5/282 [2%]). CONCLUSIONS: Shigella appears to be more ubiquitous in Asian impoverished populations than previously thought, and antibiotic-resistant strains of different species and serotypes have emerged. Focusing on prevention of shigellosis could exert an immediate benefit first by substantially reducing the overall diarrhoea burden in the region and second by preventing the spread of panresistant Shigella strains. The heterogeneous distribution of Shigella species and serotypes suggest that multivalent or cross-protective Shigella vaccines will be needed to prevent shigellosis in Asia.

BACKGROUND: The global burden of pediatric severe respiratory illness is substantial, and influenza viruses contribute to this burden. Systematic surveillance and testing for influenza among hospitalized children has expanded globally over the past decade. However, only a fraction of the data has been used to estimate influenza burden. In this analysis, we use surveillance data to provide an estimate of influenza-associated hospitalizations among children worldwide. METHODS AND FINDINGS: We aggregated data from a systematic review (n = 108) and surveillance platforms (n = 37) to calculate a pooled estimate of the proportion of samples collected from children hospitalized with respiratory illnesses and positive for influenza by age group (<6 mo, <1 y, <2 y, <5 y, 5-17 y, and <18 y). We applied this proportion to global estimates of acute lower respiratory infection hospitalizations among children aged <1 y and <5 y, to obtain the number and per capita rate of influenza-associated hospitalizations by geographic region and socio-economic status. Influenza was associated with 10% (95% CI 8%-11%) of respiratory hospitalizations in children <18 y worldwide, ranging from 5% (95% CI 3%-7%) among children <6 mo to 16% (95% CI 14%-20%) among children 5-17 y. On average, we estimated that influenza results in approximately 374,000 (95% CI 264,000 to 539,000) hospitalizations in children <1 y-of which 228,000 (95% CI 150,000 to 344,000) occur in children <6 mo-and 870,000 (95% CI 610,000 to 1,237,000) hospitalizations in children <5 y annually. Influenza-associated hospitalization rates were more than three times higher in developing countries than in industrialized countries (150/100,000 children/year versus 48/100,000). However, differences in hospitalization practices between settings are an important limitation in interpreting these findings. CONCLUSIONS: Influenza is an important contributor to respiratory hospitalizations among young children worldwide. Increasing influenza vaccination coverage among young children and pregnant women could reduce this burden and protect infants <6 mo.

BACKGROUND: Since 2003, the widespread ongoing epizootic of avian influenza A (H5N1) among poultry and birds has resulted in human H5N1 cases in 10 countries. The first case of H5N1 virus infection in Indonesia was identified in July 2005. METHODS: We investigated three clusters of Indonesian cases with at least two ill persons hospitalized with laboratory evidence of H5N1 virus infection from June through October 2005. Epidemiologic, clinical, and virologic data on these patients were collected and analyzed. RESULTS: Severe disease occurred among all three clusters, including deaths in two clusters. Mild illness in children was documented in two clusters. The median age of the eight patients was 8.5 years (range, 1 to 38). Four patients required mechanical ventilation, and four of the eight patients (50%) died. In each cluster, patients with H5N1 virus infection were members of the same family, and most lived in the same home. In two clusters, the source of H5N1 virus infection in the index patient was not determined. Virus isolates were available for one patient in each of two clusters, and molecular sequence analyses determined that the isolates were clade 2 H5N1 viruses of avian origin. CONCLUSIONS: In 2005 in Indonesia, clusters of human infection with clade 2 H5N1 viruses included mild, severe, and fatal cases among family members.

To the Editor: Dengue is the most prevalent arthropod-borne viral disease in tropical and subtropical countries. Every year, dengue virus (DENV) infections cause more than 50 million cases, 500,000 hospitalizations, and 12,500 deaths worldwide (1). DENV belongs to the genus Flavivirus and is transmitted by Aedes spp. mosquitoes. There are 4 distinct serotypes (DENV-1 to DENV-4), and infection with 1 serotype does not provide long-term, cross-protective immunity against the other 3 serotypes.

Avian influenza A H5N1 viruses continue to spread globally among birds, resulting in occasional transmission of virus from infected poultry to humans. Probable human-to-human transmission has been documented rarely, but H5N1 viruses have not yet acquired the ability to transmit efficiently among humans, an essential property of a pandemic virus. The pandemics of 1957 and 1968 were caused by avian-human reassortant influenza viruses that had acquired human virus-like receptor binding properties. However, the relative contribution of human internal protein genes or other molecular changes to the efficient transmission of influenza viruses among humans remains poorly understood. Here, we report on a comparative ferret model that parallels the efficient transmission of H3N2 human viruses and the poor transmission of H5N1 avian viruses in humans. In this model, an H3N2 reassortant virus with avian virus internal protein genes exhibited efficient replication but inefficient transmission, whereas H5N1 reassortant viruses with four or six human virus internal protein genes exhibited reduced replication and no transmission. These findings indicate that the human virus H3N2 surface protein genes alone did not confer efficient transmissibility and that acquisition of human virus internal protein genes alone was insufficient for this 1997 H5N1 virus to develop pandemic capabilities, even after serial passages in a mammalian host. These results highlight the complexity of the genetic basis of influenza virus transmissibility and suggest that H5N1 viruses may require further adaptation to acquire this essential pandemic trait.

Indonesia is ranked fifth among countries with the highest burden of stunting in children under five. This study aims to examine the determinants of stunting in children aged 0-2 years in Indonesia using data derived from the 2013 Indonesia Basic Health Survey. Twenty potential predictors of stunting, categorized into household and housing characteristics; maternal and paternal characteristics; antenatal care services and child characteristics were analyzed. Multilevel analyses were performed to examine the role of cluster/district/provincial differences, as well as individual/household level characteristics and stunting status. Of 24,657 children analyzed, 33.7% (95%CI: 32.8%-34.7%) were stunted. The odds of stunting increased significantly among children living in households with three or more children under five-years-old (aOR = 1.33, 95%CI: 1.03-1.72), households with five to seven household members (aOR =1.11; 95%CI: 1.03-1.20), children whose mothers during pregnancy attended less than four antenatal care services (aOR = 1.22, 95%CI: 1.08-1.39), boys (aOR = 1.33, 95%CI: 1.22-1.45), children aged 12-23 months (aOR = 1.89; 95%CI: 1.54-2.32), and children who weighed <2500 g at birth (aOR = 2.55; 95%CI: 2.05-3.15). The odds also increased significantly with the reduction of household wealth index. Integrated interventions to address environment, an individual level associated with stunting in Indonesia, from the environment- to individual-level factors are important.

The 2014 west African Ebola epidemic shone a harsh light on the health systems of Guinea, Liberia, and Sierra Leone. While decades of domestic and international investment had contributed to substantial progress on the Millennium Development Goals, national health systems remained weak and were unable to cope with the epidemic. Routine care of the population also deteriorated during the outbreak. Surveillance systems did not function effectively, allowing Ebola to spread within and between the countries. Global institutions were slow to respond to the crisis, squandering an opportunity to stem its course.

BACKGROUND: For more than three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has provided a framework to quantify health loss due to diseases, injuries, and associated risk factors. This paper presents GBD 2023 findings on disease and injury burden and risk-attributable health loss, offering a global audit of the state of world health to inform public health priorities. This work captures the evolving landscape of health metrics across age groups, sexes, and locations, while reflecting on the remaining post-COVID-19 challenges to achieving our collective global health ambitions. METHODS: The GBD 2023 combined analysis estimated years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 375 diseases and injuries, and risk-attributable burden associated with 88 modifiable risk factors. Of the more than 310 000 total data sources used for all GBD 2023 (about 30% of which were new to this estimation round), more than 120 000 sources were used for estimation of disease and injury burden and 59 000 for risk factor estimation, and included vital registration systems, surveys, disease registries, and published scientific literature. Data were analysed using previously established modelling approaches, such as disease modelling meta-regression version 2.1 (DisMod-MR 2.1) and comparative risk assessment methods. Diseases and injuries were categorised into four levels on the basis of the established GBD cause hierarchy, as were risk factors using the GBD risk hierarchy. Estimates stratified by age, sex, location, and year from 1990 to 2023 were focused on disease-specific time trends over the 2010-23 period and presented as counts (to three significant figures) and age-standardised rates per 100 000 person-years (to one decimal place). For each measure, 95% uncertainty intervals [UIs] were calculated with the 2·5th and 97·5th percentile ordered values from a 250-draw distribution. FINDINGS: Total numbers of global DALYs grew 6·1% (95% UI 4·0-8·1), from 2·64 billion (2·46-2·86) in 2010 to 2·80 billion (2·57-3·08) in 2023, but age-standardised DALY rates, which account for population growth and ageing, decreased by 12·6% (11·0-14·1), revealing large long-term health improvements. Non-communicable diseases (NCDs) contributed 1·45 billion (1·31-1·61) global DALYs in 2010, increasing to 1·80 billion (1·63-2·03) in 2023, alongside a concurrent 4·1% (1·9-6·3) reduction in age-standardised rates. Based on DALY counts, the leading level 3 NCDs in 2023 were ischaemic heart disease (193 million [176-209] DALYs), stroke (157 million [141-172]), and diabetes (90·2 million [75·2-107]), with the largest increases in age-standardised rates since 2010 occurring for anxiety disorders (62·8% [34·0-107·5]), depressive disorders (26·3% [11·6-42·9]), and diabetes (14·9% [7·5-25·6]). Remarkable health gains were made for communicable, maternal, neonatal, and nutritional (CMNN) diseases, with DALYs falling from 874 million (837-917) in 2010 to 681 million (642-736) in 2023, and a 25·8% (22·6-28·7) reduction in age-standardised DALY rates. During the COVID-19 pandemic, DALYs due to CMNN diseases rose but returned to pre-pandemic levels by 2023. From 2010 to 2023, decreases in age-standardised rates for CMNN diseases were led by rate decreases of 49·1% (32·7-61·0) for diarrhoeal diseases, 42·9% (38·0-48·0) for HIV/AIDS, and 42·2% (23·6-56·6) for tuberculosis. Neonatal disorders and lower respiratory infections remained the leading level 3 CMNN causes globally in 2023, although both showed notable rate decreases from 2010, declining by 16·5% (10·6-22·0) and 24·8% (7·4-36·7), respectively. Injury-related age-standardised DALY rates decreased by 15·6% (10·7-19·8) over the same period. Differences in burden due to NCDs, CMNN diseases, and injuries persisted across age, sex, time, and location. Based on our risk analysis, nearly 50% (1·27 billion [1·18-1·38]) of the roughly 2·80 billion total global DALYs in 2023 were attributable to the 88 risk factors analysed in GBD. Globally, the five level 3 risk factors contributing the highest proportion of risk-attributable DALYs were high systolic blood pressure (SBP), particulate matter pollution, high fasting plasma glucose (FPG), smoking, and low birthweight and short gestation-with high SBP accounting for 8·4% (6·9-10·0) of total DALYs. Of the three overarching level 1 GBD risk factor categories-behavioural, metabolic, and environmental and occupational-risk-attributable DALYs rose between 2010 and 2023 only for metabolic risks, increasing by 30·7% (24·8-37·3); however, age-standardised DALY rates attributable to metabolic risks decreased by 6·7% (2·0-11·0) over the same period. For all but three of the 25 leading level 3 risk factors, age-standardised rates dropped between 2010 and 2023-eg, declining by 54·4% (38·7-65·3) for unsafe sanitation, 50·5% (33·3-63·1) for unsafe water source, and 45·2% (25·6-72·0) for no access to handwashing facility, and by 44·9% (37·3-53·5) for child growth failure. The three leading level 3 risk factors for which age-standardised attributable DALY rates rose were high BMI (10·5% [0·1 to 20·9]), drug use (8·4% [2·6 to 15·3]), and high FPG (6·2% [-2·7 to 15·6]; non-significant). INTERPRETATION: Our findings underscore the complex and dynamic nature of global health challenges. Since 2010, there have been large decreases in burden due to CMNN diseases and many environmental and behavioural risk factors, juxtaposed with sizeable increases in DALYs attributable to metabolic risk factors and NCDs in growing and ageing populations. This long-observed consequence of the global epidemiological transition was only temporarily interrupted by the COVID-19 pandemic. The substantially decreasing CMNN disease burden, despite the 2008 global financial crisis and pandemic-related disruptions, is one of the greatest collective public health successes known. However, these achievements are at risk of being reversed due to major cuts to development assistance for health globally, the effects of which will hit low-income countries with high burden the hardest. Without sustained investment in evidence-based interventions and policies, progress could stall or reverse, leading to widespread human costs and geopolitical instability. Moreover, the rising NCD burden necessitates intensified efforts to mitigate exposure to leading risk factors-eg, air pollution, smoking, and metabolic risks, such as high SBP, BMI, and FPG-including policies that promote food security, healthier diets, physical activity, and equitable and expanded access to potential treatments, such as GLP-1 receptor agonists. Decisive, coordinated action is needed to address long-standing yet growing health challenges, including depressive and anxiety disorders. Yet this can be only part of the solution. Our response to the NCD syndemic-the complex interaction of multiple health risks, social determinants, and systemic challenges-will define the future landscape of global health. To ensure human wellbeing, economic stability, and social equity, global action to sustain and advance health gains must prioritise reducing disparities by addressing socioeconomic and demographic determinants, ensuring equitable health-care access, tackling malnutrition, strengthening health systems, and improving vaccination coverage. We live in times of great opportunity. FUNDING: Gates Foundation and Bloomberg Philanthropies.

Severe falciparum malaria (SM) is associated with tissue ischemia related to cytoadherence of parasitized erythrocytes to microvascular endothelium and reduced levels of NO and its precursor, l-arginine. Endothelial function has not been characterized in SM but can be improved by l-arginine in cardiovascular disease. In an observational study in Indonesia, we measured endothelial function using reactive hyperemia-peripheral arterial tonometry (RH-PAT) in 51 adults with SM, 48 patients with moderately severe falciparum malaria (MSM), and 48 controls. The mean RH-PAT index was lower in SM (1.41; 95% confidence interval [CI] = 1.33-1.47) than in MSM (1.82; 95% CI = 1.7-2.02) and controls (1.93; 95% CI = 1.8-2.06; P < 0.0001). Endothelial dysfunction was associated with elevated blood lactate and measures of hemolysis. Exhaled NO was also lower in SM relative to MSM and controls. In an ascending dose study of intravenous l-arginine in 30 more patients with MSM, l-arginine increased the RH-PAT index by 19% (95% CI = 6-34; P = 0.006) and exhaled NO by 55% (95% CI = 32-73; P < 0.0001) without important side effects. Hypoargininemia and hemolysis likely reduce NO bioavailability. Endothelial dysfunction in malaria is nearly universal in severe disease, is reversible with l-arginine, and likely contributes to its pathogenesis. Clinical trials in SM of adjunctive agents to improve endothelial NO bioavailability, including l-arginine, are warranted.

BACKGROUND: Treatment failure of chloroquine for P. vivax infections has reached high levels in the eastern provinces of Indonesia, however, in vitro characterization of chloroquine resistance and its associated molecular profile have yet to be determined. METHODS: Using a modified schizont maturation assay we investigated the in vitro chloroquine susceptibility profile and molecular polymorphisms of P. vivax isolates collected from Papua, Indonesia, where high levels of clinical chloroquine treatment failure have been reported, and from Thailand, where chloroquine treatment is generally effective. RESULTS: The geometric mean chloroquine IC(50) for P. vivax isolates from Papua (n = 145) was 312 nM [95%CI: 237-411 nM] compared to 46.8 nM [95%CI: 34.7-63.1 nM] from Thailand (n = 81); p<0.001. Correlating with the known clinical efficacy of the area, a cut off for chloroquine resistance was defined as 220 nM, a level exceeded in 13.6% (11/81) of Thai isolates and 65% (94/145) of Papuan isolates; p<0.001. Several sequence polymorphisms in pvcrt-o and pvmdr1, and difference in pvmdr1 copy number were identified. A Y976F mutation in pvmdr1 was present in 96% (123/128) of Papuan isolates and 25% (17/69) of Thai isolates; p<0.001. Overall, the geometric mean chloroquine IC(50) in isolates with the Y976F mutation was 283 nM [95%CI: 211-379], compared to 44.5 nM [95%CI: 31.3-63.4] in isolates with the wild type; p< 0.001. Pvmdr1 amplification occurred in 23% (15/66) of Thai isolates compared to none (0/104) of Indonesian isolates (p<0.001), but was not associated with increased chloroquine resistance after controlling for geographical location. CONCLUSIONS: In vitro susceptibility testing of P. vivax discriminates between populations with differing levels of clinical efficacy of chloroquine. The pvmdr1 polymorphism at Y976F may provide a useful tool to highlight areas of emerging chloroquine resistance, although further studies defining its clinical correlates are needed.

BACKGROUND: The reported case-fatality rate associated with severe malaria varies widely. Whether age is an independent risk factor is uncertain. METHODS: In a large, multicenter treatment trial conducted in Asia, the presenting manifestations and outcome of severe malaria were analyzed in relation to age. RESULTS: Among 1050 patients with severe malaria, the mortality increased stepwise, from 6.1% in children (age, <10 years) to 36.5% in patients aged >50 years (P<0.001). Compared with adults aged 21-50 years, the decreased risk of death among children (adjusted odds ratio, 0.06; 95% confidence interval, 0.01-0.23; P<0.001) and the increased risk of death among patients aged >50 years (adjusted odds ratio, 1.88; 95% confidence interval, 1.01-3.52; P<0.001) was independent of the variation in presenting manifestations. The incidence of anemia and convulsions decreased with age, whereas the incidence of hyperparasitemia, jaundice, and renal insufficiency increased with age. Coma and metabolic acidosis did not vary with age and were the strongest predictors of a fatal outcome. The number of severity signs at hospital admission also had a strong prognostic value. CONCLUSION: Presenting syndromes in severe malaria depend on age, although the incidence and the strong prognostic significance of coma and acidosis are similar at all ages. Age is an independent risk factor for a fatal outcome of the disease.

Adherence of parasitized erythrocytes to activated endothelium causes microvascular obstruction, tissue ischemia, and clinical complications in severe malaria (SM); however, the mechanisms leading to endothelial activation remain unclear. The angiogenic factors, angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) are modulators of endothelial activation, with Ang-2 release from Weibel-Palade bodies (WPBs) being regulated by endothelial nitric oxide (NO). We explored the relationships between endothelial NO bioavailability, Ang-2, VEGF, tissue perfusion, and clinical outcomes in SM. We measured plasma Ang-2 and VEGF, together with biomarkers of severity from 146 adults with and without SM, in parallel with longitudinal measures of endothelial function by using reactive hyperemia peripheral arterial tonometry (a measure of endothelial NO bioavailability). Regression was used to relate concentrations of Ang-2/VEGF with malaria disease severity, biomarkers of perfusion, endothelial activation, and parasite biomass. The longitudinal relationship between Ang-2 and endothelial function was assessed by using a mixed-effects model. Ang-2 concentrations were elevated in SM and associated with increased venous lactate, plasma intercellular cell adhesion molecule-1 concentrations, parasite biomass, and mortality. In contrast, VEGF concentrations were inversely associated with these biomarkers. Ang-2 concentrations were significantly better predictors of death than venous lactate (P = 0.03). Recovery of endothelial function was associated with falling concentrations of Ang-2. Ang-2 release from endothelial cells with reduced NO bioavailability is likely to contribute to endothelial activation, sequestered parasite biomass, impaired perfusion, and poor outcome in severe falciparum malaria. Agents that improve endothelial NO, reduce WPB exocytosis, and/or antagonize Ang-2 may have therapeutic roles in SM.

Stunting among toddlers is highly prevalent in Indonesia. As a chronic malnutrition problem, stunting is closely related to internal (maternal health) and external factors such as feeding practices, illness and socio-economics of the community. The purpose of this study was to analyze the relationship between low birth weight (LBW), child feeding practices and neonatal illness with stunting among Indonesian toddlers. For this study, we took data from the 2010 Indonesian National Basic Health Survey (RISKESDAS). Totally 3024 children aged of 12–23 months included in this analysis. Stunting was measured using standardized body length and was defined based on criteria from WHO AnthroII.PC2007. Data analysis was done through bivariate and multivariate logistic regressions. The results showed that the prevalence of stunting among Indonesian toddlers (12 23 months) was 40.4%. Early initiation of breast-feeding and exclusive breast feeding was experienced by 42.7% and 19.7% of the babies. More than half of the babies were given pre-lacteal feeds, while early complementary feeding was given to 68.5% of the subjects. Multivariate analysis showed infants born with LBW were 1.74 times more likely to be stunted (95% CI 1.38–2.19) than those born with normal weight. Boys were 1.27 times (95% CI 1.10–1.48) more likely to be stunted than girls. Infants with a history of neonatal illness, they were 1.23 times (95% CI 0.99–1.50) more susceptible to stunting. Being poor was another indirect variable that significantly associated with stunting (OR = 1.3, 95% CI 1.12–1.51). LBW, gender (boys), history of neonatal illness and poverty are factors related to stunting among children aged 12–23 months in Indonesia, with LBW being the major determinant of stunting.

BACKGROUND: The grading of radiological severity in clinical trials in tuberculosis (TB) remains unstandardised. The aim of this study was to generate and validate a numerical score for grading chest x-ray (CXR) severity and predicting response to treatment in adults with smear-positive pulmonary TB. METHODS: At a TB clinic in Papua, Indonesia, serial CXRs were performed at diagnosis, 2 and 6 months in 115 adults with smear-positive pulmonary TB. Radiographic findings predictive of 2-month sputum microscopy status were used to generate a score. The validity of the score was then assessed in a second data set of 139 comparable adults with TB, recruited 4 years later at the same site. Relationships between the CXR score and other measures of TB severity were examined. RESULTS: The estimated proportion of lung affected and presence of cavitation, but not cavity size or other radiological findings, significantly predicted outcome and were combined to derive a score given by percentage of lung affected plus 40 if cavitation was present. As well as predicting 2-month outcome, scores were significantly associated with sputum smear grade at diagnosis (p<0.001), body mass index, lung function, haemoglobin, exercise tolerance and quality of life (p<0.02 for each). In the validation data set, baseline CXR score predicted 2-month smear status significantly more accurately than did the proportion of lung affected alone. In both data sets, CXR scores decreased over time (p<0.001). CONCLUSION: This simple, validated method for grading CXR severity in adults with smear-positive pulmonary TB correlates with baseline clinical and microbiological severity and response to treatment, and is suitable for use in clinical trials.