Optical Imaging Demonstrates Tissue-Specific Metabolic Perturbations in Mblac1 Knockout Mice.

OBJECTIVE: Metabolic changes have been extensively documented in neurodegenerative brain disorders, including Parkinson's disease and Alzheimer's disease (AD). Mutations in the C. elegans swip-10 gene result in dopamine (DA) dependent motor dysfunction accompanied by DA neuron degeneration. Recently, the putative human ortholog of swip-10 (MBLAC1) was implicated as a risk factor in AD, a disorder that, like PD, has been associated with mitochondrial dysfunction. Interestingly, the AD risk associated with MBLAC1 arises in subjects with cardiovascular morbidity, suggesting a broader functional insult arising from reduced MBLAC1 protein expression and one possibly linked to metabolic alterations. METHODS: Our current studies, utilizing Mblac1 knockout (KO) mice, seek to determine whether mitochondrial respiration is affected in the peripheral tissues of these mice. We quantified the levels of mitochondrial coenzymes, NADH, FAD, and their redox ratio (NADH/FAD, RR) in livers and kidneys of wild-type (WT) mice and their homozygous KO littermates of males and females, using 3D optical cryo-imaging. RESULTS: Compared to WT, the RR of livers from KO mice was significantly reduced, without an apparent sex effect, driven predominantly by significantly lower NADH levels. In contrast, no genotype and sex differences were observed in kidney samples. Serum analyses of WT and KO mice revealed significantly elevated glucose levels in young and aged KO adults and diminished cholesterol levels in the aged KOs, consistent with liver dysfunction. DISCUSSION/CONCLUSION: As seen with C. elegans swip-10 mutants, loss of MBLAC1 protein results in metabolic changes that are not restricted to neural cells and are consistent with the presence of peripheral comorbidities accompanying neurodegenerative disease in cases where MBLAC1 expression changes impact risk.

Optical Imaging Reveals Liver Metabolic Perturbations in Mblac1 Knockout Mice.

Metabolic changes have been extensively documented in brain tissue undergoing neurodegeneration, including Parkinson's disease and Alzheimer's disease (AD). Mutations in the C. elegans swip-10 gene result in dopamine (DA) dependent motor dysfunction accompanied by DA neuron degeneration. Recently, the putative human ortholog of swip-10 (MBLAC1) was implicated as a risk factor in AD, that like PD, has been associated with mitochondrial dysfunction. Interestingly, the AD risk associated with MBLAC1 arises in subjects with cardiovascular morbidity, suggesting the possibility of a broader functional insult arising from reduced MBLAC1 protein expression, and one possibly linked to metabolic alterations. Our current studies, utilizing Mblac1 knockout (KO) mice, seeks to determine whether mitochondrial respiration is affected in peripheral tissues of these animals in this model. To initiate these studies, we quantified the levels of mitochondrial coenzymes, NADH, FAD, and their redox ratio (NADH/FAD, RR) in the livers of wild type (WT) mice and their homozygous KO littermates, using 3D optical cryo-imaging. We found that Mblac1 KO mice exhibited a greater oxidized redox state compared to WT mice. When compared to the WT group, the redox ratio of KO mice was decreased by 46.32%, driven predominantly by significantly lower NADH levels (more oxidized state). We speculate that, as seen with C. elegans swip-10 mutants, that loss of MBLAC1 protein results in deficits in tricarboxylic acid cycle (TCA) production of NADH and FAD TCA that leads to diminished cellular ATP production and oxidative stress. Such observations are consistent with changes that in the central nervous system (CNS) could support neurodegeneration and in the periphery account for comorbidities.

Sink or swim: Does a worm paralysis phenotype hold clues to neurodegenerative disease?

Receiving a neurodegenerative disease (NDD) diagnosis, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis, is devastating, particularly given the limited options for treatment. Advances in genetic technologies have allowed for efficient modeling of NDDs in animals and brought hope for new disease-modifying medications. The complexity of the mammalian brain and the costs and time needed to identify and develop therapeutic leads limits progress. Modeling NDDs in invertebrates, such as the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, offers orders of magnitude increases in speed of genetic analysis and manipulation, and can be pursued at substantially reduced cost, providing an important, platform complement and inform research with mammalian NDD models. In this review, we describe how our efforts to exploit C. elegans for the study of neural signaling and health led to the discovery of a paralytic phenotype (swimming-induced paralysis) associated with altered dopamine signaling and, surprisingly, to the discovery of a novel gene and pathway whose dysfunction in glial cells triggers neurodegeneration. Research to date on swip-10 and its putative mammalian ortholog MBLAC1, suggests that a tandem analysis will offer insights into NDD mechanisms and insights into novel, disease-modifying therapeutics.

Mortality Associated with Ambient PM2.5 Exposure in India: Results from the Million Death Study.

BACKGROUND: Studies on the extent to which long-term exposure to ambient particulate matter (PM) with aerodynamic diameter ≤2.5µm (PM2.5) contributes to adult mortality in India are few, despite over 99% of Indians being exposed to levels that the World Health Organization (WHO) considers unsafe. OBJECTIVE: We conducted a retrospective cohort study within the Million Death Study (MDS) to provide the first-ever quantification of national mortality from exposure to PM2.5 in India from 1999 to 2014. METHODS: We calculated relative risks (RRs) by linking a total of ten 3-y intervals of satellite-based estimated PM2.5 exposure to deaths 3 to 5 y later in over 7,400 small villages or urban blocks covering a total population of 6.8 million. We applied using a model-based geostatistical model, adjusted for individual age, sex, and year of death; smoking prevalence, rural/urban residency, area-level female illiteracy, languages, and spatial clustering and unit-level variation. RESULTS: PM2.5 exposure levels increased from 1999 to 2014, particularly in central and eastern India. Among 212,573 deaths at ages 15-69 y, after spatial adjustment, we found a significant RR of 1.09 [95% credible interval (CI): 1.04, 1.14] for stroke deaths per 10-µg/m3 increase in PM2.5 exposure, but no significant excess for deaths from chronic respiratory disease and ischemic heart disease (IHD), all nonaccidental causes, and total mortality (after excluding stroke). Spatial adjustment attenuated the RRs for chronic respiratory disease and IHD but raised those for stroke. The RRs were consistent in various sensitivity analyses with spatial adjustment, including stratifying by levels of solid fuel exposure, by sex, and by age group, addition of climatic variables, and in supplementary case-control analyses using injury deaths as controls. DISCUSSION: Direct epidemiological measurements, despite inherent limitations, yielded associations between mortality and long-term PM2.5 inconsistent with those reported in earlier models used by the WHO to derive estimates of PM2.5 mortality in India. The modest RRs in our study are consistent with near or null mortality effects. They suggest suitable caution in estimating deaths from PM2.5 exposure based on MDS results and even more caution in extrapolating model-based associations of risk derived mostly from high-income countries to India. https://doi.org/10.1289/EHP9538.

Assessment of SARS-CoV-2 Seropositivity During the First and Second Viral Waves in 2020 and 2021 Among Canadian Adults.

Importance: The incidence of infection during SARS-CoV-2 viral waves, the factors associated with infection, and the durability of antibody responses to infection among Canadian adults remain undocumented. Objective: To assess the cumulative incidence of SARS-CoV-2 infection during the first 2 viral waves in Canada by measuring seropositivity among adults. Design, Setting, and Participants: The Action to Beat Coronavirus study conducted 2 rounds of an online survey about COVID-19 experience and analyzed immunoglobulin G levels based on participant-collected dried blood spots (DBS) to assess the cumulative incidence of SARS-CoV-2 infection during the first and second viral waves in Canada. A sample of 19 994 Canadian adults (aged ≥18 years) was recruited from established members of the Angus Reid Forum, a public polling organization. The study comprised 2 phases (phase 1 from May 1 to September 30, 2020, and phase 2 from December 1, 2020, to March 31, 2021) that generally corresponded to the first (April 1 to July 31, 2020) and second (October 1, 2020, to March 1, 2021) viral waves. Main Outcomes and Measures: SARS-CoV-2 immunoglobulin G seropositivity (using a chemiluminescence assay) by major geographic and demographic variables and correlation with COVID-19 symptom reporting. Results: Among 19 994 adults who completed the online questionnaire in phase 1, the mean (SD) age was 50.9 (15.4) years, and 10 522 participants (51.9%) were female; 2948 participants (14.5%) had self-identified racial and ethnic minority group status, and 1578 participants (8.2%) were self-identified Indigenous Canadians. Among participants in phase 1, 8967 had DBS testing. In phase 2, 14 621 adults completed online questionnaires, and 7102 of those had DBS testing. Of 19 994 adults who completed the online survey in phase 1, fewer had an educational level of some college or less (4747 individuals [33.1%]) compared with the general population in Canada (45.0%). Survey respondents were otherwise representative of the general population, including in prevalence of known risk factors associated with SARS-CoV-2 infection. The cumulative incidence of SARS-CoV-2 infection among unvaccinated adults increased from 1.9% in phase 1 to 6.5% in phase 2. The seropositivity pattern was demographically and geographically heterogeneous during phase 1 but more homogeneous by phase 2 (with a cumulative incidence ranging from 6.4% to 7.0% in most regions). The exception was the Atlantic region, in which cumulative incidence reached only 3.3% (odds ratio [OR] vs Ontario, 0.46; 95% CI, 0.21-1.02). A total of 47 of 188 adults (25.3%) reporting COVID-19 symptoms during phase 2 were seropositive, and the OR of seropositivity for COVID-19 symptoms was 6.15 (95% CI, 2.02-18.69). In phase 2, 94 of 444 seropositive adults (22.2%) reported having no symptoms. Of 134 seropositive adults in phase 1 who were retested in phase 2, 111 individuals (81.8%) remained seropositive. Participants who had a history of diabetes (OR, 0.58; 95% CI, 0.38-0.90) had lower odds of having detectable antibodies in phase 2. Conclusions and Relevance: The Action to Beat Coronavirus study found that the incidence of SARS-CoV-2 infection in Canada was modest until March 2021, and this incidence was lower than the levels of population immunity required to substantially reduce transmission of the virus. Ongoing vaccination efforts remain central to reducing viral transmission and mortality. Assessment of future infection-induced and vaccine-induced immunity is practicable through the use of serial online surveys and participant-collected DBS.

Is Malaria an Important Cause of Death among Adults?

A long-held assumption has been that nearly all malaria deaths in high-transmission areas are of children younger than 5 years and pregnant women. Most global malaria mortality estimates incorporate this assumption in their calculations. In 2010, the Indian Million Death Study, which assigns cause of death by verbal autopsy (VA), challenged the reigning perception, producing a U-shaped mortality age curve, with rates rising after age 45 years in areas of India with substantial malaria transmission. Similar patterns are seen in Africa in the International Network for the Demographic Evaluation of Populations and Their Health (INDEPTH) network, also relying on VA. Whether these results are accurate or are misidentified deaths can be resolved by improving the evidence for assigning causes for adult acute infectious deaths in high malaria transmission areas. The options for doing so include improving the accuracy of VA and adding postmortem biological evidence, steps we believe should be initiated without delay.

Mortality attributable to hot and cold ambient temperatures in India: a nationally representative case-crossover study.

BACKGROUND: Most of the epidemiological studies that have examined the detrimental effects of ambient hot and cold temperatures on human health have been conducted in high-income countries. In India, the limited evidence on temperature and health risks has focused mostly on the effects of heat waves and has mostly been from small scale studies. Here, we quantify heat and cold effects on mortality in India using a nationally representative study of the causes of death and daily temperature data for 2001-2013. METHODS AND FINDINGS: We applied distributed-lag nonlinear models with case-crossover models to assess the effects of heat and cold on all medical causes of death for all ages from birth (n = 411,613) as well as on stroke (n = 19,753), ischaemic heart disease (IHD) (n = 40,003), and respiratory diseases (n = 23,595) among adults aged 30-69. We calculated the attributable risk fractions by mortality cause for extremely cold (0.4 to 13.8°C), moderately cold (13.8°C to cause-specific minimum mortality temperatures), moderately hot (cause-specific minimum mortality temperatures to 34.2°C), and extremely hot temperatures (34.2 to 39.7°C). We further calculated the temperature-attributable deaths using the United Nations' death estimates for India in 2015. Mortality from all medical causes, stroke, and respiratory diseases showed excess risks at moderately cold temperature and hot temperature. For all examined causes, moderately cold temperature was estimated to have higher attributable risks (6.3% [95% empirical confidence interval (eCI) 1.1 to 11.1] for all medical deaths, 27.2% [11.4 to 40.2] for stroke, 9.7% [3.7 to 15.3] for IHD, and 6.5% [3.5 to 9.2] for respiratory diseases) than extremely cold, moderately hot, and extremely hot temperatures. In 2015, 197,000 (121,000 to 259,000) deaths from stroke, IHD, and respiratory diseases at ages 30-69 years were attributable to moderately cold temperature, which was 12- and 42-fold higher than totals from extremely cold and extremely hot temperature, respectively. The main limitation of this study was the coarse spatial resolution of the temperature data, which may mask microclimate effects. CONCLUSIONS: Public health interventions to mitigate temperature effects need to focus not only on extremely hot temperatures but also moderately cold temperatures. Future absolute totals of temperature-related deaths are likely to depend on the large absolute numbers of people exposed to both extremely hot and moderately cold temperatures. Similar large-scale and nationally representative studies are required in other low- and middle-income countries to better understand the impact of future temperature changes on cause-specific mortality.

Glial loss of the metallo ß-lactamase domain containing protein, SWIP-10, induces age- and glutamate-signaling dependent, dopamine neuron degeneration.

Across phylogeny, glutamate (Glu) signaling plays a critical role in regulating neural excitability, thus supporting many complex behaviors. Perturbed synaptic and extrasynaptic Glu homeostasis in the human brain has been implicated in multiple neuropsychiatric and neurodegenerative disorders including Parkinson's disease, where theories suggest that excitotoxic insults may accelerate a naturally occurring process of dopamine (DA) neuron degeneration. In C. elegans, mutation of the glial expressed gene, swip-10, results in Glu-dependent DA neuron hyperexcitation that leads to elevated DA release, triggering DA signaling-dependent motor paralysis. Here, we demonstrate that swip-10 mutations induce premature and progressive DA neuron degeneration, with light and electron microscopy studies demonstrating the presence of dystrophic dendritic processes, as well as shrunken and/or missing cell soma. As with paralysis, DA neuron degeneration in swip-10 mutants is rescued by glial-specific, but not DA neuron-specific expression of wildtype swip-10, consistent with a cell non-autonomous mechanism. Genetic studies implicate the vesicular Glu transporter VGLU-3 and the cystine/Glu exchanger homolog AAT-1 as potential sources of Glu signaling supporting DA neuron degeneration. Degeneration can be significantly suppressed by mutations in the Ca2+ permeable Glu receptors, nmr-2 and glr-1, in genes that support intracellular Ca2+ signaling and Ca2+-dependent proteolysis, as well as genes involved in apoptotic cell death. Our studies suggest that Glu stimulation of nematode DA neurons in early larval stages, without the protective actions of SWIP-10, contributes to insults that ultimately drive DA neuron degeneration. The swip-10 model may provide an efficient platform for the identification of molecular mechanisms that enhance risk for Parkinson's disease and/or the identification of agents that can limit neurodegenerative disease progression.

Renal failure deaths and their risk factors in India 2001-13: nationally representative estimates from the Million Death Study.

BACKGROUND: Renal failure represents a growing but mostly undocumented cause of premature mortality in low-income and middle-income countries. We investigated changes in adult renal failure mortality and its key risk factors in India using the nationally representative Million Death Study. METHODS: In this cross-sectional analysis of population-based data, two trained physicians independently assigned underlying causes to 150 018 deaths at ages 15-69 years from a nationally-representative mortality survey in India for 2001-03 and 2010-13, using the International Classification of Diseases, 10th version (ICD-10). We applied the age-specific proportion of renal failure deaths for the 2010-13 period to the 2015 UN estimates of total deaths in India and calculated age-standardised death rates for renal failure by rural or urban residence, state, and age group. We used proportional mortality of renal deaths (cases) to injuries (controls) to calculate the odds of renal death in the presence of different comorbidities and stratified risks by decade of birth. FINDINGS: In 2001-03, 2·1% of total deaths among 15-69 year olds were from renal failure (1266 [2·2%] of 58 871; unweighted). By 2010-13, the proportion of deaths from renal failure had risen to 2·9% (2943 [3·2%] of 91 147; unweighted) of total deaths and corresponding to 136 000 renal failure deaths (range 108 000-150 000) of 4 688 000 total deaths nationally in 2015. Age-standardised renal death rates were highest in the southern and eastern states, particularly among adults aged 45-69 years in 2010-13. Diabetes, hypertension, and cardiovascular disease were all significantly associated with increased renal failure deaths, with diabetes the strongest predictor-odds ratio (OR) vs control 9·2 (95% CI 6·7-12·7) in 2001-03, rising to 15·1 (12·6-18·1) in 2010-13. In the 2010-13 study population, the diabetes to non-diabetes OR was twice as large in adults born in the 1970s (25·5, 95% CI 17·6-37·1) as in those individuals born during or before the 1950s (11·7, 9·1-14·9). INTERPRETATION: Renal failure is a growing cause of premature death in India. Poorly treated diabetes is the most probable reason for this increase. Strategies aimed at diabetes prevention, and early detection and treatment are urgently needed in India, as well as greater access to renal replacement therapy. FUNDING: US National Institutes of Health, International Development Research Centre, Centre for Global Health Research, University of Toronto.

Age-specific and sex-specific adult mortality risk in India in 2014: analysis of 0·27 million nationally surveyed deaths and demographic estimates from 597 districts.

BACKGROUND: As child mortality decreases rapidly worldwide, premature adult mortality is becoming an increasingly important contributor to global mortality. Any possible worldwide reduction of premature adult mortality before the age of 70 years will depend on progress in India. Indian districts increasingly have responsibility for implementing public health programmes. We aimed to assess age-specific and sex-specific adult mortality risks in India at the district level. METHODS: We analysed data from five national surveys of 0·27 million adult deaths at an age of 15-69 years together with 2014 demographic data to estimate age-specific and sex-specific adult mortality risks for 597 districts. Cause of death data were drawn from the verbal autopsies in the Registrar General of India's ongoing Million Death Study. FINDINGS: In 2014, about two-fifths of India's men aged 15-69 years lived in the 253 districts where the conditional probability of a man dying at these ages exceeded 50%, and more than a third of India's women aged 15-69 years lived in the 222 districts where the conditional probability of a woman dying exceeded 40%. The probabilities of a man or woman dying by the age of 70 years in high-mortality districts was 62% and 54%, respectively, whereas the probability of a man or woman dying by the age of 70 years in low-mortality districts was 40% and 30%, respectively. The roughly 10-year survival gap between high-mortality and low-mortality districts was nearly as extreme as the survival gap between the entire Indian population and people living in high-income countries. Adult mortality risks at ages 15-69 years was highest in east India and lowest in west India, by contrast with the north-south divide for child mortality. Vascular disease, tuberculosis, malaria and other infections, and respiratory diseases accounted for about 60% of the absolute gap in adult mortality risk at ages 15-69 years between high-mortality and low-mortality districts. Most of the variation in adult mortality could not be explained by known determinants or risk factors for premature mortality. INTERPRETATION: India's large variation in adult mortality by district, notably the higher death rates in eastern India, requires further aetiological research, particularly to explore whether high levels of adult mortality risks from infections and non-communicable diseases are a result of historical childhood malnutrition and infection. Such research can be complemented by an expanded coverage of known effective interventions to reduce adult mortality, especially in high-mortality districts. FUNDING: National Institutes of Health, Canadian Institutes of Health Research, University of Toronto.

Deaths from acute abdominal conditions and geographical access to surgical care in India: a nationally representative spatial analysis.

BACKGROUND: Few population-based studies quantify mortality from surgical conditions and relate mortality to access to surgical care in low-income and middle-income countries. METHODS: We linked deaths from acute abdominal conditions within a nationally representative, population-based mortality survey of 1·1 million households in India to nationally representative facility data. We calculated total and age-standardised death rates for acute abdominal conditions. Using 4064 postal codes, we undertook a spatial clustering analysis to compare geographical access to well-resourced government district hospitals (24 h surgical and anaesthesia services, blood bank, critical care beds, basic laboratory, and radiology) in high-mortality or low-mortality clusters from acute abdominal conditions. FINDINGS: 923 (1·1%) of 86,806 study deaths at ages 0-69 years were identified as deaths from acute abdominal conditions, corresponding to 72,000 deaths nationally in 2010 in India. Most deaths occurred at home (71%) and in rural areas (87%). Compared with 567 low-mortality geographical clusters, the 393 high-mortality clusters had a nine times higher age-standardised acute abdominal mortality rate and significantly greater distance to a well-resourced hospital. The odds ratio (OR) of being a high-mortality cluster was 4·4 (99% CI 3·2-6·0) for living 50 km or more from well-resourced district hospitals (rising to an OR of 16·1 [95% CI 7·9-32·8] for >100 km). No such relation was seen for deaths from non-acute surgical conditions (ie, oral, breast, and uterine cancer). INTERPRETATION: Improvements in human and physical resources at existing government hospitals are needed to reduce deaths from acute abdominal conditions in India. Full access to well-resourced hospitals within 50 km by all of India's population could have avoided about 50,000 deaths from acute abdominal conditions, and probably more from other emergency surgical conditions. FUNDING: Bill & Melinda Gates Foundation, Dalla Lana School of Public Health, Canadian Institute of Health Research.

Deaths from acute abdominal conditions and geographic access to surgical care in India: a nationally representative population-based spatial analysis.

BACKGROUND: Acute abdominal conditions have high case-fatality rates in the absence of timely surgical care. In India, and many other low-income and middle-income countries, few population-based studies have quantified mortality from surgical conditions and related mortality to access to surgical care. We aimed to describe the spatial and socioeconomic distributions of deaths from acute abdomen (DAA) in India and to quantify potential access to surgical facilities in relation to such deaths. METHODS: We examined deaths from acute abdominal conditions within a nationally representative, population-based mortality survey of 1·1 million Indian households and linked these to nationally representative facility data. Spatial clustering of deaths from acute abdominal conditions was calculated with the Getis-Ord Gi* statistic from about 4000 postal codes. We compared high or low acute abdominal mortality clusters for their geographic access to well-resourced surgical care (24 h surgical and anaesthesia services, blood bank, critical care beds, basic laboratory, and radiology). FINDINGS: 923 (1·1%) of 86 806 study deaths in those aged 0-69 years were identified as deaths from acute abdominal conditions, corresponding to an estimated 72 000 deaths nationally in India in 2010. Most deaths occurred at home (71%), in rural areas (87%), and were caused by peptic ulcer disease (79%). There was wide variation in rates of deaths from acute abdominal conditions. We identified 393 high-mortality geographic clusters and 567 low-mortality clusters. High-mortality clusters of acute abdominal conditions were located significantly further from well-resourced hospitals than were low-mortality clusters. The odds ratio of a postal code area being a high-mortality cluster was 4·4 (99% CI 3·2-6·0) for living 50 km or more from well-resourced district hospitals (rising to an OR of 16·1 for >100 km), after adjustment for socioeconomic status and caste. INTERPRETATION: Improvements in human and physical resources at existing public hospitals are required to reduce deaths from acute abdominal conditions in India. Had all of the Indian population had access to well-resourced hospitals within 50 km, more than 50 000 deaths from acute abdominal conditions could have been averted in 2010, and likely more from other emergency surgical conditions. Our geocoded facility data were limited to public district hospitals. However, noting the high rate of catastrophic health expenditures in India, we chose to focus on publicly provided services which are the only option usually available to the poor. FUNDING: The Bill & Melinda Gates Foundation, Dalla Lana School of Public Health, and Canadian Institute of Health Research.

Snakebite mortality in India: a nationally representative mortality survey.

BACKGROUND: India has long been thought to have more snakebites than any other country. However, inadequate hospital-based reporting has resulted in estimates of total annual snakebite mortality ranging widely from about 1,300 to 50,000. We calculated direct estimates of snakebite mortality from a national mortality survey. METHODS AND FINDINGS: We conducted a nationally representative study of 123,000 deaths from 6,671 randomly selected areas in 2001-03. Full-time, non-medical field workers interviewed living respondents about all deaths. The underlying causes were independently coded by two of 130 trained physicians. Discrepancies were resolved by anonymous reconciliation or, failing that, by adjudication. A total of 562 deaths (0.47% of total deaths) were assigned to snakebites. Snakebite deaths occurred mostly in rural areas (97%), were more common in males (59%) than females (41%), and peaked at ages 15-29 years (25%) and during the monsoon months of June to September. This proportion represents about 45,900 annual snakebite deaths nationally (99% CI 40,900 to 50,900) or an annual age-standardised rate of 4.1/100,000 (99% CI 3.6-4.5), with higher rates in rural areas (5.4/100,000; 99% CI 4.8-6.0), and with the highest state rate in Andhra Pradesh (6.2). Annual snakebite deaths were greatest in the states of Uttar Pradesh (8,700), Andhra Pradesh (5,200), and Bihar (4,500). CONCLUSIONS: Snakebite remains an underestimated cause of accidental death in modern India. Because a large proportion of global totals of snakebites arise from India, global snakebite totals might also be underestimated. Community education, appropriate training of medical staff and better distribution of antivenom, especially to the 13 states with the highest prevalence, could reduce snakebite deaths in India.

Adult and child malaria mortality in India: a nationally representative mortality survey.

BACKGROUND: National malaria death rates are difficult to assess because reliably diagnosed malaria is likely to be cured, and deaths in the community from undiagnosed malaria could be misattributed in retrospective enquiries to other febrile causes of death, or vice-versa. We aimed to estimate plausible ranges of malaria mortality in India, the most populous country where the disease remains common. METHODS: Full-time non-medical field workers interviewed families or other respondents about each of 122,000 deaths during 2001-03 in 6671 randomly selected areas of India, obtaining a half-page narrative plus answers to specific questions about the severity and course of any fevers. Each field report was sent to two of 130 trained physicians, who independently coded underlying causes, with discrepancies resolved either via anonymous reconciliation or adjudication. FINDINGS: Of all coded deaths at ages 1 month to 70 years, 2681 (3·6%) of 75,342 were attributed to malaria. Of these, 2419 (90%) were in rural areas and 2311 (86%) were not in any health-care facility. Death rates attributed to malaria correlated geographically with local malaria transmission ratesderived independently from the Indian malaria control programme. The adjudicated results show 205,000 malaria deaths per year in India before age 70 years (55,000 in early childhood, 30,000 at ages 5-14 years, 120,000 at ages 15-69 years); 1·8% cumulative probability of death from malaria before age 70 years. Plausible lower and upper bounds (on the basis of only the initial coding) were 125,000-277,000. Malaria accounted for a substantial minority of about 1·3 million unattended rural fever deaths attributed to infectious diseases in people younger than 70 years. INTERPRETATION: Despite uncertainty as to which unattended febrile deaths are from malaria, even the lower bound greatly exceeds the WHO estimate of only 15,000 malaria deaths per year in India (5000 early childhood, 10 000 thereafter). This low estimate should be reconsidered, as should the low WHO estimate of adult malaria deaths worldwide. FUNDING: US National Institutes of Health, Canadian Institute of Health Research, Li Ka Shing Knowledge Institute.

The Summary Index of Malaria Surveillance (SIMS): a stable index of malaria within India.

BACKGROUND: Malaria in India has been difficult to measure. Mortality and morbidity are not comprehensively reported, impeding efforts to track changes in disease burden. However, a set of blood measures has been collected regularly by the National Malaria Control Program in most districts since 1958. METHODS: Here, we use principal components analysis to combine these measures into a single index, the Summary Index of Malaria Surveillance (SIMS), and then test its temporal and geographic stability using subsets of the data. RESULTS: The SIMS correlates positively with all its individual components and with external measures of mortality and morbidity. It is highly consistent and stable over time (1995-2005) and regions of India. It includes measures of both vivax and falciparum malaria, with vivax dominant at lower transmission levels and falciparum dominant at higher transmission levels, perhaps due to ecological specialization of the species. CONCLUSIONS: This measure should provide a useful tool for researchers looking to summarize geographic or temporal trends in malaria in India, and can be readily applied by administrators with no mathematical or scientific background. We include a spreadsheet that allows simple calculation of the index for researchers and local administrators. Similar principles are likely applicable worldwide, though further validation is needed before using the SIMS outside India.