Alan A. Cohen

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.

No simple answers for ecological immunology: relationships among immune indices at the individual level break down at the species level in waterfowl

Understanding immune function in the context of other life-history traits is crucial to understand the evolution of life histories, at both the individual and species levels. As the interest in assessing immune function for these comparative purposes grows, an important question remains unanswered: can immune function be broadly characterized using one or two simple measures? Often, interpretation of individual assays is ambiguous and relationships among different measures of immune function remain poorly understood. Thus, we employed five protocols to measure 13 variables of immune function in ten species of waterfowl (Anseriformes). All assays were based on a single blood sample subdivided into leukocyte (blood smear) and plasma (frozen until analysis) components. All assays were run using samples from every individual, and a nested analysis was used to partition variation/covariation at the levels of species and individuals within species. We detected positive correlations between functionally related measures of immunity within species, but these were absent from comparisons between species. A canonical correlation analysis revealed no significant relationships between the plasma and leukocyte assays at the levels of both individual and species, suggesting that these measures of immunity are neither competitive nor synergistic. We conclude that one measure of each assay type may be required to maximally characterize immune function in studies of a single species, while the same is not true in studies among species.

Female post-reproductive lifespan: a general mammalian trait

Traditional explanations for the evolution of menopause and post‐reproductive lifespan in human females have been based on the benefits of maternal or grand‐maternal care outweighing the cost of lost reproduction. These explanations assume an evolutionary origin of menopause since human divergence with the most recent common ancestor. In this study, I conduct a literature survey of studies of 42 mammal species from eight orders, showing that post‐reproductive lifespan appears to be widespread among mammals. I then propose an alternative to traditional hypotheses: following accepted theories of trade‐offs and senescence, I suggest that the cost of extending reproductive lifespan might be relatively high in female mammals. Somatic and reproductive senescence appear to follow separate trajectories, so it is not surprising that the two processes should occur on different schedules. The timing of each process is probably determined by maximization of reproductive performance and survival early in adulthood, with consequent trajectories resulting in a post‐reproductive lifespan. The early end of reproduction relative to lifespan may be due to the cost of production and/or maintenance of oocytes, which decline exponentially over time. Oocyte number below a threshold may trigger an end to normal hormonal cycling.

Physiological regulatory networks: ecological roles and evolutionary constraints

Ecological and evolutionary physiology has traditionally focused on one aspect of physiology at a time. Here, we discuss the implications of considering physiological regulatory networks (PRNs) as integrated wholes, a perspective that reveals novel roles for physiology in organismal ecology and evolution. For example, evolutionary response to changes in resource abundance might be constrained by the role of dietary micronutrients in immune response regulation, given a particular pathogen environment. Because many physiological components impact more than one process, organismal homeostasis is maintained, individual fitness is determined and evolutionary change is constrained (or facilitated) by interactions within PRNs. We discuss how PRN structure and its system-level properties could determine both individual performance and patterns of physiological evolution.

Interspecific associations between circulating antioxidant levels and life-history variation in birds

Antioxidants play an important role in protecting tissues against aging‐associated oxidative damage and are thus prime candidates for relating physiological mechanisms to variation in life histories. We measured total antioxidant capacity, antioxidant response to stress, and levels of uric acid, vitamin E, and four carotenoids in 95 avian species, mostly passerines from Michigan or Panama. We compared antioxidant measures to seven variables related to life histories (clutch size, survival rate, incubation period, nestling period, basal metabolic rate, body mass, and whether the species lived in a tropical or temperate climate). Life‐history‐related traits varied over at least three statistically independent axes. Higher antioxidant levels were generally characteristic of more rapid development, lower survival rate, smaller body size, larger clutch size, and higher mass‐adjusted metabolic rate, but the relationships of particular antioxidants with individual life‐history traits showed considerable complexity. Antioxidant–life history associations differed between tropical and temperate species and varied with respect to taxonomic sampling. Vitamin E showed few relationships with life‐history traits. Overall, our results partly support the hypothesis that antioxidant levels evolve to mirror free radical production. Clearly, however, the complex patterns of physiological diversification observed here result from the interplay of many factors, likely including not just investment in somatic maintenance but also phylogenetic constraint, diet, and other aspects of ecology.

What does carotenoid-dependent coloration tell? Plasma carotenoid level signals immunocompetence and oxidative stress state in birds–A meta-analysis

Abstract Mechanisms maintaining honesty of sexual signals are far from resolved, limiting our understanding of sexual selection and potential important parts of physiology. Carotenoid pigmented visual signals are among the most extensively studied sexual displays, but evidence regarding hypotheses on how carotenoids ensure signal honesty is mixed. Using a phylogenetically controlled meta-analysis of 357 effect sizes across 88 different species of birds, we tested two prominent hypotheses in the field: that carotenoid-dependent coloration signals i) immunocompetence and/or ii) oxidative stress state. Separate meta-analyses were performed for the relationships of trait coloration and circulating carotenoid level with different measures of immunocompetence and oxidative stress state. For immunocompetence we find that carotenoid levels (r = 0.20) and trait color intensity (r = 0.17) are significantly positively related to PHA response. Additionally we find that carotenoids are significantly positively related to antioxidant capacity (r = 0.10), but not significantly related to oxidative damage (r = −0.02). Thus our analyses provide support for both hypotheses, in that at least for some aspects of immunity and oxidative stress state the predicted correlations were found. Furthermore, we tested for differences in effect size between experimental and observational studies; a larger effect in observational studies would indicate that co-variation might not be causal. However, we detected no significant difference, suggesting that the relationships we found are causal. The overall effect sizes we report are modest and we discuss potential factors contributing to this, including differences between species. We suggest complementary mechanisms maintaining honesty rather than the involvement of carotenoids in immune function and oxidative stress and suggest experiments on how to test these.

Serum antioxidant levels in wild birds vary in relation to diet, season, life history strategy, and species

Micronutrient antioxidants are thought to be generally important for health in many animals, but factors determining levels in individuals and species are not well understood. Diet and season are obvious environmental variables that might predict the degree to which species can accumulate such nutrients. We analyzed antioxidant levels [Trolox-equivalent antioxidant capacity (TEAC), uric acid (UA), vitamin E, and four carotenoids] in 95 bird species and compared these to species-level data on diet from the literature. Using compositional principal components analysis, we identified two main axes of diet variation: invertebrate consumption and seed-to-fruit ratio. We then examined associations between diet axes and antioxidant measures, with and without control for life-history variation and phylogeny. We also analyzed a subset of 13 species for which we had data on seasonality of antioxidant levels and diet, assessing the variance in antioxidant levels explained by seasonality, diet, and species. Unsurprisingly, there were strong associations between antioxidant levels and diet. TEAC and UA concentration were consistently positively associated with invertebrate consumption and seed-to-fruit ratio, and carotenoid concentrations (e.g. zeaxanthin and β-carotene) were negatively associated with invertebrate consumption. However, vitamin E was not associated with diet as measured here. Importantly, there is much variation in antioxidants that is not explained by diet, and we are able to identify diet-independent effects of species, season/breeding stage, and life history on antioxidant levels. Circulating antioxidant concentrations within and across species can therefore be viewed as a function of multiple factors, including but not limited to diet, and antioxidant metabolism appears to differ across species and seasons irrespective of diet.

Inflamm‐aging does not simply reflect increases in pro‐inflammatory markers

Many biodemographic studies use biomarkers of inflammation to understand or predict chronic disease and aging. Inflamm-aging, i.e. chronic low-grade inflammation during aging, is commonly characterized by pro-inflammatory biomarkers. However, most studies use just one marker at a time, sometimes leading to conflicting results due to complex interactions among the markers. A multidimensional approach allows a more robust interpretation of the various relationships between the markers. We applied principal component analysis (PCA) to 19 inflammatory biomarkers from the InCHIANTI study. We identified a clear, stable structure among the markers, with the first axis explaining inflammatory activation (both pro- and anti-inflammatory markers loaded strongly and positively) and the second axis innate immune response. The first but not the second axis was strongly correlated with age (r=0.56, p<0.0001, r=0.08 p=0.053), and both were strongly predictive of mortality (hazard ratios per PCA unit (95% CI): 1.33 (1.16-1.53) and 0.87 (0.76-0.98) respectively) and multiple chronic diseases, but in opposite directions. Both axes were more predictive than any individual markers for baseline chronic diseases and mortality. These results show that PCA can uncover a novel biological structure in the relationships among inflammatory markers, and that key axes of this structure play important roles in chronic disease.

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

BackgroundMalaria 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.MethodsHere, 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.ResultsThe 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.ConclusionsThis 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.

Detection of a Novel, Integrative Aging Process Suggests Complex Physiological Integration

Many studies of aging examine biomarkers one at a time, but complex systems theory and network theory suggest that interpretations of individual markers may be context-dependent. Here, we attempted to detect underlying processes governing the levels of many biomarkers simultaneously by applying principal components analysis to 43 common clinical biomarkers measured longitudinally in 3694 humans from three longitudinal cohort studies on two continents (Women’s Health and Aging I & II, InCHIANTI, and the Baltimore Longitudinal Study on Aging). The first axis was associated with anemia, inflammation, and low levels of calcium and albumin. The axis structure was precisely reproduced in all three populations and in all demographic sub-populations (by sex, race, etc.); we call the process represented by the axis “integrated albunemia.” Integrated albunemia increases and accelerates with age in all populations, and predicts mortality and frailty – but not chronic disease – even after controlling for age. This suggests a role in the aging process, though causality is not yet clear. Integrated albunemia behaves more stably across populations than its component biomarkers, and thus appears to represent a higher-order physiological process emerging from the structure of underlying regulatory networks. If this is correct, detection of this process has substantial implications for physiological organization more generally.