Fitness consequences of altered feeding behavior in immune-challenged mosquitoes

Background: Malaria-infected mosquitoes have been reported to be more likely to take a blood meal when parasites are infectious than when non-infectious. This change in feeding behavior increases the likelihood of malaria transmission, and has been considered an example of parasite manipulation of host behavior. However, immune challenge with heat-killed Escherichia coli induces the same behavior, suggesting that altered feeding behavior may be driven by adaptive responses of hosts to cope with an immune response, rather than by parasite-specific factors. Here we tested the alternative hypothesis that down-regulated feeding behavior prior to infectiousness is a mosquito adaptation that increases fitness during infection. Methods: We measured the impact of immune challenge and blood feeding on the fitness of individual mosquitoes. After an initial blood meal, Anopheles stephensi Liston mosquitoes were experimentally challenged with heat-killed E. coli at a dose known to mimic the same temporal changes in mosquito feeding behavior as active malaria infection. We then tracked daily egg production and survivorship of females maintained on blood-feeding regimes that either mimicked down-regulated feeding behaviors observed during early malaria infection, or were fed on a four-day feeding cycle typically associated with uninfected mosquitoes. Results: Restricting access to blood meals enhanced mosquito survival but lowered lifetime reproduction. Immune-challenge did not impact either fitness component. Combining fecundity and survival to estimate the population-scale intrinsic rate of increase (r), we found that, contrary to the mosquito adaptation hypothesis, mosquito fitness decreased if blood feeding was delayed following an immune challenge. Conclusions: Our data provide no support for the idea that malaria-induced suppression of blood feeding is an adaptation by mosquitoes to reduce the impact of immune challenge. Alternatively, the behavioral alterations may be neither host nor parasite adaptations, but rather a consequence of constraints imposed on feeding by activation of the mosquito immune response, i.e. non-adaptive illness-induced anorexia. Future work incorporating field conditions and different immune challenges could further clarify the effect of altered feeding on mosquito and parasite fitness

Healthcare Access and Quality Index based on mortality from causes amenable to personal health care in 195 countries and territories, 1990-2015 : a novel analysis from the Global Burden of Disease Study 2015

Background National levels of personal health-care access and quality can be approximated by measuring mortality rates from causes that should not be fatal in the presence of effective medical care (ie, amenable mortality). Previous analyses of mortality amenable to health care only focused on high-income countries and faced several methodological challenges. In the present analysis, we use the highly standardised cause of death and risk factor estimates generated through the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to improve and expand the quantification of personal health-care access and quality for 195 countries and territories from 1990 to 2015. Methods We mapped the most widely used list of causes amenable to personal health care developed by Nolte and McKee to 32 GBD causes. We accounted for variations in cause of death certification and misclassifications through the extensive data standardisation processes and redistribution algorithms developed for GBD. To isolate the effects of personal health-care access and quality, we risk-standardised cause-specific mortality rates for each geography-year by removing the joint effects of local environmental and behavioural risks, and adding back the global levels of risk exposure as estimated for GBD 2015. We employed principal component analysis to create a single, interpretable summary measure-the Healthcare Quality and Access (HAQ) Index-on a scale of 0 to 100. The HAQ Index showed strong convergence validity as compared with other health-system indicators, including health expenditure per capita (r= 0.88), an index of 11 universal health coverage interventions (r= 0.83), and human resources for health per 1000 (r= 0.77). We used free disposal hull analysis with bootstrapping to produce a frontier based on the relationship between the HAQ Index and the Socio-demographic Index (SDI), a measure of overall development consisting of income per capita, average years of education, and total fertility rates. This frontier allowed us to better quantify the maximum levels of personal health-care access and quality achieved across the development spectrum, and pinpoint geographies where gaps between observed and potential levels have narrowed or widened over time. Findings Between 1990 and 2015, nearly all countries and territories saw their HAQ Index values improve; nonetheless, the difference between the highest and lowest observed HAQ Index was larger in 2015 than in 1990, ranging from 28.6 to 94.6. Of 195 geographies, 167 had statistically significant increases in HAQ Index levels since 1990, with South Korea, Turkey, Peru, China, and the Maldives recording among the largest gains by 2015. Performance on the HAQ Index and individual causes showed distinct patterns by region and level of development, yet substantial heterogeneities emerged for several causes, including cancers in highest-SDI countries; chronic kidney disease, diabetes, diarrhoeal diseases, and lower respiratory infections among middle-SDI countries; and measles and tetanus among lowest-SDI countries. While the global HAQ Index average rose from 40.7 (95% uncertainty interval, 39.0-42.8) in 1990 to 53.7 (52.2-55.4) in 2015, far less progress occurred in narrowing the gap between observed HAQ Index values and maximum levels achieved; at the global level, the difference between the observed and frontier HAQ Index only decreased from 21.2 in 1990 to 20.1 in 2015. If every country and territory had achieved the highest observed HAQ Index by their corresponding level of SDI, the global average would have been 73.8 in 2015. Several countries, particularly in eastern and western sub-Saharan Africa, reached HAQ Index values similar to or beyond their development levels, whereas others, namely in southern sub-Saharan Africa, the Middle East, and south Asia, lagged behind what geographies of similar development attained between 1990 and 2015. Interpretation This novel extension of the GBD Study shows the untapped potential for personal health-care access and quality improvement across the development spectrum. Amid substantive advances in personal health care at the national level, heterogeneous patterns for individual causes in given countries or territories suggest that few places have consistently achieved optimal health-care access and quality across health-system functions and therapeutic areas. This is especially evident in middle-SDI countries, many of which have recently undergone or are currently experiencing epidemiological transitions. The HAQ Index, if paired with other measures of health-systemcharacteristics such as intervention coverage, could provide a robust avenue for tracking progress on universal health coverage and identifying local priorities for strengthening personal health-care quality and access throughout the world. Copyright (C) The Author(s). Published by Elsevier Ltd.Peer reviewe

Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy (HALE), 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.

BACKGROUND: Healthy life expectancy (HALE) and disability-adjusted life-years (DALYs) provide summary measures of health across geographies and time that can inform assessments of epidemiological patterns and health system performance, help to prioritise investments in research and development, and monitor progress toward the Sustainable Development Goals (SDGs). We aimed to provide updated HALE and DALYs for geographies worldwide and evaluate how disease burden changes with development. METHODS: We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015. We calculated DALYs by summing years of life lost (YLLs) and years of life lived with disability (YLDs) for each geography, age group, sex, and year. We estimated HALE using the Sullivan method, which draws from age-specific death rates and YLDs per capita. We then assessed how observed levels of DALYs and HALE differed from expected trends calculated with the Socio-demographic Index (SDI), a composite indicator constructed from measures of income per capita, average years of schooling, and total fertility rate. FINDINGS: Total global DALYs remained largely unchanged from 1990 to 2015, with decreases in communicable, neonatal, maternal, and nutritional (Group 1) disease DALYs offset by increased DALYs due to non-communicable diseases (NCDs). Much of this epidemiological transition was caused by changes in population growth and ageing, but it was accelerated by widespread improvements in SDI that also correlated strongly with the increasing importance of NCDs. Both total DALYs and age-standardised DALY rates due to most Group 1 causes significantly decreased by 2015, and although total burden climbed for the majority of NCDs, age-standardised DALY rates due to NCDs declined. Nonetheless, age-standardised DALY rates due to several high-burden NCDs (including osteoarthritis, drug use disorders, depression, diabetes, congenital birth defects, and skin, oral, and sense organ diseases) either increased or remained unchanged, leading to increases in their relative ranking in many geographies. From 2005 to 2015, HALE at birth increased by an average of 2·9 years (95% uncertainty interval 2·9-3·0) for men and 3·5 years (3·4-3·7) for women, while HALE at age 65 years improved by 0·85 years (0·78-0·92) and 1·2 years (1·1-1·3), respectively. Rising SDI was associated with consistently higher HALE and a somewhat smaller proportion of life spent with functional health loss; however, rising SDI was related to increases in total disability. Many countries and territories in central America and eastern sub-Saharan Africa had increasingly lower rates of disease burden than expected given their SDI. At the same time, a subset of geographies recorded a growing gap between observed and expected levels of DALYs, a trend driven mainly by rising burden due to war, interpersonal violence, and various NCDs. INTERPRETATION: Health is improving globally, but this means more populations are spending more time with functional health loss, an absolute expansion of morbidity. The proportion of life spent in ill health decreases somewhat with increasing SDI, a relative compression of morbidity, which supports continued efforts to elevate personal income, improve education, and limit fertility. Our analysis of DALYs and HALE and their relationship to SDI represents a robust framework on which to benchmark geography-specific health performance and SDG progress. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform financial and research investments, prevention efforts, health policies, and health system improvement initiatives for all countries along the development continuum. FUNDING: Bill & Melinda Gates Foundation

The Influence of Physical Growth and Maturation on The Static Force Production of Boys Ages Six Through Twelve Years

145 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1973.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD

Data from: Fitness consequences of altered feeding behavior in immune-challenged mosquitoes

Background: Malaria-infected mosquitoes have been reported to be more likely to take a blood meal when parasites are infectious than when non-infectious. This change in feeding behavior increases the likelihood of malaria transmission, and has been considered an example of parasite manipulation of host behavior. However, immune challenge with heat-killed Escherichia coli induces the same behavior, suggesting that altered feeding behavior may be driven by adaptive responses of hosts to cope with an immune response, rather than by parasite-specific factors. Here we tested the alternative hypothesis that down-regulated feeding behavior prior to infectiousness is a mosquito adaptation that increases fitness during infection. Methods: We measured the impact of immune challenge and blood feeding on the fitness of individual mosquitoes. After an initial blood meal, Anopheles stephensi Liston mosquitoes were experimentally challenged with heat-killed E. coli at a dose known to mimic the same temporal changes in mosquito feeding behavior as active malaria infection. We then tracked daily egg production and survivorship of females maintained on blood-feeding regimes that either mimicked down-regulated feeding behaviors observed during early malaria infection, or were fed on a four-day feeding cycle typically associated with uninfected mosquitoes. Results: Restricting access to blood meals enhanced mosquito survival but lowered lifetime reproduction. Immune- challenge did not impact either fitness component. Combining fecundity and survival to estimate the population- scale intrinsic rate of increase (r), we found that, contrary to the mosquito adaptation hypothesis, mosquito fitness decreased if blood feeding was delayed following an immune challenge. Conclusions: Our data provide no support for the idea that malaria-induced suppression of blood feeding is an adaptation by mosquitoes to reduce the impact of immune challenge. Alternatively, the behavioral alterations may be neither host nor parasite adaptations, but rather a consequence of constraints imposed on feeding by activation of the mosquito immune response, i.e. non-adaptive illness-induced anorexia. Future work incorporating field conditions and different immune challenges could further clarify the effect of altered feeding on mosquito and parasite fitness

Data for: Phenotypic adaptation to temperature in the mosquito vector, Aedes aegypti

<p><span>Most models exploring the effects of climate change on </span><span>mosquito-borne disease ignore thermal adaptation. However, if local adaptation leads to changes in mosquito thermal responses, 'one size fits all' models could fail to capture current variation between populations and future adaptive responses to changes in temperature. Here we assess phenotypic adaptation to temperature in <em>Aedes aegypti</em>, the primary vector of dengue, Zika, and chikungunya viruses. First, to explore whether there is any difference in existing thermal response of mosquitoes between populations we used a thermal knockdown assay to examine five populations of <em>Ae. aegypti </em>collected from climatically diverse locations in Mexico, together with a longstanding laboratory strain. We identified significant phenotypic variation in thermal tolerance between populations. Next, to explore whether such variation can be generated by differences in temperature we conducted an experimental passage study by establishing six replicate lines from a single field-derived population of <em>Ae. aegypti </em>from Mexico, maintaining half at 27<strong><span class="nounderlines">°</span></strong>C and the other half at 31<strong><span class="nounderlines">°</span></strong>C. After 10 generations we found a significant difference in mosquito performance, with the lines maintained under elevated temperatures showing greater thermal tolerance. Moreover, these differences in thermal tolerance translated to shifts in the thermal performance curves for multiple life history traits, leading to differences in overall fitness. Together, these novel findings provide compelling evidence that <em>Ae. aegypti </em>populations can and do differ in thermal response, suggesting that simplified thermal performance models might be insufficient for predicting the effects of climate on vector-borne disease transmission. </span></p><p>Funding provided by: National Science Foundation<br>Crossref Funder Registry ID: https://ror.org/021nxhr62<br>Award Number: DEB-1518681</p><p><strong><span>Mosquito Collection</span></strong></p> <p><em><span>Aedes aegypti</span></em><span><em> </em>mosquitoes were collected from the field using ovitraps in five different locations in Mexico (Cabo San Lucas, Acapulco, Monterrey, Ciudad Juárez, and Jojutla) and compared to a standard laboratory population (Rockefeller strain) maintained at Penn State University. The field locations were chosen to capture a gradient of the landscape and climate, driven primarily by variation in altitude. Populations were founded with </span>sufficient viable eggs collected from multiple ovitraps across the cities to yield at least 100 adult mosquitoes in the F1 laboratory generation. <span>Mosquitoes were reared for a generation (F2) in standard laboratory conditions (27°C, 80% humidity, 12:12hr photoperiod, 0.60 mg of bovine liver powder per 600 larvae and ad libitum access to 10% sugar solution for the adults) prior to experimentation to remove the influence of any maternal effects. Two populations, Jojutla and Juárez, were reared for an additional generation (F3) to ensure a large enough population for subsequent experiments. </span></p> <p><strong><span>Knockdown assays to estimate thermal tolerance</span></strong></p> <p>We followed methods developed recently by Ware-Gilmore et al. to examine the thermal tolerance of adult <em>Ae. aegypti</em> mosquitoes. These methods were adapted from numerous studies in <em>Drosophila</em> and were shown to be sufficiently sensitive to demonstrate the effects of infection with either dengue virus or the bacterial endosymbiont, <em>Wolbachia</em>, on thermal sensitivity<span>. In brief, three-to-four-day-old female mosquitoes were placed into individual sealed 40mL glass vials. </span>The vials were submerged into a tank filled with water at a regulated temperature of 41°C. Individuals were allowed two minutes to acclimate, after which they were monitored and the time to knockdown (immobility or death) was recorded. <span>We monitored mosquitoes until all were knocked down. In the common garden experiment, we conducted six replicate runs of 10 mosquitoes giving a total of 60 mosquitoes per population. The passage experiment had 18 total replicates (6 per independent passaged line) of 10 mosquitoes for each temperature treatment.</span></p> <p><strong><span>Experimental passage </span></strong></p> <p><span>We used the F1 population of <em>Ae. aegypti </em>mosquitoes collected from Monterrey, Mexico, to establish six replicate lines, half of which were maintained at a standard insectary temperature of 27°C (80% humidity, 12:12hr photoperiod), which also approximates the overall mean temperature in Monterrey summer months, and the other half were maintained at an elevated temperature of 31°C (80% humidity, 12:12hr photoperiod) (SI Appendix, Fig. S1 and S2, Table S1). The elevated temperature of 31°C represents an increase of 4°C as might be expected under future climate warming. However, neither temperature simulates realistic environmental variation in the natural home environment and so both treatments were under some level of artificial selection to lab conditions.</span></p> <p><span>Each replicate line was initiated with 600 first instar larvae. Larvae were added into 5.7 L containers containing 3 L of deionized water and 0.60mg of bovine liver powder (MP Biomedicals) and placed in controlled temperature incubators (3 replicate containers at 27</span>°<span>C and 3 containers at 31</span>°<span>C). Every other day we added 0.60 mg of bovine liver powder to each container until larvae began to pupate when we scaled the food to the number of remaining larvae. We removed pupae and placed them in a small cup (30 mL) with water from their original environment to allow for eclosion. Cups containing pupae were added to a large cage with ad libitum access to 10% sugar solution made with dextrose anhydrous and deionized water to sustain the adults as they emerged.</span> <span>We counted total pupae per container, along with the number of pupae that eclosed successfully. When the adult mosquitoes were of reproductive age (3-5 days after eclosion), any dead adult mosquitoes were counted. These measures were used to get an accurate count of surviving adult mosquitoes in each cage.  To ensure balanced selection between lines and account for potential effects of genetic bottlenecks or drift that could result from different population sizes, adult mosquitoes were culled (3-5 days after eclosion) before blood feeding so that each line had the same number of mosquitoes. The lines were culled </span><span>in pairs, for example replicate one at 27</span>°<span>C was paired with replicate one in 31</span>°<span>C, for all ten generations to ensure independence between replicates. Mosquitoes were culled </span><span>with a 50:50 sex ratio </span><span>to maintain possible differences in selection on sex</span><span>. Once the adult cages were established, mosquitoes were fed a human blood meal every four days for 16 days using a standard membrane feeder. Eggs were collected every day and maintained on dry filter paper to prevent hatching. At the end of the 16-day egg laying period, the eggs were transferred to larval containers to initiate hatching, thus maintaining a uniform age structure. Mosquitoes were reared through to adult as described. We followed this protocol for ten generations (SI Appendix, Fig. S5).</span></p> <p><span>At the end of the experimental period, we measured thermal tolerance for the six lines using the knockdown methods described above. In addition, t</span>o extend beyond this proxy variable and fully explore the effects of the passage treatments, egg-to-adult survival, mosquito development rate, mean adult survival, and fecundity were measured in mosquitoes reared in environmentally controlled incubators at 13°C, 17°C, 21°C, 25°C, 27°C, 29°C, 31°C, 33°C, 35°C, 37°C, each ± 0.2°C and 80%± 10% relative humidity. Eggs from the 6 passaged lines were hatched at 27°C.  After 24 hours, 200 first instar larvae were put into 1.89 L containers with 1 L of deionized water and 0.20 mg of larvae bovine liver powder (MP Biomedicals) and placed in the respective incubator. We fed larvae 0.20 mg of liver powder every other day until pupation. Once larvae began to pupate, we scaled their food to the number of remaining larvae. We removed and counted living and dead pupae the day of pupation and placed them in a small cup (30 mL) with water from their original environment to allow for eclosion. Cups containing pupae were added to a small cage (17.5 cm3) with ad libitum access to 10% sugar solution made with dextrose anhydrous and deionized water. We then counted the number of adults that eclosed every day. After 95% of females emerged, we blood fed females who were then 3-5 days old.  We used blood from de-identified human donors (BioIVT, Corp.) so IRB approval and human subjects' approval was not needed. Immediately after blood-feeding, we counted the total number of blood-fed females and placed up to 10 individual females into separate containers (50 mL polypropylene centrifuge tubes) lined with filter paper that contained 7 mL deionized water to measure individual fecundity. We recorded the day that females in individual containers first laid eggs and let them lay eggs for three total days, after which we removed them from their containers. We extracted the water from the containers to let the filter paper dry in their respective incubators and then we counted the eggs. We counted and determined the sex of the number of adults that died every day. We censored this experiment 4 weeks after the first egg lay at each temperature (SI Appendix, Fig. S5).</p&gt

Additional file 1: of Fitness consequences of altered feeding behavior in immune-challenged mosquitoes

Additional details of model development, simplification, parameterization, and analysis. (PDF 374 kb

Additional file 2: of Fitness consequences of altered feeding behavior in immune-challenged mosquitoes

Tables S1-S7. This file contains additional data on feeding treatment complience and details of model outputs. (DOCX 503 kb

Phenotypic adaptation to temperature in the mosquito vector, Aedes aegypti

Most models exploring the effects of climate change on mosquito‐borne disease ignore thermal adaptation. However, if local adaptation leads to changes in mosquito thermal responses, “one size fits all” models could fail to capture current variation between populations and future adaptive responses to changes in temperature. Here, we assess phenotypic adaptation to temperature in Aedes aegypti, the primary vector of dengue, Zika, and chikungunya viruses. First, to explore whether there is any difference in existing thermal response of mosquitoes between populations, we used a thermal knockdown assay to examine five populations of Ae. aegypti collected from climatically diverse locations in Mexico, together with a long‐standing laboratory strain. We identified significant phenotypic variation in thermal tolerance between populations. Next, to explore whether such variation can be generated by differences in temperature, we conducted an experimental passage study by establishing six replicate lines from a single field‐derived population of Ae. aegypti from Mexico, maintaining half at 27°C and the other half at 31°C. After 10 generations, we found a significant difference in mosquito performance, with the lines maintained under elevated temperatures showing greater thermal tolerance. Moreover, these differences in thermal tolerance translated to shifts in the thermal performance curves for multiple life‐history traits, leading to differences in overall fitness. Together, these novel findings provide compelling evidence that Ae. aegypti populations can and do differ in thermal response, suggesting that simplified thermal performance models might be insufficient for predicting the effects of climate on vector‐borne disease transmission