Mark Booth

Current interventions against malaria have significantly reduced the number of people infected and the number of deaths. Concerns about emerging resistance of both mosquitoes and parasites to intervention have been raised, and questions remain about how best to generate wider knowledge of the underlying evolutionary processes. The pedagogical and research principles of evolutionary medicine may provide an answer to this problem. Eight programme managers and five academic researchers were interviewed by telephone or videoconference to elicit their first-hand views and experiences of malaria control given that evolution is a constant threat to sustainable control. Interviewees were asked about their views on the relationship between practit groups and academics and for their thoughts on whether or not evolutionary medicine may provide a solution to reported tensions. There was broad agreement that evolution of both parasites and vectors presents an obstacle to sustainable control. It was also widely agreed that through more efficient monitoring, evolution could be widely monitored. Interviewees also expressed the view that even well planned interventions may fail if the evolutionary biology of the disease is not considered, potentially making current tools redundant. This scoping study suggests that it is important to make research, including evolutionary principles, available and easily applicable for programme managers and key decision-makers, including donors and politicians. The main conclusion is that sharing knowledge through the educational and research processes embedded within evolutionary medicine has potential to relieve tensions and facilitate sustainable control of malaria and other parasitic infections.

Survival and fitness attributes of free-living and sporocyst schistosome life-stages and their intermediate host snails are sensitive to water temperature. Climate change may alter the geographical distribution of schistosomiasis by affecting the suitability of freshwater bodies for hosting parasite and snail populations. We have developed an agent-based model of the temperature-sensitive stages of the Schistosoma mansoni and intermediate host snail lifecycles. The model was run using low, moderate and high warming climate projections over eastern Africa. For each climate projection, eight model scenarios were used to determine the sensitivity of predictions to different relationships between air and water temperature, and different snail mortality rates. Maps were produced showing predicted changes in risk as a result of increasing temperatures over the next 20 and 50 years. Baseline model output compared to prevalence data indicates suitable temperatures are necessary but not sufficient for both S. mansoni transmission and high infection prevalences. All else being equal, infection risk may increase by up to 20% over most of eastern Africa over the next 20 and 50 years. Increases may be higher in Rwanda, Burundi, south-west Kenya and eastern Zambia, and S. mansoni may become newly endemic in some areas. Results for 20-year projections are robust to changes in simulated intermediate host snail habitat conditions. There is greater uncertainty about the effects of different habitats on changes in risk in 50 years’ time. Temperatures are likely to become suitable for increased S. mansoni transmission over much of eastern Africa. This may reduce the impact of control and elimination programmes. S. mansoni may also spread to new areas outside existing control programmes. We call for increased surveillance in areas defined as potentially suitable for emergent transmission.

Adrenarche is a key early life event that marks middle childhood at approximately 7 years of age. Earlier work with British-Bangladeshi migrant women suggested that environmental conditions experienced before adrenarche influence adult reproductive function. We therefore investigated whether Bangladeshi children who migrate to the United Kingdom (UK) reach adrenarche earlier than non-migrants in Bangladesh or the United Kingdom. Healthy girls, aged 5–16 years, were recruited from schools in Sylhet, Bangladesh and London, England comprising four groups: Sylhetis (n = 165), first-generation migrants to the United Kingdom (n = 42), second-generation girls (n = 162), and British girls of European origin (n = 50). Anthropometric measurements were collected together with questionnaire data for migration and socioeconomic characteristics. Saliva samples were assayed for dehydroepiandrosterone (DHEAS) using enzyme-linked immunosorbent assays. Multiple linear regressions tested for group differences in anthropometric and socioeconomic variables and DHEAS levels. Median ages at adrenarche (DHEAS>400 pg/ml) were estimated using Weibull regression models for parametric survival analysis. Hazard ratios for reaching adrenarche earlier and 95% confidence intervals (CI), both unadjusted and adjusted for anthropometric variables, were estimated from the survival analyses. First-generation migrants had a median age at adrenarche (5.3 years) that was significantly earlier than Sylheti (7.2), second-generation (7.4), and European (7.1) girls. In univariate analyses, first-generation girls reached adrenarche significantly earlier than Sylhetis [HR (CI): 2.8 (1.4–5.5]. In multivariate models, first generation girls still reached adrenarche earlier than Sylhetis after adjusting for height [HR(CI): 1.9 (0.9–4.1)] and weight [HR(CI):1.7 (0.8–3.8)], but these results were attenuated. We suggest that rapid catch-up growth experienced by first generation girls during early childhood may explain their advanced adrenarche. The environmental conditions leading to an earlier adrenarche, as well as the health implications of this early transition, merit further exploration.

There is increasing interest in the control and elimination of schistosomiasis. Little is known, however, about the likely effects of increasing water-body temperatures on transmission. We have developed an agent-based model of the temperature-sensitive stages of the Schistosoma and intermediate host snail life-cycles, parameterised using data from S. mansoni and Biomphalaria pfeifferi laboratory and field-based observations. Infection risk is calculated as the number of cercariae in the model, adjusted for their probability of causing infection. The number of snails in the model is approximately constant between 15–31°C. Outside this range, snail numbers drop sharply, and the snail population cannot survive outside the range 14–32°C. Mean snail generation time decreases with increasing temperature from 176 days at 14°C to 46 days at 26°C. Human infection risk is highest between 16–18°C and 1 pm and 6–10 pm in calm water, and 20–25°C and 12–4 pm in flowing water. Infection risk increases sharply when temperatures increase above the minimum necessary for sustained transmission. The model suggests that, in areas where S. mansoni is already endemic, warming of the water at transmission sites will have differential effects on both snails and parasites depending on abiotic properties of the water-body. Snail generation times will decrease in most areas, meaning that snail populations will recover faster from natural population reductions and from snail-control efforts. We suggest a link between the ecological properties of transmission sites and infection risk which could significantly affect the outcomes of interventions designed to alter water contact behaviour – proposing that such interventions are more likely to reduce infection levels at river locations than lakes, where infection risk remains high for longer. In cooler areas where snails are currently found, increasing temperatures may significantly increase infection risk, potentially leading to new, high-intensity foci of infection.

A number of studies have attempted to predict the effects of climate change on schistosomiasis risk. The importance of considering different species of intermediate host snails separately has never previously been explored. An agent-based model of water temperature and Biomphalaria pfeifferi population dynamics and Schistosoma mansoni transmission was parameterised to two additional species of snail: B. glabrata and B. alexandrina. Simulated B. alexandrina populations had lower minimum and maximum temperatures for survival than B. pfeifferi populations (12.5–29.5°C vs. 14.0–31.5°C). B. glabrata populations survived over a smaller range of temperatures than either B. pfeifferi or B. alexandrina (17.0°C–29.5°C). Infection risk peaked at 16.5°C, 25.0°C and 19.0°C respectively when B. pfeifferi, B. glabrata and B. alexandrina were simulated. For all species, infection risk increased sharply once a minimum temperature was reached. The results from all three species suggest that infection risk may increase dramatically with small increases in temperature in areas at or near the currents limits of schistosome transmission. The effect of small increases in temperature in areas where schistosomiasis is currently found will depend both on current temperatures and on the species of snail acting as intermediate host(s) in the area. In most areas where B. pfeifferi is the host, infection risk is likely to decrease. In cooler areas where B. glabrata is the host, infection risk may increase slightly. In cooler areas where B. alexandrina is the host, infection risk may more than double with only 2°C increase in temperature. Our results show that it is crucial to consider the species of intermediate host when attempting to predict the effects of climate change on schistosomiasis.

Information on the long-term effectiveness and tolerability of efavirenz- or nevirapine-based antiretroviral therapy (ART) in Africa is lacking. The primary objective of this retrospective observational study was to compare the long-term clinical and immunological outcomes of efavirenz- versus nevirapine-based first-line ART in a large government clinic in Ghana. The main outcomes were AIDS, death, ART-related toxicity, discontinuation of ART and a composite endpoint of death, AIDS or ART discontinuation. These time-to-event outcomes were compared using a Cox proportional hazards regression model. CD4 counts on ART were compared using a mixed-effects model. A total of 3990 patients started non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART between 2004 and 2010, of which 2369 (59%) were on efavirenz. No significant differences were apparent between each NNRTI for subsequent risk of AIDS, death or the composite of treatment failure; however, stavudine use was independently associated with an increased risk of death [adjusted hazard ratio (HR) 1.60 (95% CI: 1.21–2.11)]. There was an increased risk of early toxicity with nevirapine leading to discontinuation [adjusted HR 1.53 (95% CI: 1.23–1.97)], mostly due to excess skin rashes in the first 2 months of treatment; however, overall discontinuation rates were low. There was no difference in the long-term effectiveness of efavirenz- and nevirapine-based ART in this population; however, patients initiating nevirapine were more likely to develop early toxicity and discontinue this drug. The excess mortality observed in patients taking stavudine is of concern and should prompt increased efforts to replace it with alternative antiretroviral drugs in developing countries.

Background: Schistosoma mansoni infection is a persistent public health problemin many Kenyan communities. Although praziquantel is available, re-infectionafter chemotherapy treatment is inevitable, especially among children.Chemotherapy followed by intermittent mollusciciding of habitats ofBiomphalaria pfeifferi, the intermediate host snail, may havelonger term benefits, especially if timed to coincide with naturalfluctuations in snail populations. Methods: In this cohort study, the Kambu River (Intervention area) was molluscicidedintermittently for 4 years, after mass chemotherapy with praziquantelin the adjacent community of Darajani in January 1997. The nearby ThangeRiver was selected as a control (Non-intervention area), and its adjacentcommunity of Ulilinzi was treated with praziquantel in December 1996. Snailnumbers were recorded monthly at 9–10 sites along each river, whilerainfall data were collected monthly, and annual parasitological surveyswere undertaken in each village. The mollusciciding protocol was adapted tolocal conditions, and simplified to improve prospects for widespreadapplication. Results: After the initial reduction in prevalence attributable to chemotherapy, therewas a gradual increase in the prevalence and intensity of infection in thenon-intervention area, and significantly lower levels of re-infectionamongst inhabitants of the intervention area. Incidence ratio between areasadjusted for age and gender at the first follow-up survey, 5 weeksafter treatment in the non-intervention area and 4 months aftertreatment in the intervention area was not significant (few people turnedpositive), while during the following 4 annual surveys these ratios were0.58 (0.39-0.85), 0.33 (0.18-0.60), 0.14 (0.09-0.21) and 0.45 (0.26-0.75),respectively. Snail numbers were consistently low in the intervention areaas a result of the mollusciciding. Following termination of themollusciciding at the end of 2000, snail populations and infections insnails increased again in the intervention area. Conclusion: The results of this study demonstrate that in the Kenyan setting acombination of chemotherapy followed by intermittent mollusciciding can havelonger term benefits than chemotherapy alone.

In line with the NICE guidance, an NHS-commissioned case management intervention was provided for individuals receiving Incapacity Benefit payments for ≥3 years in the North East of England. The intervention aimed to improve the health of the participants. A total of 131 participants receiving the intervention were compared over 9 months with a (non-equivalent) comparison group of 229 receiving Incapacity Benefit payments and usual care. Health was measured using EQ-5D, EQ-VAS, SF-8, HADS and the Nordic Musculoskeletal questionnaire. Socio-demographic and health behaviour data were also collected. Fixed-effects linear models with correlated errors were used to compare health changes between groups over time. A preliminary cost–utility analysis was also conducted. The comparison group measures of health were stable over time. Starting from comparatively poor initial levels, case-management group generic (EQ5D, EQ-VAS) and mental health (HADS-A, HADS-D and SF8-MCS) measures improved within 6 months to similar levels found in the comparison group. Musculoskeletal (Nordic 2) and health behaviours did not improve. Tentative estimates of cost–utility suggest an intervention cost in the region of £16 700–£23 500 per QALY. Case management interventions may improve the health of Incapacity Benefit recipients. Further research is required to help confirm these pilot findings.