Publications

Most adults dying from falciparum malaria will die within 48 hours of their hospitalisation. An essential component of early supportive care is the rapid identification of patients at greatest risk. In resource-poor settings, where most patients with falciparum malaria are managed, decisions regarding patient care must frequently be made using clinical evaluation alone.We retrospectively analysed 4 studies of 1801 adults with severe falciparum malaria to determine whether the presence of simple clinical findings might assist patient triage.If present on admission, shock, oligo-anuria, hypo- or hyperglycaemia, an increased respiratory rate, a decreased Glasgow Coma Score and an absence of fever were independently predictive of death. The variables were used to construct a simple clinical algorithm. When applied to the 1801 patients, this algorithm's positive predictive value for survival to 48 hours was 99.4 (95% confidence interval (CI) 97.8-99.9) and for survival to discharge 96.9% (95% CI 94.3-98.5). In the 712 patients receiving artesunate, the algorithm's positive predictive value for survival to 48 hours was 100% (95% CI 97.3-100) and to discharge was 98.5% (95% CI 94.8-99.8).Simple clinical findings are closely linked to the pathophysiology of severe falciparum malaria in adults. A basic algorithm employing these indices can facilitate the triage of patients in settings where intensive care services are limited. Patients classified as low-risk by this algorithm can be safely managed initially on a general ward whilst awaiting senior clinical review and laboratory data.

No abstract is provided for this article.

The specialization of individuals in specific behavioural tasks is often attributed either to irreversible differences in development, which generate functionally divergent cooperative phenotypes, or to age-related changes in the relative frequency with which individuals perform different cooperative activities; both of which are common in many insect caste systems. However, contrasts in cooperative behaviour can take other forms and, to date, few studies of cooperative behaviour in vertebrates have explored the effects of age, adult phenotype and early development on individual differences in cooperative behaviour in sufficient detail to discriminate between these alternatives. Here, we used multinomial models to quantify the extent of behavioural specialization within nonreproductive Damaraland mole-rats, Fukomys damarensis, at different ages. We showed that, although there were large differences between individuals in their contribution to cooperative activities, there was no evidence of individual specialization in cooperative activities that resembled the differences found in insect societies with distinct castes where individual contributions to different activities are negatively related to each other. Instead, individual differences in helping behaviour appeared to be the result of age-related changes in the extent to which individuals committed to all forms of helping. A similar pattern is observed in cooperatively breeding meerkats, Suricata suricatta, and there is no unequivocal evidence of caste differentiation in any cooperative vertebrate. The multinomial models we employed offer a powerful heuristic tool to explore task specialization and developmental divergence across social taxa and provide an analytical approach that may be useful in exploring the distribution of different forms of helping behaviour in other cooperative species.

Summary Resource availability plays a key role in driving variation in somatic growth and body condition, and the factors determining access to resources vary considerably across life stages. Parents and carers may exert important influences in early life, when individuals are nutritionally dependent, with abiotic environmental effects having stronger influences later in development as individuals forage independently. Most studies have measured specific factors influencing growth across development or have compared relative influences of different factors within specific life stages. Such studies may not capture whether early‐life factors continue to have delayed effects at later stages, or whether social factors change when individuals become nutritionally independent and adults become competitors for, rather than providers of, food. Here, we examined variation in the influence of the abiotic, social and maternal environment on growth across life stages in a wild population of cooperatively breeding meerkats. Cooperatively breeding vertebrates are ideal for investigating environmental influences on growth. In addition to experiencing highly variable abiotic conditions, cooperative breeders are typified by heterogeneity both among breeders, with mothers varying in age and social status, and in the number of carers present. Recent rainfall had a consistently marked effect on growth across life stages, yet other seasonal terms only influenced growth during stages when individuals were growing fastest. Group size and maternal dominance status had positive effects on growth during the period of nutritional dependence on carers, but did not influence mass at emergence (at 1 month) or growth at independent stages (>4 months). Pups born to older mothers were lighter at 1 month of age and subsequently grew faster as subadults. Males grew faster than females during the juvenile and subadult stage only. Our findings demonstrate the complex ways in which the external environment influences development in a cooperative mammal. Individuals are most sensitive to social and maternal factors during the period of nutritional dependence on carers, whereas direct environmental effects are relatively more important later in development. Understanding the way in which environmental sensitivity varies across life stages is likely to be an important consideration in predicting trait responses to environmental change.

Abstract Background The antirelapse efficacy of primaquine is related to the total dose administered, whereas the risks of haemolysis and gastrointestinal intolerance are associated with the daily dose administered. National Malaria Control Programmes require local information on efficacy, tolerability and safety to optimize antimalarial treatment policies for Plasmodium vivax malaria control and elimination efforts. Methods A living systematic review identified efficacy studies of uncomplicated P. vivax malaria including patients treated with daily primaquine regimens, published since January 1, 2000. Available data were pooled and an R Shiny app was developed to integrate statistical analyses performed using R and Stata that assessed the impact of primaquine mg/kg dose on efficacy, hematological safety and gastrointestinal tolerability. Results As of January 16, 2025, a total of 9,270 individual patient data records from 41 studies have been collated into the standardized repository. Open-access automated reports were generated for user-selected countries or regions to investigate location specific effects of primaquine dose on efficacy, safety and tolerability. The reports include visual and tabular displays of the outcomes. Conclusions These automated reports leverage a large database to provide accessible data for national and regional policy makers and researchers to assess the clinical consequences of different primaquine regimens in different endemic settings. The reports will inform local and regional policy decisions and research priorities in vivax-endemic areas.

Social structure, limited dispersal, and spatial heterogeneity in resources are ubiquitous in wild vertebrate populations. As a result, relatives share environments as well as genes, and environmental and genetic sources of similarity between individuals are potentially confounded. Quantitative genetic studies in the wild therefore typically account for easily captured shared environmental effects (e.g., parent, nest, or region). Fine-scale spatial effects are likely to be just as important in wild vertebrates, but have been largely ignored. We used data from wild red deer to build "animal models" to estimate additive genetic variance and heritability in four female traits (spring and rut home range size, offspring birth weight, and lifetime breeding success). We then, separately, incorporated spatial autocorrelation and a matrix of home range overlap into these models to estimate the effect of location or shared habitat on phenotypic variation. These terms explained a substantial amount of variation in all traits and their inclusion resulted in reductions in heritability estimates, up to an order of magnitude up for home range size. Our results highlight the potential of multiple covariance matrices to dissect environmental, social, and genetic contributions to phenotypic variation, and the importance of considering fine-scale spatial processes in quantitative genetic studies.

Background. Antipyretics reduce the prolonged, high fever characteristic of typhoid fever. The benefits of nonsteroidal drugs in this role have not been quantified. There have been concerns about the safety of antipyretics in typhoid. Methods. In a double blind randomized study, 80 Vietnamese children with uncomplicated typhoid fever were randomized to receive identical syrup preparations of ibuprofen (10 mg/kg) or paracetamol (12 mg/kg) every 6 h until 36 h after defervescence. Children with a nalidixic acid-susceptible (NaS) isolate of Salmonella typhi were treated with ofloxacin (15 mg/kg/day) for 3 days and those with a nalidixic acid-resistant (NaR) isolate were treated for 7 days. Results. S. typhi was isolated from 36 of 40 children randomized to ibuprofen (11 isolates NaR) and 37 of 40 randomized to paracetamol (13 isolates NaR). The median (range) fever clearance time (hours) was shorter in the ibuprofen group than the paracetamol group (68, 4 to 260 vs. 104, 12 to 404; P = 0.055) as was the area under the temperature time curve above 37°C (74, 0 to 237 vs. 127, 0 to 573; P = 0.013). The differences occurred predominantly in the children infected with a NaRS. typhi whose infections responded more slowly to antibiotic treatment. There were no major side effects associated with the use of either drug. There were no differences between the two treatment arms in the concentrations of circulating interleukin-6 and tumor necrosis factor α during the course of treatment. Conclusion. The antipyretic effect of ibuprofen is superior to that of paracetamol in children with typhoid fever, particularly those with prolonged fever. Both antipyretics appeared to be safe.

Artemether-lumefantrine is the most widely used antimalarial artemisinin-based combination treatment. Recent studies have suggested that day 7 plasma concentrations of the potent metabolite desbutyl-lumefantrine correlate better with treatment outcomes than those of lumefantrine. Low cure rates have been reported in pregnant women with uncomplicated falciparum malaria treated with artemether-lumefantrine in northwest Thailand. A simultaneous pharmacokinetic drug-metabolite model was developed based on dense venous and sparse capillary lumefantrine and desbutyl-lumefantrine plasma samples from 116 pregnant patients on the Thailand-Myanmar border. The best model was used to evaluate therapeutic outcomes with a time-to-event approach. Lumefantrine and desbutyl-lumefantrine concentrations, implemented in an Emax model, both predicted treatment outcomes, but lumefantrine provided better predictive power. A combined model including both lumefantrine and desbutyl-lumefantrine did not improve the model further. Simulations suggested that cure rates in pregnant women with falciparum malaria could be increased by prolonging the treatment course. (These trials were registered at controlled-trials.com [ISRCTN 86353884].).

No abstract is provided for this article.

No abstract is provided for this article.

A simple and rapid liquid chromatographic assay for the evaluation of potentially counterfeit oseltamivir (Tamiflu®) has been developed and assessed. The assay uses approximately 1mg Tamiflu® powder when used for authentication and content estimate. The procedure was validated using 50 replicates analysed during five independent series with a total R.S.D. of 11.2%. The assay can also be used to monitor the exact content of oseltamivir in Tamiflu® capsules. One Tamiflu® capsule was transferred to a 250mL volumetric flask and 150mL water was added. The flask was placed in an ultrasonic bath at 40°C for 20min to dissolve the capsule. The solution was allowed to cool to room temperature before the flask was filled up to the mark (250mL). A small aliquot was centrifuged and then directly injected into the LC-system for quantification. Oseltamivir was analysed by liquid chromatography with UV detection on a Hypersil Gold column (150mm×4.6mm) using a mobile phase containing methanol–phosphate buffer (pH 2.5; 0.1M) (50:50, v/v) at a flow rate of 1.0mL/min. The assay was implemented for the analysis of Tamiflu® purchased over the Internet and at local pharmacies in Thailand and Vietnam.

Between 1991 and 1996, 372 pregnant women with uncomplicated, multidrug-resistant Plasmodium falciparum malaria, living on the western border of Thailand, were treated with either mefloquine (N = 194), quinine (N = 93) or both drugs (N = 85). Antimalarial treatment was generally well tolerated; the most common side-effects were dizziness (42%) and tinnitus (35%) following quinine, and anorexia (23%) and dizziness (36%) following mefloquine. In the patients treated for primary infections with melfloquine, 6% failed to clear their parasitaemia by day 7 and 28% failed by day 42. The corresponding figures for quinine were 4% and 23%, respectively. The failure rates in the 117 women treated for recrudescent infections were higher, the increase being significant for quinine (38%; P = 0.03) but not for mefloquine (37%). The percentage of pregnant women who had patent gametocytaemia on presentation ranged from 4%-19%. Over 50% of the patients were anaemic (haematocrit < 30%) on presentation and 52% of those not anaemic on enrolment developed anaemia during follow-up. Mefloquine and quinine, the only antimalarials generally available for the treatment of highly drug-resistant P. falciparum in pregnancy, give unsatisfactory treatment responses when used as single agents. New, safe and effective regimens are needed for the treatment of pregnant women with multidrug-resistant falciparum malaria.

Van Tienderen recently published a method that links selection gradients between a phenotypic trait and multiple fitness components with the effects of these fitness components on the population growth rate (mean absolute fitness). The method allows selection to be simultaneously estimated across multiple fitness components in a population dynamic framework. In this paper we apply the method to a population of red deer living in the North Block of the Isle of Rum, Scotland. We show that (1) selection on birth date and birth weight can operate through multiple fitness components simultaneously; (2) our estimates of the response to selection are consistent with the observed change in trait values that we cannot explain with environmental and phenotypic covariates; (3) selection on both traits has fluctuated over the course of the study; (4) selection operates through different fitness components in different years; and (5) no environmental covariates correlate with selection because different fitness components respond to density and climatic variation in contrasting ways.

<ns4:p><ns4:bold>Background</ns4:bold>: Inherited red blood cell disorders are prevalent in populations living in malaria endemic areas; G6PD deficiency is associated with oxidant-induced haemolysis and abnormal haemoglobin variants may cause chronic anaemia. In pregnant women, microcytic anaemia caused by haemoglobinopathies mimics iron deficiency, complicating diagnosis and treatment. Anaemia during pregnancy is associated with morbidity and mortality. The aim of this study was to characterise the prevalence of G6PD deficiency and haemoglobinopathies among the pregnant population living along the Thailand-Myanmar border. Pregnant women attending antenatal clinics in this area belong to several distinct ethnic groups.</ns4:p><ns4:p> <ns4:bold>Methods</ns4:bold>: Data were available for 13,520 women attending antenatal care between July 2012 and September 2016. Screening for G6PD deficiency was done by fluorescent spot test routinely. G6PD genotyping and quantitative phenotyping by spectrophotometry were analysed in a subsample of women. Haemoglobin variants were diagnosed by HPLC or capillary electrophoresis and molecular methods. The prevalence and distribution of inherited red blood cell disorders was analysed with respect to ethnicity.</ns4:p><ns4:p> <ns4:bold>Results</ns4:bold>: G6PD deficiency was common, especially in the Sgaw Karen ethnic group, in whom the G6PD Mahidol variant allele frequency was 20.7%. Quantitative G6PD phenotyping showed that 60.5% of heterozygous women had an intermediate enzymatic activity between 30% and 70% of the population median. HbE, beta-thalassaemia trait and Hb Constant Spring were found overall in 15.6% of women. Only 45.2% of women with low percentage of HbA<ns4:sub>2</ns4:sub> were carriers of mutations on the alpha globin genes.</ns4:p><ns4:p> <ns4:bold>Conclusions</ns4:bold>: Distribution of G6PD and haemoglobin variants varied among the different ethnic groups, but the prevalence was generally high throughout the cohort. These findings encourage the implementation of an extended program of information and genetic counselling to women of reproductive age and will help inform future studies and current clinical management of anaemia in the pregnant population in this region.</ns4:p>