Publications

confers a 2•5-8•5-fold increased risk of death in children with severe malaria, and the artemisinins do not have substantial antimicrobial eff ects, the inclusion of children with concomitant invasive bacterial infection in our trial will have diluted the lifesaving benefi t of artesunate over quinine.This dilution might be an important contributor to the lower relative risk of death for artesunate versus quinine in African children (23%) than in Asian adults (35%) since bacteraemia is much less common in adults with severe malaria.The high incidence of concomitant bacterial infection does raise the important question of whether all children with a diagnosis of severe falciparum malaria should also receive a broad-spectrum parenteral antibiotic such as a third-generation cephalosporin.

No abstract is provided for this article.

Environmental change, including climate change, can cause rapid phenotypic change via both ecological and evolutionary processes. Because ecological and evolutionary dynamics are intimately linked, a major challenge is to identify their relative roles. We exactly decomposed the change in mean body weight in a free-living population of Soay sheep into all the processes that contribute to change. Ecological processes contribute most, with selection--the underpinning of adaptive evolution--explaining little of the observed phenotypic trend. Our results enable us to explain why selection has so little effect even though weight is heritable, and why environmental change has caused a decline in the body size of Soay sheep.

In malaria-endemic areas, Plasmodium falciparum parasitemia is common in apparently healthy children and severe malaria is commonly misdiagnosed in patients with incidental parasitemia. We assessed whether the plasma Plasmodium falciparum DNA concentration is a useful datum for distinguishing uncomplicated from severe malaria in African children and Asian adults. P. falciparum DNA concentrations were measured by real-time polymerase chain reaction (PCR) in 224 African children (111 with uncomplicated malaria and 113 with severe malaria) and 211 Asian adults (100 with uncomplicated malaria and 111 with severe malaria) presenting with acute falciparum malaria. The diagnostic accuracy of plasma P. falciparum DNA concentrations in identifying severe malaria was 0.834 for children and 0.788 for adults, similar to that of plasma P. falciparum HRP2 levels and substantially superior to that of parasite densities (P < .0001). The diagnostic accuracy of plasma P. falciparum DNA concentrations plus plasma P. falciparum HRP2 concentrations was significantly greater than that of plasma P. falciparum HRP2 concentrations alone (0.904 for children [P = .004] and 0.847 for adults [P = .003]). Quantitative real-time PCR measurement of parasite DNA in plasma is a useful method for diagnosing severe falciparum malaria on fresh or archived plasma samples.

Aims Experimental studies have suggested that constant intravenous infusion would be preferable to conventional intermittent bolus administration of beta‐lactam antibiotics for serious Gram‐negative infections. Severe melioidosis ( Burkholderia pseudomallei infection) carries a mortality over 40% despite treatment with high dose ceftazidime. The aim of this study was to measure the pharmacokinetic and pharmacodynamic effects of continuous infusion of ceftazidime vs intermittent bolus dosing in septicaemic melioidosis. Methods Patients with suspected septicaemic melioidosis were randomised to receive ceftazidime 40 mg kg −1 8 hourly by bolus injection or 4 mg kg −1 h −1 by constant infusion following a 12 mg kg −1 priming dose and pharmacokinetic and pharmacodynamic parameters were compared. Results Of the 34 patients studied 16 (59%) died. Twenty patients had cultures positive for B. pseudomallei of whom 12 (60%) died. The median MIC 90 of B. pseudomallei was 2 mg l −1 , giving a minimum target concentration (4*MIC) of 8 mg l −1 . The median (range) estimated total apparent volume of distribution, systemic clearance and terminal elimination half‐lives of ceftazidime were 0.468 (0.241–0.573) l kg −1 , 0.058 (0.005–0.159) l kg −1 h −1 and 7.74 (1.95–44.71) h, respectively. Clearance of ceftazidime and creatinine clearance were correlated closely ( r = 0.71; P &lt; 0.001) and there was no evidence of significant nonrenal clearance. Conclusions Simulations based on these data and the ceftazidime sensitivity of the B. pseudomallei isolates indicated that administration by constant infusion would allow significant dose reduction and cost saving. With conventional 8 h intermittent dosing to patients with normal renal function, plasma ceftazidime concentrations could fall below the target concentration but this would be unlikely with a constant infusion. Correction for renal failure, which is common in patients with meliodosis is Clearance = k * creatinine clearance where k = 0.72. Calculation of a loading dose gives median (range) values of loading dose, D L of 18.7 mg kg −1 (9.5–23) and infusion rate I = 3.5 mg kg −1 h −1 (0.4–13) (which equals 84 mg kg −1 day −1 ). A nomogram for adjustment in renal failure is given.

No abstract is provided for this article.

<title>Abstract</title> Pathogen-mediated balancing selection shapes host ecology and evolution across the tree of life, fueling a co-evolutionary arms race based on frequency-dependent adaptations of hosts and counter-adaptations of pathogens. While rare immune genotypes are predicted to be more resistant to pathogens, evidence for this rare allele-advantage and negative frequency-dependent feedbacks has only been observed in model species or inferred from short-term field observations. Evidence from long-term data and wild populations is missing. Here, we leverage two decades of immune genetic and disease surveillance data from over 1,500 wild meerkats (<italic>Suricata suricatta</italic>) to reveal co-evolutionary dynamics between the Major Histocompatibility Complex (MHC) and <italic>Mycobacterium suricattae</italic>, causing tuberculosis (TB). We uncover fluctuating adaptive MHC allelic, functional and haplotypic diversity over time compared with stable neutral genetic diversity. Crucially, we show that meerkats carrying the MHC allele Susu-DRB*13 faced initially higher TB infection probability, with the effect reversing over the course of the study, followed again by an increase in frequency of Susu-DRB*13. Similarly, TB progression first accelerated in meerkats carrying Susu-DRB*13, but decelerated thereafter. Susu-DRB*13 (and its supertype/haplotype) also prolonged survival in individuals with clinical TB. Our results present strong evidence that the rare allele-advantage propels negative frequency-dependent selection in a wild mammal. We discuss meerkats’ social structure as possible reasons for these comparably rapid co-evolutionary dynamics.

Artemisinin (qinghaosu) and its derivatives are rapidly effective antimalarial drugs derived from a Chinese plant. Preliminary studies suggest that these drugs may be more effective than quinine in the treatment of severe malaria. We studied artemether in Vietnam, where Plasmodium falciparum has reduced sensitivity to quinine.

Southeast Asia, a vibrant region that has recently undergone unprecedented economic development, is regarded as a global hotspot for the emergence and spread of antimicrobial resistance (AMR). Understanding AMR in Southeast Asia is crucial for assessing how to control AMR on an international scale. Here we (i) describe the current AMR situation in Southeast Asia, (ii) explore the mechanisms that make Southeast Asia a focal region for the emergence of AMR, and (iii) propose ways in which Southeast Asia could contribute to a global solution.

Background Primaquine is the only drug consistently effective against mature gametocytes of Plasmodium falciparum. The transmission blocking dose of primaquine previously recommended was 0.75mg/kg (adult dose 45mg) but its deployment was limited because of concerns over haemolytic effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency is an inherited X-linked enzymatic defect that affects an estimated 400 million people around the world with high frequencies (15–20%) in populations living in malarious areas. To reduce transmission in low transmission settings and facilitate elimination of P. falciparum, the World Health Organization now recommends adding a single dose of 0.25mg/kg (adult dose 15mg) to Artemisinin-based Combination Therapies (ACTs) without G6PD testing. Direct evidence of the safety of this low dose is lacking. Adverse events and haemoglobin variations after this treatment were assessed in both G6PD normal and deficient subjects in the context of targeted malaria elimination in a malaria endemic area on the North-Western Myanmar-Thailand border where prevalence of G6PD deficiency (Mahidol variant) approximates 15%. Methods and Findings The tolerability and safety of primaquine (single dose 0.25 mg base/kg) combined with dihydroartemisinin-piperaquine (DHA-PPQ) given three times at monthly intervals was assessed in 819 subjects. Haemoglobin concentrations were estimated over the six months preceding the ACT + primaquine rounds of mass drug administration. G6PD deficiency was assessed with a phenotypic test and genotyping was performed in male subjects with deficient phenotypes and in all females. Fractional haemoglobin changes in relation to G6PD phenotype and genotype and primaquine round were assessed using linear mixed-effects models. No adverse events related to primaquine were reported during the trial. Mean fractional haemoglobin changes after each primaquine treatment in G6PD deficient subjects (-5.0%, -4.2% and -4.7%) were greater than in G6PD normal subjects (0.3%, -0.8 and -1.7%) but were clinically insignificant. Fractional drops in haemoglobin concentration larger than 25% following single dose primaquine were observed in 1.8% of the population but were asymptomatic. Conclusions The single low dose (0.25mg/kg) of primaquine is clinically well tolerated and can be used safely without prior G6PD testing in populations with high prevalence of G6PD deficiency. The present evidence supports a broader use of low dose primaquine without G6PD testing for the treatment and elimination of falciparum malaria. Trial Registration ClinicalTrials.gov NCT01872702

Melioidosis is a tropical infectious disease associated with significant mortality. Most deaths occur early and are caused by fulminant sepsis.In this randomized, placebo-controlled trial, we assessed the efficacy of lenograstim (granulocyte colony-stimulating factor [G-CSF], 263 mu g per day administered intravenously) in ceftazidime-treated patients with severe sepsis caused by suspected melioidosis in Thailand.Over a 27-month period, 60 patients were enrolled to receive either G-CSF (30 patients, 18 of whom had culture-confirmed melioidosis) or placebo (30 patients, 23 of whom had culture-confirmed melioidosis). Mortality rates were similar in both groups (G-CSF group, 70%; placebo group, 87%; risk ratio, 0.81; 95% confidence interval, 0.61-1.06; P=.2), including among patients with confirmed melioidosis (83% vs. 96%; P=.3). The duration of survival was longer for patients who received G-CSF than for patients who received placebo (33 h vs. 18.6 h; hazard ratio, 0.56; 95% confidence interval, 0.31-1.00; P=.05).Receipt of G-CSF is associated with a longer duration of survival but is not associated with a mortality benefit in patients with severe sepsis who are suspected of having melioidosis in Thailand. We hypothesize that G-CSF may "buy time" for severely septic patients, but survival is more likely to be improved by management of associated metabolic abnormalities and organ dysfunction associated with severe sepsis.

Responses of natural populations to climate change are driven by how multiple climatic and biotic factors affect survival and reproduction, and ultimately shape population dynamics. Yet, we lack a general understanding of the role of such mechanisms in moderating climate-change impacts across different species. Here, we synthesize how the joint effects of climate and biotic interactions on different vital rates impact population change, using 41 species from trees to primates. We show that the effects of multiple climatic drivers tend to exacerbate population responses to climate change in most species. Importantly however, density feedbacks consistently buffer the effects of climate drivers on populations. In all species considered in our analyses, such interactions among climate and density had starkly different effects depending on the age, size, or life-cycle stage of individuals, highlighting that climate-change impacts can hardly be inferred from single drivers or ages or life-cycle stages, regardless of the life-history of species. Our work thus advances our ability to make generalizations about key pathways of climate-change impacts on populations.