Publications

In societies of cooperative vertebrates, individual differences in contributions to offspring care are commonly substantial. Recent attempts to explain the causes of this variation have focused on correlations between contributions to care and the protein hormone prolactin, or the steroid hormone testosterone. However, such studies have seldom considered the importance of other hormones or controlled for non-hormonal factors that are correlative with both individual hormone levels and contributions to care. Using multivariate statistics, we show that hormone levels explain significant variation in contributions to pup-feeding by male meerkats, even after controlling for non-hormonal effects. However, long-term contributions to pup provisioning were significantly and positively correlated with plasma levels of cortisol rather than prolactin, while plasma levels of testosterone were not related to individual patterns of pup-feeding. Furthermore, a playback experiment that used pup begging calls to increase the feeding rates of male helpers gave rise to parallel increases in plasma cortisol levels, whilst prolactin and testosterone levels remained unchanged. Our findings confirm that hormones can explain significant amounts of variation in contributions to offspring feeding, and that cortisol, not prolactin, is the hormone most strongly associated with pup-feeding in cooperative male meerkats.

No abstract is provided for this article.

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.

Amodiaquine is effective for the treatment of Plasmodium vivax malaria, but there is little information on the pharmacokinetic and pharmacodynamic properties of amodiaquine in pregnant women with malaria. This study evaluated the population pharmacokinetic and pharmacodynamic properties of amodiaquine and its biologically active metabolite, desethylamodiaquine, in pregnant women with P. vivax infection and again after delivery. Twenty-seven pregnant women infected with P. vivax malaria on the Thai-Myanmar border were treated with amodiaquine monotherapy (10 mg/kg/day) once daily for 3 days. Nineteen women, with and without P. vivax infections, returned to receive the same amodiaquine dose postpartum. Nonlinear mixed-effects modeling was used to evaluate the population pharmacokinetic and pharmacodynamic properties of amodiaquine and desethylamodiaquine. Amodiaquine plasma concentrations were described accurately by lagged first-order absorption with a two-compartment disposition model followed by a three-compartment disposition of desethylamodiaquine under the assumption of complete in vivo conversion. Body weight was implemented as an allometric function on all clearance and volume parameters. Amodiaquine clearance decreased linearly with age, and absorption lag time was reduced in pregnant patients. Recurrent malaria infections in pregnant women were modeled with a time-to-event model consisting of a constant-hazard function with an inhibitory effect of desethylamodiaquine. Amodiaquine treatment reduced the risk of recurrent infections from 22.2% to 7.4% at day 35. In conclusion, pregnancy did not have a clinically relevant impact on the pharmacokinetic properties of amodiaquine or desethylamodiaquine. No dose adjustments are required in pregnancy.

Nalidixic acid-resistant Salmonella typhi (NARST) was first isolated in Viet Nam in 1993. Analysis of the quinolone resistance-determining region of gyrA in 20 NARST isolates by polymerase chain reaction and single-stranded conformational polymorphism yielded two novel patterns: pattern II corresponding to a point mutation at nucleotide 87 Asp → Gly (n = 17), and pattern III corresponding to a point mutation at nucleotide 83 Ser → Phe (n = 3). In trials of short-course ofloxacin therapy for uncomplicated typhoid, 117 (78%) of 150 patients were infected with multidrug-resistant S. typhi, 18 (15%) of which were NARST. The median time to fever clearance was 156 hours (range, 30-366 hours) for patients infected with NARST and 84 hours (range, 12-378 hours) for those infected with nalidixic acid-susceptible strains (P < .001). Six (33.3%) of 18 NARST infections required retreatment, whereas 1 (0.8%) of 132 infections due to susceptible strains required retreatment (relative risk = 44; 95% confidence interval = 5.6-345; P < .0001). We recommend that short courses of quinolones not be used in patients infected with NARST.

Paul Newton and colleagues argue that public health, and not intellectual property or trade issues, should be the prime consideration in defining and combating counterfeit medicines, and that the World Health Organization (WHO) should take a more prominent role.

Dihydroartemisinin-piperaquine is a fixed-dose artemisinin-based combination treatment. Some antimalarials have altered pharmacokinetics in pregnancy. Pregnant women in the 2nd or 3rd trimester and matched nonpregnant women with uncomplicated falciparum malaria were treated with a total of 6.4 mg/kg of body weight dihydroartemisinin and 51.2 mg/kg piperaquine once daily for 3 days. Venous blood samples were drawn at prespecified time points over 9 weeks. Plasma dihydroartemisinin and piperaquine concentrations were analyzed by liquid chromatography-mass spectrometry. Piperaquine and dihydroartemisinin pharmacokinetics were well described. There were no significant differences in total piperaquine exposure ( P = 0.80) or drug exposure during the terminal elimination phase (72 h to infinity) ( P = 0.64) between the two groups. The apparent volume of distribution of piperaquine was significantly smaller (602 liters/kg versus 877 liters/kg) in pregnant women than in nonpregnant women ( P = 0.0057), and the terminal elimination half-life was significantly shorter (17.8 days versus 25.6 days; P = 0.0023). Dihydroartemisinin exposure after the first dose was significantly lower (844 h × ng/ml versus 1,220 h × ng/ml, P = 0.0021) in pregnant women, but there were no significant differences in total dihydroartemisinin exposure or maximum concentrations between the two groups. There were no significant differences in any pharmacokinetic parameters between the second and third trimester. These results obtained through noncompartmental analysis suggest that in the treatment of falciparum malaria, there are no clinically important differences in the pharmacokinetics of dihydroartemisinin or piperaquine between pregnant and nonpregnant women. However, a more detailed analysis using population pharmacokinetic modeling is needed to fully investigate the differences found for some of the pharmacokinetic parameters, such as the terminal half-life.

The production of substandard and fake drugs is a vast and underreported problem, particularly affecting poorer countries. Cockburn and colleagues argue that the pharmaceutical industry and governments must both take action.

There are ~660,000 deaths from severe malaria each year. Intravenous artesunate (i.v. ARS) is the first‐line treatment in adults and children. To optimize the dosing regimen of i.v. ARS, the largest pooled population pharmacokinetic study to date of the active metabolite dihydroartemisinin (DHA) was performed. The pooled dataset consisted of 71 adults and 195 children with severe malaria, with a mixture of sparse and rich sampling within the first 12 h after drug administration. A one‐compartment model described the population pharmacokinetics of DHA adequately. Body weight had the greatest impact on DHA pharmacokinetics, resulting in lower DHA exposure for smaller children (6–10 kg) than adults. Post hoc estimates of DHA exposure were not significantly associated with parasitological outcomes. Comparable DHA exposure in smaller children and adults after i.v. ARS was achieved under a dose modification for intramuscular ARS proposed in a separate analysis of children. CPT Pharmacometrics Syst. Pharmacol . (2014) 3, e145; doi: 10.1038/psp.2014.43 ; published online 05 November 2014

The pathogenesis of tuberculous meningitis remains unclear, and there are few data describing the kinetics of the immune response during the course of its treatment. We measured concentrations of pro- and anti-inflammatory cytokines in serial blood and cerebrospinal fluid (CSF) samples from 21 adults who were being treated for tuberculous meningitis. CSF concentrations of soluble tumor necrosis factor-alpha receptors and of matrix metalloprotein-9 and its tissue inhibitor were also measured, and blood-brain barrier permeability was assessed by the albumin and IgG partition indices. CSF concentrations of lactate, interleukin-8, and interferon-gamma were high before treatment and then decreased rapidly with antituberculosis chemotherapy. However, significant immune activation and blood-brain barrier dysfunction were still apparent after 60 days of treatment. Death was associated with high initial CSF concentrations of lactate, low numbers of white blood cells, in particular neutrophils, and low CSF glucose levels.

The emergence and spread of Plasmodium falciparum lineages resistant to artemisinins is threatening the efficacy of Artemisinin Combination Therapies (ACTs), the global first-line treatment for falciparum malaria. Artemisinin resistance is a complex genetic trait in which nonsynonymous SNPs in PfK13 cooperate with other, currently unknown, genetic variations to mediate the resistance phenotype. To identify these new molecular factors, we carried out population genomic/transcriptomic analyses of P. falciparum collected from patients with uncomplicated malaria in Cambodia and Vietnam between 2018 and 2020. GWAS confirmed the strong association of mutations in PfK13, in particular C580Y, with artemisinin resistance, but also uncovered significant associations with several additional polymorphisms, including PfRad5 in which two nonsynonymous mutations (N1131I and N821K) were independently associated with artemisinin resistance since its emergence. In addition, an intronic SNP in the gene encoding a WD40 repeat-containing protein on chromosome 11 ( PfWD11 ) was associated. Population transcriptome analyses revealed a defined set of genes whose steady-state levels of mRNA and/or alternatively spliced or antisense transcripts correlated with artemisinin resistance. Using transcriptomics of sequential parasite samples after the start of ACT treatment, we also characterized in vivo transcriptional responses to artemisinins and demonstrated the capacity of the resistant parasites to decelerate their intraerythrocytic developmental cycle, which can contribute to the resistant phenotype. During this process, both PfRAD5 and PfWD11 appear to upregulate an alternatively spliced isoform suggesting a contribution to the protective response to artemisinins. Comparison with historical samples indicated that PfRad5 and PfWD11 have been under selective pressure since the emergence of artemisinin resistance in the Greater Mekong Subregion as covariates of PfK13. Hence both genes now represent new high-confidence markers presumably as the key elements of the artemisinin resistance genetic background.