Publications

Mass primaquine treatment to eliminate vivax malaria: lessons from the past

Recent successes in malaria control have put malaria eradication back on the public health agenda. A significant obstacle to malaria elimination in Asia is the large burden of Plasmodium vivax, which is more difficult to eliminate than Plasmodium falciparum. Persistent P. vivax liver stages can be eliminated only by radical treatment with a ≥ seven-day course of an 8-aminoquinoline, with the attendant risk of acute haemolytic anaemia in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Primaquine is the only generally available 8-aminoquinoline. Testing for G6PD deficiency is not widely available, and so whilst it is widely recommended, primaquine is often not prescribed. In the past, some countries aiming for vivax malaria eradication deployed mass treatments with primaquine on a massive scale, without G6PD testing. In Azerbaijan, Tajikistan (formerly USSR), North Afghanistan and DPR Korea 8,270,185 people received either a 14-day "standard" or a 17-day "interrupted" primaquine treatment to control post-eradication malaria epidemics. These mass primaquine preventive treatment campaigns were conducted by dedicated teams who administered the drugs under supervision and then monitored the population for adverse events. Despite estimated G6PD prevalences up to 38.7%, the reported frequency of severe adverse events related to primaquine was very low. This experience shows that with careful planning and implementation of mass treatment strategies using primaquine and adequate medical support to manage haemolytic toxicity, it is possible to achieve high population coverage, substantially reduce malaria transmission, and manage the risk of severe acute haemolytic anaemia in communities with a relatively high prevalence of G6PD deficiency safely.

Multiple spatial behaviours govern social network positions in a wild ungulate

The structure of wild animal social systems depends on a complex combination of intrinsic and extrinsic drivers. Population structuring and spatial behaviour are key determinants of individuals’ observed social behaviour, but quantifying these spatial components alongside multiple other drivers remains difficult due to data scarcity and analytical complexity. We used a 43-year dataset detailing a wild red deer population to investigate how individuals’ spatial behaviours drive social network positioning, while simultaneously assessing other potential contributing factors. Using Integrated Nested Laplace Approximation (INLA) multi-matrix animal models, we demonstrate that social network positions are shaped by two-dimensional landscape locations, pairwise space sharing, individual range size, and spatial and temporal variation in population density, alongside smaller but detectable impacts of a selection of individual-level phenotypic traits. These results indicate strong, multifaceted spatiotemporal structuring in this society, emphasising the importance of considering multiple spatial components when investigating the causes and consequences of sociality. Authorship Statement GFA conceived the study, analysed the data, and wrote the manuscript, advised by JAF. AM and SM collected the data. JAF, JMP, THCB, and DN commented on the manuscript. Data Accessibility Statement The code used here is available at https://github.com/gfalbery/Spocial_Deer . On acceptance, the data will be uploaded to the same repo, which will be archived on Zenodo.

NOVEL CLINICAL STUDY AND PHARMACOMETRIC MODELLING TO FIND THE MINIMUM INHIBITORY CONCENTRATION (MIC) OF A NEW ANTIMALARIAL

No abstract is provided for this article.

Correction to ‘Estimation of gestational age from fundal height: a solution for resource-poor settings’

Defining Falciparum-Malaria-Attributable Severe Febrile Illness in Moderate-to-High Transmission Settings on the Basis of Plasma PfHRP2 Concentration

Background. In malaria-endemic settings, asymptomatic parasitemia complicates the diagnosis of malaria. Histidine-rich protein 2 (HRP2) is produced by Plasmodium falciparum, and its plasma concentration reflects the total body parasite burden. We aimed to define the malaria-attributable fraction of severe febrile illness, using the distributions of plasma P. falciparum HRP2 (PfHRP2) concentrations from parasitemic children with different clinical presentations.

Level 1 fluid warmer and Gelofusine

No abstract is provided for this article.

The transcriptome of <i>Plasmodium vivax</i> reveals divergence and diversity of transcriptional regulation in malaria parasites

Plasmodium vivax causes over 100 million clinical infections each year. Primarily because of the lack of a suitable culture system, our understanding of the biology of this parasite lags significantly behind that of the more deadly species P. falciparum . Here, we present the complete transcriptional profile throughout the 48-h intraerythrocytic cycle of three distinct P. vivax isolates. This approach identifies strain specific patterns of expression for subsets of genes predicted to encode proteins associated with virulence and host pathogen interactions. Comparison to P. falciparum revealed significant differences in the expression of genes involved in crucial cellular functions that underpin the biological differences between the two parasite species. These data provide insights into the biology of P. vivax and constitute an important resource for the development of therapeutic approaches.

Ecological correlates of extra-group paternity in mammals

Extra-group paternity (EGP) can form an important part of the mating system in birds and mammals. However, our present understanding of its extent and ecology comes primarily from birds. Here, we use data from 26 species and phylogenetic comparative methods to explore interspecific variation in EGP in mammals and test prominent ecological hypotheses for this variation. We found extensive EGP (46% of species showed more than 20% EGP), indicating that EGP is likely to play an important role in the mating system and the dynamics of sexual selection in mammals. Variation in EGP was most closely correlated with the length of the mating season. As the length of the mating season increased, EGP declined, suggesting that it is increasingly difficult for males to monopolize their social mates when mating seasons are short and overlap among females in oestrus is likely to be high. EGP was secondarily correlated with the number of females in a breeding group, consistent with the idea that as female clustering increases, males are less able to monopolize individual females. Finally, EGP was not related to social mating system, suggesting that the opportunities for the extra-group fertilizations and the payoffs involved do not consistently vary with social mating system.

Advancing breeding phenology in response to environmental change in a wild red deer population

Most evidence for advances in phenology of in response to recent climate warming in wild vertebrate populations has come from long-term studies of birds. Few studies have either documented phenological advances or tested their climatic causes and demographic consequences in wild mammal systems. Using a long-term study of red deer on the Isle of Rum, Scotland, we present evidence of significant temporal trends in six phenological traits: oestrus date and parturition date in females, and antler cast date, antler clean date, rut start date and rut end date in males. These traits advanced by between 5 and 12 days across a 28-year study period. Local climate measures associated with plant growth in spring and summer (growing degree days) increased significantly over time and explained a significant amount of variation in all six phenological traits, largely accounting for temporal advances observed in some of the traits. However, there was no evidence for temporal changes in key female reproductive performance traits (offspring birth weight and offspring survival) in this population, despite significant relationships between these traits and female phenology. In males, average antler weights increased over time presumably as a result of improved resource availability and physiological condition through spring and summer. There was no evidence for any temporal change in average male annual breeding success, as might be expected if the timing of male rutting behaviour was failing to track advances in the timing of oestrus in females. Our results provide rare evidence linking phenological advances to climate warming in a wild mammal and highlight the potential complexity of relationships between climate warming, phenology and demography in wild vertebrates.

Higher temperature extremes exacerbate negative disease effects in a social mammal

No abstract is provided for this article.

Association of Genetic Mutations in Plasmodium vivax dhfr with Resistance to Sulfadoxine-Pyrimethamine: Geographical and Clinical Correlates

No abstract is provided for this article.

Development of Rectodispersible Tablets and Granulate Capsules for the Treatment of Serious Neonatal Sepsis in Developing Countries

Current pediatric antibiotic therapies often use oral and parenteral routes of administration. Neither are suitable for treating very sick neonates who cannot take oral medication and may be several hours away from hospital in developing countries. Here, we report on the development of rectal forms of ceftriaxone, a third-generation cephalosporin. Rectodispersible tablets and capsules were developed and successfully passed 6-month accelerated stability tests. Rabbit bioavailability showed plasma concentrations above the minimal inhibitory concentrations for 3 formulations of rectodispersible tablets and 2 formulations of hard capsules. Clinical batches are currently being prepared for human evaluation with the prospect of offering therapeutic alternatives for treating critically ill neonates. This proof of concept for efficient rectal delivery of antibiotics could help the development of other rectal antibiotic treatments and increase options for noninvasive drug development for pediatric patients.

How antimalarial drug resistance affects post-treatment prophylaxis

Slowly eliminated antimalarial drugs suppress malaria reinfections for a period of time determined by the dose, the pharmacokinetic properties of the drug, and the susceptibility of the infecting parasites. This effect is called post-treatment prophylaxis (PTP). The clinical benefits of preventing recrudescence (reflecting treatment efficacy) compared with preventing reinfection (reflecting PTP) need further assessment. Antimalarial drug resistance shortens PTP. While blood concentrations are in the terminal elimination phase, the degree of shortening may be estimated from measurements of in-vitro susceptibility and the terminal elimination half-life. More information is needed on PTP following intermittent preventive treatments, and on the relationship between the duration of PTP and immunity, so that policy recommendations can have a firmer evidence base.

Predictors of reproductive cost in female Soay sheep

Summary We investigate factors influencing the trade‐off between survival and reproduction in female Soay sheep ( Ovis aries ). Multistate capture–recapture models are used to incorporate the state‐specific recapture probability and to investigate the influence of age and ecological conditions on the cost of reproduction, defined as the difference between survival of breeder and non‐breeder ewes on a logistic scale. The cost is identified as a quadratic function of age, being greatest for females breeding at 1 year of age and when more than 7 years old. Costs, however, were only present during severe environmental conditions (wet and stormy winters occurring when population density was high). Winter severity and population size explain most of the variation in the probability of breeding for the first time at 1 year of life, but did not affect the subsequent breeding probability. The presence of a cost of reproduction was confirmed by an experiment where a subset of females was prevented from breeding in their first year of life. Our results suggest that breeding decisions are quality or condition dependent. We show that the interaction between age and time has a significant effect on variation around the phenotypic trade‐off function: selection against weaker individuals born into cohorts that experience severe environmental conditions early in life can progressively eliminate low‐quality phenotypes from these cohorts, generating population‐level effects.

VARIANCES AND COVARIANCES OF PHENOLOGICAL TRAITS IN A WILD MAMMAL POPULATION

In a seasonal environment, there are multiple aspects of timing, or phenology, that contribute to an individual's fitness. Several studies have shown a genetic basis to variation between individuals in breeding time, but we know little about the heritability of other phenological traits in wild populations. Furthermore, the presence of genetic correlations between phenological variables could act to constrain or promote any response to selection, but less is known of the multivariate genetic relationships underlying phenological traits in the wild. Here, we use data from a wild population of red deer on the Isle of Rum, Scotland, to investigate covariances between eight phenological traits. Variation was characterized at the level of the phenotype, genotype, and year, and traits measured in different sexes enabled us to test for cross‐sex genetic correlations. Phenotypic correlations were broadly strong and positive, as were correlations between traits expressed in the same year. We found evidence of significant additive genetic variation in five of the eight phenological traits studied. However there was little evidence of genetic correlations between traits, implying that much of the observed phenotypic correlation was environmentally induced. Our results suggest that different phenological traits may be free to move along independent evolutionary trajectories.

Studies of the neurotoxicity of oral artemisinin derivatives in mice.

Intramuscular injections of high doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether produce an unusual pattern of selective damage to brain stem centers in experimental mammals, predominantly those involved in auditory processing and vestibular reflexes. We have shown recently in adult Swiss albino mice that parenteral artesunate, a water-soluble derivative, is significantly less neurotoxic than intramuscular artemether in this murine model. Using the same model, in which the drugs were administered daily for 28 days, the neurotoxic potential of the oral drugs was assessed and compared with the parenteral routes of administration. The dose causing neurotoxicity or death in 50% of animals (ED50), was approximately 300 mg/kg/day of oral artemether and artesunate compared to 50 mg/kg/day of intramuscular artemether. Doses of intramuscular artemether &gt; 100 mg/kg/day were uniformly lethal. When oral artemether was given in peanut oil there was an increase in neurotoxicity and mortality compared with the aqueous suspension (P = 0.002), and when the food pellets were coated with artemether in oil, giving relatively constant oral intake, neurotoxicity was further increased; ED50 = 150 mg/kg/day (P = 0.017). These data indicate that once-daily oral administration of artesunate or artemether is relatively safe, presumably because the central nervous system is exposed transiently, whereas constant exposure either from depot intramuscular injection of oil-based drug, or constant oral intake carries relatively greater neurotoxic potential.

The Quality of Life in Adult Patients With Syndromic Craniosynostosis From Their Perspective

Introduction: Clinical intuition may perceive those adults with syndromic craniosynostosis to have a lower quality of life (QOL) compared with the normative population. Classification of facial difference; standardization of cognitive capacity and selection of an appropriate QOL measurement tool provides a less intuitive and more evidence-based method of assessing QOL in this particular group of patients. Methods: Adults with syndromic craniosynostosis treated by the same surgeons underwent Whittaker Classification for facial difference by an independent observer. Neuropsychology screening ensured cognitive ability in patients for independent answering of a World Health Organization QOL postal questionnaire. Data analysis using descriptive and z test statistics allowed comparison to nonsyndromic adult United Kingdom data provided by the World Health Organization. Results: Forty adult patients met authors’ inclusion criteria. Whittaker Classification of facial difference ranged from I (31 patients) to II (8 patients) and III (1 patient). Quality of life showed no correlation to facial difference. Quality of life was better in the physical, psychological, and environmental domains compared with the normative adult UK population. However, no statistical difference was found in the social domain. Female Apert syndrome patients had a worse QOL than males in the social domain. Conclusions: The counterintuitive findings show that adult syndromic patients with similar cognitive capacity perceive their quality of life as being above that experienced in a normative UK nonsyndromic population with no correlation to the degree of facial difference.

Emergence in Vietnam of <i>Streptococcus pneumoniae</i> Resistant to Multiple Antimicrobial Agents as a Result of Dissemination of the Multiresistant Spain ^23F -1 Clone

Surveillance for Streptococcus pneumoniae resistant to penicillin and other antimicrobial agents is necessary to define the optimal empirical antibiotic therapy for meningitis in resource-poor countries such as Vietnam. The clinical and microbiological features of 100 patients admitted to the Centre for Tropical Diseases in Ho Chi Minh City, Vietnam, between 1993 and 2002 with invasive pneumococcal disease were studied. A penicillin-nonsusceptible pneumococcus (MIC, > or =0.1 micro g/ml) was isolated from the blood or cerebrospinal fluid of 8% of patients (2 of 24) between 1993 and 1995 but 56% (20 of 36) during 1999 to 2002 (P < 0.0001). Pneumococcal isolates resistant to penicillin (MIC, > or =2.0 micro g/ml) increased from 0% (0 of 24) to 28% (10 of 36) (P = 0.002). Only one isolate was ceftriaxone resistant (MIC, 2.0 micro g/ml). Penicillin-nonsusceptible pneumococci were isolated from 78% of children younger than 15 years (28 of 36) compared with 25% of adults (16 of 64) (P = 0.0001). Isolation of a penicillin-nonsusceptible pneumococcus in adults with meningitis was independently associated with referral from another hospital (P = 0.005) and previous antibiotic therapy (P = 0.025). Multilocus sequence typing showed that 86% of the invasive penicillin-resistant pneumococcus isolates tested (12 of 14) were of the Spain(23F)-1 clone. The serotypes of >95% of the penicillin-nonsusceptible pneumococci were included in the currently available pneumococcal vaccines. Our findings point to the recent introduction and spread of the Spain(23F)-1 clone of penicillin-resistant pneumococci in Vietnam. Simple clinical predictors can be used to guide empirical antibiotic therapy of meningitis. Pneumococcal vaccination may help to control this problem.