Publications

Most evidence on the association between malaria in pregnancy and adverse pregnancy outcomes focuses on falciparum malaria detected at birth. We assessed the association between the number and timing of falciparum and vivax malaria episodes during pregnancy on small-for-gestational-age (SGA) and preterm birth.We analysed observational data collected from antenatal clinics on the Thailand-Myanmar border (1986-2015). We assessed the effects of the total number of malaria episodes in pregnancy on SGA and the effects of malaria in pregnancy on SGA, very preterm birth, and late preterm birth, by the gestational age at malaria detection and treatment using logistic regression models with time-dependent malaria variables (monthly intervals). World Health Organisation definitions of very preterm birth (≥28 and <32 weeks) and late preterm birth (≥32 and <37 weeks) and international SGA standards were used.Of 50,060 pregnant women followed, 8221 (16%) had malaria during their pregnancy. Of the 50,060 newborns, 10,005 (21%) were SGA, 540 (1%) were very preterm, and 4331 (9%) were late preterm. The rates of falciparum and vivax malaria were highest at 6 and 5 weeks' gestation, respectively. The odds of SGA increased linearly by 1.13-fold (95% confidence interval: 1.09, 1.17) and 1.27-fold (1.21, 1.33) per episode of falciparum and vivax malaria, respectively. Falciparum malaria at any gestation period after 12-16 weeks and vivax malaria after 20-24 weeks were associated with SGA (falciparum odds ratio, OR range: 1.15-1.63 [p range: <0.001-0.094]; vivax OR range: 1.12-1.54 [p range: <0.001-0.138]). Falciparum malaria at any gestation period after 24-28 weeks was associated with either very or late preterm birth (OR range: 1.44-2.53; p range: <0.001-0.001). Vivax malaria at 24-28 weeks was associated with very preterm birth (OR: 1.79 [1.11, 2.90]), and vivax malaria at 28-32 weeks was associated with late preterm birth (OR: 1.23 [1.01, 1.50]). Many of these associations held for asymptomatic malaria.Protection against malaria should be started as early as possible in pregnancy. Malaria control and elimination efforts in the general population can avert the adverse consequences associated with treated asymptomatic malaria in pregnancy.

Artemisinin resistance in Plasmodium falciparum has emerged and spread in Southeast Asia. In areas where resistance is established longer courses of artemisinin-based combination therapy have improved cure rates.The standard 3-day course of artemether-lumefantrine (AL) was compared with an extended 5-day regimen for the treatment of uncomplicated falciparum malaria in Kayin state in South-East Myanmar, an area of emerging artemisinin resistance. Late parasite clearance dynamics were described by microscopy and quantitative ultra-sensitive PCR. Patients were followed up for 42 days.Of 154 patients recruited (105 adults and 49 children < 14 years) 78 were randomized to 3 days and 76 to 5 days AL. Mutations in the P. falciparum kelch13 propeller gene (k13) were found in 46% (70/152) of infections, with F446I the most prevalent propeller mutation (29%; 20/70). Both regimens were well-tolerated. Parasite clearance profiles were biphasic with a slower submicroscopic phase which was similar in k13 wild-type and mutant infections. The cure rates were 100% (70/70) and 97% (68/70) in the 3- and 5-day arms respectively. Genotyping of the two recurrences was unsuccessful.Despite a high prevalence of k13 mutations, the current first-line treatment, AL, was still highly effective in this area of South-East Myanmar. The extended 5 day regimen was very well tolerated, and would be an option to prolong the useful therapeutic life of AL. Trial registration NCT02020330. Registered 24 December 2013, https://clinicaltrials.gov/NCT02020330.

Data for survival analysis

Antifolate drugs have an important role in the treatment of malaria. Polymorphisms in the genes encoding the dihydrofolate reductase and dihydropteroate synthetase enzymes cause resistance to the antifol and sulfa drugs, respectively. Rwanda has the highest levels of antimalarial drug resistance in Africa. We correlated the efficacy of chlorproguanil-dapsone plus artesunate (CPG-DDS+A) and amodiaquine plus sulfadoxine-pyrimethamine (AQ+SP) in children with uncomplicated malaria caused by Plasmodium falciparum parasites with pfdhfr and pfdhps mutations, which are known to confer reduced drug susceptibility, in two areas of Rwanda. In the eastern province, where the cure rates were low, over 75% of isolates had three or more pfdhfr mutations and two or three pfdhps mutations and 11% had the pfdhfr 164-Leu polymorphism. In the western province, where the cure rates were significantly higher (P < 0.001), the prevalence of multiple resistance mutations was lower and the pfdhfr I164L polymorphism was not found. The risk of treatment failure following the administration of AQ+SP more than doubled for each additional pfdhfr resistance mutation (odds ratio [OR] = 2.4; 95% confidence interval [CI] = 1.01 to 5.55; P = 0.048) and each pfdhps mutation (OR = 2.1; 95% CI = 1.21 to 3.54; P = 0.008). The risk of failure following CPG-DDS+A treatment was 2.2 times higher (95% CI = 1.34 to 3.7) for each additional pfdhfr mutation, whereas there was no association with mutations in the pfdhps gene (P = 0.13). The pfdhfr 164-Leu polymorphism is prevalent in eastern Rwanda. Antimalarial treatments with currently available antifol-sulfa combinations are no longer effective in Rwanda because of high-level resistance.

Summary 1. For social species, the link between individual behaviour and population dynamics is mediated by group‐level demography. 2. Populations of obligate cooperative breeders are structured into social groups, which may be subject to inverse density dependence (Allee effects) that result from a dependence on conspecific helpers, but evidence for population‐wide Allee effects is rare. 3. We use field data from a long‐term study of cooperative meerkats ( Suricata suricatta ; Schreber, 1776) – a species for which local Allee effects are not reflected in population‐level dynamics – to empirically model interannual group dynamics. 4. Using phenomenological population models, modified to incorporate environmental conditions and potential Allee effects, we first investigate overall patterns of group dynamics and find support only for conventional density dependence that increases after years of low rainfall. 5. To explain the observed patterns, we examine specific demographic rates and assess their contributions to overall group dynamics. Although per‐capita meerkat mortality is subject to a component Allee effect, it contributes relatively little to observed variation in group dynamics, and other (conventionally density dependent) demographic rates – especially emigration – govern group dynamics. 6. Our findings highlight the need to consider demographic processes and density dependence in subpopulations before drawing conclusions about how behaviour affects population processes in socially complex systems.

Introduction: Posterior calvarial distraction (PCD) is an effective method to increase the intracranial volume in children with craniosynostosis. Children with multi-suture and lambdoid synostosis often have concurrent Chiari malformation type I (CM1). This study investigated the efficacy of PCD in posterior fossa (PF) volume expansion and treatment of CM1. Methods: Ten-year retrospective study in a quaternary craniofacial unit. Results: Sixteen children were identified (8M, 8F). The mean age was 5.1 years (8m to 19y). Fourteen children had pansynostosis and two lamboid synostosis; 8 were syndromic. Ten patients had raised intracranial pressure (ICP); 4 had syringomyelia. Clinically, 9 patients improved, 7 remained stable, none deteriorated. The average distraction distance was 23mm (16-28mm). An osteotomy extending inferior to the torcula was associated with a larger PF AP distance increase (13 v 6mm, p=0.028). The average tonsillar descent improved (9.3 to 6.0mm). Syrinx dimensions also improved: superior-inferior (203 to 136mm), anterior-posterior (7.9 to 3.1mm). Conclusion: Cranial volume expansion following PCD also includes PF volume expansion. This results in improvement of tonsillar descent and syrinx. PCD is a safe and efficacious first-line treatment for children with concurrent multi-suture craniosynostosis, CM1, and syrinx. The findings add to existing hypotheses that Chiari malformation is not a condition per se, but a manifestation of an insufficient intracranial volume.

The production of counterfeit or substandard anti-infective drugs is a widespread and under-recognised problem that contributes to morbidity, mortality, and drug resistance, and leads to spurious reporting of resistance and toxicity and loss of confidence in health-care systems. Counterfeit drugs particularly affect the most disadvantaged people in poor countries. Although advances in forensic chemical analysis and simple field tests will enhance drug quality monitoring, improved access to inexpensive genuine medicines, support of drug regulatory authorities, more open reporting, vigorous law enforcement, and more international cooperation with determined political leadership will be essential to counter this threat.

The emergence and spread of multidrug-resistant Plasmodium falciparum compromises the treatment of malaria, especially during pregnancy, where the choice of antimalarials is already limited. Artesunate (n=528) or artemether (n=11) was used to treat 539 episodes of acute P. falciparum malaria in 461 pregnant women, including 44 first-trimester episodes. Most patients (310 [57.5%]) received re-treatments after earlier treatment with quinine or mefloquine. By use of survival analysis, the cumulative artemisinin failure rate for primary infections was 6.6% (95% confidence interval, 1.0-12.3), compared with the re-treatment failure rate of 21.7% (95% confidence interval, 15.4-28.0; P=.004). The artemisinins were well tolerated with no evidence of adverse effects. Birth outcomes did not differ significantly to community rates for abortion, stillbirth, congenital abnormality, and mean gestation at delivery. These results are reassuring, but further information about the safety of these valuable antimalarials in pregnancy is needed.

Local synthesis of immunoglobulin within the central nervous system has been evaluated in 37 patients with acute cerebral malaria; seven patients were also studied in the convalescent phase. There was evidence in the cerebrospinal fluid (CSF) of 21 patients that intrathecal IgG synthesis occurs in the acute phase. There were raised IgG: albumin ratios in 43% of acute patients. Oligoclonal IgG bands or cathodal IgG was seen in the CSF of 43% of patients tested by polyacrylamide electrophoresis. Only eight out of 37 acute patients (22%) had no evidence of intrathecal IgG synthesis by either method. The serial studies showed that most patients had IgG-CSF abnormalities when tested in convalescence. These studies suggest that an immune stimulus (perhaps malarial antigens or mitogens) may be present in the brain in acute cerebral malaria.

Journal Article A Safe and Effective Consecutive-Infusion Regimen for Rapid Quinine Loading in Severe Falciparum Malaria Get access Timothy M. E. Davis, Timothy M. E. Davis Search for other works by this author on: Oxford Academic PubMed Google Scholar Wichai Supanaranond, Wichai Supanaranond Search for other works by this author on: Oxford Academic PubMed Google Scholar Sasithon Pukrittayakamee, Sasithon Pukrittayakamee Search for other works by this author on: Oxford Academic PubMed Google Scholar Juntra Karbwang, Juntra Karbwang Search for other works by this author on: Oxford Academic PubMed Google Scholar Pidist Molunto, Pidist Molunto Search for other works by this author on: Oxford Academic PubMed Google Scholar Sopon Mekthon, Sopon Mekthon Search for other works by this author on: Oxford Academic PubMed Google Scholar Nicholas J. White Nicholas J. White Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 161, Issue 6, June 1990, Pages 1305–1308, https://doi.org/10.1093/infdis/161.6.1305 Published: 01 June 1990 Article history Received: 22 November 1989 Published: 01 June 1990

The therapeutic responses to the eight most widely used antimalarial drugs were assessed in 207 adult patients with Plasmodium vivax malaria. This parasite does not cause marked sequestration, so parasite clearance can be used as a direct measure of antimalarial activity. The activities of these drugs in descending order were artesunate, artemether, chloroquine, mefloquine, quinine, halofantrine, primaquine, and pyrimethamine-sulfadoxine (PS). Therapeutic responses to PS were poor; parasitemias did not clear in 5 of the 12 PS-treated patients, whereas all the other patients made an initial recovery. Of 166 patients monitored for ≥28 days, 35% had reappearance of vivax malaria 11 to 65 days later and 7% developed falciparum malaria 5 to 21 days after the start of treatment. There were no significant differences in the times taken for vivax malaria reappearance among the different groups except for those given mefloquine and chloroquine, in which all vivax malaria reappearances developed &gt;28 days after treatment, suggesting suppression of the first relapse by these slowly eliminated drugs. There was no evidence of chloroquine resistance. The antimalarial drugs vary considerably in their intrinsic activities and stage specificities of action.

Aims Artesunate and artemether are the two most widely used artemisinin derivatives in the treatment of uncomplicated Plasmodium falciparum malaria, but there is little information on their comparative pharmacokinetics. The aim of this study was to examine the relative oral antimalarial bioavailability and pharmacokinetics of the two derivatives. Methods The pharmacokinetic properties of oral artesunate and artemether (4 mg kg −1 ) were compared in a randomized cross‐over study of 14 adult patients in western Thailand with acute uncomplicated Plasmodium falciparum malaria. Antimalarial activity was compared using a previously validated, sensitive bioassay. Results Despite a 29% lower molar dose, oral artesunate administration resulted in significantly larger mean area under the plasma antimalarial activity time curve and median maximum plasma antimalarial activity than after oral artemether ( P ≤ 0.02). The mean (95% CI) oral antimalarial bioavailability of artemether, relative to oral artesunate, corrected for molar dose was 58 (40–76)%. The mean (95% CI) relative antimalarial bioavailability of artemether was lower on the first day of treatment, 31 (17–100)%, compared to the second day, 72 (44–118)% ( P = 0.018). In vivo parasite clearance and time above the in vitro I C 90 were similar for the two drugs, despite considerable differences in C max and AUC. Conclusions The oral antimalarial bioavailability following artemether was significantly lower than that after artesunate. Artemether oral antimalarial bioavailability is reduced in acute malaria.

In a prospective infant cohort, 21 infants developed Plasmodium vivax malaria during their first year. Twelve of their mothers also had vivax malaria in the corresponding pregnancies or postpartum period. The genotypes of the maternal and infant infections were all different. Eight of the 12 mothers and 9 of the 21 infants had recurrent infections. Relapse parasite genotypes were different to the initial infection in 13 of 20 (65%) mothers compared with 5 of 24 (21%) infants (P = .02). The first P. vivax relapses of life are usually genetically homologous, whereas relapse in adults may result from activation of heterologous latent hypnozoites acquired from previous inoculations.

The emergence and spread of resistance in Plasmodium falciparum malaria to artemisinin combination therapies in the Greater Mekong subregion poses a major threat to malaria control and elimination. The current study is part of a multi-country, open-label, randomised clinical trial (TRACII, 2015-18) evaluating the efficacy, safety, and tolerability of triple artemisinin combination therapies. A very high rate of treatment failure after treatment with dihydroartemisinin-piperaquine was observed in Thailand, Cambodia, and Vietnam. The immediate public health importance of our findings prompted us to report the efficacy data on dihydroartemisinin-piperaquine and its determinants ahead of the results of the overall trial, which will be published later this year.