Efficacy and safety of atovaquone-proguanil in treating imported malaria in Japan: the second report from the research group

Malaria remains an important health risk among travelers to tropical/subtropical regions. However, in Japan, only 2 antimalarials are licensed for clinical use - oral quinine and mefloquine. The Research Group on Chemotherapy of Tropical Diseases introduced atovaquone-proguanil in 1999, and reported on its excellent antimalarial efficacy and safety for treating non-immune patients with uncomplicated Plasmodium falciparum malaria (20 adult and 3 pediatric cases) in 2006. In the present study, additional cases of malaria were analyzed to confirm the efficacy and safety of this antimalarial drug. Fourteen adult and 2 pediatric cases of P. falciparum malaria and 13 adult cases and 1 pediatric case of P. vivax/ovale malaria were successfully treated with atovaquone-proguanil, including 3 P. falciparum cases in which the antecedent treatment failed. Two patients with P. vivax malaria were treated twice due to primaquine treatment failure as opposed to atovaquone-proguanil treatment failure. Except for 1 patient with P. falciparum malaria who developed a moderate liver function disturbance, no significant adverse effects were observed. Despite the intrinsic limitations of this study, which was not a formal clinical trial, the data showed that atovaquone-proguanil was an effective and well-tolerated therapeutic option; licensure of this drug in Japan could greatly contribute to individually appropriate treatment options.     

Can We Predict Oral Antibiotic Treatment Failure in Children with Fast-Breathing Pneumonia Managed at the Community Level? A Prospective Cohort Study in Malawi

BackgroundPneumonia is the leading cause of infectious death amongst children globally, with the highest burden in Africa. Early identification of children at risk of treatment failure in the community and prompt referral could lower mortality. A number of clinical markers have been independently associated with oral antibiotic failure in childhood pneumonia. This study aimed to develop a prognostic model for fast-breathing pneumonia treatment failure in sub-Saharan Africa.MethodWe prospectively followed a cohort of children (2–59 months), diagnosed by community health workers with fast-breathing pneumonia using World Health Organisation (WHO) integrated community case management guidelines. Cases were followed at days 5 and 14 by study data collectors, who assessed a range of pre-determined clinical features for treatment outcome. We built the prognostic model using eight pre-defined parameters, using multivariable logistic regression, validated through bootstrapping.ResultsWe assessed 1,542 cases of which 769 were included (32% ineligible; 19% defaulted). The treatment failure rate was 15% at day 5 and relapse was 4% at day 14. Concurrent malaria diagnosis (OR: 1.62; 95% CI: 1.06, 2.47) and moderate malnutrition (OR: 1.88; 95% CI: 1.09, 3.26) were associated with treatment failure. The model demonstrated poor calibration and discrimination (c-statistic: 0.56).ConclusionThis study suggests that it may be difficult to create a pragmatic community-level prognostic child pneumonia tool based solely on clinical markers and pulse oximetry in an HIV and malaria endemic setting. Further work is needed to identify more accurate and reliable referral algorithms that remain feasible for use by community health workers.     

Clinical Malaria Transmission Trends and Its Association with Climatic Variables in Tubu Village,Botswana: A Retrospective Analysis

Good knowledge on the interactions between climatic variables and malaria can be very useful for predicting outbreaks and preparedness interventions. We investigated clinical malaria transmission patterns and its temporal relationship with climatic variables in Tubu village, Botswana. A 5-year retrospective time series data analysis was conducted to determine the transmission patterns of clinical malaria cases at Tubu Health Post and its relationship with rainfall, flood discharge, flood extent, mean minimum, maximum and average temperatures. Data was obtained from clinical records and respective institutions for the period July 2005 to June 2010, presented graphically and analysed using the Univariate ANOVA and Pearson cross-correlation coefficient tests. Peak malaria season occurred between October and May with the highest cumulative incidence of clinical malaria cases being recorded in February. Most of the cases were individuals aged >5 years. Associations between the incidence of clinical malaria cases and several factors were strong at lag periods of 1 month; rainfall (r = 0.417), mean minimum temperature (r = 0.537), mean average temperature (r = 0.493); and at lag period of 6 months for flood extent (r = 0.467) and zero month for flood discharge (r = 0.497). The effect of mean maximum temperature was strongest at 2-month lag period (r = 0.328). Although malaria transmission patterns varied from year to year the trends were similar to those observed in sub-Saharan Africa. Age group >5 years experienced the greatest burden of clinical malaria probably due to the effects of the national malaria elimination programme. Rainfall, flood discharge and extent, mean minimum and mean average temperatures showed some correlation with the incidence of clinical malaria cases.     

Therapeutic efficacy of 3 treatment protocols for non-complicated Plasmodium falciparum malaria, Antioquia, Colombia, 2002

High resistance of Plasmodium falciparum malaria to chloroquine poses malaria as a major public health problem in Colombia. In this context, the therapeutic response of uncomplicated P. falciparum malaria patients to chloroquine (CQ), sulfadoxine/pirymethamine (SDXP) and combined therapy (SDXP/CQ) was evaluated according to the WHO/PAHO protocols of 1998. The comparisons were based on a sample of 160 patients with uncomplicated P. falciparum malaria in Turbo and Zaragoza (Antioquia, Colombia). Patients were randomly assigned each of the treatment categories. The results were statistically similar in each municipality. In Turbo percentage of treatment failure was 87.5%, 22.2% and 22.6% for CQ, SDXP and SDXP/CQ, respectively, whereas in Zaragoza, the corresponding treatment failure was 77.7%, 26.5% and 12.1%. During follow up, 50% of subjects with late treatment failure were asymptomatic in Turbo, while 33.3% were asymptomatic in Zaragoza. A high level of treatment failure occurred with CQ monotherapy, while SDXP and SDXP/CQ had acceptable levels of failure, i.e., below 25%. The high percentage of late treatment failure in asymptomatic patients may contribute to increased risk of persistent transmission.     

Efficacy of amodiaquine and sulfadoxine/pyrimethamine in the treatment of malaria not complicated by Plasmodium falciparum in Nariño,Colombia, 1999-2002

The resurgence and spread of antimalarial drug resistance is one of the causes of the worldwide increase of malaria. In Colombia, uncomplicated Plasmodium falciparum malaria has been treated with a combination of amodiaquine (AQ) and sulfadoxine/pyrimethamine (SP) since 2000. The efficacy of these two antimalarials was evaluated after the implementation of the new malaria treatment scheme. In the municipalities of El Charco and Tumaco (Nari?o) on the Pacific Coast region, the standard PAHO protocol was used to evaluate antimalarial efficacy in areas of low to moderate malaria transmission. Patients were randomly allocated to treatment regime in two cities of Nari?o, El Charco (n = 48) and Tumaco (n = 50). After 14 days none of El Charco patients presented therapeutic failure to either antimalarial. However, in Tumaco after 28 days, 12 of 24 (95% CI: 30.6-69.4) patients presented AQ treatment failure while 4 of 26 (95% CI: 5.1-33.1) patients had SP treatment failure. The high level of AQ treatment failure in Tumaco was unexpected because it had been introduced only recently as an antimalarial treatment in Colombia. The results suggest that the use of the current dose of AQ in combination with SP will be therapeutically useful for less time than expected. Use of combined therapies is a key strategy to delay antimalarial resistance. Unfortunately, its success depends on the efficacy of antimalarial drugs individually.     

Molecular monitoring of the Leu-164 mutation of dihydrofolate reductase in a highly sulfadoxine/pyrimethamine-resistant area in Africa

Background

Procalcitonin (PCT) is closely correlated with parasite burden and clinical outcome in falciparum malaria. The role of PCT in tertian malaria has not previously been investigated.

Patients and methods

PCT serum levels in 37 patients with tertian malaria were analysed. Clinical and laboratory parameters were assessed and statistically correlated both to the initial PCT levels and during the course of the disease.

Results

PCT levels rose for one day after commencing treatment and declined thereafter. However, there was no significant correlation with parasite burden, clinical parameters, laboratory values, or the presence of semi-immunity. Before treatment, the majority of patients showed normal or slightly elevated PCT levels (< 2.5 ng/ml), but PCT was markedly elevated (4.8 – 47 ng/ml) in one third of the population. The two groups did not differ by any other of the assessed parameters. Thus, while the post-treatment course of PCT resembles falciparum malaria, the lack of correlation between disease severity and even high PCT levels in a large proportion of patients is intriguing.

Conclusions

There is a fundamental difference in the relationship of PCT with tertian malaria not seen in other infectious diseases in which elevated PCT levels have been observed. This suggests distinct pathophysiological pathways in malaria.     

A Novel Approach for Measuring the Burden of Uncomplicated Plasmodium falciparum Malaria: Application to Data from Zambia

Measurement of malaria burden is fraught with complexity, due to the natural history of the disease, delays in seeking treatment or failure of case management. Attempts to establish an appropriate case definition for a malaria episode has often resulted in ambiguities and challenges because of poor information about treatment seeking, patterns of infection, recurrence of fever and asymptomatic infection. While the primary reason for treating malaria is to reduce disease burden, the effects of treatment are generally ignored in estimates of the burden of malaria morbidity, which are usually presented in terms of numbers of clinical cases or episodes, with the main data sources being reports from health facilities and parasite prevalence surveys. The use of burden estimates that do not consider effects of treatment, leads to under-estimation of the impact of improvements in case management. Official estimates of burden very likely massively underestimate the impact of the roll-out of ACT as first-line therapy across Africa. This paper proposes a novel approach for estimating burden of disease based on the point prevalence of malaria attributable disease, or equivalently, the days with malaria fever in unit time. The technique makes use of data available from standard community surveys, analyses of fever patterns in malaria therapy patients, and data on recall bias. Application of this approach to data from Zambia for 2009–2010 gave an estimate of 2.6 (95% credible interval: 1.5–3.7) malaria attributable fever days per child-year. The estimates of recall bias, and of the numbers of days with illness contributing to single illness recalls, could be applied more generally. To obtain valid estimates of the overall malaria burden using these methods, there remains a need for surveys to include the whole range of ages of hosts in the population and for data on seasonality patterns in confirmed case series.     

Iron status predicts malaria risk in malawian preschool children

Introduction

Iron deficiency is highly prevalent in pre-school children in developing countries and an important health problem in sub-Saharan Africa. A debate exists on the possible protective effect of iron deficiency against malaria and other infections; yet consensus is lacking due to limited data. Recent studies have focused on the risks of iron supplementation but the effect of an individual''s iron status on malaria risk remains unclear. Studies of iron status in areas with a high burden of infections often are exposed to bias. The aim of this study was to assess the predictive value of baseline iron status for malaria risk explicitly taking potential biases into account.

Methods and materials

We prospectively assessed the relationship between baseline iron deficiency (serum ferritin <30 µg/L) and malaria risk in a cohort of 727 Malawian preschool children during a year of follow-up. Data were analyzed using marginal structural Cox regression models and confounders were selected using causal graph theory. Sensitivity of results to bias resulting from misclassification of iron status by concurrent inflammation and to bias from unmeasured confounding were assessed using modern causal inference methods.

Results and Conclusions

The overall incidence of malaria parasitemia and clinical malaria was 1.9 (95% CI 1.8–2.0) and 0.7 (95% CI 0.6–0.8) events per person-year, respectively. Children with iron deficiency at baseline had a lower incidence of malaria parasitemia and clinical malaria during a year of follow-up; adjusted hazard ratio''s 0.55 (95%-CI:0.41–0.74) and 0.49 (95%-CI:0.33–0.73), respectively. Our results suggest that iron deficiency protects against malaria parasitemia and clinical malaria in young children. Therefore the clinical importance of treating iron deficiency in a pre-school child should be weighed carefully against potential harms. In malaria endemic areas treatment of iron deficiency in children requires sustained prevention of malaria.     

Plasmodium falciparum: evaluation of a quantitative nucleic acid sequence-based amplification assay to predict the outcome of sulfadoxine-pyrimethamine treatment of uncomplicated malaria

A quantitative nucleic acid sequence-based amplification (QT-NASBA) assay was employed to predict retrospectively the outcome of sulfadoxine-pyrimethamine (SP) treatment of uncomplicated malaria in children aged <6 years in an endemic region. Blood samples were collected at initial diagnosis and during follow-up. Mutation-specific nested PCR methods to analyse DHFR (Arg-59) and DHPS (Glu-540) mutations that are associated with SP drug resistance were applied. Parasite genotyping was performed to distinguish between re-infection and recrudescence. Eighty-six patients were recruited of which 66 were available for follow-up. Nine children were classified as early treatment failure, 13 cases were classified as late clinical failure, 32 as late parasitological failure, and only 12 children had an adequate clinical and parasitological response. DHFR and DHPS mutations conferring SP resistance were abundant in the Plasmodium population. Blood samples obtained 7 days after treatment were used to predict retrospectively the outcome of SP treatment. QT-NASBA was able to give a correct prediction of treatment outcome in 85.7% of the cases. Positive predictive value (PPV) of QT-NASBA case was 95% (95% confidence interval = 88.3-100) and negative predictive value (NPV) was 63% (95% CI = 39.5-86.5). In contrast, microscopy correctly predicted outcome in only 37.5% of the cases. PPV of microscopy was 100% (95% CI = 73.9-100) and the NPV was 25.5% (95% CI = 13.0-38.0). The analysis of a day 7 blood sample with QT-NASBA allows for the prediction of late clinical or parasitological treatment failure in the majority of the cases analysed in the present study.     

Imported Malaria in Korea: a 13-Year Experience in a Single Center

The incidence of imported malaria has been increasing in Korea. We reviewed data retrospectively to evaluate the epidemiology, clinical features, and outcomes of imported malaria from 1995 to 2007 in a university hospital. All patients diagnosed with imported malaria were included. Imported malaria was defined as a positive smear for malaria that was acquired in a foreign country. A total of 49 patients (mean age, 35.7 year; M : F = 38 : 11) were enrolled. The predominant malarial species was Plasmodium falciparum (73.5%), and the most frequent area of acquisition was Africa (55.1%), followed by Southeast Asia (22.4%) and South Asia (18.4%). Fourteen-patients (30.6%) suffered from severe malaria caused by P. falciparum and 1 patient (2.0%) died of multiorgan failure. Most of the patients were treated with mefloquine (79.2%) or quinine (10.2%); other antimalarial agents had to be given in 13.2% treated with mefloquine and 44.4% with quinine due to adverse drug events (ADEs). P. falciparum was the most common cause of imported malaria, with the majority of cases acquired from Africa, and a significant number of patients had severe malaria. Alternative antimalarial agents with lower rates of ADEs might be considered for effective treatment instead of mefloquine and quinine.     

Investigation of host candidate malaria-associated risk/protective SNPs in a Brazilian Amazonian population

The Brazilian Amazon is a hypo-endemic malaria region with nearly 300,000 cases each year. A variety of genetic polymorphisms, particularly in erythrocyte receptors and immune response related genes, have been described to be associated with susceptibility and resistance to malaria. In order to identify polymorphisms that might be associated with malaria clinical outcomes in a Brazilian Amazonian population, sixty-four human single nucleotide polymorphisms in 37 genes were analyzed using a Sequenom massARRAY iPLEX platform. A total of 648 individuals from two malaria endemic areas were studied, including 535 malaria cases (113 individuals with clinical mild malaria, 122 individuals with asymptomatic infection and 300 individuals with history of previous mild malaria) and 113 health controls with no history of malaria. The data revealed significant associations (p<0.003) between one SNP in the IL10 gene (rs1800896) and one SNP in the TLR4 gene (rs4986790) with reduced risk for clinical malaria, one SNP in the IRF1 gene (rs2706384) with increased risk for clinical malaria, one SNP in the LTA gene (rs909253) with protection from clinical malaria and one SNP in the TNF gene (RS1800750) associated with susceptibility to clinical malaria. Also, a new association was found between a SNP in the CTL4 gene (rs2242665), located at the major histocompatibility complex III region, and reduced risk for clinical malaria. This study represents the first association study from an Amazonian population involving a large number of host genetic polymorphisms with susceptibility or resistance to Plasmodium infection and malaria outcomes. Further studies should include a larger number of individuals, refined parameters and a fine-scale map obtained through DNA sequencing to increase the knowledge of the Amazonian population genetic diversity.     

Gametocyte levels in response to differing malaria treatments in two municipalities of Colombia

Plasmodium falciparum gametocyte levels are influenced by level of regional endemicity, the antimalarial treatment, and the therapeutic response of patients. Few previous studies have related these factors in Colombia. Here, gametocytaemia was evaluated with respect to two treatment schemes (sulfadoxine/pyrimethamine and sulfadoxine/pyrimethamine plus chloroquine), the patient response (adequate or failure), and the locality (two areas of varying case frequency). One hundred forty-eight residents of Turbo and Zaragoza (Antioquia), all with uncomplicated malaria, were evaluated. The gametocytaemia and the rates of clinical malaria at the beginning of treatment were greater in Turbo than in Zaragoza. No statistically significant differences in the gametocytaemia by treatment schemes or therapeutic responses were noted, although the patients who received SP had more gametocytes than those treated with SP+CQ. Gametocytaemia was not correlated with asexual parasitemia or sex and age of patient. The difference in the level of gametocytaemia between Turbo and Zaragoza appears to be influenced by the time elapsed between the appearance of symptoms and the beginning of treatment.     

The PSD95-nNOS interface: a target for inhibition of excitotoxic p38 stress-activated protein kinase activation and cell death

The stress-activated protein kinase p38 and nitric oxide (NO) are proposed downstream effectors of excitotoxic cell death. Although the postsynaptic density protein PSD95 can recruit the calcium-dependent neuronal NO synthase (nNOS) to the mouth of the calcium-permeable NMDA receptor, and depletion of PSD95 inhibits excitotoxicity, the possibility that selective uncoupling of nNOS from PSD95 might be neuroprotective is unexplored. The relationship between excitotoxic stress-generated NO and activation of p38, and the significance of the PSD95-nNOS interaction to p38 activation also remain unclear. We find that NOS inhibitors reduce both glutamate-induced p38 activation and the resulting neuronal death, whereas NO donor has effects consistent with NO as an upstream regulator of p38 in glutamate-induced cell death. Experiments using a panel of decoy constructs targeting the PSD95-nNOS interaction suggest that this interaction and subsequent NO production are critical for glutamate-induced p38 activation and the ensuing cell death, and demonstrate that the PSD95-nNOS interface provides a genuine possibility for design of neuroprotective drugs with increased selectivity.     

Environmental, pharmacological and genetic influences on the spread of drug-resistant malaria

Plasmodium falciparum malaria is subject to artificial selection from antimalarial drugs that select for drug-resistant parasites. We describe and apply a flexible new approach to investigate how epistasis, inbreeding, selection heterogeneity and multiple simultaneous drug deployments interact to influence the spread of drug-resistant malaria. This framework recognizes that different human 'environments' within which treatment may occur (such as semi- and non-immune humans taking full or partial drug courses) influence the genetic interactions between parasite loci involved in resistance. Our model provides an explanation for how the rate of spread varies according to different malaria transmission intensities, why resistance might stabilize at intermediate frequencies and also identifies several factors that influence the decline of resistance after a drug is removed. Results suggest that studies based on clinical outcomes might overestimate the spread of resistant parasites, especially in high-transmission areas. We show that when transmission decreases, prevalence might decrease without a corresponding change in frequency of resistance and that this relationship is heavily influenced by the extent of linkage disequilibrium between loci. This has important consequences on the interpretation of data from areas where control is being successful and suggests that reducing transmission might have less impact on the spread of resistance than previously expected.     

重复经颅磁刺激对卒中后抑郁的治疗效果及机制

卒中后抑郁（post-stroke depression,PSD）是并发于脑血管病的一种情感障碍疾病，发病率高，预后差。重复经颅磁刺激（repetitive transcranial magnetic stimulation,r TMS）是通过磁场变化在大脑中产生感应电流来刺激皮层的非创伤性脑刺激技术，是临床上治疗PSD的一种重要非药物治疗方法，可以显著改善PSD患者的抑郁症状。但目前rTMS的作用机制不明确。本文总结了PSD治疗中有效的rTMS刺激方案，并结合PSD的单胺类神经递质相关致病假说及PSD的临床治疗手段，探索了rTMS通过对单胺类神经递质的调控参与PSD治疗的可能机制。rTMS刺激诱导的皮层单胺类递质释放增加、葡萄糖代谢上升、皮层兴奋性增加，提高了单胺类神经递质和脑源性神经营养因子（brain-derived neurotrophic factor,BDNF）水平，进而引发前额叶抑制功能上升、与下游脑区连接改变、脑网络功能的调整，可能是rTMS治疗PSD的重要机制之一。     

Deaths due to Plasmodium knowlesi malaria in Sabah, Malaysia: association with reporting as Plasmodium malariae and delayed parenteral artesunate

ABSTRACT: BACKGROUND: The simian parasite Plasmodium knowlesi is recognized as a common cause of severe and fatal human malaria in Sabah, Malaysia, but is morphologically indistinguishable from and still commonly reported as Plasmodium malariae, despite the paucity of this species in Sabah. Since December 2008 Sabah Department of Health has recommended intravenous artesunate and referral to a general hospital for all severe malaria cases of any species. This paper reviews all malaria deaths in Sabah subsequent to the introduction of these measures. Reporting of malaria deaths in Malaysia is mandatory. METHODS: Details of reported malaria deaths during 2010-2011 were reviewed to determine the proportion of each Plasmodium species. Demographics, clinical presentations and management of severe malaria caused by each species were compared. RESULTS: Fourteen malaria deaths were reported, comprising seven Plasmodium falciparum, six P. knowlesi and one Plasmodium vivax (all PCR-confirmed). Of the six P. knowlesi deaths, five were attributable to knowlesi malaria and one was attributable to P. knowlesi-associated enterobacter sepsis. Patients with directly attributable P. knowlesi deaths (N = 5) were older than those with P. falciparum (median age 51 [IQR 50-65] vs 22 [IQR 9-55] years, p = 0.06). Complications in fatal P. knowlesi included respiratory distress (N = 5, 100%), hypotension (N = 4, 80%), and renal failure (N = 4, 80%). All patients with P. knowlesi were reported as P. malariae by microscopy. Only two of five patients with severe knowlesi malaria on presentation received immediate parenteral anti-malarial treatment. The patient with P. vivaxassociated severe illness did not receive parenteral treatment. In contrast six of seven patients with severe falciparum malaria received immediate parenteral treatment. CONCLUSION: Plasmodium knowlesi was responsible, either directly or through gram-negative bacteraemia, for almost half of malaria deaths in Sabah. Patients with severe non-falciparum malaria were less likely to receive immediate parenteral therapy. This highlights the need in Sabah for microscopically diagnosed P. malariae to be reported as P. knowlesi to improve recognition and management of this potentially fatal species. Clinicians need to be better informed of the potential for severe and fatal malaria from non-falciparum species, and the need to treat all severe malaria with immediate intravenous artesunate.     

Asymptomatic infection with Plasmodium falciparum and Plasmodium vivax in the Brazilian Amazon Basin: to treat or not to treat?

In this study, we determined whether the treatment of asymptomatic parasites carriers (APCs), which are frequently found in the riverside localities of the Brazilian Amazon that are highly endemic for malaria, would decrease the local malaria incidence by decreasing the overall pool of parasites available to infect mosquitoes. In one village, the treatment of the 19 Plasmodium falciparum-infected APCs identified among the 270 residents led to a clear reduction (Z = -2.39, p = 0.017) in the incidence of clinical cases, suggesting that treatment of APCs is useful for controlling falciparum malaria. For vivax malaria, 120 APCs were identified among the 716 residents living in five villages. Comparing the monthly incidence of vivax malaria in two villages where the APCs were treated with the incidence in two villages where APCs were not treated yielded contradictory results and no clear differences in the incidence were observed (Z = -0.09, p = 0.933). Interestingly, a follow-up study showed that the frequency of clinical relapse in both the treated and untreated APCs was similar to the frequency seen in patients treated for primary clinical infections, thus indicating that vivax clinical immunity in the population is not species specific but only strain specific.     

Artemether-lumefantrine to treat malaria in pregnancy is associated with reduced placental haemozoin deposition compared to quinine in a randomized controlled trial

ABSTRACT: BACKGROUND: Data on efficacy of artemisinin-based combination therapy (ACT) to treat Plasmodium falciparum during pregnancy in sub-Saharan Africa is scarce. A recent open label, randomized controlled trial in Mbarara, Uganda demonstrated that artemether-lumefantrine (AL) is not inferior to quinine to treat uncomplicated malaria in pregnancy. Haemozoin can persist in the placenta following clearance of parasites, however there is no data whether ACT can influence the amount of haemozoin or the dynamics of haemozoin clearance. METHODS: Women attending antenatal clinics with weekly screening and positive blood smears by microscopy were eligible to participate in the trial and were followed to delivery. Placental haemozoin deposition and inflammation were assessed by histology. To determine whether AL was associated with increased haemozoin clearance, population haemozoin clearance curves were calculated based on the longitudinal data. RESULTS: Of 152 women enrolled in each arm, there were 97 and 98 placental biopsies obtained in the AL and quinine arms, respectively. AL was associated with decreased rates of moderate to high grade haemozoin deposition (13.3% versus 25.8%), which remained significant after correcting for gravidity, time of infection, re-infection, and parasitaemia. The amount of haemozoin proportionately decreased with the duration of time between treatment and delivery and this decline was greater in the AL arm. Haemozoin was not detected in one third of biopsies and the prevalence of inflammation was low, reflecting the efficacy of antenatal care with early detection and prompt treatment of malaria. CONCLUSIONS: Placental haemozoin deposition was decreased in the AL arm demonstrating a relationship between pharmacological properties of drug to treat antenatal malaria and placental pathology at delivery. Histology may be considered an informative outcome for clinical trials to evaluate malaria control in pregnancy. Trial registration REGISTRY: http://clinicaltrials.gov/ct2/show/NCT00495508.