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The magnitude and trend of artemether-lumefantrine stock-outs at public health facilities in Kenya
Background:
Health facility stock-outs of artemether-lumefantrine (AL), the common first-line therapy for uncomplicated malaria across Africa, adversely affect effective malaria case-management. They have been previously reported on various scales in time and space, however the magnitude of the problem and trends over time are less clear. Here, 2010-2011 data are reported from public facilities in Kenya where alarming stock-outs were revealed in 2008.
Methods:
Data were collected between January 2010 and June 2011 as part of 18 monthly cross-sectional surveys undertaken at nationally representative samples of public health facilities. The primary monitoring indicator was total stock-out of all four weight-specific AL packs. The secondary indicators were stock-outs of at least one AL pack and individual stock-outs for each AL pack. Monthly proportions and summary means of the proportions over the monitoring period were measured for each indicator. Stock-out trends were assessed using linear regression.
Results:
The number of surveyed facilities across 18 time points ranged between 162 and 176 facilities. The stock-out means of the proportion of health facilities were 11.6% for total AL stock-out, 40.6% for stock-out of at least one AL pack, and between 20.5% and 27.4% for stock-outs of individual AL packs. Monthly decrease of the total AL stock-out was 0.005% (95% CI: 0.5 to +0.5; p = 0.983). Monthly decrease in the stock-out of at least one AL pack was 0.7% (95% CI: 1.5 to +0.3; p = 0.058) while stock-outs of individual AL packs decreased monthly between 0.2% for AL 24-pack and 0.7% for AL six-pack without statistical significance for any of the weight-specific packs.
Conclusions:
Despite lower levels of AL stock-outs compared to the reports in 2008, the stock-outs at Kenyan facilities during 2010-2011 are still substantial and of particular worry for the most detrimental:- simultaneous absence of any AL pack. Only minor decrease was observed in the stock-outs of individual AL packs. Recently launched interventions to eliminate AL stock-outs in Kenya are fully justified.
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Human Plasmodium knowlesi infection in Ranong province, southwestern border of Thailand
Background:
Plasmodium knowlesi, a simian malaria parasite, has been reported in humans in many Southeast Asian countries. In Thailand, most of the limited numbers of cases reported so far were from areas near neighbouring countries, including Myanmar.
Methods:
Blood samples collected from 171 Thai and 248 Myanmese patients attending a malaria clinic in Ranong province, Thailand, located near the Myanmar border were investigated for P. knowlesi using nested PCR assays. Positive samples were also investigated by PCR for Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovale, and were confirmed by sequencing the gene encoding the circumsporozoite protein (csp).
Results:
Two samples, one obtained from a Thai and the other a Myanmese, were positive for P. knowlesi only. Nucleotide sequences of the csp gene derived from these two patients were identical and phylogenetically indistinguishable from other P. knowlesi sequences derived from monkeys and humans. Both patients worked in Koh Song, located in the Kawthoung district of Myanmar, which borders Thailand.
Conclusion:
This study indicates that transmission of P. knowlesi is occurring in the Ranong province of Thailand or the Kawthoung district of Myanmar. Further studies are required to assess the incidence of knowlesi malaria and whether macaques in these areas are the source of the infections.
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Human cerebral malaria and Plasmodium falciparum genotypes in Malawi
Background:
Cerebral malaria, a severe form of Plasmodium falciparum infection, is an important cause of mortality in sub-Saharan African children. A Taqman 24 Single Nucleotide Polymorphisms (SNP) molecular barcode assay was developed for use in laboratory parasites which estimates genotype number and identifies the predominant genotype.
Methods:
The 24 SNP assay was used to determine predominant genotypes in blood and tissues from autopsy and clinical patients with cerebral malaria.
Results:
Single genotypes were shared between the peripheral blood, the brain, and other tissues of cerebral malaria patients, while malaria-infected patients who died of non-malarial causes had mixed genetic signatures in tissues examined. Children with retinopathy-positive cerebral malaria had significantly less complex infections than those without retinopathy (OR = 3.7, 95% CI [1.51-9.10]).The complexity of infections significantly decreased over the malaria season in retinopathy-positive patients compared to retinopathy-negative patients.
Conclusions:
Cerebral malaria patients harbour a single or small set of predominant parasites; patients with incidental parasitaemia sustain infections involving diverse genotypes. Limited diversity in the peripheral blood of cerebral malaria patients and correlation with tissues supports peripheral blood samples as appropriate for genome-wide association studies of parasite determinants of pathogenicity.
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Anti-malarial drugs: how effective are they against Plasmodium falciparum gametocytes?
Background:
Recent renewed emphasis on the eradication of malaria has highlighted the need for more tools with which to achieve this ambitious goal. One high priority area is the need to determine the gametocytocidal activity of both currently used anti-malarial drugs and those in the development pipeline. However, testing the activity of compounds against Plasmodium falciparum gametocytes is technically challenging both in vivo and in vitro.
Methods:
Here the use of a simple robust assay to screen a panel of currently used and experimental anti-malarial drugs against mature P. falciparum gametocytes is described.
Results:
Eight of 44 compounds tested reduced gametocyte viability by at least 50% and three showed IC50 values in nM range.
Conclusions:
There is a need to identify new compounds with activity against late stage gametocytes and the information provided by this in vitro assay is a valuable first step, which can guide future clinical studies.
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Cytoadherence and virulence - the case of Plasmodium knowlesi malaria
Background:
Cytoadherence of infected red blood cells to brain endothelium is causally implicated in malarial coma, one of the severe manifestations of falciparum malaria. Cytoadherence is mediated by specific binding of variant parasite antigens, expressed on the surface of infected erythrocytes, to endothelial receptors including, ICAM-1, VCAM and CD36. In fatal cases of severe falciparum malaria with coma, blood vessels in the brain are characteristically congested with infected erythrocytes. Brain sections from a fatal case of knowlesi malaria, but without coma, were similarly congested with infected erythrocytes. The objective of this study was to determine the binding phenotype of Plasmodium knowlesi infected human erythrocytes to recombinant human ICAM-1, VCAM and CD36.
Methods:
Five patients with PCR-confirmed P. knowlesi malaria were recruited into the study with consent between April and August 2010. Pre-treatment venous blood was washed and cultured ex vivo to increase the proportion of schizont-infected erythrocytes. Cultured blood was seeded into Petri dishes with triplicate areas coated with ICAM-1, VCAM and CD36. Following incubation at 37degreesC for one hour the dishes were washed and the number of infected erythrocytes bound/mm2 to PBS control areas and to recombinant human ICAM-1 VCAM and CD36 coated areas were recorded. Each assay was performed in duplicate. Assay performance was monitored with the Plasmodium falciparum clone HB3.
Results:
Blood samples were cultured ex vivo for up to 14.5 h (mean 11.3 +/- 1.9 h) to increase the relative proportion of mature trophozoite and schizont-infected red blood cells to at least 50% (mean 65.8 +/- 17.51%). Three (60%) isolates bound significantly to ICAM-1 and VCAM, one (20%) isolate bound to VCAM and none of the five bound significantly to CD36.
Conclusions:
Plasmodium knowlesi infected erythrocytes from human subjects bind in a specific but variable manner to the inducible endothelial receptors ICAM-1 and VCAM. Binding to the constitutively-expressed endothelial receptor CD36 was not detected. Further work will be required to define the pathological consequences of these interactions.
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Can universal insecticide-treated net campaigns achieve equity in coverage and use? The case of northern Nigeria
Background:
Insecticide-treated nets (ITNs) are effective tools for malaria prevention and can significantly reduce severe disease and mortality due to malaria, especially among children under five in endemic areas. However, ITN coverage and use remain low and inequitable among different socio-economic groups in sub-Saharan Africa, particularly in Nigeria. Several strategies have been proposed to increase coverage and use and reduce inequity in Nigeria, including free distribution campaigns recently conducted by the Nigerian federal government. Using data from the first post-campaign survey, the authors investigated the effect of the mass free distribution campaigns in achieving equity in household ownership and use of ITNs.
Methods:
A post-campaign survey was undertaken in November 2009 in northern Nigeria to assess the effect of the campaigns in addressing equity across different socio-economic groups. The survey included 987 households randomly selected from 60 clusters in Kano state. Using logistic regression and the Lorenz concentration curve and index, the authors assessed equity in ITN coverage and use.
Results:
ITN ownership coverage increased from 10% before the campaigns to 70%-a more than fivefold increase. The campaigns reduced the ownership coverage gap by 75%, effectively reaching parity among wealth quintiles (Concentration index 0.02, 95% CI (0.02; 0.05) versus 0.21 95%CI (0.08; 0.34) before the campaigns). ITN use (individuals reporting having slept under an ITN the night before the survey visit) among individuals from households owning at least one ITN, was 53.1% with no statistically significant difference between the lowest, second, third and fourth wealth quintiles and the highest wealth quintile (lowest: odds ratio (OR) 0.87, 95% confidence interval (CI) (0.67;1.13); second: OR 0.85, 95% CI (0.66;1.24); third: OR 1.10 95% CI (0.86;1.4) and fourth OR 0.91 95% CI (0.72;1.15).
Conclusion:
The campaign had a significant impact by increasing ITN coverage and reducing inequity in ownership and use. Free ITN distribution campaigns should be sustained to increase equitable coverage. These campaigns should be supplemented with other ITN distribution strategies to cover newborns and replace aging nets.
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Attractive toxic sugar bait (ATSB) methods decimate populations of Anopheles malaria vectors in arid environments regardless of the local availability of favoured sugar-source blossoms
Background:
Attractive toxic sugar bait (ATSB) methods are a new and promising "attract and kill" strategy for mosquito control. Sugar-feeding female and male mosquitoes attracted to ATSB solutions, either sprayed on plants or in bait stations, ingest an incorporated low-risk toxin such as boric acid and are killed. This field study in the arid malaria-free oasis environment of Israel compares how the availability of a primary natural sugar source for Anopheles sergentii mosquitoes: flowering Acacia raddiana trees, affects the efficacy of ATSB methods for mosquito control.
Methods:
A 47-day field trial was conducted to compare impacts of a single application of ATSB treatment on mosquito densities and age structure in isolated uninhabited sugar-rich and sugar-poor oases relative to an untreated sugar-rich oasis that served as a control.
Results:
ATSB spraying on patches of non-flowering vegetation around freshwater springs reduced densities of female An. sergentii by 95.2% in the sugar-rich oasis and 98.6% in the sugar-poor oasis; males in both oases were practically eliminated. It reduced daily survival rates of female An. sergentii from 0.77 to 0.35 in the sugar-poor oasis and from 0.85 to 0.51 in the sugar-rich oasis. ATSB treatment reduced the proportion of older more epidemiologically dangerous mosquitoes (three or more gonotrophic cycles) by 100% and 96.7%, respectively, in the sugar-poor and sugar-rich oases. Overall, malaria vectorial capacity was reduced from 11.2 to 0.0 in the sugar-poor oasis and from 79.0 to 0.03 in the sugar-rich oasis. Reduction in vector capacity to negligible levels days after ATSB application in the sugar-poor oasis, but not until after 2 weeks in the sugar-rich oasis, show that natural sugar sources compete with the applied ATSB solutions.
Conclusion:
While readily available natural sugar sources delay ATSB impact, they do not affect overall outcomes because the high frequency of sugar feeding by mosquitoes has an accumulating effect on the probability they will be attracted to and killed by ATSB methods. Operationally, ATSB methods for malaria vector control are highly effective in arid environments regardless of competitive, highly attractive natural sugar sources in their outdoor environment.
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Apoptosis of the fibrocytes type 1 in the spiral ligament and blood labyrinth barrier disturbance cause hearing impairment in murine cerebral malaria
Background:
Experimental murine malaria has been shown to result in significant hearing impairment. Microscopic evaluation of the temporal bones of these animals has revealed regular morphology of the cochlea duct. Furthermore, the known vascular pathologic changes being associated with malaria could not be found. Immunohistochemistry for ICAM1 showed a strong marking in the stria vascularis, indicating a disturbance of the endocochlear potential. The aim of this study was to evaluate the role of apoptosis and the disturbance of the blood labyrinth barrier in the murine malaria associated hearing impairment.
Methods:
The temporal bones of seven mice with cerebral malaria--four with hearing impairment, three without hearing impairment--were evaluated with immunohistochemistry for cleaved caspase 3 to detect apoptosis and connexin 26, a gap junction protein being a cornerstone in the endocochlear potassium recirculation. Furthermore five animals with cerebral malaria were treated with Evans blue prior to sacrification to detect disturbances of the blood labyrinth barrier.
Results:
Cleaved caspase 3 could clearly be detected by immunohistochemistry in the fibrocytes of the spiral ligament, more intensively in animals with hearing impairment, less intensively in those without. Apoptosis signal was equally distributed in the spiral ligament as was the connexin 26 gap junction protein. The Evans blue testing revealed a strong signal in the malaria animals and no signal in the healthy control animals.
Conclusion:
Malfunction of the fibrocytes type 1 in the spiral ligament and disruption of the blood labyrinth barrier, resulting in a breakdown of the endocochlear potential, are major causes for hearing impairment in murine cerebral malaria.
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The complexities of malaria disease manifestations with a focus on asymptomatic malaria
Malaria is a serious parasitic disease in the developing world, causing high morbidity and mortality. The pathogenesis of malaria is complex, and the clinical presentation of disease ranges from severe and complicated, to mild and uncomplicated, to asymptomatic malaria. Despite a wealth of studies on the clinical severity of disease, asymptomatic malaria infections are still poorly understood. Asymptomatic malaria remains a challenge for malaria control programs as it significantly influences transmission dynamics. A thorough understanding of the interaction between hosts and parasites in the development of different clinical outcomes is required. In this review, the problems and obstacles to the study and control of asymptomatic malaria are discussed. The human and parasite factors associated with differential clinical outcomes are described and the management and treatment strategies for the control of the disease are outlined. Further, the crucial gaps in the knowledge of asymptomatic malaria that should be the focus of future research towards development of more effective malaria control strategies are highlighted.
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Strengthening the policy setting process for global malaria control and elimination
The scale-up of malaria control efforts in recent years, coupled with major investments in malaria research, has produced impressive public health impact in a number of countries and has led to the development of new tools and strategies aimed at further consolidating malaria control goals. As a result, there is a growing need for the malaria policy setting process to rapidly review increasing amounts of evidence.The World Health Organization Global Malaria Programme, in keeping with its mandate to set evidence-informed policies for malaria control, has convened the Malaria Policy Advisory Committee as a mechanism to increase the timeliness, transparency, independence and relevance of its recommendations to World Health Organization member states in relation to malaria control and elimination.The Malaria Policy Advisory Committee, composed of 15 world-renowned malaria experts, will meet in full twice a year, with the inaugural meeting scheduled for 31 January to 2 February 2012 in Geneva. Policy recommendations, and the evidence to support them, will be published within two months of every meeting as part of an open access Malaria Journal thematic series. This article is a prelude to that series and provides the global malaria community with the background and overview of the Committee and its terms of reference.
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