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Characterizing the spatial and temporal variation of
malaria incidence in Bangladesh, 2007
Background:
Malaria remains a significant health problem in Bangladesh affecting 13 of 64 districts. Therisk of malaria is variable across the endemic areas and throughout the year. A betterunderstanding of the spatial and temporal patterns in malaria risk and the determinantsdriving the variation are crucial for the appropriate targeting of interventions under theNational Malaria Control and Prevention Programme.
Methods:
Numbers of Plasmodium falciparum and Plasmodium vivax malaria cases reported by monthin 2007, across the 70 endemic thanas (sub-districts) in Bangladesh, were assembled fromhealth centre surveillance reports. Bayesian Poisson regression models of incidence wereconstructed, with fixed effects for monthly rainfall, maximum temperature and elevation, andrandom effects for thanas, with a conditional autoregressive prior spatial structure.
Results:
The annual incidence of reported cases was 34.0 and 9.6 cases/10,000 population for P.falciparum and P. vivax respectively and the population of the 70 malaria-endemic thanaswas approximately 13.5 million in 2007. Incidence of reported cases for both types of malariawas highest in the mountainous south-east of the country (the Chittagong Hill Tracts).Models revealed statistically significant positive associations between the incidence ofreported P. vivax and P. falciparum cases and rainfall and maximum temperature.
Conclusions:
The risk of P. falciparum and P. vivax was spatially variable across the endemic thanas ofBangladesh and also highly seasonal, suggesting that interventions should be targeted andtimed according to the risk profile of the endemic areas. Rainfall, temperature and elevationare major factors driving the spatiotemporal patterns of malaria in Bangladesh.
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Post-treatment haemolysis in severe imported
malaria after intravenous artesunate: case report of
three patients with hyperparasitaemia
Parenteral artesunate has been shown to be a superior treatment option compared toparenteral quinine in adults and children with severe malaria. Little evidence, however, isavailable on long-term safety. Recently, cases of late-onset haemolysis after parenteraltreatment with artesunate have been reported in European travellers with importedPlasmodium falciparum malaria. Therefore, an extended follow-up of adult patients treatedfor severe imported malaria was started in August 2011 at the University Medical CenterHamburg-Eppendorf.Until January 2012, three patients with hyperparasitaemia (range: 14-21%) were included foranalysis. In all three patients, delayed haemolysis was detected in the second week after thefirst dose of intravenous artesunate. Reticulocyte production index remained inadequatelylow in the 7 - 14 days following the first dose of artesunate despite rapid parasite clearance.Post-treatment haemolysis after parenteral artesunate may be of clinical relevance inparticular in imported severe malaria characterized by high parasite levels. Extended followupof at least 30 days including controls of haematological parameters after artesunatetreatment seems to be indicated. Further investigations are needed to assess frequency andpathophysiological background of this complication.
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Toll-like receptor 9 (TLR9) polymorphism
associated with symptomatic malaria: a cohort study
Background:
In areas mesoendemic for malaria transmission, symptomatic individuals play a significantrole as reservoirs for malaria infection. Understanding the pathogenesis of symptomaticmalaria is important in devising tools for augmenting malaria control. In this study, the effectof TLR9 polymorphisms on susceptibility to symptomatic malaria was investigated amongGhanaian children.
Methods:
Four hundred and twenty nine (429) healthy Ghanaian children, aged three to eleven years(3-11 years), were enrolled into a cohort study and actively followed up for symptomaticmalaria for one year. Four TLR9 single nucleotide polymorphisms (SNPs) namely: rs187084(C-1486 T), rs5743836(C-1237 T), rs352139 (G + 1174A) and rs352140 (G + 2848A) weregenotyped by direct sequencing, and their attributable and relative risks for symptomaticmalaria determined. TLR9 haplotypes were inferred using the PHASE software and analysedfor the risk of symptomatic malaria. A luciferase assay was performed to investigate whetherthe TLR9 haplotypes influence TLR9 promoter activity.
Results:
The rs352139 GG genotype showed a significantly increased relative risk of 4.8 forsymptomatic malaria (P = 0.0024) and a higher mean parasitaemia (P = 0.04). Conversely,the rs352140 GG genotype showed a significantly reduced relative risk of 0.34 (P = 0.048).TLR9 haplotypes analyses showed that TTAG haplotype was significantly associated withreduced relative risk of 0.2 for symptomatic malaria (P = 4x10-6) and a lower meanparasitaemia (0.007), while CTGA haplotype had an increased relative risk of 3.3 (P =0.005). Functional luciferase reporter gene expression assay revealed that the TTA haplotypehad a significantly higher promoter activity than the CCG, CTG and TCG haplotypes.
Conclusions:
Taken together, these findings indicate a significant association of TLR9 genepolymorphisms with symptomatic malaria among Ghanaian children in Dangme-Westdistrict.
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Efficacy of ICON(R) Maxx in the laboratory and against insecticide-resistant Anopheles gambiae in central Cote d'Ivoire
Background:
Long-lasting treatment kits, designed to transform untreated nets into long-lasting insecticidal nets (LLINs), may facilitate high coverage with LLINs where non-treated nets are in place. In this study, the efficacy of ICON(R) Maxx (Syngenta) was evaluated under laboratory conditions and in an experimental hut trial in central Cote d'Ivoire, where Anopheles gambiae s.s. are resistant to pyrethroid insecticides.
Methods:
In the laboratory, polyester and polyethylene net samples were treated with ICON(R) Maxx, washed up to 20 times and their efficacy determined in World Health Organization (WHO) cone assays against a susceptible laboratory An. gambiae s.s. colony. Over a 12-month period, the polyester nets were evaluated in a hut trial to determine mosquito deterrence, induced exophily, blood-feeding inhibition and mortality.
Results:
In the laboratory, ICON(R) Maxx-treated polyethylene nets showed higher efficacy against pyrethroid-susceptible mosquitoes than polyester nets. After 20 washings, insecticidal efficacy in bioassays was 59.4% knockdown (KD) and 22.3% mortality for polyethylene, and 55.3% KD and 17.9% mortality for polyester nets. In experimental huts, treated nets showed strong deterrence, induced exophily and an over three-fold reduction in blood-fed mosquitoes. More than half (61.8%) of the mosquitoes entering the huts with treated nets were found dead the next morning despite high levels of KD resistance. After washing the treated nets, KD and mortality rates were close to or exceeded predefined WHO thresholds in cone bioassays.
Conclusion:
In contrast to previous laboratory investigation, ICON(R) Maxx-treated nets showed only moderate KD and mortality rates. However, under semi-field conditions, in an area where mosquitoes are resistant to pyrethroids, ICON(R) Maxx showed high deterrence, induced exophily and provided a significant reduction in blood-feeding rates; features that are likely to have a positive impact in reducing malaria transmission. The WHO cone test may not always be a good proxy for predicting product performance under field conditions.
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Improved methods for haemozoin quantification in tissues
yield organ- and parasite-specific information in malariainfected mice
Background:
Despite intensive research, malaria remains a major health concern for non-immune residentsand travelers in malaria-endemic regions. Efficient adjunctive therapies against lifethreateningcomplications such as severe malarial anaemia, encephalopathy, placental malariaor respiratory problems are still lacking. Therefore, new insights into the pathogenesis ofsevere malaria are imperative. Haemozoin (Hz) or malaria pigment is produced during intraerythrocyticparasite replication, released in the circulation after schizont rupture andaccumulates inside multiple organs. Many in vitro and ex vivoimmunomodulating effects aredescribed for Hz but in vivo data are limited. This study aimed to improve methods for Hzquantification in tissues and to investigate the accumulation of Hz in different organs frommice infected with Plasmodium parasites with a varying degree of virulence.
Methods:
An improved method for extraction of Hz from tissues was elaborated and coupled to anoptimized, quantitative, microtiter plate-based luminescence assay with a high sensitivity. Inaddition, a technique for measuring Hz by semi-quantitative densitometry, applicable ontransmitted light images, was developed. The methods were applied to measure Hz in variousorgans of C57BL/6J mice infected with Plasmodium berghei ANKA, P. berghei NK65 orPlasmodium chabaudi AS. The used statistical methods were the Mann-Whitney U test andPearsons correlation analysis.
Results:
Most Hz was detected in livers and spleens, lower levels in lungs and kidneys, whereas subnanomolaramounts were observed in brains and hearts from infected mice, irrespectively ofthe parasite strain used. Furthermore, total Hz contents correlated with peripheralparasitaemia and were significantly higher in mice with a lethal P. berghei ANKA or P.berghei NK65-infection than in mice with a self-resolving P. chabaudi AS-infection, despitesimilar peripheral parasitaemia levels.
Conclusions:
The developed techniques were useful to quantify Hz in different organs with a highreproducibility and sensitivity. An organ-specific Hz deposition pattern was found and wasindependent of the parasite strain used. Highest Hz levels were identified in mice infectedwith lethal parasite strains suggesting that Hz accumulation in tissues is associated withmalaria-related mortality.
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Remote sensing-based time series models for malaria
early warning in the highlands of Ethiopia
Background:
Malaria is one of the leading public health problems in most of sub-Saharan Africa,particularly in Ethiopia. Almost all demographic groups are at risk of malaria because ofseasonal and unstable transmission of the disease. Therefore, there is a need to developmalaria early-warning systems to enhance public health decision making for control andprevention of malaria epidemics. Data from orbiting earth-observing sensors can monitorenvironmental risk factors that trigger malaria epidemics. Remotely sensed environmentalindicators were used to examine the influences of climatic and environmental variability ontemporal patterns of malaria cases in the Amhara region of Ethiopia.
Methods:
In this study seasonal auto regressive integrated moving average (SARIMA) models wereused to quantify the relationship between malaria cases and remotely sensed environmentalvariables, including rainfall, land-surface temperature (LST), vegetation indices (NDVI andEVI), and actual evapotranspiration (ETa) with lags ranging from one to three months.Predictions from the best model with environmental variables were compared to the actualobservations from the last 12 months of the time series.
Results:
Malaria cases exhibited positive associations with LST at a lag of one month and positiveassociations with indicators of moisture (rainfall, EVI and ETa) at lags from one to threemonths. SARIMA models that included these environmental covariates had better fits andmore accurate predictions, as evidenced by lower AIC and RMSE values, than modelswithout environmental covariates.
Conclusions:
Malaria risk indicators such as satellite-based rainfall estimates, LST, EVI, and ETa exhibitedsignificant lagged associations with malaria cases in the Amhara region and improved modelfit and prediction accuracy. These variables can be monitored frequently and extensivelyacross large geographic areas using data from earth-observing sensors to support publichealth decisions.
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Spatial repellents: from discovery and development to
evidence-based validation
International public health workers are challenged by a burden of arthropod-borne disease thatremains elevated despite best efforts in control programmes. With this challenge comes theopportunity to develop novel vector control paradigms to guide product development andprogramme implementation. The role of vector behaviour modification in disease control wasfirst highlighted several decades ago but has received limited attention within the public healthcommunity. This paper presents current evidence highlighting the value of sub-lethal agents,specifically spatial repellents, and their use in global health, and identifies the primary challengestowards establishing a clearly defined and recommended role for spatial repellent products indisease control.
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Isolation of Plasmodium falciparum by flow-cytometry: implications for single-trophozoite genotyping and parasite DNA purification for whole-genome high-throughput sequencing of archival samples
Background:
Flow cytometry and cell sorting are powerful tools enabling the selection of particular cell types within heterogeneous cell mixtures. These techniques, combined with whole genome amplification that non-specifically amplify small amounts of starting DNA, offer exciting new opportunities for the study of malaria genetics. Among them, two are tested in this paper: (1) single cell genotyping and (2) parasite DNA purification for subsequent whole genome sequencing using shotgun technologies.
Methods:
The method described allows isolation of Plasmodium falciparum trophozoites, genotyping and whole genome sequencing from the blood of infected patients. For trophozoite isolation, parasite and host nuclei are stained using propidium iodide (PI) followed by flow cytometry and cell sorting to separate trophozoites from host cells. Before genotyping or sequencing, whole genome amplification is used to increase the amount of DNA within sorted samples. The method has been specifically designed to deal with frozen blood samples.Results and conclusionThe results demonstrate that single trophozoite genotyping is possible and that cell sorting can be successfully applied to reduce the contaminating host DNA for subsequent whole genome sequencing of parasites extracted from infected blood samples.
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B cell analysis of ethnic groups in Mali with differential susceptibility to malaria
Background:
Several studies indicate that people of the Fulani ethnic group are less susceptible to malaria compared to those of other ethnic groups living sympatrically in Africa, including the Dogon ethnic group. Although the mechanisms of this protection remain unclear, the Fulani are known to have higher levels of Plasmodium falciparum-specific antibodies of all Ig classes as compared to the Dogon. However, the proportions of B cell subsets in the Fulani and Dogon that may account for differences in the levels of Ig have not been characterized.
Methods:
In this cross-sectional study, venous blood was collected from asymptomatic Fulani (n=25) and Dogon (n=25) adults in Mali during the malaria season, and from P. falciparum-naive adults in the U.S. (n=8). At the time of the blood collection, P. falciparum infection was detected by blood-smear in 16% of the Fulani and 40% of the Dogon volunteers. Thawed lymphocytes were analysed by flow cytometry to quantify B cell subsets, including immature and naive B cells; plasma cells; and classical, activated, and atypical memory B cells (MBCs).
Results:
The overall distribution of B cell subsets was similar between Fulani and Dogon adults, although the percentage of activated MBCs was higher in the Fulani group (Fulani: 11.07% [95% CI: 9.317 - 12.82]; Dogon: 8.31% [95% CI: 6.378 - 10.23]; P=0.016). The percentage of atypical MBCs was similar between Fulani and Dogon adults (Fulani: 28.3% [95% CI: 22.73 - 34.88]; Dogon: 29.3% [95% CI: 25.06 - 33.55], but higher than U.S. adults (U.S.: 3.0% [95% CI: -0.21 - 6.164]; P<0.001). Plasmodium falciparum infection was associated with a higher percentage of plasma cells among Fulani (Fulani infected: 3.3% [95% CI: 1.788 - 4.744]; Fulani uninfected: 1.71% [95% CI: 1.33 - 2.08]; P=0.011), but not Dogon adults.
Conclusion:
These data show that the malaria-resistant Fulani have a higher percentage of activated MBCs compared to the Dogon, and that P. falciparum infection is associated with a higher percentage of plasma cells in the Fulani compared to the Dogon, findings that may account for the higher levels of P. falciparum antibodies in the Fulani.
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Mapping malaria risk among children in Cote
d'Ivoire using Bayesian geo-statistical models
Background:
In Cote d'Ivoire, an estimated 767,000 disability-adjusted life years are due to malaria,placing the country at position number 14 with regard to the global burden of malaria. Riskmaps are important to guide control interventions, and hence, the aim of this study was topredict the geographical distribution of malaria infection risk in children aged <16 years inCote d'Ivoire at high spatial resolution.
Methods:
Using different data sources, a systematic review was carried out to compile and georeferencesurvey data on Plasmodium spp. infection prevalence in Cote d'Ivoire, focusing onchildren aged <16 years. The period from 1988 to 2007 was covered. A suite of Bayesiangeo-statistical logistic regression models was fitted to analyse malaria risk. Non-spatialmodels with and without exchangeable random effect parameters were compared tostationary and non-stationary spatial models. Non-stationarity was modelled assuming thatthe underlying spatial process is a mixture of separate stationary processes in each ecologicalzone. The best fitting model based on the deviance information criterion was used to predictPlasmodium spp. infection risk for entire Cote d'Ivoire, including uncertainty.
Results:
Overall, 235 data points at 170 unique survey locations with malaria prevalence data forindividuals aged <16 years were extracted. Most data points (n = 182, 77.4%) were collectedbetween 2000 and 2007. A Bayesian non-stationary regression model showed the best fit withannualized rainfall and maximum land surface temperature identified as significantenvironmental covariates. This model was used to predict malaria infection risk at nonsampledlocations. High-risk areas were mainly found in the north-central and western area,while relatively low-risk areas were located in the north at the country border, in the northeast,in the south-east around Abidjan, and in the central-west between two high prevalenceareas.
Conclusion:
The malaria risk map at high spatial resolution gives an important overview of thegeographical distribution of the disease in Cote d'Ivoire. It is a useful tool for the nationalmalaria control programme and can be utilized for spatial targeting of control interventionsand rational resource allocation.
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