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This paper grew out of a meeting organized in September 2014 in London on 'Re-imagining malaria'. The focus of that meeting was on malaria today; only afterwards did the idea emerge that re-imagining the past might serve as a useful way for guiding present re-thinking. Sub-Saharan Africa is the logical place for such a re-examination for, as argued in this paper, the approaches that emerged following the collapse of the global eradication campaign were available to WHO in the 1950s, but these were not pursued as Africa was not encouraged to seek solutions outside those being advocated for eradication elsewhere. [ABSTRACT FROM AUTHOR]

Background Under-five mortality has been declining rapidly in a number of sub-Saharan African settings. Malaria-related mortality is known to be a major component of childhood causes of death and malaria remains a major focus of health interventions. The paper explored the contribution of malaria relative to other specific causes of under-five deaths to these trends. Methods This paper uses longitudinal demographic surveillance data to examine trends and causes of death of under-five mortality in Rufiji, whose population has been followed for over nine years (1999-2007). Causes of death, determined by the verbal autopsy technique, are analysed with Arriaga's decomposition method to assess the contribution of declining malaria-related mortality relative to other causes of death as explaining a rapid decline in overall childhood mortality. Results Over the 1999-2007 period, under-five mortality rate in Rufiji declined by 54.3%, from 33.3 to 15.2 per 1,000 person-years. If this trend is sustained, Rufiji will be a locality that achieves MDG4 target. Although hypotrophy at birth remained the leading cause of death for neonates, malaria remains as the leading cause of death for post-neonates followed by pneumonia. However, declines in malaria death rates accounted for 49.9% of the observed under-five mortality decline while all perinatal causes accounted for only 19.9%. Conclusion To achieve MDG 4 in malaria endemic settings, health programmes should continue efforts to reduce malaria mortality and more efforts are also needed to improve newborn survival. [ABSTRACT FROM AUTHOR]

Background As malaria transmission declines, continued improvements of prevention and control interventions will increasingly rely on accurate knowledge of risk factors and an ability to define high-risk areas and populations at risk for focal targeting of interventions. This paper explores the independent association between living in a hotspot and prospective risk of malaria infection. Methods Malaria infection status defined by nPCR and AMA-1 status in year 1 were used to define geographic hotspots using two geospatial statistical methods (SaTScan and Kernel density smoothing). Other malaria risk factors for malaria infection were explored by fitting a multivariable model. Results This study demonstrated that residing in infection hotspot of malaria transmission is an independent predictor of malaria infection in the future. Conclusion It is likely that targeting such hotspots with better coverage and improved malaria control strategies will result in more cost-efficient uses of resources to move towards malaria elimination. [ABSTRACT FROM AUTHOR]

Background: Timely molecular surveillance of Plasmodium falciparum kelch 13 (k13) gene mutations is essential for monitoring the emergence and stemming the spread of artemisinin resistance. Widespread artemisinin resistance, as observed in Southeast Asia, would reverse significant gains that have been made against the malaria burden in Africa. The purpose of this study was to assess the prevalence of k13 polymorphisms in western Kenya and Ethiopia at sites representing varying transmission intensities between 2018 and 2022. Methods: Dried blood spot samples collected through ongoing passive surveillance and malaria epidemiological studies, respectively, were investigated. The k13 gene was genotyped in P. falciparum isolates with high parasitaemia: 775 isolates from four sites in western Kenya (Homa Bay, Kakamega, Kisii, and Kombewa) and 319 isolates from five sites across Ethiopia (Arjo, Awash, Gambella, Dire Dawa, and Semera). DNA sequence variation and neutrality were analysed within each study site where mutant alleles were detected. Results: Sixteen Kelch13 haplotypes were detected in this study. Prevalence of nonsynonymous k13 mutations was low in both western Kenya (25/783, 3.19%) and Ethiopia (5/319, 1.57%) across the study period. Two WHO-validated mutations were detected: A675V in three isolates from Kenya and R622I in four isolates from Ethiopia. Seventeen samples from Kenya carried synonymous mutations (2.17%). No synonymous mutations were detected in Ethiopia. Genetic variation analyses and tests of neutrality further suggest an excess of low frequency polymorphisms in each study site. Fu and Li's F test statistic in Semera was 0.48 (P > 0.05), suggesting potential population selection of R622I, which appeared at a relatively high frequency (3/22, 13.04%). Conclusions: This study presents an updated report on the low frequency of k13 mutations in western Kenya and Ethiopia. The WHO-validated R622I mutation, which has previously only been reported along the north-west border of Ethiopia, appeared in four isolates collected from eastern Ethiopia. The rapid expansion of R622I across Ethiopia signals the need for enhanced monitoring of the spread of drug-resistant P. falciparum parasites in East Africa. Although ACT remains currently efficacious in the study areas, continued surveillance is necessary to detect early indicators of artemisinin partial resistance. [ABSTRACT FROM AUTHOR]

Background: Although malaria is highly prevalent throughout Malawi, little is known of its transmission dynamics. This paper describes the seasonal activity of the different vectors, human biting indices, sporozoite rates and the entomological inoculation rate in a low-lying rural area in southern Malawi. Methods: Vectors were sampled over 52 weeks from January 2002 to January 2003, by pyrethrum knockdown catch in two villages in Chikhwawa district, in the Lower Shire Valley. Results: In total, 7,717 anophelines were collected of which 55.1% were Anopheles gambiae sensu lato and 44.9% were Anopheles funestus. Three members of the An. gambiae complex were identified by PCR: Anopheles arabiensis (75%) was abundant throughout the year, An. gambiae s.s. (25%) was most common during the wet season and Anopheles quadriannulatus occurred at a very low frequency (n=16). An. funestus was found in all samples but was most common during the dry season. Anopheles gambiae s.s. and An. funestus were highly anthropophilic with human blood indices of 99.2% and 96.3%, respectively. Anopheles arabiensis had fed predominantly on humans (85.0%) and less commonly on cattle (10.9%; 1.2% of blood meals were of mixed origin). Plasmodium falciparum (192/3,984) and Plasmodium malariae (1/3,984) sporozoites were detected by PCR in An. arabiensis (3.2%) and An. funestus (4.5%), and in a significantly higher proportion of An. gambiae s.s. (10.6%)(p<0.01). All three vectors were present throughout the year and malaria transmission occurred in every month, although with greatest intensity during the rainy season (January to April). The combined human blood index exceeded 92% and the P. falciparum sporozoite rate was 4.8%, resulting in estimated inoculation rates of 183 infective bites/ person per annum, or an average rate of ~15 infective bites/ person/month. Conclusions: The results demonstrate the importance of An. gambiae s.s., An. arabiensis and An. funestus in driving the high levels of malaria transmission in the south of Malawi. Sustained and high coverage or roll out of current approaches to malaria control (primarily insecticide-treated bed nets and indoor residual house spraying) in the area are likely to reduce the observed high malaria transmission rate and consequently the incidence of human infections, unless impeded by increasing resistance of vectors to insecticides. [ABSTRACT FROM AUTHOR]

Background: Artemisinin-based combination therapy (ACT) has been recommended as the first-line treatment by the World Health Organization to treat uncomplicated Plasmodium falciparum malaria. However, the emergence and spread of P. falciparum resistant to artemisinins and their partner drugs is a significant risk for the global effort to reduce disease burden facing the world. Currently, dihydroartemisinin-piperaquine (DHA-PPQ) is the most common drug used to treat P. falciparum, but little evidence about the resistance status targeting DHA (ACT drug) and its partner drug (PPQ) has been reported in Shandong Province, China. Methods: A retrospective study was conducted to explore the prevalence and spatial distribution of Pfk13 and Pfcrt polymorphisms (sites of 72–76, and 93–356) among imported P. falciparum isolates between years 2015–2019 in Shandong Province in eastern China. Individual epidemiological information was collected from a web-based reporting system were reviewed and analysed. Results: A total of 425 P. falciparum blood samples in 2015–2019 were included and 7.3% (31/425) carried Pfk13 mutations. Out of the isolates that carried Pfk13 mutations, 54.8% (17/31) were nonsynonymous polymorphisms. The mutant alleles A578S, Q613H, C469C, and S549S in Pfk13 were the more frequently detected allele, the mutation rate was the same as 9.7% (3/31). Another allele Pfk13 C580Y, closely associated with artemisinin (ART) resistance, was found as 3.2% (2/31), which was found in Cambodia. A total of 14 mutant isolates were identified in Western Africa countries (45.2%, 14/31). For the Pfcrt gene, the mutation rate was 18.1% (77/425). T76T356 and T76 were more frequent in all 13 different haplotypes with 26.0% (20/77) and 23.4% (18/77). The CVIET and CVIKT mutant at loci 72–76 have exhibited a prevalence of 19.5% (15/77) and 3.9% (3/77), respectively. The CVIET was mainly observed in samples from Congo (26.7%, 4/15) and Mozambique (26.7%, 4/15). No mutations were found at loci 97, 101 and 145. For polymorphisms at locus 356, a total of 24 isolates were identified and mainly from Congo (29.2%, 7/24). Conclusion: These findings indicate a low prevalence of Pfk13 in the African isolates. However, the emergence and increase in the new alleles Pfcrt I356T, reveals a potential risk of drug pressure in PPQ among migrant workers returned from Africa. Therefore, continuous molecular surveillance of Pfcrt mutations and in vitro susceptibility tests related to PPQ are necessary. [ABSTRACT FROM AUTHOR]

Background: Independent emergence and spread of artemisinin-resistant Plasmodium falciparum malaria have recently been confirmed in Africa, with molecular markers associated with artemisinin resistance increasingly detected. Surveillance to promptly detect and effectively respond to anti-malarial resistance is generally suboptimal in Africa, especially in low transmission settings where therapeutic efficacy studies are often not feasible due to recruitment challenges. However, these communities may be at higher risk of anti-malarial resistance. Methods: From March 2018 to February 2020, a sequential mixed-methods study was conducted to evaluate the feasibility of the near-real-time linkage of individual patient anti-malarial resistance profiles with their case notifications and treatment response reports, and map these to fine scales in Nkomazi sub-district, Mpumalanga, a pre-elimination area in South Africa. Results: Plasmodium falciparum molecular marker resistance profiles were linked to 55.1% (2636/4787) of notified malaria cases, 85% (2240/2636) of which were mapped to healthcare facility, ward and locality levels. Over time, linkage of individual malaria case demographic and molecular data increased to 75.1%. No artemisinin resistant validated/associated Kelch-13 mutations were detected in the 2385 PCR positive samples. Almost all 2812 samples assessed for lumefantrine susceptibility carried the wildtype mdr86ASN and crt76LYS alleles, potentially associated with decreased lumefantrine susceptibility. Conclusion: Routine near-real-time mapping of molecular markers associated with anti-malarial drug resistance on a fine spatial scale provides a rapid and efficient early warning system for emerging resistance. The lessons learnt here could inform scale-up to provincial, national and regional malaria elimination programmes, and may be relevant for other antimicrobial resistance surveillance. [ABSTRACT FROM AUTHOR]

Background: Use of intermittent preventive treatment (IPTp) is a proven cost-effective intervention for preventing malaria in pregnancy. However, despite the roll-out of IPTp policies across Africa more than ten years ago, utilization levels remain low. This review sought to consolidate scattered evidence as to the health system barriers for IPTp coverage in the continent. Methods and findings: Relevant literature from Africa was systematically searched, reviewed and synthesized. Only studies containing primary data were considered. Studies reveal that: (i) poor leadership and governance contribute to slow decentralization of programme management, lack of harmonized guidelines, poor accountability mechanisms, such as robust monitoring and evaluation systems; (ii) low budgetary allocation towards policy implementation slows scale-up, while out-of-pocket expenditure deters women from seeking antenatal services that include IPTp; (iii) there are rampant human resource challenges including low staff motivation levels attributed to such factors as incorrect knowledge of IPTp recommendations and inadequate staffing; (iv) implementation of IPTp policies is hampered by prevailing service delivery barriers, such as long waiting time, long distances to health facilities and poor service provider/client relations; and (v) drug stock-outs and poor management of information and supply chains impair sustained availability of drugs for IPTp. Conclusions: For successful IPTp policy implementation, it is imperative that malaria control programmes target health system barriers that result in low coverage and hence programme ineffectiveness. [ABSTRACT FROM AUTHOR]

Background: The emergence and spread of multidrug resistance poses a significant risk to malaria control and eradication goals in the world. There has been no indigenous malaria cases reported in China since 2017, and China is approaching national malaria elimination. Therefore, anti-malarial drug resistance surveillance and tracking the emergence and spread of imported drug-resistant malaria cases will be necessary in a post-elimination phase in China. Methods: Dried blood spots were obtained from Plasmodium falciparum-infected cases returned from Africa to China between 2012 and 2015, prior to anti-malarial drug treatment. Whole DNA were extracted and known polymorphisms relating to drug resistance of pfcrt, pfmdr1 gene, and the propeller domain of pfk13 were evaluated by nested PCR and sequencing. The haplotypes and prevalence of these three genes were evaluated separately. Chi-squared test and Fisher's exact test were used to evaluate differences among the different sub-regions of Africa. A P value < 0.05 was used to evaluate differences with statistical significance. The maps were created using ArcGIS. Results: A total of 731 P. falciparum isolates were sequenced at the pfcrt locus. The wild type CVMNK was the most prevalent haplotype with prevalence of 62.8% and 29.8% of the isolates showed the triple mutant haplotype CVIET. A total of 434 P. falciparum isolates were successfully sequenced and pfmdr1 allelic variants were observed in only codons 86, 184 and 1246. Twelve haplotypes were identified and the prevalence of the wild type pfmdr1 NYD was 44.1%. The single mutant pfmdr1 in codons 86 and 184 was predominant but the haplotype NYY with single mutation in codon 1246 was not observed. The double mutant haplotype YFD was common in Africa. About 1,357 isolates were successfully sequenced of pfk13-propeller domain, the wild type was found in 1,308 samples (96.4%) whereby 49 samples (3.6%) had mutation in pfk13. Of 49 samples with pfk13 mutations, 22 non-synonymous and 4 synonymous polymorphic sites were confirmed. The A578S was the most common mutation in pfk13-propeller domain and three mutations associated with artemisinin resistance (M476I, R539T, P553L) were identified in three isolates. Conclusion: This study provides evidence that could give insight into potential issues with anti-malarial drug resistance to inform national drug policy in China in order to treat imported cases. [ABSTRACT FROM AUTHOR]

Background: Malaria continues to be a disease of massive burden in Africa, and the public health resources targeted at surveillance, prevention, control, and intervention comprise large outlays of expense. Malaria transmission is largely constrained by the suitability of the climate for Anopheles mosquitoes and Plasmodium parasite development. Thus, as climate changes, shifts in geographic locations suitable for transmission, and differing lengths of seasons of suitability will occur, which will require changes in the types and amounts of resources. Methods: The shifting geographic risk of malaria transmission was mapped, in context of changing seasonality (i.e. endemic to epidemic, and vice versa), and the number of people affected. A published temperature-dependent model of malaria transmission suitability was applied to continental gridded climate data for multiple future AR5 climate model projections. The resulting outcomes were aligned with programmatic needs to provide summaries at national and regional scales for the African continent. Model outcomes were combined with population projections to estimate the population at risk at three points in the future, 2030, 2050, and 2080, under two scenarios of greenhouse gas emissions (RCP4.5 and RCP8.5). Results: Estimated geographic shifts in endemic and seasonal suitability for malaria transmission were observed across all future scenarios of climate change. The worst-case regional scenario (RCP8.5) of climate change predicted an additional 75.9 million people at risk from endemic (10-12 months) exposure to malaria transmission in Eastern and Southern Africa by the year 2080, with the greatest population at risk in Eastern Africa. Despite a predominance of reduction in season length, a net gain of 51.3 million additional people is predicted be put at some level of risk in Western Africa by midcentury. Conclusions: This study provides an updated view of potential malaria geographic shifts in Africa under climate change for the more recent climate model projections (AR5), and a tool for aligning findings with programmatic needs at key scales for decision-makers. In describing shifting seasonality, it was possible to capture transitions between endemic and epidemic risk areas, to facilitate the planning for interventions aimed at year-round risk versus anticipatory surveillance and rapid response to potential outbreak locations. [ABSTRACT FROM AUTHOR]

Recent publications and statements have drawn attention to a sustainable system of managing malaria control interventions globally but especially on the Continent of Africa. Arbitrary and unstable governments often interfere with health programmes, causing upsurges in malaria transmission as well as other health issues. A well-run health infrastructure will deal with public health as a whole. This commentary follows historical conditions in Zimbabwe where much original work on malaria control was initiated and implemented and where unstable conditions happened through local politics. These periodic conditions of instability on the ground challenge the current philosophical thrust to eradication and stress the need and role of an established and well-staffed health infrastructure in each country. Such facilities should be well staffed and supplied with drugs and point-of care diagnostic tests to manage malaria and should be sustained to serve the community even after tools that can eradicate malaria are developed. [ABSTRACT FROM AUTHOR]

In spite of massive progress in the control of African malaria since the turn of the century, there is a clear and recognized need for additional tools beyond long-lasting insecticide-treated bed nets (LLINs) and indoor residual spraying (IRS) of insecticides, to progress towards elimination. Moreover, widespread and intensifying insecticide resistance requires alternative control agents and delivery systems to enable development of effective insecticide resistance management strategies. This series of articles presents a novel concept for malaria vector control, the 'eave tube', which may fulfil these important criteria. From its conceptualization to laboratory and semi-field testing, to demonstration of potential for implementation, the stepwise development of this new vector control approach is described. These studies suggest eave tubes (which comprise a novel way of delivering insecticides plus screening to make the house more 'mosquito proof') could be a viable, cost-effective, and acceptable control tool for endophilic and endophagic anophelines, and possibly other (nuisance) mosquitoes. The approach could be applicable in a wide variety of housing in sub-Saharan Africa, and possibly beyond, for vectors that use the eave as their primary house entry point. The results presented in these articles were generated during an EU-FP7 funded project, the mosquito contamination device (MCD) project, which ran between 2012 and 2015. This was a collaborative project undertaken by vector biologists, product developers, modellers, materials scientists, and entrepreneurs from five different countries. [ABSTRACT FROM AUTHOR]

Background: Plasmodium vivax is very rarely seen in West Africa, although specific detection methods are not widely applied in the region, and it is now considered to be absent from North Africa. However, this parasite species has recently been reported to account for most malaria cases in Nouakchott, the capital of Mauritania, which is a large country at the interface of sub-Saharan West Africa and the Maghreb region in northwest Africa. Methods: To determine the distribution of malaria parasite species throughout Mauritania, malaria cases were sampled in 2012 and 2013 from health facilities in 12 different areas. These sampling sites were located in eight major administrative regions of the country, within different parts of the Sahara and Sahel zones. Blood spots from finger-prick samples of malaria cases were processed to identify parasite DNA by species-specific PCR. Results: Out of 472 malaria cases examined, 163 (34.5 %) had P. vivax alone, 296 (62.7 %) Plasmodium falciparum alone, and 13 (2.8 %) had mixed P. falciparum and P. vivax infection. All cases were negative for Plasmodium malariae and Plasmodium ovale. The parasite species distribution showed a broad spectrum, P. vivax being detected at six of the different sites, in five of the country's major administrative regions (Tiris Zemmour, Tagant, Brakna, Assaba, and the capital Nouakchott). Most cases in Nouakchott were due to P. vivax, although proportions vary significantly among different health facilities in the city. In the northern town of Zouérat, all cases were due to P. vivax, whereas almost all cases in the south of the country were due to P. falciparum. All P. vivax cases tested were Duffy blood group positive. Conclusions: It is important that P. vivax is recognized to be a widespread cause of malaria in Mauritania, occurring in diverse regions. This should be noted by the World Health Organization, as it has significant implications for diagnosis, treatment and control of malaria in the northwestern part of Africa. [ABSTRACT FROM AUTHOR]

Background: Non-Plasmodium falciparum malaria infections are found in many parts of sub-Saharan Africa but little is known about their importance in pregnancy. Methods: Blood samples were collected at first antenatal clinic attendance from 2526 women enrolled in a trial of intermittent screening and treatment of malaria in pregnancy (ISTp) versus intermittent preventive treatment (IPTp) conducted in Burkina Faso, The Gambia, Ghana and Mali. DNA was extracted from blood spots and tested for P. falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovale using a nested PCR test. Risk factors for a nonfalciparum malaria infection were investigated and the influence of these infections on the outcome of pregnancy was determined. Results: P. falciparum infection was detected frequently (overall prevalence by PCR: 38.8 %, [95 % CI 37.0, 40.8]), with a prevalence ranging from 10.8 % in The Gambia to 56.1 % in Ghana. Non-falciparum malaria infections were found only rarely (overall prevalence 1.39 % [95 % CI 1.00, 1.92]), ranging from 0.17 % in the Gambia to 3.81 % in Mali. Ten non-falciparum mono-infections and 25 mixed falciparum and non-falciparum infections were found. P. malariae was the most frequent non-falciparum infection identified; P. vivax was detected only in Mali. Only four of the non-falciparum mono-infections were detected by microscopy or rapid diagnostic test. Recruitment during the late rainy season and low socio-economic status were associated with an increased risk of non-falciparum malaria as well as falciparum malaria. The outcome of pregnancy did not differ between women with a non-falciparum malaria infection and those who were not infected with malaria at first ANC attendance. Conclusions: Non-falciparum infections were infrequent in the populations studied, rarely detected when present as a mono-infection and unlikely to have had an important impact on the outcome of pregnancy in the communities studied due to the small number of women infected with non-falciparum parasites. [ABSTRACT FROM AUTHOR]

Background: Studies in Southeast Asia reported a strong relationship between polymorphisms at the propeller domain of the Kelch 13 (K13) protein encoded by the Plasmodium falciparum k13 (pfk13) gene and delayed parasite clearance after artemisinin treatment. In Africa, P. falciparum remains susceptible and combination therapy regimens which include an artemisinin component display good efficacy. Using quantitative real-time PCR (qPCR), sub-microscopic persistence of P. falciparum has previously been reported in one-third of children treated with artemisinin combination therapy (ACT) in western Kenya. In this study, further investigation was made to evaluate whether these sub-microscopic residual parasites also harbour mutations at the propeller region of pfk13 and whether the mutations, if any, affect treatment outcome. Methods: The pfk13 propeller domain was genotyped in DNA samples obtained in 2009 from Kenyan children treated with artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP). Paired samples at pre-treatment (day 0) and day of treatment failure (day 28 or 42) for 32 patients with documented recurrent parasitaemia were available for genotyping. Additional day 3 DNA samples were available for 10 patients. Results: No mutation associated with artemisinin resistance in Southeast Asia was observed. Only one DP-treated patient harboured a non-synonymous mutation at codon 578 (A578S) of pfk13-propeller gene in the day 0 sample, but this allele was replaced by the wild-type (A578) form on day 3 and on the day of recurrent parasitaemia. The mutation at amino acid codon 578 showed no association with any phenotype. Polymorphisms in pfk13 were not responsible for parasite persistence and gametocyte carriage in the children treated with ACT. Conclusion: This study contributes to the ongoing surveillance of suspected artemisinin resistance parasites in Africa by providing baseline prevalence of k13-propeller mutations in western Kenya with samples collected from a longitudinal study. [ABSTRACT FROM AUTHOR]

Background: Global ambitions to eliminate malaria are intensifying, underscoring a critical need for transmission blocking tools. In 2012, the WHO recommended the use of 0.25 mg/kg of single low-dose (SLD) primaquine to stop Plasmodium falciparum transmission. To ensure the availability of SLD primaquine to countries in need of this tool, more information on the supply, programmatic, and regulatory barriers to the rollout of SLD primaquine is required. Methods: Challenges to the rollout of SLD primaquine in sub-Saharan Africa were established through semi-structured qualitative interviews with three primaquine manufacturers, 43 key informants from Ethiopia, Senegal, Swaziland, Zambia, and Tanzania, and 16 malaria research experts. Results: Sanofi and Remedica are the only two sources of SRA-approved primaquine suitable for procurement by international donors. Neither manufacturer produces primaquine tablet strengths suitable for the transmission blocking indication. In-country key informants revealed that the WHO weight-based recommendation to use SLD primaquine is challenging to implement in actual field settings. Malaria programmes expressed safety concerns of SLD primaquine use in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, as well as potential interactions between primaquine and co-morbidities, and drug-drug interactions with HIV and/or tuberculosis treatments. Regulatory processes are a major barrier to the rollout of SLD primaquine, requiring multiple steps at both the country and global level. Despite these barriers, demand for SLD primaquine is growing, and malaria researchers are interested in primaquine deployment through mass screen and treat and/or mass drug administration campaigns. Conclusion: Demand for primaquine as a transmission blocking agent is growing rapidly yet multiple barriers to SLD primaquine use exist. Research is needed to define the therapeutic dose range, which will guide dosing regimens in the field, inform the development of new, lower strength primaquine tablets and/or formulation(s), and allay programmatic safety concerns in individuals with G6PD deficiency. Potential interactions between primaquine and co-morbidities and treatments should be explored. To minimize regulatory delays, countries need to prepare for product registration at an early stage, WHO prequalification for suitable primaquine tablet strengths and/or new formulations should be sought, and in the meanwhile only Stringent Regulatory Authority (SRA)-approved primaquine should be used. [ABSTRACT FROM AUTHOR]

Background: This randomized, open-label study was conducted to establish the non-inferiority of a combination of azithromycin (AZ) and chloroquine (CQ) to artemether-lumefantrine (AL) for treatment of uncomplicated malaria in children from six sites in sub-Saharan Africa. Methods: Children with uncomplicated Plasmodium falciparum malaria between six and 59 months of age were randomized 1:1 to either AZCQ (30 mg/kg AZ + 10 mg/kg CQ base) or AL per prescribing information for three days (Days 0, 1, 2). Each site could enrol in the study population once the treatment of uncomplicated malaria in five children five to 12 years of age was deemed to be effective and well tolerated. The primary efficacy evaluation was the proportion of subjects in both the modified intent-to-treat (MITT) and per-protocol (PP) populations with an adequate clinical and parasitological response (PCR corrected) at Day 28. Non-inferiority was concluded if the lower bound of the 95% confidence interval comparing the two groups was 10 percentage points or greater. Results: A total of 255 children were enrolled in the efficacy analysis (AZCQ, n = 124; AL, n = 131). The PCR corrected clearance rates were 89% (AZCQ) versus 98% (AL) for MITT, a difference of -9.10 (95% confidence interval; -16.02, -2.18) and 93% (AZCQ) versus 99% (AL) for PP, a difference of -6.08 (-12.10, -0.05). Early and late treatment failures were more common in subjects receiving AZCQ. Adverse events were more common in subjects treated with AZCQ. Drug concentrations obtained at specified time points following AZCQ administration had a large coefficient of variation partially due to sparse sampling with sample collection time window. Conclusions: In this study, non-inferiority of AZCQ to AL was not demonstrated. Trial registration: ClinicalTrials.gov NCT00677833. [ABSTRACT FROM AUTHOR]

Background: HIV and malaria are among the leading causes of morbidity and mortality during pregnancy in Africa. However, data from Congolese pregnant women are lacking. The aim of the study was to determine the magnitude, predictive factors, clinical, biologic and anthropometric consequences of malaria infection, HIV infection, and interactions between malaria and HIV infections in pregnant women. Methods: A cross-sectional study was conducted among pregnant women admitted and followed up at Camp Kokolo Military Hospital from 2009 to 2012 in Kinshasa, the Democratic Republic of Congo. Differences in means between malaria-positive and malaria-negative cases or between HIV-positive and HIV-negative cases were compared using the Student’s t-test or a non-parametric test, if appropriate. Categorical variables were compared using the Chi-square or Fisher’s exact test, if appropriate. Backward multivariable analysis was used to evaluate the potential risk factors of malaria and HIV infections. The odds ratios with their 95% confidence interval (95% CI) were estimated to measure the strengths of the associations. Analyses resulting in values of P < 0.05 were considered significant. Results: A malaria infection was detected in 246/332 (74.1%) pregnant women, and 31.9% were anaemic. Overall, 7.5% (25/332) of mothers were infected by HIV, with a median CD4 count of 375 (191; 669) cells/μL. The mean (±SD) birth weight was 2,613 ± 227 g, with 35.7% of newborns weighing less than 2,500 g (low birth weight). Low birth weight, parity and occupation were significantly different between malaria-infected and uninfected women in adjusted models. However, fever, anemia, placenta previa, marital status and district of residence were significantly associated to HIV infection. Conclusion: The prevalence of malaria infection was high in pregnant women attending the antenatal facilities or hospitalized and increased when associated with HIV infection. [ABSTRACT FROM AUTHOR]

Background: Malaria risk maps play an increasingly important role in disease control planning, implementation, and evaluation. The construction of these maps using modern geospatial techniques relies on covariate grids: continuous surfaces quantifying environmental factors that partially explain spatial heterogeneity in malaria endemicity. Although crucial, past variable selection processes for this purpose have often been subjective and ad-hoc, with many covariates used in modeling with little quantitative justification. Methods: This research consists of an extensive covariate construction and selection process for predicting Plasmodium falciparum parasite rates (PfPR) in Africa for years 2000-2012. First, a literature review was conducted to establish a comprehensive list of covariates used for malaria mapping. Second, a library of covariate data was assembled to reflect this list, a process that included the construction of multiple, temporally dynamic datasets. Third, the resulting set of covariates was leveraged to create more than 50 million possible covariate terms via factorial combinations of different spatial and temporal aggregations, transformations, and pairwise interactions. Fourth, the expanded set of covariates was reduced via successive selection criteria to yield a robust covariate subset that was assessed using an out-of-sample validation approach. Results: The final covariate subset included predominately dynamic covariates and it substantially out-performed earlier sets used by the Malaria Atlas Project (MAP) for creating global malaria risk maps, with the pseudo-R² value for the out-of-sample validation increasing from 0.43 to 0.52. Dynamic covariates improved the model, with 17 of the 20 new covariates consisting of monthly or annual products, but the selected covariates were typically interaction terms that included both dynamic and synoptic datasets. Thus the interplay between normal (i.e., long-term averages) and immediate conditions may be key for characterizing environmental controls on parasite rate. Conclusions: This analysis represents the first effort to systematically audit covariate utility for malaria mapping and then derive an objective, empirically based set of environmental covariates for modeling PfPR. The new covariates produce more reliable representations of malaria risk patterns and how they are changing through time, and these covariates will be used to characterize spatially and temporally varying environmental conditions affecting PfPR within a geostatistical-modeling framework, thus building upon previous research by MAP that produced global malaria maps for 2007 and 2010. [ABSTRACT FROM AUTHOR]

Background: Malaria epidemics remain a serious threat to human populations living in the highlands of East Africa where transmission is unstable and climate sensitive. An existing early malaria epidemic prediction model required further development, validations and automation before its wide use and application in the region. The model has a lead-time of two to four months between the detection of the epidemic signal and the evolution of the epidemic. The validated models would be of great use in the early detection and prevention of malaria epidemics. Methods: Confirmed inpatient malaria data were collected from eight sites in Kenya, Tanzania and Uganda for the period 1995-2009. Temperature and rainfall data for the period 1960-2009 were collected from meteorological stations closest to the source of the malaria data. Process-based models were constructed for computing the risk of an epidemic in two general highland ecosystems using temperature and rainfall data. The sensitivity, specificity and positive predictive power were used to validate the models. Results: Depending on the availability and quality of the malaria and meteorological data, the models indicated good functionality at all sites. Only two sites in Kenya had data that met the criteria for the full validation of the models. The additive model was found most suited for the poorly drained U-shaped valley ecosystems while the multiplicative model was most suited for the well-drained V-shaped valley ecosystem. The +18°C model was adaptable to any of the ecosystems and was designed for conditions where climatology data were not available. The additive model scored 100% for sensitivity, specificity and positive predictive power. The multiplicative model had a sensitivity of 75% specificity of 99% and a positive predictive power of 86%. Conclusions: The additive and multiplicative models were validated and were shown to be robust and with high climate-based, early epidemic predictive power. They are designed for use in the common, well- and poorly drained valley ecosystems in the highlands of East Africa. [ABSTRACT FROM AUTHOR]

Background Temperature suitability for malaria transmission is a useful predictor variable for spatial models of malaria infection prevalence. Existing continental or global models, however, are synoptic in nature and so do not characterize inter-annual variability in seasonal patterns of temperature suitability, reducing their utility for predicting malaria risk. Methods A malaria Temperature Suitability Index (TSI) was created by first modeling minimum and maximum air temperature with an eight-day temporal resolution from gap-filled MODerate Resolution Imaging Spectroradiometer (MODIS) daytime and night-time Land Surface Temperature (LST) datasets. An improved version of an existing biological model for malaria temperature suitability was then applied to the resulting temperature information for a 13- year data series. The mechanism underlying this biological model is simulation of emergent mosquito cohorts on a two-hour time-step and tracking of each cohort throughout its life to quantify the impact air temperature has on both mosquito survival and sporozoite development. Results The results of this research consist of 154 monthly raster surfaces that characterize spatiotemporal patterns in TSI across Africa from April 2000 through December 2012 at a 1 km spatial resolution. Generalized TSI patterns were as expected, with consistently high values in equatorial rain forests, seasonally variable values in tropical savannas (wet and dry) and montane areas, and low values in arid, subtropical regions. Comparisons with synoptic approaches demonstrated the additional information available within the dynamic TSI dataset that is lost in equivalent synoptic products derived from long-term monthly averages. Conclusions The dynamic TSI dataset presented here provides a new product with far richer spatial and temporal information than any other presently available for Africa. As spatiotemporal malaria modeling endeavors evolve, dynamic predictor variables such as the malaria temperature suitability data developed here will be essential for the rational assessment of changing patterns of malaria risk. [ABSTRACT FROM AUTHOR]

Background Within affected communities, Plasmodium falciparum infections may be skewed in distribution such that single or small clusters of households consistently harbour a disproportionate number of infected individuals throughout the year. Identifying these hotspots of malaria transmission would permit targeting of interventions and a more rapid reduction in malaria burden across the whole community. This study set out to compare different statistical methods of hotspot detection (SaTScan, kernel smoothing, weighted local prevalence) using different indicators (PCR positivity, AMA-1 and MSP-1 antibodies) for prediction of infection the following year. Methods Two full surveys of four villages in Mwanza, Tanzania were completed over consecutive years, 2010-2011. In both surveys, infection was assessed using nested polymerase chain reaction (nPCR). In addition in 2010, serologic markers (AMA-1 and MSP-119 antibodies) of exposure were assessed. Baseline clustering of infection and serological markers were assessed using three geospatial methods: spatial scan statistics, kernel analysis and weighted local prevalence analysis. Methods were compared in their ability to predict infection in the second year of the study using random effects logistic regression models, and comparisons of the area under the receiver operating curve (AUC) for each model. Sensitivity analysis was conducted to explore the effect of varying radius size for the kernel and weighted local prevalence methods and maximum population size for the spatial scan statistic. Results Guided by AUC values, the kernel method and spatial scan statistics appeared to be more predictive of infection in the following year. Hotspots of PCR-detected infection and seropositivity to AMA-1 were predictive of subsequent infection. For the kernel method, a 1 km window was optimal. Similarly, allowing hotspots to contain up to 50% of the population was a better predictor of infection in the second year using spatial scan statistics than smaller maximum population sizes. Conclusions Clusters of AMA-1 seroprevalence or parasite prevalence that are predictive of infection a year later can be identified using geospatial models. Kernel smoothing using a 1 km window and spatial scan statistics both provided accurate prediction of future infection. [ABSTRACT FROM AUTHOR]