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EY Lukianova-Hleb et al. Hemozoin-generated vapor nanobubbles for transdermal reagent- and needle-free detection of malaria. Proc Natl Acad Sci U S A

High Impact Journal from Malaria Portal - 31 December 2014 - 12:00am
Successful diagnosis, screening, and elimination of malaria critically depend on rapid and sensitive detection of this dangerous infection, preferably transdermally and without sophisticated reagents or blood drawing. . . .
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KJ Vogel et al. Phylogenetic investigation of Peptide hormone and growth factor receptors in five dipteran genomes. Front Endocrinol (Lausanne)

High Impact Journal from Malaria Portal - 31 December 2014 - 12:00am
Peptide hormones and growth factors bind to membrane receptors and regulate a myriad of processes in insects and other metazoans. . . .
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J Rydzak et al. Human erythrocyte glycophorin C as the receptor for EBA-140 Plasmodium falciparum merozoite ligand. Postepy Hig Med Dosw (Online)

High Impact Journal from Malaria Portal - 31 December 2014 - 12:00am
Erythrocyte invasion by the blood-stage Plasmodium falciparum parasites is a multistep process involving specific interactions between parasites and red blood cells. . . .
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R Sundararajan et al. Barriers to Malaria Control among Marginalized Tribal Communities: A Qualitative Study. PLoS One

High Impact Journal from Malaria Portal - 30 December 2014 - 12:00am
Malaria infection accounts for over one million deaths worldwide annually. . . .
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DV Canyon et al. Insights in public health: systems thinking: basic constructs, application challenges, misuse in health, and how public health leaders can pave the way forward. Hawaii J Med Public Health

High Impact Journal from Malaria Portal - 30 December 2014 - 12:00am
The strengthening of health systems is fundamental to improving health outcomes, crisis preparedness, and our capacity to meet global challenges, such as accelerating progress towards the Millennium Development Goals, reducing maternal and child mortality, combating HIV, malaria and other diseases, limiting the effects of a new influenza pandemic, and responding appropriately to climate change. . . .
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The genetics of resistant malaria

CiteULike malaria tags - 19 December 2014 - 9:05pm
Science, Vol. 346, No. 6215. (12 December 2014), pp. 1276-1277, doi:10.1126/science.346.6215.1276
Gretchen Vogel
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Plasmodium falciparum merozoite surface protein 2: epitope mapping and fine specificity of human antibody response against non-polymorphic domains

Malaria Journal - 19 December 2014 - 12:00am
Background: Two long synthetic peptides representing the dimorphic and constant C-terminal domains of the two allelic families of Plasmodium falciparum merozoite surface proteins 2 are considered promising malaria vaccine candidates. The aim of the current study is to characterize the immune response (epitope mapping) in naturally exposed individuals and relate immune responses to the risk of clinical malaria. Methods: To optimize their construction, the fine specificity of human serum antibodies from donors of different age, sex and living in four distinct endemic regions was determined in ELISA by using overlapping 20 mer peptides covering the two domains. Immune purified antibodies were used in Western blot and immunofluorescence assay to recognize native parasite derivate proteins. Results: Immunodominant epitopes were characterized, and their distribution was similar irrespective of geographic origin, age group and gender. Acquisition of a 3D7 family and constant region-specific immune response and antibody avidity maturation occur early in life while a longer period is needed for the corresponding FC27 family response. In addition, the antibody response to individual epitopes within the 3D7 family-specific region contributes to protection from malaria infection with different statistical weight. It is also illustrated that affinity-purified antibodies against the dimorphic or constant regions recognized homologous and heterologous parasites in immunofluorescence and homologous and heterologous MSP2 and other polypeptides in Western blot. Conclusion: Data from this current study may contribute to a development of MSP2 vaccine candidates based on conserved and dimorphic regions thus bypassing the complexity of vaccine development related to the polymorphism of full-length MSP2.
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Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance

CiteULike malaria tags - 18 December 2014 - 1:13pm
Science (11 December 2014), doi:10.1126/science.1260403

Artemisinin resistance in Plasmodium falciparum threatens global efforts to control and eliminate malaria. Polymorphisms in the kelch domain-carrying protein K13 are associated with artemisinin resistance, but the underlying molecular mechanisms are unknown. Here we analyze the in-vivo transcriptomes of 1,043 P. falciparum isolates from patients with acute malaria, and show that artemisinin resistance is associated with increased expression of unfolded protein response (UPR) pathways involving the major PROSC and TRiC chaperone complexes. Artemisinin resistant parasites also exhibit decelerated progression through the first part of the asexual intraerythrocytic development cycle. These findings suggest that artemisinin resistant parasites remain in a state of decelerated development at the young ring stage while their upregulated UPR pathways mitigate protein damage caused by artemisinin. The expression profiles of UPR-related genes also associate with the geographical origin of parasite isolates, further suggesting their role in emerging artemisinin resistance in the Greater Mekong Subregion.
Sachel Mok, Elizabeth Ashley, Pedro Ferreira, Lei Zhu, Zhaoting Lin, Tomas Yeo, Kesinee Chotivanich, Mallika Imwong, Sasithon Pukrittayakamee, Mehul Dhorda, Chea Nguon, Pharath Lim, Chanaki Amaratunga, Seila Suon, Tran Hien, Ye Htut, Abul Faiz, Marie Onyamboko, Mayfong Mayxay, Paul Newton, Rupam Tripura, Charles Woodrow, Olivo Miotto, Dominic Kwiatkowski, François Nosten, Nicholas Day, Peter Preiser, Nicholas White, Arjen Dondorp, Rick Fairhurst, Zbynek Bozdech
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Pooled PCR testing strategy and prevalence estimation of submicroscopic infections using Bayesian latent class models in pregnant women receiving intermittent preventive treatment at Machinga District Hospital, Malawi, 2010

Malaria Journal - 18 December 2014 - 12:00am
Background: Low malaria parasite densities in pregnancy are a diagnostic challenge. PCR provides high sensitivity and specificity in detecting low density of parasites, but cost and technical requirements limit its application in resources-limited settings. Pooling samples for PCR detection was explored to estimate prevalence of submicroscopic malaria infection in pregnant women at delivery. Previous work uses gold-standard based methods to calculate sensitivity and specificity of tests, creating a challenge when newer methodologies are substantially more sensitive than the gold standard. Thus prevalence was estimated using Bayesian latent class models (LCMs) in this study. Methods: Nested PCR (nPCR) for the 18S rRNA gene subunit of Plasmodium falciparum was conducted to detect malaria infection in microscopy-negative Malawian women on IPTp. Two-step sample pooling used dried blood spot samples (DBSs) collected from placenta or periphery at delivery. Results from nPCR and histology as well as previously published data were used to construct LCMs to estimate assay sensitivity and specificity. Theoretical confidence intervals for prevalence of infection were calculated for two-step and one-step pooling strategies. Results: Of 617 microscopy-negative Malawian women, 39 (6.3%) were identified as actively infected by histology while 52 (8.4%) were positive by nPCR. One hundred forty (22.7%) individuals had past infection assessed by histology. With histology as a reference, 72% of women in the active infection group, 7.1% in the past infection group and 3.2% in histology-negative group were nPCR positive. Using latent class models without a gold standard, histology had a median sensitivity of 49.7% and specificity of 97.6% for active infection while PCR had a median sensitivity of 96.0% and specificity of 99.1%. The true prevalence of active infection was estimated at 8.0% (CI: 5.8-10.5%) from PCR. PCR also had similar sensitivity for detecting either peripheral or placental malaria for submicroscopic infections. One-step pooling would give similar confidence intervals for pool sizes less than 20 while reducing the number of tests performed. Conclusions: Pooled nPCR testing was a sensitive and resource-efficient strategy and LCMs provided precise prevalence estimates of submicroscopic infections. Compared to two-step pooling, one-step pooling could provide similar prevalence estimates at population levels with many fewer tests required.
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Strengthening malaria diagnosis and appropriate treatment in Namibia: a test of case management training interventions in Kavango Region

Malaria Journal - 18 December 2014 - 12:00am
Background: Despite its importance in control and elimination settings, malaria diagnosis rates tend to be low in many African countries. An operational research pilot was conducted in Namibia to identify the key barriers to appropriate diagnosis of malaria in public health facilities and to evaluate the effectiveness of various training approaches in improving the uptake and adherence to rapid diagnostic tests (RDTs). Methods: After identifying case management weaknesses through healthcare worker focus group discussions, training interventions were designed to address these barriers over a six-month period. The study had three intervention districts and one control within the Kavango region of Namibia where poor case management practices were observed. The interventions included an enhanced training model, clinical mentorship, and SMS reminders. Monthly data on testing and treatment were collected for the period of April to September 2012 and, for comparison, the same months during the prior year from all 52 health facilities in Kavango. The same indicators were also obtained at district level for a follow-up period of 15 months from October 2012 to December 2013 to observe whether any improvements were sustained over time. Results: All intervention arms produced significant improvements in case management practices compared to the control district where no interventions were implemented (all p < 0.02). Overall, districts receiving any training improved testing rates from 25% to 66% at minimum compared to the control. The enhanced training plus mentorship arm resulted in a significantly greater proportion of fevers receiving RDTs compared to the district receiving enhanced training alone, increasing from 27% to over 90% at endline. No ACT was prescribed to untested patients after caregivers received mentorship or SMS reminders. These improvements were all sustained over the 15-month follow-up. Conclusions: These changes show almost a complete reversal of improper case management practices over the six-month study period and demonstrate that implementing simple training interventions can have a significant, sustainable impact on the uptake of and adherence to malaria RDTs. Findings from this work have already informed Namibia's roll out of a more robust case management training programme. The approaches used in Namibia may be applicable to other resource-constrained countries, providing practical guidance on sustainable approaches to febrile illness management.
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(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

CiteULike malaria tags - 17 December 2014 - 12:00am
Proceedings of the National Academy of Sciences, Vol. 111, No. 50. (16 December 2014), pp. E5455-E5462, doi:10.1073/pnas.1414221111

Drug discovery for malaria has been transformed in the last 5 years by the discovery of many new lead compounds identified by phenotypic screening. The process of developing these compounds as drug leads and studying the cellular responses they induce is revealing new targets that regulate key processes in the Plasmodium parasites that cause malaria. We disclose herein that the clinical candidate (+)-SJ733 acts upon one of these targets, ATP4. ATP4 is thought to be a cation-transporting ATPase responsible for maintaining low intracellular Na+ levels in the parasite. Treatment of parasitized erythrocytes with (+)-SJ733 in vitro caused a rapid perturbation of Na+ homeostasis in the parasite. This perturbation was followed by profound physical changes in the infected cells, including increased membrane rigidity and externalization of phosphatidylserine, consistent with eryptosis (erythrocyte suicide) or senescence. These changes are proposed to underpin the rapid (+)-SJ733-induced clearance of parasites seen in vivo. Plasmodium falciparum ATPase 4 (pfatp4) mutations that confer resistance to (+)-SJ733 carry a high fitness cost. The speed with which (+)-SJ733 kills parasites and the high fitness cost associated with resistance-conferring mutations appear to slow and suppress the selection of highly drug-resistant mutants in vivo. Together, our data suggest that inhibitors of PfATP4 have highly attractive features for fast-acting antimalarials to be used in the global eradication campaign.
María Jiménez-Díaz, Daniel Ebert, Yandira Salinas, Anupam Pradhan, Adele Lehane, Marie-Eve Myrand-Lapierre, Kathleen O’Loughlin, David Shackleford, Mariana de Almeida, Angela Carrillo, Julie Clark, Adelaide Dennis, Jonathon Diep, Xiaoyan Deng, Sandra Duffy, Aaron Endsley, Greg Fedewa, Armand Guiguemde, María Gómez, Gloria Holbrook, Jeremy Horst, Charles Kim, Jian Liu, Marcus Lee, Amy Matheny, María Martínez, Gregory Miller, Ane Rodríguez-Alejandre, Laura Sanz, Martina Sigal, Natalie Spillman, Philip Stein, Zheng Wang, Fangyi Zhu, David Waterson, Spencer Knapp, Anang Shelat, Vicky Avery, David Fidock, Francisco-Javier Gamo, Susan Charman, Jon Mirsalis, Hongshen Ma, Santiago Ferrer, Kiaran Kirk, Iñigo Angulo-Barturen, Dennis Kyle, Joseph DeRisi, David Floyd, Kiplin Guy
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Enantioselective metabolism of primaquine by human CYP2D6

Malaria Journal - 17 December 2014 - 12:00am
Background: Primaquine, currently the only approved drug for the treatment and radical cure of Plasmodium vivax malaria, is still used as a racemic mixture. Clinical use of primaquine has been limited due to haemolytic toxicity in individuals with genetic deficiency in glucose-6-phosphate dehydrogenase. Earlier studies have linked its therapeutic effects to CYP2D6-generated metabolites. The aim of the current study was to investigate the differential generation of the CYP2D6 metabolites by racemic primaquine and its individual enantiomers. Methods: Stable isotope 13C-labelled primaquine and its two enantiomers were incubated with recombinant cytochrome-P450 supersomes containing CYP2D6 under optimized conditions. Metabolite identification and time-point quantitative analysis were performed using LC-MS/MS. UHPLC retention time, twin peaks with a mass difference of 6, MS-MS fragmentation pattern, and relative peak area with respect to parent compound were used for phenotyping and quantitative analysis of metabolites. Results: The rate of metabolism of (+)-(S)-primaquine was significantly higher (50% depletion of 20 muM in 120 min) compared to (-)-(R)-primaquine (30% depletion) when incubated with CYP2D6. The estimated Vmax (mumol/min/mg) were 0.75, 0.98 and 0.42, with Km (muM) of 24.2, 33.1 and 21.6 for (+/-)-primaquine, (+)-primaquine and (-)-primaquine, respectively. Three stable mono-hydroxylated metabolites, namely, 2-, 3- and 4-hydroxyprimaquine (2-OH-PQ, 3-OH-PQ, and 4-OH-PQ), were identified and quantified. 2-OH-PQ was preferentially formed from (+)-primaquine in a ratio of 4:1 compared to (-)-primaquine. The racemic (+/-)-primaquine showed a pattern similar to the (-)-primaquine; 2-OH-PQ accounted for about 15-17% of total CYP2D6-mediated conversion of (+)-primaquine. In contrast, 4-OH-PQ was preferentially formed with (-)-primaquine (5:1), accounting for 22% of the total (-)-primaquine conversion. 3-OH-PQ was generated from both enantiomers and racemate. 5-hydroxyprimaquine was unstable. Its orthoquinone degradation product (twice as abundant in (+)-primaquine compared to (-)-primaquine) was identified and accounted for 18-20% of the CYP2D6-mediated conversion of (+)-primaquine. Other minor metabolites included dihydroxyprimaquine species, two quinone-imine products of dihydroxylated primaquine, and a primaquine terminal alcohol with variable generation from the individual enantiomers. Conclusion: The metabolism of primaquine by human CYP2D6 and the generation of its metabolites display enantio-selectivity regarding formation of hydroxylated product profiles. This may partly explain differential pharmacologic and toxicologic properties of primaquine enantiomers.
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Pregnant women are a reservoir of malaria transmission in Blantyre, Malawi

Malaria Journal - 17 December 2014 - 12:00am
Background: During pregnancy, women living in malaria-endemic regions are at increased risk of malaria infection and can harbour chronic placental infections. Intermittent preventive treatment with sulphadoxine-pyrimethamine (SP-IPTp) is administered to reduce malaria morbidity. It was hypothesized that the presence of placental malaria infection and SP-IPTp use would increase the risk of peripheral blood gametocytes, the parasite stage that is transmissible to mosquitoes. This would suggest that pregnant women may be important reservoirs of malaria transmission. Methods: Light microscopy was used to assess peripheral gametocytaemia in pregnant women enrolled in a longitudinal, observational study in Blantyre, Malawi to determine the association between placental malaria and maternal gametocytaemia. The relationship between SP-IPTp and gametocytaemia was also examined. Results: 2,719 samples from 448 women were analysed and 32 episodes of microscopic gametocytaemia were detected in 27 women. At the time of enrolment 22 of 446 women (4.9%) had gametocytaemia and of the 341 women for whom there was sufficient sampling to analyse infection over the entire course of pregnancy, 27 (7.9%) were gametocytaemic at least once. Gametocytaemia at enrolment was associated with placental malaria, defined as malaria pigment or parasites detected by histology or qPCR, respectively (OR: 32.4, 95% CI: 4.2-250.2), but was not associated with adverse maternal or foetal outcomes. Administration of SP-IPTp did not affect gametocyte clearance or release into peripheral blood. Conclusions: Gametocytaemia is present in 5% of pregnant women at their first antenatal visit and associated with placental malaria. SP-IPTp does not alter the risk of gametocytaemia. These data suggest that pregnant women are a significant reservoir of gametocyte transmission and should not be overlooked in elimination efforts. Interventions targeting this population would benefit from reaching women prior to first antenatal visit.
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Harmonization of malaria rapid diagnostic tests: best practices in labelling including instructions for use

Malaria Journal - 17 December 2014 - 12:00am
Background: Rapid diagnostic tests (RDTs) largely account for the scale-up of malaria diagnosis in endemic settings. However, diversity in labelling including the instructions for use (IFU) limits their interchangeability and user-friendliness. Uniform, easy to follow and consistent labelling, aligned with international standards and appropriate for the level of the end user's education and training, is crucial but a consolidated resource of information regarding best practices for IFU and labelling of RDT devices, packaging and accessories is not available. Methods: The Roll Back Malaria Partnership (RBM) commissioned the compilation of international standards and regulatory documents and published literature containing specifications and/or recommendations for RDT design, packaging and labelling of in vitro diagnostics (IVD) (which includes RDTs), complemented with a questionnaire based survey of RDT manufacturers and implementers. A summary of desirable RDT labelling characteristics was compiled, which was reviewed and discussed during a RBM Stakeholder consultation meeting and subsequently amended and refined by a dedicated task force consisting of country programme implementers, experts in RDT implementation, IVD regulatory experts and manufacturers. Results: This process led to the development of consensus documents with a list of suggested terms and abbreviations as well as specifications for labelling of box, device packaging, cassettes, buffer bottle and accessories (lancets, alcohol swabs, transfer devices, desiccants). Emphasis was placed on durability (permanent printing or water-resistant labels), legibility (font size, letter type), comprehension (use of symbols) and ease of reference (e.g. place of labelling on the box or cassette packaging allowing quick oversight). A generic IFU template was developed, comprising background information, a template for procedure and reading/interpretation, a selection of appropriate references and a symbol key of internationally recognized symbols together with suggestions about appropriate lay-out, style and readability. Conclusions: The present document together with its additional files compiled proposes best practices in labelling and IFU for malaria RDTs. It is expected that compliance with these best practices will increase harmonization among the different malaria RDT products available on the market and improve their user-friendliness.
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"It is about how the net looks": a qualitative study of perceptions and practices related to mosquito net care and repair in two districts in eastern Uganda

Malaria Journal - 17 December 2014 - 12:00am
Background: Prolonging net durability has important implications for reducing both malaria transmission and the frequency of net replacement. Protective behaviour, such as net care and repair, offers promise for improving net integrity and durability. Given the potential cost-savings and public health benefit associated with extending the useful life of long-lasting insecticidal nets (LLINs), prevention and mitigation of damage will become ever more critical to ensuring adequate net coverage at the population level. Methods: A qualitative assessment was conducted in two districts in central eastern Uganda in September 2013. Data on household net care and repair behaviour, attitudes and practices were collected from 30 respondents through in-depth interviews (IDIs), observations, photos, and video to gather an in-depth understanding of these behaviours. Results: Net damage was common and the most cited causes were children and rodents. Responses revealed strong social norms about net cleanliness and aesthetics, and strong expectations that others should care for and repair their own nets. Respondents were receptive and able to repair nets, though longer-term repair methods, such as sewing and patching, were not as commonly reported or observed. Self-reported behaviour was not always consistent with observed or demonstrated behaviour, revealing potential misconceptions and the need for clear and consistent net care and repair messaging. Conclusions: Respondents considered both aesthetics and malaria protection important when deciding whether, when, and how to care for and repair nets. BCC should continue to emphasize the importance of maintaining net integrity for malaria prevention purposes as well as for maintaining aesthetic appeal. Additional research is needed, particularly surrounding washing, drying, daily storage routines, and gender roles in care and repair, in order to understand the complexity of these behaviours, and refine existing or develop new behaviour change communication (BCC) messages for net care and repair.
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Correction: disrupting rhythms in Plasmodium chabaudi: costs accrue quickly and independently of how infections are initiated

Malaria Journal - 17 December 2014 - 12:00am
CorrectionSome of the data in the article [1] were inadvertently mislabelled. Specifically, for infections initiated with trophozoite stage parasites, the schedule "matched" treatment group was incorrectly analysed as "mismatched" and vice-versa. The data have been re-analysed and the effects of perturbing the schedules of parasites relative to the host circadian rhythm are more complex than presented in the original paper. However, the differences between initiating infections with ring stages versus trophozoite stages, and via intraperitoneal injection or intravenous injection remain unchanged. The affected sections of the paper (data analysis method, results, discussion) have been re-written and new figures drawn. The authors apologize for any inconvenience or confusion that this may have caused.
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Perceptions of malaria and acceptance of rapid diagnostic tests and related treatment practises among community members and health care providers in Greater Garissa, North Eastern Province, Kenya

Malaria Journal - 17 December 2014 - 12:00am
Background: Conventional diagnosis of malaria has relied upon either clinical diagnosis or microscopic examination of peripheral blood smears. These methods, if not carried out exactly, easily result in the over- or under-diagnosis of malaria. The reliability and accuracy of malaria RDTs, even in extremely challenging health care settings, have made them a staple in malaria control programmes. Using the setting of a pilot introduction of malaria RDTs in Greater Garissa, North Eastern Province, Kenya, this study aims to identify and understand perceptions regarding malaria diagnosis, with a particular focus on RDTs, and treatment among community members and health care workers (HCWs). Methods: The study was conducted in five districts of Garissa County. Focus group discussions (FGD) were performed with community members that were recruited from health facilities (HFs) supported by the MENTOR Initiative. In-depth interviews (IDIs) and FGDs with HCWs were also carried out. Interview transcripts were then coded and analysed for major themes. Two researchers reviewed all codes, first separately and then together, discussed the specific categories, and finally characterized, described, and agreed upon major important themes. Results: Thirty-four FGDs were carried out with a range of two to eight participants (median of four). Of 157 community members, 103 (65.6%) were women. The majority of participants were illiterate and the highest level of education was secondary school. Some 76% of participants were of Somali ethnicity. Whilst community members and HCWs demonstrated knowledge of aspects of malaria transmission, prevention, diagnosis, and treatment, gaps and misconceptions were identified. Poor adherence to negative RDT results, unfamiliarity and distrust of RDTs, and an inconsistent RDT supply were the main challenges to become apparent in FGDs and IDIs. Conclusion: Gaps in knowledge or incorrect beliefs exist in Greater Garissa and have the potential to act as barriers to complete and correct malaria case management. Addressing these knowledge gaps requires comprehensive education campaigns and a reliable and constant RDT supply. The results of this study highlight education and supply chain as key factors to be addressed in order to make large scale roll out of RDTs as successful and effective as possible.
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Microbes Thwart Malaria

CiteULike malaria tags - 16 December 2014 - 11:50pm
Science Signaling, Vol. 7, No. 356. (16 December 2014), pp. ec346-ec346, doi:10.1126/scisignal.aaa4753
Jason Berndt
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