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Malaria afflicts around 200 million people annually, with a mortality number close to 600,000.,The mortality rate in Human Cerebral Malaria (HCM) is unacceptably high (15-20%), despite the availability of artemisinin-based therapy.,An effective adjunct therapy is urgently needed.,Experimental Cerebral Malaria (ECM) in mice manifests many of the neurological features of HCM.,Migration of T cells and parasite-infected RBCs (pRBCs) into the brain are both necessary to precipitate the disease.,We have been able to simultaneously target both these parameters of ECM.,Curcumin alone was able to reverse all the parameters investigated in this study that govern inflammatory responses, CD8+ T cell and pRBC sequestration into the brain and blood brain barrier (BBB) breakdown.,But the animals eventually died of anemia due to parasite build-up in blood.,However, arteether-curcumin (AC) combination therapy even after the onset of symptoms provided complete cure.,AC treatment is a promising therapeutic option for HCM. | Earlier studies in this laboratory have shown the potential of artemisinin-curcumin combination therapy in experimental malaria.,In a parasite recrudescence model in mice infected with Plasmodium berghei (ANKA), a single dose of alpha,beta-arteether (ART) with three oral doses of curcumin prevented recrudescence, providing almost 95% protection.,The parasites were completely cleared in blood with ART-alone (AE) or ART+curcumin (AC) treatments in the short-term, although the clearance was faster in the latter case involving increased ROS generation.,But, parasites in liver and spleen were not cleared in AE or AC treatments, perhaps, serving as a reservoir for recrudescence.,Parasitemia in blood reached up to 60% in AE-treated mice during the recrudescence phase, leading to death of animals.,A transient increase of up to 2-3% parasitemia was observed in AC-treatment, leading to protection and reversal of splenomegaly.,A striking increase in spleen mRNA levels for TLR2, IL-10 and IgG-subclass antibodies but a decrease in those for INFγ and IL-12 was observed in AC-treatment.,There was a striking increase in IL-10 and IgG subclass antibody levels but a decrease in INFγ levels in sera leading to protection against recrudescence.,AC-treatment failed to protect against recrudescence in TLR2−/− and IL-10−/− animals.,IL-10 injection to AE-treated wild type mice and AC-treated TLR2−/− mice was able to prolong survival.,Blood from the recrudescence phase in AE-treatment, but not from AC-treatment, was able to reinfect and kill naïve animals.,Sera from the recrudescence phase of AC-treated animals reacted with several parasite proteins compared to that from AE-treated animals.,It is proposed that activation of TLR2-mediated innate immune response leading to enhanced IL-10 production and generation of anti-parasite antibodies contribute to protective immunity in AC-treated mice.,These results indicate a potential for curcumin-based combination therapy to be tested for prevention of recrudescence in falciparum and relapse in vivax malaria. | 1 |
Stopping interventions is a critical decision for parasite elimination programmes.,Quantifying the probability that elimination has occurred due to interventions can be facilitated by combining infection status information from parasitological surveys with extinction thresholds predicted by parasite transmission models.,Here we demonstrate how the integrated use of these two pieces of information derived from infection monitoring data can be used to develop an analytic framework for guiding the making of defensible decisions to stop interventions.,We present a computational tool to perform these probability calculations and demonstrate its practical utility for supporting intervention cessation decisions by applying the framework to infection data from programmes aiming to eliminate onchocerciasis and lymphatic filariasis in Uganda and Nigeria, respectively.,We highlight a possible method for validating the results in the field, and discuss further refinements and extensions required to deploy this predictive tool for guiding decision making by programme managers.,The decision when to stop an intervention is a critical component of parasite elimination programmes, but reliance on surveillance data alone can be inaccurate.,Here, Michael et al. combine parasite transmission model predictions with disease survey data to more reliably determine when interventions can be stopped. | Concern is growing regarding the prospects of achieving the global elimination of lymphatic filariasis (LF) by 2020.,Apart from operational difficulties, evidence is emerging which points to unique challenges that could confound achieving LF elimination as extinction targets draw near.,Diethylcarbamazine (DEC)-medicated salt may overcome these complex challenges posed by the endgame phase of parasite elimination.,We calibrated LF transmission models using Bayesian data-model assimilation techniques to baseline and follow-up infection data from 11 communities that underwent DEC salt medication.,The fitted models were used to assess the utility of DEC salt treatment for achieving LF elimination, in comparison with other current and proposed drug regimens, during the endgame phase.,DEC-medicated salt consistently reduced microfilaria (mf) prevalence from 1% mf to site-specific elimination thresholds more quickly than the other investigated treatments.,The application of DEC salt generally required less than one year to achieve site-specific LF elimination, while annual and biannual MDA options required significantly longer durations to achieve the same task.,The use of DEC-medicated salt also lowered between-site variance in extinction timelines, especially when combined with vector control.,These results indicate that the implementation of DEC-medicated salt, where feasible, can overcome endgame challenges facing LF elimination programs. | 1 |
There is significant evidence that brain-infiltrating CD8+ T cells play a central role in the development of experimental cerebral malaria (ECM) during Plasmodium berghei ANKA infection of C57BL/6 mice.,However, the mechanisms through which they mediate their pathogenic activity during malaria infection remain poorly understood.,Utilizing intravital two-photon microscopy combined with detailed ex vivo flow cytometric analysis, we show that brain-infiltrating T cells accumulate within the perivascular spaces of brains of mice infected with both ECM-inducing (P. berghei ANKA) and non-inducing (P. berghei NK65) infections.,However, perivascular T cells displayed an arrested behavior specifically during P. berghei ANKA infection, despite the brain-accumulating CD8+ T cells exhibiting comparable activation phenotypes during both infections.,We observed T cells forming long-term cognate interactions with CX3CR1-bearing antigen presenting cells within the brains during P. berghei ANKA infection, but abrogation of this interaction by targeted depletion of the APC cells failed to prevent ECM development.,Pathogenic CD8+ T cells were found to colocalize with rare apoptotic cells expressing CD31, a marker of endothelial cells, within the brain during ECM.,However, cellular apoptosis was a rare event and did not result in loss of cerebral vasculature or correspond with the extensive disruption to its integrity observed during ECM.,In summary, our data show that the arrest of T cells in the perivascular compartments of the brain is a unique signature of ECM-inducing malaria infection and implies an important role for this event in the development of the ECM-syndrome. | Whole-parasite immunization remains the benchmark in malaria vaccine development.,A major bottleneck in the translation of whole-parasite immunization towards routine vaccination is the mode of administration, since high degrees of protection are currently only achieved by intravenous, and not by intradermal or subcutaneous injection of viable parasites.,It is known that only a small proportion of subcutaneously administered parasites reach the subsequent liver stage and low parasite liver load was shown to be associated with low protective efficacy.,The objective of this analysis was to evaluate whether the liver load following subcutaneous parasite injection could be augmented by co-administration of pro-inflammatory or anti-coagulatory drugs.,In the C57BL/6 Plasmodium berghei ANKA model, the clinical outcome (time to patent blood stage infection and survival) and relative parasite liver load was assessed in mice infected by subcutaneous or intramuscular sporozoite (SPZ) administration in the presence or absence of histamine and heparin supplementation in comparison to intravenously administered SPZ.,In addition, a vaccination experiment was carried out to assess the protective efficacy of an improved, histamine-supplemented subcutaneous immunization regimen.,The parasite liver load following subcutaneous SPZ administration can be significantly increased by co-administration of histamine and heparin.,A dose-dependent relation between parasite liver load and histamine dosage was observed.,However, despite a relatively high parasite liver load, the protective efficacy of histamine-supplemented subcutaneous immunization remains inferior as compared to intravenous SPZ administration.,Histamine supplementation might facilitate the future development of a non-intravenous whole-parasite vaccine.,Further investigations are needed to reveal the effect of histamine supplementation and subcutaneous SPZ administration on the acquisition of protective immunity.,The online version of this article (doi:10.1186/s12936-015-0552-3) contains supplementary material, which is available to authorized users. | 1 |
Chagas disease, caused by Trypanosoma cruzi, is endemic in southern parts of the American continent.,Herein, we have tested the protective efficacy of a DNA-prime/T. rangeli-boost (TcVac4) vaccine in a dog (Canis familiaris) model.,Dogs were immunized with two-doses of DNA vaccine (pcDNA3.1 encoding TcG1, TcG2, and TcG4 antigens plus IL-12- and GM-CSF-encoding plasmids) followed by two doses of glutaraldehyde-inactivated T. rangeli epimastigotes (TrIE); and challenged with highly pathogenic T. cruzi (SylvioX10/4) isolate.,Dogs given TrIE or empty pcDNA3.1 were used as controls.,We monitored post-vaccination and post-challenge infection antibody response by an ELISA, parasitemia by blood analysis and xenodiagnosis, and heart function by electrocardiography.,Post-mortem anatomic and pathologic evaluation of the heart was conducted.,TcVac4 induced a strong IgG response (IgG2>IgG1) that was significantly expanded post-infection, and moved to a nearly balanced IgG2/IgG1 response in chronic phase.,In comparison, dogs given TrIE or empty plasmid DNA only developed high IgG titers with IgG2 predominance in response to T. cruzi infection.,Blood parasitemia, tissue parasite foci, parasite transmission to triatomines, electrocardiographic abnormalities were significantly lower in TcVac4-vaccinated dogs than was observed in dogs given TrIE or empty plasmid DNA only.,Macroscopic and microscopic alterations, the hallmarks of chronic Chagas disease, were significantly decreased in the myocardium of TcVac4-vaccinated dogs.,We conclude that TcVac4 induced immunity was beneficial in providing resistance to T. cruzi infection, evidenced by control of chronic pathology of the heart and preservation of cardiac function in dogs.,Additionally, TcVac4 vaccination decreased the transmission of parasites from vaccinated/infected animals to triatomines. | MHC-restricted CD8+ T cells are important during infection with the intracellular protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease.,Experimental studies performed in the past 25 years have elucidated a number of features related to the immune response mediated by these T cells, which are important for establishing the parasite/host equilibrium leading to chronic infection.,CD8+ T cells are specific for highly immunodominant antigens expressed by members of the trans-sialidase family.,After infection, their activation is delayed, and the cells display a high proliferative activity associated with high apoptotic rates.,Although they participate in parasite control and elimination, they are unable to clear the infection due to their low fitness, allowing the parasite to establish the chronic phase when these cells then play an active role in the induction of heart immunopathology.,Vaccination with a number of subunit recombinant vaccines aimed at eliciting specific CD8+ T cells can reverse this path, thereby generating a productive immune response that will lead to the control of infection, reduction of symptoms, and reduction of disease transmission.,Due to these attributes, activation of CD8+ T lymphocytes may constitute a path for the development of a veterinarian or human vaccine. | 1 |
Triatoma infestans -the principal vector of the infection that causes Chagas disease- defies elimination efforts in the Gran Chaco region.,This study identifies the types of human-made or -used structures that are key sources of these bugs in the initial stages of house reinfestation after an insecticide spraying campaign.,We measured demographic and blood-feeding parameters at two geographic scales in 11 rural communities in Figueroa, northwest Argentina.,Of 1,297 sites searched in spring, 279 (21.5%) were infested.,Bug abundance per site and female fecundity differed significantly among habitat types (ecotopes) and were highly aggregated.,Domiciles (human sleeping quarters) had maximum infestation prevalence (38.7%), human-feeding bugs and total egg production, with submaximal values for other demographic and blood-feeding attributes.,Taken collectively peridomestic sites were three times more often infested than domiciles.,Chicken coops had greater bug abundance, blood-feeding rates, engorgement status, and female fecundity than pig and goat corrals.,The host-feeding patterns were spatially structured yet there was strong evidence of active dispersal of late-stage bugs between ecotopes.,Two flight indices predicted that female fliers were more likely to originate from kitchens and domiciles, rejecting our initial hypothesis that goat and pig corrals would dominate.,Chicken coops and domiciles were key source habitats fueling rapid house reinfestation.,Focusing control efforts on ecotopes with human-fed bugs (domiciles, storerooms, goat corrals) would neither eliminate the substantial contributions to bug population growth from kitchens, chicken coops, and pig corrals nor stop dispersal of adult female bugs from kitchens.,Rather, comprehensive control of the linked network of ecotopes is required to prevent feeding on humans, bug population growth, and bug dispersal simultaneously.,Our study illustrates a demographic approach that may be applied to other regions and triatomine species for the design of innovative, improved vector control strategies. | Chagas disease is a systemic pathology caused by Trypanosoma cruzi.,This parasite reveals remarkable genetic variability, evinced in six Discrete Typing Units (DTUs) named from T. cruzi I to T. cruzi VI (TcI to TcVI).,Recently newly identified genotypes have emerged such as TcBat in Brazil, Colombia and Panama associated to anthropogenic bats.,The genotype with the broadest geographical distribution is TcI, which has recently been associated to severe cardiomyopathies in Argentina and Colombia.,Therefore, new studies unraveling the genetic structure and natural history of this DTU must be pursued.,We conducted a spatial and temporal analysis on 50 biological clones of T. cruzi I (TcI) isolated from humans with different clinical phenotypes, triatomine bugs and mammal reservoirs across three endemic regions for Chagas disease in Colombia.,These clones were submitted to a nuclear Multilocus Sequence Typing (nMLST) analysis in order to elucidate its genetic diversity and clustering.,After analyzing 13 nuclear housekeeping genes and obtaining a 5821 bp length alignment, we detected two robust genotypes within TcI henceforth named TcIDOM (associated to human infections) and a second cluster associated to peridomestic and sylvatic populations.,Additionaly, we detected putative events of recombination and an intriguing lack of linkage disequilibrium.,These findings reinforce the emergence of an enigmatic domestic T. cruzi genotype (TcIDOM), and demonstrates the high frequency of recombination at nuclear level across natural populations of T. cruzi.,Therefore, the need to pursue studies focused on the diferential virulence profiles of TcI strains.,The biological and epidemiological implications of these findings are herein discussed. | 1 |
Sequestration of Plasmodium falciparum-infected erythrocytes in host blood vessels is a key triggering event in the pathogenesis of severe childhood malaria, which is responsible for about one million deaths every year1.,Sequestration is mediated by specific interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family and receptors on the endothelial lining2.,Severe malaria is associated with expression of specific PfEMP1 subtypes containing domain cassettes (DC) 8 and 133, but the endothelial receptor for parasites expressing these proteins was unknown4,5.,Here, we identify endothelial protein C receptor (EPCR), which mediates cytoprotective effects of activated protein C6, as the endothelial receptor for DC8 and DC13 PfEMP1.,We show that EPCR binding is mediated through the N-terminal cysteine-rich interdomain region (CIDRα1) of DC8 and group A PfEMP1 subfamilies and that CIDRα1 interferes with protein C binding to EPCR.,This PfEMP1 adhesive property links P. falciparum cytoadhesion to a host receptor involved in anticoagulation and endothelial cytoprotective pathways and has implications for understanding malaria pathology and the development of new malaria interventions. | During blood stage infection, Plasmodium falciparum infected erythrocytes (IE) bind to host blood vessels.,This virulence determinant enables parasites to evade spleen-dependent killing mechanisms, but paradoxically in some cases may reduce parasite fitness by killing the host.,Adhesion of infected erythrocytes is mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1), a family of polymorphic adhesion proteins encoded by var genes.,Whereas cerebral binding and severe malaria are associated with parasites expressing DC8 and DC13 var genes, relatively little is known about the non-brain endothelial selection on severe malaria adhesive types.,In this study, we selected P. falciparum-IEs on diverse endothelial cell types and demonstrate that DC8 and DC13 var genes were consistently among the major var transcripts selected on non-brain endothelial cells (lung, heart, bone marrow).,To investigate the molecular basis for this avid endothelial binding activity, recombinant proteins were expressed from the predominant upregulated DC8 transcript, IT4var19.,In-depth binding comparisons revealed that multiple extracellular domains from this protein bound brain and non-brain endothelial cells, and individual domains largely did not discriminate between different endothelial cell types.,Additionally, we found that recombinant DC8 and DC13 CIDR1 domains exhibited a widespread endothelial binding activity and could compete for DC8-IE binding to brain endothelial cells, suggesting they may bind the same host receptor.,Our findings provide new insights into the interaction of severe malaria adhesive types and host blood vessels and support the hypothesis that parasites causing severe malaria express PfEMP1 variants with a superior ability to adhere to diverse endothelial cell types, and may therefore endow these parasites with a growth and transmission advantage. | 1 |
Identifying the parasites transmitted by a particular vector and the factors that render this vector susceptible to the parasite are key steps to understanding disease transmission.,Although avian malaria has become a model system for the investigation of the ecological and evolutionary dynamics of Plasmodium parasites, little is still known about the field prevalence, diversity and distribution of avian Plasmodium species within the vectors, or about the extrinsic factors affecting Plasmodium population dynamics in the wild.,We examined changes in avian malaria prevalence and Plasmodium lineage composition in female Culex pipiens caught throughout one field season in 2006, across four sampling sites in southern France.,Using site occupancy models, we correct the naive estimates of Plasmodium prevalence to account for PCR-based imperfect detection.,To establish the importance of different factors that may bear on the prevalence and diversity of avian Plasmodium in field mosquitoes, we focus on Wolbachia and filarial parasite co-infections, as well as on the insecticide resistance status of the mosquito.,Plasmodium prevalence in Cx. pipiens increased from February (0%) to October (15.8%) and did not vary significantly among the four sampling sites.,The application of site occupancy models leads to a 4% increase in this initial (naive) estimate of prevalence.,The parasite community was composed of 15 different haemosporidian lineages, 13 of which belonged to the Plasmodium genus, and 2 to the Haemoproteus genus.,Neither the presence of different Wolbachia types and of filarial parasites co-infecting the mosquitoes, nor their insecticide resistance status were found to affect the Plasmodium prevalence and diversity.,We found that haemosporidian parasites are common and diverse in wild-caught Cx. pipiens mosquitoes in Southern France.,The prevalence of the infection in mosquitoes is unaffected by Wolbachia and filarial co-infections as well as the insecticide resistant status of the vector.,These factors may thus have a negligible impact on the transmission of avian malaria.,In contrast, the steady increase in prevalence from February to October indicates that the dynamics of avian malaria is driven by seasonality and supports that infected birds are the reservoir of a diverse community of lineages in southern France.,The online version of this article (doi:10.1186/1756-3305-7-437) contains supplementary material, which is available to authorized users. | This study was conducted to (i) determine the prevalence of African Animal Trypanosomosis (AAT) in tsetse challenged areas, (ii) compare conventional with qPCR detection systems and (iii) evaluate the host genetic background and biology as risk factors.,AAT prevalence studies are often confronted with low levels of parasitaemia.,Hence, we designed a novel qPCR assay using primers and species specific probes amplifying the Internal Transcribed Spacer 1 (ITS1) gene.,Thereby all three AAT species could be detected simultaneously. 368 individuals from three cattle types (Baoulé, Zebu and hybrids) originating from 72 farms in Burkina Faso were analysed.,Farmers were interviewed and morphometric measurements of the cattle taken.,A chi-squared test and a logistic regression model were calculated to detect associations with infection.,In our study, the overall rate of prevalence detected with the novel qPCR assay was 11.14%.,Compared to conventional PCR we identified a concordance of 91.30%.,We tested 41 animals positive for trypanosome DNA, five animals showed multiple infections.,Zebus were twice as often infected (21.74%) compared to Baoulé (9.70%) and hybrids (9.57%).,Trypanosoma vivax is the dominant species (9.24%), as compared to T. congolense (2.44%) and T. brucei (0.82%).,The chi-squared tests linking the infection events to the breeds (Zebu vs.,Baoulé and Zebu vs. hybrids) were on the border of significance.,No significant association with other tested parameters could be detected.,We introduce a novel qPCR technique for the fast, sensitive and simultaneous detection of the three AAT species.,Our results suggest that associations with breed and infection exist since Zebu cattle are more likely to be infected compared to Baoulé and hybrids.,Indigenous taurine cattle breeds, like the Baoulé, therefore provide a unique and valuable genetic resource. | 1 |
Despite the continuous efforts to improve the quality of life of Orang Asli (Aborigines) communities, these communities are still plagued with a wide range of health problems including parasitic infections.,The first part of this study aimed at determining the prevalence of soil-transmitted helminth (STH) infections and identifying their associated factors among rural Orang Asli children.,A cross-sectional study was carried out among 484 Orang Asli children aged ≤ 15 years (235 females and 249 males) belonging to 215 households from 13 villages in Lipis district, Pahang, Malaysia.,Faecal samples were collected and examined by using formalin-ether sedimentation, Kato Katz and Harada Mori techniques.,Demographic, socioeconomic, environmental and behavioural information were collected by using a pre-tested questionnaire.,Overall, 78.1% of the children were found to be infected with one or more STH species.,The prevalence of trichuriasis, ascariasis and hookworm infections were 71.7%, 37.4% and 17.6%, respectively.,Almost all, three quarters and one fifth of trichuriasis, ascariasis and hookworm infections, respectively, were of moderate-to-heavy intensities.,Multiple logistic regression analysis showed that age of ≥ 6 years (school-age), using unsafe water supply as a source for drinking water, absence of a toilet in the house, large family size (≥ 7 members), not washing hands before eating, and not washing hands after defecation were the key factors significantly associated with STH among these children.,This study reveals an alarmingly high prevalence of STH among Orang Asli children and clearly brings out an urgent need to implement school-based de-worming programmes and other control measures like providing a proper sanitation, as well as a treated drinking water supply and proper health education regarding good personal hygiene practices.,Such an integrated control program will help significantly in reducing the prevalence and intensity of STH in Orang Asli communities. | In Ethiopia, because of low quality drinking water supply and latrine coverage, helminths infections are the second most predominant causes of outpatient morbidity.,Indeed, there is a scarcity of information on the prevalence of soil transmitted helminths and Schistosomiasis in Ethiopia, special in study area.,Therefore, the aim of this study was to determine the prevalence and associated risk factors of soil transmitted helminths and intestinal Schistosomiasis.,Cross-sectional study was conducted among 319 school children of Zarima town from April 1 to May 25, 2009.,A pre-tested structured questionnaire was used to collect socio-demographic data and possible risk factors exposure.,Early morning stool samples were collected and a Kato Katz semi concentration technique was used to examine and count parasitic load by compound light microscope.,Data entry and analysis was done using SPSS-15 version and p-value < 0.05 considered statistically significant.,Out of 319 study subjects, 263 (82.4%) of the study participants infected with one or more parasites.,From soil transmitted helminths, Ascaris lumbricoides was the predominant isolate (22%) followed by Hookworms (19%) and Trichuris trichiura (2.5%).,Schistosoma mansoni was also isolated in 37.9% of the study participants.,Hookworm and S. mansoni infections showed statistically significant associations with shoe wearing and swimming habit of school children, respectively.,Prevalence of soil transmitted helminths (STH) and S.mansoni was high and the diseases were still major health problem in the study area which alerts public health intervention as soon as possible. | 1 |
Understanding the interactions between increased insecticide resistance and resting behaviour patterns of malaria mosquitoes is important for planning of adequate vector control.,This study was designed to investigate the resting behavior, host preference and rates of Plasmodium falciparum infection in relation to insecticide resistance of malaria vectors in different ecologies of western Kenya.,Anopheles mosquito collections were carried out during the dry and rainy seasons in Kisian (lowland site) and Bungoma (highland site), both in western Kenya using pyrethrum spray catches (PSC), mechanical aspiration (Prokopack) for indoor collections, clay pots, pit shelter and Prokopack for outdoor collections.,WHO tube bioassay was used to determine levels of phenotypic resistance of indoor and outdoor collected mosquitoes to deltamethrin.,PCR-based molecular diagnostics were used for mosquito speciation, genotype for knockdown resistance mutations (1014S and 1014F) and to determine specific host blood meal origins.,Enzyme-linked Immunosorbent Assay (ELISA) was used to determine mosquito sporozoite infections.,Anopheles gambiae s.l. was the most predominant species (75%, n = 2706) followed by An. funestus s.l. (25%, n = 860).,An. gambiae s.s hereafter (An. gambiae) accounted for 91% (95% CI: 89-93) and An. arabiensis 8% (95% CI: 6-9) in Bungoma, while in Kisian, An. arabiensis composition was 60% (95% CI: 55-66) and An. gambiae 39% (95% CI: 34-44).,The resting densities of An. gambiae s.l and An. funestus were higher indoors than outdoor in both sites (An. gambiae s.l; F1, 655 = 41.928, p < 0.0001, An. funestus; F1, 655 = 36.555, p < 0.0001).,The mortality rate for indoor and outdoor resting An. gambiae s.l F1 progeny was 37% (95% CI: 34-39) vs 67% (95% CI: 62-69) respectively in Bungoma.,In Kisian, the mortality rate was 67% (95% CI: 61-73) vs 76% (95% CI: 71-80) respectively.,The mortality rate for F1 progeny of An. funestus resting indoors in Bungoma was 32% (95% CI: 28-35).,The 1014S mutation was only detected in indoor resitng An. arabiensis.,Similarly, the 1014F mutation was present only in indoor resting An. gambiae.,The sporozoite rates were highest in An. funestus followed by An. gambiae, and An. arabiensis resting indoors at 11% (34/311), 8% (47/618) and 4% (1/27) respectively in Bungoma.,Overall, in Bungoma, the sporozoite rate for indoor resting mosquitoes was 9% (82/956) and 4% (8/190) for outdoors.,In Kisian, the sporozoite rate was 1% (1/112) for indoor resting An. gambiae.,None of the outdoor collected mosquitoes in Kisian tested positive for sporozoite infections (n = 73).,The study reports high indoor resting densities of An. gambiae and An. funestus, insecticide resistance, and persistence of malaria transmission indoors regardless of the use of long-lasting insecticidal nets (LLINs).,These findings underline the difficulties of controlling malaria vectors resting and biting indoors using the current interventions.,Supplemental vector control tools and implementation of sustainable insecticide resistance management strategies are needed in western Kenya. | Preventing malaria used to seem as simple as killing the vector, the mosquito; however, a recent study shows that this concept is now anything but simple.,The highly effective use of insecticide-treated bed nets and indoor insecticide spraying is being challenged by mosquito resistance to insecticides.,In West Africa, populations of this mosquito vector are now resistant to all 4 classes of insecticide approved for this use.,And no new classes of insecticide are anticipated until 2020, at the earliest.,Development of newer classes of insecticide is crucial because if resistance continues unchecked, the hard-earned progress in malaria control in Africa could be quickly reversed.,Malaria control depends on mosquito susceptibility to insecticides.,We tested Anopheles gambiae mosquitoes from Côte d’Ivoire for resistance and screened a subset for target site mutations.,Mosquitoes were resistant to insecticides of all approved classes.,Such complete resistance, which includes exceptionally strong phenotypes, presents a major threat to malaria control. | 1 |
Plasmodium ovale spp. and P. malariae cause illness in endemic regions and returning travellers.,Far less is known about these species than P. falciparum and P. vivax.,The UK national surveillance data, collected 1987 to 2015, were collated with the International Passenger Survey and climatic data to determine geographical, temporal and seasonal trends of imported P. ovale spp. and P. malariae infection.,Of 52,242 notified cases of malaria, 6.04% (3157) were caused by P. ovale spp. and 1.61% (841) by P. malariae; mortality was 0.03% (1) and 0.12% (1), respectively.,Almost all travellers acquired infection in West or East Africa.,Infection rate per travel episode fell fivefold during the study period.,The median latency of P. malariae and P. ovale spp. was 18 and 76 days, respectively; delayed presentation occurred with both species.,The latency of P. ovale spp. infection imported from West Africa was significantly shorter in those arriving in the UK during the West African peak malarial season compared to those arriving outside it (44 days vs 94 days, p < 0.0001), implying that relapse synchronises with the period of high malarial transmission.,This trend was not seen in P. ovale spp. imported from East Africa nor in P. malariae.,In West Africa, where malaria transmission is highly seasonal, P. ovale spp. may have evolved to relapse during the malarial high transmission season.,This has public health implications.,Deaths are very rare, supporting current guidelines emphasising outpatient treatment.,However, late presentations do occur. | Epidemiological data in the border area of the northern Myanmar near China are either of little accuracy or sparse of information, due to the poor public health system in these areas, and malaria cases may be severely underestimated.,This study aimed to investigate malaria prevalence and health facilities for malaria services, and to provide the baseline information for malaria control in these areas.,A cluster, randomized, cross-sectional survey was conducted in four special regions of northern Myanmar, near China: 5,585 people were selected for a malaria prevalence survey and 1,618 households were selected for a mosquito net-owning survey.,Meanwhile, a total of 97 health facilities were surveyed on their malaria services.,The data were analysed and descriptive statistics were used.,A total of 761 people were found positive through microscopy test, including 290 people for Plasmodium falciparum, 460 for Plasmodium vivax, two for Plasmodium malariae, and nine for mixed infection.,The average prevalence of malaria infection was 13.6% (95% CI: 12.7-14.6%).,There were significant differences of prevalence of malaria infection among the different regions (P < 0.01); 38.1% (95% CI: 28.3-48.0%) of health facilities had malaria microscope examination service, and 35.1% (95% CI: 25.4-44.7%) of these had malaria treatment services, 23.7% (95% CI: 15.1-32.3%) had malaria outreach services.,28.3% (95% CI: 26.1-30.6%) of households owned one or more long-lasting insecticidal bed nets (LLINs).,The prevalence of malaria infection was high in the four special regions of northern Myanmar, near China.,Malaria services in health facilities in these areas were weak.,ITNs/LLINs owning rate was also low.,The cross-border cooperation mechanism should be further strengthened to share the epidemical data about malaria, support technical assistance, and conduct joint malaria control or elimination activities. | 1 |
Fundamental gaps remain in our understanding of how immunity to malaria develops.,We used detailed clinical and entomological data from parallel cohort studies conducted across the malaria transmission spectrum in Uganda to quantify the development of immunity against symptomatic P. falciparum as a function of age and transmission intensity.,We focus on: anti-parasite immunity (i.e. ability to control parasite densities) and anti-disease immunity (i.e. ability to tolerate higher parasite densities without fever).,Our findings suggest a strong effect of age on both types of immunity, not explained by cumulative-exposure.,They also show an independent effect of exposure, where children living in moderate/high transmission settings develop immunity faster as transmission increases.,Surprisingly, children in the lowest transmission setting appear to develop immunity more efficiently than those living in moderate transmission settings.,Anti-parasite and anti-disease immunity develop in parallel, reducing the probability of experiencing symptomatic malaria upon each subsequent P. falciparum infection.,Malaria kills around 500,000 children every year.,The disease occurs when an infected mosquito bites a human and passes on a Plasmodium parasite.,One parasite in particular, Plasmodium falciparum, is responsible for most malaria-related deaths across the globe.,A person can be infected by P. falciparum many times throughout their life.,However, after children have had multiple infections, they become less likely to develop symptoms of malaria, such as high fever.,In other words, they gradually acquire immunity.,This immunity to malaria can come in two forms: “anti-parasite immunity”, where the body fights the parasites and keeps their numbers low; and “anti-disease immunity”, where the body is more likely to tolerate an infection without developing a fever.,To date, scientists do not fully understand how either kind of immunity arises in children.,Is it because they have simply been exposed to more malaria?,Or does being older and having a more mature immune system also help?,Now, Rodriguez-Barraquer et al. have followed more than 1,000 children living in places with high, moderate and low rates of malaria infection in Uganda.,Over three years, regular blood samples were taken to see if the children were infected with P. falciparum.,Mosquitoes were also collected from their houses to estimate how often the children were being bitten and infected.,Using this information, Rodriguez-Barraquer et al. studied the different factors that affect how children develop anti-parasite and anti-disease immunity.,Both types of immunity develop differently in places with high, moderate and low rates of infection, so being infected multiple times is important.,Yet, the findings also show that growing older itself contributes to the development of immunity regardless of how often a child is infected.,Children who get infected most often - in other words, those living in houses with the most mosquitoes - develop immunity faster than those who get infected at a moderate rate.,Unexpectedly, however, children living in places with low rates of infection also develop immunity faster than those living in places with moderate rates.,Understanding how children acquire immunity to malaria is important for people trying to control the disease.,These results suggest that reducing rates of infection to very low levels may not interfere with development of immunity and may even improve it.,However, future research should see if these findings apply to other parts of the world as well, and, if so, why children develop immunity faster in places with lower rates of malaria infection. | The major challenge in designing a protective Duffy binding protein region II (DBPII)-based vaccine against blood-stage vivax malaria is the high number of polymorphisms in critical residues targeted by binding-inhibitory antibodies.,Here, longevity of antibody and memory B cell response (MBCs) to DBL-TH variants, DBL-TH2, -TH4, -TH5, -TH6 and -TH9 were analyzed in P. vivax-exposed individuals living in a low malaria transmission area of southern Thailand.,Antibody to DBL-TH variants were significantly detected during P. vivax infection and it was persisted for up to 9 months post-infection.,However, DBL-TH-specific MBC responses were stably maintained longer than antibody response, at least 3 years post-infection in the absence of re-infection.,Phenotyping of B cell subsets showed the expansion of activated and atypical MBCs during acute and recovery phase of infection.,While the persistence of DBL-TH-specific MBCs was found in individuals who had activated and atypical MBC expansion, anti-DBL-TH antibody responses was rapidly declined in plasma.,The data suggested that these two MBCs were triggered by P. vivax infection, its expansion and stability may have impact on antibody responses.,Our results provided evidence for ability of DBPII variant antigens in induction of long-lasting MBCs among individuals who were living in low malaria endemicity. | 1 |
We evaluated a battery of Glucose-6-Phosphate Dehydrogenase diagnostic point-of-care tests (PoC) to assess the most suitable product in terms of performance and operational characteristics for remote areas.,Samples were collected in Puerto Princesa City, Palawan, Philippines and tested for G6PD deficiency with a fluorescent spot test (FST; Procedure 203, Trinity Biotech, Ireland), the semiquantitative WST8/1-methoxy PMS (WST; Dojindo, Japan) and the Carestart G6PD Rapid Diagnostic Test (CSG; AccessBio, USA).,Results were compared to spectrophotometry (Procedure 345, Trinity Biotech, Ireland).,Sensitivity and specificity were calculated for each test with cut-off activities of 10%, 20%, 30% and 60% of the adjusted male median.,The adjusted male median was 270.5 IU/1012 RBC.,FST and WST were tested on 621 capillary blood samples, the CSG was tested on venous and capillary blood on 302 samples.,At 30% G6PD activity, sensitivity for the FST was between 87.7% (95%CI: 76.8% to 93.9%) and 96.5% (95%CI: 87.9% to 99.5%) depending on definition of intermediate results; the WST was 84.2% (95%CI: 72.1% to 92.5%); and the CSG was between 68.8% (95%CI: 41.3% to 89.0%) and 93.8% (95%CI: 69.8% to 99.8%) when the test was performed on capillary or venous blood respectively.,Sensitivity of FST and CSG (tested with venous blood) were comparable (p>0.05).,The analysis of venous blood samples by the CSG yielded significantly higher results than FST and CSG performed on capillary blood (p<0.05).,Sensitivity of the CSG varied depending on source of blood used (p<0.05).,The operational characteristics of the CSG were superior to all other test formats.,Performance and operational characteristics of the CSG performed on venous blood suggest the test to be a good alternative to the FST. | The dynamics of Plasmodium vivax infection is characterized by reactivation of hypnozoites at varying time intervals.,The relative contribution of new P. vivax infection and reactivation of dormant liver stage hypnozoites to initiation of blood stage infection is unclear.,In this study, we investigate the contribution of new inoculations of P. vivax sporozoites to primary infection versus reactivation of hypnozoites by modeling the dynamics of P. vivax infection in Thailand in patients receiving treatment for either blood stage infection alone (chloroquine), or the blood and liver stages of infection (chloroquine + primaquine).,In addition, we also analysed rates of infection in a study in Papua New Guinea (PNG) where patients were treated with either artesunate, or artesunate + primaquine.,Our results show that up to 96% of the P. vivax infection is due to hypnozoite reactivation in individuals living in endemic areas in Thailand.,Similar analysis revealed the around 70% of infections in the PNG cohort were due to hypnozoite reactivation.,We show how the age of the cohort, primaquine drug failure, and seasonality may affect estimates of the ratio of primary P. vivax infection to hypnozoite reactivation.,Modeling of P. vivax primary infection and hypnozoite reactivation provides important insights into infection dynamics, and suggests that 90-96% of blood stage infections arise from hypnozoite reactivation.,Major differences in infection kinetics between Thailand and PNG suggest the likelihood of drug failure in PNG. | 1 |
Objective To evaluate efficacies of anthelmintic drugs against soil transmitted helminths in terms of cure rates and egg reduction rates.,Design Systematic review and network meta-analysis.,Data Sources PubMed, ISI Web of Science, Embase, ScienceDirect, the Cochrane Central Register of Clinical Trials, and the World Health Organization library database from 1960 until 31 December 2016.,Study selection Randomised controlled trials evaluating the efficacy of a single dose regimen of albendazole, mebendazole, levamisole, and pyrantel pamoate against Ascaris lumbricoides, hookworm (Necator americanus and Ancylostoma duodenale) and Trichuris trichiura.,The primary outcomes included cure rates analysed by network meta-analysis with mixed logistic regression models and egg reduction rates with mixed linear models.,Results 55 and 46 randomised controlled trials were included in the analysis of cure rates and egg reduction rates, respectively.,All drugs were highly efficacious against A lumbricoides.,Albendazole showed the highest efficacy against hookworm infections with a cure rate of 79.5% (95% confidence interval 71.5% to 85.6%) and an egg reduction rate of 89.6% (81.9% to 97.3%).,All drugs had low efficacy against T trichiura, with mebendazole showing the highest cure rate of 42.1% (25.9% to 60.2%) and egg reduction rate of 66.0% (54.6% to 77.3%).,Estimates for the years 1995 and 2015 showed significant reductions in efficacy of albendazole against T trichiura: by 2015 the egg reduction rates fell from 72.6% (53.7% to 91.5%) to 43.4% (23.5% to 63.3%; P=0.049) and the cure rates fell from 38.6% (26.2% to 52.7%) to 16.4 (7.7% to 31.3%; P=0.027).,Conclusions All four currently recommended drugs show limitations in their efficacy profile.,While only albendazole showed good efficacy against hookworm infection, all drugs had low efficacy against T trichiura.,The decrease in efficacy of albendazole against T trichiura over the past two decades is of concern.,The findings indicate the need for strengthening efforts to develop new drug treatments, with a particular focus on drugs against T trichiura. | The control of soil-transmitted helminth (STH) infections currently relies on the large-scale administration of single-dose oral albendazole or mebendazole.,However, these treatment regimens have limited efficacy against hookworm and Trichuris trichiura in terms of cure rates (CR), whereas fecal egg reduction rates (ERR) are generally high for all common STH species.,We compared the efficacy of single-dose versus triple-dose treatment against hookworm and other STHs in a community-based randomized controlled trial in the People's Republic of China.,The hookworm CR and fecal ERR were assessed in 314 individuals aged ≥5 years who submitted two stool samples before and 3-4 weeks after administration of single-dose oral albendazole (400 mg) or mebendazole (500 mg) or triple-dose albendazole (3×400 mg over 3 consecutive days) or mebendazole (3×500 mg over 3 consecutive days).,Efficacy against T. trichiura, Ascaris lumbricoides, and Taenia spp. was also assessed.,Albendazole cured significantly more hookworm infections than mebendazole in both treatment regimens (single dose: respective CRs 69% (95% confidence interval [CI]: 55-81%) and 29% (95% CI: 20-45%); triple dose: respective CRs 92% (95% CI: 81-98%) and 54% (95% CI: 46-71%)).,ERRs followed the same pattern (single dose: 97% versus 84%; triple dose: 99.7% versus 96%).,Triple-dose regimens outperformed single doses against T. trichiura; three doses of mebendazole - the most efficacious treatment tested - cured 71% (95% CI: 57-82%).,Both single and triple doses of either drug were highly efficacious against A. lumbricoides (CR: 93-97%; ERR: all >99.9%).,Triple dose regimens cured all Taenia spp. infections, whereas single dose applications cured only half of them.,Single-dose oral albendazole is more efficacious against hookworm than mebendazole.,To achieve high CRs against both hookworm and T. trichiura, triple-dose regimens are warranted.,www.controlled-trials.comISRCTN47375023 | 1 |
Malaria endemic countries need to assess efficacy of anti-malarial treatments on a regular basis.,Moreover, resistance to artemisinin that is established across mainland South-East Asia represents today a major threat to global health.,Monitoring the efficacy of artemisinin-based combination therapies is of paramount importance to detect as early as possible the emergence of resistance in African countries that toll the highest burden of malaria morbidity and mortality.,A WHO standard protocol was used to assess efficacy of the combinations artesunate-amodiaquine (AS-AQ Winthrop®), dihydroartemisinin-piperaquine (DHA-PPQ, Eurartesim®) and artemether-lumefantrine (AM-LM, Coartem®) taken under supervision and respecting pharmaceutical recommendations.,The study enrolled for each treatment arm 212 children aged 6-59 months living in Maradi (Niger) and suffering with uncomplicated falciparum malaria.,The Kaplan-Meier 42-day PCR-adjusted cure rate was the primary outcome.,A standardized parasite clearance estimator was used to assess delayed parasite clearance as surrogate maker of suspected artemisinin resistance.,No early treatment failures were found in any of the study treatment arms.,The day-42 PCR-adjusted cure rate estimates were 99.5, 98.4 and 99.0% in the AS-AQ, DHA-PPQ and AM-LM arms, respectively.,The reinfection rate (expressed also as Kaplan-Meier estimates) was higher in the AM-LM arm (32.4%) than in the AS-AQ (13.8%) and the DHA-PPQ arm (24.9%).,The parasite clearance rate constant was 0.27, 0.26 and 0.25 per hour for AS-AQ, DHA-PPQ and AM-LM, respectively.,All the three treatments evaluated largely meet WHO criteria (at least 95% efficacy).,AS-AQ and AL-LM may continue to be used and DHA-PPQ may be also recommended as first-line treatment for uncomplicated falciparum malaria in Maradi.,The parasite clearance rate were consistent with reference values indicating no suspected artemisinin resistance.,Nevertheless, the monitoring of anti-malarial drug efficacy should continue.,Trial registration details Registry number at ClinicalTrial.gov: NCT01755559 | Evidence suggests that the PfKelch13 mutations that confer artemisinin resistance in falciparum malaria have multiple independent origins across the Greater Mekong subregion, which has motivated a regional malaria elimination agenda.,We aimed to use molecular genotyping to assess antimalarial drug resistance selection and spread in the Greater Mekong subregion.,In this observational study, we tested Plasmodium falciparum isolates from Myanmar, northeastern Thailand, southern Laos, and western Cambodia for PfKelch13 mutations and for Pfplasmepsin2 gene amplification (indicating piperaquine resistance).,We collected blood spots from patients with microscopy or rapid test confirmed uncomplicated falciparum malaria.,We used microsatellite genotyping to assess genetic relatedness.,As part of studies on the epidemiology of artemisinin-resistant malaria between Jan 1, 2008, and Dec 31, 2015, we collected 434 isolates.,In 2014-15, a single long PfKelch13 C580Y haplotype (−50 to +31·5 kb) lineage, which emerged in western Cambodia in 2008, was detected in 65 of 88 isolates from northeastern Thailand, 86 of 111 isolates from southern Laos, and 14 of 14 isolates from western Cambodia, signifying a hard transnational selective sweep.,Pfplasmepsin2 amplification occurred only within this lineage, and by 2015 these closely related parasites were found in ten of the 14 isolates from Cambodia and 15 of 15 isolates from northeastern Thailand.,C580Y mutated parasites from Myanmar had a different genetic origin.,Our results suggest that the dominant artemisinin-resistant P falciparum C580Y lineage probably arose in western Cambodia and then spread to Thailand and Laos, outcompeting other parasites and acquiring piperaquine resistance.,The emergence and spread of fit artemisinin-resistant P falciparum parasite lineages, which then acquire partner drug resistance across the Greater Mekong subregion, threatens regional malaria control and elimination goals.,Elimination of falciparum malaria from this region should be accelerated while available antimalarial drugs still remain effective.,The Wellcome Trust and the Bill and Melinda Gates Foundation. | 1 |
Methods for analyzing individual-level geo-located disease data have existed for some time, but have rarely been used to analyze endemic human diseases.,Here we apply such methods to nearly a decade’s worth of uniquely detailed epidemiological data on incidence of the deadly vector-borne disease visceral leishmaniasis (VL) and its secondary condition, post-kala-azar dermal leishmaniasis (PKDL), to quantify the spread of infection around cases in space and time by inferring who infected whom, and estimate the relative contribution of different infection states to transmission.,Our findings highlight the key role long diagnosis delays and PKDL play in maintaining VL transmission.,This detailed characterization of the spatiotemporal transmission of VL will help inform targeting of interventions around VL and PKDL cases.,Understanding of spatiotemporal transmission of infectious diseases has improved significantly in recent years.,Advances in Bayesian inference methods for individual-level geo-located epidemiological data have enabled reconstruction of transmission trees and quantification of disease spread in space and time, while accounting for uncertainty in missing data.,However, these methods have rarely been applied to endemic diseases or ones in which asymptomatic infection plays a role, for which additional estimation methods are required.,Here, we develop such methods to analyze longitudinal incidence data on visceral leishmaniasis (VL) and its sequela, post-kala-azar dermal leishmaniasis (PKDL), in a highly endemic community in Bangladesh.,Incorporating recent data on VL and PKDL infectiousness, we show that while VL cases drive transmission when incidence is high, the contribution of PKDL increases significantly as VL incidence declines (reaching 55% in this setting).,Transmission is highly focal: 85% of mean distances from inferred infectors to their secondary VL cases were <300 m, and estimated average times from infector onset to secondary case infection were <4 mo for 88% of VL infectors, but up to 2.9 y for PKDL infectors.,Estimated numbers of secondary cases per VL and PKDL case varied from 0 to 6 and were strongly correlated with the infector’s duration of symptoms.,Counterfactual simulations suggest that prevention of PKDL could have reduced overall VL incidence by up to 25%.,These results highlight the need for prompt detection and treatment of PKDL to achieve VL elimination in the Indian subcontinent and provide quantitative estimates to guide spatiotemporally targeted interventions against VL. | Leishmania donovani causes visceral leishmaniasis (VL), the second most deadly vector-borne parasitic disease.,A recent epidemic in the Indian subcontinent (ISC) caused up to 80% of global VL and over 30,000 deaths per year.,Resistance against antimonial drugs has probably been a contributing factor in the persistence of this epidemic.,Here we use whole genome sequences from 204 clinical isolates to track the evolution and epidemiology of L. donovani from the ISC.,We identify independent radiations that have emerged since a bottleneck coincident with 1960s DDT spraying campaigns.,A genetically distinct population frequently resistant to antimonials has a two base-pair insertion in the aquaglyceroporin gene LdAQP1 that prevents the transport of trivalent antimonials.,We find evidence of genetic exchange between ISC populations, and show that the mutation in LdAQP1 has spread by recombination.,Our results reveal the complexity of L. donovani evolution in the ISC in response to drug treatment.,DOI:http://dx.doi.org/10.7554/eLife.12613.001,The parasite Leishmania donovani causes a disease called visceral leishmaniasis that affects many of the world's poorest people.,Around half a million new cases develop every year, but health authorities lack safe and effective drugs to treat them.,Up to 80% of these cases occur in the Indian subcontinent, where devastating epidemics have occurred in the last decades.,One reason these epidemics continue to occur is that the parasites develop genetic mutations allowing them to adapt to and resist the drugs used to kill them.,As there are few existing drugs that can kill L. donovani, it is crucial to understand how drug resistance emerges and spreads among parasite populations.,Imamura, Downing, Van den Broeck et al. have now investigated the history of visceral leishmaniasis epidemics by characterising the complete genetic sequence - or genome - of 204 L. donovani parasite samples.,This revealed that the majority of parasites in the Indian subcontinent first appeared in the nineteenth century, matching the first historical records of visceral leishmaniasis epidemics.,The genomes show that most of the parasites are genetically similar and can be clustered into several closely related groups.,These groups first appeared in the 1960s following the end of a regional campaign to eradicate malaria.,The most common parasite group is particularly resistant to drugs called antimonials, which were the main treatment for leishmaniasis until recently.,These parasites have a small genetic change that scrambles most of a protein known to be involved in the uptake of antimonials.,Parasites may also be able to develop resistance to drugs through additional mechanisms that allow them to produce many copies of the same gene.,These mechanisms could allow the parasites to rapidly adapt to new drugs or changes in the populations it infects.,The work of Imamura et al. looks only at parasites isolated from patients then grown in the laboratory, so further research is now needed to explore how variable the Leishmania genome is in both of the parasite’s hosts: humans and sandflies.,Imamura et al.’s study reveals how L. donovani has spread throughout the Indian subcontinent in fine detail.,The genome data can be used to create simple molecular tools that could form an "early warning system" to track the success of disease control programs and to determine how well the current drugs are working.,DOI:http://dx.doi.org/10.7554/eLife.12613.002 | 1 |
Naturally acquired humoral immunity to the malarial parasite Plasmodium falciparum can protect against disease, although the precise mechanisms remain unclear.,Although antibody levels can be measured by ELISA, few studies have investigated functional antibody assays in relation to clinical outcomes.,In this study we applied a recently developed functional assay of antibody-mediated opsonisation of merozoites, to plasma samples from a longitudinal cohort study conducted in a malaria endemic region of Papua New Guinea (PNG).,Phagocytic activity was quantified by flow cytometry using a standardized and high-throughput protocol, and was subsequently evaluated for association with protection from clinical malaria and high-density parasitemia.,Opsonising antibody responses were found to: i) increase with age, ii) be enhanced by concurrent infection, and iii) correlate with protection from clinical episodes and high-density parasitemia.,Stronger protective associations were observed in individuals with no detectable parasitemia at baseline.,This study presents the first evidence for merozoite phagocytosis as a correlate of acquired immunity and clinical protection against P. falciparum malaria. | Effective vaccines to combat malaria are urgently needed, but have proved elusive in the absence of validated correlates of natural immunity.,Repeated blood stage infections induce antibodies considered to be the main arbiters of protection from pathology, but their essential functions have remained speculative.,This study evaluated antibody dependent respiratory burst (ADRB) activity in polymorphonuclear neutrophils (PMN) induced by Plasmodium falciparum merozoites and antibodies in the sera of two different African endemic populations, and investigated its association with naturally acquired clinical protection.,Respiratory bursts by freshly isolated PMN were quantified by chemiluminescence readout in the presence of isoluminol, which preferentially detects extra-cellular reactive oxygen species (ROS).,Using a standardized, high throughput protocol, 230 sera were analyzed from individuals of all age groups living in meso- (Ndiop) or holo-endemic (Dielmo) Senegalese villages, and enrolled in a cross-sectional prospective study with intensive follow-up.,Statistical significance was determined using non-parametric tests and Poisson regression models.,The most important finding was that PMN ADRB activity was correlated with acquired clinical protection from malaria in both high and low transmission areas (P = 0.006 and 0.036 respectively).,Strikingly, individuals in Dielmo with dichotomized high ADRB indexes were seventeen fold less susceptible to malaria attacks (P = 0.006).,Complementary results showed that ADRB activity was (i) dependent on intact merozoites and IgG opsonins, but not parasitized erythrocytes, or complement, (ii) correlated with merozoite specific cytophilic IgG1 and IgG3 antibody titers (P<0.001 for both), and (iii) stronger in antisera from a holo-endemic compared to a meso-endemic site (P = 0.002), and reduced in asymptomatic carriers (P<0.001).,This work presents the first clearly demonstrated functional antibody immune correlate of clinical protection from Plasmodium falciparum malaria, and begs the question regarding the importance of ADRB by PMN for immune protection against malaria in vivo. | 1 |
Malaria is a major public health problem worldwide.,In Brazil, an average of 420,000 cases of malaria have been reported annually in the last 12 years, of which 99.7 % occurred in the Amazon region.,This study aimed to analyse the distribution of malaria in the State of Amazonas and the influence of indigenous malaria in this scenario, to evaluate the correlation between incidence rates and socio-economic and environmental factors, and to evaluate the performance of health surveillance services.,This ecological study used secondary data obtained from the SIVEP-MALARIA malaria surveillance programme.,The relationship between demographic, socio-economic and environmental factors, the performance of health surveillance services and the incidence of malaria in Amazonas, a multiple linear regression model was used.,The crude rate of malaria in Amazonas was 4142.72 cases per 100,000 inhabitants between 2003 and 2012.,The incidence rates for the indigenous and non-indigenous populations were 12,976.02 and 3749.82, respectively, with an indigenous population attributable fraction of only 8 %.,The results of the linear regression analysis indicated a negative correlation between the two socio-economic indicators (municipal human development index (MHDI) and poverty rate) and the incidence of malaria in the period.,With regard to the environmental indicators (average annual deforestation rate and percentage of areas under the influence of watercourses), the correlation with the incidence rate was positive.,The findings underscore the importance of implementing economic and social development policies articulated with strategic actions of environmental protection and health care for the population. | The nine countries sharing the Amazon forest accounted for 89% of all malaria cases reported in the Americas in 2008.,Remote sensing can help identify the environmental determinants of malaria transmission and their temporo-spatial evolution.,Seventeen studies characterizing land cover or land use features, and relating them to malaria in the Amazon subregion, were identified.,These were reviewed in order to improve the understanding of the land cover/use class roles in malaria transmission.,The indicators affecting the transmission risk were summarized in terms of temporal components, landscape fragmentation and anthropic pressure.,This review helps to define a framework for future studies aiming to characterize and monitor malaria. | 1 |
Mass anti-malarial administration has been proposed as a key component of the Plasmodium falciparum malaria elimination strategy in the Greater Mekong sub-Region.,Its effectiveness depends on high levels of coverage in the target population.,This article explores the factors that influenced mass anti-malarial administration coverage within a clinical trial in Battambang Province, western Cambodia.,Qualitative data were collected through semi-structured interviews and focus group discussions with villagers, in-depth interviews with study staff, trial drop-outs and refusers, and observations in the communities.,Interviews were audio-recorded, transcribed and translated from Khmer to English for qualitative content analysis using QSR NVivo.,Malaria was an important health concern and villagers reported a demand for malaria treatment.,This was in spite of a fall in incidence over the previous decade and a lack of familiarity with asymptomatic malaria.,Participants generally understood the overall study aim and were familiar with study activities.,Comprehension of the study rationale was however limited.,After the first mass anti-malarial administration, seasonal health complaints that participants attributed to the anti-malarial as “side effects” contributed to a decrease of coverage in round two.,Staff therefore adapted the community engagement approach, bringing to prominence local leaders in village meetings.,This contributed to a subsequent increase in coverage.,Future mass anti-malarial administration must consider seasonal disease patterns and the importance of local leaders taking prominent roles in community engagement.,Further research is needed to investigate coverage in scenarios that more closely resemble implementation i.e. without participation incentives, blood sampling and free healthcare. | A targeted malaria elimination project, including mass drug administrations (MDA) of dihydroartemisinin/piperaquine plus a single low dose primaquine is underway in villages along the Thailand Myanmar border.,The intervention has multiple components but the success of the project will depend on the participation of the entire communities.,Quantitative surveys were conducted to study reasons for participation or non-participation in the campaign with the aim to identify factors associated with the acceptance and participation in the mass drug administrations.,The household heads in four study villages in which MDAs had taken place previously were interviewed between January 2014 and July 2015.,174/378 respondents (46 %) completed three rounds of three drug doses each, 313/378 (83 %) took at least three consecutive doses and 56/378 (15 %) did not participate at all in the MDA.,The respondents from the two villages (KNH and TPN) were much more likely to participate in the MDA than respondents from the other two villages (HKT and TOT).,The more compliant villages KNH and TPN had both an appearance of cohesive communities with similar demographic and ethnic backgrounds.,By contrast the villages with low participation were unique.,One village was fragmented following years of armed conflict and many respondents gave little inclination to cooperate with outsiders.,The other village with low MDA coverage was characterised by a high percentage of short-term residents with little interest in community interventions.,A universal reason for non-participation in the MDA applicable to all villages was an inadequate understanding of the intervention.,It is unlikely that community engagement can unite fragmented communities in participating in an intervention, which benefits the community.,Understanding the purpose and the reasons underlying the intervention is an important pre-condition for participation.,In the absence of direct benefits and a complete understanding of the indirect benefits trust in the investigators is critical for participation. | 1 |
Many countries have made significant progress in the implementation of World Health Organization recommended preventive chemotherapy strategy, to eliminate lymphatic filariasis (LF).,However, pertinent challenges such as the existence of areas of residual infections in disease endemic districts pose potential threats to the achievements made.,Thus, this study was undertaken to assess the importance of these areas in implementation units (districts) where microfilaria (MF) positive individuals could not be found during the mid-term assessment after three rounds of mass drug administration.,This study was undertaken in Bo and Pujehun, two LF endemic districts of Sierra Leone, with baseline MF prevalence of 2 % and 0 % respectively in sentinel sites for monitoring impact of the national programme.,Study communities in the districts were purposefully selected and an assessment of LF infection prevalence was conducted together with entomological investigations undertaken to determine the existence of areas with residual MF that could enable transmission by local vectors.,The transmission Assessment Survey (TAS) protocol described by WHO was applied in the two districts to determine infection of LF in 6-7 year old children who were born before MDA against LF started.,The results indicated the presence of MF infected children in Pujehun district.,An. gambiae collected in the district were also positive for W. bancrofti, even though the prevalence of infection was below the threshold associated with active transmission.,Residual infection was detected after three rounds of MDA in Pujehun - a district of 0 % Mf prevalence at the sentinel site.,Nevertheless, our results showed that the transmission was contained in a small area.,With the scale up of vector control in Anopheles transmission zones, some areas of residual infection may not pose a serious threat for the resurgence of LF if the prevalence of infections observed during TAS are below the threshold required for active transmission of the parasite.,However, robust surveillance strategies capable of detecting residual infections must be implemented, together with entomological assessments to determine if ongoing vector control activities, biting rates and infection rates of the vectors can support the transmission of the disease.,Furthermore, in areas where mid-term assessments reveal MF prevalence below 1 % or 2 % antigen level, in Anopheles transmission areas with active and effective malaria vector control efforts, the minimum 5 rounds of MDA may not be required before implementing TAS.,Thus, we propose a modification of the WHO recommendation for the timing of sentinel and spot-check site assessments in national programs. | In November 2010, Sierra Leone distributed over three million long-lasting insecticide-treated nets (LLINs) with the objective of providing protection from malaria to individuals in all households in the country.,We conducted a nationally representative survey six months after the mass distribution campaign to evaluate its impact on household insecticide-treated net (ITN) ownership and use.,We examined factors associated with household ITN possession and use with logistic regression models.,The survey included 4,620 households with equal representation in each of the 14 districts.,Six months after the campaign, 87.6% of households own at least one ITN, which represents an increase of 137% over the most recent estimate of 37% in 2008.,Thirty-six percent of households possess at least one ITN per two household members; rural households were more likely than urban households to have ≥1∶2 ITN to household members, but there was no difference by socio-economic status or household head education.,Among individuals in households possessing ≥1 ITN, 76.5% slept under an ITN the night preceding the survey.,Individuals in households where the household head had heard malaria messaging, had correct knowledge of malaria transmission, and where at least one ITN was hanging, were more likely to have slept under an ITN.,The mass distribution campaign was effective at achieving high coverage levels across the population, notably so among rural households where the malaria burden is higher.,These important gains in equitable access to malaria prevention will need to be maintained to produce long-term reductions in the malaria burden. | 1 |
Extensive employment of long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) has substantially reduced malaria morbidity and mortality in sub-Saharan Africa.,These tools target indoor resting and biting vectors, and may select for vectors that bite and rest outdoors.,Thus, to significantly impact this residual malaria transmission outdoors, tools targeting outdoor transmission are required.,Repellents, used for personal protection, offer one solution.,However, the effectiveness of this method hinges upon its community acceptability.,This study assessed the feasibility of using repellents as a malaria prevention tool in Mbingu village, Ulanga, Southern Tanzania.,Change in knowledge, attitude and practice (KAP) in relation to repellent use was assessed before and after the implementation of a cluster randomized clinical trial on topical repellents in rural Tanzania where repellent and placebo lotion were provided free of charge to 940 households for a period of 14 months between July 2009 and August 2010.,Compliance, defined as the number of evenings that participants applied the recommended dose of repellent every month during the study period, was assessed using questionnaires, administered monthly during follow up of participants in the clinical trial.,Focus group discussions (FGDs) were conducted in the same community three years later to assess the community’s KAP in relation to repellents and preference to different repellent formats.,At baseline, only 0.32% (n = 2) households in the intervention arm and no households in the control arm had ever used topical repellents.,During follow-up surveys, significantly more households, 100% (n = 457) in intervention arm relative to the control, 84.03% (n = 379), (p = <0.001) perceived the repellent to be effective.,Post-study, 99.78% (n = 462) and 99.78% (n = 463), (p = 0.999) in the intervention and control arms respectively, were willing to continue repellent use.,Mosquito nuisance motivated repellent use.,From the FGDs, it emerged that most respondents preferred bed nets to repellents because of their longevity and cost effectiveness.,High repellent acceptability indicates their feasibility for malaria control in this community.,However, to improve the community’s uptake of repellents for use complimentary to LLINs for early evening and outdoor protection from mosquito bites, longer lasting and cheap formats are required.,The online version of this article (doi:10.1186/1475-2875-13-347) contains supplementary material, which is available to authorized users. | To improve access to treatment in the private retail sector a new class of outlets known as accredited drug dispensing outlets (ADDO) was created in Tanzania.,Tanzania changed its first-line treatment for malaria from sulphadoxine-pyrimethamine (SP) to artemether-lumefantrine (ALu) in 2007.,Subsidized ALu was made available in both health facilities and ADDOs.,The effect of these interventions on access to malaria treatment was studied in rural Tanzania.,The study was carried out in the villages of Kilombero and Ulanga Demographic Surveillance System (DSS) and in Ifakara town.,Data collection consisted of: 1) yearly censuses of shops selling drugs; 2) collection of monthly data on availability of anti-malarials in public health facilities; and 3) retail audits to measure anti-malarial sales volumes in all public, mission and private outlets.,The data were complemented with DSS population data.,Between 2004 and 2008 access to malaria treatment greatly improved and the number of anti-malarial treatment doses dispensed increased by 78%.,Particular improvements were observed in the availability (from 0.24 shops per 1,000 people in 2004 to 0.39 in 2008) and accessibility (from 71% of households within 5 km of a shop in 2004 to 87% in 2008) of drug shops.,Despite no improvements in affordability this resulted in an increase of the market share from 49% of anti-malarial sales 2005 to 59% in 2008.,The change of treatment policy from SP to ALu led to severe stock-outs of SP in health facilities in the months leading up to the introduction of ALu (only 40% months in stock), but these were compensated by the wide availability of SP in shops.,After the introduction of ALu stock levels of the drug were relatively high in public health facilities (over 80% months in stock), but the drug could only be found in 30% of drug shops and in no general shops.,This resulted in a low overall utilization of the drug (19% of all anti-malarial sales),The public health and private retail sector are important complementary sources of treatment in rural Tanzania.,Ensuring the availability of ALu in the private retail sector is important for its successful uptake. | 1 |
Ethiopia bears a high burden of visceral leishmaniasis (VL).,Early access to VL diagnosis and care improves clinical prognosis and reduces transmission from infected humans; however, significant obstacles exist.,The approximate 250,000 seasonal mobile workers (MW) employed annually in northwestern Ethiopia may be particularly disadvantaged and at risk of VL acquisition and death.,Our study aimed to assess barriers, and recommend interventions to increase access, to VL diagnosis and care among MWs.,In 2017, 50 interviews and 11 focus group discussions were conducted with MWs, mobile residents, VL patients and caretakers, community leaders and healthcare workers in Kafta Humera District, Tigray.,Participants reported high vulnerability to VL among MWs and residents engaged in transitory work.,Multiple visits to health facilities were consistently needed to access VL diagnosis.,Inadequate healthcare worker training, diagnostic test kit unavailability at the primary healthcare level, lack of VL awareness, insufficient finances for care-seeking and prioritization of income-generating activities were significant barriers to diagnosis and care.,Social (decision-making and financial) support strongly and positively influenced care-seeking; workers unable to receive salary advances, compensation for partial work, or peer assistance for contract completion were particularly disadvantaged.,Participants recommended the government/stakeholders intervene to ensure: MWs access to bed-nets, food, shelter, water, and healthcare at farms or sick leave; decentralization of diagnostic tests to primary healthcare facilities; surplus medications/staff during the peak season; improved referral/feedback/reporting/training within the health system; free comprehensive healthcare for all VL-related services; and community health education.,Contrary to what health policy for VL dictates in this endemic setting, study participants reported very poor access to diagnosis and, consequently, significantly delayed access to treatment.,Interventions tailored to the socio-economic and health needs of MWs (and other persons suffering from VL) are urgently needed to reduce health disparities and the VL burden. | In 2005, a nationwide survey estimated that 6.5% of households in Ethiopia owned an insecticide-treated net (ITN), 17% of households had been sprayed with insecticide, and 4% of children under five years of age with a fever were taking an anti-malarial drug.,Similar to other sub-Saharan African countries scaling-up malaria interventions, the Government of Ethiopia set an ambitious national goal in 2005 to (i) provide 100% ITN coverage in malarious areas, with a mean of two ITNs per household; (ii) to scale-up indoor residual spraying of households with insecticide (IRS) to cover 30% of households targeted for IRS; and (iii) scale-up the provision of case management with rapid diagnostic tests (RDTs) and artemisinin-based combination therapy (ACT), particularly at the peripheral level.,A nationally representative malaria indicator survey (MIS) was conducted in Ethiopia between September and December 2007 to determine parasite and anaemia prevalence in the population at risk and to assess coverage, use and access to scaled-up malaria prevention and control interventions.,The survey used a two-stage random cluster sample of 7,621 households in 319 census enumeration areas.,A total of 32,380 people participated in the survey.,Data was collected using standardized Roll Back Malaria Monitoring and Evaluation Reference Group MIS household and women's questionnaires, which were adapted to the local context.,Data presented is for households in malarious areas, which according to the Ethiopian Federal Ministry of Health are defined as being located <2,000 m altitude.,Of 5,083 surveyed households, 3,282 (65.6%) owned at least one ITN.,In ITN-owning households, 53.2% of all persons had slept under an ITN the prior night, including 1,564/2,496 (60.1%) children <5 years of age, 1,891/3,009 (60.9%) of women 15 - 49 years of age, and 166/266 (65.7%) of pregnant women.,Overall, 906 (20.0%) households reported to have had IRS in the past 12 months.,Of 747 children with reported fever in the two weeks preceding the survey, 131 (16.3%) sought medical attention within 24 hours.,Of those with fever, 86 (11.9%) took an anti-malarial drug and 41 (4.7%) took it within 24 hours of fever onset.,Among 7,167 surveyed individuals of all ages, parasitaemia as estimated by microscopy was 1.0% (95% CI 0.5 - 1.5), with 0.7% and 0.3% due to Plasmodium falciparum and Plasmodium vivax, respectively.,Moderate-severe anaemia (haemoglobin <8 g/dl) was observed in 239/3,366 (6.6%, 95% CI 4.9-8.3) children <5 years of age.,Since mid-2005, the Ethiopian National Malaria Control Programme has considerably scaled-up its malaria prevention and control interventions, demonstrating the impact of strong political will and a committed partnership.,The MIS showed, however, that besides sustaining and expanding malaria intervention coverage, efforts will have to be made to increase intervention access and use.,With ongoing efforts to sustain and expand malaria intervention coverage, to increase intervention access and use, and with strong involvement of the community, Ethiopia expects to achieve its targets in terms of coverage and uptake of interventions in the coming years and move towards eliminating malaria. | 1 |
Despite malaria, malnutrition and anaemia being major public-health challenges in Cameroon, very little has been reported on the interaction between these interconnected health determinants.,This study therefore sought to investigate the relationship between malaria, anaemia, nutritional and socio-economic status amongst under-ten children living in six localities within two health districts in the North Region of Cameroon.,Accordingly, a cross- sectional survey was conducted during the peak malaria season in November 2014, in Pitoa and Mayo-Oulo Health Districts.,Three hundred and sixty eight children aged 6months-10 years were enrolled.,Structured questionnaires were used to assess socio-economic status.,Anthropometric indices were taken using standard methods and nutritional status assessed by calculating Height for Age (HA), Weight for Age (WA) and Weight for Height (WH) z-scores to determine stunting, underweight and wasting respectively.,Finger-prick blood samples were used to prepare thin and thick blood smears for microscopy.,Whole blood was collected to determine the PCV and blood spots on filter paper were used to extract plasmodium DNA for speciation by PCR.,Overall prevalence rates of malaria, malnutrition and anaemia were 32.9%, 54.1% and 20.6% respectively.,Stunting, underweight and wasting were detected in 56.9%, 63.5% and 34.8% of the children respectively.,There was a significant association between malaria and malnutrition [OR = 1.89, (95% CI: 1.12-3.19); (p = 0.017)].,Malnutrition was also strongly associated with malaria status [OR = 2.07, (95% CI: 1.22-3.53); (p = 0.007)].,The prevalence rates of mild, moderate and severe anaemia were 8.1%, 9.2% and 3.3% respectively.,Both malaria status and anaemia correlated with development index [OR = 0.75, (95% CI: 0.58-0.99); (p = 0.042)] and [OR = 1.45, (95% CI: 1.05-2.00); (p = 0.023)] respectively.,Our findings show a synergistic relationship between malaria and malnutrition.,Effective collaboration between malaria control and nutrition intervention programmes is essential for proper case management and improved socio-economic status. | The malaria parasite Plasmodium vivax is known to be majorly endemic to Asian and Latin American countries with no or very few reports of Africans infected with this parasite.,Since the human Duffy antigens act as receptors for P. vivax to invade human RBCs and Africans are generally Duffy-negative, non-endemicity of P. vivax in Africa has been attributed to this fact.,However, recent reports describing P. vivax infections in Duffy-negative Africans from West and Central parts of Africa have been surfaced including a recent report on P. vivax infection in native Cameroonians.,In order to know if Cameroonians living in the southern regions are also susceptible to P. vivax infection, we collected finger-prick blood samples from 485 malarial symptomatic patients in five locations and followed PCR diagnostic assays with DNA sequencing of the 18S ribosomal RNA gene.,Out of the 201 malaria positive cases detected, 193 were pure P. falciparum, six pure P. vivax and two mixed parasite infections (P. falciparum + P. vivax).,The eight P. vivax infected samples (six single + two mixed) were further subjected to DNA sequencing of the P. vivax multidrug resistance 1 (pvmdr1) and the P.vivax circumsporozoite (pvcsp) genes.,Alignment of the eight Cameroonian pvmdr1 sequences with the reference sequence showed high sequence similarities, reconfirming P. vivax infection in all the eight patients.,DNA sequencing of the pvcsp gene indicated all the eight P. vivax to be of VK247 type.,Interestingly, DNA sequencing of a part of the human Duffy gene covering the promoter region in the eight P. vivax-infected Cameroonians to identify the T-33C mutation revealed all these patients as Duffy-negative.,The results provide evidence of single P. vivax as well as mixed malaria parasite infection in native Cameroonians and add knowledge to the growing evidences of P. vivax infection in Duffy-negative Africans. | 1 |
Malaria is a major health problem in the tropical and subtropical world.,In India, 95% of the population resides in malaria endemic regions and it is major public health problem in most parts of the country.,The present work has developed malaria maps by integrating socio-economic, epidemiology and geographical dimensions of three eastern districts of Uttar Pradesh, India.,The area has been studied in each dimension separately, and later integrated to find a list of vulnerable pockets/villages, called as malarial hotspots.,The study has been done at village level.,Seasonal variation of malaria, comparison of epidemiology indices and progress of the medical facility were studied.,Ten independent geographical information system (GIS) maps of socio-economic aspects (population, child population, literacy, and work force participation), epidemiology (annual parasitic index (API) and slides collected and examined) and geographical features (settlement, forest cover, water bodies, rainfall, relative humidity, and temperature) were drawn and studied.,These maps were overlaid based on computed weight matrix to find malarial hotspot.,It was found that the studied dimensions were inter-weaving factors for malaria epidemic and closely affected malaria situations as evidenced from the obtained correlation matrix.,The regions with water logging, high rainfall and proximity to forest, along with poor socio-economic conditions, are primarily hotspot regions.,The work is presented through a series of GIS maps, tables, figures and graphs.,A total of 2,054 out of 8,973 villages studied were found to be malarial hotspots and consequently suggestions were made to the concerned government malaria offices.,With developing technology, information tools such as GIS, have captured almost every field of scientific research especially of vector-borne diseases, such as malaria.,Malarial mapping enables easy update of information and effortless accessibility of geo-referenced data to policy makers to produce cost-effective measures for malaria control in endemic regions.,The online version of this article (doi:10.1186/s12936-015-0685-4) contains supplementary material, which is available to authorized users. | Malaria incidence worldwide has steadily declined over the past decades.,Consequently, increasingly more countries will proceed from control to elimination.,The malaria distribution in low incidence settings appears patchy, and local transmission hotspots are a continuous source of infection.,In this study, species-specific clusters and associated risk factors were identified based on malaria prevalence data collected in the north-east of Cambodia.,In addition, Plasmodium falciparum genetic diversity, population structure and gene flows were studied.,In 2012, blood samples from 5793 randomly selected individuals living in 117 villages were collected from Ratanakiri province, Cambodia.,Malariometric data of each participant were simultaneously accumulated using a standard questionnaire.,A two-step PCR allowed for species-specific detection of malaria parasites, and SNP-genotyping of P. falciparum was performed.,SaTScan was used to determine species-specific areas of elevated risk to infection, and univariate and multivariate risk analyses were carried out.,PCR diagnosis found 368 positive individuals (6.4%) for malaria parasites, of which 22% contained mixed species infections.,The occurrence of these co-infections was more frequent than expected.,Specific areas with elevated risk of infection were detected for all Plasmodium species.,The clusters for Falciparum, Vivax and Ovale malaria appeared in the north of the province along the main river, while the cluster for Malariae malaria was situated elsewhere.,The relative risk to be a malaria parasite carrier within clusters along the river was twice that outside the area.,The main risk factor associated with three out of four malaria species was overnight stay in the plot hut, a human behaviour associated with indigenous farming.,Haplotypes did not show clear geographical population structure, but pairwise Fst value comparison indicated higher parasite flow along the river.,Spatial aggregation of malaria parasite carriers, and the identification of malaria species-specific risk factors provide key insights in malaria epidemiology in low transmission settings, which can guide targeted supplementary interventions.,Consequently, future malaria programmes in the province should implement additional specific policies targeting households staying overnight at their farms outside the village, in addition to migrants and forest workers.,The online version of this article (doi:10.1186/1475-2875-13-387) contains supplementary material, which is available to authorized users. | 1 |
Toxoplasma gondii infection is a great health concern to pregnant women and the developing fetus.,The aim of this study was to determine the seroprevalence of T. gondii and its associated factors in Adwa district.,A facility based cross-sectional study was conducted from January to June 2018 in Adwa district.,Structured, a pre-tested questionnaire was used to collect the demographic and risk factor related data.,Serum sample, collected from each of the study subjects was tested for IgG and IgM anti T.godii specific antibodies using Enzyme-Linked Immunosorbent Assay.,A bivariable and multivariable logistic regression model was applied to show association between the dependent and independent variables considering P < 0.05 and the 95% confidence interval.,Out of the 360, 128 (35.6%) pregnant women were found to be positive for antibodies specific to T. gondii.,Furthermore, 117 (32.5%) women were positive only for IgG, and 11 (3.1%) were positive both for IgM and IgG antibodies.,Age, educational level, habit of hand washing after contact with garden soil or domestic animals, presence of domestic cat, history of contact with domestic dog and consumption of raw vegetables were significantly associated with T. gondii.,The seroprevalence of T. gondii among pregnant women in the study area is low compared to the other regions of Ethiopia, and within the range of the seroprevalences in the central and East Africa region.,However, efforts should be done to create awareness on the potential risk factors of the parasite in the community. | One way that people get infected with intestinal parasites is through the consumption of contaminated vegetables and fruits.,This study aimed at determining the prevalence and predictors of parasitic contamination of fruits and vegetables collected from four local markets in Arba Minch town, Southern Ethiopia.,A cross-sectional study was conducted from 1 to 21 September 2014 to determine the level of parasitic contamination of fruits and vegetables sold in Arba Minch town.,A total of 360 samples of different types of fruits and vegetables were soaked in physiological saline, followed by vigorous shaking with the aid of a mechanical shaker for 15 minutes and then examined using the sedimentation concentration technique.,Out of the 360 samples examined, 196 (54.4%) were contaminated with at least one type of parasite.,Ascaris lumbricoides (20.83%) was the most frequently detected parasite and Isospora belli (3.06%) was the least frequently detected one.,It was also observed that decreased parasitic contamination was significantly associated with washing the products before displaying it for selling (P < 0.001).,The findings of this study provide evidence that there is a potentially high risk of acquiring parasitic infections from the consumption of raw vegetables and fruits in Arba Minch, Ethiopia.,The authors believe that an effort should be made by the relevant bodies to reduce the rate of contamination of products with medically important parasites by educating the vendors and the community.,The online version of this article (doi:10.1186/s40249-016-0226-6) contains supplementary material, which is available to authorized users. | 1 |
Plasmodium vivax imposes substantial morbidity and mortality burdens in endemic zones.,Detailed understanding of the contemporary spatial distribution of this parasite is needed to combat it.,We used model based geostatistics (MBG) techniques to generate a contemporary map of risk of Plasmodium vivax malaria in Indonesia in 2010.,Plasmodium vivax Annual Parasite Incidence data (2006-2008) and temperature masks were used to map P. vivax transmission limits.,A total of 4,658 community surveys of P. vivax parasite rate (PvPR) were identified (1985-2010) for mapping quantitative estimates of contemporary endemicity within those limits.,After error-checking a total of 4,457 points were included into a national database of age-standardized 1-99 year old PvPR data.,A Bayesian MBG procedure created a predicted PvPR1-99 endemicity surface with uncertainty estimates.,Population at risk estimates were derived with reference to a 2010 human population surface.,We estimated 129.6 million people in Indonesia lived at risk of P. vivax transmission in 2010.,Among these, 79.3% inhabited unstable transmission areas and 20.7% resided in stable transmission areas.,In western Indonesia, the predicted P. vivax prevalence was uniformly low.,Over 70% of the population at risk in this region lived on Java and Bali islands, where little malaria transmission occurs.,High predicted prevalence areas were observed in the Lesser Sundas, Maluku and Papua.,In general, prediction uncertainty was relatively low in the west and high in the east.,Most Indonesians living with endemic P. vivax experience relatively low risk of infection.,However, blood surveys for this parasite are likely relatively insensitive and certainly do not detect the dormant liver stage reservoir of infection.,The prospects for P. vivax elimination would be improved with deeper understanding of glucose-6-phosphate dehydrogenase deficiency (G6PDd) distribution, anti-relapse therapy practices and manageability of P. vivax importation risk, especially in Java and Bali. | Countries aiming for malaria elimination require a detailed understanding of the current intensity of malaria transmission within their national borders.,National household sample surveys are now being used to define infection prevalence but these are less efficient in areas of exceptionally low endemicity.,Here we present the results of a national malaria indicator survey in the Republic of Djibouti, the first in sub-Saharan Africa to combine parasitological and serological markers of malaria, to evaluate the extent of transmission in the country and explore the potential for elimination.,A national cross-sectional household survey was undertaken from December 2008 to January 2009.,A finger prick blood sample was taken from randomly selected participants of all ages to examine for parasitaemia using rapid diagnostic tests (RDTs) and confirmed using Polymerase Chain Reaction (PCR).,Blood spots were also collected on filter paper and subsequently used to evaluate the presence of serological markers (combined AMA-1 and MSP-119) of Plasmodium falciparum exposure.,Multivariate regression analysis was used to determine the risk factors for P. falciparum infection and/or exposure.,The Getis-Ord G-statistic was used to assess spatial heterogeneity of combined infections and serological markers.,A total of 7151 individuals were tested using RDTs of which only 42 (0.5%) were positive for P. falciparum infections and confirmed by PCR.,Filter paper blood spots were collected for 5605 individuals.,Of these 4769 showed concordant optical density results and were retained in subsequent analysis.,Overall P. falciparum sero-prevalence was 9.9% (517/4769) for all ages; 6.9% (46/649) in children under the age of five years; and 14.2% (76/510) in the oldest age group (≥ 50 years).,The combined infection and/or antibody prevalence was 10.5% (550/4769) and varied from 8.1% to 14.1% but overall regional differences were not statistically significant (χ2 = 33.98, p = 0.3144).,Increasing age (p < 0.001) and decreasing household wealth status (p < 0.001) were significantly associated with increasing combined P. falciparum infection and/or antibody prevalence.,Significant P. falciparum hot spots were observed in Dikhil region.,Malaria transmission in the Republic of Djibouti is very low across all regions with evidence of micro-epidemiological heterogeneity and limited recent transmission.,It would seem that the Republic of Djibouti has a biologically feasible set of pre-conditions for elimination, however, the operational feasibility and the potential risks to elimination posed by P. vivax and human population movement across the sub-region remain to be properly established. | 1 |
To accelerate malaria elimination in areas where core interventions such as insecticide-treated nets (ITNs) are already widely used, it is crucial to consider additional factors associated with persistent transmission.,Qualitative data on human behaviours and perceptions regarding malaria risk was triangulated with quantitative data on Anopheles mosquito bites occurring indoors and outdoors in south-eastern Tanzania communities where ITNS are already used but lower level malaria transmission persists.,Each night (18:00h-07:00h), trained residents recorded human activities indoors, in peri-domestic outdoor areas, and in communal gatherings.,Host-seeking mosquitoes were repeatedly collected indoors and outdoors hourly, using miniaturized exposure-free double net traps (DN-Mini) occupied by volunteers.,In-depth interviews were conducted with household representatives to explore perceptions on persistent malaria and its control.,Higher proportions of people stayed outdoors than indoors in early-evening and early-morning hours, resulting in higher exposures outdoors than indoors during these times.,However, exposure during late-night hours (22:00h-05:00h) occurred mostly indoors.,Some of the popular activities that kept people outdoors included cooking, eating, relaxing and playing.,All households had at least one bed net, and 83.9% of people had access to ITNs.,Average ITN use was 96.3%, preventing most indoor exposure.,Participants recorgnized the importance of ITNs but also noted that the nets were not perfect.,No complementary interventions were reported being used widely.,Most people believed transmission happens after midnight.,We conclude that insecticide-treated nets, where properly used, can still prevent most indoor exposures, but significant risk continues unabated before bedtime, outdoors and at communal gatherings.,Such exposure is greatest for rural and low-income households.,There is therefore an urgent need for complementary interventions, particularly those targeting outdoor-biting and are applicable for all people including the marginalised populations such as migratory farmers and fishermen.,Besides, the differences in community understanding of ongoing transmission, and feedback on imperfections of ITNs should be considered when updating malaria-related communication and interventions. | Humans move frequently and tend to carry parasites among areas with endemic malaria and into areas where local transmission is unsustainable.,Human-mediated parasite mobility can thus sustain parasite populations in areas where they would otherwise be absent.,Data describing human mobility and malaria epidemiology can help classify landscapes into parasite demographic sources and sinks, ecological concepts that have parallels in malaria control discussions of transmission foci.,By linking transmission to parasite flow, it is possible to stratify landscapes for malaria control and elimination, as sources are disproportionately important to the regional persistence of malaria parasites.,Here, we identify putative malaria sources and sinks for pre-elimination Namibia using malaria parasite rate (PR) maps and call data records from mobile phones, using a steady-state analysis of a malaria transmission model to infer where infections most likely occurred.,We also examined how the landscape of transmission and burden changed from the pre-elimination setting by comparing the location and extent of predicted pre-elimination transmission foci with modeled incidence for 2009.,This comparison suggests that while transmission was spatially focal pre-elimination, the spatial distribution of cases changed as burden declined.,The changing spatial distribution of burden could be due to importation, with cases focused around importation hotspots, or due to heterogeneous application of elimination effort.,While this framework is an important step towards understanding progressive changes in malaria distribution and the role of subnational transmission dynamics in a policy-relevant way, future work should account for international parasite movement, utilize real time surveillance data, and relax the steady state assumption required by the presented model. | 1 |
Indoor residual spraying (IRS) combined with insecticide treated nets (ITN) has been implemented together in several sub-Saharan countries with inconclusive evidence that the combined intervention provides added benefit.,The impact on malaria transmission was evaluated in a cluster randomised trial comparing two rounds of IRS with bendiocarb plus universal coverage ITNs, with ITNs alone in northern Tanzania.,From April 2011 to December 2012, eight houses in 20 clusters per study arm were sampled monthly for one night with CDC light trap collections.,Anopheles gambiae s.l. were identified to species using real time PCR Taq Man and tested for the presence of Plasmodium falciparum circumsporozoite protein.,ITN and IRS coverage was estimated from household surveys.,IRS coverage was more than 85% in two rounds of spraying in January and April 2012.,Household coverage with at least one ITN per house was 94.7% after the universal coverage net campaign in the baseline year and the proportion of household with all sleeping places covered by LLIN was 50.1% decreasing to 39.1% by the end of the intervention year.,An.gambiae s.s. comprised 80% and An.arabiensis 18.3% of the anopheline collection in the baseline year.,Mean An.gambiae s.l. density in the ITN+IRS arm was reduced by 84% (95%CI: 56%-94%, p = 0.001) relative to the ITN arm.,In the stratum of clusters categorised as high anopheline density at baseline EIR was lower in the ITN+IRS arm compared to the ITN arm (0.5 versus 5.4 per house per month, Incidence Rate Ratio: 0.10, 95%CI: 0.01-0.66, p-value for interaction <0.001).,This trial provides conclusive evidence that combining carbamate IRS and ITNs produces major reduction in Anopheles density and entomological inoculation rate compared to ITN alone in an area of moderate coverage of LLIN and high pyrethroid resistance in An.gambiae s.s. | Standard advice regarding vector control is to prefer interventions that reduce the lifespan of adult mosquitoes.,The basis for this advice is a decades-old sensitivity analysis of ‘vectorial capacity’, a concept relevant for most malaria transmission models and based solely on adult mosquito population dynamics.,Recent advances in micro-simulation models offer an opportunity to expand the theory of vectorial capacity to include both adult and juvenile mosquito stages in the model.,In this study we revisit arguments about transmission and its sensitivity to mosquito bionomic parameters using an elasticity analysis of developed formulations of vectorial capacity.,We show that reducing adult survival has effects on both adult and juvenile population size, which are significant for transmission and not accounted for in traditional formulations of vectorial capacity.,The elasticity of these effects is dependent on various mosquito population parameters, which we explore.,Overall, control is most sensitive to methods that affect adult mosquito mortality rates, followed by blood feeding frequency, human blood feeding habit, and lastly, to adult mosquito population density.,These results emphasise more strongly than ever the sensitivity of transmission to adult mosquito mortality, but also suggest the high potential of combinations of interventions including larval source management.,This must be done with caution, however, as policy requires a more careful consideration of costs, operational difficulties and policy goals in relation to baseline transmission. | 1 |
The use of molecular techniques to detect malaria parasites has been advocated to improve the accuracy of parasite prevalence estimates, especially in moderate to low endemic settings.,Molecular work is time-consuming and costly, thus the effective gains of this technique need to be carefully evaluated.,Light microscopy (LM) and rapid diagnostic tests (RDT) are commonly used to detect malaria infection in resource constrained areas, but their limited sensitivity results in underestimation of the proportion of people infected with Plasmodium falciparum.,This study aimed to evaluate the extent of missed infections via a community survey in Tanzania, using polymerase chain reaction (PCR) to detect P. falciparum parasites and gametocytes.,Three hundred and thirty individuals of all ages from the Kilombero and Ulanga districts (Tanzania) were enrolled in a cross-sectional survey.,Finger prick blood samples were collected for parasite detection by RDT, LM and molecular diagnosis using quantitative 18S rRNA PCR and msp2 nPCR.,Gametocytes were detected by LM and by amplifying transcripts of the gametocyte-specific marker pfs25.,Results from all three diagnostic methods were available for a subset of 226 individuals.,Prevalence of P. falciparum was 38% (86/226; 95% CI 31.9-44.4%) by qPCR, 15.9% (36/226; 95% CI 11.1-20.7%) by RDT and 5.8% (13/226; 95% CI 2.69- 8.81%) by LM. qPCR was positive for 72% (26/36) of the RDT-positive samples.,Gametocyte prevalence was 10.6% (24/226) by pfs25-qRT-PCR and 1.2% by LM.,LM showed the poorest performance, detecting only 15% of P. falciparum parasite carriers identified by PCR.,Thus, LM is not a sufficiently accurate technique from which to inform policies and malaria control or elimination efforts.,The diagnostic performance of RDT was superior to that of LM.,However, it is also insufficient when precise prevalence data are needed for monitoring intervention success or for determining point prevalence rates in countrywide surveillance.,Detection of gametocytes by PCR was 10-times more sensitive than by LM.,These findings support the need for molecular techniques to accurately estimate the human infectious reservoir and hence the transmission potential in a population. | The heterogeneity of malaria transmission makes widespread elimination a difficult goal to achieve.,Most of the current vector control measures insufficiently target outdoor transmission.,Also, insecticide resistance threatens to diminish the efficacy of the most prevalent measures, indoor residual spray and insecticide treated nets.,Innovative approaches are needed.,The use of endectocides, such as ivermectin, could be an important new addition to the toolbox of anti-malarial measures.,Ivermectin effectively targets outdoor transmission, has a novel mechanism of action that could circumvent resistance and might be distributed over the channels already in place for the control of onchocerciasis and lymphatic filariasis.,The previous works involving ivermectin and Anopheles vectors are reviewed and summarized.,A review of ivermectin’s safety profile is also provided.,Finally three definitive clinical trials are described in detail and proposed as the evidence needed for implementation.,Several smaller and specific supportive studies are also proposed.,The use of ivermectin solves many challenges identified for future vector control strategies.,It is an effective and safe endectocide that was approved for human use more than 25 years ago.,Recent studies suggest it might become an effective and complementary strategy in malaria elimination and eradication efforts; however, intensive research will be needed to make this a reality. | 1 |
To calculate prevalence estimates and evaluate the quality of studies reporting Plasmodium falciparum lacking histidine-rich proteins 2 and 3, to inform an international response plan.,We searched five online databases, without language restriction, for articles reporting original data on Plasmodium falciparum-infected patients with deletions of the pfhrp2 and/or pfhrp3 genes (pfhrp2/3).,We calculated prevalence estimates of pfhrp2/3 deletions and mapped the data by country.,The denominator was all P. falciparum-positive samples testing positive by microscopy and confirmed positive by species-specific polymerase chain reaction testing (PCR).,If microscopy was not performed, we used the number of samples based on a different diagnostic method or PCR alone.,We scored studies for risk of bias and the quality of laboratory methods using a standardized scoring system.,A total of 38 articles reporting 55 studies from 32 countries and one territory worldwide were included in the review.,We found considerable heterogeneity in the populations studied, methods used and estimated prevalence of P. falciparum parasites with pfhrp2/3 deletions.,The derived prevalence of pfhrp2 deletions ranged from 0% to 100%, including focal areas in South America and Africa.,Only three studies (5%) fulfilled all seven criteria for study quality.,The lack of representative surveys or consistency in study design impairs evaluations of the risk of false-negative results in malaria diagnosis due to pfhrp2/3 deletions.,Accurate mapping and strengthened monitoring of the prevalence of pfhrp2/3 deletions is needed, along with harmonized methods that facilitate comparisons across studies. | Plasmodium falciparum and Plasmodium vivax, the two protozoan parasite species that cause the majority of cases of human malaria, have developed resistance to nearly all known antimalarials.,The ability of malaria parasites to develop resistance is primarily due to the high numbers of parasites in the infected person’s bloodstream during the asexual blood stage of infection in conjunction with the mutability of their genomes.,Identifying the genetic mutations that mediate antimalarial resistance has deepened our understanding of how the parasites evade our treatments and reveals molecular markers that can be used to track the emergence of resistance in clinical samples.,In this review, we examine known genetic mutations that lead to resistance to the major classes of antimalarial medications: the 4-aminoquinolines (chloroquine, amodiaquine and piperaquine), antifolate drugs, aryl amino-alcohols (quinine, lumefantrine and mefloquine), artemisinin compounds, antibiotics (clindamycin and doxycycline) and a napthoquinone (atovaquone).,We discuss how the evolution of antimalarial resistance informs strategies to design the next generation of antimalarial therapies. | 1 |
Plasmodium spp. and helminths are co-endemic in many parts of the tropics; hence, co-infection is a common phenomenon.,Interactions between Plasmodium and helminth infections may alter the host’s immune response and susceptibility and thus impact on morbidity.,There is little information on the direction and magnitude of such interactions and results are conflicting.,This study aimed at shedding new light on the potential interactions of Plasmodium and helminth co-infections on anemia and splenomegaly in different population groups in Côte d’Ivoire.,Parasitologic and clinical data were obtained from four cross-sectional community-based studies and a national school-based survey conducted between 2011 and 2013 in Côte d’Ivoire.,Six scenarios of co-infection pairs defined as Plasmodium infection or high parasitemia, combined with one of three common helminth infections (i.e., Schistosoma mansoni, S. haematobium, and hookworm) served for analysis.,Adjusted logistic regression models were built for each scenario and interaction measures on additive scale calculated according to Rothman et al., while an interaction term in the model served as multiplicative scale measure.,All identified significant interactions were of antagonistic nature but varied in magnitude and species combination.,In study participants aged 5-18 years from community-based studies, Plasmodium-hookworm co-infection showed an antagonistic interaction on additive scale on splenomegaly, while Plasmodium-Schistosoma co-infection scenarios showed protective effects on multiplicative scale for anemia and splenomegaly in participants aged 5-16 years from a school-based study.,No exacerbation from co-infection with Plasmodium and helminths was observed, neither in participants aged 5-18 years nor in adults from the community-based studies.,Future studies should unravel underlying mechanisms of the observed interactions, as this knowledge might help shaping control efforts against these diseases of poverty. | This study described altered platelet indices in patients with acute malaria caused by Plasmodium vivax and determined whether these alterations are associated with warning signs of severe and complicated malaria.,A total of 186 patients attending the Malaria Clinic at the University Hospital from the Federal University of Mato Grosso, Brazil, between 2008 and 2013 were included in this study.,After parasitological confirmation of exclusive infection by P. vivax, blood cell counts and platelet indices were determined.,Disease gravity was evaluated on the basis of classic signs of Plasmodium falciparum severe malaria, including severe anemia, or by changes in serum levels of glucose, bilirubin, aminotransferases and creatinine at the time of the patient’s admission.,Patients with a longer duration of symptoms or those identified as primo infected were considered potential candidates for evolution into the severe form of malaria.,The mean platelet volume (MPV), platelet distribution width (PDW), and plateletcrit (PCT) values exhibited significant variability.,A significant inverse relationship was observed between parasitaemia and PCT.,Patients with warning signs for evolution into severe disease, with primo infection, or presenting with symptoms for over three days had the highest MPV and PDW.,The adjusted analyses showed the presence of warning signs for the development of severe and complicated malaria remained independently linked to elevated MPV and PDW.,Altered platelet indices should be analysed as potential markers for the severity of malaria caused by P. vivax.,Future studies with appropriate methodology for prognostic evaluation could confirm the potential use of these indices in clinical practice. | 1 |
Background: Prompt and effective case detection and treatment are vital components of the malaria case management strategy as malaria-endemic countries implement the testing, treating and tracking policy.,The implementation of this policy in public and formal private sectors continue to receive great attention while the informal private retail sector (mostly the patent and propriety medicine vendors [PPMVs]) where about 60% of patients with fever in Nigeria seek treatment is yet to be fully integrated.,The PPMVs sell artemisinin combination therapies (ACTs) without prior testing and are highly patronized.,Without prior testing, malaria is likely to be over-treated.,The need to expand access to diagnosis in the huge informal private health sector among PPMVs is currently being explored to ensure that clients that patronize retail drug stores are tested before sales of ACTs.,Methods: A cross-sectional multistage study was conducted among 1279 adult clients, 20 years and above, who purchased malaria medicines from 119 selected PPMVs in five administrative areas (States) of Nigeria, namely: Adamawa, Cross River, Enugu, Lagos and Kaduna, as well as the Federal Capital Territory, Abuja.,Exit interviews using a standard case report questionnaire was conducted after the purchase of the antimalarial medicine and thick/thin blood smears from the clients’ finger-prick were prepared to confirm malaria by expert microscopy.,Results: Of the 1279 clients who purchased malaria medicines from the PPMV outlets, 107 (8.4%) were confirmed to have malaria parasites.,The malaria prevalence in the various study areas ranged from 3.5% to 16%.,A high proportion of clients in the various study sites who had no need for malaria medicines (84%-96.5%) purchased and used antimalarial medicines from the PPMVs.,This indicated a high level of over-treatment and misuse of antimalarials.,Common symptoms that are widely used as indicators for malaria such as, fever, headache, and tiredness were not significantly associated with malaria.,Nausea/vomiting, poor appetite, chills, bitter taste in the mouth and dark urine were symptoms that were significantly associated with malaria among the adult clients (P<.05) but not fever (P=.06).,Conclusion: Misuse of ACTs following overtreatment of malaria based on clinical diagnosis occurs when suspected cases of malaria are not prior confirmed with a test.,Non-testing before sales of malaria medicines by PPMVs will perpetuate ACT misuse with the patients not benefiting due to poor treatment outcomes, waste of medicines and financial loss from out-of-pocket payment for unneeded medicines. | In malaria elimination settings, all malaria cases must be identified, documented and investigated.,To facilitate complete and timely reporting of all malaria cases and effective case management and follow-up, engagement with private providers is essential, particularly in settings where the private sector is a major source of healthcare.,However, research on the role and performance of the private sector in malaria diagnosis, case management and reporting in malaria elimination settings is limited.,Moreover, the most effective strategies for private sector engagement in malaria elimination settings remain unclear.,Twenty-five experts in malaria elimination, disease surveillance and private sector engagement were purposively sampled and interviewed.,An extensive review of grey and peer-reviewed literature on private sector testing, treatment, and reporting for malaria was performed.,Additional in-depth literature review was conducted for six case studies on eliminating and neighbouring countries in Southeast Asia and Southern Africa.,The private health sector can be categorized based on their commercial orientation or business model (for-profit versus nonprofit) and their regulation status within a country (formal vs informal).,A number of potentially effective strategies exist for engaging the private sector.,Conducting a baseline assessment of the private sector is critical to understanding its composition, size, geographical distribution and quality of services provided.,Facilitating reporting, referral and training linkages between the public and private sectors and making malaria a notifiable disease are important strategies to improve private sector involvement in malaria surveillance.,Financial incentives for uptake of rapid diagnostic tests and artemisinin-based combination therapy should be combined with training and community awareness campaigns for improving uptake.,Private sector providers can also be organized and better engaged through social franchising, effective regulation, professional organizations and government outreach.,This review highlights the importance of engaging private sector stakeholders early and often in the development of malaria elimination strategies.,The online version of this article (doi:10.1186/s12936-017-1901-1) contains supplementary material, which is available to authorized users. | 1 |
American cutaneous leishmaniasis (ACL) is a vector-transmitted infectious disease with an estimated 1.5 million new cases per year.,In Brazil, ACL represents a significant public health problem, with approximately 30,000 new reported cases annually, representing an incidence of 18.5 cases per 100,000 inhabitants.,Corte de Pedra is in a region endemic for ACL in the state of Bahia (BA), northeastern Brazil, with 500-1,300 patients treated annually.,Over the last decade, population and family-based candidate gene studies were conducted in Corte de Pedra, founded on previous knowledge from studies on mice and humans.,Notwithstanding limitations related to sample size and power, these studies contribute important genetic biomarkers that identify novel pathways of disease pathogenesis and possible new therapeutic targets.,The present paper is a narrative review about ACL immunogenetics in BA, highlighting in particular the interacting roles of the wound healing gene FLI1 with interleukin-6 and genes SMAD2 and SMAD3 of the transforming growth factor beta signalling pathway.,This research highlights the need for well-powered genetic and functional studies on Leishmania braziliensis infection as essential to define and validate the role of host genes in determining resistance/susceptibility regarding this disease. | Leishmania donovani causes visceral leishmaniasis (VL) where the parasite infects and resides inside liver and spleen tissue macrophages.,Given the abnormal lipid profile observed in VL patients, we examined the status of serum lipids in an experimental murine model of VL.,The murine VL liver displayed altered expression of lipid metabolic genes, many of which are direct or indirect targets of the liver-specific microRNA-122.,Concomitant reduction of miR-122 expression was observed in VL liver.,High serum cholesterol caused resistance to L. donovani infection, while downregulation of miR-122 is coupled with low serum cholesterol in VL mice.,Exosomes secreted by the infective parasites caused reduction in miR-122 activity in hepatic cells.,Leishmania surface glycoprotein gp63, a Zn-metalloprotease, targets pre-miRNA processor Dicer1 to prevent miRNP formation in L. donovani-interacting hepatic cells.,Conversely, restoration of miR-122 or Dicer1 levels in VL mouse liver increased serum cholesterol and reduced liver parasite burden.,► Leishmania infection reduces liver miR-122 and lowers serum cholesterol ► Leishmania metalloprotease gp63 is required for inhibition of hepatic miR-122 activity ► gp63 cleaves DICER1 to downregulate miRNP-122 formation in hepatocytes ► Restoration of miR-122 elevates serum cholesterol to reduce liver parasite load | 1 |
Deciphering the dynamics and evolution of insecticide resistance in malaria vectors is crucial for successful vector control.,This study reports an increase of resistance intensity and a rise of multiple insecticide resistance in Anopheles funestus in Malawi leading to reduced bed net efficacy.,Anopheles funestus group mosquitoes were collected in southern Malawi and the species composition, Plasmodium infection rate, susceptibility to insecticides and molecular bases of the resistance were analysed.,Mosquito collection revealed a predominance of An. funestus group mosquitoes with a high hybrid rate (12.2 %) suggesting extensive species hybridization.,An. funestus sensu stricto was the main Plasmodium vector (4.8 % infection).,Consistently high levels of resistance to pyrethroid and carbamate insecticides were recorded and had increased between 2009 and 2014.,Furthermore, the 2014 collection exhibited multiple insecticide resistance, notably to DDT, contrary to 2009.,Increased pyrethroid resistance correlates with reduced efficacy of bed nets (<5 % mortality by Olyset® net), which can compromise control efforts.,This change in resistance dynamics is mirrored by prevalent resistance mechanisms, firstly with increased over-expression of key pyrethroid resistance genes (CYP6Pa/b and CYP6M7) in 2014 and secondly, detection of the A296S-RDL dieldrin resistance mutation for the first time.,However, the L119F-GSTe2 and kdr mutations were absent.,Such increased resistance levels and rise of multiple resistance highlight the need to rapidly implement resistance management strategies to preserve the effectiveness of existing insecticide-based control interventions.,The online version of this article (doi:10.1186/s12936-015-0877-y) contains supplementary material, which is available to authorized users. | The efficacy of amodiaquine (AQ), sulphadoxine-pyrimethamine (SP) and the combination of SP+AQ in the treatment of Cameroonian children with clinical malaria was investigated.,The prevalence of molecular markers for resistance to these drugs was studied to set the baseline for surveillance of their evolution with time.,Seven hundred and sixty children aged 6-59 months with uncomplicated falciparum malaria were studied in three ecologically different regions of Cameroon - Mutengene (littoral equatorial forest), Yaoundé (forest-savannah mosaic) and Garoua (guinea-savannah).,Study children were randomized to receive either AQ, SP or the combination AQ+SP.,Clinical outcome was classified according to WHO criteria, as either early treatment failure (ETF), late clinical failure (LCF), late parasitological failure (LPF) or adequate clinical and parasitological response (ACPR).,The occurrence of mutations in pfcrt, pfmdr1, dhfr and dhps genes was studied by either RFLP or dot blot techniques and the prevalence of these mutations related to parasitological and therapeutic failures.,After correction for the occurrence of re-infection by PCR, ACPRs on day 28 for AQ, SP and AQ+SP were 71.2%, 70.1% and 80.9%, in Garoua, 79.2%, 62.5%, and 81.9% in Mutengene, and 80.3%, 67.5% and 76.2% in Yaoundé respectively.,High levels of Pfcrt 76T (87.11%) and Pfmdr1 86Y mutations (73.83%) were associated with quinoline resistance in the south compared to the north, 31.67% (76T) and 22.08% (86Y).,There was a significant variation (p < 0.001) of the prevalence of the SGK haplotype between Garoua in the north (8.33%), Yaoundé (36.29%) in the savannah-forest mosaic and Mutengene (66.41%) in the South of Cameroon and a weak relation between SGK haplotype and SP failure.,The 540E mutation on the dhps gene was extremely rare (0.3%) and occurred only in Mutengene while the pfmdr1 1034K and 1040D mutations were not detected in any of the three sites.,In this study the prevalence of molecular markers for quinoline and anti-folate resistances showed high levels and differed between the south and north of Cameroon.,AQ, SP and AQ+SP treatments were well tolerated but with low levels of efficacy that suggested alternative treatments were needed in Cameroon since 2005. | 1 |
Host-directed therapy (HDT) is gaining traction as a strategy to combat infectious diseases caused by viruses and intracellular bacteria, but its implementation in the context of parasitic diseases has received less attention.,Here, we provide a brief overview of this field and advocate HDT as a promising strategy for antimalarial intervention based on untapped targets.,HDT provides a basis from which repurposed drugs could be rapidly deployed and is likely to strongly limit the emergence of resistance.,This strategy can be applied to any intracellular pathogen and is particularly well placed in situations in which rapid identification of treatments is needed, such as emerging infections and pandemics, as starkly illustrated by the current COVID-19 crisis.,Drug resistance threatens to reverse progress achieved in malaria control.,Host-directed therapy (HDT) provides a barrier to drug resistance: since the target is not under the genetic control of the parasite, resistance-conferring mutations in the target cannot be selected under treatment.,Wei et al. review opportunities for HDT in the fight against malaria. | The study of antigenic targets of naturally-acquired immunity is essential to identify and prioritize antigens for further functional characterization.,We measured total IgG antibodies to 38 P. vivax antigens, investigating their relationship with prospective risk of malaria in a cohort of 1-3 years old Papua New Guinean children.,Using simulated annealing algorithms, the potential protective efficacy of antibodies to multiple antigen-combinations, and the antibody thresholds associated with protection were investigated for the first time.,High antibody levels to multiple known and newly identified proteins were strongly associated with protection (IRR 0.44-0.74, p<0.001-0.041).,Among five-antigen combinations with the strongest protective effect (>90%), EBP, DBPII, RBP1a, CyRPA, and PVX_081550 were most frequently identified; several of them requiring very low antibody levels to show a protective association.,These data identify individual antigens that should be prioritized for further functional testing and establish a clear path to testing a multicomponent P. vivax vaccine. | 1 |
Artemether-lumefantrine (AL) is the recommended first-line artemisinin-based combination therapy (ACT) for the treatment of uncomplicated falciparum malaria in most of the malaria-endemic countries, including Tanzania.,Recently, dihydroartemisinin-piperaquine (DP) has been recommended as the alternative anti-malarial to ensure effective case management in Tanzania.,This study assessed the parasite clearance rate and efficacy of AL and DP among patients aged 6 months to 10 years with uncomplicated falciparum malaria in two sites with different malaria transmission intensity.,This was an open-label, randomized trial that was conducted at two sites of Muheza Designated District Hospital and Ujiji Health Centre in Tanga and Kigoma regions, respectively.,Patients meeting inclusion criteria were enrolled, treated with either AL or DP and followed up for 28 (extended to 42) and 42 (63) days for AL and DP, respectively.,Parasite clearance time was monitored in the first 72 h post treatment and the clearance rate constant and half-life were calculated using an established parasite clearance estimator.,The primary outcome was parasitological cure on days 28 and 42 for AL and DP, respectively, while secondary outcome was extended parasitological cure on days 42 and 63 for AL and DP, respectively.,Of the 509 children enrolled (192 at Muheza and 317 at Ujiji), there was no early treatment failure and PCR uncorrected cure rates on day 28 in the AL group were 77.2 and 71.2% at Muheza and Ujiji, respectively.,In the DP arm, the PCR uncorrected cure rate on day 42 was 73.6% at Muheza and 72.5% at Ujiji.,With extended follow-up (to day 42 for AL and 63 for DP) cure rates were lower at Ujiji compared to Muheza (AL: 60.2 and 46.1%, p = 0.063; DP: 57.6 and 40.3% in Muheza and Ujiji, respectively, p = 0.021).,The PCR corrected cure rate ranged from 94.6 to 100% for all the treatment groups at both sites.,Parasite clearance rate constant was similar in the two groups and at both sites (< 0.28/h); the slope half-life was < 3.0 h and all but only one patient cleared parasites by 72 h.,These findings confirm high efficacy of the first- and the newly recommended alternative ACT for treatments for uncomplicated falciparum malaria in Tanzania.,The high parasite clearance rate suggests absence of suspected artemisinin resistance, defined as delayed parasite clearance.,Trial registration This trial is registered at ClinicalTrials.gov under registration number NCT02590627 | A regular evaluation of therapeutic efficacy in sentinel sites and a system of surveillance are required to establish treatment guidelines and adapt national anti-malarial drug policy to the rapidly changing epidemiology of drug-resistant malaria.,The current anti-malarial treatment guideline in Mauritania, officially recommended since 2006, is based on artemisinin-based combination therapy.,The aim of the present study was to evaluate clinical efficacy and tolerance of artesunate-amodiaquine, the first-line treatment for acute uncomplicated malaria, in Mauritanian paediatric and adult patients to validate its continued use in the country.,Plasmodium falciparum-infected symptomatic patients aged > six months were enrolled in Kobeni and Timbedra in southern Mauritania in September to October 2013.,Co-formulated artesunate-amodiaquine was administered at the recommended dose over three days.,Patients were followed until day 28.,Parasitological and clinical response was classified according to the standard 2009 World Health Organization protocol.,A total of 130 patients (65 in Kobeni and 65 in Timbedra) were enrolled in the study.,Seventeen patients (13.1%) were either excluded (before PCR correction) or lost to follow-up.,Based on the per protocol analysis, artesunate-amodiaquine efficacy (i.e., the proportion of adequate clinical and parasitological response) was 96.6% in Kobeni and 98.2% in Timbedra before PCR correction.,Late clinical failure was observed in two patients in Kobeni and one patient in Timbedra.,After PCR correction, the efficacy rate in the two study sites was 98.2%.,On day 3, all patients were afebrile and had negative smears.,Treatment was well tolerated.,Artesunate-amodiaquine is well tolerated and highly efficacious for the treatment of uncomplicated P. falciparum malaria.,In the majority of patients, fever and parasitaemia were rapidly cleared before day 3.,The results support the national anti-malarial drug guideline for a continued use of artesunate-amodiaquine as a first-line drug for uncomplicated malaria in southern Mauritania. | 1 |
2015 was the target year for malaria goals set by the World Health Assembly and other international institutions to reduce malaria incidence and mortality.,A review of progress indicates that malaria programme financing and coverage have been transformed since the beginning of the millennium, and have contributed to substantial reductions in the burden of disease.,Investments in malaria programmes increased by more than 2.5 times between 2005 and 2014 from US$ 960 million to US$ 2.5 billion, allowing an expansion in malaria prevention, diagnostic testing and treatment programmes.,In 2015 more than half of the population of sub-Saharan Africa slept under insecticide-treated mosquito nets, compared to just 2 % in 2000.,Increased availability of rapid diagnostic tests and antimalarial medicines has allowed many more people to access timely and appropriate treatment.,Malaria incidence rates have decreased by 37 % globally and mortality rates by 60 % since 2000.,It is estimated that 70 % of the reductions in numbers of cases in sub-Saharan Africa can be attributed to malaria interventions.,Reductions in malaria incidence and mortality rates have been made in every WHO region and almost every country.,However, decreases in malaria case incidence and mortality rates were slowest in countries that had the largest numbers of malaria cases and deaths in 2000; reductions in incidence need to be greatly accelerated in these countries to achieve future malaria targets.,Progress is made challenging because malaria is concentrated in countries and areas with the least resourced health systems and the least ability to pay for system improvements.,Malaria interventions are nevertheless highly cost-effective and have not only led to significant reductions in the incidence of the disease but are estimated to have saved about US$ 900 million in malaria case management costs to public providers in sub-Saharan Africa between 2000 and 2014.,Investments in malaria programmes can not only reduce malaria morbidity and mortality, thereby contributing to the health targets of the Sustainable Development Goals, but they can also transform the well-being and livelihood of some of the poorest communities across the globe.,The online version of this article (doi:10.1186/s40249-016-0151-8) contains supplementary material, which is available to authorized users. | The influence of host genetics on susceptibility to Plasmodium falciparum malaria has been extensively studied over the past twenty years.,It is now clear that malaria parasites have imposed strong selective forces on the human genome in endemic regions.,Different genes have been identified that are associated with different malaria related phenotypes.,Factors that promote severity of malaria include parasitaemia, parasite induced inflammation, anaemia and sequestration of parasitized erythrocytes in brain microvasculature.,Recent advances in human genome research technologies such as genome-wide association studies (GWAS) and fine genotyping tools have enabled the discovery of several genetic polymorphisms and biomarkers that warrant further study in host-parasite interactions.,This review describes and discusses human gene polymorphisms identified thus far that have been shown to be associated with susceptibility or resistance to P. falciparum malaria.,Although some polymorphisms play significant roles in susceptibility to malaria, several findings are inconclusive and contradictory and must be considered with caution.,The discovery of genetic markers associated with different malaria phenotypes will help elucidate the pathophysiology of malaria and enable development of interventions or cures.,Diversity in human populations as well as environmental effects can influence the clinical heterogeneity of malaria, thus warranting further investigations with a goal of developing new interventions, therapies and better management against malaria. | 1 |
Primaquine is the only licensed drug for eradicating Plasmodium vivax hypnozoites and, therefore, preventing relapses of vivax malaria.,It is a vital component of global malaria elimination efforts.,Primaquine is efficacious when supervised in clinical trials, but its effectiveness in real-world settings is unknown.,We aimed to determine whether unsupervised primaquine was effective for preventing re-presentation to hospital with vivax malaria in southern Papua, Indonesia.,Routinely-collected hospital surveillance data were used to undertake a pragmatic comparison of the risk of re-presentation to hospital with vivax malaria in patients prescribed dihydroartemisinin-piperaquine (DHP) combined with primaquine versus those patients prescribed DHP alone.,The omission of primaquine was predominantly due to 3 stock outages.,Individual clinical, pharmacy, and laboratory data were merged using individual hospital identification numbers and the date of presentation to hospital.,Between April 2004 and December 2013, there were 86,797 documented episodes of vivax malaria, of which 62,492 (72.0%) were included in the analysis.,The risk of re-presentation with vivax malaria within 1 year was 33.8% (95% confidence Interval [CI] 33.1%-34.5%) after initial monoinfection with P. vivax and 29.2% (95% CI 28.1%-30.4%) after mixed-species infection.,The risk of re-presentation with P. vivax malaria was higher in children 1 to <5 years of age (49.6% [95% CI 48.4%-50.9%]) compared to patients 15 years of age or older (24.2% [95% CI 23.4-24.9%]); Adjusted Hazard Ratio (AHR) = 2.23 (95% CI 2.15-2.31), p < 0.001.,Overall, the risk of re-presentation was 37.2% (95% CI 35.6%-38.8%) in patients who were prescribed no primaquine compared to 31.6% (95% CI 30.9%-32.3%) in those prescribed either a low (≥1.5 mg/kg and <5 mg/kg) or high (≥5 mg/kg) dose of primaquine (AHR = 0.90 [95% CI 0.86-0.95, p < 0.001]).,Limiting the comparison to high dose versus no primaquine in the period during and 12 months before and after a large stock outage resulted in minimal change in the estimated clinical effectiveness of primaquine (AHR 0.91, 95% CI 0.85-0.97, p = 0.003).,Our pragmatic study avoided the clinical influences associated with prospective study involvement but was subject to attrition bias caused by passive follow-up.,Unsupervised primaquine for vivax malaria, prescribed according to the current World Health Organization guidelines, was associated with a minimal reduction in the risk of clinical recurrence within 1 year in Papua, Indonesia.,New strategies for the effective radical cure of vivax malaria are needed in resource-poor settings.,In a pragmatic hospital-based cohort study, Ric Price and colleagues compared risk of re-presentation with vivax malaria in patients prescribed dihydroartemisinin-piperaquine combined with primaquine versus patients who could not be given primaquine due to stock outages. | Primaquine has been the only widely available hypnozoitocidal anti-malarial drug for half a century.,Despite this its clinical efficacy is poorly characterized resulting in a lack of consensus over the optimal regimen for the radical cure of Plasmodium vivax.,Published studies since 1950 of the use of primaquine regimens for preventing P. vivax relapse were reviewed.,Data were extracted systematically from available papers.,Primaquine regimens were categorized according to the total dose administered: very low (≤2.5 mg/kg), low (>2.5 mg/kg- < 5.0 mg/kg) and high (≥ 5.0 mg/kg).,The risk of recurrent infection were summarized across geographical regions and the odds ratios between treatment regimens calculated after stratifying by total treatment dose and duration of study follow up.,Data could be retrieved from 87 clinical trials presenting data in 59,735 patients enrolled into 156 treatment arms, conducted in 20 countries.,There was marked heterogeneity in study design, particularly primaquine dosing and duration of follow up.,The median rate of recurrence following very low dose of primaquine (n = 44) was 25% (range 0-90%) at 4-6 months, compared to 6.7 % (range 0-59%) following low dose primaquine (n = 82).,High dose primaquine regimens were assessed in 28 treatment arms, and were associated with a median recurrence rate of 0% (Range: 0-15%) at one month.,In 18 studies with control arms, the effectiveness of a very low dose primaquine regimen was no different from patients who did not receive primaquine (OR = 0.60, 95%CI 0.33-1.09, p = 0.09), whereas for the low dose regimens a significant difference was reported in 50% (6/12) of studies (overall OR = 0.14, 95%CI: 0.06-0.35, p < 0.001).,Two studies enrolling 171 patients demonstrated high effectiveness of high dose primaquine compared to a control arm (OR = 0.03 (95%CI: 0.01-0.13); p < 0.0001).,Low dose regimens retain adequate efficacy in some areas, but this is not uniform.,The efficacy and safety of pragmatic high dose primaquine regimens needs to be assessed in a range of endemic and geographical locations.,Such studies will require a prolonged period of follow up and comparison with control arms to account for confounding factors. | 1 |
A multidrug-resistant co-lineage of Plasmodium falciparum malaria, named KEL1/PLA1, spread across Cambodia in 2008-13, causing high rates of treatment failure with the frontline combination therapy dihydroartemisinin-piperaquine.,Here, we report on the evolution and spread of KEL1/PLA1 in subsequent years.,For this genomic epidemiology study, we analysed whole genome sequencing data from P falciparum clinical samples collected from patients with malaria between 2007 and 2018 from Cambodia, Laos, northeastern Thailand, and Vietnam, through the MalariaGEN P falciparum Community Project.,Previously unpublished samples were provided by two large-scale multisite projects: the Tracking Artemisinin Resistance Collaboration II (TRAC2) and the Genetic Reconnaissance in the Greater Mekong Subregion (GenRe-Mekong) project.,By investigating genome-wide relatedness between parasites, we inferred patterns of shared ancestry in the KEL1/PLA1 population.,We analysed 1673 whole genome sequences that passed quality filters, and determined KEL1/PLA1 status in 1615.,Before 2009, KEL1/PLA1 was only found in western Cambodia; by 2016-17 its prevalence had risen to higher than 50% in all of the surveyed countries except for Laos.,In northeastern Thailand and Vietnam, KEL1/PLA1 exceeded 80% of the most recent P falciparum parasites.,KEL1/PLA1 parasites maintained high genetic relatedness and low diversity, reflecting a recent common origin.,Several subgroups of highly related parasites have recently emerged within this co-lineage, with diverse geographical distributions.,The three largest of these subgroups (n=84, n=79, and n=47) mostly emerged since 2016 and were all present in Cambodia, Laos, and Vietnam.,These expanding subgroups carried new mutations in the crt gene, which arose on a specific genetic background comprising multiple genomic regions.,Four newly emerging crt mutations were rare in the early period and became more prevalent by 2016-17 (Thr93Ser, rising to 19·8%; His97Tyr to 11·2%; Phe145Ile to 5·5%; and Ile218Phe to 11·1%).,After emerging and circulating for several years within Cambodia, the P falciparum KEL1/PLA1 co-lineage diversified into multiple subgroups and acquired new genetic features, including novel crt mutations.,These subgroups have rapidly spread into neighbouring countries, suggesting enhanced fitness.,These findings highlight the urgent need for elimination of this increasingly drug-resistant parasite co-lineage, and the importance of genetic surveillance in accelerating malaria elimination efforts.,Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and UK Department for International Development. | Plasmodium falciparum in western Cambodia has developed resistance to artemisinin and its partner drugs, causing frequent treatment failure.,Understanding this evolution can inform the deployment of new therapies.,We investigated the genetic architecture of 78 falciparum isolates using whole-genome sequencing, correlating results to in vivo and ex vivo drug resistance and exploring the relationship between population structure, demographic history, and partner drug resistance.,Principle component analysis, network analysis and demographic inference identified a diverse central population with three clusters of clonally expanding parasite populations, each associated with specific K13 artemisinin resistance alleles and partner drug resistance profiles which were consistent with the sequential deployment of artemisinin combination therapies in the region.,One cluster displayed ex vivo piperaquine resistance and mefloquine sensitivity with a high rate of in vivo failure of dihydroartemisinin-piperaquine.,Another cluster displayed ex vivo mefloquine resistance and piperaquine sensitivity with high in vivo efficacy of dihydroartemisinin-piperaquine.,The final cluster was clonal and displayed intermediate sensitivity to both drugs.,Variations in recently described piperaquine resistance markers did not explain the difference in mean IC90 or clinical failures between the high and intermediate piperaquine resistance groups, suggesting additional loci may be involved in resistance.,The results highlight an important role for partner drug resistance in shaping the P. falciparum genetic landscape in Southeast Asia and suggest that further work is needed to evaluate for other mutations that drive piperaquine resistance. | 1 |
Artemisinin-based combination therapy has been first-line treatment for falciparum malaria in Myanmar since 2005.,The wide extent of artemisinin resistance in the Greater Mekong sub-region and the presence of mefloquine resistance at the Myanmar-Thailand border raise concerns over resistance patterns in Myanmar.,The availability of molecular markers for resistance to both drugs enables assessment even in remote malaria-endemic areas.,A total of 250 dried blood spot samples collected from patients with Plasmodium falciparum malarial infection in five malaria-endemic areas across Myanmar were analysed for kelch 13 sequence (k13) and pfmdr1 copy number variation.,K13 mutations in the region corresponding to amino acids 210-726 (including the propeller region of the protein) were detected by nested PCR amplification and sequencing, and pfmdr1 copy number variation by real-time PCR.,In two sites, a sub-set of patients were prospectively followed up for assessment of day-3 parasite clearance rates after a standard course of artemether-lumefantrine.,K13 mutations and pfmdr1 amplification were successfully analysed in 206 and 218 samples, respectively.,Sixty-nine isolates (33.5 %) had mutations within the k13 propeller region with 53 of these (76.8 %) having mutations already known to be associated with artemisinin resistance.,F446I (32 isolates) and P574L (15 isolates) were the most common examples.,K13 mutation was less common in sites in western border regions (29 of 155 isolates) compared to samples from the east and north (40 of 51 isolates; p < 0.0001).,The overall proportion of parasites with multiple pfmdr1 copies (greater than 1.5) was 5.5 %.,Seven samples showed both k13 mutation and multiple copies of pfmdr1.,Only one of 36 patients followed up after artemether-lumefantrine treatment still had parasites at day 3; molecular analysis indicated wild-type k13 and single copy pfmdr1.,The proportion of P. falciparum isolates with mutations in the propeller region of k13 indicates that artemisinin resistance extends across much of Myanmar.,There is a low prevalence of parasites with multiple pfmdr1 copies across the country.,The efficacy of artemisinin-based combination therapy containing mefloquine and lumefantrine is, therefore, expected to be high, although regular monitoring of efficacy will be important.,The online version of this article (doi:10.1186/s12936-016-1147-3) contains supplementary material, which is available to authorized users. | Severe malaria is a major cause of childhood death and often the main reason for paediatric hospital admission in sub-Saharan Africa.,Quinine is still the established treatment of choice, although evidence from Asia suggests that artesunate is associated with a lower mortality.,We compared parenteral treatment with either artesunate or quinine in African children with severe malaria.,This open-label, randomised trial was undertaken in 11 centres in nine African countries.,Children (<15 years) with severe falciparum malaria were randomly assigned to parenteral artesunate or parenteral quinine.,Randomisation was in blocks of 20, with study numbers corresponding to treatment allocations kept inside opaque sealed paper envelopes.,The trial was open label at each site, and none of the investigators or trialists, apart from for the trial statistician, had access to the summaries of treatment allocations.,The primary outcome measure was in-hospital mortality, analysed by intention to treat.,This trial is registered, number ISRCTN50258054.,5425 children were enrolled; 2712 were assigned to artesunate and 2713 to quinine.,All patients were analysed for the primary outcome. 230 (8·5%) patients assigned to artesunate treatment died compared with 297 (10·9%) assigned to quinine treatment (odds ratio [OR] stratified for study site 0·75, 95% CI 0·63-0·90; relative reduction 22·5%, 95% CI 8·1-36·9; p=0·0022).,Incidence of neurological sequelae did not differ significantly between groups, but the development of coma (65/1832 [3·5%] with artesunate vs 91/1768 [5·1%] with quinine; OR 0·69 95% CI 0·49-0·95; p=0·0231), convulsions (224/2712 [8·3%] vs 273/2713 [10·1%]; OR 0·80, 0·66-0·97; p=0·0199), and deterioration of the coma score (166/2712 [6·1%] vs 208/2713 [7·7%]; OR 0·78, 0·64-0·97; p=0·0245) were all significantly less frequent in artesunate recipients than in quinine recipients.,Post-treatment hypoglycaemia was also less frequent in patients assigned to artesunate than in those assigned to quinine (48/2712 [1·8%] vs 75/2713 [2·8%]; OR 0·63, 0·43-0·91; p=0·0134).,Artesunate was well tolerated, with no serious drug-related adverse effects.,Artesunate substantially reduces mortality in African children with severe malaria.,These data, together with a meta-analysis of all trials comparing artesunate and quinine, strongly suggest that parenteral artesunate should replace quinine as the treatment of choice for severe falciparum malaria worldwide.,The Wellcome Trust. | 1 |
Following the observed increase of malaria prevalence among older children in Gabon, a descriptive observational study was carried out in 2012 to determine the prevalence of malaria in adults presenting with fever in two health centres of Libreville, the capital city of Gabon.,Thick- and thin-blood smears for malaria diagnosis were performed in febrile individuals aged more than 15 years old.,Age, use of bed nets, previous antimalarial drug treatment, clinical symptoms, chest radiography results, and available haemoglobin data were also recorded.,Among the 304 patients screened, the global malaria frequency was of 42.1% (n = 128/34).,Plasmodium (P). falciparum was the only species identified.,The proportion of patients with a clinical malaria requiring parenteral treatment was 38.5%, whereas 47.5% of outpatients had uncomplicated malaria.,According to WHO classification, 14 (19.7%) infected patients had severe malaria; neurological and respiratory symptoms tended to be more frequent in case of P. falciparum infection.,Anaemia was found in 51.5% adults and none had severe anaemia.,Almost half of adults consulting for fever in two health centres of the urban city of Libreville have malaria.,The use of insecticide-treated bed nets, the screening, and the treatment of individuals with P. falciparum microscopic and submicroscopic asymptomatic infection or clinical malaria should be emphasized to reduce the transmission. | In Gabon, vector transmission has been poorly studied.,Since the implementation of the Roll Back malaria recommendations, clinical studies have shown a decline in the burden of malaria in Libreville, the capital city of Gabon.,To better understand the transmission dynamic in Libreville, an entomological survey was conducted in five districts of the city.,Mosquitoes were sampled by human landing collection during 1 year in five districts of Libreville: Alibandeng, Beauséjour, Camp des Boys and Sotega.,Mosquitoes were identified morphologically and by molecular methods.,The Plasmodium falciparum circumsporozoïte indices were measured by ELISA, and the entomological inoculation rates (EIR) were calculated for all areas.,Molecular assessments of pyrethroid knock down resistance (kdr) and of insensitive acetylcholinesterase resistance were conducted.,A total of 57,531 mosquitoes were caught during 341 person-nights (161 person-nights indoor and 180 person-nights outdoor) among which, 4,223 were Anopheles gambiae s.l.,The average Human Biting Rate fell from 15.5 bites per person during the rainy season to 4.7 during the dry season.,The An. gambiae complex population was composed of An. gambiae s.s molecular form S (99.5%), Anopheles melas (0.3%) and An. gambiae s.s. form M (0.2%).,Thirty-three out of 4,223 An. gambiae s.l. were found to be infected by P. falciparum (CSP index = 0.78%).,The annual EIR was estimated at 33.9 infected bites per person per year ranging from 13 in Alibandeng to 88 in Sotega.,No insensitive AChE mutation was identified but both kdr-w and kdr-e mutations were present in An. gambiae molecular form S with a higher frequency of the kdr-w allele (76%) than the kdr-e allele (23.5%).,Malaria transmission in Libreville occurred mainly during the rainy season but also during the dry season in the five districts.,Transmission level is high and seems to be very heterogeneous in the town.,Interestingly, the highest EIR was recorded in the most central and urbanized quarter and the lowest in a peripheral area.,The decrease of transmission usually seen from peri-urban areas to urban centers is probably more dependent of the socio-economic level of a quarter than of its location in the city.,Urban malaria control programmes need to consider the socio economic level of an area rather than the location in the city in order to determine the areas most favourable to malaria transmission. | 1 |
Two recombinant Fasciola hepatica antigens, saposin-like protein-2 (recSAP2) and cathepsin L-1 (recCL1), were assessed individually and in combination in enzyme-linked immunosorbent assays (ELISA) for the specific serodiagnosis of human fasciolosis in areas of low endemicity as encountered in Central Europe.,Antibody detection was conducted using ProteinA/ProteinG (PAG) conjugated to alkaline phosphatase.,Test characteristics as well as agreement with results from an ELISA using excretory-secretory products (FhES) from adult stage liver flukes was assessed by receiver operator characteristic (ROC) analysis, specificity, sensitivity, Youdens J and overall accuracy.,Cross-reactivity was assessed using three different groups of serum samples from healthy individuals (n = 20), patients with other parasitic infections (n = 87) and patients with malignancies (n = 121).,The best combined diagnostic results for recombinant antigens were obtained using the recSAP2-ELISA (87% sensitivity, 99% specificity and 97% overall accuracy) employing the threshold (cut-off) to discriminate between positive and negative reactions that maximized Youdens J.,The findings showed that recSAP2-ELISA can be used for the routine serodiagnosis of chronic fasciolosis in clinical laboratories; the use of the PAG-conjugate offers the opportunity to employ, for example, rabbit hyperimmune serum for the standardization of positive controls. | The liver fluke Fasciola hepatica is a parasite of ruminants with a worldwide distribution and an apparent increasing incidence in EU member states.,Effective control in dairy cattle is hampered by the lack of flukicides with a zero-withdrawal time for milk, leaving the dry period as the only time that preventive treatment can be applied.,Here, we present the results of a blinded, randomized and placebo-controlled trial on 11 dairy herds (402 animals) exposed to F. hepatica to 1) assess the effect of closantel treatment at dry-off (or 80-42 days before calving in first-calving heifers) on milk production parameters and 2) evaluate if a number of easy-to-use animal parameters is related to the milk production response after treatment.,Closantel treatment resulted in a noticeable decrease of anti-F. hepatica antibody levels from 3-6 months after treatment onwards, a higher peak production (1.06 kg) and a slightly higher persistence (9%) of the lactation, resulting in a 305-day milk production increase of 303 kg.,No effects of anthelmintic treatment were found on the average protein and fat content of the milk.,Milk production responses after treatment were poor in meagre animals and clinically relevant higher milk production responses were observed in first-lactation animals and in cows with a high (0.3-0.5 optical density ratio (ODR)), but not a very high (≥0.5 ODR) F. hepatica ELISA result on a milk sample from the previous lactation.,We conclude that in dairy herds exposed to F. hepatica, flukicide treatment at dry-off is a useful strategy to reduce levels of exposure and increase milk production in the subsequent lactation.,Moreover, the results suggest that treatment approaches that only target selected animals within a herd can be developed based on easy-to-use parameters. | 1 |
The emergence of artemisinin resistance in the Greater Mekong Subregion (GMS) has prompted urgent containment measures.,One possible approach is mass drug administration (MDA).,This article explores attitudes towards and perceptions of MDA for malaria elimination among policymakers and leading malariologists.,Thirty-two semistructured interviews (SSI) were conducted with policymakers (n=17) and principal investigators (n=15) selected based on their involvement in malaria prevention, control and elimination in the GMS.,Interviews were audio recorded and transcribed for qualitative content (thematic) analysis using NVivo (QSR International, Doncaster, Victoria, Australia).,Researchers and policymakers described reluctance and consequently delays to pilot MDA for malaria elimination.,Most policymakers and some researchers reported concerns around the evidence base, citing a lack of data on its effectiveness and appropriate target populations.,There were also worries about promoting resistance.,Other issues included a previous lack of support from the World Health Organization, past MDAs, the remoteness of target populations and challenges explaining the rationale for MDA.,The complex rationale for MDA for malaria elimination, mistaking pilot studies for implementation, past experiences with MDA, difficulties in selecting appropriate sites and the WHO’s lack of clear backing undermined the support for MDA for malaria elimination. | Community engagement and participation has played a critical role in successful disease control and elimination campaigns in many countries.,Despite this, its benefits for malaria control and elimination are yet to be fully realized.,This may be due to a limited understanding of the influences on participation in developing countries as well as inadequate investment in infrastructure and resources to support sustainable community participation.,This paper reports the findings of an atypical systematic review of 60 years of literature in order to arrive at a more comprehensive awareness of the constructs of participation for communicable disease control and elimination and provide guidance for the current malaria elimination campaign.,Evidence derived from quantitative research was considered both independently and collectively with qualitative research papers and case reports.,All papers included in the review were systematically coded using a pre-determined qualitative coding matrix that identified influences on community participation at the individual, household, community and government/civil society levels.,Colour coding was also carried out to reflect the key primary health care period in which community participation programmes originated.,These processes allowed exhaustive content analysis and synthesis of data in an attempt to realize conceptual development beyond that able to be achieved by individual empirical studies or case reports.,Of the 60 papers meeting the selection criteria, only four studies attempted to determine the effect of community participation on disease transmission.,Due to inherent differences in their design, interventions and outcome measures, results could not be compared.,However, these studies showed statistically significant reductions in disease incidence or prevalence using various forms of community participation.,The use of locally selected volunteers provided with adequate training, supervision and resources are common and important elements of the success of the interventions in these studies.,In addition, qualitative synthesis of all 60 papers elucidates the complex architecture of community participation for communicable disease control and elimination which is presented herein.,The current global malaria elimination campaign calls for a health systems strengthening approach to provide an enabling environment for programmes in developing countries.,In order to realize the benefits of this approach it is vital to provide adequate investment in the 'people' component of health systems and understand the multi-level factors that influence their participation.,The challenges of strengthening this component of health systems are discussed, as is the importance of ensuring that current global malaria elimination efforts do not derail renewed momentum towards the comprehensive primary health care approach.,It is recommended that the application of the results of this systematic review be considered for other diseases of poverty in order to harmonize efforts at building 'competent communities' for communicable disease control and optimising health system effectiveness. | 1 |
The high level of functional diversity and plasticity in monocytes/macrophages has been defined within in vitro systems as M1 (classically activated), M2 (alternatively activated) and deactivated macrophages, of which the latter two subtypes are associated with suppression of cell mediated immunity, that confers susceptibility to intracellular infection.,Although the Leishmania parasite modulates macrophage functions to ensure its survival, what remains an unanswered yet pertinent question is whether these macrophages are deactivated or alternatively activated.,This study aimed to characterize the functional plasticity and polarization of monocytes/macrophages and delineate their importance in the immunopathogenesis of Post kala-azar dermal leishmaniasis (PKDL), a chronic dermatosis of human leishmaniasis.,Monocytes from PKDL patients showed a decreased expression of TLR-2/4, along with an attenuated generation of reactive oxidative/nitrosative species.,At disease presentation, an increased mRNA expression of classical M2 markers CD206, ARG1 and PPARG in monocytes and lesional macrophages indicated M2 polarization of macrophages which was corroborated by increased expression of CD206 and arginase-1.,Furthermore, altered vitamin D signaling was a key feature in PKDL, as disease presentation was associated with raised plasma levels of monohydroxylated vitamin D3 and vitamin D3- associated genes, features of M2 polarization.,Taken together, in PKDL, monocyte/macrophage subsets appear to be alternatively activated, a phenotype that might sustain disease chronicity.,Importantly, repolarization of these monocytes to M1 by antileishmanial drugs suggests that switching from M2 to M1 phenotype might represent a therapeutic opportunity, worthy of future pharmacological consideration. | One of the major challenges for management of visceral leishmaniasis (VL) is early diagnosis of cases to improve treatment outcome and reduce transmission.,We have therefore investigated active case detection of VL with the help of accredited social health activists (ASHA).,ASHAs are women who live in the community and receive performance-based incentives for overseeing maternal and other health-related issues in their village.,Through conducting interviews with 400 randomly selected ASHAs from four primary health care centers (PHCs), it was observed that their level of knowledge about visceral leishmaniasis (VL) regarding transmission, diagnosis, and treatment was limited.,The baseline data indicated that less than 10% of VL cases seeking treatment at the PHCs were referred by ASHAs.,To increase the knowledge and the referral rate of VL cases by ASHAs, training sessions were carried out during the monthly ASHA meetings at their respective PHCs.,Following a single training session, the referral rate increased from less than 10% to over 27% and the overall knowledge about VL substantially improved.,It was not possible, however, to demonstrate that ASHA training reduced the time that individuals had fever before treatment at the PHC.,Training ASHAs to identify VL cases in villages for early diagnosis and treatment at the local PHC is feasible and should be undertaken routinely to improve knowledge about VL. | 1 |
We report xenodiagnosis results for 47 post-kala-azar dermal leishmaniasis (PKDL) and 15 visceral leishmaniasis (VL) patients.,Skin parasite load was strongly associated with positive xenodiagnosis.,Compared to VL (66.7%), nodular PKDL was more likely (86%) and macular PKDL less likely (35%) to result in positive xenodiagnosis.,On the Indian subcontinent, visceral leishmaniasis (VL) incidence is on track to reach elimination goals by 2020 in nearly all endemic districts.,Although not included in official targets, previous data suggest post-kala-azar dermal leishmaniasis (PKDL) patients can act as an infection reservoir.,We conducted xenodiagnosis on 47 PKDL patients and 15 VL patients using laboratory-reared Phlebotomus argentipes.,In direct xenodiagnosis, flies were allowed to feed on the patient’s skin for 15 minutes.,For indirect xenodiagnosis, flies were fed through a membrane on the patient’s blood.,Five days later, blood-fed flies were dissected and examined by microscopy and/or polymerase chain reaction (PCR).,A 3-mm skin snip biopsy (PKDL) or venous blood (VL) was processed by quantitative PCR.,Twenty-seven PKDL patients (57.4%) had positive results by direct and/or indirect xenodiagnosis.,Direct was significantly more sensitive than indirect xenodiagnosis (55.3% vs 6.4%, P < .0001).,Those with positive xenodiagnosis had median skin parasite loads >1 log10 unit higher than those with negative results (2.88 vs 1.66, P < .0001).,In a multivariable model, parasite load, nodular lesions, and positive skin microscopy were significantly associated with positive xenodiagnosis.,Blood parasite load was the strongest predictor for VL.,Compared to VL, nodular PKDL was more likely and macular PKDL less likely to result in positive xenodiagnosis, but neither difference reached statistical significance.,Nodular and macular PKDL, and VL, can be infectious to sand flies.,Active PKDL case detection and prompt treatment should be instituted and maintained as an integral part of VL control and elimination programs. | Visceral leishmaniasis has been targeted for elimination as a public health problem (less than 1 case per 10,000 people per year) in the Indian sub-continent by 2017.,However, there is still a high degree of uncertainty about the natural history of the disease, in particular about the duration of asymptomatic infection and the proportion of asymptomatically infected individuals that develop clinical visceral leishmaniasis.,Quantifying these aspects of the disease is key for guiding efforts to eliminate visceral leishmaniasis and maintaining elimination once it is reached.,Data from a detailed epidemiological study in Bangladesh in 2002-2004 was analysed to estimate key epidemiological parameters.,The role of diagnostics in determining the probability and rate of progression to clinical disease was estimated by fitting Cox proportional hazards models.,A multi-state Markov model of the natural history of visceral leishmaniasis was fitted to the data to estimate the asymptomatic infection period and the proportion of asymptomatic individuals going on to develop clinical symptoms.,At the time of the study, individuals were taking several months to be diagnosed with visceral leishmaniasis, leading to many opportunities for ongoing transmission.,The probability of progression to clinical disease was strongly associated with initial seropositivity and even more strongly with seroconversion, with most clinical symptoms developing within a year.,The estimated average durations of asymptomatic infection and symptomatic infection for our model of the natural history are 147 days (95 % CI 130-166) and 140 days (95 % CI 123-160), respectively, and are significantly longer than previously reported estimates.,We estimate from the data that 14.7 % (95 % CI 12.6-20.0 %) of asymptomatic individuals develop clinical symptoms-a greater proportion than previously estimated.,Extended periods of asymptomatic infection could be important for visceral leishmaniasis transmission, but this depends critically on the relative infectivity of asymptomatic and symptomatic individuals to sandflies.,These estimates could be informed by similar analysis of other datasets.,Our results highlight the importance of reducing times from onset of symptoms to diagnosis and treatment to reduce opportunities for transmission.,The online version of this article (doi:10.1186/s13071-015-1136-3) contains supplementary material, which is available to authorized users. | 1 |
The ability of mosquitoes to evade fatal exposure to insecticidal nets and sprays represents the primary obstacle to eliminating malaria.,However, it remains unclear which behaviours are most important for buffering mosquito and parasite populations against vector control.,Simulated life histories were used to compare the impact of alternative feeding behaviour strategies upon overall lifetime feeding success, and upon temporal distributions of successful feeds and biting rates experienced by unprotected humans, in the presence and absence of insecticidal nets.,Strictly nocturnal preferred feeding times were contrasted with 1) a wider preference window extending to dawn and dusk, and 2) crepuscular preferences wherein foraging is suppressed when humans sleep and can use nets but is maximal immediately before and after.,Simulations with diversion and mortality parameters typical of endophagic, endophilic African vectors, such as Anopheles gambiae and Anopheles funestus, were compared with those for endophagic but exophilic species, such as Anopheles arabiensis, that also enter houses but leave earlier before lethal exposure to insecticide-treated surfaces occurs.,Insecticidal nets were predicted to redistribute successful feeding events to dawn and dusk where these were included in the profile of innately preferred feeding times.,However, predicted distributions of biting unprotected humans were unaffected because extended host-seeking activity was redistributed to innately preferred feeding times.,Recently observed alterations of biting activity distributions therefore reflect processes not captured in this model, such as evolutionary selection of heritably modified feeding time preferences or phenotypically plastic expression of feeding time preference caused by associative learning.,Surprisingly, endophagy combined with exophily, among mosquitoes that enter houses but then feed and/or rest briefly before rapidly exiting, consistently attenuated predicted insecticide impact more than any feeding time preference trait.,Regardless of underlying cause, recent redistributions of host-biting activity to dawn and dusk necessitate new outdoor control strategies.,However, persistently indoor-feeding vectors, that evade intradomiciliary insecticide exposure, are at least equally important.,Fortunately, recent evaluations of occupied houses or odour-baited stations, with baffled entrances that retain An. arabiensis within insecticide-treated structures, illustrate how endophagic but exophilic vectors may be more effectively tackled using existing insecticides. | Mosquitoes, which evade contact with long-lasting insecticidal nets and indoor residual sprays, by feeding outdoors or upon animals, are primary malaria vectors in many tropical countries.,They can also dominate residual transmission where high coverage of these front-line vector control measures is achieved.,Complementary strategies, which extend insecticide coverage beyond houses and humans, are required to eliminate malaria transmission in most settings.,The overwhelming diversity of the world's malaria transmission systems and optimal strategies for controlling them can be simply conceptualized and mapped across two-dimensional scenario space defined by the proportion of blood meals that vectors obtain from humans and the proportion of human exposure to them which occurs indoors. | 1 |
China has made remarkable progress in reducing schistosomiasis caused by Schistosoma japonicum over the past 7 decades but now faces a severe threat from imported schistosomiasis.,Results from national surveillance during 2010-2018 indicate integrating active surveillance into current surveillance models for imported cases is urgently needed to achieve schistosomiasis elimination in China. | In Brazil, Biomphalaria glabrata, B. tenagophila, and B. straminea are naturally infected by the trematode Schistosoma mansoni, the causative agent of schistosomiasis.,Despite decades of governmental efforts through official control programs, schistosomiasis remains an important public health problem in the country: thousands of people are infected with the trematode each year and millions live in endemic areas.,The World Health Organization recommends using a combination of molluscicide (niclosamide) and mass chemotherapy to control the transmission of schistosomiasis, with this treatment successfully reducing the morbidity of the disease.,In the past, niclosamide has been used in official schistosomiasis control programs in Brazil.,However, as B. glabrata recolonizes even after molluscicide application, the use of molluscicides has gradually decreased in the country until they were discontinued in 2002, mainly due to the rising global pressure to preserve the environment and the difficulties of obtaining licenses from the Brazilian Ministry of Environment to use toxic substances in aquatic ecosystems.,Therefore, the discovery of new molluscicides, which could be more selective to Biomphalaria species and less harmful to the aquatic ecosystem, is necessary.,In addition, political efforts to sensitize funders to provide grants for this field of research are required.,In this context, this article aims to make a critical analysis of molluscicide application in schistosomiasis control programs in Brazil.,The online version of this article (doi:10.1186/s40249-016-0153-6) contains supplementary material, which is available to authorized users. | 1 |
All symptoms of malaria disease are associated with the asexual blood stages of development, involving cycles of red blood cell (RBC) invasion and egress by the Plasmodium spp. merozoite.,Merozoite invasion is rapid and is actively powered by a parasite actomyosin motor.,The current accepted model for actomyosin force generation envisages arrays of parasite myosins, pushing against short actin filaments connected to the external milieu that drive the merozoite forwards into the RBC.,In Plasmodium falciparum, the most virulent human malaria species, Myosin A (PfMyoA) is critical for parasite replication.,However, the precise function of PfMyoA in invasion, its regulation, the role of other myosins and overall energetics of invasion remain unclear.,Here, we developed a conditional mutagenesis strategy combined with live video microscopy to probe PfMyoA function and that of the auxiliary motor PfMyoB in invasion.,By imaging conditional mutants with increasing defects in force production, based on disruption to a key PfMyoA phospho-regulation site, the absence of the PfMyoA essential light chain, or complete motor absence, we define three distinct stages of incomplete RBC invasion.,These three defects reveal three energetic barriers to successful entry: RBC deformation (pre-entry), mid-invasion initiation, and completion of internalisation, each requiring an active parasite motor.,In defining distinct energetic barriers to invasion, these data illuminate the mechanical challenges faced in this remarkable process of protozoan parasitism, highlighting distinct myosin functions and identifying potential targets for preventing malaria pathogenesis. | Malaria infection starts with injection of Plasmodium sporozoites by an Anopheles mosquito into the skin of the mammalian host.,How sporozoites locate and enter a blood vessel is a critical, but poorly understood process.,In this study, we examine sporozoite motility and their interaction with dermal blood vessels, using intravital microscopy in mice.,Our data suggest that sporozoites exhibit two types of motility: in regions far from blood vessels, they exhibit ‘avascular motility’, defined by high speed and less confinement, while in the vicinity of blood vessels their motility is more constrained.,We find that curvature of sporozoite tracks engaging with vasculature optimizes contact with dermal capillaries.,Imaging of sporozoites with mutations in key adhesive proteins highlight the importance of the sporozoite's gliding speed and its ability to modulate adhesive properties for successful exit from the inoculation site.,DOI:http://dx.doi.org/10.7554/eLife.07789.001,Malaria remains a devastating disease in many parts of the world.,Malaria parasites enter the host via the skin, where they are deposited by infected mosquitoes as they look for blood.,The parasites must exit the skin to reach the liver, where they multiply and ultimately infect red blood cells, where they cause the symptoms of the disease.,In the skin, the parasites must move to find blood vessels that they enter to travel via the blood circulation to the liver.,Only about 10-20% of parasites make it out of the skin, making this a bottleneck for the parasite.,Scientists have been working to develop vaccines that would protect people against malaria.,One way these could work would be to stop malaria parasites from leaving the skin and entering the blood vessels.,But to do that, more needs to be learnt about how the parasites move in the skin and enter the blood vessels.,Hopp et al., using a mouse model of malaria, created malaria parasites that produce a fluorescent protein that allows the parasites to be tracked after they have been injected into the skin of a mouse's ear.,This revealed that the parasites have two ways of moving.,After first being injected, the parasites move quickly and freely.,The parasites slow down when they come close to a blood vessel and move on or around the vessel for some time before entering it.,During this stage of movement, the parasites tend to move in paths that follow the curvature of the blood vessels, which may improve how well they make contact with the blood vessel surface and may enable them to find the areas of the vessels best suited for entry.,Next, Hopp et al. investigated how two parasite mutants move through mouse skin.,Both mutants had previously been found to be less likely than wild-type parasites to exit the inoculation site.,Hopp et al. found that one of the mutants moves slowly after being injected and so explores a smaller tissue volume than normal and encounters fewer blood vessels.,The second mutant parasite spends more time than normal moving on the surface of the blood vessels, but finds it difficult to enter them.,Continuing this work will allow us to learn more about the interactions between the parasite and the blood vessels, which in turn could reveal key events that could be targeted by a vaccine.,Furthermore, the significant amount of time that the parasites spend moving and looking for blood vessels in the skin could be a good time to target them with antibodies and prevent malaria infection.,DOI:http://dx.doi.org/10.7554/eLife.07789.002 | 1 |
Schistosoma haematobium causes urogenital schistosomiasis and is widely distributed in Tanzania.,In girls and women, the parasite can cause Female Genital Schistosomiasis (FGS), a gynecological manifestation of schistosomiasis that is highly neglected and overlooked by public health professionals and policy makers.,This study explored community members’ knowledge, attitudes and perceptions (KAP) on and health seeking behavior for FGS.,Using qualitative research methods-including 40 Focus Group Discussions (FGDs) and 37 Key Informant Interviews (KIIs)-we collected data from 414 participants (Males n = 204 [49.3%] and Females n = 210 [50.7%]).,The study engaged 153 participants from Zanzibar and 261 participants from northwestern Tanzania and was conducted in twelve (12) purposively selected districts (7 districts in Zanzibar and 5 districts in northwestern Tanzania).,Most participants were aware of urogenital schistosomiasis.,Children were reported as the most affected group and blood in urine was noted as a common symptom especially in boys.,Adults were also noted as a risk group due to their involvement in activities like paddy farming that expose them to infection.,Most participants lacked knowledge of FGS and acknowledged having no knowledge that urogenital schistosomiasis can affect the female reproductive system.,A number of misconceptions on the symptoms of FGS and how it is transmitted were noted.,Adolescent girls and women presenting with FGS related symptoms were reported to be stigmatized, perceived as having a sexually transmitted infection (STI), and sometimes labeled as “prostitutes”.,Health seeking behavior for FGS included a combination of traditional medicine, self-treatment and modern medicine.,Community members living in two very different areas of Tanzania exhibited major, similar gaps in knowledge about FGS.,Our data illustrate a critical need for the national control program to integrate public health education about FGS during the implementation of school- and community-based mass drug administration (MDA) programs and the improvement of water, sanitation and hygiene (WASH) facilities. | The World Health Organization (WHO) calls for schistosomiasis endemic countries to integrate schistosomiasis control measures into the primary health care (PHC) services; however, in Tanzania, little is known about the capacity of the primary health care system to assume this role.,The objective of this study was to assess the capacity of the primary health care system to diagnose and treat schistosomiasis in endemic regions of north-western Tanzania.,A total of 80 randomly-selected primary health care facilities located in the Uyui, Geita and Ukerewe districts of North-western Tanzania participated in the study.,At each facility, the in-charge clinician, or any other healthcare worker appointed by the in-charge clinician, participated in the questionnaire survey.,A quantitative questionnaire installed in a Data Tool Kit software was used to collect data.,Healthcare workers working at various stations (laboratory, pharmacy, data clerks, outpatient section) were interviewed.,The questionnaire collected information related to healthcare workers’ knowledge about urogenital and intestinal schistosomiasis symptoms, human and material resources, laboratory services, data capture, and anti-schistosomiasis treatment availability.,A total of 80 healthcare workers were interviewed.,Bloody stool (78.3 %) and haematuria (98.7 %) were the most common symptoms of intestinal and urogenital schistosomiasis mentioned by healthcare workers.,Knowledge on the chronic symptoms such as hepatosplenomegaly and hematemesis for intestinal schistosomiasis, and oliguria and dysuria for urogenital schistosomiasis, were inadequate.,Laboratory services were only available in 33.8 % (27/80) of the health facilities and direct wet preparation was the most common diagnostic technique used for both urine and stool samples.,All healthcare workers knew that praziquantel was the drug of choice for the treatment of schistosomiasis and the drug was available in 91.3 % (73/80) of the health facilities.,The capacity of the primary health care facilities included in the current study is inadequate in terms of diagnosis, treatment, reporting and healthcare workers’ knowledge of schistosomiasis.,Thus, the integration of schistosomiasis control activities into the primary healthcare system requires these gaps to be addressed.,The online version contains supplementary material available at 10.1186/s12913-021-06531-z. | 1 |
Falciparum malaria persists in hard-to-reach areas or demographic groups that are missed by conventional healthcare systems but could be reached by trained community members in a malaria post (MP).,The main focus of a MP is to provide uninterrupted and rapid access to rapid diagnostic tests (RDTs) and artemisinin-based combination therapy (ACT) too all inhabitants of a village.,RDTs allow trained community members to perform malaria diagnosis accurately and prescribe appropriate treatment, reducing as much as possible any delay between the onset of fever and treatment.,Early treatment with ACT and with a low-dose of primaquine prevents further transmission from human to mosquito.,A functioning MP represents an essential component of any malaria elimination strategy.,Implementing large-scale, high-coverage, community-based early diagnosis and treatment through MPs requires few technological innovations but relies on a very well structured organization able to train, supervise and supply MPs, to monitor activity and to perform strict malaria surveillance.,The online version of this article (doi:10.1186/s12936-016-1399-y) contains supplementary material, which is available to authorized users. | Remarkable progress has been made towards the elimination of malaria in China since the National Malaria Elimination Programme (NMEP) was launched in 2010.,The incidence of locally-acquired malaria cases has declined rapidly and endemic areas have also dramatically shrunk.,In total, 3 078 malaria cases were reported in 2014, but only 56 cases were indigenous.,In order to further promote the elimination programme, we reviewed the progress of and experiences associated with malaria elimination in China, and identified the challenges and priorities for the next stage of the programme.,Data were collected from the web-based China Information System for Disease Control and Prevention, and the China Annual Report of Malaria Elimination.,The progress towards the elimination of malaria from 2010 to 2014 was measured.,During the implementation of the NMEP from 2010 to 2014, local malaria incidence has declined continuously, only remaining in the Yunnan Province and Tibet Autonomous Region in 2014.,By the end of 2015, 75.6 % (1 636/2 163) of the malaria-endemic counties passed the sub-national elimination assessment.,The main challenges are cases of border malaria and imported malaria from other countries.,Sustainable support and investment from the government, the establishment of an effective surveillance and response system, and risk assessments for the potential reintroduction of malaria are priorities for the next stage of the elimination programme.,The NMEP in China has been successfully implemented thus far and the malaria map has shrunk dramatically.,The priorities for malaria elimination are interventions to block transmission at border areas, management of imported malaria cases, preventing malaria reintroduction, capacity building, and sustainability of malaria surveillance and response.,The online version of this article (doi:10.1186/s40249-016-0146-5) contains supplementary material, which is available to authorized users. | 1 |
Preventive measures and treatment guidelines are needed to address the sizeable prevalence of disease in this population.,The prevalence and consequences of malaria among infants are not well characterized and may be underestimated.,A better understanding of the risk for malaria in early infancy is critical for drug development and informed decision making.,In a cross-sectional survey in Guinea, The Gambia, and Benin, countries with different malaria transmission intensities, the overall prevalence of malaria among infants <6 months of age was 11.8% (Guinea, 21.7%; The Gambia, 3.7%; and Benin, 10.2%).,Seroprevalence ranged from 5.7% in The Gambia to 41.6% in Guinea.,Mean parasite densities in infants were significantly lower than those in children 1-9 years of age in The Gambia (p<0.0001) and Benin (p = 0.0021).,Malaria in infants was significantly associated with fever or recent history of fever (p = 0.007) and anemia (p = 0.001).,Targeted preventive interventions, adequate drug formulations, and treatment guidelines are needed to address the sizeable prevalence of malaria among young infants in malaria-endemic countries. | Malaria transmission is spatially heterogeneous.,This reduces the efficacy of control strategies, but focusing control strategies on clusters or ‘hotspots’ of transmission may be highly effective.,Among 1500 homesteads in coastal Kenya we calculated (a) the fraction of febrile children with positive malaria smears per homestead, and (b) the mean age of children with malaria per homestead.,These two measures were inversely correlated, indicating that children in homesteads at higher transmission acquire immunity more rapidly.,This inverse correlation increased gradually with increasing spatial scale of analysis, and hotspots of febrile malaria were identified at every scale.,We found hotspots within hotspots, down to the level of an individual homestead.,Febrile malaria hotspots were temporally unstable, but 4 km radius hotspots could be targeted for 1 month following 1 month periods of surveillance.,DOI:http://dx.doi.org/10.7554/eLife.02130.001,Malaria remains a formidable threat to public health in tropical regions.,The parasite that causes the disease is transmitted to humans by bites from infected mosquitoes, and the complicated lifecycle of the parasite makes developing vaccines difficult.,However, preventive strategies are effective at reducing the spread of malaria.,The two most widely used and effective strategies are the use of pesticide-treated bed nets to create a barrier between sleeping families and biting mosquitoes, and indoor residual spraying to reduce the numbers of mosquitoes biting sleeping families in homesteads.,Other potential preventive strategies include killing mosquito larvae in breeding sites and mass anti-malarial drug treatment for infected humans.,Targeting preventive efforts to malaria hotspots-the areas where the risk of malaria transmission is greatest-may help to eliminate malaria more efficiently.,Unfortunately, identifying hotspots is complicated as there are many different factors that affect how malaria spreads.,These factors range from ecological conditions such as rainfall and soil type, to human effects like population density and migration.,Bejon et al. have examined the patterns of malaria transmission in Kenya over 9 years.,Over this period, 54% of children who went to health clinics with a fever tested positive for the parasite that causes malaria.,Infected children from areas with the highest rate of malaria infection were, on average, younger than those from less infected regions.,This makes sense as in highly affected areas children have a greater chance of encountering the parasite at an early age.,They are therefore more likely to get malaria when younger and, as exposure to the parasite can provide some immunity to a child, they are also less likely to get infected again when older.,In addition, mapping the spread of malaria reveals hotspots at different geographical scales.,Bejon et al. could see hotspots within hotspots, and in some cases could go as far as identifying the individual homesteads most at risk of malaria.,Public health workers could potentially use these analyses to identify areas that are likely to be hotspots and then target preventive measures there for the next month.,However, the constantly changing locations of the hotspots means workers would have to reanalyse the data and retarget their interventions at the end of each month.,DOI:http://dx.doi.org/10.7554/eLife.02130.002 | 1 |
Defining mechanisms by which Plasmodium virulence is regulated is central to understanding the pathogenesis of human malaria.,Serial blood passage of Plasmodium through rodents1-3, primates4 or humans5 increases parasite virulence, suggesting that vector transmission regulates Plasmodium virulence within the mammalian host.,In agreement, disease severity can be modified by vector transmission6-8, which is assumed to ‘reset’ Plasmodium to its original character3.,However, direct evidence that vector transmission regulates Plasmodium virulence is lacking.,Here we utilise mosquito transmission of serially blood passaged (SBP) Plasmodium chabaudi chabaudi9 to interrogate regulation of parasite virulence.,Analysis of SBP P.c. chabaudi before and after mosquito transmission demonstrates that vector transmission intrinsically modifies the asexual blood-stage parasite, which in turn, modifies the elicited mammalian immune response, which in turn, attenuates parasite growth and associated pathology.,Attenuated parasite virulence associates with modified expression of the pir multi-gene family.,Vector transmission of Plasmodium therefore regulates gene expression of probable variant antigens in the erythrocytic cycle, modifies the elicited mammalian immune response, and thus regulates parasite virulence.,These results place the mosquito at the centre of our efforts to dissect mechanisms of protective immunity to malaria for the development of an effective vaccine. | Malaria infections containing multiple parasite genotypes are ubiquitous in nature, and play a central role in models of recombination, intra-host dynamics, virulence, sex ratio, immunity and drug resistance evolution in Plasmodium.,While these multiple infections (MIs) are often assumed to result from superinfection (bites from multiple infected mosquitoes), we know remarkably little about their composition or generation.,We isolated 336 parasite clones from eight patients from Malawi (high transmission) and six from Thailand (low transmission) by dilution cloning.,These were genotyped using 384 single-nucleotide polymorphisms, revealing 22 independent haplotypes in Malawi (2-6 per MI) and 15 in Thailand (2-5 per MI).,Surprisingly, all six patients from Thailand and six of eight from Malawi contained related haplotypes, and haplotypes were more similar within- than between-infections.,These results argue against a simple superinfection model.,Instead, the observed kinship patterns may be explained by inoculation of multiple related haploid sporozoites from single mosquito bites, by immune suppression of parasite subpopulations within infections, and serial transmission of related parasites between people.,That relatedness is maintained in endemic areas in the face of repeated bites from infected mosquitoes has profound implications for understanding malaria transmission, immunity and intra-host dynamics of co-infecting parasite genotypes. | 1 |
The ECUAVIDA birth cohort is studying the impact of exposures to soil-transmitted helminth (STH) parasites and early-life microbial exposures on the development of atopy, allergic diseases and immune responses in childhood.,A total of 2404 newborns were recruited between 2006 and 2009 in a public hospital serving the rural district of Quininde, Esmeraldas Province, in a tropical region of coastal Ecuador.,Detailed measurements were done around the time of the birth, at 7 and 13 months and at 2 and 3 years, and data collection is ongoing at 5 and 8 years.,Data being collected include questionnaires for: sociodemographic, lifestyle, psychosocial (at 4-6 years only) and dietary (at 6-7 years only) factors; childhood morbidity and clinical outcomes; stool samples for parasites; blood samples for DNA, measurements of vaccine responses and other measures of immune function/inflammation; and anthropometrics.,Allergen skin prick test reactivity is done from 2 years and measures of airway function and inflammation at 8 years. | Soil-transmitted helminths (STH) infect more than 2 billion humans worldwide, causing significant morbidity in children.,There are few data on the epidemiology and risk factors for infection in pre-school children.,To investigate risk factors for infection in early childhood, we analysed data prospectively collected in the ECUAVIDA birth cohort in Ecuador.,Children were recruited at birth and followed up to 3 years of age with periodic collection of stool samples that were examined microscopically for STH parasites.,Data on social, demographic, and environmental risk factors were collected from the mother at time of enrolment.,Associations between exposures and detection of STH infections were analysed by multivariable logistic regression.,Data were analysed from 1,697 children for whom a stool sample was obtained at 3 years.,42.3% had at least one STH infection in the first 3 years of life and the most common infections were caused by A. lumbricoides (33.2% of children) and T. trichiura (21.2%).,Hookworm infection was detected in 0.9% of children.,Risk of STH infection was associated with factors indicative of poverty in our study population such as Afro-Ecuadorian ethnicity and low maternal educational level.,Maternal STH infections during pregnancy were strong risk factors for any childhood STH infection, infections with either A. lumbricoides or T. trichiura, and early age of first STH infection.,Children of mothers with moderate to high infections intensities with A. lumbricoides were most at risk.,Our data show high rates of infection with STH parasites during the first 3 years of life in an Ecuadorian birth cohort, an observation that was strongly associated with maternal STH infections during pregnancy.,The targeted treatment of women of childbearing age, in particular before pregnancy, with anthelmintic drugs could offer a novel approach to the prevention of STH infections in pre-school children. | 1 |
Malaria continues to place a disease burden on millions of people throughout the tropics, especially in sub-Saharan Africa.,Although efforts to control mosquito populations and reduce human-vector contact, such as long-lasting insecticidal nets and indoor residual spraying, have led to significant decreases in malaria incidence, further progress is now threatened by the widespread development of physiological and behavioural insecticide-resistance as well as changes in the composition of vector populations.,A mosquito-directed push-pull system based on the simultaneous use of attractive and repellent volatiles offers a complementary tool to existing vector-control methods.,In this study, the combination of a trap baited with a five-compound attractant and a strip of net-fabric impregnated with micro-encapsulated repellent and placed in the eaves of houses, was tested in a malaria-endemic village in western Kenya.,Using the repellent delta-undecalactone, mosquito house entry was reduced by more than 50%, while the traps caught high numbers of outdoor flying mosquitoes.,Model simulations predict that, assuming area-wide coverage, the addition of such a push-pull system to existing prevention efforts will result in up to 20-fold reductions in the entomological inoculation rate.,Reductions of such magnitude are also predicted when mosquitoes exhibit a high resistance against insecticides.,We conclude that a push-pull system based on non-toxic volatiles provides an important addition to existing strategies for malaria prevention. | As successful malaria control programmes re-orientate towards elimination, the identification of transmission foci, targeting of attack measures to high-risk areas and management of importation risk become high priorities.,When resources are limited and transmission is varying seasonally, approaches that can rapidly prioritize areas for surveillance and control can be valuable, and the most appropriate attack measure for a particular location is likely to differ depending on whether it exports or imports malaria infections.,Here, using the example of Namibia, a method for targeting of interventions using surveillance data, satellite imagery, and mobile phone call records to support elimination planning is described.,One year of aggregated movement patterns for over a million people across Namibia are analyzed, and linked with case-based risk maps built on satellite imagery.,By combining case-data and movement, the way human population movements connect transmission risk areas is demonstrated.,Communities that were strongly connected by relatively higher levels of movement were then identified, and net export and import of travellers and infection risks by region were quantified.,These maps can aid the design of targeted interventions to maximally reduce the number of cases exported to other regions while employing appropriate interventions to manage risk in places that import them.,The approaches presented can be rapidly updated and used to identify where active surveillance for both local and imported cases should be increased, which regions would benefit from coordinating efforts, and how spatially progressive elimination plans can be designed.,With improvements in surveillance systems linked to improved diagnosis of malaria, detailed satellite imagery being readily available and mobile phone usage data continually being collected by network providers, the potential exists to make operational use of such valuable, complimentary and contemporary datasets on an ongoing basis in infectious disease control and elimination. | 1 |
Identification of genomic regions that are identical by descent (IBD) has proven useful for human genetic studies where analyses have led to the discovery of familial relatedness and fine-mapping of disease critical regions.,Unfortunately however, IBD analyses have been underutilized in analysis of other organisms, including human pathogens.,This is in part due to the lack of statistical methodologies for non-diploid genomes in addition to the added complexity of multiclonal infections.,As such, we have developed an IBD methodology, called isoRelate, for analysis of haploid recombining microorganisms in the presence of multiclonal infections.,Using the inferred IBD status at genomic locations, we have also developed a novel statistic for identifying loci under positive selection and propose relatedness networks as a means of exploring shared haplotypes within populations.,We evaluate the performance of our methodologies for detecting IBD and selection, including comparisons with existing tools, then perform an exploratory analysis of whole genome sequencing data from a global Plasmodium falciparum dataset of more than 2500 genomes.,This analysis identifies Southeast Asia as having many highly related isolates, possibly as a result of both reduced transmission from intensified control efforts and population bottlenecks following the emergence of antimalarial drug resistance.,Many signals of selection are also identified, most of which overlap genes that are known to be associated with drug resistance, in addition to two novel signals observed in multiple countries that have yet to be explored in detail.,Additionally, we investigate relatedness networks over the selected loci and determine that one of these sweeps has spread between continents while the other has arisen independently in different countries.,IBD analysis of microorganisms using isoRelate can be used for exploring population structure, positive selection and haplotype distributions, and will be a valuable tool for monitoring disease control and elimination efforts of many diseases. | Malaria rapid diagnostic tests (RDTs) play a critical role in malaria case management, surveillance and case investigations.,Test performance is largely determined by design and quality characteristics, such as detection sensitivity, specificity, and thermal stability.,However, parasite characteristics such as variable or absent expression of antigens targeted by RDTs can also affect RDT performance.,Plasmodium falciparum parasites lacking the PfHRP2 protein, the most common target antigen for detection of P. falciparum, have been reported in some regions.,Therefore, accurately mapping the presence and prevalence of P. falciparum parasites lacking pfhrp2 would be an important step so that RDTs targeting alternative antigens, or microscopy, can be preferentially selected for use in such regions.,Herein the available evidence and molecular basis for identifying malaria parasites lacking PfHRP2 is reviewed, and a set of recommended procedures to apply for future investigations for parasites lacking PfHRP2, is proposed. | 1 |
The primary aim of this study was to assess the utilization of an insecticide-treated bed net on the preceding night and associated factors among households of Kola Diba town in 2017.,Of the 260 households, 239 (91.9%) (95% CI = 88.5-95%) utilized insecticide-treated bed net on the night preceding the interview.,242 (93.1%) households didn’t treat the bed net whereas 18 (6.9%) treat the bed net by chemical regularly.,Household structure and knowledge about malaria transmission were found to be associated with insecticide-treated bed net utilization.,The online version of this article (10.1186/s13104-018-3697-7) contains supplementary material, which is available to authorized users. | Malaria is the notorious impediment of public health and economic development.,Long-lasting insecticide-treated bed nets/insecticide-treated bed nets (LLINs/ITNs) are among major intervention strategies to avert the impact the disease.,However, effectiveness of LLINs/ITNs depends on, inter alia, possessing sufficient number, proper utilization and timely replacement of nets.,Thus, the World Health Organization (WHO) recommends surveys to evaluate possession and proper use of LLINs/ITNs by households.,A cross-sectional comparative household survey was conducted during peak malaria transmission season using interviewer-introduced questionnaires in southwest Ethiopia.,A study site was selected from villages around a man-made lake, Gilgel-Gibe (GG) and a control site, with similar geographic and socio-economic features but far away from the lake, was identified.,A total of 2,373 households from randomly selected cluster of households were included into the study and heads/spouses of the households responded to interviews.,Binary and multinomial logistic regressions were used to identify predictors of LLIN ownership and utilization.,LLIN/ITN ownership among the study populations was 56.6%, while 43.4% of households did not own a net.,A higher proportion of households in GG reported owning at least one LLITN/ITN compared to control village (OR =2.,2, P <0.001) and more households in GG reported having only one LLITN/ITN in contrast to households in the control village (OR = 2.1, P <0.001).,The mean number of LLINs/ITNs owned was 1.6 for GG residents and 1.8 for control village with a mean difference of -0.26 (95% CI = - 0.34, -0.19).,The age of household heads, household relative wealth index (RWI), distance to nearest health service and accessibility to transportation showed a significant association with ownership of LLINs/ITNs.,The probability of owning two or more LLINs/ITNs was positively associated with age of household head.,Marital status of household heads, RWI, distance to nearest health service, accessibility to transport, residence and household size showed a significant association with utilization of LLINs/ITNs.,Attention needs to be given to the poor, distant and inaccessible households in the efforts of malaria intervention programmes, such as free distribution of LLINs/ITNs.,Well-tailored information, education and communication is needed to address the problem of non-users. | 1 |
Schistosomiasis is a parasitic disease caused by trematodes of the genus Schistosoma.,Five species of Schistosoma are known to infect humans, out of which S. haematobium is the most prevalent, causing the chronic parasitic disease schistosomiasis that still represents a major problem of public health in many regions of the world and especially in tropical areas, leading to serious manifestations and mortality in developing countries.,Since the 1970s, praziquantel (PZQ) is the drug of choice for the treatment of schistosomiasis, but concerns about relying on a single drug to treat millions of people, and the potential appearance of drug resistance, make identification of alternative schistosomiasis chemotherapies a high priority.,Alkylphospholipid analogs (APLs), together with their prototypic molecule edelfosine (EDLF), are a family of synthetic antineoplastic compounds that show additional pharmacological actions, including antiparasitic activities against several protozoan parasites.,We found APLs ranked edelfosine> perifosine> erucylphosphocholine> miltefosine for their in vitro schistosomicidal activity against adult S. mansoni worms.,Edelfosine accumulated mainly in the worm tegument, and led to tegumental alterations, membrane permeabilization, motility impairment, blockade of male-female pairing as well as induction of apoptosis-like processes in cells in the close vicinity to the tegument.,Edelfosine oral treatment also showed in vivo schistosomicidal activity and decreased significantly the egg burden in the liver, a key event in schistosomiasis.,Our data show that edelfosine is the most potent APL in killing S. mansoni adult worms in vitro.,Edelfosine schistosomicidal activity seems to depend on its action on the tegumental structure, leading to tegumental damage, membrane permeabilization and apoptosis-like cell death.,Oral administration of edelfosine diminished worm and egg burdens in S. mansoni-infected CD1 mice.,Here we report that edelfosine showed promising antischistosomal properties in vitro and in vivo. | Helminths are parasitic organisms that can be broadly described as “worms” due to their elongated body plan, but which otherwise differ in shape, development, migratory routes and the predilection site of the adults and larvae.,They are divided into three major groups: trematodes (flukes), which are leaf-shaped, hermaphroditic (except for blood flukes) flatworms with oral and ventral suckers; cestodes (tapeworms), which are segmented, hermaphroditic flatworms that inhabit the intestinal lumen; and nematodes (roundworms), which are dioecious, cylindrical parasites that inhabit intestinal and peripheral tissue sites.,Helminths exhibit a sublime co-evolution with the host´s immune system that has enabled them to successfully colonize almost all multicellular species present in every geographical environment, including over two billion humans.,In the face of this challenge, the host immune system has evolved to strike a delicate balance between attempts to neutralize the infectious assault versus limitation of damage to host tissues.,Among the most important cell types during helminthic invasion are granulocytes: eosinophils, neutrophils and basophils.,Depending on the specific context, these leukocytes may have pivotal roles in host protection, immunopathology, or facilitation of helminth establishment.,This review provides an overview of the function of granulocytes in helminthic infections. | 1 |
The National Malaria Control Program (NMCP) has been using pirimiphos methyl for the first time for indoor residual spraying (IRS) in Benin.,The first round was a success with a significant decrease of entomological indicators of malaria transmission in the treated districts.,We present the results of the entomological impact on malaria transmission.,Entomologic parameters in the control area were compared with those in intervention sites.,Mosquito collections were carried out in three districts in the Atacora-Dongo region of which two were treated with pirimiphos methyl (Actellic 50EC) (Tanguiéta and Kouandé) and the untreated (Copargo) served as control.,Anopheles gambiae s.l. populations were sampled monthly by human landing catch.,In addition, window exit traps and pyrethrum spray catches were performed to assess exophagic behavior of Anopheles vectors.,In the three districts, mosquito collections were organized to follow the impact of pirimiphos methyl IRS on malaria transmission and possible changes in the behavior of mosquitoes.,The residual activity of pirimiphos methyl in the treated walls was also assessed using WHO bioassay test.,A significant reduction (94.25%) in human biting rate was recorded in treated districts where an inhabitant received less than 1 bite of An. gambiae per night.,During this same time, the entomological inoculation rate (EIR) dramatically declined in the treated area (99.24% reduction).,We also noted a significant reduction in longevity of the vectors and an increase in exophily induced by pirimiphos methyl on An. gambiae.,However, no significant impact was found on the blood feeding rate.,Otherwise, the low residual activity of Actellic 50 EC, which is three months, is a disadvantage.,Pirimiphos methyl was found to be effective for IRS in Benin.,However, because of the low persistence of Actellic 50EC used in this study on the treated walls, the recourse to another more residual formulation of pirimiphos methyl is required. | We describe and analyze a periodically-forced difference equation model for malaria in mosquitoes that captures the effects of seasonality and allows the mosquitoes to feed on a heterogeneous population of hosts.,We numerically show the existence of a unique globally asymptotically stable periodic orbit and calculate periodic orbits of field-measurable quantities that measure malaria transmission.,We integrate this model with an individual-based stochastic simulation model for malaria in humans to compare the effects of insecticide-treated nets (ITNs) and indoor residual spraying (IRS) in reducing malaria transmission, prevalence, and incidence.,We show that ITNs are more effective than IRS in reducing transmission and prevalence though IRS would achieve its maximal effects within 2 years while ITNs would need two mass distribution campaigns over several years to do so.,Furthermore, the combination of both interventions is more effective than either intervention alone.,However, although these interventions reduce transmission and prevalence, they can lead to increased clinical malaria; and all three malaria indicators return to preintervention levels within 3 years after the interventions are withdrawn. | 1 |
Malaria accounts for the largest portion of healthcare demand in Angola.,A pillar of malaria control in Angola is the appropriate management of malaria illness, including testing of suspect cases with rapid diagnostic tests (RDTs) and treatment of confirmed cases with artemisinin-based combination therapy (ACT).,Periodic systematic evaluations of malaria case management are recommended to measure health facility readiness and adherence to national case management guidelines.,Cross-sectional health facility surveys were performed in low-transmission Huambo and high-transmission Uíge Provinces in early 2016.,In each province, 45 health facilities were randomly selected from among all public health facilities stratified by level of care.,Survey teams performed inventories of malaria commodities and conducted exit interviews and re-examinations, including RDT testing, of a random selection of all patients completing outpatient consultations.,Key health facility readiness and case management indicators were calculated adjusting for the cluster sampling design and utilization.,Availability of RDTs or microscopy on the day of the survey was 71% (54-83) in Huambo and 85% (67-94) in Uíge.,At least one unit dose pack of one formulation of an ACT (usually artemether-lumefantrine) was available in 83% (66-92) of health facilities in Huambo and 79% (61-90) of health facilities in Uíge.,Testing rates of suspect malaria cases in Huambo were 30% (23-38) versus 69% (53-81) in Uíge.,Overall, 28% (13-49) of patients with uncomplicated malaria, as determined during the re-examination, were appropriately treated with an ACT with the correct dose in Huambo, compared to 60% (42-75) in Uíge.,Incorrect case management of suspect malaria cases was associated with lack of healthcare worker training in Huambo and ACT stock-outs in Uíge.,The results reveal important differences between provinces.,Despite similar availability of testing and ACT, testing and treatment rates were lower in Huambo compared to Uíge.,A majority of true malaria cases seeking care in health facilities in Huambo were not appropriately treated with anti-malarials, highlighting the importance of continued training and supervision of healthcare workers in malaria case management, particularly in areas with decreased malaria transmission.,The online version of this article (doi:10.1186/s12936-017-1843-7) contains supplementary material, which is available to authorized users. | Malaria rapid diagnostics tests (RDTs) can increase availability of laboratory-based diagnosis and improve the overall management of febrile patients in malaria endemic areas.,In preparation to scale-up RDTs in health facilities in Malawi, an evaluation of four RDTs to help guide national-level decision-making was conducted.,A cross sectional study of four histidine rich-protein-type-2- (HRP2) based RDTs at four health centres in Blantyre, Malawi, was undertaken to evaluate the sensitivity and specificity of RDTs, assess prescriber adherence to RDT test results and explore operational issues regarding RDT implementation.,Three RDTs were evaluated in only one health centre each and one RDT was evaluated in two health centres.,Light microscopy in a reference laboratory was used as the gold standard.,A total of 2,576 patients were included in the analysis.,All of the RDTs tested had relatively high sensitivity for detecting any parasitaemia [Bioline SD (97%), First response malaria (92%), Paracheck (91%), ICT diagnostics (90%)], but low specificity [Bioline SD (39%), First response malaria (42%), Paracheck (68%), ICT diagnostics (54%)].,Specificity was significantly lower in patients who self-treated with an anti-malarial in the previous two weeks (odds ratio (OR) 0.5; p-value < 0.001), patients 5-15 years old versus patients > 15 years old (OR 0.4, p-value < 0.001) and when the RDT was performed by a community health worker versus a laboratory technician (OR 0.4; p-value < 0.001).,Health workers correctly prescribed anti-malarials for patients with positive RDT results, but ignored negative RDT results with 58% of patients with a negative RDT result treated with an anti-malarial.,The results of this evaluation, combined with other published data and global recommendations, have been used to select RDTs for national scale-up.,In addition, the study identified some key issues that need to be further delineated: the low field specificity of RDTs, variable RDT performance by different cadres of health workers and the need for a robust quality assurance system.,Close monitoring of RDT scale-up will be needed to ensure that RDTs truly improve malaria case management. | 1 |
Malaria affects millions of people around the world and a small subset of those infected develop cerebral malaria.,The clinical presentation of cerebral malaria differs between children and adults, and it has been suggested that age-related changes in the endothelial response may account for some of these differences.,During cerebral malaria, parasites sequester within the brain microvasculature but do not penetrate into the brain parenchyma and yet, the infection causes severe neurological symptoms.,Endothelial dysfunction is thought to play an important role in mediating these adverse clinical outcomes.,During infection, the endothelium becomes activated and more permeable, which leads to increased inflammation, hemorrhages, and edema in the surrounding tissue.,We hypothesize that post-natal developmental changes, occurring in both endothelial response and the neurovascular unit, account for the differences observed in the clinical presentations of cerebral malaria in children compared with adults. | Cerebral malaria (CM) is the most severe manifestation of Plasmodium falciparum infection in children and non-immune adults.,Previous work has documented a persistent cognitive impairment in children who survive an episode of CM that is mimicked in animal models of the disease.,Potential therapeutic interventions for this complication have not been investigated, and are urgently needed.,HMG-CoA reductase inhibitors (statins) are widely prescribed for cardiovascular diseases.,In addition to their effects on the inhibition of cholesterol synthesis, statins have pleiotropic immunomodulatory activities.,Here we tested if statins would prevent cognitive impairment in a murine model of cerebral malaria.,Six days after infection with Plasmodium berghei ANKA (PbA) mice displayed clear signs of CM and were treated with chloroquine, or chloroquine and lovastatin.,Intravital examination of pial vessels of infected animals demonstrated a decrease in functional capillary density and an increase in rolling and adhesion of leukocytes to inflamed endothelium that were reversed by treatment with lovastatin.,In addition, oedema, ICAM-1, and CD11b mRNA levels were reduced in lovastatin-treated PbA-infected mice brains.,Moreover, HMOX-1 mRNA levels are enhanced in lovastatin-treated healthy and infected brains.,Oxidative stress and key inflammatory chemokines and cytokines were reduced to non-infected control levels in animals treated with lovastatin.,Fifteen days post-infection cognitive dysfunction was detected by a battery of cognition tests in animals rescued from CM by chloroquine treatment.,In contrast, it was absent in animals treated with lovastatin and chloroquine.,The outcome was similar in experimental bacterial sepsis, suggesting that statins have neuroprotective effects in severe infectious syndromes in addition to CM.,Statin treatment prevents neuroinflammation and blood brain barrier dysfunction in experimental CM and related conditions that are associated with cognitive sequelae, and may be a valuable adjuvant therapeutic agent for prevention of cognitive impairment in patients surviving an episode of CM. | 1 |
Malaria in pregnancy (MiP) is one of the major causes of mortality and morbidity in tropical regions, causing maternal anemia, intrauterine growth retardation, preterm birth, and low birth weight (LBW).,The integration of the information systems on pregnancy and malaria could prove to be a useful method of improved decision making for better maternal-child health.,A population-based observational study acquired information retrospectively from all live births that occurred between 2006 and 2014 in Cruzeiro do Sul (Acre, Brazil).,Social and clinical data of the mother and newborn was extracted from the Information System of Live Births.,Malaria episodes information was obtained from the Brazilian Epidemiological Surveillance Information System Malaria.,A deterministic record linkage was performed to assess malaria impact on pregnancy.,The studied population presented a malaria incidence of 8.9% (1283 pregnant women infected), of which 63.9% infected by Plasmodium (P.) vivax.,Reduction of newborn birth weight at term (small for gestational age (SGA) and LBW) has been found associated with P. vivax infection during pregnancy (SGA-OR 1.24, 95% CI 1.02-1.52, p = 0.035; term LBW-OR 1.39, 95% CI 1.03-1.88, p = 0.033).,Additionally, P. falciparum infection during pregnancy has been found to be associated with preterm births (OR 1.54, 95% CI 1.09-2.18, p = 0.016), which is related with late preterm births (OR 1.59, 95% CI 1.11-2.27, p = 0.011).,Despite the decrease of malaria cases during the evaluation period and regardless of Plasmodium species, we present evidence of the deleterious effects of MiP in a low transmission area in the Amazonian region. | Histological evidence of Plasmodium in the placenta is indicative of placental malaria, a condition associated with severe outcomes for mother and child.,Histological lesions found in placentas from Plasmodium-exposed women include syncytial knotting, syncytial rupture, thickening of the placental barrier, necrosis of villous tissue and intervillositis.,These histological changes have been associated with P. falciparum infections, but little is known about the contribution of P. vivax to such changes.,We conducted a cross-sectional study with pregnant women at delivery and assigned them to three groups according to their Plasmodium exposure during pregnancy: no Plasmodium exposure (n = 41), P. vivax exposure (n = 59) or P. falciparum exposure (n = 19).,We evaluated their placentas for signs of Plasmodium and placental lesions using ten histological parameters: syncytial knotting, syncytial rupture, placental barrier thickness, villi necrosis, intervillous space area, intervillous leucocytes, intervillous mononucleates, intervillous polymorphonucleates, parasitized erythrocytes and hemozoin.,Placentas from P. vivax-exposed women showed little evidence of Plasmodium or hemozoin but still exhibited more lesions than placentas from women not exposed to Plasmodium, especially when infections occurred twice or more during pregnancy.,In the Brazilian state of Acre, where diagnosis and primary treatment are readily available and placental lesions occur in the absence of detected placental parasites, relying on the presence of Plasmodium in the placenta to evaluate Plasmodium-induced placental pathology is not feasible.,Multivariate logistic analysis revealed that syncytial knotting (odds ratio [OR], 4.21, P = 0.045), placental barrier thickness (OR, 25.59, P = 0.021) and mononuclear cells (OR, 4.02, P = 0.046) were increased in placentas from P. vivax-exposed women when compared to women not exposed to Plasmodium during pregnancy.,A vivax-score was developed using these three parameters (and not evidence of Plasmodium) that differentiates between placentas from P. vivax-exposed and unexposed women.,This score illustrates the importance of adequate management of P. vivax malaria during pregnancy. | 1 |
The antibody response generated during malaria infections is of particular interest, since the production of specific IgG antibodies is required for acquisition of clinical immunity.,However, variations in antibody responses could result from genetic polymorphism of the HLA class II genes.,Given the increasing focus on the development of subunit vaccines, studies of the influence of class II alleles on the immune response in ethnically diverse populations is important, prior to the implementation of vaccine trials.,In this study, we evaluated the influence of HLA-DRB1* and -DQB1* allelic groups on the naturally acquired humoral response from Brazilian Amazon individuals (n = 276) against P. vivax Merozoite Surface Protein-1 (MSP-1), MSP-3α and MSP-9 recombinant proteins.,Our results provide information concerning these three P. vivax antigens, relevant for their role as immunogenic surface proteins and vaccine candidates.,Firstly, the studied population was heterogeneous presenting 13 HLA-DRB1* and 5 DQB1* allelic groups with a higher frequency of HLA-DRB1*04 and HLA-DQB1*03.,The proteins studied were broadly immunogenic in a naturally exposed population with high frequency of IgG antibodies against PvMSP1-19 (86.7%), PvMSP-3 (77%) and PvMSP-9 (76%).,Moreover, HLA-DRB1*04 and HLA-DQB1*03 alleles were associated with a higher frequency of IgG immune responses against five out of nine antigens tested, while HLA-DRB1*01 was associated with a high frequency of non-responders to repetitive regions of PvMSP-9, and the DRB1*16 allelic group with the low frequency of responders to PvMSP3 full length recombinant protein.,HLA-DRB1*04 alleles were associated with high frequency of antibody responses to five out of nine recombinant proteins tested in Rondonia State, Brazil.,These features could increase the success rate of future clinical trials based on these vaccine candidates. | Mortality from severe pediatric falciparum malaria appears low in Oceania but Plasmodium vivax is increasingly recognized as a cause of complications and death.,The features and prognosis of mixed Plasmodium species infections are poorly characterized.,Detailed prospective studies that include accurate malaria diagnosis and detection of co-morbidities are lacking.,We followed 340 Papua New Guinean (PNG) children with PCR-confirmed severe malaria (77.1% P. falciparum, 7.9% P. vivax, 14.7% P. falciparum/vivax) hospitalized over a 3-year period.,Bacterial cultures were performed to identify co-incident sepsis.,Clinical management was under national guidelines.,Of 262 children with severe falciparum malaria, 30.9%, 24.8% and 23.2% had impaired consciousness, severe anemia, and metabolic acidosis/hyperlactatemia, respectively.,Two (0.8%) presented with hypoglycemia, seven (2.7%) were discharged with neurologic impairment, and one child died (0.4%).,The 27 severe vivax malaria cases presented with similar phenotypic features to the falciparum malaria cases but respiratory distress was five times more common (P = 0.001); one child died (3.7%).,The 50 children with P. falciparum/vivax infections shared phenotypic features of mono-species infections, but were more likely to present in deep coma and had the highest mortality (8.0%; P = 0.003 vs falciparum malaria).,Overall, bacterial cultures were positive in only two non-fatal cases.,83.6% of the children had alpha-thalassemia trait and seven with coma/impaired consciousness had South Asian ovalocytosis (SAO).,The low mortality from severe falciparum malaria in PNG children may reflect protective genetic factors other than alpha-thalassemia trait/SAO, good nutrition, and/or infrequent co-incident sepsis.,Severe vivax malaria had similar features but severe P. falciparum/vivax infections were associated with the most severe phenotype and worst prognosis. | 1 |
Genetic resistance in cattle is considered a suitable way to control tick burden and its consequent losses for livestock production.,Exploring tick-resistant (R) and tick-susceptible (S) hosts, we investigated the genetic mechanisms underlying the variation of Braford resistance to tick infestation.,Skin biopsies from four-times-artificially infested R (n = 20) and S (n = 19) hosts, obtained before the first and 24 h after the fourth tick infestation were submitted to RNA-Sequencing.,Differential gene expression, functional enrichment, and network analysis were performed to identify genetic pathways and transcription factors (TFs) affecting host resistance.,Intergroup comparisons of hosts before (Rpre vs.,Spre) and after (Rpost vs.,Spost) tick infestation found 51 differentially expressed genes (DEGs), of which almost all presented high variation (TopDEGs), and 38 were redundant genes.,Gene expression was consistently different between R and S hosts, suggesting the existence of specific anti-tick mechanisms.,In the intragroup comparisons, Rpost vs.,Rpre and Spost vs.,Spre, we found more than two thousand DEGs in response to tick infestation in both resistance groups.,Redundant and non-redundant TopDEGs with potential anti-tick functions suggested a role in the development of different levels of resistance within the same breed.,Leukocyte chemotaxis was over-represented in both hosts, whereas skin degradation and remodeling were only found in TopDEGs from R hosts.,Also, these genes indicated the participation of cytokines, such as IL6 and IL22, and the activation of Wingless (WNT)-signaling pathway.,A central gene of this pathway, WNT7A, was consistently modulated when hosts were compared.,Moreover, the findings based on a genome-wide association study (GWAS) corroborate the prediction of the WNT-signaling pathway as a candidate mechanism of resistance.,The regulation of immune response was the most relevant pathway predicted for S hosts.,Members of Ap1 and NF-kB families were the most relevant TFs predicted for R and S, respectively.,This work provides indications of genetic mechanisms presented by Braford cattle with different levels of resistance in response to tick infestation, contributing to the search of candidate genes for tick resistance in bovine. | Ticks are able to transmit tick-borne infectious agents to vertebrate hosts which cause major constraints to public and livestock health.,The costs associated with mortality, relapse, treatments, and decreased production yields are economically significant.,Ticks adapted to a hematophagous existence after the vertebrate hemostatic system evolved into a multi-layered defense system against foreign invasion (pathogens and ectoparasites), blood loss, and immune responses.,Subsequently, ticks evolved by developing an ability to suppress the vertebrate host immune system with a devastating impact particularly for exotic and crossbred cattle.,Host genetics defines the immune responsiveness against ticks and tick-borne pathogens.,To gain an insight into the naturally acquired resistant and susceptible cattle breed against ticks, studies have been conducted comparing the incidence of tick infestation on bovine hosts from divergent genetic backgrounds.,It is well-documented that purebred and crossbred Bos taurus indicus cattle are more resistant to ticks and tick-borne pathogens compared to purebred European Bos taurus taurus cattle.,Genetic studies identifying Quantitative Trait Loci markers using microsatellites and SNPs have been inconsistent with very low percentages relating phenotypic variation with tick infestation.,Several skin gene expression and immunological studies have been undertaken using different breeds, different samples (peripheral blood, skin with tick feeding), infestation protocols and geographic environments.,Susceptible breeds were commonly found to be associated with the increased expression of toll like receptors, MHC Class II, calcium binding proteins, and complement factors with an increased presence of neutrophils in the skin following tick feeding.,Resistant breeds had higher levels of T cells present in the skin prior to tick infestation and thus seem to respond to ticks more efficiently.,The skin of resistant breeds also contained higher numbers of eosinophils, mast cells and basophils with up-regulated proteases, cathepsins, keratins, collagens and extracellular matrix proteins in response to feeding ticks.,Here we review immunological and molecular determinants that explore the cattle tick Rhipicephalus microplus-host resistance phenomenon as well as contemplating new insights and future directions to study tick resistance and susceptibility, in order to facilitate interventions for tick control. | 1 |
Recent studies of captive and wild-living apes in Africa have uncovered evidence of numerous new Plasmodium species, one of which was identified as the immediate precursor of human Plasmodium falciparum.,These findings raise the question whether wild apes could be a recurrent source of Plasmodium infections in humans.,This question is not new, but was the subject of intense investigation by researchers in the first half of the last century.,Re-examination of their work in the context of recent molecular findings provides a new framework to understand the diversity of Plasmodium species and to assess the risk of future cross-species transmissions to humans in the context of proposed malaria eradication programs. | Plasmodium falciparum genotyping has recently undergone a revolution, and genome-wide genotype datasets are now being collected for large numbers of parasite isolates.,By contrast, phenotyping technologies have lagged behind, with few high throughput phenotyping platforms available.,Invasion of human erythrocytes by Plasmodium falciparum is a phenotype of particular interest because of its central role in parasite development.,Invasion is a variable phenotype influenced by natural genetic variation in both the parasite and host and is governed by multiple overlapping and in some instances redundant parasite-erythrocyte interactions.,To facilitate the scale-up of erythrocyte invasion phenotyping, we have developed a novel platform based on two-color flow cytometry that distinguishes parasite invasion from parasite growth.,Target cells that had one or more receptors removed using enzymatic treatment were prelabeled with intracellular dyes CFDA-SE or DDAO-SE, incubated with P. falciparum parasites, and parasites that had invaded either labeled or unlabeled cells were detected with fluorescent DNA-intercalating dyes Hoechst 33342 or SYBR Green I.,Neither cell label interfered with erythrocyte invasion, and the combination of cell and parasite dyes recapitulated known invasion phenotypes for three standard laboratory strains.,Three different dye combinations with minimal overlap have been validated, meaning the same assay can be adapted to instruments harboring several different combinations of laser lines.,The assay is sensitive, operates in a 96-well format, and can be used to quantitate the impact of natural or experimental genetic variation on erythrocyte invasion efficiency.,© 2010 International Society for Advancement of Cytometry | 1 |
Malaria is one of the leading public health problems in sub-Saharan Africa that contributes to significant patient morbidity and mortality.,The aim of the study was to investigate adherence to malaria diagnosis and treatment guidelines by private health sector providers and compare their performance against the public private partnership (PPP) status.,A facility-based retrospective clinical audit was conducted between October 2016 and January 2017 in 11 medium clinics in the West Gojjam zone of the Amhara Region, North-west Ethiopia.,Data was extracted from patient medical records using pretested data abstraction forms.,Descriptive statistics were employed to present the findings and adherence of health workers against the national and international standards were classified as ideal, acceptable, minor error and major error for both malaria diagnosis and treatment.,A chi-square (X2) test was used to test for a statistically significant relationship after the data had been categorized using public private partnership status at P < 0.05.,One thousand six hundred fifty clinical files were audited.,All malaria suspected patients were investigated either with microscopy or rapid diagnostics test (RDT) for parasitological confirmation.,The proportion of malaria treated cases was 23.7% (391/1650).,Of which 16.6% (274/1650) were uncomplicated, 3.69% (61 /1650) were severe and complicated and the rest 3.39% (56/1650) were clinical diagnosed malaria cases.,And the malaria parasite positivity rate was 20.30% (335/1650).,All malaria suspected patients were not investigated with ideal malaria diagnosis recommendations; only 19.4% (320/1650) were investigated with acceptable malaria diagnosis (public private partnership (PPP) 19.4%; 176/907; and non-public private partnership (NPPP) 19.38%; 144/743, X2 (1) = 0.0With regards to treatments of malaria cases, the majority 82.9% of Plasmodium vivax cases were managed with ideal recommended treatment (X2 (1) = 0.35, P = 0.55); among Plasmodium falciparum, mixed (Plasmodium falciparum and Plasmodium vivax).,The clinical audit revealed that the majority of malaria patients had received minor error malaria diagnostic services.,In addition, only one fifth of malaria patients had received ideal malaria treatment services.,To understand the reasons for the low levels of malaria diagnosis and treatment adherence with national guidelines, a qualitative exploratory descriptive study is recommended. | Malaria remains a major public health threat accounting for 30.4 % of disease morbidity in outpatient clinic visits across all age groups in Uganda.,Consequently, malaria control remains a major public health priority in endemic countries such as Uganda.,Experiences from other countries in Africa that revised their malaria case management suggest that health workers adherence may be problematic.,A descriptive, cross-sectional design was used and collected information on health system, health workers and patients.,Using log-binomial regression model, adjusted prevalence risk ratios (PRRs) and their associated 95 % confidence intervals were determined in line with adherence to new treatment guidelines of parasitological diagnosis and prompt treatment with artemisinin combination therapy (ACT).,Nine health centres, 24 health workers and 240 patient consultations were evaluated.,Overall adherence to national malaria treatment guidelines (NMTG) was 50.6 % (122/241).,It was significantly high at HC III [115 (53 %)] than at HC IV (29 %) [PRR = 0.28 (95 % CI 0.148 0.52), p = 0.000].,Compared to the nursing aide, the adherence level was 1.57 times higher among enrolled nurses (p = 0.004) and 1.68 times higher among nursing officers, p = 0.238, with statistical significance among the former.,No attendance of facility malaria-specific continuing medical education (CME) sessions [PRR = 1.9 (95 % CI 1.29 2.78), p = 0.001] and no display of malaria treatment job aides in consultation rooms [PRR = 0.64 (95 % CI 0.4 1.03), p = 0.07] was associated with increased adherence to guidelines with the former showing a statistical significance and the association of the latter borderline statistical significance.,The adherence was higher when the laboratory was functional [PRR = 0.47 (95 % CI 0.35 0.63)] when the laboratory was functional in previous 6 months.,Age of health worker, duration of employment, supervision, educational level, and age of patient were found not associated with adherence to new treatment guidelines.,Adherence to malaria treatment guidelines in Uganda is sub-optimal.,There is an urgent need for deliberate interventions to improve adherence to these guidelines.,Possible interventions to be explored should include: provision of job aides and improved access to laboratory services.,There is also a need for continuous medical educational sessions for health workers, especially those at higher-level facilities and higher cadres, on adherence to guidelines in management of fever, including management of other causes of fever. | 1 |
Little is known about the effects of intermittent preventive treatment of malaria in pregnancy (IPTp) on the health of sub-Saharan African infants.,We have evaluated the safety of IPTp with mefloquine (MQ) compared to sulfadoxine-pyrimethamine (SP) for important infant health and developmental outcomes.,In the context of a multicenter randomized controlled trial evaluating the safety and efficacy of IPTp with MQ compared to SP in pregnancy carried out in four sub-Saharan countries (Mozambique, Benin, Gabon, and Tanzania), 4,247 newborns, 2,815 born to women who received MQ and 1,432 born to women who received SP for IPTp, were followed up until 12 mo of age.,Anthropometric parameters and psychomotor development were assessed at 1, 9, and 12 mo of age, and the incidence of malaria, anemia, hospital admissions, outpatient visits, and mortality were determined until 12 mo of age.,No significant differences were found in the proportion of infants with stunting, underweight, wasting, and severe acute malnutrition at 1, 9, and 12 mo of age between infants born to women who were on IPTp with MQ versus SP.,Except for three items evaluated at 9 mo of age, no significant differences were observed in the psychomotor development milestones assessed.,Incidence of malaria, anemia, hospital admissions, outpatient visits, and mortality were similar between the two groups.,Information on the outcomes at 12 mo of age was unavailable in 26% of the infants, 761 (27%) from the MQ group and 377 (26%) from the SP group.,Reasons for not completing the study were death (4% of total study population), study withdrawal (6%), migration (8%), and loss to follow-up (9%).,No significant differences were found between IPTp with MQ and SP administered in pregnancy on infant mortality, morbidity, and nutritional outcomes.,The poorer performance on certain psychomotor development milestones at 9 mo of age in children born to women in the MQ group compared to those in the SP group may deserve further studies.,ClinicalTrials.gov NCT00811421,In a cohort study, Clara Menéndez and colleagues evaluate mortality, morbidity, and developmental outcomes in infants born to women who were enrolled in a randomized controlled trial of intermittent preventive treatment of malaria in pregnancy,Malaria is a mosquito-borne parasitic disease that kills more than 600,000 people every year.,Most of these deaths occur among young children living in sub-Saharan Africa, but pregnant women living in Africa and their unborn children are also very vulnerable to malaria.,Infection with malaria during pregnancy can cause severe maternal anemia (reduced red blood cell numbers), stillbirths, and pre-term and low-birth-weight babies, and is responsible for the deaths of many women and their babies.,To prevent this loss of life, the World Health Organization (WHO) recommends that pregnant women living in areas of moderate to high transmission in Africa receive the antimalarial drug sulfadoxine-pyrimethamine (SP) at each scheduled antenatal visit after the first trimester (intermittent preventive treatment of malaria in pregnancy [IPTp]).,In addition, WHO advises pregnant women to sleep under insecticide-treated bed nets to protect themselves from the bites of infected mosquitoes and recommends effective case management of pregnant women with malarial illness.,Because malaria parasites are becoming resistant to SP, other antimalarial drugs are being investigated for use in IPTp.,A recent randomized controlled trial (a study that compares outcomes in participants assigned at random to receive different interventions) compared the efficacy and safety of IPTp with SP and with mefloquine (MQ, an antimalarial drug that, like SP, is considered safe throughout pregnancy) in pregnant women living in four countries in sub-Saharan Africa.,In the trial, the women taking MQ had fewer episodes of clinical malaria than the women taking SP, but the tolerability of MQ was poorer than that of SP.,Importantly, the prevalence of stillbirth and of low-birth-weight babies was similar in both trial arms (the prevalence of a condition is the proportion of the population with that condition).,Here, by following the babies born to the women participating in this trial for up to 12 months, the researchers evaluate the longer term effects of IPTp with SP and MQ during pregnancy on infant health and development.,The researchers followed 2,815 babies born to women who received MQ for IPTp and 1,432 babies born to women who received SP for IPTp for up to 12 months after birth.,They measured the babies’ weight and length at 1, 9, and 12 months, assessed the babies’ psychomotor development (the development of language, hearing and social skills, and motor skills such as limb movement and grasping) at the same ages, and recorded the incidence of malaria, anemia, hospital admissions, outpatient visits, and death among the babies during the first year of life.,The researchers found no significant differences in the nutritional outcomes of the infants born to women who received MQ compared to the infants born to women who received SP (significant differences are differences in outcomes that are unlikely to have arisen by chance).,There were also no significant differences in psychomotor development between the two groups of infants apart from an increased risk of being unable to stand without help, walk without support, or bring food to the mouth at 9 months among the children born to women who received MQ.,Finally, the incidence of malaria, anemia, hospital admissions, outpatient visits, and death was similar in the infants born to the two groups of women.,Information on the outcomes was not available for 26% of the babies at 12 months, which may limit the accuracy of these findings.,Nevertheless, these findings suggest that IPTp with MQ was not associated with any increased risk of undernutrition, illness, or death among infants compared to IPTp with SP.,The poorer performance on three psychomotor development milestones among the children born to women given MQ may be due to multiple testing rather than to true differences between the groups of infants-as more outcomes are investigated in a randomized trial, it becomes more likely that the intervention groups will differ on at least one outcome by chance.,It might therefore be worth investigating psychomotor development further in children whose mothers have been exposed to MQ during pregnancy.,Although the lower tolerability of MQ compared to SP for pregnant women in this trial that was reported previously means that MQ is unlikely to be used for IPTp, these findings are important because antimalarial regimens containing MQ are recommended for malaria treatment during pregnancy and MQ alone is recommended for malaria prevention in pregnant women traveling to countries affected by malaria.,This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001964.,Two PLOS Medicine Research Articles by Gonzalez et al. describe the randomized controlled trial of the efficacy and safety of IPTp with MQ versus SP in HIV-negative women and in HIV-infected women; additional information about the trial is available from ClinicalTrials.gov and the Pan African Clinical Trials Registry,Information is available from the World Health Organization on malaria (in several languages) and on malaria in pregnancy; information on IPTp and the current WHO policy recommendation on IPTp with SP are available; the World Malaria Report 2015 provides details of the current global malaria situation, including information on malaria in individual African countries,The US Centers for Disease Control and Prevention also provides information on malaria and recommendations for the use of MQ during pregnancy; a personal story about malaria in pregnancy is available,Information is available from the Roll Back Malaria Partnership on all aspects of global malaria control,The Malaria in Pregnancy Consortium is undertaking research into the prevention and treatment of malaria in pregnancy,MedlinePlus provides links to additional information on malaria (in English and Spanish) | In 2006, the first-line anti-malarial drug treatment in Tanzania was changed from sulphadoxine-pyrimethamine (SP) to artemether-lumefantrine (ALu), an artemisinin-based combination (ACT), since when the use of SP has been restricted for intermittent preventive treatment in pregnancy (IPTp).,A number of Plasmodium falciparum mutations are known to be associated with resistance to SP, but it is not known if the prevalence of these mutations is increasing or decreasing under the conditions of reduced levels of SP use.,This study reports on the current SP resistant quintuple Pfdhfr-Pfdhps mutations in six regions of Tanzania.,Finger-prick blood on filter paper and rapid diagnostic test strips from P. falciparum-positive individuals of all age groups attending health facilities in six regions of Tanzania between June 2010 and August 2011 were obtained.,Using chelex-100 extracted DNA, genotyping was done for mutations on codons 51, 59 and 108 of Pfdhfr and 437 and 540 of Pfdhps genes using PCR-RFLP technique.,A total of 802 malaria-positive samples were screened and genotyped.,The prevalence of Pfdhfr 51I, Pfdhps 437G and 540E varied between the regions (p < 0.001) whereas Pfdhfr 59R (FE 10.79, p = 0.225) and 108 N (FE 10.61, p = 0.239) did not vary between the regions.,The Pfdhfr triple mutant was above 84% and close to fixation levels in all regions, whereas the Pfdhps double mutation ranged from 43.8 to 97% between the regions.,The quintuple mutant (IRNGE) was the most prevalent in all regions and it varied significantly from 37.5 to 90.2% (χ2 = 1.11, p <0.001).,There is evidence of persistent high levels of SP resistance markers in Tanzania with evidence of quintuple mutations that are likely to become fixed in the population.,This threatens the future of SP not only in IPTp programmes, but as a combination drug for ACT.,Continuous monitoring of SP-IPTp efficacy should be encouraged subsequent to searching for alternative drugs for IPTp in East Africa. | 1 |
Schistosomiasis is one of the major parasitic diseases in the world in terms of people infected and those at risk.,Infection occurs through contact with water contaminated with larval forms of the parasite, which are released by freshwater snails and then penetrate the skin of people.,Schistosomiasis infection and human water contact are thus essentially linked, and more knowledge about their relationship will help us to develop appropriate control measures.,So far, only few studies have related water contact patterns to infection levels.,We have conducted detailed direct water contact observations in a village in Northern Senegal during the first years of a massive Schistosoma mansoni outbreak to determine the role of human water contact in the extent of the epidemic.,We quantified water contact activities in terms of frequency and duration, and described how these vary with age and sex.,Moreover, we assessed the relationship between water contact- and infection intensity patterns to further elucidate the contribution of exposure to the transmission of schistosomiasis.,This resulted in over 120,000 recorded water contacts for 1651 subjects over 175 observation days.,Bathing was the main activity, followed by household activities.,Frequency and duration of water contact depended on age and sex rather than season.,Water contacts peaked in adolescents, women spent almost twice as much time in the water as men, and water contacts were more intense in the afternoon than in the morning, with sex-specific intensity peaks.,The average number of water contacts per person per day in this population was 0.42; the average time spent in the water per person per day was 4.3 minutes.,The observed patterns of water contact behavior are not unusual and have been described before in various other settings in sub-Saharan Africa.,Moreover, water contact levels were not exceptionally high and thus cannot explain the extremely high S. mansoni infection intensities as observed in Northern Senegal.,Comparison with fecal egg counts in the respective age and sex groups further revealed that water contact levels did not unambiguously correspond with infection levels, indicating that factors other than exposure also play a role in determining intensity of infection. | Mass chemotherapy with praziquantel is the main control strategy for schistosomiasis in Mali.,However, in the national control programme for schistosomiasis and soil-transmitted helminthiasis, infants and preschool-aged children are overlooked in preventive chemotherapy campaigns.,We therefore determined the prevalence and intensity of urinary schistosomiasis in children between the ages 1-4 years in three villages across Diema health district, a rural community with endemic schistosomiasis in Mali.,For Schistosoma haematobium diagnosis, a single urine sample of 10 ml obtained from each child was subjected to the standard urine filtration method.,Of the 338 children examined 173 (51.2%) were infected.,Both prevalence and intensity of infection varied significantly between communities (p < 0.01).,There was no significant difference (p = 0.94) in infection rates between boys (51.2%) and girls (50.3%).,Likewise, prevalence did not significantly increase with age (p = 0.86).,The overall geometric mean of Williams (GMw) was 18.41 eggs/10 ml urine, with no significant association (p = 0.91) between boys (17.48 eggs/10 ml urine) and girls (19.69 eggs/10 ml urine).,However, the GMw significantly increased with age (p = 0.04).,Infection of preschool children would occur through early exposure to infected water bodies through both passive and active process.,Our study showed that preschool children living closely to lakes across in Mali are at high risk to be infected by schistosomiasis and contributed largely to the transmission; therefore schistosomiasis control interventions should also target infants in addition to school children and adults in endemic areas. | 1 |
Seroepidemiology can provide evidence for temporal changes in malaria transmission and is an important tool to evaluate the effectiveness of control interventions.,During the early 2000s, Vanuatu experienced an acute increase in malaria incidence due to a lapse in funding for vector control.,After the distribution of subsidised insecticide-treated nets (ITNs) resumed in 2003, malaria incidence decreased in the subsequent years.,This study was conducted to find the serological evidence supporting the impact of ITN on exposure to Anopheles vector bites and parasite prevalence.,On Ambae Island, blood samples were collected from 231 and 282 individuals in 2003 and 2007, respectively.,Parasite prevalence was determined by microscopy.,Antibodies to three Plasmodium falciparum (PfSE, PfMSP-119, and PfAMA-1) and three Plasmodium vivax (PvSE, PvMSP-119, and PvAMA-1) antigens, as well as the Anopheles-specific salivary antigen gSG6, were detected by ELISA.,Age-specific seroprevalence was analysed using a reverse catalytic modelling approach to estimate seroconversion rates (SCRs).,Parasite rate decreased significantly (P < 0.001) from 19.0% in 2003 to 3.2% in 2007, with a shift from P. falciparum predominance to P. falciparum-P. vivax co-dominance.,Significant (P < 0.001) decreases were observed in seroprevalence to all three P. falciparum antigens but only two of three P. vivax antigens (except PvAMA-1; P = 0.153), consistent with the more pronounced decrease in P. falciparum prevalence.,Seroprevalence to gSG6 also decreased significantly (P < 0.001), suggesting that reduced exposure to vector bites was important to the decrease in parasite prevalence between 2003 and 2007.,Analyses of age-specific seroprevalence showed a three-fold decrease in P. falciparum transmission, but the evidence for the decrease in P. vivax transmission was less clear.,Serological markers pointed to the effectiveness of ITNs in reducing malaria prevalence on Ambae Island between 2003 and 2007.,The recombinant gSG6 antigen originally developed to indicate exposure to the Afrotropical vector An. gambiae may be used in the Pacific to complement the traditional measure of entomological inoculation rate (EIR). | The prevalence of malaria has reduced significantly in some areas over the past decade.,These reductions have made local elimination possible and the research agenda has shifted to this new priority.,However, there are critical issues that arise when studying malaria in low transmission settings, particularly identifying asymptomatic infections, accurate detection of individuals with microparasitaemic infections, and achieving a sufficient sample size to have an adequately powered study.,These challenges could adversely impact the study of malaria elimination if they remain unanswered. | 1 |
Artemisinin and partner drug resistant malaria parasites have emerged in Southeast Asia.,If resistance were to emerge in Africa it could have a devastating impact on malaria-related morbidity and mortality.,This study estimates the potential impact of artemisinin and partner drug resistance on disease burden in Africa if it were to emerge.,Using data from Asia and Africa, five possible artemisinin and partner drug resistance scenarios are characterized.,An individual-based malaria transmission model is used to estimate the impact of each resistance scenario on clinical incidence and parasite prevalence across Africa.,Artemisinin resistance is characterized by slow parasite clearance and partner drug resistance is associated with late clinical failure or late parasitological failure.,Scenarios with high levels of recrudescent infections resulted in far greater increases in clinical incidence compared to scenarios with high levels of slow parasite clearance.,Across Africa, it is estimated that artemisinin and partner drug resistance at levels similar to those observed in Oddar Meanchey province in Cambodia could result in an additional 78 million cases over a 5 year period, a 7 % increase in cases compared to a scenario with no resistance.,A scenario with high levels of slow clearance but no recrudescence resulted in an additional 10 million additional cases over the same period.,Artemisinin resistance is potentially a more pressing concern than partner drug resistance due to the lack of viable alternatives.,However, it is predicted that a failing partner drug will result in greater increases in malaria cases and morbidity than would be observed from artemisinin resistance only.,The online version of this article (doi:10.1186/s12936-015-1075-7) contains supplementary material, which is available to authorized users. | Artemisinin-resistant falciparum malaria has arisen in western Cambodia.,A concerted international effort is underway to contain artemisinin-resistant Plasmodium falciparum, but containment strategies are dependent on whether resistance has emerged elsewhere.,We aimed to establish whether artemisinin resistance has spread or emerged on the Thailand-Myanmar (Burma) border.,In malaria clinics located along the northwestern border of Thailand, we measured six hourly parasite counts in patients with uncomplicated hyperparasitaemic falciparum malaria (≥4% infected red blood cells) who had been given various oral artesunate-containing regimens since 2001.,Parasite clearance half-lives were estimated and parasites were genotyped for 93 single nucleotide polymorphisms.,3202 patients were studied between 2001 and 2010.,Parasite clearance half-lives lengthened from a geometric mean of 2·6 h (95% CI 2·5-2·7) in 2001, to 3·7 h (3·6-3·8) in 2010, compared with a mean of 5·5 h (5·2-5·9) in 119 patients in western Cambodia measured between 2007 and 2010.,The proportion of slow-clearing infections (half-life ≥6·2 h) increased from 0·6% in 2001, to 20% in 2010, compared with 42% in western Cambodia between 2007 and 2010.,Of 1583 infections genotyped, 148 multilocus parasite genotypes were identified, each of which infected between two and 13 patients.,The proportion of variation in parasite clearance attributable to parasite genetics increased from 30% between 2001 and 2004, to 66% between 2007 and 2010.,Genetically determined artemisinin resistance in P falciparum emerged along the Thailand-Myanmar border at least 8 years ago and has since increased substantially.,At this rate of increase, resistance will reach rates reported in western Cambodia in 2-6 years.,The Wellcome Trust and National Institutes of Health. | 1 |
Since the year 2000, a concerted campaign against malaria has led to unprecedented levels of intervention coverage across sub-Saharan Africa.,Understanding the effect of this control effort is vital to inform future control planning.,However, the effect of malaria interventions across the varied epidemiological settings of Africa remains poorly understood owing to the absence of reliable surveillance data and the simplistic approaches underlying current disease estimates.,Here we link a large database of malaria field surveys with detailed reconstructions of changing intervention coverage to directly evaluate trends from 2000 to 2015 and quantify the attributable effect of malaria disease control efforts.,We found that Plasmodium falciparum infection prevalence in endemic Africa halved and the incidence of clinical disease fell by 40% between 2000 and 2015.,We estimate that interventions have averted 663 (542-753 credible interval) million clinical cases since 2000.,Insecticide-treated nets, the most widespread intervention, were by far the largest contributor (68% of cases averted).,Although still below target levels, current malaria interventions have substantially reduced malaria disease incidence across the continent.,Increasing access to these interventions, and maintaining their effectiveness in the face of insecticide and drug resistance, should form a cornerstone of post-2015 control strategies. | The sensitivity of a rapid diagnostic test (RDT) for malaria was compared with that of a polymerase chain reaction assay in pregnant West African women.,The sensitivity of the RDT was high at enrollment but lower at delivery.,Background.,Intermittent screening and treatment in pregnancy (ISTp) is a potential strategy for the control of malaria during pregnancy.,However, the frequency and consequences of malaria infections missed by a rapid diagnostic test (RDT) for malaria are a concern.,Methods.,Primigravidae and secundigravidae who participated in the ISTp arm of a noninferiority trial in 4 West African countries were screened with an HRP2/pLDH RDT on enrollment and, in Ghana, at subsequent antenatal clinic (ANC) visits.,Blood samples were examined subsequently by microscopy and by a polymerase chain reaction (PCR) assay.,Results.,The sensitivity of the RDT to detect peripheral blood infections confirmed by microscopy and/or PCR at enrollment ranged from 91% (95% confidence interval [CI], 88%, 94%) in Burkina Faso to 59% (95% CI, 48%, 70% in The Gambia.,In Ghana, RDT sensitivity was 89% (95% CI, 85%, 92%), 83% (95% CI, 76%, 90%) and 77% (95% CI, 67%, 86%) at enrollment, second and third ANC visits respectively but only 49% (95% CI, 31%, 66%) at delivery.,Screening at enrollment detected 56% of all infections detected throughout pregnancy.,Seventy-five RDT negative PCR or microscopy positive infections were detected in 540 women; these were not associated with maternal anemia, placental malaria, or low birth weight.,Conclusions.,The sensitivity of an RDT to detect malaria in primigravidae and secundigravidae was high at enrollment in 3 of 4 countries and, in Ghana, at subsequent ANC visits.,In Ghana, RDT negative malaria infections were not associated with adverse birth outcomes but missed infections were uncommon. | 1 |
The malaria burden of Myanmar still remains high within the Greater Mekong Subregion of Southeast Asia.,An important indicator of progress towards malaria elimination is the prevalence of parasite infections in endemic populations.,Information about malaria epidemiology is mostly derived from reports of confirmed acute malaria cases through passive case detection, whereas the prevalence of baseline subclinical malaria infections is much less known.,In this study, cross-sectional surveys were conducted during the rainy season of 2017 in four townships (Bilin, Thabeikkyin, Banmauk and Paletwa) of Myanmar with divergent annual malaria incidences.,A total of 1991 volunteers were recruited from local villages and Plasmodium subclinical infections were estimated by light microscopy (LM), rapid diagnostic tests (RDTs) and nested PCR.,The nested PCR analysis was performed with a modified pooling strategy that was optimized based on an initial estimate the infection prevalence.,The overall malaria infection prevalence based on all methods was 13.9% (277/1991) and it differed drastically among the townships, with Paletwa in the western border having the highest infection rate (22.9%) and Thabeikkyin in central Myanmar having the lowest (3.9%).,As expected, nested PCR was the most sensitive and identified 226 (11.4%) individuals with parasite infections.,Among the parasite species, Plasmodium vivax was the most prevalent in all locations, while Plasmodium falciparum also accounted for 32% of infections in the western township Paletwa.,Two RDTs based on the detection of the hrp2 antigen detected a total of 103 P. falciparum infections, and the ultrasensitive RDT detected 20% more P. falciparum infections than the conventional RDT.,In contrast, LM missed the majority of the subclinical infections and only identified 14 Plasmodium infections.,Cross-sectional surveys identified considerable levels of asymptomatic Plasmodium infections in endemic populations of Myanmar with P. vivax becoming the predominant parasite species.,Geographical heterogeneity of subclinical infections calls for active surveillance of parasite infections in endemic areas.,The pooling scheme designed for nested PCR analysis offers a more practical strategy for large-scale epidemiological studies of parasite prevalence.,Such information is important for decision-makers to put forward a more realistic action plan for malaria elimination.,The online version of this article (10.1186/s13071-019-3330-1) contains supplementary material, which is available to authorized users. | The World Health Organization recommends parasitological confirmation of malaria prior to treatment.,Malaria rapid diagnostic tests (RDTs) represent one diagnostic method that is used in a variety of contexts to overcome limitations of other diagnostic techniques.,Malaria RDTs increase the availability and feasibility of accurate diagnosis and may result in improved quality of care.,Though RDTs are used in a variety of contexts, no studies have compared how well or effectively RDTs are used across these contexts.,This review assesses the diagnostic use of RDTs in four different contexts: health facilities, the community, drug shops and schools.,A comprehensive search of the Pubmed database was conducted to evaluate RDT execution, test accuracy, or adherence to test results in sub-Saharan Africa.,Original RDT and Plasmodium falciparum focused studies conducted in formal health care facilities, drug shops, schools, or by CHWs between the year 2000 and December 2016 were included.,Studies were excluded if they were conducted exclusively in a research laboratory setting, where staff from the study team conducted RDTs, or in settings outside of sub-Saharan Africa.,The literature search identified 757 reports.,A total of 52 studies were included in the analysis.,Overall, RDTs were performed safely and effectively by community health workers provided they receive proper training.,Analogous information was largely absent for formal health care workers.,Tests were generally accurate across contexts, except for in drug shops where lower specificities were observed.,Adherence to RDT results was higher among drug shop vendors and community health workers, while adherence was more variable among formal health care workers, most notably with negative test results.,Malaria RDTs are generally used well, though compliance with test results is variable - especially in the formal health care sector.,If low adherence rates are extrapolated, thousands of patients may be incorrectly diagnosed and receive inappropriate treatment resulting in a low quality of care and unnecessary drug use.,Multidisciplinary research should continue to explore determinants of good RDT use, and seek to better understand how to support and sustain the correct use of this diagnostic tool.,The online version of this article (doi:10.1186/s12889-017-4398-1) contains supplementary material, which is available to authorized users. | 1 |
The surface molecule gp82 of metacyclic trypomastigote (MT) forms of Trypanosoma cruzi, the protozoan parasite that causes Chagas disease, mediates the host cell invasion, a process critical for the establishment of infection.,Gp82 is known to bind to the target cell in a receptor-dependent manner, triggering Ca2+ signal, actin cytoskeleton rearrangement and lysosome spreading.,The host cell receptor for gp82 was recently identified as LAMP2, the major lysosome membrane-associated protein.,To further clarify the mechanisms of MT invasion, we aimed in this study at identifying the LAMP2 domain that interacts with gp82 and investigated whether target cell PKC and ERK1/2, previously suggested to be implicated in MT invasion, are activated by gp82.,Interaction of MT, or the recombinant gp82 (r-gp82), with human epithelial HeLa cells induced the activation of Ca2+-dependent PKC and ERK1/2.,The LAMP2 sequence predicted to bind gp82 was mapped and the synthetic peptide based on that sequence inhibited MT invasion, impaired the binding of r-gp82 to HeLa cells, and blocked the PKC and ERK1/2 activation induced by r-gp82.,Treatment of HeLa cells with specific inhibitor of focal adhesion kinase resulted in inhibition of r-gp82-induced PKC and ERK1/2 activation, as well as in alteration of the actin cytoskeleton architecture.,PKC activation by r-gp82 was also impaired by treatment of HeLa cells with inhibitor of phospholipase C, which mediates the production of diacylglycerol, which activates PKC, and inositol 1,4,5-triphosphate that releases Ca2+ from intracellular stores.,Taken together, our results indicate that recognition of MT gp82 by LAMP2 induces in the host cell the activation of phosholipase C, with generation of products that contribute for PKC activation and the downstream ERK1/2.,This chain of events leads to the actin cytoskeleton disruption and lysosome spreading, promoting MT internalization. | Outbreaks of acute Chagas disease by oral infection have been reported frequently over the last ten years, with higher incidence in northern South America, where Trypanosoma cruzi lineage TcI predominates, being responsible for the major cause of resurgent human disease, and a small percentage is identified as TcIV.,Mechanisms of oral infection and host-cell invasion by these parasites are poorly understood.,To address that question, we analyzed T. cruzi strains isolated from chagasic patients in Venezuela, Guatemala and Brazil.,Trypanosoma cruzi metacyclic trypomastigotes were orally inoculated into mice.,The mouse stomach collected four days later, as well as the stomach and the heart collected 30 days post-infection, were processed for histological analysis.,Assays to mimic parasite migration through the gastric mucus layer were performed by counting the parasites that traversed gastric mucin-coated transwell filters.,For cell invasion assays, human epithelial HeLa cells were incubated with metacyclic forms and the number of internalized parasites was counted.,All TcI and TcIV T. cruzi strains were poorly infective by the oral route.,Parasites were either undetectable or were detected in small numbers in the mouse stomach four days post oral administration.,Replicating parasites were found in the stomach and/or in the heart 30 days post-infection.,As compared to TcI lineage, the migration capacity of TcIV parasites through the gastric mucin-coated filter was higher but lower than that exhibited by TcVI metacyclic forms previously shown to be highly infective by the oral route.,Expression of pepsin-resistant gp90, the surface molecule that downregulates cell invasion, was higher in TcI than in TcIV parasites and, accordingly, the invasion capacity of TcIV metacyclic forms was higher.,Gp90 molecules spontaneously released by TcI metacyclic forms inhibited the parasite entry into host cells.,TcI parasites exhibited low intracellular replication rate.,Our findings indicate that the poor capacity of TcI lineage, and to a lesser degree of TcIV parasites, in invading gastric epithelium after oral infection of mice may be associated with the inefficiency of metacyclic forms, in particular of TcI parasites, to migrate through the gastric mucus layer, to invade target epithelial cells and to replicate intracellularly.,The online version of this article (doi:10.1186/s13071-016-1455-z) contains supplementary material, which is available to authorized users. | 1 |
Toxoplasma gondii infects up to one third of the world's population.,A key to the success of T. gondii as a parasite is its ability to persist for the life of its host as bradyzoites within tissue cysts.,The glycosylated cyst wall is the key structural feature that facilitates persistence and oral transmission of this parasite.,Because most of the antibodies and reagents that recognize the cyst wall recognize carbohydrates, identification of the components of the cyst wall has been technically challenging.,We have identified CST1 (TGME49_064660) as a 250 kDa SRS (SAG1 related sequence) domain protein with a large mucin-like domain.,CST1 is responsible for the Dolichos biflorus Agglutinin (DBA) lectin binding characteristic of T. gondii cysts.,Deletion of CST1 results in reduced cyst number and a fragile brain cyst phenotype characterized by a thinning and disruption of the underlying region of the cyst wall.,These defects are reversed by complementation of CST1.,Additional complementation experiments demonstrate that the CST1-mucin domain is necessary for the formation of a normal cyst wall structure, the ability of the cyst to resist mechanical stress, and binding of DBA to the cyst wall.,RNA-seq transcriptome analysis demonstrated dysregulation of bradyzoite genes within the various cst1 mutants.,These results indicate that CST1 functions as a key structural component that confers essential sturdiness to the T. gondii tissue cyst critical for persistence of bradyzoite forms. | Toxoplasma gondii is a zoonotic protozoan parasite which infects nearly one third of the human population and is found in an extraordinary range of vertebrate hosts.,Its epidemiology depends heavily on horizontal transmission, especially between rodents and its definitive host, the cat.,Neospora caninum is a recently discovered close relative of Toxoplasma, whose definitive host is the dog.,Both species are tissue-dwelling Coccidia and members of the phylum Apicomplexa; they share many common features, but Neospora neither infects humans nor shares the same wide host range as Toxoplasma, rather it shows a striking preference for highly efficient vertical transmission in cattle.,These species therefore provide a remarkable opportunity to investigate mechanisms of host restriction, transmission strategies, virulence and zoonotic potential.,We sequenced the genome of N. caninum and transcriptomes of the invasive stage of both species, undertaking an extensive comparative genomics and transcriptomics analysis.,We estimate that these organisms diverged from their common ancestor around 28 million years ago and find that both genomes and gene expression are remarkably conserved.,However, in N. caninum we identified an unexpected expansion of surface antigen gene families and the divergence of secreted virulence factors, including rhoptry kinases.,Specifically we show that the rhoptry kinase ROP18 is pseudogenised in N. caninum and that, as a possible consequence, Neospora is unable to phosphorylate host immunity-related GTPases, as Toxoplasma does.,This defense strategy is thought to be key to virulence in Toxoplasma.,We conclude that the ecological niches occupied by these species are influenced by a relatively small number of gene products which operate at the host-parasite interface and that the dominance of vertical transmission in N. caninum may be associated with the evolution of reduced virulence in this species. | 1 |
The Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) was funded in 2008 to conduct research that would support country schistosomiasis control programs.,As schistosomiasis prevalence decreases in many places and elimination is increasingly within reach, a sensitive and specific test to detect infection with Schistosoma mansoni and Schistosoma haematobium has become a pressing need.,After obtaining broad input, SCORE supported Leiden University Medical Center (LUMC) to modify the serum-based antigen assay for use with urine, simplify the assay, and improve its sensitivity.,The urine assay eventually contributed to several of the larger SCORE studies.,For example, in Zanzibar, we demonstrated that urine filtration, the standard parasite egg detection diagnostic test for S. haematobium, greatly underestimated prevalence in low-prevalence settings.,In Burundi and Rwanda, the circulating anodic antigen (CAA) assay provided critical information about the limitations of the stool-based Kato-Katz parasite egg-detection assay for S. mansoni in low-prevalence settings.,Other SCORE-supported CAA work demonstrated that frozen, banked urine specimens yielded similar results to fresh ones; pooling of specimens may be a useful, cost-effective approach for surveillance in some settings; and the assay can be performed in local laboratories equipped with adequate centrifuge capacity.,These improvements in the assay continue to be of use to researchers around the world.,However, additional work will be needed if widespread dissemination of the CAA assay is to occur, for example, by building capacity in places besides LUMC and commercialization of the assay.,Here, we review the evolution of the CAA assay format during the SCORE period with emphasis on urine-based applications. | Kato-Katz examination of stool smears is the field-standard method for detecting Schistosoma mansoni infection.,However, Kato-Katz misses many active infections, especially of light intensity.,Point-of-care circulating cathodic antigen (CCA) is an alternative field diagnostic that is more sensitive than Kato-Katz when intensity is low, but interpretation of CCA-trace results is unclear.,To evaluate trace results, we tested urine and stool specimens from 398 pupils from eight schools in Burundi using four approaches: two in Burundi and two in a laboratory in Leiden, the Netherlands.,In Burundi, we used Kato-Katz and point-of-care CCA (CCAB).,In Leiden, we repeated the CCA (CCAL) and also used Up-Converting Phosphor Circulating Anodic Antigen (CAA).,We applied Bayesian latent class analyses (LCA), first considering CCA traces as negative and then as positive.,We used the LCA output to estimate validity of the prevalence estimates of each test in comparison to the population-level infection prevalence and estimated the proportion of trace results that were likely true positives.,Kato-Katz yielded the lowest prevalence (6.8%), and CCAB with trace considered positive yielded the highest (53.5%).,There were many more trace results recorded by CCA in Burundi (32.4%) than in Leiden (2.3%).,Estimated prevalence with CAA was 46.5%.,LCA indicated that Kato-Katz had the lowest sensitivity: 15.9% [Bayesian Credible Interval (BCI): 9.2-23.5%] with CCA-trace considered negative and 15.0% with trace as positive (BCI: 9.6-21.4%), implying that Kato-Katz missed approximately 85% of infections.,CCAB underestimated disease prevalence when trace was considered negative and overestimated disease prevalence when trace was considered positive, by approximately 12 percentage points each way, and CAA overestimated prevalence in both models.,Our results suggest that approximately 52.2% (BCI: 37.8-5.8%) of the CCAB trace readings were true infections.,Whether measured in the laboratory or the field, CCA outperformed Kato-Katz at the low infection intensities in Burundi.,CCA with trace as negative likely missed many infections, whereas CCA with trace as positive overestimated prevalence.,In the absence of a field-friendly gold standard diagnostic, the use of a variety of diagnostics with differing properties will become increasingly important as programs move towards elimination of schistosomiasis.,It is clear that CCA is a valuable tool for the detection and mapping of S. mansoni infection in the field and CAA may be a valuable field tool in the future.,The online version of this article (10.1186/s13071-018-2700-4) contains supplementary material, which is available to authorized users. | 1 |
We report xenodiagnosis results for 47 post-kala-azar dermal leishmaniasis (PKDL) and 15 visceral leishmaniasis (VL) patients.,Skin parasite load was strongly associated with positive xenodiagnosis.,Compared to VL (66.7%), nodular PKDL was more likely (86%) and macular PKDL less likely (35%) to result in positive xenodiagnosis.,On the Indian subcontinent, visceral leishmaniasis (VL) incidence is on track to reach elimination goals by 2020 in nearly all endemic districts.,Although not included in official targets, previous data suggest post-kala-azar dermal leishmaniasis (PKDL) patients can act as an infection reservoir.,We conducted xenodiagnosis on 47 PKDL patients and 15 VL patients using laboratory-reared Phlebotomus argentipes.,In direct xenodiagnosis, flies were allowed to feed on the patient’s skin for 15 minutes.,For indirect xenodiagnosis, flies were fed through a membrane on the patient’s blood.,Five days later, blood-fed flies were dissected and examined by microscopy and/or polymerase chain reaction (PCR).,A 3-mm skin snip biopsy (PKDL) or venous blood (VL) was processed by quantitative PCR.,Twenty-seven PKDL patients (57.4%) had positive results by direct and/or indirect xenodiagnosis.,Direct was significantly more sensitive than indirect xenodiagnosis (55.3% vs 6.4%, P < .0001).,Those with positive xenodiagnosis had median skin parasite loads >1 log10 unit higher than those with negative results (2.88 vs 1.66, P < .0001).,In a multivariable model, parasite load, nodular lesions, and positive skin microscopy were significantly associated with positive xenodiagnosis.,Blood parasite load was the strongest predictor for VL.,Compared to VL, nodular PKDL was more likely and macular PKDL less likely to result in positive xenodiagnosis, but neither difference reached statistical significance.,Nodular and macular PKDL, and VL, can be infectious to sand flies.,Active PKDL case detection and prompt treatment should be instituted and maintained as an integral part of VL control and elimination programs. | Immunosuppression contributes significantly to the caseload of visceral leishmaniasis (VL).,HIV coinfection, solid organ transplantation, malnutrition, and helminth infections are the most important immunosuppression-related factors.,This review briefly describes the challenges of these associations.,East Africa and the Indian subcontinent are the places where HIV imposes the highest burden in VL.,In the highlands of Northern Ethiopia, migrant rural workers are at a greater risk of coinfection and malnutrition, while in India, HIV reduces the sustainability of a successful elimination programme.,As shown from a longitudinal cohort in Madrid, VL is an additional threat to solid organ transplantation.,The association with malnutrition is more complex since it can be both a cause and a consequence of VL.,Different regimes for therapy and secondary prevention are discussed as well as the role of nutrients on the prophylaxis of VL in poverty-stricken endemic areas. | 1 |
Control of schistosomiasis presently relies largely on preventive chemotherapy with praziquantel through mass drug administration (MDA) programs.,The Schistosomiasis Consortium for Operational Research and Evaluation has concluded five studies in four countries (Côte d’Ivoire, Kenya, Mozambique, and Tanzania) to evaluate alternative approaches to MDA.,Studies involved four intervention years, with final evaluation in the fifth year.,Mass drug administration given annually or twice over 4 years reduced average prevalence and intensity of schistosome infections, but not all villages that were treated in the same way responded similarly.,There are multiple ways by which responsiveness to MDA, or the lack thereof, could be measured.,In the analyses presented here, we defined persistent hotspots (PHS) as villages that achieved less than 35% reduction in prevalence and/or less than 50% reduction in infection intensity after 4 years of either school-based or community-wide MDA, either annually or twice in 4 years.,By this definition, at least 30% of villages in each of the five studies were PHSs.,We found no consistent relationship between PHSs and the type or frequency of intervention, adequacy of reported MDA coverage, and prevalence or intensity of infection at baseline.,New research is warranted to identify PHSs after just one or a few rounds of MDA, and new adaptive strategies need to be advanced and validated for turning PHSs into responder villages. | Elimination of urogenital schistosomiasis transmission is a priority for the Zanzibar Ministry of Health.,Preventative chemotherapy together with additional control interventions have successfully alleviated much of the disease burden.,However, a persistently high Schistosoma haematobium prevalence is found in certain areas.,Our aim was to characterise and evaluate these persistent “hot-spots” of transmission and reinfection in comparison with low-prevalence areas, to support the intervention planning for schistosomiasis elimination in Zanzibar.,Prevalences of S. haematobium were annually determined by a single urine filtration in schoolchildren from 45 administrative areas (shehias) in Unguja in 2012, 2013 and 2014.,Coverage data for biannual treatment with praziquantel were available from ministerial databases and internal surveys.,Among the 45 shehias, five hot-spot (≥ 15 % prevalence) and two low-prevalence (≤ 5 %) shehias were identified and surveyed in mid-2014.,Human-water contact sites (HWCSs) and the presence of S. haematobium-infected and uninfected Bulinus globosus, as well as safe water sources (SWSs) and their reliability in terms of water availability were determined and mapped.,We found no major difference in the treatment coverage between persistent hot-spot and low-prevalence shehias.,On average, there were considerably more HWCSs containing B. globosus in hot-spot than in low-prevalence shehias (n = 8 vs n = 2) and also more HWCSs containing infected B. globosus (n = 2 vs n = 0).,There was no striking difference in the average abundance of SWSs in hot-spot and low-prevalence shehias (n = 45 vs n = 38) and also no difference when considering SWSs with a constant water supply (average: 62 % vs 62 %).,The average number of taps with a constant water supply, however, was lower in hot-spot shehias (n = 7 vs n = 14).,Average distances from schools to the nearest HWCS were considerably shorter in hot-spot shehias (n = 229 m vs n = 722 m).,The number of HWCSs, their infestation with B. globosus and their distance to schools seem to play a major role for a persistently high S. haematobium prevalence in children.,In addition to treatment, increasing access to reliably working taps, targeted snail control at HWCSs near schools and enhanced behaviour change measures are needed to reduce prevalences in hot-spot areas and to finally reach elimination.,ISRCTN48837681.,The online version of this article (doi:10.1186/s13071-016-1847-0) contains supplementary material, which is available to authorized users. | 1 |
Primaquine is the only drug consistently effective against mature gametocytes of Plasmodium falciparum.,The transmission blocking dose of primaquine previously recommended was 0.75mg/kg (adult dose 45mg) but its deployment was limited because of concerns over haemolytic effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.,G6PD deficiency is an inherited X-linked enzymatic defect that affects an estimated 400 million people around the world with high frequencies (15-20%) in populations living in malarious areas.,To reduce transmission in low transmission settings and facilitate elimination of P. falciparum, the World Health Organization now recommends adding a single dose of 0.25mg/kg (adult dose 15mg) to Artemisinin-based Combination Therapies (ACTs) without G6PD testing.,Direct evidence of the safety of this low dose is lacking.,Adverse events and haemoglobin variations after this treatment were assessed in both G6PD normal and deficient subjects in the context of targeted malaria elimination in a malaria endemic area on the North-Western Myanmar-Thailand border where prevalence of G6PD deficiency (Mahidol variant) approximates 15%.,The tolerability and safety of primaquine (single dose 0.25 mg base/kg) combined with dihydroartemisinin-piperaquine (DHA-PPQ) given three times at monthly intervals was assessed in 819 subjects.,Haemoglobin concentrations were estimated over the six months preceding the ACT + primaquine rounds of mass drug administration.,G6PD deficiency was assessed with a phenotypic test and genotyping was performed in male subjects with deficient phenotypes and in all females.,Fractional haemoglobin changes in relation to G6PD phenotype and genotype and primaquine round were assessed using linear mixed-effects models.,No adverse events related to primaquine were reported during the trial.,Mean fractional haemoglobin changes after each primaquine treatment in G6PD deficient subjects (-5.0%, -4.2% and -4.7%) were greater than in G6PD normal subjects (0.3%, -0.8 and -1.7%) but were clinically insignificant.,Fractional drops in haemoglobin concentration larger than 25% following single dose primaquine were observed in 1.8% of the population but were asymptomatic.,The single low dose (0.25mg/kg) of primaquine is clinically well tolerated and can be used safely without prior G6PD testing in populations with high prevalence of G6PD deficiency.,The present evidence supports a broader use of low dose primaquine without G6PD testing for the treatment and elimination of falciparum malaria.,ClinicalTrials.gov NCT01872702 | In areas of low malaria transmission, it is currently recommended that a single dose of primaquine (0.75 mg base/kg; 45 mg adult dose) be added to artemisinin combination treatment (ACT) in acute falciparum malaria to block malaria transmission.,Review of studies of transmission-blocking activity based on the infectivity of patients or volunteers to anopheline mosquitoes, and of haemolytic toxicity in glucose 6-dehydrogenase (G6PD) deficient subjects, suggests that a lower primaquine dose (0.25 mg base/kg) would be safer and equally effective.,This lower dose could be deployed together with ACTs without G6PD testing wherever use of a specific gametocytocide is indicated. | 1 |
Diarrhoeal diseases are major contributors to the global burden of disease, particularly in children.,However, comprehensive estimates of the incidence and mortality due to specific aetiologies of diarrhoeal diseases are not available.,The objective of this study is to provide estimates of the global and regional incidence and mortality of diarrhoeal diseases caused by nine pathogens that are commonly transmitted through foods.,We abstracted data from systematic reviews and, depending on the overall mortality rates of the country, applied either a national incidence estimate approach or a modified Child Health Epidemiology Reference Group (CHERG) approach to estimate the aetiology-specific incidence and mortality of diarrhoeal diseases, by age and region.,The nine diarrhoeal diseases assessed caused an estimated 1.8 billion (95% uncertainty interval [UI] 1.1-3.3 billion) cases and 599,000 (95% UI 472,000-802,000) deaths worldwide in 2010.,The largest number of cases were caused by norovirus (677 million; 95% UI 468-1,153 million), enterotoxigenic Escherichia coli (ETEC) (233 million; 95% UI 154-380 million), Shigella spp. (188 million; 95% UI 94-379 million) and Giardia lamblia (179 million; 95% UI 125-263); the largest number of deaths were caused by norovirus (213,515; 95% UI 171,783-266,561), enteropathogenic E. coli (121,455; 95% UI 103,657-143,348), ETEC (73,041; 95% UI 55,474-96,984) and Shigella (64,993; 95% UI 48,966-92,357).,There were marked regional differences in incidence and mortality for these nine diseases.,Nearly 40% of cases and 43% of deaths caused by these nine diarrhoeal diseases occurred in children under five years of age.,Diarrhoeal diseases caused by these nine pathogens are responsible for a large disease burden, particularly in children.,These aetiology-specific burden estimates can inform efforts to reduce diarrhoeal diseases caused by these nine pathogens commonly transmitted through foods. | This study was carried out to investigate the prevalence and risk factors of Giardia infection among indigenous people in rural Malaysia.,Faecal samples were collected from 1,330 participants from seven states of Malaysia and examined by wet mount and formalin-ether sedimentation methods while demographic, socioeconomic and environmental information was collected using a pre-tested questionnaire.,The overall prevalence of Giardia infection was 11.6% and was significantly higher among those aged ≤ 12 years compared to their older counterparts.,Multivariate logistic regression identified age of ≤12 years, lacking of toilet at household, not washing hands before eating, not washing hands after playing with animals, not boiling water before consumption, bathing in the river, and not wearing shoes when outside as the significant risk factors of Giardia infection among these communities.,Based on a multilocus genotyping approach (including tpi, gdh and bg gene sequences), 69 isolates were identified as assemblage A, and 69 as assemblage B.,No association between the assemblages and presence of symptoms was found.,Providing proper sanitation, as well as provision of clean drinking water and proper health education regarding good personal hygiene practices will help significantly in reducing the prevalence and burden of Giardia infection in these communities. | 1 |
Intermittent preventive treatment of malaria in pregnancy is a highly cost-effective intervention which significantly improves maternal and birth outcomes among mothers and their newborns who live in areas of moderate to high malaria transmission.,However, coverage in sub-Saharan Africa remains unacceptably low, calling for urgent action to increase uptake dramatically and maximize its public health impact.,The ‘Global Call to Action’ outlines priority actions that will pave the way to success in achieving national and international coverage targets.,Immediate action is needed from national health institutions in malaria-endemic countries, the donor community, the research community, members of the pharmaceutical industry and private sector, along with technical partners at the global and local levels, to protect pregnant women and their babies from the preventable, adverse effects of malaria in pregnancy. | The Affordable Medicines Facility for malaria (AMFm) is a pilot supra-national subsidy program that aims to increase access and affordability of artemisinin combination therapy (ACT) in public sector clinics and private retail shops.,It is unclear to what extent the AMFm model will translate into wide scale availability and price reductions in ACT, particularly for rural, remote areas where disparities in access to medicines often exist.,This study is the first to rigorously examine the availability and price of subsidized ACT during the first year of the AMFm, measured through retail audits in remote regions of Tanzania.,Periodic retail audits of Accredited Drug Dispensing Outlets (ADDOs) were conducted in two remote regions of Tanzania (Mtwara and Rukwa).,Temporal and spatial variation in ACT availability and pricing were explored.,A composite measure of ADDO remoteness, using variables, such as distance to suppliers and towns, altitude and population density, was used to explore whether ACT availability and price vary systematically with remoteness.,Between February 2011 and January 2012, the fraction of ADDOs stocking AMFm-ACT increased from 25% to 88% in Mtwara and from 3% to 62% in Rukwa.,Availability was widespread, though diffusion throughout the region was achieved more quickly in Mtwara.,No significant relationship was found between ACT availability and remoteness.,Adult doses of AMFm-ACT were much more widely available than any other age/weight band.,Average prices fell from 1529 TZS (1.03 USD) to 1272 TZS (0.81 USD) over the study period, with prices in Rukwa higher than Mtwara.,The government recommended retail price for AMFm- ACT is 1,000 TZS ($0.64 USD).,The median retail ACT price in the final round of data collection was 1,000 TZS.,The AMFm led to large increases in availability of low priced ACT in Tanzania, with no significant variation in availability based on remoteness.,Availability did remain lower and prices remained higher in Rukwa, which is a more remote region overall.,Low availability of child and adolescent ACT doses could be due in part to lower quantities of non-adult packs imported into Tanzania.,Future research will explore whether increased availability and affordability persists and whether it translates into higher ACT use in Tanzania. | 1 |
Molecular epidemiology leverages genetic information to study the risk factors that affect the frequency and distribution of malaria cases.,This article describes molecular epidemiologic investigations currently being carried out by the International Centers of Excellence for Malaria Research (ICEMR) network in a variety of malaria-endemic settings.,First, we discuss various novel approaches to understand malaria incidence and gametocytemia, focusing on Plasmodium falciparum and Plasmodium vivax.,Second, we describe and compare different parasite genotyping methods commonly used in malaria epidemiology and population genetics.,Finally, we discuss potential applications of molecular epidemiological tools and methods toward malaria control and elimination efforts. | We describe a case series of 17 patients hospitalized in Manaus (western Brazilian Amazon) with PCR-confirmed Plasmodium vivax infection who were treated with chloroquine and primaquine.,The major complications were jaundice and severe anemia.,No in vivo chloroquine resistance was detected.,These data help characterize the clinical profile of severe P. vivax malaria in Latin America. | 1 |
Cerebral malaria (CM) is a severe complication resulting from Plasmodium falciparum infection.,This condition has usually been associated with cognitive, behavioural and motor dysfunctions, being the retinopathy the most serious consequence resulting from the disease.,The pathophysiological mechanisms underlying this complication remain incompletely understood.,Several experimental models of CM have already been developed in order to clarify those mechanisms related to this syndrome.,In this context, the present work has been performed to investigate which possible electrophysiological and neurochemistry alterations could be involved in the CM pathology.,Experimental CM was induced in Plasmodium berghei-infected male and female C57Bl/6 mice.,The survival and neurological symptoms of CM were registered.,Brains and retina were assayed for TNF levels and NOS2 expression.,Electroretinography measurements were recorded to assessed a- and b-wave amplitudes and neurochemicals changes were evaluated by determination of glutamate and glutathione levels by HPLC.,Susceptible C57Bl/6 mice infected with ≈ 106 parasitized red blood cells (P. berghei ANKA strain), showed a low parasitaemia, with evident clinical signs as: respiratory failure, ataxia, hemiplegia, and coma followed by animal death.,In parallel to the clinical characterization of CM, the retinal electrophysiological analysis showed an intense decrease of a- and-b-wave amplitude associated to cone photoreceptor response only at the 7 days post-infection.,Neurochemical results demonstrated that the disease led to a decrease in the glutathione levels with 2 days post inoculation.,It was also demonstrated that the increase in the glutathione levels during the infection was followed by the increase in the 3H-glutamate uptake rate (4 and 7 days post-infection), suggesting that CM condition causes an up-regulation of the transporters systems.,Furthermore, these findings also highlighted that the electrophysiological and neurochemical alterations occurs in a manner independent on the establishment of an inflammatory response, once tumour necrosis factor levels and inducible nitric oxide synthase expression were altered only in the cerebral tissue but not in the retina.,In summary, these findings indicate for the first time that CM induces neurochemical and electrophysiological impairment in the mice retinal tissue, in a TNF-independent manner. | Persistent neurocognitive impairments occur in a fifth of children hospitalized with severe falciparum malaria.,There is little data on the association between different neurological phenotypes of severe malaria (seizures, impaired consciousness and prostration) and impairments in executive function.,Executive functioning of children exposed to severe malaria with different neurological phenotypes (N = 58) and in those unexposed (N = 56) was examined using neuropsychological tests such as vigilance test, test for everyday attention test for children (TEA-Ch), contingency naming test (CNT) and self-ordered pointing test (SOPT).,Linear regression was used to determine the association between neurological phenotypes of severe malaria and executive function performance scores, accounting for potential confounders.,Children with complex seizures in severe malaria performed more poorly than unexposed controls in the vigilance (median efficiency scores (interquartile range) = 4.84 (1.28-5.68) vs.,5.84 (4.71-6.42), P = 0.030) and SOPT (mean errors (standard deviation) = 29.50 (8.82) vs.,24.80 (6.50), P = 0.029) tests, but no differences were observed in TEA-Ch and CNT tests.,Performance scores for other neurological phenotypes of severe malaria were similar with those of unexposed controls.,After accounting for potential confounders, such as child’s age, sex, schooling; maternal age, schooling and economic activity; perinatal factors and history of seizures, complex seizures remained associated with efficiency scores in the vigilance test (beta coefficient (β) (95% confidence interval (CI)) = -0.40 (-0.67, -0.13), P = 0.006) and everyday attention scores of the TEA-Ch test (β (95% CI) = -0.57 (-1.04, -0.10), P = 0.019); the association with SOPT error scores was weak (β (95% CI) = 4.57 (-0.73-9.89), P = 0.089).,Combined neurological phenotypes were not significantly associated with executive function performance scores.,Executive function impairment in children with severe malaria is associated with specific neurological phenotypes, particularly complex seizures.,Effective prophylaxis and management of malaria-associated acute seizures may improve executive functioning performance scores of children. | 1 |
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.,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.,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.,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. | Intermittent Preventive Treatment of malaria in infants using sulfadoxine-pyrimethamine (SP-IPTi) is recommended by WHO for implementation in settings where resistance to SP is not high.,Here we examine the relationship between the protective efficacy of SP-IPTi and measures of SP resistance.,We analysed the relationship between protective efficacy reported in the 7 SP-IPTi trials and contemporaneous data from 6 in vivo efficacy studies using SP and 7 molecular studies reporting frequency of dhfr triple and dhps double mutations within 50km of the trial sites.,We found a borderline significant association between frequency of the dhfr triple mutation and protective efficacy to 12 months of age of SP-IPTi.,This association is significantly biased due to differences between studies, namely number of doses of SP given and follow up times.,However, fitting a simple probabilistic model to determine the relationship between the frequency of the dhfr triple, dhps double and dhfr/dhps quintuple mutations associated with resistance to SP and protective efficacy, we found a significant inverse relationship between the dhfr triple mutation frequency alone and the dhfr/dhps quintuple mutations and efficacy at 35 days post the 9 month dose and up to 12 months of age respectively.,A significant relationship was found between the frequency of the dhfr triple mutation and SP-IPTi protective efficacy at 35 days post the 9 month dose.,An association between the protective efficacy to 12 months of age and dhfr triple and dhfr/dhps quintuple mutations was found but should be viewed with caution due to bias.,It was not possible to define a more definite relationship based on the data available from these trials. | 1 |
Global malaria has been on the decline over the past decade due to expansion of interventions.,The present study aimed at determining the current status of malaria epidemiology in the context of sustained interventions and seasonal variations in Bolifamba, which represents a typical semi-urban malaria endemic community in the Cameroonian rainforest.,A monthly cross-sectional survey was carried out in Bolifamba, a multi ethnic semi-urban locality on the eastern flanks of Mt Cameroon, for a year during which blood samples were collected from participants and examined for malaria parasites by microscopy.,Correlation analysis of seasonal/monthly malaria prevalence was done with weather data from Ekona, a nearby village with a meteorological station.,Intervention strategy such as use of Insecticide Treated Bed Net (ITBN) and risk factors such as duration of stay in the locality, age and housing type were also investigated.,The results revealed a malaria prevalence of 38.3 % in the rainy season, which was significantly higher than 24.4 % observed in the dry season (P < 0.0001).,A high prevalence of asymptomatic malaria which was more than double the prevalence of symptomatic malaria on a monthly basis was observed, 30.7 % vs 17.8 % in the rainy and dry season respectively (p < 0.0001) and asymptomatic malaria was significantly associated with anemia (p < 0.005).,April was the peak month of malaria prevalence and coincided with peak periods of both asymptomatic and symptomatic malaria.,The Plasmodium falciparum parasite rates in the 2- up to 10-years age group (PfPR(2-10)) was 40.8 %.,The regular use of ITBN was significantly associated with low prevalence of 31.7 % as opposed to irregular or non-usage of ITBN 38.2 % (p < 0.05).,Log of parasite load was found to initially increase to 2.49 with less than 5 years of stay, and decreased gradually with increasing duration of stay in the locality (p = 0.046).,Climatic factors were significantly and positively associated with monthly malaria prevalence and the strongest predictors of malaria prevalence were rainfall and minimum temperature with r values of 0.563 and 0.6 respectively.,The study highlights the role of seasonal change in modifying malaria prevalence during the year and the beneficial effect of ITBN.,It also underscores a sublime problem of asymptomatic malaria associated with anemia, and indicates that partial immunity is acquired with prolonged stay in Bolifamba.,This preliminary result is the basis of ongoing work to identify the antigens involved in acquired immunity. | Human co-infection with malaria and helmimths is ubiquitous throughout Africa.,Nevertheless, its public health significance on malaria severity remains poorly understood.,To contribute to a better understanding of epidemiology and control of this co-infection in Cameroon, a cross-sectional study was carried out to assess the prevalence of concomitant intestinal geohelminthiasis and malaria, and to evaluate its association with malaria and anaemia in Nkassomo and Vian.,Finger prick blood specimens from a total of 263 participants aged 1-95 years were collected for malaria microscopy, assessment of haemoglobin levels, and molecular identification of Plasmodium species by PCR.,Fresh stool specimens were also collected for the identification and quantification of geohelminths by the Kato-Katz method.,The prevalence of malaria, geohelminths, and co-infections were 77.2%, 28.6%, and 22.1%, respectively.,Plasmodium falciparum was the only malaria parasite species identified with mean parasite density of 111 (40; 18,800) parasites/µl of blood.,The geohelminths found were Ascaris lumbricoides (21.6%) and Trichuris trichiura (10.8%), with mean parasite densities of 243 (24; 3,552) and 36 (24; 96) eggs/gram of faeces, respectively.,Co-infections of A. lumbricoides and P. falciparum were the most frequent and correlated positively.,While no significant difference was observed on the prevalences of single and co-infections between the two localities, there was a significant difference in the density of A. lumbricoides infection between the two localities.,The overall prevalence of anaemia was 42%, with individuals co-infected with T. trichiura and P. falciparum (60%) being the most at risk.,While the prevalence of malaria and anaemia were inversely related to age, children aged 5-14 years were more susceptible to geohelminthiasis and their co-infections with malaria.,Co-existence of geohelminths and malaria parasites in Nkassomo and Vian enhances the occurrence of co-infections, and consequently, increases the risk for anaemia. | 1 |
Merozoite proteins of the malaria parasites involved in the invasion of red blood cells are selected by host immunity and their diversity is greatly influenced by changes in malaria epidemiology.,In the Greater Mekong Subregion (GMS), malaria transmission is concentrated along the international borders and there have been major changes in malaria epidemiology with Plasmodium vivax becoming the dominant species in many regions.,Here, we aimed to evaluate the genetic diversity of P. vivax Duffy-binding protein gene domain II (pvdbp-II) in isolates from the eastern and western borders of Myanmar, and compared it with that from global P. vivax populations.,pvdbp-II sequences were obtained from 85 and 82 clinical P. vivax isolates from the eastern and western Myanmar borders, respectively.,In addition, 504 pvdbp-II sequences from nine P. vivax populations of the world were retrieved from GenBank and used for comparative analysis of genetic diversity, recombination and population structure of the parasite population.,The nucleotide diversity of the pvdbp-II sequences from the Myanmar border parasite isolates was not uniform, with the highest diversity located between nucleotides 1078 and 1332.,Western Myanmar isolates had a unique R391C mutation.,Evidence of positive natural selection was detected in pvdbp-II gene in P. vivax isolates from the eastern Myanmar area.,P. vivax parasite populations in the GMS, including those from the eastern, western, and central Myanmar as well as Thailand showed low-level genetic differentiation (FST, 0.000-0.099).,Population genetic structure analysis of the pvdbp-II sequences showed a division of the GMS populations into four genetic clusters.,A total of 60 PvDBP-II haplotypes were identified in 210 sequences from the GMS populations.,Among the epitopes in PvDBP-II, high genetic diversity was found in epitopes 45 (379-SIFGT(D/G)(E/K)(K/N)AQQ(R/H)(R/C)KQ-393, π = 0.029) and Ia (416-G(N/K)F(I/M)WICK(L/I)-424], Ib [482-KSYD(Q/E)WITR-490, π = 0.028) in P. vivax populations from the eastern and western borders of Myanmar.,The pvdbp-II gene is genetically diverse in the eastern and western Myanmar border P. vivax populations.,Positive natural selection and recombination occurred in pvdbp-II gene.,Low-level genetic differentiation was identified, suggesting extensive gene flow of the P. vivax populations in the GMS.,These results can help understand the evolution of the P. vivax populations in the course of regional malaria elimination and guide the design of PvDBP-II-based vaccine. | Plasmodium vivax Duffy binding protein (PvDBP) plays an essential role in erythrocyte invasion and a potential asexual blood stage vaccine candidate antigen against P. vivax.,The polymorphic nature of PvDBP, particularly amino terminal cysteine-rich region (PvDBPII), represents a major impediment to the successful design of a protective vaccine against vivax malaria.,In this study, the genetic polymorphism and natural selection at PvDBPII among Myanmar P. vivax isolates were analysed.,Fifty-four P. vivax infected blood samples collected from patients in Myanmar were used.,The region flanking PvDBPII was amplified by PCR, cloned into Escherichia coli, and sequenced.,The polymorphic characters and natural selection of the region were analysed using the DnaSP and MEGA4 programs.,Thirty-two point mutations (28 non-synonymous and four synonymous mutations) were identified in PvDBPII among the Myanmar P. vivax isolates.,Sequence analyses revealed that 12 different PvDBPII haplotypes were identified in Myanmar P. vivax isolates and that the region has evolved under positive natural selection.,High selective pressure preferentially acted on regions identified as B- and T-cell epitopes of PvDBPII.,Recombination may also be played a role in the resulting genetic diversity of PvDBPII.,PvDBPII of Myanmar P. vivax isolates displays a high level of genetic polymorphism and is under selective pressure.,Myanmar P. vivax isolates share distinct types of PvDBPII alleles that are different from those of other geographical areas.,These results will be useful for understanding the nature of the P. vivax population in Myanmar and for development of PvDBPII-based vaccine. | 1 |
Sensitive diagnostic tools are required for an accurate assessment of prevalence and intensity of helminth infections in areas undergoing regular deworming, and for monitoring anthelmintic drug efficacy.,We compared the diagnostic accuracy of the Kato-Katz and FLOTAC techniques in the frame of a drug efficacy trial.,Stool samples from 343 Zanzibari children were subjected to duplicate Kato-Katz thick smears and the FLOTAC basic technique in a baseline screening in early 2009.,The FLOTAC showed a higher sensitivity than the Kato-Katz method for the diagnosis of Trichuris trichiura (95% vs. 88%, p = 0.012) and Ascaris lumbricoides (88% vs. 68%, p = 0.098), but a lower sensitivity for hookworm diagnosis (54% vs. 81%, p = 0.006).,Considering the combined results from both methods as ‘gold’ standard, the prevalences of T. trichiura, hookworm and A. lumbricoides were 71% (95% confidence interval (CI): 66-75%), 22% (95% CI: 17-26%) and 12% (95% CI: 8-15%), respectively.,At follow-up, 3-5 weeks after 174 among the 269 re-examined children were administered anthelmintic drugs, we observed cure rates (CRs) against A. lumbricoides, hookworm and T. trichiura of 91% (95% CI: 80-100%), 61% (95% CI: 48-75%) and 41% (95% CI: 34-49%), respectively, when using the Kato-Katz method.,FLOTAC revealed lower CRs against A. lumbricoides (83%, 95% CI: 67-98%) and T. trichiura (36%, 95% CI: 29-43%), but a higher CR against hookworm (69%, 95% CI: 57-82%).,These differences, however, lacked statistical significance.,Considerable differences were observed in the geometric mean fecal egg counts between the two methods with lower egg reduction rates (ERRs) determined by FLOTAC.,Our results suggest that the FLOTAC technique, following further optimization, might become a viable alternative to the Kato-Katz method for anthelmintic drug efficacy studies and for monitoring and evaluation of deworming programs.,The lower CRs and ERRs determined by FLOTAC warrant consideration and could strategically impact future helminth control programs. | Although accurate assessment of the prevalence of Schistosoma mansoni is important for the design and evaluation of control programs, the most widely used tools for diagnosis are limited by suboptimal sensitivity, slow turn-around-time, or inability to distinguish current from former infections.,Recently, two tests that detect circulating cathodic antigen (CCA) in urine of patients with schistosomiasis became commercially available.,As part of a larger study on schistosomiasis prevalence in young children, we evaluated the performance and diagnostic accuracy of these tests-the carbon test strip designed for use in the laboratory and the cassette format test intended for field use.,In comparison to 6 Kato-Katz exams, the carbon and cassette CCA tests had sensitivities of 88.4% and 94.2% and specificities of 70.9% and 59.4%, respectively.,However, because of the known limitations of the Kato-Katz assay, we also utilized latent class analysis (LCA) incorporating the CCA, Kato-Katz, and schistosome-specific antibody results to determine their sensitivities and specificities.,The laboratory-based CCA test had a sensitivity of 91.7% and a specificity of 89.4% by LCA while the cassette test had a sensitivity of 96.3% and a specificity of 74.7%.,The intensity of the reaction in both urine CCA tests reflected stool egg burden and their performance was not affected by the presence of soil transmitted helminth infections.,Our results suggest that urine-based assays for CCA may be valuable in screening for S. mansoni infections. | 1 |
Defining spatial and temporal occurrences of triatomine vectors of Trypanosoma cruzi, the agent of Chagas disease, in the US is critical for public health protection.,Through a citizen science program and field collections from 2012 to 2016, we collected 3,215 triatomines, mainly from Texas.,Using morphological and molecular approaches, we identified seven Triatoma species and report sex, length, and blood engorgement status.,Many citizen-collected triatomines (92.9%) were encountered indoors, in peridomestic settings, or in dog kennels and represent spillover transmission risk of T. cruzi to humans and domestic animals.,The most commonly collected species were Triatoma gerstaeckeri and Triatoma sanguisuga.,Adult T. gerstaeckeri were collected from May to September, peaking from June to July, whereas adult T. sanguisuga were active later, from June to October, peaking from July to September.,Based on cross correlation analyses, peaks of captures varied by species and across years.,Point pattern analyses revealed unique occurrences of T. sanguisuga in north and east Texas, T. gerstaeckeri in south and west Texas, Triatoma indictiva and Triatoma lecticularia in central Texas, and Triatoma rubida in west Texas.,These relatively unique spatial occurrences suggest associations with different suitable habitats and serve as a basis for future models evaluating the ecological niches of different vector species.,Understanding the temporal and spatial heterogeneity of triatomines in the southern United States will improve targeted interventions of vector control and will guide public outreach and education to reduce human and animal contact with vectors and reduce the risk of exposure to T. cruzi. | In Colombia, Rhodnius prolixus and Triatoma dimidiata are the main domestic triatomine species known to transmit T. cruzi.,However, there are multiple reports of T. cruzi transmission involving secondary vectors.,In this work, we carried out an eco-epidemiological study on Margarita Island, located in the Caribbean region of Colombia, where Chagas disease is associated with non-domiciliated vectors.,To understand the transmission dynamics of Trypanosoma cruzi in this area, we designed a comprehensive, multi-faceted study including the following: (i) entomological evaluation through a community-based insect-surveillance campaign, blood meal source determination and T. cruzi infection rate estimation in triatomine insects; (ii) serological determination of T. cruzi prevalence in children under 15 years old, as well as in domestic dogs and synanthropic mammals; (iii) evaluation of T. cruzi transmission capacity in dogs and Didelphis marsupialis, and (iv) genetic characterization of T. cruzi isolates targeting spliced-leader intergene region (SL-IR) genotypes.,Out of the 124 triatomines collected, 94 % were Triatoma maculata, and 71.6 % of them were infected with T. cruzi.,Blood-meal source analysis showed that T. maculata feeds on multiple hosts, including humans and domestic dogs.,Serological analysis indicated 2 of 803 children were infected, representing a prevalence of 0.25 %.,The prevalence in domestic dogs was 71.6 % (171/224).,Domestic dogs might not be competent reservoir hosts, as inferred from negative T. cruzi xenodiagnosis and haemoculture tests.,However, 61.5 % (8/13) of D. marsupialis, the most abundant synanthropic mammal captured, were T. cruzi-positive on xenodiagnosis and haemocultures.,This study reveals the role of peridomestic T. maculata and dogs in T. cruzi persistence in this region and presents evidence that D. marsupialis are a reservoir mediating peridomestic-zoonotic cycles.,This picture reflects the complexity of the transmission dynamics of T. cruzi in an endemic area with non-domiciliated vectors where active human infection exists.,There is an ongoing need to control peridomestic T. maculata populations and to implement continuous reservoir surveillance strategies with community participation.,The online version of this article (doi:10.1186/s13071-015-1100-2) contains supplementary material, which is available to authorized users. | 1 |
The last two decades have seen a surge in antimalarial drug development with product development partnerships taking a leading role.,Resistance of Plasmodium falciparum to the artemisinin derivatives, piperaquine and mefloquine in Southeast Asia means new antimalarials are needed with some urgency.,There are at least 13 agents in clinical development.,Most of these are blood schizonticides for the treatment of uncomplicated falciparum malaria, under evaluation either singly or as part of two-drug combinations.,Leading candidates progressing through the pipeline are artefenomel-ferroquine and lumefantrine-KAF156, both in Phase 2b.,Treatment of severe malaria continues to rely on two parenteral drugs with ancient forebears: artesunate and quinine, with sevuparin being evaluated as an adjuvant therapy.,Tafenoquine is under review by stringent regulatory authorities for approval as a single-dose treatment for Plasmodium vivax relapse prevention.,This represents an advance over standard 14-day primaquine regimens; however, the risk of acute haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency remains.,For disease prevention, several of the newer agents show potential but are unlikely to be recommended for use in the main target groups of pregnant women and young children for some years.,Latest predictions are that the malaria burden will continue to be high in the coming decades.,This fact, coupled with the repeated loss of antimalarials to resistance, indicates that new antimalarials will be needed for years to come.,Failure of the artemisinin-based combinations in Southeast Asia has stimulated a reappraisal of current approaches to combination therapy for malaria with incorporation of three or more drugs in a single treatment under consideration. | Mass anti-malarial administration has been proposed as a key component of the malaria elimination strategy in South East Asia.,The success of this approach depends on the local malaria epidemiology, nature of the anti-malarial regimen and population coverage.,Community engagement is used to promote population coverage but little research has systematically analysed its impact.,This systematic review examines population coverage and community engagement in programmes of mass anti-malarial drug administration.,This review builds on a previous review that identified 3049 articles describing mass anti-malarial administrations published between 1913 and 2011.,Further search and application of a set of criteria conducted in the current review resulted in 51 articles that were retained for analysis.,These 51 papers described the population coverage and/or community engagement in mass anti-malarial administrations.,Population coverage was quantitatively assessed and a thematic analysis was conducted on the community engagement activities.,The studies were conducted in 26 countries: in diverse healthcare and social contexts where various anti-malarial regimens under varied study designs were administered.,Twenty-eight articles reported only population coverage; 12 described only community engagement activities; and 11 community engagement and population coverage.,Average population coverage was 83% but methods of calculating coverage were frequently unclear or inconsistent.,Community engagement activities included providing health education and incentives, using community structures (e.g. existing hierarchies or health infrastructure), mobilizing human resources, and collaborating with government at some level (e.g. ministries of health).,Community engagement was often a process involving various activities throughout the duration of the intervention.,The mean population coverage was over 80% but incomplete reporting of calculation methods limits conclusions and comparisons between studies.,Various community engagement activities and approaches were described, but many articles contained limited or no details.,Other factors relevant to population coverage, such as the social, cultural and study context were scarcely reported.,Further research is needed to understand the factors that influence population coverage and adherence in mass anti-malarial administrations and the role community engagement activities and approaches play in satisfactory participation.,The online version of this article (doi:10.1186/s12936-016-1593-y) contains supplementary material, which is available to authorized users. | 1 |
We reviewed survey data deposited in the Global Neglected Tropical Diseases database and many other articles on the prevalence and distribution of Schistosoma haematobium in Nigeria.,Schistosoma haematobium surveys conducted over the period of 50 years under review using different diagnostic tools revealed that Ogun State has the highest prevalence, followed by Ekiti state, while the lowest prevalence was recorded in Adamawa.,No incidence of Schistosoma haematobium was recorded for states such as Akwa Ibom, Bayelsa, Nasarawa, Jigawa and Gombe.,In terms of endemicity, this review has shown that Nigeria is divided into four zones: hyperendemic, moderately endemic, low endemic, and no endemic zones.,A survey of 47 (15%) of the 323 dams in Nigeria revealed that 45 out of the 47 dams are located in the hyperendemic zone, while the remaining two are located in the moderately endemic zone.,Twenty (43%) of the total surveyed dams harboured Bulinus globosus and/or Biomphalaria pfeifferi, the local intermediate hosts of schistosomes, and 18 of these are located in the hyperendemic zone, while the other two are in the moderately endemic zone.,We conclude that there is an urgent need to carry out a nationwide survey to help in planning, coordinating, and evaluating schistosomiasis control activities. | Infections with schistosomes and soil-transmitted helminths exert a considerable yet underappreciated economic and public health burden on afflicted populations.,Accurate diagnosis is crucial for patient management, drug efficacy evaluations, and monitoring of large-scale community-based control programs.,The diagnostic accuracy of four copromicroscopic techniques (i.e., Kato-Katz, Koga agar plate, ether-concentration, and FLOTAC) for the detection of Schistosoma mansoni and soil-transmitted helminth eggs was compared using stool samples from 112 school children in Côte d'Ivoire.,Combined results of all four methods served as a diagnostic ‘gold’ standard and revealed prevalences of S. mansoni, hookworm, Trichuris trichiura, Strongyloides stercoralis and Ascaris lumbricoides of 83.0%, 55.4%, 40.2%, 33.9% and 28.6%, respectively.,A single FLOTAC from stool samples preserved in sodium acetate-acetic acid-formalin for 30 or 83 days showed a higher sensitivity for S. mansoni diagnosis (91.4%) than the ether-concentration method on stool samples preserved for 40 days (85.0%) or triplicate Kato-Katz using fresh stool samples (77.4%).,Moreover, a single FLOTAC detected hookworm, A. lumbricoides and T. trichiura infections with a higher sensitivity than any of the other methods used, but resulted in lower egg counts.,The Koga agar plate method was the most accurate diagnostic assay for S. stercoralis.,We have shown that the FLOTAC method holds promise for the diagnosis of S. mansoni.,Moreover, our study confirms that FLOTAC is a sensitive technique for detection of common soil-transmitted helminths.,For the diagnosis of S. stercoralis, the Koga agar plate method remains the method of choice. | 1 |
The Neglected Tropical Disease onchocerciasis is a parasitic disease.,Despite many control programmes by the World Health Organization (WHO), large communities in West and Central Africa are still affected.,Besides logistic challenges during biannual mass drug administration, the lack of a robust, point-of-care diagnostic is limiting successful eradication of onchocerciasis.,Towards the implementation of a non-invasive and point-of-care diagnostic, we have recently reported the discovery of the biomarker N-acetyltyramine-O-glucuronide (NATOG) in human urine samples using a metabolomics-mining approach.,NATOG’s biomarker value was enhanced during an investigation in a rodent model.,Herein, we further detail the specificity of NATOG in active onchocerciasis infections as well as the co-infecting parasites Loa loa and Mansonella perstans.,Our results measured by liquid chromatography coupled with mass spectrometry (LC-MS) reveal elevated NATOG values in mono- and co-infection samples only in the presence of the nematode Onchocerca volvulus.,Metabolic pathway investigation of l-tyrosine/tyramine in all investigated nematodes uncovered an important link between the endosymbiotic bacterium Wolbachia and O. volvulus for the biosynthesis of NATOG.,Based on these extended studies, we suggest NATOG as a biomarker for tracking active onchocerciasis infections and provide a threshold concentration value of NATOG for future diagnostic tool development. | Since the mid-2000s, the immunochromatographic card test (ICT), a point-of-care test for detecting Wuchereria bancrofti circulating filarial antigens (CFAs), has been the backbone for mapping and monitoring lymphatic filariasis (LF) worldwide.,Recently, there have been instances in which CFA positivity has been associated with Loa loa microfilaremia.,Here, we examined the association, at both the community and individual levels, between L. loa and CFA using additional diagnostic tools (quantitative polymerase chain reaction [qPCR], Og4C3 enzyme-linked immunosorbent assay, and IgG4 antibodies to Wb123 assays) to demonstrate the relationship between L. loa microfilaremia and ICT positivity.,In May 2013, peripheral blood was collected during the day from 1,812 individuals living in southern Cameroon.,ICT tests were done on the spot, and positive individuals were resampled at night.,Results of qPCR and Wb123 assays concurred proving the absence of W. bancrofti infection.,Og4C3 assays indicate a quantitative relationship between the level of L. loa microfilaremia and that of CFA.,This was confirmed by epidemiological analyses, which reveal a strong association between L. loa microfilaremia and ICT positivity, with 50% of ICT reacting to L. loa when its microfilarial density exceeds 30,000 microfilariae/mL.,At the community level, the proportion of positive ICT would exceed 2% when the prevalence of L. loa microfilaremia in the total population is above 20%.,This has significant implications in terms of mapping and control of LF caused by W. bancrofti in Loa-endemic areas.,Cross-reactivity of ICT with L. loa has to be considered in the context of both individual and community diagnostics. | 1 |
The leading malaria vaccine in development is the circumsporozoite protein (CSP)-based particle vaccine, RTS,S, which targets the pre-erythrocytic stage of Plasmodium falciparum infection.,It induces modest levels of protective efficacy, thought to be mediated primarily by CSP-specific antibodies.,We aimed to enhance vaccine efficacy by generating a more immunogenic CSP-based particle vaccine and therefore developed a next-generation RTS,S-like vaccine, called R21.,The major improvement is that in contrast to RTS,S, R21 particles are formed from a single CSP-hepatitis B surface antigen (HBsAg) fusion protein, and this leads to a vaccine composed of a much higher proportion of CSP than in RTS,S.,We demonstrate that in BALB/c mice R21 is immunogenic at very low doses and when administered with the adjuvants Abisco-100 and Matrix-M it elicits sterile protection against transgenic sporozoite challenge.,Concurrent induction of potent cellular and humoral immune responses was also achieved by combining R21 with TRAP-based viral vectors and protective efficacy was significantly enhanced.,In addition, in contrast to RTS,S, only a minimal antibody response to the HBsAg carrier was induced.,These studies identify an anti-sporozoite vaccine component that may improve upon the current leading malaria vaccine RTS,S.,R21 is now under evaluation in Phase 1/2a clinical trials. | Transmission-blocking vaccines (TBV) target the sexual-stages of the malaria parasite in the mosquito midgut and are widely considered to be an essential tool for malaria elimination.,High-titer functional antibodies are required against target antigens to achieve effective transmission-blocking activity.,We have fused Pfs25, the leading malaria TBV candidate antigen to IMX313, a molecular adjuvant and expressed it both in ChAd63 and MVA viral vectors and as a secreted protein-nanoparticle.,Pfs25-IMX313 expressed from viral vectors or as a protein-nanoparticle is significantly more immunogenic and gives significantly better transmission-reducing activity than monomeric Pfs25.,In addition, we demonstrate that the Pfs25-IMX313 protein-nanoparticle leads to a qualitatively improved antibody response in comparison to soluble Pfs25, as well as to significantly higher germinal centre (GC) responses.,These results demonstrate that antigen multimerization using IMX313 is a very promising strategy to enhance antibody responses against Pfs25, and that Pfs25-IMX313 is a highly promising TBV candidate vaccine. | 1 |
Preventative chemotherapy without community hygiene and animal health programs may be leading to emergence of this zoonosis.,Ancylostoma ceylanicum, a hookworm of canids and felids in Asia, is becoming the second most common hookworm infecting humans.,In 2012, we investigated the prevalence and infection dynamics of and risk factors for hookworm infections in humans and dogs in a rural Cambodian village.,Over 57% of the population was infected with hookworms; of those, 52% harbored A. ceylanicum hookworms.,The greatest intensities of A. ceylanicum eggs were in persons 21-30 years of age.,Over 90% of dogs also harbored A. ceylanicum hookworms.,Characterization of the cytochrome oxidase-1 gene divided isolates of A. ceylanicum hookworms into 2 groups, 1 containing isolates from humans only and the other a mix of isolates from humans and animals.,We hypothesize that preventative chemotherapy in the absence of concurrent hygiene and animal health programs may be a factor leading to emergence of A. ceylanicum infections; thus, we advocate for a One Health approach to control this zoonosis. | Infections with schistosomes and soil-transmitted helminths exert a considerable yet underappreciated economic and public health burden on afflicted populations.,Accurate diagnosis is crucial for patient management, drug efficacy evaluations, and monitoring of large-scale community-based control programs.,The diagnostic accuracy of four copromicroscopic techniques (i.e., Kato-Katz, Koga agar plate, ether-concentration, and FLOTAC) for the detection of Schistosoma mansoni and soil-transmitted helminth eggs was compared using stool samples from 112 school children in Côte d'Ivoire.,Combined results of all four methods served as a diagnostic ‘gold’ standard and revealed prevalences of S. mansoni, hookworm, Trichuris trichiura, Strongyloides stercoralis and Ascaris lumbricoides of 83.0%, 55.4%, 40.2%, 33.9% and 28.6%, respectively.,A single FLOTAC from stool samples preserved in sodium acetate-acetic acid-formalin for 30 or 83 days showed a higher sensitivity for S. mansoni diagnosis (91.4%) than the ether-concentration method on stool samples preserved for 40 days (85.0%) or triplicate Kato-Katz using fresh stool samples (77.4%).,Moreover, a single FLOTAC detected hookworm, A. lumbricoides and T. trichiura infections with a higher sensitivity than any of the other methods used, but resulted in lower egg counts.,The Koga agar plate method was the most accurate diagnostic assay for S. stercoralis.,We have shown that the FLOTAC method holds promise for the diagnosis of S. mansoni.,Moreover, our study confirms that FLOTAC is a sensitive technique for detection of common soil-transmitted helminths.,For the diagnosis of S. stercoralis, the Koga agar plate method remains the method of choice. | 1 |
Visceral Leishmaniasis (VL) causes high morbidity and mortality in low-to-middle-income countries worldwide.,In this study, we used Laser Direct-Write (LDW) technology to develop a new Lateral Flow Device (LFD) with double-channel geometry on a low-cost paper platform as a rapid and accurate serodiagnostic assay for human VL.,This Duplex VL-LFD was based on a laser-patterned microfluidic device using two recombinant Leishmania proteins, β-tubulin and LiHyp1, as novel diagnostic antigens.,The VL-LFD assay was tested with blood/serum samples from patients diagnosed with VL, Tegumentary Leishmaniasis, Leishmaniasis of unknown identity, other parasitic diseases with similar clinical symptoms, i.e.,Leprosy Disease and Chagas Disease, and blood from healthy donors, and compared in parallel with commercial rK39 IT-LEISH® Kit.,Clinical diagnosis and real-time Polymerase Chain Reaction assay were used as reference standards.,VL-LFD Sensitivity (S ± 95% Confidence Intervals (CI)) of 90.9 (78.9-100) and Specificity (Sp ± 95% CI) of 98.7 (96.1-100) outperformed the IT-LEISH® Kit [S = 77.3 (59.8-94.8), Sp = 94.7 (89.6-99.8)].,This is the first study reporting successful development of an LFD assay using the LDW technology and the VL-LFD warrants comparative testing in larger patient cohorts and in areas with endemic VL in order to improve diagnosis and disease management. | Visceral leishmaniasis (VL), the most severe form of leishmaniasis, is endemic in Europe with Mediterranean countries reporting endemic status alongside a worrying northward spread.,Serological diagnosis, including immunochromatographic test based on the recombinant antigen rK39 (rK39-ICT) and a direct agglutination test (DAT) based on the whole parasite antigen, have been validated in regions with high VL burden, such as eastern Africa and the Indian subcontinent.,To date, no studies using a large set of patients have performed an assessment of both methods within Europe.,We selected a range of clinical serum samples from patients with confirmed VL (including HIV co-infection), Chagas disease, malaria, other parasitic infections and negative samples (n = 743; years 2009-2015) to test the performance of rK39-ICT rapid test (Kalazar Detect Rapid Test; InBios International, Inc., USA) and DAT (ITM-DAT/VLG; Institute of Tropical Medicine Antwerp, Belgium).,An in-house immunofluorescence antibody test (IFAT), was included for comparison.,Estimated sensitivities for rK39-ICT and DAT in HIV-negative VL patients were 83.1% [75.1-91.2] and 84.2% [76.3-92.1], respectively.,Sensitivity was reduced to 67.3% [52.7-82.0] for rK39 and increased to 91.3% [82.1-100.0] for DAT in HIV/VL co-infected patients.,The in-house IFAT was more sensitive in HIV-negative VL patients, 84.2% [76.3-92.1] than in HIV/VL patients, 79.4% [73.3-96.2].,DAT gave 32 false positives in sera from HIV-negative VL suspects, compared to 0 and 2 for rK39 and IFAT, respectively, but correctly detected more HIV/VL patients (42/46) than rK39 (31/46) and IFAT (39/46).,Though rK39-ICT and DAT exhibited acceptable sensitivity and specificity a combination with other tests is required for highly sensitive diagnosis of VL cases in Spain.,Important variation in the performance of the tests were seen in patients co-infected with HIV or with other parasitic infections.,This study can help inform the choice of serological test to be used when screening or diagnosing VL in a European Mediterranean setting. | 1 |
Malaria burden in Uganda has declined disproportionately among regions despite overall high intervention coverage across all regions.,The Uganda Malaria Indicator Survey (MIS) 2014-15 was the second nationally representative survey conducted to provide estimates of malaria prevalence among children less than 5 years, and to track the progress of control interventions in the country.,In this present study, 2014-15 MIS data were analysed to assess intervention effects on malaria prevalence in Uganda among children less than 5 years, assess intervention effects at regional level, and estimate geographical distribution of malaria prevalence in the country.,Bayesian geostatistical models with spatially varying coefficients were used to determine the effect of interventions on malaria prevalence at national and regional levels.,Spike-and-slab variable selection was used to identify the most important predictors and forms.,Bayesian kriging was used to predict malaria prevalence at unsampled locations.,Indoor Residual Spraying (IRS) and Insecticide Treated Nets (ITN) ownership had a significant but varying protective effect on malaria prevalence.,However, no effect was observed for Artemisinin Combination-based Therapies (ACTs).,Environmental factors, namely, land cover, rainfall, day and night land surface temperature, and area type were significantly associated with malaria prevalence.,Malaria prevalence was higher in rural areas, increased with the child’s age, and decreased with higher household socioeconomic status and higher level of mother’s education.,The highest prevalence of malaria in children less than 5 years was predicted for regions of East Central, North East and West Nile, whereas the lowest was predicted in Kampala and South Western regions, and in the mountainous areas in Mid-Western and Mid-Eastern regions.,IRS and ITN ownership are important interventions against malaria prevalence in children less than 5 years in Uganda.,The varying effects of the interventions calls for selective implementation of control tools suitable to regional ecological settings.,To further reduce malaria burden and sustain malaria control in Uganda, current tools should be supplemented by health system strengthening, and socio-economic development. | Recent increases in funding for malaria control have led to the reduction in transmission in many malaria endemic countries, prompting the national control programmes of 36 malaria endemic countries to set elimination targets.,Accounting for human population movement (HPM) in planning for control, elimination and post-elimination surveillance is important, as evidenced by previous elimination attempts that were undermined by the reintroduction of malaria through HPM.,Strategic control and elimination planning, therefore, requires quantitative information on HPM patterns and the translation of these into parasite dispersion.,HPM patterns and the risk of malaria vary substantially across spatial and temporal scales, demographic and socioeconomic sub-groups, and motivation for travel, so multiple data sets are likely required for quantification of movement.,While existing studies based on mobile phone call record data combined with malaria transmission maps have begun to address within-country HPM patterns, other aspects remain poorly quantified despite their importance in accurately gauging malaria movement patterns and building control and detection strategies, such as cross-border HPM, demographic and socioeconomic stratification of HPM patterns, forms of transport, personal malaria protection and other factors that modify malaria risk.,A wealth of data exist to aid filling these gaps, which, when combined with spatial data on transport infrastructure, traffic and malaria transmission, can answer relevant questions to guide strategic planning.,This review aims to (i) discuss relevant types of HPM across spatial and temporal scales, (ii) document where datasets exist to quantify HPM, (iii) highlight where data gaps remain and (iv) briefly put forward methods for integrating these datasets in a Geographic Information System (GIS) framework for analysing and modelling human population and Plasmodium falciparum malaria infection movements. | 1 |
Since the year 2000, a concerted campaign against malaria has led to unprecedented levels of intervention coverage across sub-Saharan Africa.,Understanding the effect of this control effort is vital to inform future control planning.,However, the effect of malaria interventions across the varied epidemiological settings of Africa remains poorly understood owing to the absence of reliable surveillance data and the simplistic approaches underlying current disease estimates.,Here we link a large database of malaria field surveys with detailed reconstructions of changing intervention coverage to directly evaluate trends from 2000 to 2015 and quantify the attributable effect of malaria disease control efforts.,We found that Plasmodium falciparum infection prevalence in endemic Africa halved and the incidence of clinical disease fell by 40% between 2000 and 2015.,We estimate that interventions have averted 663 (542-753 credible interval) million clinical cases since 2000.,Insecticide-treated nets, the most widespread intervention, were by far the largest contributor (68% of cases averted).,Although still below target levels, current malaria interventions have substantially reduced malaria disease incidence across the continent.,Increasing access to these interventions, and maintaining their effectiveness in the face of insecticide and drug resistance, should form a cornerstone of post-2015 control strategies. | The efficacy of bendiocarb against pyrethroid resistant An. gambiae and the residual life of this insecticide on different substrates were evaluated under laboratory and field conditions.,Bioassays according to the WHO (World Health Organization) standard protocol were carried out on different substrates impregnated with bendiocarb.,Data were analyzed using a binomial regression model with R software.,A good efficacy of the bendiocarb against pyrethroid resistant An. gambiae and a high variation of its residual life according to the surfaces treated was observed.,The probability that a female mosquito died after exposure to a treated substrate was below 80% after 13 weeks for the teak wood; 7 weeks for the wall made with a mixture of sand and cement and 6 weeks for walls made with red clay and those made with a mixture of the red clay and cement.,Considering the residual life of bendiocarb on walls made with red clay, the main substrates treated during IRS campaigns in rural areas in Benin, more than 2 treatments rounds per year would be necessary to achieve a long term efficacy of IRS using bendiocarb in these areas.,Financial and logistical resources required to achieve such levels of coverage need more political will from leaders of African endemic countries.,While waiting for innovative malaria control tool, alternative insecticides or combinations of insecticides have to be used for insecticide resistance management in Benin. | 1 |
In humans, immunity to Plasmodium sp. generally takes the form of protection from symptomatic malaria (i.e., 'clinical immunity') rather than infection ('sterilizing immunity').,In contrast, mice infected with Plasmodium develop sterilizing immunity, hindering progress in understanding the mechanistic basis of clinical immunity.,Here we present a novel model in which mice persistently infected with P. chabaudi exhibit limited clinical symptoms despite sustaining patent parasite burdens for many months.,Characterization of immune responses in persistently infected mice revealed development of CD4+ T cell exhaustion, increased production of IL-10, and expansion of B cells with an atypical surface phenotype.,Additionally, persistently infected mice displayed a dramatic increase in circulating nonclassical monocytes, a phenomenon that we also observed in humans with both chronic Plasmodium exposure and asymptomatic infection.,Following pharmacological clearance of infection, previously persistently infected mice could not control a secondary challenge, indicating that persistent infection disrupts the sterilizing immunity that typically develops in mouse models of acute infection.,This study establishes an animal model of asymptomatic, persistent Plasmodium infection that recapitulates several central aspects of the immune response in chronically exposed humans.,As such, it provides a novel tool for dissection of immune responses that may prevent development of sterilizing immunity and limit pathology during infection. | Most patients with cerebral malaria (CM) sustain cerebral microvascular sequestration of Plasmodium falciparum-infected red blood cells (iRBCs).,Although many young children are infected with P. falciparum, CM remains a rare outcome; thus, we hypothesized that specific host conditions facilitate iRBC cerebral sequestration.,To identify these host factors, we compared the peripheral whole-blood transcriptomes of Malawian children with iRBC cerebral sequestration, identified as malarial-retinopathy-positive CM (Ret+CM), to the transcriptomes of children with CM and no cerebral iRBC sequestration, defined as malarial-retinopathy-negative CM (Ret-CM).,Ret+CM was associated with upregulation of 103 gene set pathways, including cytokine, blood coagulation, and extracellular matrix (ECM) pathways (P < 0.01; false-discovery rate [FDR] of <0.05).,Neutrophil transcripts were the most highly upregulated individual transcripts in Ret+CM patients.,Activated neutrophils can modulate diverse host processes, including the ECM, inflammation, and platelet biology to potentially facilitate parasite sequestration.,Therefore, we compared plasma neutrophil proteins and neutrophil chemotaxis between Ret+CM and Ret-CM patients.,Plasma levels of human neutrophil elastase, myeloperoxidase, and proteinase 3, but not lactoferrin or lipocalin, were elevated in Ret+CM patients, and neutrophil chemotaxis was impaired, possibly related to increased plasma heme.,Neutrophils were rarely seen in CM brain microvasculature autopsy samples, and no neutrophil extracellular traps were found, suggesting that a putative neutrophil effect on endothelial cell biology results from neutrophil soluble factors rather than direct neutrophil cellular tissue effects.,Meanwhile, children with Ret-CM had lower levels of inflammation, higher levels of alpha interferon, and upregulation of Toll-like receptor pathways and other host transcriptional pathways, which may represent responses that do not favor cerebral iRBC sequestration.,There were approximately 198 million cases of malaria worldwide in 2013, with an estimated 584,000 deaths occurring mostly in sub-Saharan African children.,CM is a severe and rare form of Plasmodium falciparum infection and is associated with high rates of mortality and neurological morbidity, despite antimalarial treatment.,A greater understanding of the pathophysiology of CM would allow the development of adjunctive therapies to improve clinical outcomes.,A hallmark of CM is cerebral microvasculature sequestration of P. falciparum-infected red blood cells (iRBCs), which results in vasculopathy in some patients.,Our data provide a global analysis of the host pathways associated with CM and newly identify an association of activated neutrophils with brain iRBC sequestration.,Products of activated neutrophils could alter endothelial cell receptors and coagulation to facilitate iRBC adherence.,Future studies can now examine the role of neutrophils in CM pathogenesis to improve health outcomes. | 1 |
The main clinical forms of leishmaniasis in Bangladesh are visceral leishmaniasis and post-kala-azar dermal leishmaniasis, which are caused by Leishmania donovani.,Imported cutaneous leishmaniasis (CL) is emerging globally due mainly to increased human mobility.,In recent years, several imported CL cases have also been reported in Bangladesh.,Sporadic atypical cases of CL can be challenging for diagnosis and clinical management, while occurrence of infection on a frequent basis can be alarming.,We report of a case of a Bangladeshi temporary-migrant worker who, upon return, presented development of skin lesions that are characteristic of CL.,A serum sample was collected and tested with an rK39 immunochromatographic test.,Nucleic acid from skin biopsy derived culture sample was extracted and screened with a real-time PCR assay which targets the conserved REPL repeat region of L. donovani complex.,The internal transcribed spacer 2 region of the ribosomal RNA gene cluster was amplified and sequenced.,The suspect had a history of travel in both CL and VL endemic areas and had a positive rK39 test result.,Based on clinical presentation, travel history and demonstration of the parasite in the skin biopsy, CL was diagnosed and the patient underwent a combination therapy with Miltefosine and liposomal amphotericin B.,While typical endemic species were not detected, we identified Leishmania major, a species that, to our knowledge, has never been reported in Bangladesh.,Proper monitoring and reporting of imported cases should be given careful consideration for both clinical and epidemiological reasons.,Molecular tests should be performed in diagnosis to avoid dilemma, and identification of causative species should be prioritized. | Visceral leishmaniasis (VL) is distinguished by a complex interplay of immune response and parasite multiplication inside host cells.,However, the direct association between different immunological correlates and parasite numbers remains largely unknown.,We examined the plasma levels of different disease promoting/protective as well as Th17 cytokines and found IL-10, TGFβ and IL-17 to be significantly correlated with parasite load in VL patients (r = 0.52, 0.53 and 0.51 for IL-10, TGFβ and IL-17, respectively).,We then extended our investigation to a more antigen-specific response and found leishmanial antigen stimulated levels of both IL-10 and TGFβ to be significantly associated with parasite load (r = 0.71 and 0.72 for IL-10 and TGFβ respectively).,In addition to cytokines we also looked for different cellular subtypes that could contribute to cytokine secretion and parasite persistence.,Our observations manifested an association between different Treg cell markers and disease progression as absolute numbers of CD4+CD25+ (r = 0.55), CD4+CD25hi (r = 0.61) as well as percentages of CD4+CD25+FoxP3+ T cells (r = 0.68) all correlated with parasite load.,Encouraged by these results, we investigated a link between these immunological components and interestingly found both CD4+CD25+ and CD4+CD25+FoxP3+ Treg cells to secrete significantly (p<0.05) higher amounts of not only IL-10 but also TGFβ in comparison to corresponding CD25- T cells.,Our findings shed some light on source(s) of TGFβ and suggest an association between these disease promoting cytokines and Treg cells with parasite load during active disease.,Moreover, the direct evidence of CD4+CD25+FoxP3+ Treg cells as a source of IL-10 and TGFβ during active VL could open new avenues for immunotherapy towards cure of this potentially fatal disease. | 1 |
This paper presents the results of a qualitative study to investigate the perceptions and experiences of health workers involved in a a cluster-randomized controlled trial of a novel intervention to improve health worker malaria case-management in 107 government health facilities in Kenya.,The intervention involved sending text-messages about paediatric outpatient malaria case-management accompanied by “motivating” quotes to health workers’ mobile phones.,Ten malaria messages were developed reflecting recommendations from the Kenyan national guidelines.,Two messages were delivered per day for 5 working days and the process was repeated for 26 weeks (May to October 2009).,The accompanying quotes were unique to each message.,The intervention was delivered to 119 health workers and there were significant improvements in correct artemether-lumefantrine (AL) management both immediately after the intervention (November 2009) and 6 months later (May 2010).,In-depth interviews with 24 health workers were undertaken to investigate the possible drivers of this change.,The results suggest high acceptance of all components of the intervention, with the active delivery of information in an on the job setting, the ready availability of new and stored text messages and the perception of being kept ‘up to date’ as important factors influencing practice.,Applying the construct of stages of change we infer that in this intervention the SMS messages were operating primarily at the action and maintenance stages of behaviour change achieving their effect by creating an enabling environment and providing a prompt to action for the implementation of case management practices that had already been accepted as the clinical norm by the health workers.,Future trials testing the effectiveness of SMS reminders in creating an enabling environment for the establishment of new norms in clinical practice as well as in providing a prompt to action for the implementation of the new case-management guidelines are justified. | Molecular monitoring of parasite resistance has become an important complementary tool in establishing rational anti-malarial drug policies.,Community surveys provide a representative sample of the parasite population and can be carried out more rapidly than accrual of samples from clinical cases, but it is not known whether the frequencies of genetic resistance markers in clinical cases differ from those in the overall population, or whether such community surveys can provide good predictions of treatment failure rates.,Between 2003 and 2005, in vivo drug efficacy of amodiaquine or chloroquine plus sulphadoxine-pyrimethamine was determined at three sites in Papua New Guinea.,The genetic drug resistance profile (i.e., 33 single nucleotide polymorphisms in Plasmodium falciparum crt, mdr1, dhfr, dhps, and ATPase6) was concurrently assessed in 639 community samples collected in the catchment areas of the respective health facilities by using a DNA microarray-based method.,Mutant allele and haplotype frequencies were determined and their relationship with treatment failure rates at each site in each year was investigated.,PCR-corrected in vivo treatment failure rates were between 12% and 28% and varied by site and year with variable longitudinal trends.,In the community samples, the frequencies of mutations in pfcrt and pfmdr1 were high and did not show significant changes over time.,Mutant allele frequencies in pfdhfr were moderate and those in pfdhps were low.,No mutations were detected in pfATPase6.,There was much more variation between sites than temporal, within-site, variation in allele and haplotype frequencies.,This variation did not correlate well with treatment failure rates.,Allele and haplotype frequencies were very similar in clinical and community samples from the same site.,The relationship between parasite genetics and in vivo treatment failure rate is not straightforward.,The frequencies of genetic anti-malarial resistance markers appear to be very similar in community and clinical samples, but cannot be used to make precise predictions of clinical outcome.,Thus, indicators based on molecular data have to be considered with caution and interpreted in the local context, especially with regard to prior drug usage and level of pre-existing immunity.,Testing community samples for molecular drug resistance markers is a complementary tool that should help decision-making for the best treatment options and appropriate potential alternatives. | 1 |
The first-line therapy for the intermittent preventive treatment of malaria in pregnancy (IPTp) is sulphadoxine-pyrimethamine (SP).,There is an urgent need to identify safe, well-tolerated and efficacious alternatives to SP due to widespread Plasmodium falciparum resistance.,Combination therapy using azithromycin and chloroquine is one possibility that has demonstrated adequate parasitological response > 95% in clinical trials of non-pregnant adults in sub-Saharan Africa and where IPTp is a government policy in 33 countries.,Key safety, tolerability and efficacy data are presented for azithromycin and chloroquine, alone and/or in combination, when used to prevent and/or treat P. falciparum, P. vivax, and several curable sexually transmitted and reproductive tract infections (STI/RTI).,Pharmacokinetic evidence from pregnant women is also summarized for both compounds.,The azithromycin-chloroquine regimen that has demonstrated consistent efficacy in non-pregnant adults has been a 3-day course containing daily doses of 1 g of azithromycin and 600 mg base of chloroquine.,The pharmacokinetic evidence of these compounds individually suggests that dose adjustments may not be necessary when used in combination for treatment efficacy against P. falciparum, P. vivax, as well as several curable STI/ RTI among pregnant women, although clinical confirmation will be necessary.,Mass trachoma-treatment campaigns have shown that azithromycin selects for macrolide resistance in the pneumococcus, which reverses following the completion of therapy.,Most importantly, no evidence to date suggests that azithromycin induces pneumococcal resistance to penicillin. | Over 1 billion of the world's poorest inhabitants are afflicted by neglected tropical diseases (NTDs).,Integrated control programmes aimed at tackling these debilitating NTDs have been recently initiated, mainly using preventative chemotherapy.,Monitoring and evaluation (M&E) of these integrated programs presents particular challenges over and above those required for single disease vertical programmes.,We used baseline data from the National NTD Control Programme in Burkina Faso in order to assess the feasibility of an integrated survey design, as well as to elucidate the contribution of environmental variables to the risk of either Schistosoma haematobium, trachoma, or both among school-aged children.,S. haematobium infection was diagnosed by detecting eggs in urine.,A trachoma case was defined by the presence of Trachomatous inflammation-Follicular (TF) and/or Trachomatous inflammation-Intense (TI) in either eye.,Baseline data collected from 3,324 children aged 7-11 years in 21 sentinel sites across 11 regions of Burkina Faso were analyzed using simple and multivariable hierarchical binomial logistic regression models fitted by Markov Chain Monte Carlo estimation methods.,Probabilities of the risk of belonging to each infection/disease category were estimated as a function of age, gender (individual level), and environmental variables (at sentinel site level, interpolated from national meteorological stations).,Overall prevalence at the sentinel sites was 11.79% (95% CI: 10.70-12.89) for S. haematobium; 13.30% (12.14-14.45) for trachoma and 0.84% (0.53-1.15) for co-infections.,The only significant predictor of S. haematobium infection was altitude.,There were significant negative associations between the prevalence of active trachoma signs and minimum temperature, and air pressure.,Conditional upon these predictors, these data are consistent with the two pathogens being independent.,Urogenital schistosomiasis and trachoma constitute public health problems in Burkina Faso.,Sentinel site (at school level) surveys for these two NTDs can be implemented simultaneously.,However, to support MDA treatment decisions in Burkina Faso, the protocol used in this study would only be applicable to hypoendemic trachoma areas.,More research is needed to confirm if these findings can be generalized to West Africa and beyond. | 1 |
The efforts to control and eradicate polio as a global health burden have been successful to the point where currently only three countries now report endemic polio, and the number of cases of polio continues to decrease.,The success of the polio programme has been dependant on a well-developed network of laboratories termed the global polio laboratory network (GPLN).,Here we explore collaborative opportunities with the GPLN to target two of the 18 diseases listed as a neglected tropical diseases (NTD) namely soil transmitted helminthiasis (STH) and Schistosomiasis (SCH).,These were chosen based on prevalence and the use of faecal materials to identify both polio, STH and SCH.,Our study screened 448 faecal samples from the Ghana GPLN using three triplex TaqMan assays to identify Ascaris lumbricoides, Necator americanus, Ancylostoma spp, Trichuris trchiura, Strongyloides stercoralis and Schistosoma spp.,Our results found a combined helminth prevalence of 22%.,The most common helminth infection was A. lumbricoides with a prevalence of 15% followed by N. americanus (5%), Ancylostoma spp.,(2.5%), Schistosoma spp.,(1.6%) and S. stercoralis (1%).,These results show that it is possible to identify alternative pathogens to polio in the samples collected by the GPLN platform and to introduce new diagnostic assays to their laboratories.,The diagnostic methods employed were also able to identify S. stercoralis positive samples, which are difficult to identify using parasitological methods such as Kato-Katz.,This study raises the possibility of collaboration with the GPLN for the surveillance of a wider range of diseases which would both benefit the efforts to control the NTDs and also increase the scope of the GPLN as a diagnostic platform. | Two Kato-Katz thick smears (Kato-Katzs) from a single stool are currently recommended for diagnosing Schistosoma mansoni infections to map areas for intervention.,This ‘gold standard’ has low sensitivity at low infection intensities.,The urine point-of-care circulating cathodic antigen test (POC-CCA) is potentially more sensitive but how accurately they detect S. mansoni after repeated praziquantel treatments, their suitability for measuring drug efficacy and their correlation with egg counts remain to be fully understood.,We compared the accuracies of one to six Kato-Katzs and one POC-CCA for the diagnosis of S. mansoni in primary-school children who have received zero to ten praziquantel treatments.,We determined the impact each diagnostic approach may have on monitoring and evaluation (M&E) and drug-efficacy findings.,In a high S. mansoni endemic area of Uganda, three days of consecutive stool samples were collected from primary school-aged children (six - 12 years) at five time-points in year one: baseline, one-week-post-, four-weeks-post-, six-months-post-, and six-months-one-week-post-praziquantel and three time-points in years two and three: pre-, one-week-post- and four-weeks-post-praziquantel-treatment/retreatment (n = 1065).,Two Kato-Katzs were performed on each stool.,In parallel, one urine sample was collected and a single POC-CCA evaluated per child at each time-point in year one (n = 367).,At baseline, diagnosis by two Kato-Katzs (sensitivity = 98.6%) or one POC-CCA (sensitivity = 91.7%, specificity = 75.0%) accurately predicted S. mansoni infections.,However, one year later, a minimum of three Kato-Katzs, and two years later, five Kato-Katzs were required for accurate diagnosis (sensitivity >90%) and drug-efficacy evaluation.,The POC-CCA was as sensitive as six Kato-Katzs four-weeks-post and six-months-post-treatment, if trace readings were classified as positive.,Six Kato-Katzs (two/stool from three stools) and/or one POC-CCA are required for M&E or drug-efficacy studies.,Although unable to measure egg reduction rates, one POC-CCA appears to be more sensitive than six Kato-Katzs at four-weeks-post-praziquantel (drug efficacy) and six-months-post-praziquantel (M&E). | 1 |
A large proportion of malaria-infected individuals in endemic areas do not experience symptoms that prompt treatment-seeking.,These asymptomatically infected individuals may retain their infections for many months during which sexual-stage parasites (gametocytes) are produced that may be transmissible to mosquitoes.,Reductions in malaria transmission could be achieved by detecting and treating these infections early.,This study assesses the impact of enhanced community case management (CCM) and monthly screening and treatment (MSAT) on the prevalence and transmissibility of malaria infections.,This cluster-randomised trial will take place in Sapone, an area of intense, highly seasonal malaria in Burkina Faso.,In total, 180 compounds will be randomised to one of three interventions: arm 1 - current standard of care with passively monitored malaria infections; arm 2 - standard of care plus enhanced CCM, comprising active weekly screening for fever, and detection and treatment of infections in fever positive individuals using conventional rapid diagnostic tests (RDTs); or arm 3 - standard of care and enhanced CCM, plus MSAT using RDTs.,The study will be conducted over approximately 18 months covering two high-transmission seasons and the intervening dry season.,The recruitment strategy aims to ensure that overall transmission and force of infection is not affected so we are able to continuously evaluate the impact of interventions in the context of ongoing intense malaria transmission.,The main objectives of the study are to determine the impact of enhanced CCM and MSAT on the prevalence and density of parasitaemia and gametocytaemia and the transmissibility of infections.,This will be achieved by molecular detection of infections in all study participants during start and end season cross-sectional surveys and routine sampling of malaria-positive individuals to assess their infectiousness to mosquitoes.,The study has been reviewed and approved by the London School of Hygiene and Tropical Medicine (LSHTM) (Review number: 14724) and The Centre National de Recherche et de Formation sur le Paludisme institutional review board (IRB) (Deliberation N° 2018/000002/MS/SG/CNRFP/CIB) and Burkina Faso national medical ethics committees (Deliberation N° 2018-01-010).,Findings of the study will be shared with the community via local opinion leaders and community meetings.,Results may also be shared through conferences, seminars, reports, theses and peer-reviewed publications; disease occurrence data and study outcomes will be shared with the Ministry of Health.,Data will be published in an online digital repository.,NCT03705624. | The Gambia has successfully reduced malaria transmission.,The human reservoir of infection could further decrease if malaria-infected individuals could be identified by highly sensitive, field-based, diagnostic tools and then treated.,A cross-sectional survey was done at the peak of the 2017 malaria season in 47 Gambian villages.,From each village, 100 residents were randomly selected for finger-prick blood samples to detect Plasmodium falciparum infections using highly sensitive rapid diagnostic tests (HS-RDT) and PCR.,The sensitivity and specificity of the HS-RDT were estimated (assuming PCR as the gold standard) across varying transmission intensities and in different age groups.,A deterministic, age-structured, dynamic model of malaria transmission was used to estimate the impact of mass testing and treatment (MTAT) with HS-RDT in four different scenarios of malaria prevalence by PCR: 5, 15, 30, and 60%, and with seasonal transmission.,The impact was compared both to MTAT with conventional RDT and mass drug administration (MDA).,Malaria prevalence by HS-RDT was 15% (570/3798; 95% CI 13.9-16.1).,The HS-RDT sensitivity and specificity were 38.4% (191/497, 95% CI 34.2-42.71) and 88.5% (2922/3301; 95% CI 87.4-89.6), respectively.,Sensitivity was the highest (50.9%, 95% CI 43.3-58.5%) in high prevalence villages (20-50% by PCR).,The model predicted that in very low transmission areas (≤ 5%), three monthly rounds of MTAT with HS-RDT, starting towards the end of the dry season and testing 65 or 85% of the population for 2 consecutive years, would avert 62 or 78% of malaria cases (over 2 years), respectively.,The effect of the intervention would be lower in a moderate transmission setting.,In all settings, MDA would be superior to MTAT with HS-RDT which would be superior to MTAT with conventional RDT.,The HS-RDT’s field sensitivity was modest and varied by transmission intensity.,In low to very low transmission areas, three monthly rounds per year of MTAT with HS-RDT at 85% coverage for 2 consecutive years would reduce malaria prevalence to such low levels that additional strategies may achieve elimination.,The model prediction would need to be confirmed by cluster-randomized trials. | 1 |
African trypanosomiasis is a chronic debilitating disease affecting the health and economic well-being of many people in developing countries.,The pathogenicity associated with this disease involves a persistent inflammatory response, whereby M1-type myeloid cells, including Ly6Chigh inflammatory monocytes, are centrally implicated.,A comparative gene analysis between trypanosusceptible and trypanotolerant animals identified MIF (macrophage migrating inhibitory factor) as an important pathogenic candidate molecule.,Using MIF-deficient mice and anti-MIF antibody treated mice, we show that MIF mediates the pathogenic inflammatory immune response and increases the recruitment of inflammatory monocytes and neutrophils to contribute to liver injury in Trypanosoma brucei infected mice.,Moreover, neutrophil-derived MIF contributed more significantly than monocyte-derived MIF to increased pathogenic liver TNF production and liver injury during trypanosome infection.,MIF deficient animals also featured limited anemia, coinciding with increased iron bio-availability, improved erythropoiesis and reduced RBC clearance during the chronic phase of infection.,Our data suggest that MIF promotes the most prominent pathological features of experimental trypanosome infections (i.e. anemia and liver injury), and prompt considering MIF as a novel target for treatment of trypanosomiasis-associated immunopathogenicity. | To date, human African trypanosomiasis (HAT) still threatens millions of people throughout sub-Sahara Africa, and new approaches to disease prevention and treatment remain a priority.,It is commonly accepted that HAT is fatal unless treatment is provided.,However, despite the well-described general symptoms of disease progression during distinct stages of the infection, leading to encephalitic complications, coma and death, a substantial body of evidence has been reported suggesting that natural acquired immunity could occur.,Hence, if under favorable conditions natural infections can lead to correct immune activation and immune protection against HAT, the development of an effective anti-HAT vaccine should remain a central goal in the fight against this disease.<br /> In this review, we will (1) discuss the vaccine candidates that have been proposed over the past years, (2) highlight the main obstacles that an efficient anti-trypanosomiasis vaccine needs to overcome and (3) critically reflect on the validity of the widely used murine model for HAT. | 1 |
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