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Intestinal parasitic infection is one of the parasitic infections affecting people living in prison.,Helminths and intestinal protozoan infections are the most common parasitic infection that may cause serious life-threatening diseases in inmates living in developing countries.,This study was aimed to investigate the prevalence and associated factors of intestinal parasitic infections (IPIs) among inmates living in Arba Minch prison, southern Ethiopia.,Institutional based cross sectional study was conducted on Arba Minch inmates, southern Ethiopian.,Pre-tested semi-structured questionnaire was used to gather the data of socio-demographic characteristics, hygiene status of the prisoners, sanitation condition of the prison, and associated factors for IPIs by face to face interview.,Direct wet-mount examination and formol-ether sedimentation techniques were used to examine intestinal parasitic infection from stool specimens.,Binary logistic regression analysis was used to see the association between different variables and the IPI.,Odds ratio with 95% CI was computed to determine the presence association and strength of the associated factors.,A total of 320 prisoners were participated in this study.,Of these, 154(48.1%) of them were infected with one or more intestinal parasites.,Eight different intestinal parasites species were identified and Giardia lamblia was the predominant parasite.,Among infected inmates, nearly one out of four of them had multiple parasitic infections dominated by Giardia lamblia and E. histolytica/dispar co-infection.,Sleeping in group [AOR = 1.9; 95% CI: (1.0-3.8)], married prisoners [AOR = 1.8; 95% CI: (1.1-2.9)], and hand washing habits after handling soil [AOR = 2.4; 95% CI: (1.0-5.6)] were independently associated with IPI.,High prevalence of intestinal parasitic infection was detected in Arba Minch inmates, southern Ethiopian.,Absence of hand washing, marital status, and way of sleeping were the factors associated with the IPI.,Implementation of mass drug administration, education on water, sanitation and hygiene (WASH) and periodic screening of intestinal parasitic infection is very important to reduce the high prevalence IPIs in prison.
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Strongyloides stercoralis infection is a neglected tropical disease which can lead to severe symptoms and even death in immunosuppressed people.,Unfortunately, its diagnosis is hampered by the lack of a gold standard, as the sensitivity of traditional parasitological tests (including microscopic examination of stool samples and coproculture) is low.,Hence, alternative diagnostic methods, such as molecular biology techniques (mostly polymerase chain reaction, PCR) have been implemented.,However, there are discrepancies in the reported accuracy of PCR.,A systematic review with meta-analysis was conducted in order to evaluate the accuracy of PCR for the diagnosis of S. stercoralis infection.,The protocol was registered with PROSPERO International Prospective Register of Systematic Reviews (record: CRD42016054298).,Fourteen studies, 12 of which evaluating real-time PCR, were included in the analysis.,The specificity of the techniques resulted high (ranging from 93 to 95%, according to the reference test(s) used).,When all molecular techniques were compared to parasitological methods, the sensitivity of PCR was assessed at 71.8% (95% CI 52.2-85.5), that decreased to 61.8% (95% CI 42.0-78.4) when serology was added among the reference tests.,Similarly, sensitivity of real-time PCR resulted 64.4% (95% CI 46.2-77.7) when compared to parasitological methods only, 56.5% (95% CI 39.2-72.4) including serology.,PCR might not be suitable for screening purpose, whereas it might have a role as a confirmatory test.
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We examined the mitogenomes of a large global collection of human malaria parasites to explore how and when Plasmodium falciparum and P. vivax entered the Americas.,We found evidence of a significant contribution of African and South Asian lineages to present-day New World malaria parasites with additional P. vivax lineages appearing to originate from Melanesia that were putatively carried by the Australasian peoples who contributed genes to Native Americans.,Importantly, mitochondrial lineages of the P. vivax-like species P. simium are shared by platyrrhine monkeys and humans in the Atlantic Forest ecosystem, but not across the Amazon, which most likely resulted from one or a few recent human-to-monkey transfers.,While enslaved Africans were likely the main carriers of P. falciparum mitochondrial lineages into the Americas after the conquest, additional parasites carried by Australasian peoples in pre-Columbian times may have contributed to the extensive diversity of extant local populations of P. vivax.
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Simian malaria is still an open question concerning the species of Plasmodium parasites and species of New World monkeys susceptible to the parasites.,In addition, the lingering question as to whether these animals are reservoirs for human malaria might become important especially in a scenario of eradication of the disease.,To aid in the answers to these questions, monkeys were surveyed for malaria parasite natural infection in the Amazonian state of Rondônia, Brazil, a state with intense environmental alterations due to human activities, which facilitated sampling of the animals.,Parasites were detected and identified in DNA from blood of monkeys, by PCR with primers for the 18S rRNA, CSP and MSP1 genes and sequencing of the amplified fragments.,Multiplex PCR primers for the 18S rRNA genes were designed for the parasite species Plasmodium falciparum and Plasmodium vivax, Plasmodium malariae/Plasmodium brasilianum and Plasmodium simium.,An overall infection rate of 10.9% was observed or 20 out 184 monkey specimens surveyed, mostly by P. brasilianum.,However, four specimens of monkeys were found infected with P. falciparum, two of them doubly infected with P. brasilianum and P. falciparum.,In addition, a species of monkey of the family Aotidae, Aotus nigriceps, is firstly reported here naturally infected with P. brasilianum.,None of the monkeys surveyed was found infected with P. simium/P. vivax.,The rate of natural Plasmodium infection in monkeys in the Brazilian state of Rondônia is in line with previous surveys of simian malaria in the Amazon region.,The fact that a monkey species was found that had not previously been described to harbour malaria parasites indicates that the list of monkey species susceptible to Plasmodium infection is yet to be completed.,Furthermore, finding monkeys in the region infected with P. falciparum clearly indicates parasite transfer from humans to the animals.,Whether this parasite can be transferred back to humans and how persistent the parasite is in monkeys in the wild so to be efficient reservoirs of the disease, is yet to be evaluated.,Finding different species of monkeys infected with this parasite species suggests indeed that these animals can act as reservoirs of human malaria.
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In order to understand the importance of functional proteins in mosquito behavior, following blood meal, a baseline proteomic dataset is essential for providing insights into the physiology of blood feeding.,Therefore, in this study as first step, in solution and 1-D electrophoresis digestion approach combined with tandem mass spectrometry (nano LC-MS/MS) and computational bioinformatics for data mining was used to prepare a baseline proteomic catalogue of salivary gland proteins of sugar fed An. culicifacies mosquitoes.,A total of 106 proteins were identified and analyzed by SEQUEST algorithm against mosquito protein database from Uniprot/NCBI.,Importantly, D7r1, D7r2, D7r4, salivary apyrase, anti-platelet protein, calreticulin, antigen 5 family proteins were identified and grouped on the basis of biological and functional roles.,Secondly, differential protein expression and annotations between salivary glands of sugar fed vs blood fed mosquitoes was analyzed using 2-Delectrophoresis combined with MALDI-TOF mass spectrometry.,The alterations in the differential expression of total 38 proteins was observed out of which 29 proteins like beclin-1, phosphorylating proteins, heme oxygenase 1, ferritin, apoptotic proteins, coagulation and immunity like, serine proteases, serpins, c-type lectin and protein in regulation of blood feeding behavior were found to be up regulated while 9 proteins related to blood feeding, juvenile hormone epoxide hydrolase ii, odorant binding proteins and energy metabolic enzymes were found to be down regulated.,To our knowledge, this study provides a first time baseline proteomic dataset and functional annotations of An. culicifacies salivary gland proteins that may be involved during the blood feeding.,Identification of differential salivary proteins between sugar fed and blood fed mosquitoes and their plausible role may provide insights into the physiological processes associated with feeding behavior and sporozoite transmission during the process of blood feeding.
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Salivary proteins injected by blood feeding arthropods into their hosts evoke a saliva-specific humoral response which can be useful to evaluate exposure to bites of disease vectors.,However, saliva of hematophagous arthropods is a complex cocktail of bioactive factors and its use in immunoassays can be misleading because of potential cross-reactivity to other antigens.,Toward the development of a serological marker of exposure to Afrotropical malaria vectors we expressed the Anopheles gambiae gSG6, a small anopheline-specific salivary protein, and we measured the anti-gSG6 IgG response in individuals from a malaria hyperendemic area of Burkina Faso, West Africa.,The gSG6 protein was immunogenic and anti-gSG6 IgG levels and/or prevalence increased in exposed individuals during the malaria transmission/rainy season.,Moreover, this response dropped during the intervening low transmission/dry season, suggesting it is sensitive enough to detect variation in vector density.,Members of the Fulani ethnic group showed higher anti-gSG6 IgG response as compared to Mossi, a result consistent with the stronger immune reactivity reported in this group.,Remarkably, anti-gSG6 IgG levels among responders were high in children and gradually declined with age.,This unusual pattern, opposite to the one observed with Plasmodium antigens, is compatible with a progressive desensitization to mosquito saliva and may be linked to the continued exposure to bites of anopheline mosquitoes.,Overall, the humoral anti-gSG6 IgG response appears a reliable serological indicator of exposure to bites of the main African malaria vectors (An. gambiae, Anopheles arabiensis and, possibly, Anopheles funestus) and it may be exploited for malaria epidemiological studies, development of risk maps and evaluation of anti-vector measures.,In addition, the gSG6 protein may represent a powerful model system to get a deeper understanding of molecular and cellular mechanisms underlying the immune tolerance and progressive desensitization to insect salivary allergens.
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SMC has been introduced widely in the Sahel since its recommendation by WHO in 2012.,This study, which provided evidence of feasibility that supported the recommendation, included school-age and pre-school children.,School-age children were not included in the 2012 recommendation but bear an increasing proportion of cases.,In 2006, consultations with health-staff were held to choose delivery methods.,The preferred approach, door-to-door with the first daily-dose supervised by a community-health-worker (CHW), was piloted and subsequently evaluated on a large-scale in under-5’s in 2008 and then in under-10’s 2009-2010.,Coverage was higher among school-age children (96%(95%CI 94%,98%) received three treatments in 2010) than among under 5’s (90%(86%,94%)).,SMC was more equitable than LLINs (odds-ratio for increase in coverage for a one-level rise in socioeconomic-ranking (a 5-point scale), was 1.1 (0.95,1.2) in 2009, compared with OR 1.3 (1.2,1.5) for sleeping under an LLIN.,Effective communication was important in achieving high levels of uptake.,Continued training and supervision were needed to ensure CHWs adhered to treatment guidelines.,SMC door-to-door can, if carefully supervised, achieve high equitable coverage and high-quality delivery.,SMC programmes can be adapted to include school-age children, a neglected group that bears a substantial burden of malaria.
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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.
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Chronic Chagas Disease (CD) diagnosis is based on serological methods employing crude, semipurified or recombinant antigens, which may result in low sensitivity or cross-reactivity.,To reduce these restrictions, we developed a strategy involving use of molecules containing repetitive fragments of Trypanosoma cruzi conserved proteins.,Diagnostic performance of IBMP-8.1 and IBMP-8.4 chimeric antigens (Molecular Biology Institute of Paraná - IBMP in Portuguese acronym) was assessed to diagnose T. cruzi-infected and non-infected immigrants living in Barcelona (Spain), a non-endemic setting for Chagas disease.,Reactivity of IBMP-8.1 and IBMP-8.4 was assessed using an in-house automated ELISA with 347 positive and 331 negative individuals to Chagas disease.,Antigenic cross-reactivity was measured with sera samples from pregnant women with Toxoplasma gondii (n = 98) and Zika virus (n = 75) antibodies.,The area under the curve values was 1 and 0.99 for the IBMP-8.1 and IBMP-8.4 proteins, respectively, demonstrating excellent diagnostic accuracy.,The reactivity index was higher for IBMP-8.1 than IBMP-8.4 in positive samples and no significant difference in reactivity index was observed in negative samples.,Sensitivity ranged from 99.4% for IBMP-8.1 to 99.1% for IBMP-8.4 and was not statistically different.,Specificity for IBMP-8.1 reached 100 and 99.7% for IBMP-8.4, both nearly 100% accurate.,No antigenic cross-reactivity was observed and reactivity index was similar to that for negative Chagas disease individuals.,Our results showed an outstanding performance of IBMP-8.1 and IBMP-8.4 chimeric antigens by ELISA and suggest both chimeric antigens could also be used for Chagas disease diagnosis in immigrants living in non-endemic settings.
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The performance of current serologic tests for diagnosing chronic Chagas disease (CD) is highly variable.,The search for new diagnostic markers has been a constant challenge for improving accuracy and reducing the number of inconclusive results.,Here, four chimeric proteins (IBMP-8.1 to -8.4) comprising immunodominant regions of different Trypanosoma cruzi antigens were tested by enzyme-linked immunosorbent assay.,The proteins were used to detect specific anti-T. cruzi antibodies in the sera of 857 chagasic and 689 non-chagasic individuals to evaluate their accuracy for chronic CD diagnosis.,The antigens were recombinantly expressed in Escherichia coli and purified by chromatographic methods.,The sensitivity and specificity values ranged from 94.3% to 99.3% and 99.4% to 100%, respectively.,The diagnostic odds ratio (DOR) values were 6,462 for IBMP-8.1, 3,807 for IBMP-8.2, 32,095 for IBMP-8.3, and 283,714 for IBMP-8.4.,These chimeric antigens presented DORs that were higher than the commercial test Pathozyme Chagas.,The antigens IBMP-8.3 and -8.4 also showed DORs higher than the Gold ELISA Chagas test.,Mixtures with equimolar concentrations were tested in order to improve the diagnosis accuracy of negative samples with high signal and positive samples with low signal.,However, no gain in accuracy was observed relative to the individual antigens.,A total of 1,079 additional sera were used to test cross-reactivity to unrelated diseases.,The cross-reactivity rates ranged from 0.37% to 0.74% even for Leishmania spp., a pathogen showing relatively high genome sequence identity to T. cruzi.,Imprecision analyses showed that IBMP chimeras are very stable and the results are highly reproducible.,Our findings indicate that the IBMP-8.4 antigen can be safely used in serological tests for T. cruzi screening in blood banks and for chronic CD laboratory diagnosis.
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Leishmaniasis remains a major public health problem worldwide and is classified as Category I by the TDR/WHO, mainly due to the absence of control.,Many experimental models like rodents, dogs and monkeys have been developed, each with specific features, in order to characterize the immune response to Leishmania species, but none reproduces the pathology observed in human disease.,Conflicting data may arise in part because different parasite strains or species are being examined, different tissue targets (mice footpad, ear, or base of tail) are being infected, and different numbers (“low” 1×102 and “high” 1×106) of metacyclic promastigotes have been inoculated.,Recently, new approaches have been proposed to provide more meaningful data regarding the host response and pathogenesis that parallels human disease.,The use of sand fly saliva and low numbers of parasites in experimental infections has led to mimic natural transmission and find new molecules and immune mechanisms which should be considered when designing vaccines and control strategies.,Moreover, the use of wild rodents as experimental models has been proposed as a good alternative for studying the host-pathogen relationships and for testing candidate vaccines.,To date, using natural reservoirs to study Leishmania infection has been challenging because immunologic reagents for use in wild rodents are lacking.,This review discusses the principal immunological findings against Leishmania infection in different animal models highlighting the importance of using experimental conditions similar to natural transmission and reservoir species as experimental models to study the immunopathology of the disease.
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Human African trypanosomiasis (HAT), also known as sleeping sickness, is a fatal parasitic disease caused by trypanosomes.,Current treatment options for HAT are scarce, toxic, no longer effective, or very difficult to administer, in particular for the advanced, fatal stage of the disease (stage 2, chronic HAT).,New safe, effective and easy-to-use treatments are urgently needed.,Here it is shown that fexinidazole, a 2-substituted 5-nitroimidazole rediscovered by the Drugs for Neglected Diseases initiative (DNDi) after extensive compound mining efforts of more than 700 new and existing nitroheterocycles, could be a short-course, safe and effective oral treatment curing both acute and chronic HAT and that could be implemented at the primary health care level.,To complete the preclinical development and meet the regulatory requirements before initiating human trials, the anti-parasitic properties and the pharmacokinetic, metabolic and toxicological profile of fexinidazole have been assessed.,Standard in vitro and in vivo anti-parasitic activity assays were conducted to assess drug efficacy in experimental models for HAT.,In parallel, a full range of preclinical pharmacology and safety studies, as required by international regulatory guidelines before initiating human studies, have been conducted.,Fexinidazole is moderately active in vitro against African trypanosomes (IC50 against laboratory strains and recent clinical isolates ranged between 0.16 and 0.93 µg/mL) and oral administration of fexinidazole at doses of 100 mg/kg/day for 4 days or 200 mg/kg/day for 5 days cured mice with acute and chronic infection respectively, the latter being a model for the advanced and fatal stage of the disease when parasites have disseminated into the brain.,In laboratory animals, fexinidazole is well absorbed after oral administration and readily distributes throughout the body, including the brain.,The absolute bioavailability of oral fexinidazole was 41% in mice, 30% in rats, and 10% in dogs.,Furthermore, fexinidazole is rapidly metabolised in vivo to at least two biologically active metabolites (a sulfoxide and a sulfone derivative) that likely account for a significant portion of the therapeutic effect.,Key pharmacokinetic parameter after oral absorption in mice for fexinidazole and its sulfoxide and sulfone metabolites are a Cmax of 500, 14171 and 13651 ng/mL respectively, and an AUC0-24 of 424, 45031 and 96286 h.ng/mL respectively.,Essentially similar PK profiles were observed in rats and dogs.,Toxicology studies (including safety pharmacology and 4-weeks repeated-dose toxicokinetics in rat and dog) have shown that fexinidazole is well tolerated.,The No Observed Adverse Event Levels in the 4-weeks repeated dose toxicity studies in rats and dogs was 200 mg/kg/day in both species, with no issues of concern identified for doses up to 800 mg/kg/day.,While fexinidazole, like many nitroheterocycles, is mutagenic in the Ames test due to bacterial specific metabolism, it is not genotoxic to mammalian cells in vitro or in vivo as assessed in an in vitro micronucleus test on human lymphocytes, an in vivo mouse bone marrow micronucleus test, and an ex vivo unscheduled DNA synthesis test in rats.,The results of the preclinical pharmacological and safety studies indicate that fexinidazole is a safe and effective oral drug candidate with no untoward effects that would preclude evaluation in man.,The drug has entered first-in-human phase I studies in September 2009.,Fexinidazole is the first new clinical drug candidate with the potential for treating advanced-stage sleeping sickness in thirty years.
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The effects of helminth co-infection on malaria in humans remain uncertain.,This study aimed to evaluate the nature of association of intestinal helminths with prevalence and clinical outcomes of Plasmodium infection.,A cross-sectional study involving 1,065 malaria suspected febrile patients was conducted at Dore Bafeno Health Center, Southern Ethiopia, from December 2010 to February 2011.,Plasmodium and intestinal helminth infections were diagnosed using Giemsa-stained blood films and Kato-Katz technique, respectively.,Haemoglobin level was determined using a haemocue machine.,Among 1,065 malaria suspected febrile patients, 28.8% were positive for Plasmodium parasites (P. falciparum =13.0%, P. vivax =14.5%, P. falciparum and P. vivax =1.3%).,Among 702 patients who provided stool samples, 53.8%, 31.6% and 19.4% were infected with intestinal helminths, Plasmodium alone and with both Plasmodium and intestinal helminths, respectively.,The prevalence of infections with Ascaris lumbricoides (A. lumbricoides), Trichuris trichiura (T. trichiura), Schistosoma mansoni (S. mansoni) and hookworm (9.8%) were 35.9%, 15.8%, 11.7% and 9.8%, respectively.,Out of the 222 (31.6%) Plasmodium infected cases, 9 (4.1%) had severe malaria.,P. falciparum infection was more common in febrile patients infected with A. lumbricoides alone (21.3%), T. trichiura alone (23.1%) and S. mansoni alone (23.1%) compared to those without intestinal helminth infections (9.3%) (p<0.001 for all).,Prevalence of non-severe malaria was significantly higher in individuals infected with intestinal helminths than in those who were not infected with intestinal helminths (adjusted OR=1.58, 95% CI=1.13-2.22).,The chance of developing non-severe P. falciparum malaria were 2.6, 2.8 and 3.3 times higher in individuals infected with A. lumbricoides alone, T. trichiura alone and S. mansoni alone, respectively, compared to intestinal helminth-free individuals (p<0.05 for all).,The odds ratio for being infected with non-severe P. falciparum increased with the number of intestinal helminth species (p<0.001).,Mean Plasmodium density among intestinal helminth infected individuals was significantly increased with the number of intestinal helminths species (p=0.027).,Individuals who were co-infected with different species of intestinal helminths and Plasmodium showed lower mean haemoglobin concentration than individuals who were infected only with Plasmodium.,Infections with A. lumbricoides, T. trichiura and S. mansoni were positively associated with P. falciparum infection.,However, further studies are required to investigate how these helminths could contribute to increased prevalence of P. falciparum infection.
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Severe anaemia is a common complication of Plasmodium falciparum malaria in hyperendemic regions.,Premature elimination of non-parasitized red blood cells (nRBC) has been considered as one mechanism involved in the genesis of severe malaria anaemia.,It has been reported that apoptosis can occur in RBC and, consequently, this cell death process could contribute to anaemia.,This study was performed to evaluate the susceptibility of nRBC to apoptosis in a malaria anaemia murine model.,Balb/c mice were intraperitonially inoculated with 1 × 106 P. yoelii 17XL parasitized RBC (pRBC) and, then, parasitaemia and anaemia were monitored.,Apoptosis in both pRBC and nRBC was assessed during early and late phases of infection by flow cytometry using Syto 16 and annexin V-PE double staining and forward scatter measurement.,As expected, experimental infection of Balb/c mice with Plasmodium yoelii 17XL parasites was characterized by progressive increase of parasitaemia and acute anaemia, leading to death.,Flow cytometry analysis showed that a number of pRBC was in the apoptotic process.,It was noteworthy that the increase of nRBC apoptosis levels occurred in the late phase of infection, when anaemia degree was notably accentuated, while no significant alteration was observed in the early phase.,The increased levels of nRBC apoptosis herein firstly reported, in malaria infection could represent a putative mechanism worsening the severity of malarial anaemia.
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Artemisin combination therapy (ACT) is the main treatment option for malaria, which is caused by the intracellular parasite Plasmodium.,However, increased resistance to ACT highlights the importance of finding new drugs.,Recently, the aspartic proteases Plasmepsin IX and X (PMIX and PMX) were identified as promising drug targets.,In this study, we describe dual inhibitors of PMIX and PMX, including WM382, that block multiple stages of the Plasmodium life cycle.,We demonstrate that PMX is a master modulator of merozoite invasion and direct maturation of proteins required for invasion, parasite development, and egress.,Oral administration of WM382 cured mice of P. berghei and prevented blood infection from the liver.,In addition, WM382 was efficacious against P. falciparum asexual infection in humanized mice and prevented transmission to mosquitoes.,Selection of resistant P. falciparum in vitro was not achievable.,Together, these show that dual PMIX and PMX inhibitors are promising candidates for malaria treatment and prevention.,•Specific compounds against P. falciparum Plasmepsin IX and X were identified•PMIX and PMX are modulators of parasite proteins for egress, invasion, and development•Anti-PMIX and anti-PMX compounds inhibit liver, blood, and mosquito stages of Plasmodium•One compound, WM382, can clear mouse models of P. berghei and P. falciparum parasites,Specific compounds against P. falciparum Plasmepsin IX and X were identified,PMIX and PMX are modulators of parasite proteins for egress, invasion, and development,Anti-PMIX and anti-PMX compounds inhibit liver, blood, and mosquito stages of Plasmodium,One compound, WM382, can clear mouse models of P. berghei and P. falciparum parasites,We describe inhibitors of essential aspartic proteases from malaria parasites that block multiple life cycle stages.,PMIX and PMX are master modulators processing proteins required for invasion, development, and egress.,Administration of WM382 cured mice of malaria infection, showing that these inhibitors are promising candidates for malaria treatment and prevention.
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The ABO blood group influences susceptibility to severe Plasmodium falciparum malaria.,Recent evidence indicates that the protective effect of group O operates by virtue of reduced rosetting of infected red blood cells (iRBCs) with uninfected RBCs.,Rosetting is mediated by a subgroup of PfEMP1 adhesins, with RBC binding being assigned to the N-terminal DBL1α1 domain.,Here, we identify the ABO blood group as the main receptor for VarO rosetting, with a marked preference for group A over group B, which in turn is preferred to group O RBCs.,We show that recombinant NTS-DBL1α1 and NTS-DBL1α1-CIDR1γ reproduce the VarO-iRBC blood group preference and document direct binding to blood group trisaccharides by surface plasmon resonance.,More detailed RBC subgroup analysis showed preferred binding to group A1, weaker binding to groups A2 and B, and least binding to groups Ax and O.,The 2.8 Å resolution crystal structure of the PfEMP1-VarO Head region, NTS-DBL1α1-CIDR1γ, reveals extensive contacts between the DBL1α1 and CIDR1γ and shows that the NTS-DBL1α1 hinge region is essential for RBC binding.,Computer docking of the blood group trisaccharides and subsequent site-directed mutagenesis localized the RBC-binding site to the face opposite to the heparin-binding site of NTS-DBLα1.,RBC binding involves residues that are conserved between rosette-forming PfEMP1 adhesins, opening novel opportunities for intervention against severe malaria.,By deciphering the structural basis of blood group preferences in rosetting, we provide a link between ABO blood grouppolymorphisms and rosette-forming adhesins, consistent with the selective role of falciparum malaria on human genetic makeup.
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Anopheles gambiae, An. coluzzii and An. arabiensis are the three major vectors of malaria in Nigeria.,These mosquitoes have developed resistance to different insecticides.,Insecticides resistance intensity assay was recently introduced to provide insight into the potential operational significance of insecticide resistance.,Here, we present data on pyrethroids resistance intensity and resistance mechanisms from six vector surveillance sites (Lagos, Ogun, Edo, Anambra, Kwara and Niger) in Nigeria.,Adult Anopheles reared from larval collections were tested using WHO insecticides susceptibility protocol with 1x concentration of permethrin and deltamethrin followed with intensity assays with 5x and 10x concentrations of both insecticides.,Synergistic and biochemical assays were carried out and underlying resistance mechanisms determined following standard protocols.,Anopheles gambiae constituted >50% samples tested in five sites.,Permethrin and deltamethrin resistance was observed at all the sites.,The Kdt50 varied from 15 minutes (CI = 13.6-17.2) in deltamethrin to 42.1 minutes (CI = 39.4-44.1) in permethrin.,For both insecticides, Kdt95 was >30 minutes with 25% to 87% post exposure mortality at the different sites.,The West Africa knock down resistance (kdr-w) mechanism was found at each site.,Resistant An. gambiae from Lagos, Ogun and Niger synergized prior to permethrin or deltamethrin exposure showed significant mortality (89-100%) compared to unsynergized mosquitoes (Lagos, p = 0.031; Ogun, p = 0.025; Niger, p = 0.018).,Biochemical analyses revealed significant increased levels of P450 enzymes in resistant Anopheles gambiae from Lagos (p = 0.038); Ogun (p = 0.042) and Niger (p = 0.028) in addition to GST in Lagos (p = 0.028) and Ogun (p = 0.033).,Overall, the results revealed high pyrethroid resistance associated with increased activities of metabolic enzymes (P450 + GST) in An. gambiae and An. coluzzii from Lagos and Ogun.,The presence of kdr + P450 conferred moderate resistance whereas low resistance was the case where kdr was the sole resistance mechanism.,Findings thus suggests that elevated levels of cytochrome P450 enzymes together with GST were responsible for high or severe pyrethroid resistance.
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Malaria is a major public health problem in Ghana.,We present a site-specific entomological study of malaria vectors and transmission indices as part of an effort to develop a site for the testing of improved control strategies including possible vaccine trials.,Pyrethrum spray catches (PSC), and indoor and outdoor human landing collections of adult female anopheline mosquitoes were carried out over a six-month period (November 2005 - April 2006) at Kpone-on-Sea, a fishing village in southern Ghana.,These were morphologically identified to species level and sibling species of the Anopheles gambiae complex further characterized by the polymerase chain reaction (PCR).,Enzyme-linked immunosorbent assay was used to detect Plasmodium falciparum mosquito infectivity and host blood meal sources.,Parity rate was examined based on dilatation of ovarian tracheoles following dissection.,Of the 1233 Anopheles mosquitoes collected, An. gambiae s.l. was predominant (99.5%), followed by An. funestus (0.4%) and An. pharoensis (0.1%).,All An. gambiae s.l. examined (480) were identified as An. gambiae s.s. with a majority of M molecular form (98.2%) and only 1.8% S form with no record of M/S hybrid.,A significantly higher proportion of anophelines were observed outdoors relative to indoors (χ2 = 159.34, df = 1, p < 0.0000).,Only An. gambiae M molecular form contributed to transmission with a high degree of anthropophily, parity rate and an estimated entomological inoculation rate (EIR) of 62.1 infective bites/person/year.,The Majority of the infective bites occurred outdoors after 09.00 pm reaching peaks between 12.00-01.00 am and 03.00-04.00 am.,Anopheles gambiae M molecular form is responsible for maintaining the status quo of malaria in the surveyed site during the study period.,The findings provide a baseline for evidence-based planning and implementation of improved malaria interventions.,The plasticity observed in biting patterns especially the combined outdoor and early biting behavior of the vector may undermine the success of insecticide-based strategies using insecticide treated nets (ITN) and indoor residual spray (IRS).,As such, novel or improved vector interventions should be informed by the local malaria epidemiology data as it relates to vector behavior.
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While bed nets and insecticide spraying have had significant impact on malaria burden in many endemic regions, outdoor vector feeding and insecticide resistance may ultimately limit their contribution to elimination and control campaigns.,Complementary vector control methods such as endectocides or systemic insecticides, where humans or animals are treated with drugs that kill mosquitoes upon ingestion via blood meal, are therefore generating much interest.,This work explores the conditions under which long-lasting systemic insecticides would have a substantial impact on transmission and burden.,Hypothetical long-lasting systemic insecticides with effective durations ranging from 14 to 90 days are simulated using an individual-based mathematical model of malaria transmission.,The impact of systemic insecticides when used to complement existing vector control and drug campaigns is evaluated in three settings-a highly seasonal high-transmission setting, a near-elimination setting with seasonal travel to a high-risk area, and a near-elimination setting in southern Africa.,At 60% coverage, a single round of long-lasting systemic insecticide with effective duration of at least 60 days, distributed at the start of the season alongside a seasonal malaria chemoprevention campaign in a high-transmission setting, results in further burden reduction of 30-90% depending on the sub-populations targeted.,In a near-elimination setting where transmission is sustained by seasonal travel to a high-risk area, targeting high-risk travellers with systemic insecticide with effective duration of at least 30 days can result in likely elimination even if intervention coverage is as low as 50%.,In near-elimination settings with robust vector control, the addition of a 14-day systemic insecticide alongside an anti-malarial in mass drug administration (MDA) campaigns can decrease the necessary MDA coverage from about 85% to the more easily achievable 65%.,While further research into the safety profile of systemic insecticides is necessary before deployment, models predict that long-lasting systemic insecticides can play a critical role in reducing burden or eliminating malaria in a range of contexts with different target populations, existing malaria control methods, and transmission intensities.,Continued investment in lengthening the duration of systemic insecticides and improving their safety profile is needed for this intervention to achieve its fullest potential.
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Current strategies to control mosquito-transmitted infections use insecticides targeted at various stages of the mosquito life-cycle.,Control is increasingly compromised by the evolution of insecticide resistance but there is little quantitative understanding of its impact on control effectiveness.,We developed a computational approach that incorporates the stage-structured mosquito life-cycle and allows tracking of insecticide resistant genotypes.,This approach makes it possible to simultaneously investigate: (i) the population dynamics of mosquitoes throughout their whole life-cycle; (ii) the impact of common vector control interventions on disease transmission; (iii) how these interventions drive the spread of insecticide resistance; and (iv) the impact of resistance once it has arisen and, in particular, whether it is sufficient for malaria transmission to resume.,The model consists of a system of difference equations that tracks the immature (eggs, larvae and pupae) and adult stages, for males and females separately, and incorporates density-dependent regulation of mosquito larvae in breeding sites.,We determined a threshold level of mosquitoes below which transmission of malaria is interrupted.,It is based on a classic Ross-Macdonald derivation of the malaria basic reproductive number (R0) and may be used to assess the effectiveness of different control strategies in terms of whether they are likely to interrupt disease transmission.,We simulated different scenarios of insecticide deployment by changing key parameters in the model to explore the comparative impact of insecticide treated nets, indoor residual spraying and larvicides.,Our simulated results suggest that relatively low degrees of resistance (in terms of reduced mortality following insecticide contact) can induce failure of interventions, and the rate of spread of resistance is faster when insecticides target the larval stages.,The optimal disease control strategy depends on vector species demography and local environmental conditions but, in our illustrative parametrisation, targeting larval stages achieved the greatest reduction of the adult population, followed by targeting of non-host-seeking females, as provided by indoor residual spraying.,Our approach is designed to be flexible and easily generalizable to many scenarios using different calibrations and to diseases other than malaria.,The online version of this article (10.1186/s13071-018-3025-z) contains supplementary material, which is available to authorized users.
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The parasitic worms, Schistosoma mansoni and Schistosoma japonicum, reside in the mesenteric veins, where they release eggs that induce a dramatic granulomatous response in the liver and intestines.,Subsequently, infection may further develop into significant fibrosis and portal hypertension.,Over the past several years, uncovering the mechanism of immunopathology in schistosomiasis has become a major research objective.,It is known that T lymphocytes, especially CD4+ T cells, are essential for immune responses against Schistosoma species.,However, obtaining a clear understanding of how T lymphocytes regulate the pathological process is proving to be a daunting challenge.,To date, CD4+ T cell subsets have been classified into several distinct T helper (Th) phenotypes including Th1, Th2, Th17, T follicular helper cells (Tfh), Th9, and regulatory T cells (Tregs).,In the case of schistosomiasis, the granulomatous inflammation and the chronic liver pathology are critically regulated by the Th1/Th2 responses.,Animal studies suggest that there is a moderate Th1 response to parasite antigens during the acute stage, but then, egg-derived antigens induce a sustained and dominant Th2 response that mediates granuloma formation and liver fibrosis.,In addition, the newly discovered Th17 cells also play a critical role in the hepatic immunopathology of schistosomiasis.,Within the liver, Tregs are recruited to hepatic granulomas and exert an immunosuppressive role to limit the granulomatous inflammation and fibrosis.,Moreover, recent studies have shown that Tfh and Th9 cells might also promote liver granulomas and fibrogenesis in the murine schistosomiasis.,Thus, during infection, T-cell subsets undergo complicated cross-talk with antigen presenting cells that then defines their various roles in the local microenvironment for regulating the pathological progression of schistosomiasis.,This current review summarizes a vast body of literature to elucidate the contribution of T lymphocytes and their associated cytokines in the immunopathology of schistosomiasis.
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Schistosomes control inflammation in their hosts via highly effective mechanisms such as induction of Tregs, Bregs, and alternatively activated macrophages (AAMs).,Notably, IPSE/alpha-1, the major secretory product from Schistosoma mansoni eggs, triggers basophils to release interleukin (IL)-4 and IL-13.,Both cytokines are essential for AAM induction, suggesting an important role for IPSE/alpha-1 in inflammation control.,Here, we show by in vitro co-culture experiments that IPSE/alpha-1-induced basophil IL-4/IL-13 inhibited pro-inflammatory cytokine release from human LPS-activated monocytes.,This effect was cell/cell contact-independent but dependent on IL-4, since it was abrogated in the presence of anti-IL-4 antibodies.,Importantly, the IPSE/alpha-1-induced IL-4/IL-13 release from basophils was amplified in the presence of LPS.,Moreover, monocytes co-cultured in the presence of LPS with IPSE/alpha-1-stimulated basophils adopted an AAM-like phenotype as assessed by elevated expression of CD206 and CD209.,The putative in vivo relevance of these findings was supported by immunohistological staining of S. mansoni-infected murine tissue revealing close physical contact between IPSE/alpha-1 and basophils in schistosome egg granulomas.,Taken together, we found that IPSE/alpha-1 dampens inflammatory cytokine responses by triggering basophil IL-4/IL-13, in particular in the context of TLR activation, thereby turning inflammatory monocytes into anti-inflammatory AAMs.,This might represent a mechanism used by schistosomes to control inflammation in the host.
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We report a study on toxoplasmosis in pregnant women in Luanda, Angola, determining the seroprevalence, geospatial distribution and its association with socio-economic features, dietary habits and hygiene and health conditions.,Anti-Toxoplasma gondii IgG and IgM were quantified in serum samples of women attended at the Lucrecia Paim Maternity Hospital between May 2016 and August 2017.,The IgG avidity test and qPCR assay were used for dating the primary infection.,Data were collected by questionnaire after written consent, and spatial distribution was assessed through a Kernel Density Function.,The potential risk factors associated with Toxoplasma infection were evaluated using bivariate and multivariate binomial logistic regression analysis.,Anti-T. gondii antibodies were quantified in 878 pregnant women, and 346 (39.4%) samples were IgG positive, 2 (0.2%) positive for IgM and IgG, and 530 (60.4%) negative for both immunoglobulins.,The longitudinal study showed that none of the seronegative women seroconverted during the survey.,Regarding other infections, 226 (25.7%) were positive for hepatitis B, while 118 (13.4%) were HIV-positive.,The seroprevalence of toxoplasmosis was similar in most municipalities: 43.8% in Cazenga (28 of 64); 42.5% in Viana (88 of 207); 42.3% in Cacuaco (22 of 52); and 41.1% in Luanda ((179 of 435).,In contrast, the seroprevalence in municipality of Belas was lower (25.8%; 31 of 120) and bivariate and multivariate analysis has shown a lower risk for toxoplasmosis in this area (OR 0.479, CI: 0.305-0.737; OR 0.471, CI: 0.299-0.728).,The multivariate analysis has shown a significant increased risk for toxoplasmosis in women in the last trimester of pregnancy (OR 1.457, CI: 1.011-2.102), suffering spontaneous abortion (OR 1.863, CI: 1.014-3.465) and having pets at home (OR 1.658, CI: 1.212-2.269).,Also, women who tested positive for hepatitis B (OR 1.375, CI: 1.008-1.874) and HIV (OR 1.833, CI: 1.233-2.730) had a significant increased risk for T. gondii infection.,In conclusion, our study showed that a large number of pregnant women are not immunized for toxoplasmosis and identified the risk factors for this infection in Luanda.,It is crucial to establish the diagnosis of primary maternal infection as well as the diagnosis of congenital toxoplasmosis.,Our results underlined the need for diagnostic and clinical follow-up of toxoplasmosis, HIV and hepatitis B during pregnancy.
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Human African trypanosomiasis (HAT), also known as sleeping sickness, persists as a public health problem in several sub-Saharan countries.,Evidence-based, spatially explicit estimates of population at risk are needed to inform planning and implementation of field interventions, monitor disease trends, raise awareness and support advocacy.,Comprehensive, geo-referenced epidemiological records from HAT-affected countries were combined with human population layers to map five categories of risk, ranging from “very high” to “very low,” and to estimate the corresponding at-risk population.,Approximately 70 million people distributed over a surface of 1.55 million km2 are estimated to be at different levels of risk of contracting HAT.,Trypanosoma brucei gambiense accounts for 82.2% of the population at risk, the remaining 17.8% being at risk of infection from T. b. rhodesiense.,Twenty-one million people live in areas classified as moderate to very high risk, where more than 1 HAT case per 10,000 inhabitants per annum is reported.,Updated estimates of the population at risk of sleeping sickness were made, based on quantitative information on the reported cases and the geographic distribution of human population.,Due to substantial methodological differences, it is not possible to make direct comparisons with previous figures for at-risk population.,By contrast, it will be possible to explore trends in the future.,The presented maps of different HAT risk levels will help to develop site-specific strategies for control and surveillance, and to monitor progress achieved by ongoing efforts aimed at the elimination of sleeping sickness.
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Exposure to Plasmodium falciparum is associated with circulating “atypical” memory B cells (atMBCs), which appear similar to dysfunctional B cells found in HIV-infected individuals.,Functional analysis of atMBCs has been limited, with one report suggesting these cells are not dysfunctional but produce protective antibodies.,To better understand the function of malaria-associated atMBCs, we performed global transcriptome analysis of these cells, obtained from individuals living in an area of high malaria endemicity in Uganda.,Comparison of gene expression data suggested down-modulation of B cell receptor signaling and apoptosis in atMBCs compared to classical MBCs.,Additionally, in contrast to previous reports, we found upregulation of Fc receptor-like 5 (FCRL5), but not FCRL4, on atMBCs.,Atypical MBCs were poor spontaneous producers of antibody ex vivo, and higher surface expression of FCRL5 defined a distinct subset of atMBCs compromised in its ability to produce antibody upon stimulation.,Moreover, higher levels of P. falciparum exposure were associated with increased frequencies of FCRL5+ atMBCs.,Together, our findings suggest that FCLR5+ identifies a functionally distinct, and perhaps dysfunctional, subset of MBCs in individuals exposed to P. falciparum.
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When both parasite species are co-endemic, Plasmodium vivax incidence peaks in younger children compared to P. falciparum.,To identify differences in the number of blood stage infections of these species and its potential link to acquisition of immunity, we have estimated the molecular force of blood-stage infection of P. vivax (molFOB, i.e. the number of genetically distinct blood-stage infections over time), and compared it to previously reported values for P. falciparum.,P. vivaxmolFOB was estimated by high resolution genotyping parasites in samples collected over 16 months in a cohort of 264 Papua New Guinean children living in an area highly endemic for P. falciparum and P. vivax.,In this cohort, P. vivax episodes decreased three-fold over the age range of 1-4.5 years.,On average, children acquired 14.0 new P. vivax blood-stage clones/child/year-at-risk.,While the incidence of clinical P. vivax illness was strongly associated with molFOB (incidence rate ratio (IRR) = 1.99, 95% confidence interval (CI95) [1.80, 2.19]), molFOB did not change with age.,The incidence of P. vivax showed a faster decrease with age in children with high (IRR = 0.49, CI95 [0.38, 0.64] p<0.001) compared to those with low exposure (IRR = 0.63, CI95[0.43, 0.93] p = 0.02).,P. vivaxmolFOB is considerably higher than P. falciparummolFOB (5.5 clones/child/year-at-risk).,The high number of P. vivax clones that infect children in early childhood contribute to the rapid acquisition of immunity against clinical P. vivax malaria.
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Malaria remains a heavy burden across sub-Saharan Africa where transmission is maintained by some of the world’s most efficient vectors.,Indoor insecticide-based control measures have significantly reduced transmission, yet elimination remains a distant target.,Knowing the relative abundance of the primary vector species can provide transmission models with much needed information to guide targeted control measures.,Moreover, understanding how existing interventions are impacting on these relative abundances highlights where alternative control (e.g., larval source management) is needed.,Using the habitat suitability probabilities generated by predictive species distribution models combined with data collated from the literature, a multinomial generalized additive model was applied to produce relative abundance estimates for Anopheles arabiensis, Anopheles funestus and Anopheles gambiae/Anopheles coluzzii.,Using pre- and post-intervention abundance data, estimates of the effect of indoor insecticide-based interventions on these relative abundances were made and are illustrated in post-intervention maps.,Conditional effect plots and relative abundance maps illustrate the individual species’ predicted habitat suitability and how they interact when in sympatry.,Anopheles arabiensis and An. funestus show an affinity in habitat preference at the expense of An. gambiae/An. coluzzii, whereas increasing habitat suitability for An. gambiae/An. coluzzii is conversely less suitable for An. arabiensis but has little effect on An. funestus.,Indoor insecticide-based interventions had a negative impact on the relative abundance of An. funestus, and a lesser effect on An. arabiensis.,Indoor residual spraying had the greatest impact on the relative abundance of An. funestus, and a lesser effect on An. gambiae/An. coluzzii.,Insecticide-treated bed nets reduced the relative abundance of both species equally.,These results do not indicate changes in the absolute abundance of these species, which may be reduced for all species overall.,The maps presented here highlight the interactions between the primary vector species in sub-Saharan Africa and demonstrate that An. funestus is more susceptible to certain indoor-based insecticide interventions than An. gambiae/An. coluzzii, which in turn, is more susceptible than An. arabiensis.,This may provide An. arabiensis with a competitive advantage where it is found in sympatry with other more endophilic vectors, and potentially increase the need for outdoor-based vector interventions to deal with any residual transmission barring the way to malaria elimination.,The online version of this article (doi:10.1186/s12936-016-1187-8) contains supplementary material, which is available to authorized users.
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Malaria vector control in Sudan relies mainly on indoor residual spraying (IRS) and the use of long lasting insecticide treated bed nets (LLINs).,Monitoring insecticide resistance in the main Sudanese malaria vector, Anopheles arabiensis, is essential for planning and implementing an effective vector control program in this country.,WHO susceptibility tests were used to monitor resistance to insecticides from all four WHO-approved classes of insecticide at four sentinel sites in Gezira state over a three year period.,Insecticide resistance mechanisms were studied using PCR and microarray analyses.,WHO susceptibility tests showed that Anopheles arabiensis from all sites were fully susceptible to bendiocarb and fenitrothion for the duration of the study (2008-2011).,However, resistance to DDT and pyrethroids was detected at three sites, with strong seasonal variations evident at all sites.,The 1014 F kdr allele was significantly associated with resistance to pyrethroids and DDT (P < 0.001) with extremely high effects sizes (OR > 7 in allelic tests).,The 1014S allele was not detected in any of the populations tested.,Microarray analysis of the permethrin-resistant population of An. arabiensis from Wad Medani identified a number of metabolic genes that were significantly over-transcribed in the field-collected resistant samples when compared to the susceptible Sudanese An. arabiensis Dongola strain.,These included CYP6M2 and CYP6P3, two genes previously implicated in pyrethroid resistance in Anopheles gambiae s.s, and the epsilon-class glutathione-S-transferase, GSTe4.,These data suggest that both target-site mechanisms and metabolic mechanisms play an important role in conferring pyrethroid resistance in An. arabiensis from Sudan.,Identification in An. arabiensis of candidate loci that have been implicated in the resistance phenotype in An. gambiae requires further investigation to confirm the role of these genes.
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Many patients with malaria-like symptoms seek treatment in private medicine retail outlets (PMR) that distribute malaria medicines but do not traditionally provide diagnostic services, potentially leading to overtreatment with antimalarial drugs.,To achieve universal access to prompt parasite-based diagnosis, many malaria-endemic countries are considering scaling up malaria rapid diagnostic tests (RDTs) in these outlets, an intervention that may require legislative changes and major investments in supporting programs and infrastructures.,This review identifies studies that introduced malaria RDTs in PMRs and examines study outcomes and success factors to inform scale up decisions.,Published and unpublished studies that introduced malaria RDTs in PMRs were systematically identified and reviewed.,Literature published before November 2016 was searched in six electronic databases, and unpublished studies were identified through personal contacts and stakeholder meetings.,Outcomes were extracted from publications or provided by principal investigators.,Six published and six unpublished studies were found.,Most studies took place in sub-Saharan Africa and were small-scale pilots of RDT introduction in drug shops or pharmacies.,None of the studies assessed large-scale implementation in PMRs.,RDT uptake varied widely from 8%-100%.,Provision of artemisinin-based combination therapy (ACT) for patients testing positive ranged from 30%-99%, and was more than 85% in five studies.,Of those testing negative, provision of antimalarials varied from 2%-83% and was less than 20% in eight studies.,Longer provider training, lower RDT retail prices and frequent supervision appeared to have a positive effect on RDT uptake and provider adherence to test results.,Performance of RDTs by PMR vendors was generally good, but disposal of medical waste and referral of patients to public facilities were common challenges.,Expanding services of PMRs to include malaria diagnostic services may hold great promise to improve malaria case management and curb overtreatment with antimalarials.,However, doing so will require careful planning, investment and additional research to develop and sustain effective training, supervision, waste-management, referral and surveillance programs beyond the public sector.
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Correct treatment of potentially life-threatening illnesses (PLTIs) in children under 5 years, such as malaria, pneumonia, and diarrhea, can substantially reduce mortality.,The Integrated Management of Childhood Illness (IMCI) strategy has been shown to improve treatment of child illnesses, but multiple studies have shown that gaps in health worker performance remain after training.,To better understand factors related to health worker performance, we analyzed 9,330 patient consultations in Benin from 2001-2002, after training one of the first cohorts of 32 health workers in IMCI.,With data abstracted from patient registers specially designed for IMCI-trained health workers, we examined associations between health facility-, health worker-, and patient-level factors and 10 case-management outcomes for PLTIs.,Altogether, 63.6 % of children received treatment for all their PLTIs in accordance with IMCI guidelines, and 77.8 % received life-saving treatment (i.e., clinically effective treatment, even if not exactly in accordance with IMCI guidelines).,Performance of individual health workers varied greatly, from 15-88 % of patients treated correctly, on average.,Multivariate regression analyses identified several factors that might have influenced case-management quality, many outside a manager’s direct control.,Younger health workers significantly outperformed older ones, and infants received better care than older children.,Children with danger signs, those with more complex illnesses, and those with anemia received worse care.,Health worker supervision was associated with improved performance for some outcomes.,A variety of factors, some outside the direct control of program managers, can influence health worker practices.,An understanding of these influences can help inform the development of strategies to improve performance.,The online version of this article (doi:10.1186/s12913-015-0910-4) contains supplementary material, which is available to authorized users.
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Malaria surveillance is a key pillar in the control of malaria in Africa.,The value of using routinely collected data from health facilities to define malaria risk at community levels remains poorly defined.,Four cross-sectional parasite prevalence surveys were undertaken among residents at 36 enumeration zones in Kilifi county on the Kenyan coast and temporally and spatially matched to fever surveillance at 6 health facilities serving the same communities over 12 months.,The age-structured functional form of the relationship between test positivity rate (TPR) and community-based parasite prevalence (PR) was explored through the development of regression models fitted by alternating the linear, exponential and polynomial terms for PR.,The predictive ranges of TPR were explored for PR endemicity risk groups of control programmatic value using cut-offs of low (PR <5%) and high (PR ≥ 30%) transmission intensity.,Among 28,134 febrile patients encountered for malaria diagnostic testing in the health facilities, 12,143 (43.2%: 95% CI: 42.6%, 43.7%) were positive.,The overall community PR was 9.9% (95% CI: 9.2%, 10.7%) among 6,479 participants tested for malaria.,The polynomial model was the best fitting model for the data that described the algebraic relationship between TPR and PR.,In this setting, a TPR of ≥ 49% in all age groups corresponded to an age-standardized PR of ≥ 30%, while a TPR of < 40% corresponded to an age-standardized PR of < 5%.,A non-linear relationship was observed between the relative change in TPR and changes in the PR, which is likely to have important implications for malaria surveillance programs, especially at the extremes of transmission.,However, larger, more spatially diverse data series using routinely collected TPR data matched to community-based infection prevalence data are required to explore the more practical implications of using TPR as a replacement for community PR.
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Malaria control using long-lasting insecticidal nets (LLINs) and indoor residual spraying of insecticide (IRS) has been associated with reduced transmission throughout Africa.,However, the impact of transmission reduction on the age distribution of malaria cases remains unclear.,Over a 10-year period (January 2009 to July 2018), outpatient surveillance data from four health facilities in Uganda were used to estimate the impact of control interventions on temporal changes in the age distribution of malaria cases using multinomial regression.,Interventions included mass distribution of LLINs at all sites and IRS at two sites.,Overall, 896,550 patient visits were included in the study; 211,632 aged < 5 years, 171,166 aged 5-15 years and 513,752 > 15 years.,Over time, the age distribution of patients not suspected of malaria and those malaria negative either declined or remained the same across all sites.,In contrast, the age distribution of suspected and confirmed malaria cases increased across all four sites.,In the two LLINs-only sites, the proportion of malaria cases in < 5 years decreased from 31 to 16% and 35 to 25%, respectively.,In the two sites receiving LLINs plus IRS, these proportions decreased from 58 to 30% and 64 to 47%, respectively.,Similarly, in the LLINs-only sites, the proportion of malaria cases > 15 years increased from 40 to 61% and 29 to 39%, respectively.,In the sites receiving LLINs plus IRS, these proportions increased from 19 to 44% and 18 to 31%, respectively.,These findings demonstrate a shift in the burden of malaria from younger to older individuals following implementation of successful control interventions, which has important implications for malaria prevention, surveillance, case management and control strategies.
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The efficacy of long-lasting insecticidal nets (LLINs) in preventing malaria in Africa is threatened by insecticide resistance.,Bioassays assessing 24-hour mortality post-LLIN exposure have established that resistance to the concentration of pyrethroids used in LLINs is widespread.,However, although mosquitoes may no longer be rapidly killed by LLIN exposure, a delayed mortality effect has been shown to reduce the transmission potential of mosquitoes exposed to nets.,This has been postulated to partially explain the continued efficacy of LLINs against pyrethroid-resistant populations.,Burkina Faso is one of a number of countries with very high malaria burdens and pyrethroid-resistant vectors, where progress in controlling this disease has stagnated.,We measured the impact of LLIN exposure on mosquito longevity in an area of the country with intense pyrethroid resistance to establish whether pyrethroid exposure was still shortening mosquito lifespan in this setting.,We quantified the immediate and delayed mortality effects of LLIN exposure using standard laboratory WHO cone tests, tube bioassays and experimental hut trials on Anopheles gambiae populations originating from the Cascades region of Burkina Faso using survival analysis and a Bayesian state-space model.,Following single and multiple exposures to a PermaNet 2.0 LLIN only one of the four mosquito populations tested showed evidence of delayed mortality.,No delayed mortality was seen in experimental hut studies using LLINs.,A delayed mortality effect was only observed in WHO tube bioassays when deltamethrin concentration was increased above the standard diagnostic dose.,As mosquito pyrethroid-resistance increases in intensity, delayed effects from LLIN exposure are substantially reduced or absent.,Given the rapid increase in resistance occurring in malaria vectors across Africa it is important to determine whether the failure of LLINs to shorten mosquito lifespan is now a widespread phenomenon as this will have important implications for the future of this pivotal malaria control tool.
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Effective population-level interventions against Plasmodium falciparum malaria lead to age-shifts, delayed morbidity or rebounds in morbidity and mortality whenever they are deployed in ways that do not permanently interrupt transmission.,When long-term intervention programmes target specific age-groups of human hosts, the age-specific morbidity rates ultimately adjust to new steady-states, but it is very difficult to study these rates and the temporal dynamics leading up to them empirically because the changes occur over very long time periods.,This study investigates the age and magnitude of age- and time- shifting of incidence induced by either pre-erythrocytic vaccination (PEV) programmes or seasonal malaria chemo-prevention (SMC), using an ensemble of individual-based stochastic simulation models of P. falciparum dynamics.,The models made various assumptions about immunity decay, transmission heterogeneity and were parameterized with data on both age-specific infection and disease incidence at different levels of exposure, on the durations of different stages of the parasite life-cycle and on human demography.,Effects of transmission intensity, and of levels of access to malaria treatment were considered.,While both PEV and SMC programmes are predicted to have overall strongly positive health effects, a shift of morbidity into older children is predicted to be induced by either programme if transmission levels remain static and not reduced by other interventions.,Predicted shifting of burden continue into the second decade of the programme.,Even if long-term surveillance is maintained it will be difficult to avoid mis-attribution of such long-term changes in age-specific morbidity patterns to other factors.,Conversely, short-lived transient changes in incidence measured soon after introduction of a new intervention may give over-positive views of future impacts.,Complementary intervention strategies could be designed to specifically protect those age-groups at risk from burden shift.,The online version of this article (doi:10.1186/s12936-015-0805-1) contains supplementary material, which is available to authorized users.
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Malaria is the most prevalent communicable disease in Ethiopia, with 75% of the country’s landmass classified as endemic for malaria.,Accurate information on the distribution and clinical prevalence of Plasmodium vivax and Plasmodium falciparum malaria in endemic areas, as well as in Duffy-negative populations, is essential to develop integrated control strategies.,A total of 390 and 416 community and clinical samples, respectively, representing different localities and age groups across Ethiopia were examined.,Malaria prevalence was estimated using nested PCR of the 18S rRNA region.,Parasite gene copy number was measured by quantitative real-time PCR and compared between symptomatic and asymptomatic samples, as well as between children/adolescents and adults from the local community.,An approximately 500-bp segment of the human DARC gene was amplified and sequenced to identify Duffy genotype at the -33rd nucleotide position for all the clinical and community samples.,Plasmodium vivax prevalence was higher in the south while P. falciparum was higher in the north.,The prevalence of P. vivax and P. falciparum malaria is the highest in children compared to adolescents and adults.,Four P. vivax infections were detected among the Duffy-negative samples.,Samples from asymptomatic individuals show a significantly lower parasite gene copy number than those from symptomatic infections for P. vivax and P. falciparum.,Geographical and age differences influence the distribution of P. vivax and P. falciparum malaria in Ethiopia.,These findings offer evidence-based guidelines in targeting malaria control efforts in the country.,The online version of this article (doi:10.1186/s12936-015-0596-4) contains supplementary material, which is available to authorized users.
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Passive surveillance for malaria cases was conducted in Yunnan Province, China, along the China-Myanmar border.,Infection with Plasmodium vivax and P. falciparum protozoa accounted for 69% and 28% of the cases, respectively.,Most patients were adult men.,Cross-border travel into Myanmar was a key risk factor for P. falciparum malaria in China.
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Zambia continues to make strides in reducing malaria burden through the use of proven malaria interventions and has recently pledged to eliminate malaria by 2021.,Case management services have been scaled up at community level with rapid diagnostic tests (RDTs) providing antigen-based detection of falciparum malaria only.,Key to national malaria elimination goals is the ability to identify, treat and eliminate all Plasmodium species.,This study sought to determine the distribution of non-falciparum malaria and assess the performance of diagnostic tests for Plasmodium falciparum in Western and Southern Provinces of Zambia, two provinces planned for early malaria elimination.,A sub-set of individuals’ data and samples from a cross-sectional household survey, conducted during peak malaria transmission season in April and May 2017, was used.,The survey collected socio-demographic information on household members and coverage of malaria interventions.,Malaria testing was done on respondents of all ages using blood smears and RDTs while dried blood spots were collected on filter papers for analysis using photo-induced electron transfer polymerase chain reaction (PET-PCR).,Slides were stained using Giemsa stain and examined by microscopy for malaria parasites.,From the 1567 individuals included, the overall prevalence of malaria was 19.4% (CI 17.5-21.4) by PCR, 19.3% (CI 17.4-21.4) by RDT and 12.9% (CI 11.3-14.7) by microscopy.,Using PET-PCR as the gold standard, RDTs showed a sensitivity of 75.7% (CI 70.4-80.4) and specificity of 94.2% (CI 92.8-95.4).,The positive predictive value (PPV) was 75.9% (CI 70.7-80.6) and negative predictive value (NPV) was 94.1% (CI 92.1-95.4).,In contrast, microscopy for sensitivity, specificity, PPV, and NPV values were 56.9% (CI 51.1-62.5), 97.7% (CI 96.7-98.5), 85.6% (CI 80.0-90.2), 90.4% (CI 88.7-91.9), respectively.,Non-falciparum infections were found only in Western Province, where 11.6% of P. falciparum infections were co-infections with Plasmodium ovale or Plasmodium malariae.,From the sub-set of survey data analysed, non-falciparum species are present and occurred as mixed infections.,As expected, PET-PCR was slightly more sensitive than both malaria RDTs and microscopy to detecting malaria infections.
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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.
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Transfusion-transmitted malaria (TTM) is an accidental Plasmodium infection caused by whole blood or a blood component transfusion from a malaria infected donor to a recipient.,Infected blood transfusions directly release malaria parasites in the recipient’s bloodstream triggering the development of high risk complications, and potentially leading to a fatal outcome especially in individuals with no previous exposure to malaria or in immuno-compromised patients.,A systematic review was conducted on TTM case reports in non-endemic areas to describe the epidemiological characteristics of blood donors and recipients.,Relevant articles were retrieved from Pubmed, EMBASE, Scopus, and LILACS.,From each selected study the following data were extracted: study area, gender and age of blood donor and recipient, blood component associated with TTM, Plasmodium species, malaria diagnostic method employed, blood donor screening method, incubation period between the infected transfusion and the onset of clinical symptoms in the recipient, time elapsed between the clinical symptoms and the diagnosis of malaria, infection outcome, country of origin of the blood donor and time of the last potential malaria exposure.,Plasmodium species were detected in 100 TTM case reports with a different frequency: 45% Plasmodium falciparum, 30% Plasmodium malariae, 16% Plasmodium vivax, 4% Plasmodium ovale, 2% Plasmodium knowlesi, 1% mixed infection P. falciparum/P. malariae.,The majority of fatal outcomes (11/45) was caused by P. falciparum whilst the other fatalities occurred in individuals infected by P. malariae (2/30) and P. ovale (1/4).,However, non P. falciparum fatalities were not attributed directly to malaria.,The incubation time for all Plasmodium species TTM case reports was longer than what expected in natural infections.,This difference was statistically significant for P. malariae (p = 0.006).,A longer incubation time in the recipient together with a chronic infection at low parasite density of the donor makes P. malariae a subtle but not negligible risk for blood safety aside from P. falciparum.,TTM risk needs to be taken into account in order to enhance the safety of the blood supply chain from donors to recipients by means of appropriate diagnostic tools.
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Artemisinin-based combination therapy (ACT) has been promoted as a means to reduce malaria transmission due to their ability to kill both asexual blood stages of malaria parasites, which sustain infections over long periods and the immature derived sexual stages responsible for infecting mosquitoes and onward transmission.,Early studies reported a temporal association between ACT introduction and reduced malaria transmission in a number of ecological settings.,However, these reports have come from areas with low to moderate malaria transmission, been confounded by the presence of other interventions or environmental changes that may have reduced malaria transmission, and have not included a comparison group without ACT.,This report presents results from the first large-scale observational study to assess the impact of case management with ACT on population-level measures of malaria endemicity in an area with intense transmission where the benefits of effective infection clearance might be compromised by frequent and repeated re-infection.,A pre-post observational study with a non-randomized comparison group was conducted at two sites in Tanzania.,Both sites used sulphadoxine-pyrimethamine (SP) monotherapy as a first-line anti-malarial from mid-2001 through 2002.,In 2003, the ACT, artesunate (AS) co-administered with SP (AS + SP), was introduced in all fixed health facilities in the intervention site, including both public and registered non-governmental facilities.,Population-level prevalence of Plasmodium falciparum asexual parasitaemia and gametocytaemia were assessed using light microscopy from samples collected during representative household surveys in 2001, 2002, 2004, 2005 and 2006.,Among 37,309 observations included in the analysis, annual asexual parasitaemia prevalence in persons of all ages ranged from 11% to 28% and gametocytaemia prevalence ranged from <1% to 2% between the two sites and across the five survey years.,A multivariable logistic regression model was fitted to adjust for age, socioeconomic status, bed net use and rainfall.,In the presence of consistently high coverage and efficacy of SP monotherapy and AS + SP in the comparison and intervention areas, the introduction of ACT in the intervention site was associated with a modest reduction in the adjusted asexual parasitaemia prevalence of 5 percentage-points or 23% (p < 0.0001) relative to the comparison site.,Gametocytaemia prevalence did not differ significantly (p = 0.30).,The introduction of ACT at fixed health facilities only modestly reduced asexual parasitaemia prevalence.,ACT is effective for treatment of uncomplicated malaria and should have substantial public health impact on morbidity and mortality, but is unlikely to reduce malaria transmission substantially in much of sub-Saharan Africa where individuals are rapidly re-infected.
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The simian parasite Plasmodium knowlesi is a common cause of human malaria in Malaysian Borneo, with a particularly high incidence in Kudat, Sabah.,Little is known however about the epidemiology in this substantially deforested region.,Malaria microscopy records at Kudat District Hospital were retrospectively reviewed from January 2009-November 2011.,Demographics, and PCR results if available, were recorded for each positive result.,Medical records were reviewed for patients suspected of representing family clusters, and families contacted for further information.,Rainfall data were obtained from the Malaysian Meteorological Department.,“Plasmodium malariae” mixed or mono-infection was diagnosed by microscopy in 517/653 (79%) patients.,Of these, PCR was performed in 445 (86%) and was positive for P. knowlesi mono-infection in 339 (76%).,Patients with knowlesi malaria demonstrated a wide age distribution (median 33, IQR 20-50, range 0.7-89 years) with P. knowlesi predominating in all age groups except those <5 years old, where numbers approximated those of Plasmodium falciparum and Plasmodium vivax.,Two contemporaneous family clusters were identified: a father with two children (aged 10-11 years); and three brothers (aged one-11 years), all with PCR-confirmed knowlesi malaria.,Cases of P. knowlesi demonstrated significant seasonal variation, and correlated with rainfall in the preceding three to five months.,Plasmodium knowlesi is the most common cause of malaria admissions to Kudat District Hospital.,The wide age distribution and presence of family clusters suggest that transmission may be occurring close to or inside people’s homes, in contrast to previous reports from densely forested areas of Sarawak.,These findings have significant implications for malaria control.,Prospective studies of risk factors, vectors and transmission dynamics of P. knowlesi in Sabah, including potential for human-to-human transmission, are needed.
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Malaria is a major public health issue in much of the world, and the mosquito vectors which drive transmission are key targets for interventions.,Mathematical models for planning malaria eradication benefit from detailed representations of local mosquito populations, their natural dynamics and their response to campaign pressures.,A new model is presented for mosquito population dynamics, effects of weather, and impacts of multiple simultaneous interventions.,This model is then embedded in a large-scale individual-based simulation and results for local elimination of malaria are discussed.,Mosquito population behaviours, such as anthropophily and indoor feeding, are included to study their effect upon the efficacy of vector control-based elimination campaigns.,Results for vector control tools, such as bed nets, indoor spraying, larval control and space spraying, both alone and in combination, are displayed for a single-location simulation with vector species and seasonality characteristic of central Tanzania, varying baseline transmission intensity and vector bionomics.,The sensitivities to habitat type, anthropophily, indoor feeding, and baseline transmission intensity are explored.,The ability to model a spectrum of local vector species with different ecologies and behaviours allows local customization of packages of interventions and exploration of the effect of proposed new tools.
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A practical and simple regimen for all malaria species is needed towards malaria elimination in Indonesia.,It is worth to compare the efficacy and safety of a single dose of artemisinin-naphthoquine (AN) with a three-day regimen of dihydroartemisinin-piperaquine (DHP), the existing programme drug, in adults with uncomplicated symptomatic malaria.,This is a phase III, randomized, open label using sealed envelopes, multi-centre, comparative study between a single dose of AN and a three-day dose of DHP in Jayapura and Maumere.,The modified WHO inclusion and exclusion criteria for efficacy study were used in this trial.,A total of 401 eligible adult malaria subjects were hospitalized for three days and randomly treated with AN four tablets single dose on day 0 or DHP three to four tablets single daily dose for three days, and followed for 42 days for physical examination, thick and thin smears microscopy, and other necessary tests.,The efficacy of drug was assessed by polymerase chain reaction (PCR) uncorrected and corrected.,There were 153 Plasmodium falciparum, 158 Plasmodium vivax and 90 P. falciparum/P. vivax malaria.,Mean of fever clearance times were similar, 13.0 ± 10.3 hours in AN and 11.3 ± 7.3 hours in DHP groups.,The mean of parasite clearance times were longer in AN compared with DHP (28.0 ± 11.7 hours vs 25.5 ± 12.2 hours, p = 0.04).,There were only 12 PCR-corrected P. falciparum late treatment failures: seven in AN and five in DHP groups.,The PCR uncorrected and corrected on day −42 of adequate clinical and parasitological responses for treatment of any malaria were 93.7% (95% Cl: 90.3-97.2) and 96.3% (95% Cl: 93.6-99.0) in AN, 96.3% (95% Cl: 93.5-99.0) and 97.3% (95% Cl: 95.0-99.6) in DHP groups.,Few and mild adverse events were reported.,All the abnormal haematology and blood chemistry values had no clinical abnormality.,AN and DHP are confirmed very effective, safe and tolerate for treatment of any malaria.,Both drugs are promising for multiple first-line therapy policies in Indonesia.
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Intravenous (IV) artesunate is the treatment of choice for severe malaria.,In Europe, however, no GMP-manufactured product is available and treatment data in European travellers are scarce.,Fortunately, artesunate became available in the Netherlands and Belgium through a named patient programme.,This is the largest case series of artesunate treated patients with severe malaria in Europe.,Hospitalized patients treated with IV artesunate between November 2007 and December 2010 in the Netherlands and Belgium were retrospectively evaluated.,Patient characteristics, treatment and clinical outcome were recorded on a standardized form and mortality, parasite clearance times and the occurrence of adverse events were evaluated.,Of the 68 treated patients, including 55 with severe malaria, two patients died (2/55 = 3.6%).,The mean time to 50% parasite clearance (PCT50), 90% and 99% were 4.4 hours (3.9 - 5.2), 14.8 hours (13.0 - 17.2), and 29.5 hours (25.9 - 34.4) respectively.,Artesunate was well tolerated.,However, an unusual form of haemolytic anaemia was observed in seven patients.,The relationship with artesunate remains uncertain.,Data from the named patient programme demonstrate that IV artesunate is effective and well-tolerated in European travellers lacking immunity.,However, increased attention needs to be paid to the possible development of haemolytic anaemia 2-3 weeks after start of treatment.,Treatment of IV artesunate should be limited to the period that IV treatment is required and should be followed by a full oral course of an appropriate anti-malarial drug.
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In a low-endemicity/malaria elimination setting, we demonstrate limited sensitivity of Plasmodium falciparum-specific rapid diagnostic testing for suspected malaria, owing to unexpected low-density infections.,Positive predictive value was also low, requiring further investigation.,More accurate diagnostics may be needed.,The performance of Plasmodium falciparum-specific histidine-rich protein 2-based rapid diagnostic tests (RDTs) to evaluate suspected malaria in low-endemicity settings has not been well characterized.,Using dried blood spot samples from patients with suspected malaria at 37 health facilities from 2012 to 2014 in the low-endemicity country of Swaziland, we investigated the diagnostic accuracy of histidine-rich protein 2-based RDTs using qualitative polymerase chain reaction (PCR) (nested PCR targeting the cytochrome b gene) and quantitative PCR as reference standards.,To explore reasons for false-negative and/or false-positive results, we used pfhrp2/3-specific PCR and logistic regression analyses of potentially associated epidemiological factors.,From 1353 patients, 93.0% of RDT-positive (n = 185) and 31.2% of RDT-negative samples (n = 340) were available and selected for testing.,Compared with nested PCR, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of RDTs were 51.7%, 94.1%, 67.3%, and 89.1%, respectively.,After exclusion of samples with parasite densities <100/μL, which accounted for 75.7% of false-negative results and 33.3% of PCR-detectable infections, the sensitivity, specificity, PPV, and NPV were 78.8%, 93.7%, 62.3%, and 97.1%.,Deletions of pfhrp2 were not detected.,False-positivity was more likely during the second year and was not associated with demographics, recent malaria, health facility testing characteristics, or potential DNA degradation.,In the low-transmission setting of Swaziland, we demonstrated low sensitivity of RDT for malaria diagnosis, owing to an unexpectedly high proportion of low-density infection among symptomatic subjects.,The PPV was also low, requiring further investigation.,A more accurate point-of-care diagnostic may be needed to support malaria elimination efforts.
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Reactive case detection (RCD) for malaria is a strategy to identify additional malaria infections in areas of low malaria transmission and can complement passive surveillance.,This study describes experiences with RCD in two Indian sites, and aimed to synthesize experiences with RCD across endemic countries.,RCD programmes were piloted in two urban areas of India with a low prevalence of mainly Plasmodium vivax malaria in 2014.,Cases were identified in a clinic by microscopy and contacts were screened within 2 weeks; PCR, in addition to microscopy, was used to detect Plasmodium parasites.,A systematic review was conducted to identify RCD experiences in the literature.,In Chennai, 868 contacts were enrolled for 18 index cases of clinical malaria; in Nadiad, 131 contacts were enrolled for 20 index cases.,No new malaria infections were detected in Nadiad among contacts, and four new infections were detected in Chennai (three P. vivax and one Plasmodium falciparum), of which two were among household members of index cases.,An additional five studies describing results from an RCD strategy were identified in the literature: four in Africa and one in Thailand.,Including the results from India, the average number of contacts screened per index case in a total of seven studies ranged from four to 50, and 126 in a case study in Thailand with one index case.,Malaria was detected in 0-45 % of the contacted persons.,The average number of index cases needed to be traced to find one new case of malaria ranged from one to five, and could not be assessed in one study in India (no contacts positive for 20 cases).,Sharing the household with an index case was associated with a five-fold increased risk of malaria compared to contacts from households without an index case (pooled risk ratio 5.29, 95 % CI 3.31-8.47, I2 0 %, four studies).,RCD in areas of low malaria transmission is a labour-intensive strategy, and its benefit is not clear.,Studies are needed to assess how RCD can be optimized or into alternatives where interventions are targeted to family members or hotspots.
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Large datasets are often not amenable to analysis using traditional single-step approaches.,Here, our general objective was to apply imputation techniques, principal component analysis (PCA), elastic net and generalized linear models to a large dataset in a systematic approach to extract the most meaningful predictors for a health outcome.,We extracted predictors for Plasmodium falciparum infection, from a large covariate dataset while facing limited numbers of observations, using data from the People, Animals, and their Zoonoses (PAZ) project to demonstrate these techniques: data collected from 415 homesteads in western Kenya, contained over 1500 variables that describe the health, environment, and social factors of the humans, livestock, and the homesteads in which they reside.,The wide, sparse dataset was simplified to 42 predictors of P. falciparum malaria infection and wealth rankings were produced for all homesteads.,The 42 predictors make biological sense and are supported by previous studies.,This systematic data-mining approach we used would make many large datasets more manageable and informative for decision-making processes and health policy prioritization.
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After years of implementing Roll Back Malaria (RBM) interventions, the changing landscape of malaria in terms of risk factors and spatial pattern has not been fully investigated.,This paper uses the 2010 malaria indicator survey data to investigate if known malaria risk factors remain relevant after many years of interventions.,We adopted a structured additive logistic regression model that allowed for spatial correlation, to more realistically estimate malaria risk factors.,Our model included child and household level covariates, as well as climatic and environmental factors.,Continuous variables were modelled by assuming second order random walk priors, while spatial correlation was specified as a Markov random field prior, with fixed effects assigned diffuse priors.,Inference was fully Bayesian resulting in an under five malaria risk map for Malawi.,Malaria risk increased with increasing age of the child.,With respect to socio-economic factors, the greater the household wealth, the lower the malaria prevalence.,A general decline in malaria risk was observed as altitude increased.,Minimum temperatures and average total rainfall in the three months preceding the survey did not show a strong association with disease risk.,The structured additive regression model offered a flexible extension to standard regression models by enabling simultaneous modelling of possible nonlinear effects of continuous covariates, spatial correlation and heterogeneity, while estimating usual fixed effects of categorical and continuous observed variables.,Our results confirmed that malaria epidemiology is a complex interaction of biotic and abiotic factors, both at the individual, household and community level and that risk factors are still relevant many years after extensive implementation of RBM activities.
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The immunomodulatory properties of lipophosphoglycans (LPG) from New World species of Leishmania have been assessed in Leishmania infantum and Leishmania braziliensis, the causative agents of visceral and cutaneous leishmaniasis, respectively.,This glycoconjugate is highly polymorphic among species with variation in sugars that branch off the conserved Gal(β1,4)Man(α1)-PO4 backbone of repeat units.,Here, the immunomodulatory activity of LPGs from Leishmania amazonensis, the causative agent of diffuse cutaneous leishmaniasis, was evaluated in two strains from Brazil.,One strain (PH8) was originally isolated from the sand fly and the other (Josefa) was isolated from a human case.,The ability of purified LPGs from both strains was investigated during in vitro interaction with peritoneal murine macrophages and CHO cells and in vivo infection with Lutzomyia migonei.,In peritoneal murine macrophages, the LPGs from both strains activated TLR4.,Both LPGs equally activate MAPKs and the NF-κB inhibitor p-IκBα, but were not able to translocate NF-κB.,In vivo experiments with sand flies showed that both stains were able to sustain infection in L. migonei.,A preliminary biochemical analysis indicates intraspecies variation in the LPG sugar moieties.,However, they did not result in different activation profiles of the innate immune system.,Also those polymorphisms did not affect infectivity to the sand fly.
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The dominant, cell surface lipophosphoglycan (LPG) of Leishmania is a multifunctional molecule involved in the interaction with vertebrate and invertebrate hosts.,Although the role of LPG on infection has been extensively studied, it is not known if LPG interspecies variations contribute to the different immunopathologies of leishmaniases.,To investigate the issue of interspecies polymorphisms, two Leishmania species from the New World that express structural variations of side chains of LPG repeat units were examined.,In this context, the procyclic form of L. braziliensis LPG (strain M2903), is devoid of side chains, while the L. infantum LPG (strain BH46) has up to three glucoses residues in the repeat units.,Mice peritoneal macrophages from Balb/c, C57BL/6 and knock-out (TLR2 −/−, TLR4 −/−) were primed with IFN-γ and stimulated with purified LPG from both species.,Nitric oxide and cytokine production, MAPKs (ERK, p38 and JNK) and NF-kB activation were evaluated.,Macrophages stimulated with L. braziliensis LPG, had a higher TNF-α, IL-1β, IL-6 and NO production than those stimulated with that of L. infantum.,Furthermore, the LPGs from the two species resulted in differential kinetics of signaling via MAPK activation.,L. infantum LPG exhibited a gradual activation profile, whereas L. braziliensis LPG showed a sharp but transient activation.,L. braziliensis LPG was able to activate NF-kB.,These data suggest that two biochemically distinct LPGs were able to differentially modulate macrophage functions.
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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.
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Chronic infection with Schistosoma japonicum or Schistosoma mansoni results in hepatic fibrosis of the human host.,The staging of fibrosis is crucial for prognosis and to determine the need for treatment of patients with schistosomiasis.,This study aimed to determine whether there is a correlation between the levels of serum exosomal micro-ribonucleic acids (miRNAs) (exomiRs) and fibrosis progression in schistosomiasis.,Reference gene (RG) validation was initially carried out for the analysis of serum exomiRs expression in staging liver fibrosis caused by schistosome infection.,The expression levels of liver fibrosis-associated exomiRs in serum were determined in a murine schistosomiasis model and in a cohort of Filipino schistosomiasis japonica patients (n = 104) with different liver fibrosis grades.,Of twelve RG candidates validated, miR-103a-3p and miR-425-5p were determined to be the most stable genes in the murine schistosomiasis model and subjects from the schistosomiasis-endemic area, respectively.,The temporal expression profiles of nine fibrosis-associated serum exomiRs, as well as their correlations with the liver pathologies, were determined in C57BL/6 mice during S. japonicum infection.,The serum levels of three exomiRs (miR-92a-3p, miR-146a-5p and miR-532-5p) were able to distinguish subjects with fibrosis grades I-III from those with no fibrosis, but only the serum level of exosomal miR-146a-5p showed potential for distinguishing patients with mild (grades 0-I) versus severe fibrosis (grades II-III).,The current data imply that serum exomiRs can be a supplementary tool for grading liver fibrosis in hepatosplenic schistosomiasis with moderate accuracy.
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Despite the extensive implementation of control measures and achievements in morbidity reductions, malaria continues to contribute to substantial morbidity and mortality in children under-five.,Innovative approaches involving the use of mobile phones have been suggested to improve health outcomes.,However, evidence of its effect on reducing the prevalence of malaria is limited.,This study, therefore, aimed to assess the effect of a theory-driven mHealth intervention on the prevalence of malaria among children under-five living in rural districts of Ghana.,We conducted a quasi-experimental study of a 12-month intervention using a random sample of 332 caregivers with children under-five from two rural districts, assigned to either an intervention or a control group.,Caregivers in the intervention group received voice short message service (SMS) on malaria prevention based on a behavior change theory to improve their health behaviors and practice, once a week for twelve months, while caregivers in the control group received none.,Pre- and post-intervention assessment of the treatment effect (ATT) on malaria in children under-five was conducted using propensity score and difference-in-difference (DiD) analyses.,Among children whose caregivers received the intervention, the prevalence of malaria decreased from 58.4% at baseline to 37.8% at endline (difference: -20.6%; 95% CI: − 31.1, − 10.1) compared with children in the control group, where a reduction of 65.0 to 59.9% (difference − 5.1%; 95% CI: − 15.5, 5.4) was observed.,The treatment effect at endline revealed a statistically significant reduction in malaria prevalence (ATT: -0.214; 95% CI: − 0.36, − 0.07) compared with the baseline (ATT: -0.035; 95% CI: − 0.16, 0.09).,Overall, the intervention effect showed a significant reduction in the prevalence of malaria among children under-five was positive (DiD: − 0.154; p = 0.043).,The results of the study indicate the effectiveness of mobile phone SMS as a control tool for reducing the burden of malaria in children under-five.,The online version of this article (10.1186/s12889-019-7336-6) contains supplementary material, which is available to authorized users.
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BRAC, an indigenous non-governmental development organization (NGO), has been implementing a programme to prevent and control malaria in the 13 malaria-endemic districts of Bangladesh since 2007.,One of the critical preventive interventions is the distribution of insecticidal bed nets (long-lasting insecticide-treated nets, LLINs and insecticide-treated ordinary nets, ITNs) to the community free of cost.,This study aimed to assess progress in the possession, preferential use, and knowledge on use of the LLIN/ITNs including the programme's avowed pro-poor inclination one and three and half years after intervention began.,A convenient sampling strategy based on malaria endemicity in the districts was adopted.,First, thirty upazila (sub-district, with a population around 250,000)s were selected at random, with high prevalent districts contributing more upazilas; second, from each upazila, one (2008) to two (2011) villages (covered by insecticidal bed net distribution programme) were selected.,From each village, households that had either one under-five child and/or a pregnant woman were included in the survey, one household being included only once.,Data were collected using a pre-tested structured questionnaire.,In all, 3,760 households in 2008 and 7,895 households in 2011 were surveyed for collecting relevant information.,Proportion of households with at least one LLIN, and at least one LLIN/ITN increased (22-59 to 62-67% and 22-64% to 74-76% respectively) over time, including increase in the mean number of LLIN/ITNs per household (≤ 1 to 1 +).,The programme achieved > 80% coverage in sleeping under an LLIN/ITN in the case of under-five children and pregnant women, especially in the high-endemic districts.,Knowledge regarding critical time of hanging the net also increased over time (7-22 to 44-54%), but remained low.,The pro-poor inclination of the programme is reflected in the status of relevant indicators according to self-rated poverty status of the households.,There has been a substantial improvement in possession and usage of insecticidal bed nets especially for the two most vulnerable groups (under-five children and pregnant women), including a reduction of gaps between the high and low endemic districts, and the deficit and non-deficit households during the study period.
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African trypanosomosis is a disease of public health and economic importance that poses a major threat to the livelihoods of people living in the Maasai Steppe, where there is a significant interaction between people, livestock and wildlife.,The vulnerability of the Maasai people to the disease is enhanced by the interaction of their cattle, which act as vehicles for trypanosomes, and tsetse flies close to wildlife in protected areas.,This study was aimed at identification of trypanosome infections circulating in cattle and tsetse flies in order to understand their distribution and prevalence in livestock/wildlife interface areas in the Maasai Steppe.,A total of 1002 cattle and 886 tsetse flies were sampled from June 2015 to February 2016 in five villages and PCR was conducted to amplify the internal transcribed spacer 1 (ITS1) from trypanosomes.,All Trypanosoma brucei-positive samples were further tested for the presence of the serum resistance-associated (SRA) gene found in human-infective trypanosomes using the SRA-LAMP technique.,The overall prevalence of trypanosome infections was 17.2% in cattle and 3.4% in tsetse flies.,Using a nested PCR, prevalence and abundance of five trypanosome species, Trypanosoma vivax, T. brucei, T. simiae, T. theileri and T. congolense, were determined, which varied with season and location.,The highest prevalence of the identified trypanosome species was recorded at the end of wet season with an exception of T. brucei which was high at the beginning of the wet season.,No human-infective trypanosomes were detected in both cattle and tsetse fly DNA.,This study confirms that seasonality and location have a significant contribution to the prevalence of trypanosome species in both mammalian and vector hosts.,These results are important for designing of community-wide vector and disease control interventions and planning of sustainable regimes for reduction of the burden of trypanosomosis in endemic pastoral areas, such as the Maasai Steppe in northern Tanzania.
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Pathogenic animal trypanosomes affecting livestock have represented a major constraint to agricultural development in Africa for centuries, and their negative economic impact is increasing in South America and Asia.,Chemotherapy and chemoprophylaxis represent the main means of control.,However, research into new trypanocides has remained inadequate for decades, leading to a situation where the few compounds available are losing efficacy due to the emergence of drug-resistant parasites.,In this review, we provide a comprehensive overview of the current options available for the treatment and prophylaxis of the animal trypanosomiases, with a special focus on the problem of resistance.,The key issues surrounding the main economically important animal trypanosome species and the diseases they cause are also presented.,As new investment becomes available to develop improved tools to control the animal trypanosomiases, we stress that efforts should be directed towards a better understanding of the biology of the relevant parasite species and strains, to identify new drug targets and interrogate resistance mechanisms.
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The effects of malaria and its treatment in the first trimester of pregnancy remain an area of concern.,We aimed to assess the outcome of malaria-exposed and malaria-unexposed first-trimester pregnancies of women from the Thai-Burmese border and compare outcomes after chloroquine-based, quinine-based, or artemisinin-based treatments.,We analysed all antenatal records of women in the first trimester of pregnancy attending Shoklo Malaria Research Unit antenatal clinics from May 12, 1986, to Oct 31, 2010.,Women without malaria in pregnancy were compared with those who had a single episode of malaria in the first trimester.,The association between malaria and miscarriage was estimated using multivariable logistic regression.,Of 48 426 pregnant women, 17 613 (36%) met the inclusion criteria: 16 668 (95%) had no malaria during the pregnancy and 945 (5%) had a single episode in the first trimester.,The odds of miscarriage increased in women with asymptomatic malaria (adjusted odds ratio 2·70, 95% CI 2·04-3·59) and symptomatic malaria (3·99, 3·10-5·13), and were similar for Plasmodium falciparum and Plasmodium vivax.,Other risk factors for miscarriage included smoking, maternal age, previous miscarriage, and non-malaria febrile illness.,In women with malaria, additional risk factors for miscarriage included severe or hyperparasitaemic malaria (adjusted odds ratio 3·63, 95% CI 1·15-11·46) and parasitaemia (1·49, 1·25-1·78 for each ten-fold increase in parasitaemia).,Higher gestational age at the time of infection was protective (adjusted odds ratio 0·86, 95% CI 0·81-0·91).,The risk of miscarriage was similar for women treated with chloroquine (92 [26%] of 354), quinine (95 [27%) of 355), or artesunate (20 [31%] of 64; p=0·71).,Adverse effects related to antimalarial treatment were not observed.,A single episode of falciparum or vivax malaria in the first trimester of pregnancy can cause miscarriage.,No additional toxic effects associated with artesunate treatment occurred in early pregnancy.,Prospective studies should now be done to assess the safety and efficacy of artemisinin combination treatments in early pregnancy.,Wellcome Trust and Bill & Melinda Gates Foundation.
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Infection with Plasmodium falciparum during pregnancy contributes substantially to the disease burden in both mothers and offspring.,Placental malaria may lead to intrauterine growth restriction or preterm delivery resulting in low birth weight (LBW), which, in general, is associated with increased infant morbidity and mortality.,However, little is known about the possible direct impact of the specific disease processes occurring in PM on longer term outcomes such as subsequent retarded growth development independent of LBW.,In an existing West-African cohort, 783 healthy infants with a birth weight of at least 2,000 g were followed up during their first year of life.,The aim of the study was to investigate if Plasmodium falciparum infection of the placenta, assessed by placental histology, has an impact on several anthropometric parameters, measured at birth and after three, six and 12 months using generalized estimating equations models adjusting for moderate low birth weight.,Independent of LBW, first to third born infants who were exposed to either past, chronic or acute placental malaria during pregnancy had significantly lower weight-for-age (-0.43, 95% CI: -0.80;-0.07), weight-for-length (-0.47, 95% CI: -0.84; -0.10) and BMI-for-age z-scores (-0.57, 95% CI: -0.84; -0.10) compared to infants born to mothers who were not diagnosed with placental malaria (p = 0.019, 0.013, and 0.012, respectively).,Interestingly, the longitudinal data on histology-based diagnosis of PM also document a sharp decline of PM prevalence in the Sukuta cohort from 16.5% in 2002 to 5.4% in 2004.,It was demonstrated that PM has a negative impact on the infant's subsequent weight development that is independent of LBW, suggesting that the longer term effects of PM have been underestimated, even in areas where malaria transmission is declining.
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A single low dose (0.25 mg/kg) of primaquine is recommended as a gametocytocide in combination with artemisinin-based combination therapies for Plasmodium falciparum but its effect on post-treatment gametocyte circulation and infectiousness to mosquitoes has not been quantified.,In this randomised, double-blind, placebo-controlled trial, 360 asymptomatic parasitaemic children aged 2-15 years were enrolled and assigned to receive: artemether-lumefantrine (AL) and a dose of placebo; AL and a 0.25 mg/kg primaquine dose; or AL and a 0.40 mg/kg primaquine dose.,On days 0, 2, 3, 7, 10 and 14, gametocytes were detected and quantified by microscopy, Pfs25 mRNA quantitative nucleic acid sequence based amplification (QT-NASBA), and quantitative reverse-transcriptase PCR (qRT-PCR).,For a subset of participants, pre- and post-treatment infectiousness was assessed by mosquito feeding assays on days -1, 3, 7, 10 and 14.,Both primaquine arms had lower gametocyte prevalences after day 3 compared to the placebo arm, regardless of gametocyte detection method.,The mean (95 % confidence interval) number of days to gametocyte clearance in children with patent gametocytes on day 0 (N = 150) was 19.7 (14.6 - 24.8), 7.7 (6.3 - 9.1) and 8.2 (6.7 - 9.6) for the AL-placebo, the 0.25 mg/kg primaquine dose and the 0.40 mg/kg primaquine dose arms, respectively.,While 38.0 % (30/79) of selected gametocytaemic individuals were infectious before treatment, only 1/251 participant, from the AL-placebo group, infected mosquitoes after treatment.,We observed similar gametocyte clearance rates after 0.25 and 0.40 mg/kg primaquine doses.,Infectivity to mosquitoes after AL was very low and absent in primaquine arms.,NCT01935882,The online version of this article (doi:10.1186/s12916-016-0581-y) contains supplementary material, which is available to authorized users.
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Primaquine is the only generally available anti-malarial that prevents relapse in vivax and ovale malaria, and the only potent gametocytocide in falciparum malaria.,Primaquine becomes increasingly important as malaria-endemic countries move towards elimination, and although it is widely recommended, it is commonly not given to malaria patients because of haemolytic toxicity in subjects who are glucose-6-phosphate dehydrogenase (G6PD) deficient (gene frequency typically 3-30% in malaria endemic areas; >180 different genetic variants).,In six decades of primaquine use in approximately 200 million people, 14 deaths have been reported.,Confining the estimate to reports with known denominators gives an estimated mortality of one in 621,428 (upper 95% CI: one in 407,807).,All but one death followed multiple dosing to prevent vivax malaria relapse.,Review of dose-response relationships and clinical trials of primaquine in G6PD deficiency suggests that the currently recommended WHO single low dose (0.25 mg base/kg) to block falciparum malaria transmission confers a very low risk of haemolytic toxicity.
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Because ≈90% of malaria cases occur in Africa, emergence of artemisinin-resistant Plasmodium falciparum in Africa poses a serious public health threat.,To assess emergence of artemisinin-resistant parasites in Uganda during 2014-2016, we used the recently developed ex vivo ring-stage survival assay, which estimates ring-stage-specific P. falciparum susceptibility to artemisinin.,We conducted 4 cross-sectional surveys to assess artemisinin sensitivity in Gulu, Uganda.,Among 194 isolates, survival rates (ratio of viable drug-exposed parasites to drug-nonexposed controls) were high (>10%) for 4 isolates.,Similar rates have been closely associated with delayed parasite clearance after drug treatment and are considered to be a proxy for the artemisinin-resistant phenotype.,Of these, the PfKelch13 mutation was observed in only 1 isolate, A675V.,Population genetics analysis suggested that these possibly artemisinin-resistant isolates originated in Africa.,Large-scale surveillance of possibly artemisinin-resistant parasites in Africa would provide useful information about treatment outcomes and help regional malaria control.
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Complex malaria infections are defined as those containing more than one genetically distinct lineage of Plasmodium parasite.,Complexity of infection (COI) is a useful parameter to estimate from patient blood samples because it is associated with clinical outcome, epidemiology and disease transmission rate.,This manuscript describes a method for estimating COI using likelihood, called COIL, from a panel of bi-allelic genotyping assays.,COIL assumes that distinct parasite lineages in complex infections are unrelated and that genotyped loci do not exhibit significant linkage disequilibrium.,Using the population minor allele frequency (MAF) of the genotyped loci, COIL uses the binomial distribution to estimate the likelihood of a COI level given the prevalence of observed monomorphic or polymorphic genotypes within each sample.,COIL reliably estimates COI up to a level of three or five with at least 24 or 96 unlinked genotyped loci, respectively, as determined by in silico simulation and empirical validation.,Evaluation of COI levels greater than five in patient samples may require a very large collection of genotype data, making sequencing a more cost-effective approach for evaluating COI under conditions when disease transmission is extremely high.,Performance of the method is positively correlated with the MAF of the genotyped loci.,COI estimates from existing SNP genotype datasets create a more detailed portrait of disease than analyses based simply on the number of polymorphic genotypes observed within samples.,The capacity to reliably estimate COI from a genome-wide panel of SNP genotypes provides a potentially more accurate alternative to methods relying on PCR amplification of a small number of loci for estimating COI.,This approach will also increase the number of applications of SNP genotype data, providing additional motivation to employ SNP barcodes for studies of disease epidemiology or control measure efficacy.,The COIL program is available for download from GitHub, and users may also upload their SNP genotype data to a web interface for simple and efficient determination of sample COI.,The online version of this article (doi:10.1186/1475-2875-14-4) contains supplementary material, which is available to authorized users.
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Reevaluation of treatment guidelines for Old and New World leishmaniasis is urgently needed on a global basis because treatment failure is an increasing problem.,Drug resistance is a fundamental determinant of treatment failure, although other factors also contribute to this phenomenon, including the global HIV/AIDS epidemic with its accompanying impact on the immune system.,Pentavalent antimonials have been used successfully worldwide for the treatment of leishmaniasis since the first half of the 20th century, but the last 10 to 20 years have witnessed an increase in clinical resistance, e.g., in North Bihar in India.,In this review, we discuss the meaning of “resistance” related to leishmaniasis and discuss its molecular epidemiology, particularly for Leishmania donovani that causes visceral leishmaniasis.,We also discuss how resistance can affect drug combination therapies.,Molecular mechanisms known to contribute to resistance to antimonials, amphotericin B, and miltefosine are also outlined.
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Nitric oxide (NO) produced in macrophages plays a pivotal role as a leishmanicidal agent.,A previous study has demonstrated that 20% of the L.,(V.) braziliensis isolated from initial cutaneous lesions of patients from the endemic area of Corte de Pedra, Bahia, Brazil, were NO resistant.,Additionally, 5 to 11% of the patients did not respond to three or more antimony treatments" (refractory patients).,The aim of this study is to investigate if there is an association between the resistance of L.,(V.) braziliensis to NO and nonresponsiveness to antimony therapy and cytokine production.,We evaluated the in vitro toxicity of NO against the promastigotes stages of L.,(V.) braziliensis isolated from responsive and refractory patients, and the infectivity of the amastigote forms of these isolates against human macrophages.,The supernatants from Leishmania infected macrophage were used to measure TNF-α and IL-10 levels.,Using NaNO2 (pH 5.0) as the NO source, L.,(V.) braziliensis isolated from refractory patients were more NO resistant (IC50 = 5.8 ± 4.8) than L.,(V.) braziliensis isolated from responsive patients (IC50 = 2.0 ± 1.4).,Four isolates were selected to infect human macrophages: NO-susceptible and NO-resistant L.,(V.) braziliensis isolated from responsive and refractory patients.,NO-resistant L.,(V.) braziliensis isolated from refractory patients infected more macrophages stimulated with LPS and IFN-γ at 120 hours than NO-susceptible L.,(V.) braziliensis isolated from refractory patients.,Also, lower levels of TNF-α were detected in supernatants of macrophages infected with NO-resistant L.,(V.) braziliensis as compared to macrophages infected with NO-susceptible L.,(V.) braziliensis (p < 0.05 at 2, 24 and 120 hours), while no differences were detected in IL-10 levels.,These data suggest that NO resistance could be related to the nonresponsiveness to antimony therapy seen in American Tegumentary Leishmaniasis.
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As malaria transmission continues to decrease, an increasing number of countries will enter pre-elimination and elimination.,To interrupt transmission, changes in control strategies are likely to require more accurate identification of all carriers of Plasmodium parasites, both symptomatic and asymptomatic, using diagnostic tools that are highly sensitive, high throughput and with fast turnaround times preferably performed in local health service settings.,Currently available immunochromatographic lateral flow rapid diagnostic tests and field microscopy are unlikely to consistently detect infections at parasite densities less than 100 parasites/µL making them insufficiently sensitive for detecting all carriers.,Molecular diagnostic platforms, such as PCR and LAMP, are currently available in reference laboratories, but at a cost both financially and in turnaround time.,This review describes the recent progress in developing molecular diagnostic tools in terms of their capacity for high throughput and potential for performance in non-reference laboratories for malaria elimination.
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Although global efforts in the past decade have halved the number of deaths due to malaria, there are still an estimated 219 million cases of malaria a year, causing more than half a million deaths.,In this forum article, we asked experts working in malaria research and control to discuss the ways in which malaria might eventually be eradicated.,Their collective views highlight the challenges and opportunities, and explain how multi-factorial and integrated processes could eventually make malaria eradication a reality.
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In this work, we describe a molecular mechanism of heterologous immunity between two distant species of Plasmodium.,Our results suggest a mechanism that subverts the classic parasite strategy of presenting highly polymorphic epitopes in surface antigens to evade immunity to that parasite.,This alternative immune pathway can be exploited to protect pregnant women from falciparum placental malaria by designing vaccines to cryptic epitopes that elicit broadly inhibitory antibodies against variant parasite strains.,Many pathogens evolve extensive genetic variation in virulence proteins as a strategy to evade host immunity.,This poses a significant challenge for the host to develop broadly neutralizing antibodies.,In Plasmodium falciparum, we show that a mechanism to circumvent this challenge is to elicit antibodies to cryptic epitopes that are not under immune pressure.,We previously discovered that antibodies to the Plasmodium vivax invasion protein, PvDBP, cross-react with P. falciparum VAR2CSA, a distantly related virulence factor that mediates placental malaria.,Here, we describe the molecular mechanism underlying this cross-species immunity.,We identified an epitope in subdomain 1 (SD1) within the Duffy binding-like (DBL) domain of PvDBP that gives rise to cross-reactive antibodies to VAR2CSA and show that human antibodies affinity purified against a synthetic SD1 peptide block parasite adhesion to chondroitin sulfate A (CSA) in vitro.,The epitope in SD1 is subdominant and highly conserved in PvDBP, and in turn, SD1 antibodies target cryptic epitopes in P. falciparum VAR2CSA.,The epitopes in VAR2CSA recognized by vivax-derived SD1 antibodies (of human and mouse origin) are distinct from those recognized by VAR2CSA immune serum.,We mapped two peptides in the DBL5ε domain of VAR2CSA that are recognized by SD1 antibodies.,Both peptides map to regions outside the immunodominant sites, and antibodies to these peptides are not elicited following immunization with VAR2CSA or natural infection with P. falciparum in pregnancy, consistent with the cryptic nature of these target epitopes.
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Despite that over 90 million pregnancies are at risk of Plasmodium vivax infection annually, little is known about the epidemiology and impact of the infection in pregnancy.,We undertook a health facility-based prospective observational study in pregnant women from Guatemala (GT), Colombia (CO), Brazil (BR), India (IN) and Papua New Guinea PNG).,Malaria and anemia were determined during pregnancy and fetal outcomes assessed at delivery.,A total of 9388 women were enrolled at antennal care (ANC), of whom 53% (4957) were followed until delivery.,Prevalence of P. vivax monoinfection in maternal blood at delivery was 0.4% (20/4461) by microscopy [GT 0.1%, CO 0.5%, BR 0.1%, IN 0.2%, PNG 1.2%] and 7% (104/1488) by PCR.,P. falciparum monoinfection was found in 0.5% (22/4463) of women by microscopy [GT 0%, CO 0.5%, BR 0%, IN 0%, PNG 2%].,P. vivax infection was observed in 0.4% (14/3725) of placentas examined by microscopy and in 3.7% (19/508) by PCR.,P. vivax in newborn blood was detected in 0.02% (1/4302) of samples examined by microscopy [in cord blood; 0.05% (2/4040) by microscopy, and 2.6% (13/497) by PCR].,Clinical P. vivax infection was associated with increased risk of maternal anemia (Odds Ratio-OR, 5.48, [95% CI 1.83-16.41]; p = 0.009), while submicroscopic vivax infection was not associated with increased risk of moderate-severe anemia (Hb<8g/dL) (OR, 1.16, [95% CI 0.52-2.59]; p = 0.717), or low birth weight (<2500g) (OR, 0.52, [95% CI, 0.23-1.16]; p = 0.110).,In this multicenter study, the prevalence of P. vivax infection in pregnancy by microscopy was overall low across all endemic study sites; however, molecular methods revealed a significant number of submicroscopic infections.,Clinical vivax infection in pregnancy was associated with maternal anemia, which may be deleterious for infant’s health.,These results may help to guide maternal health programs in settings where vivax malaria is endemic; they also highlight the need of addressing a vulnerable population such as pregnant women while embracing malaria elimination in endemic countries.
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From 2003 through 2009, 687 of 2885 patients (23.8%) treated for Plasmodium falciparum malaria in clinical studies in Myanmar or on the Thailand-Myanmar border had recurrent Plasmodium vivax malaria within 63 days, compared with 18 of 429 patients (4.2%) from 2010 onward (risk ratio [RR], 0.176; 95% confidence interval, .112-.278; P < .0001).,Corresponding data from 42 days of follow-up revealed that 820 of 3883 patients (21.1%) had recurrent P. vivax malaria before 2010, compared with 22 of 886 (2.5%) from 2010 onward (RR, 0.117; 95% CI, .077-.177; P < .0001).,This 6-fold reduction suggests a recent decline in P. vivax transmission intensity and, thus, a substantial reduction in the proportion of individuals harboring hypnozoites.,Before 2010, 687 of 2885 patients treated for Plasmodium falciparum malaria in Myanmar had recurrent Plasmodium vivax malaria within 63 days, compared with 18 of 429 from 2010 onward.,This 6-fold reduction suggests a recent substantial decline in P. vivax transmission and consequent hypnozoite carriage.
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In 2004, a revised action plan was developed, supported by the World Health Organization, to eliminate malaria from Saudi Arabia by preventing re-introduction of malaria into regions since declared malaria free, eliminating foci of transmission in the Mecca and Medina areas and a concerted effort of foci surveillance and control, to eliminate malaria from the regions of Jazan and Aseer.,This paper provides the context, activities, progress, and possible contributions toward malaria elimination in the Aseer region since 2000, with a more detailed analysis of the spatial location of locally acquired case incidence since 2012.,This is a descriptive study of all available Ministry of Health surveillance data and process reports since 2000, with higher spatial resolution analysis of data between 2012 and 2015.,In 2000, there were 511 cases of Plasmodium falciparum locally acquired infection.,The following 4 years witnessed a dramatic decline in cases to only 18 locally acquired infections reported in 2005.,A resurgence in local infections was reported in 2006 (93) and 2007 (165), thereafter (2008-2014) local cases continued to decline to fewer than 40 per year across the region.,However, in 2015, a small rise was noted (51).,All locally acquired infections were P. falciparum.,There has been a constant flow of imported infections into Aseer since 2000, mostly among immigrant labour from Pakistan, India, Sudan, and Yemen.,Imported infections have included both Plasmodium vivax and P. falciparum.,The spatial extent of malaria appears to be changing, but there remain two intractable areas Sarat Abeda and Dhran Aljanub, where risks per reporting centre have changed little since 2001, remaining above 0.5 per 10,000 population.,Only seven villages contributed 55% of all locally acquired infection since 2012.,Aseer has reached a state of very low incidence of locally acquired infections, despite a constant source of imported infections from outside the country.,How many of the local infections are F2 generations from imported infections or how many are a result of residual active transmission between asymptomatic carriers of infections transmitted by pockets of existing Anopheles arabiensis populations remains unknown.,A more detailed investigation of the spatial and temporal patterns of infected hosts, parasites and vectors would help define whether this region has managed to effectively prevent local transmission of new infections.
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The lack of rapid, affordable, and accurate diagnostic tests represents the primary hurdle affecting malaria surveillance in resource- and expertise-limited areas.,Loop-mediated isothermal amplification (LAMP) is a sensitive, rapid, and cheap diagnostic method.,Five species-specific LAMP assays were developed based on 18S rRNA gene.,Sensitivity and specificity of LAMP results were calculated as compared with microscopic examination and nested polymerase chain reaction.,LAMP reactions were highly sensitive with the detection limit of one copy for Plasmodium vivax, Plasmodium falciparum, and Plasmodium malariae and 10 copies for Plasmodium knowlesi and Plasmodium ovale.,LAMP positively detected all human malaria species in all positive samples (N = 134; sensitivity = 100%) within 35 minutes.,All negative samples were not amplified by LAMP (N = 67; specificity = 100%).,LAMP successfully detected two samples with very low parasitemia.,LAMP may offer a rapid, simple, and reliable test for the diagnosis of malaria in areas where malaria is prevalent.
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Polyparasitism is a common condition in humans but its impact on the host immune system and clinical diseases is still poorly understood.,There are few studies of the prevalence and the effect of malaria-intestinal parasite co-infections in the immune response to malaria vaccine candidates.,The present study determines whether the presence of malaria and intestinal parasites co-infection is associated with impaired IgG responses to Plasmodium vivax AMA-1 and MSP-119 in a rural population of the Brazilian Amazon.,A cross-sectional survey was performed in a rural area of Rondonia State and 279 individuals were included in the present study.,At recruitment, whole blood was collected and Plasmodium and intestinal parasites were detected by microscopy and molecular tests.,Blood cell count and haemoglobin were also tested and antibody response specific to P. vivax AMA-1 and MSP-119 was measured in plasma by ELISA.,The participants were grouped according to their infection status: singly infected with Plasmodium (M); co-infected with Plasmodium and intestinal parasites (CI); singly infected with intestinal parasites (IP) and negative (N) for both malaria and intestinal parasites.,The prevalence of intestinal parasites was significantly higher in individuals with malaria and protozoan infections were more prevalent.,IgG antibodies to PvAMA-1 and/or PvMSP-119 were detected in 74 % of the population.,The prevalence of specific IgG was similar for both proteins in all four groups and among the groups the lowest prevalence was in IP group.,The cytophilic sub-classes IgG1 and IgG3 were predominant in all groups for PvAMA-1 and IgG1, IgG3 and IgG4 for PvMSP-119.,In the case of non-cytophilic antibodies to PvAMA-1, IgG2 was significantly higher in IP and N group when compared to M and CI while IgG4 was higher in IP group.,The presence of intestinal parasites, mainly protozoans, in malaria co-infected individuals does not seem to alter the antibody immune responses to P. vivax AMA-1 and MSP-119.,However, IgG response to both AMA1 and MSP1 were lower in individuals with intestinal parasites.
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Despite progress in malaria control, malaria remains an important public health concern in Cambodia, mostly linked to forested areas.,Large-scale vector control interventions in Cambodia are based on the free distribution of long-lasting insecticidal nets (LLINs), targeting indoor- and late-biting malaria vectors only.,The present study evaluated the vector density, early biting activity and malaria transmission of outdoor-biting malaria vectors in two forested regions in Cambodia.,In 2005 two entomological surveys were conducted in 12 villages and their related forest plots in the east and west of Cambodia.,Mosquitoes were collected outdoors by human landing collections and subjected to enzyme-linked immunosorbent assay (ELISA) to detect Plasmodium sporozoites after morphological identification.,Blood samples were collected in the same villages for serological analyses.,Collected data were analysed by the classification and regression tree (CART) method and linear regression analysis.,A total of 11,826 anophelines were recorded landing in 787 man-night collections.,The majority (82.9%) were the known primary and secondary vectors.,Most of the variability in vector densities and early biting rates was explained by geographical factors, mainly at village level.,Vector densities were similar between forest and village sites.,Based on ELISA results, 29% out of 17 Plasmodium-positive bites occurred before sleeping time, and 65% in the forest plots.,The entomological inoculation rates of survey 1 were important predictors of the respective seroconversion rates in survey 2, whereas the mosquito densities were not.,In Cambodia, outdoor malaria transmission in villages and forest plots is important.,In this context, deforestation might result in lower densities of the primary vectors, but also in higher densities of secondary vectors invading deforested areas.,Moreover, higher accessibility of the forest could result in a higher man-vector contact.,Therefore, additional vector control measures should be developed to target outdoor- and early-biting vectors.
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Francois Nosten and colleagues evaluate malaria prevalence and incidence in the mobile population on the Myanmar side of the border with Thailand between 1999 and 2011, and also assess resistance to artemisinin.,The Shoklo Malaria Research Unit has been working on the Thai-Myanmar border for 25 y providing early diagnosis and treatment (EDT) of malaria.,Transmission of Plasmodium falciparum has declined, but resistance to artesunate has emerged.,We expanded malaria activities through EDT and evaluated the impact over a 12-y period.,Between 1 October 1999 and 30 September 2011, the Shoklo Malaria Research Unit increased the number of cross-border (Myanmar side) health facilities from two to 11 and recorded the number of malaria consultations.,Changes in malaria incidence were estimated from a cohort of pregnant women, and prevalence from cross-sectional surveys.,In vivo and in vitro antimalarial drug efficacy were monitored.,Over this period, the number of malaria cases detected increased initially, but then declined rapidly.,In children under 5 y, the percentage of consultations due to malaria declined from 78% (95% CI 76-80) (1,048/1,344 consultations) to 7% (95% CI 6.2-7.1) (767/11,542 consultations), p<0.001.,The ratio of P. falciparum/P. vivax declined from 1.4 (95% CI 1.3-1.4) to 0.7 (95% CI 0.7-0.8).,The case fatality rate was low (39/75,126; 0.05% [95% CI 0.04-0.07]).,The incidence of malaria declined from 1.1 to 0.1 episodes per pregnant women-year.,The cumulative proportion of P. falciparum decreased significantly from 24.3% (95% CI 21.0-28.0) (143/588 pregnant women) to 3.4% (95% CI 2.8-4.3) (76/2,207 pregnant women), p<0.001.,The in vivo efficacy of mefloquine-artesunate declined steadily, with a sharp drop in 2011 (day-42 PCR-adjusted cure rate 42% [95% CI 20-62]).,The proportion of patients still slide positive for malaria at day 3 rose from 0% in 2000 to reach 28% (95% CI 13-45) (8/29 patients) in 2011.,Despite the emergence of resistance to artesunate in P. falciparum, the strategy of EDT with artemisinin-based combination treatments has been associated with a reduction in malaria in the migrant population living on the Thai-Myanmar border.,Although limited by its observational nature, this study provides useful data on malaria burden in a strategically crucial geographical area.,Alternative fixed combination treatments are needed urgently to replace the failing first-line regimen of mefloquine and artesunate.,Please see later in the article for the Editors' Summary,According to latest figures, the World Health Organization estimates that there are over 200 million cases of malaria each year, with over three-quarters of a million deaths.,Several Plasmodium parasites cause malaria (the most serious being Plasmodium falciparum) and are transmitted to people through the bites of infected night-flying mosquitoes.,Malaria transmission can be prevented by using insecticides to control the mosquitoes and by sleeping under insecticide-treated bed nets.,However, in Southeast Asia the effectiveness of these measures is limited.,Treating infected people with antimalarial drugs, particularly with artemisinin-based combination treatments (ACTs), is a key strategy in reducing the deaths and disability caused by malaria.,However, progress is now threatened by the emergence in Southeast Asia of P. falciparum isolates that are resistant to artesunate (a common component of ACT).,This development is concerning, as resistance to the artemisinin family of drugs, of which artesunate is a member, could trigger a resurgence in malaria in many parts of the world and compromise the progress made in the treatment of severe malaria.,P. falciparum resistance to artemisinin has been confirmed in the area around the border between Thailand and Myanmar.,Malaria control in this border area is particularly challenging, as there is a reservoir of malaria in Myanmar (where the disease burden is higher than in Thailand), frequent population movement, and differences in adequate control measures on the two sides of the border.,In this study the authors evaluated malaria prevalence and incidence in the mobile population on the Myanmar side of the border between 1 October 1999 and 30 September 2011 to assess whether increasing access to early diagnosis and treatment with ACT was associated with a decline in the malaria burden.,The Shoklo Malaria Research Unit (SMRU) has been working on the Thai-Myanmar border for 25 years providing early diagnosis and treatment of malaria and has extended its services from two to 11 health care facilities (health posts) on the Myanmar side of the border over the past few years.,In order to evaluate any changes in the malaria burden since the expansion of services, the researchers recorded the number of consultations in all SMRU clinics and health posts with confirmed malaria diagnosis and tracked changes in the prevalence of malaria in the population on the Myanmar side of the border (via cross-sectional surveys in villages).,The researchers also assessed the incidence of malaria in a cohort of pregnant women living on both sides of the border and monitored antimalarial drug efficacy over this time period.,The researchers found that although the mobile population on the Thai side of the border remained constant, the population in villages covered by the clinics and health posts in the border area increased four-fold.,Over the time period, the researchers found that the number of confirmed malaria cases (P. falciparum) increased initially, rising from just over 5,000 in 2000 to a peak of 13,764 in 2006, and then declined to just over 3,500 in 2011.,A striking finding was the predominance of infections in young adult males (50,316/90,321; 55.7%).,Encouragingly, the percentage of consultations due to malaria in children under five years fell from 78% to 7%, and the incidence of malaria declined from 1.1 to 0.1 episodes per pregnant woman-year.,In addition, the proportion of patients admitted to hospital with severe disease was stable, and the number of deaths from malaria remained extremely low, with an overall case fatality rate of 0.05%.,The researchers also found that the ratio of P. falciparum to P. vivax infections declined from 1.4 to 0.7, and the prevalence of P. falciparum decreased from 24.3% to 3.4%.,However, worryingly, in the small number of patients undertaking drug efficacy tests, the drug efficacy of artesunate declined steadily, with the proportion of patients still infected with malaria at day 3 of treatment increasing from 0% in 2000 to 28% in 2011.,These findings indicate that despite the emergence of resistance to artesunate in P. falciparum, and the decline in the efficacy of ACT, the strategy of early diagnosis and treatment with ACTs has been associated with a reduction in malaria in the population living on the Thai-Myanmar border.,Furthermore, these findings suggest that an aggressive strategy based on early detection and treatment of cases, combined with vector control and information, could be the way forward to eliminate malaria.,Although there were only a small number of patients involved in drug efficacy tests in 2011, this study shows that alternative fixed combination treatments are needed urgently to replace the failing first-line regimen of mefloquine and artesunate.,Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001398.,More information about the Shoklo Malaria Research Unit is available,The World Health Organization website has more information about antimalarial drug efficacy and drug resistance,The Bill & Melinda Gates Foundation website tells the malaria resistance story
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The Malaria Eradication Research Agenda (malERA) Consultative Group on Diagnoses and Diagnostics outline a research and development agenda to provide the diagnosis and diagnostic tools required for malaria eradication.,Many of malaria's signs and symptoms are indistinguishable from those of other febrile diseases.,Detection of the presence of Plasmodium parasites is essential, therefore, to guide case management.,Improved diagnostic tools are required to enable targeted treatment of infected individuals.,In addition, field-ready diagnostic tools for mass screening and surveillance that can detect asymptomatic infections of very low parasite densities are needed to monitor transmission reduction and ensure elimination.,Antibody-based tests for infection and novel methods based on biomarkers need further development and validation, as do methods for the detection and treatment of Plasmodium vivax.,Current rapid diagnostic tests targeting P. vivax are generally less effective than those targeting Plasmodium falciparum.,Moreover, because current drugs for radical cure may cause serious side effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, more information is needed on the distribution of G6PD-deficiency variants as well as tests to identify at-risk individuals.,Finally, in an environment of very low or absent malaria transmission, sustaining interest in elimination and maintaining resources will become increasingly important.,Thus, research is required into the context in which malaria diagnostic tests are used, into diagnostics for other febrile diseases, and into the integration of these tests into health systems.
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The Malaria Eradication Research Agenda (malERA) Consultative Group on Monitoring, Evaluation, and Surveillance present a research and development agenda for the tools required to monitor and evaluate progress toward malaria eradication.,Monitoring, evaluation, and surveillance measure how well public health programs operate over time and achieve their goals.,As countries approach malaria elimination, these activities will need to shift from measuring reductions in morbidity and mortality, to detecting infections (with or without symptoms) and measuring transmission.,Thus, the monitoring and evaluation and surveillance research and development agenda needs to develop the tools and strategies that will replace passive surveillance of morbidity with active and prompt detection of infection, including confirmation of interruption of transmission by detecting present and past infections, particularly in mobile populations.,The capacity to assess trends and respond without delay will need to be developed, so that surveillance itself becomes an intervention.,Research is also needed to develop sensitive field tests that can detect low levels of parasitaemia, together with strategies for their implementation.,Other areas to explore include the rigorous evaluation of the utility of more detailed maps of disease and infection incidence and prevalence, the development of new maps to inform programmatic responses and the use of surveillance technologies based on cell phone or real-time internet Web-based reporting.,Because any new strategies for monitoring and evaluation and surveillance for eradication have major implications for program implementation, research is also needed to test systems of delivery for acceptability, feasibility, efficiency, cost-effectiveness, and community engagement.,Finally, there is a clear need to systematically review the information from past elimination efforts for malaria and other infectious diseases.
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IL-27 is a cytokine that exerts diverse effects on the cells of innate and adaptive immune systems.,Chiefly expressed in macrophages and dendritic cells during the early phase of Leishmania infection, IL-27 contributes to the protection against L. major infection but suppresses the protective Th1 response against L. donovani, L. infantum, L. amazonensis and L. braziliensis infections, suggesting its functional duality.,During the late stage of Leishmania infection, IL-27 limits the immunopathogenic reactions and tissue damages.,Herein, we analyze the mechanism of the functional duality of IL-27 in the resistance or susceptibility to Leishmania infection, prompting IL-27 for anti-Leishmanial therapy.
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Visceral leishmaniasis (VL) or kala-azar is a chronic protozoan infection in humans associated with significant global morbidity and mortality.,The causative agent is a haemoflagellate protozoan Leishmania donovani, an obligate intracellular parasite that resides and multiplies within macrophages of the reticulo-endothelial system.,Most of the existing anti-leishmanial drugs have serious side effects that limit their clinical application.,As an alternate strategy, vaccination is also under experimental and clinical trials.,The in vitro evaluation designed to facilitate rapid testing of a large number of drugs has been focussed on the promastigotes milt little attention on the clinically relevant parasite stage, amastigotes.,Screening designed to closely reflect the situation in vivo is currently time consuming, laborious, and expensive, since it requires intracellular amastigotes and animal model.,The ability to select transgenic Leishmania expressing reporter proteins, such as the green fluorescent proteins (GFP) or the luciferase opened up new possibilities for the development of drug screening models.,Many experimental animal models like rodents, dogs and monkeys have been developed, each with specific features, but none accurately reproduces what happens in humans.,Available in vitro and in vivo methodologies for antileishmanial drug screening and their respective advantages and disadvantages are reviewed.
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Stalled progress in controlling Plasmodium falciparum malaria highlights the need for an effective and deployable vaccine.,RTS,S/AS01, the most effective malaria vaccine candidate to date, demonstrated 56% efficacy over 12 months in African children.,We therefore assessed a new candidate vaccine for safety and efficacy.,In this double-blind, randomised, controlled, phase 2b trial, the low-dose circumsporozoite protein-based vaccine R21, with two different doses of adjuvant Matrix-M (MM), was given to children aged 5-17 months in Nanoro, Burkina Faso-a highly seasonal malaria transmission setting.,Three vaccinations were administered at 4-week intervals before the malaria season, with a fourth dose 1 year later.,All vaccines were administered intramuscularly into the thigh.,Group 1 received 5 μg R21 plus 25 μg MM, group 2 received 5 μg R21 plus 50 μg MM, and group 3, the control group, received rabies vaccinations.,Children were randomly assigned (1:1:1) to groups 1-3.,An independent statistician generated a random allocation list, using block randomisation with variable block sizes, which was used to assign participants.,Participants, their families, and the local study team were all masked to group allocation.,Only the pharmacists preparing the vaccine were unmasked to group allocation.,Vaccine safety, immunogenicity, and efficacy were evaluated over 1 year.,The primary objective assessed protective efficacy of R21 plus MM (R21/MM) from 14 days after the third vaccination to 6 months.,Primary analyses of vaccine efficacy were based on a modified intention-to-treat population, which included all participants who received three vaccinations, allowing for inclusion of participants who received the wrong vaccine at any timepoint.,This trial is registered with ClinicalTrials.gov, NCT03896724.,From May 7 to June 13, 2019, 498 children aged 5-17 months were screened, and 48 were excluded. 450 children were enrolled and received at least one vaccination. 150 children were allocated to group 1, 150 children were allocated to group 2, and 150 children were allocated to group 3.,The final vaccination of the primary series was administered on Aug 7, 2019.,R21/MM had a favourable safety profile and was well tolerated.,The majority of adverse events were mild, with the most common event being fever.,None of the seven serious adverse events were attributed to the vaccine.,At the 6-month primary efficacy analysis, 43 (29%) of 146 participants in group 1, 38 (26%) of 146 participants in group 2, and 105 (71%) of 147 participants in group 3 developed clinical malaria.,Vaccine efficacy was 74% (95% CI 63-82) in group 1 and 77% (67-84) in group 2 at 6 months.,At 1 year, vaccine efficacy remained high, at 77% (67-84) in group 1.,Participants vaccinated with R21/MM showed high titres of malaria-specific anti-Asn-Ala-Asn-Pro (NANP) antibodies 28 days after the third vaccination, which were almost doubled with the higher adjuvant dose.,Titres waned but were boosted to levels similar to peak titres after the primary series of vaccinations after a fourth dose administered 1 year later.,R21/MM appears safe and very immunogenic in African children, and shows promising high-level efficacy.,The European & Developing Countries Clinical Trials Partnership, Wellcome Trust, and National Institute for Health Research Oxford Biomedical Research Centre.
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Grant Dorsey and colleagues investigate the efficacy of three antimalarial drugs for preventing malaria in children living in Uganda, an area of high transmission intensity.,Please see later in the article for the Editors' Summary,Chemoprevention offers a promising strategy for prevention of malaria in African children.,However, the optimal chemoprevention drug and dosing strategy is unclear in areas of year-round transmission and resistance to many antimalarial drugs.,To compare three available regimens, we conducted an open-label randomized controlled trial of chemoprevention in Ugandan children.,This study was conducted between June 28, 2010, and September 25, 2013. 400 infants were enrolled and 393 randomized at 6 mo of age to no chemoprevention, monthly sulfadoxine-pyrimethamine (SP), daily trimethoprim-sulfamethoxazole (TS), or monthly dihydroartemisinin-piperaquine (DP).,Study drugs were administered at home without supervision.,Piperaquine (PQ) levels were used as a measure of compliance in the DP arm.,Participants were given insecticide-treated bednets, and caregivers were encouraged to bring their child to a study clinic whenever they were ill.,Chemoprevention was stopped at 24 mo of age, and participants followed-up an additional year.,Primary outcome was the incidence of malaria during the intervention period.,During the intervention, the incidence of malaria in the no chemoprevention arm was 6.95 episodes per person-year at risk.,Protective efficacy was 58% (95% CI, 45%-67%, p<0.001) for DP, 28% (95% CI, 7%-44%, p = 0.01) for TS, and 7% for SP (95% CI, −19% to 28%, p = 0.57).,PQ levels were below the detection limit 52% of the time when malaria was diagnosed in the DP arm, suggesting non-adherence.,There were no differences between the study arms in the incidence of serious adverse events during the intervention and the incidence of malaria during the 1-y period after the intervention was stopped.,For preventing malaria in children living in an area of high transmission intensity, monthly DP was the most efficacious and safe, although adherence may pose a problem.,Monthly SP and daily TS may not be appropriate in areas with high transmission intensity and frequent resistance to antifolates.,www.ClinicalTrials.govNCT00948896,Please see later in the article for the Editors' Summary,Malaria is a parasitic disease that kills more than 600,000 people (mainly young children living in sub-Saharan Africa) every year.,Malaria parasites, which are transmitted to people through the bites of night-flying mosquitoes, cause a characteristic fever that needs to be treated promptly with antimalarial drugs to prevent anemia and organ damage.,Prompt treatment also helps to reduce malaria transmission and is a component of the Global Malaria Action Plan, which aims to control and eventually eliminate malaria.,Other components of this plan include the provision of insecticide-treated bednets for people to sleep under to avoid mosquito bites and indoor residual spraying with insecticides.,Widespread deployment of these preventative tools and the increased availability of effective antimalarial drugs have greatly reduced malaria-related deaths worldwide over the past decade, but new strategies are still urgently needed to reduce the burden of malaria among those most at risk-young children living in Africa.,One promising strategy for the prevention of malaria in African children is the use of antimalarial drugs to prevent rather than treat malaria.,In trials, giving infants sulfadoxine-pyrimethamine (SP) alongside routine vaccinations, for example, reduced the incidence of malaria (the number of new cases in the population in a year) by about 30% during the first year of life (a protective efficacy of 30%).,However, the optimal chemoprevention drug and dosing strategy for children living in African regions where there is year-round transmission of malaria and where resistance to antimalarial drugs is common remains unclear.,Here, the researchers undertake an open-label randomized controlled trial (RCT) of chemoprevention in infants in the Tororo District of eastern Uganda, an area with intense year-round malaria transmission.,RCTs compare outcomes in groups of people chosen to receive different interventions through the play of chance; in open-label RCTs, both the researchers and the participants know which treatment is being administered.,The researchers assigned 393 six-month-old infants to receive no chemoprevention, monthly SP, daily trimethoprim-sulfamethoxazole (TS), or monthly dihydroartemisinin-piperaquine (DP) until they were 24 months old.,SP and TS block the production of folic acid, which malaria needs for survival, whereas DP is a newer artemisinin-based combination therapy (ACT).,All the drugs were given at home without supervision, and caregivers were asked to bring their children to a study clinic whenever they were ill.,During the intervention, the incidence of malaria was 6.95 episodes per person-year at risk in the no chemoprevention arm but only three episodes per person-year at risk in the DP arm.,That is, the protective efficacy of DP was 58%.,By contrast, the protective efficacies of TS and SP were 28% and 7%, respectively.,However, for SP the protective efficacy was not statistically different compared to the no chemoprevention arm.,Notably, piperaquine levels on the day that malaria was diagnosed were below the detection limit in half of the malaria episodes in the DP arm, which suggests that a complete dose of DP had not been given to the infant in the previous month, despite caregivers reporting that they had administered virtually all the assigned doses.,Finally, the incidence of serious adverse events was similar in all the study arms during the intervention, as was the incidence of malaria during the year after the intervention, which suggests that the chemoprevention strategies did not affect the development of naturally acquired immunity.,These findings show that, for children living in an area of intense malaria transmission, monthly DP was the most efficacious strategy for malaria chemoprevention but that adherence to the strategy may have been a problem.,These findings also suggest that monthly SP and daily TS may not be appropriate chemoprevention strategies in areas of high transmission intensity, particularly those where resistance to antifolate drugs is common.,The accuracy of these findings may be affected by drug administration being self-reported and by the number of comparisons included in the trial, which may have increased the risk of false-positive results.,Moreover, the results of this trial may not be generalizable to other regions of sub-Saharan Africa.,Overall, however, these results suggest that monthly DP is a strategy worth considering in regions in need of improved malaria control measures, with the important caveat that widespread ACT use for chemoprevention could compromise the efficacy of ACT when used for treatment.,Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001689.,Information is available from the World Health Organization on malaria (in several languages), including information on malaria chemoprevention; the World Malaria Report 2013 provides details of the current global malaria situation, including information on malaria in Uganda,The US Centers for Disease Control and Prevention provide information on malaria, including information on ways to reduce malaria cases and deaths; it also provides a selection of personal stories about malaria, including a story about malaria in a child in Africa,Information is available from the Roll Back Malaria Partnership on the global control of malaria and on the Global Malaria Action Plan (in English and French); its website includes fact sheets about malaria in Africa and about children and malaria,MedlinePlus provides links to additional information on malaria (in English and Spanish),More information about this trial is available
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Cerebral malaria is among the major causes of malaria-associated mortality and effective adjunctive therapeutic strategies are currently lacking.,Central pathophysiological processes involved in the development of cerebral malaria include an imbalance of pro- and anti-inflammatory responses to Plasmodium infection, endothelial cell activation, and loss of blood-brain barrier integrity.,However, the sequence of events, which initiates these pathophysiological processes as well as the contribution of their complex interplay to the development of cerebral malaria remain incompletely understood.,Several cytokines and chemokines have repeatedly been associated with cerebral malaria severity.,Increased levels of these inflammatory mediators could account for the sequestration of leukocytes in the cerebral microvasculature present during cerebral malaria, thereby contributing to an amplification of local inflammation and promoting cerebral malaria pathogenesis.,Herein, we highlight the current knowledge on the contribution of cytokines and chemokines to the pathogenesis of cerebral malaria with particular emphasis on their roles in endothelial activation and leukocyte recruitment, as well as their implication in the progression to blood-brain barrier permeability and neuroinflammation, in both human cerebral malaria and in the murine experimental cerebral malaria model.,A better molecular understanding of these processes could provide the basis for evidence-based development of adjunct therapies and the definition of diagnostic markers of disease progression.
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Plasmodium falciparum in a subset of patients can lead to a diffuse encephalopathy known as cerebral malaria (CM).,Despite treatment, mortality caused by CM can be as high as 30% while 10% of survivors of the disease may experience short- and long-term neurological complications.,The pathogenesis of CM involves alterations in cytokine and chemokine expression, local inflammation, vascular injury and repair processes.,These diverse factors have limited the rate of discovery of prognostic predictors of fatal CM.,Identification of reliable early predictors of CM severity will enable clinicians to adjust this risk with appropriate management of CM.,Recent studies revealed that elevated levels of CXCL10 expression in cerebrospinal fluid and peripheral blood plasma independently predicted severe and fatal CM.,CXCR3, a promiscuous receptor of CXCL10, plays an important role in pathogenesis of mouse model of CM.,In this study the role of corresponding CXCR3 ligands (CXCL11, CXCL10, CXCL9 & CXCL4) in fatal or severe CM was evaluated by comparing their levels in 16 healthy control (HC), 26 mild malaria (MM), 26 cerebral malaria survivors (CMS) and 12 non-survivors (CMNS) using enzyme linked immunosorbent assay (ELISA).,Levels of CXCL4 and CXCL10 were significantly elevated in CMNS patients (p < 0.05) when compared with HC, MM and CMS.,Elevated plasma levels of CXCL10 and CXCL4 were tightly associated with CM mortality.,Receiver Operating Characteristic (ROC) curve analysis revealed that CXCL4 and CXCL10 can discriminate CMNS from MM (p < 0.0001) and CMS (p < 0.0001) with an area under the curve (AUC) = 1.,These results suggest that CXCL4 and CXCL10 play a prominent role in pathogenesis of CM associated death and may be used as functional or surrogate biomarkers for predicting CM severity.
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Many control programmes against neglected tropical diseases have been interrupted due to the coronavirus disease 2019 (COVID-19) pandemic, including those that rely on active case finding.,In this study we focus on gambiense human African trypanosomiasis (gHAT), where active screening was suspended in the Democratic Republic of Congo (DRC) due to the pandemic.,We use two independent mathematical models to predict the impact of COVID-19 interruptions on transmission and reporting and achievement of the 2030 elimination of transmission (EOT) goal for gHAT in two moderate-risk regions of the DRC.,We consider different interruption scenarios, including reduced passive surveillance in fixed health facilities, and whether this suspension lasts until the end of 2020 or 2021.,Our models predict an increase in the number of new infections in the interruption period only if both active screening and passive surveillance were suspended, and with a slowed reduction-but no increase-if passive surveillance remains fully functional.,In all scenarios, the EOT may be slightly pushed back if no mitigation, such as increased screening coverage, is put in place.,However, we emphasise that the biggest challenge will remain in the higher-prevalence regions where EOT is already predicted to be behind schedule without interruptions unless interventions are bolstered.
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Gambiense human African trypanosomiasis (gHAT) is a virulent disease declining in burden but still endemic in West and Central Africa.,Although it is targeted for elimination of transmission by 2030, there remain numerous questions about the drivers of infection and how these vary geographically.,In this study we focus on the Democratic Republic of Congo (DRC), which accounted for 84% of the global case burden in 2016, to explore changes in transmission across the country and elucidate factors which may have contributed to the persistence of disease or success of interventions in different regions.,We present a Bayesian fitting methodology, applied to 168 endemic health zones (∼100,000 population size), which allows for calibration of a mechanistic gHAT model to case data (from the World Health Organization HAT Atlas) in an adaptive and automated framework.,It was found that the model needed to capture improvements in passive detection to match observed trends in the data within former Bandundu and Bas Congo provinces indicating these regions have substantially reduced time to detection.,Health zones in these provinces generally had longer burn-in periods during fitting due to additional model parameters.,Posterior probability distributions were found for a range of fitted parameters in each health zone; these included the basic reproduction number estimates for pre-1998 (R0) which was inferred to be between 1 and 1.14, in line with previous gHAT estimates, with higher median values typically in health zones with more case reporting in the 2000s.,Previously, it was not clear whether a fall in active case finding in the period contributed to the declining case numbers.,The modelling here accounts for variable screening and suggests that underlying transmission has also reduced greatly-on average 96% in former Equateur, 93% in former Bas Congo and 89% in former Bandundu-Equateur and Bandundu having had the highest case burdens in 2000.,This analysis also sets out a framework to enable future predictions for the country.
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In Ethiopia, light microscopy is the gold standard for malaria diagnosis although it is not available in most peripheral health facilities.,It is time consuming, requires trained personnel and needs careful preparation and application of reagents to ensure quality results.,This study was aimed at testing the diagnostic performance of CareStart™ malaria rapid diagnostic test (RDT) with reference to light microscopy for the diagnosis of falciparum and vivax malaria in Ethiopia.,Blood samples were collected from 254 patients suspected to have malaria at Kola Diba Health Center in the late malaria transmission peak season from November 2011 to December 2011.,The samples were examined immediately by light microscopy and the RDT (CareStart™ Malaria HRP2/pLDH COMBO Test kit).,Statistical analysis was performed using SPSS version 16 and the JavaStat two-way contingency table analysis.,The overall sensitivity and specificity of CareStartTM RDT was found to be 95% (90-97.9%, 95% CI) and 94.2% (90.9-96%, 95% CI), respectively.,The sensitivity of the CareStartTM RDT for Plasmodium falciparum or mixed infection was calculated to be 92.9% (82.5-98%, 95%CI) while a sensitivity of 90.9% (74.1-98.4%, 95%CI) was found for non-falciparum species.,The specificity for P. falciparum or mixed infections was found to be 95.4% (92.5-96.8%, 95%CI) while it was 97.3% (94.8-98.4%, 95%CI) for non-falciparum species.,There was an excellent agreement between the two tests with a kappa value of 0.918.,The CareStartTM RDT test showed good sensitivity and specificity with an excellent agreement to the reference light microscopy.,The RDT could therefore be used in place of light microscopy, which in poor set-ups cannot be used routinely.
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Malaria transmission in Ethiopia is unstable and variable, caused by both Plasmodium falciparum and Plasmodium vivax.,The Federal Ministry of Health (FMoH) is scaling up parasitological diagnosis of malaria at all levels of the health system; at peripheral health facilities this will be through use of rapid diagnostic tests (RDTs).,The present study compared three RDT products to provide the FMoH with evidence to guide appropriate product selection.,Performance of three multi-species (pf-HRP2/pan-pLDH and pf-HRP2/aldolase) RDTs (CareStart®, ParaScreen® and ICT Combo®) was compared with 'gold standard' microscopy at three health centres in Jimma zone, Oromia Regional State.,Ease of RDT use by health extension workers was assessed at community health posts.,RDT heat stability was tested in a controlled laboratory setting according to WHO procedures.,A total of 2,383 patients with suspected malaria were enrolled between May and July 2009, 23.2% of whom were found to be infected with Plasmodium parasites by microscopy.,All three RDTs were equally sensitive in detecting P. falciparum or mixed infection: 85.6% (95% confidence interval 81.2-89.4).,RDT specificity was similar for detection of P. falciparum or mixed infection at around 92%.,For detecting P. vivax infection, all three RDTs had similar sensitivity in the range of 82.5 to 85.0%.,CareStart had higher specificity in detecting P. vivax (97.2%) than both ParaScreen and ICT Combo (p < 0.001 and p = 0.05, respectively).,Health extension workers preferred CareStart and ParaScreen to ICT Combo due to the clear labelling of bands on the cassette, while the 'lab in a pack' style of CareStart was the preferred design.,ParaScreen and CareStart passed all heat stability testing, while ICT Combo did not perform as well.,CareStart appeared to be the most appropriate option for use at health posts in Ethiopia, considering the combination of quantitative performance, ease of use and heat stability.,When new products become available, the choice of multi-species RDT for Ethiopia should be regularly re-evaluated, as it would be desirable to identify a test with higher sensitivity than the ones evaluated here.
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In 2016, there were more cases and deaths caused by malaria globally than in 2015.,An effective vaccine would be an ideal additional tool for reducing malaria’s impact.,Sanaria® PfSPZ Vaccine, composed of radiation-attenuated, aseptic, purified, cryopreserved Plasmodium falciparum (Pf) sporozoites (SPZ) has been well tolerated and safe in malaria-naïve and experienced adults in the United States and Mali and protective against controlled human malaria infection with Pf in the United States and field transmission of Pf in Mali, but had not been assessed in younger age groups.,We, therefore, evaluated PfSPZ Vaccine in 93 Tanzanians aged 45 years to 6 months in a randomized, double-blind, normal saline placebo-controlled trial.,There were no significant differences in adverse events between vaccinees and controls or between dosage regimens.,Because all age groups received three doses of 9.0 × 105 PfSPZ of PfSPZ Vaccine, immune responses were compared at this dosage.,Median antibody responses against Pf circumsporozoite protein and PfSPZ were highest in infants and lowest in adults.,T-cell responses were highest in 6-10-year olds after one dose and 1-5-year olds after three doses; infants had no significant positive T-cell responses.,The safety data were used to support initiation of trials in > 300 infants in Kenya and Equatorial Guinea.,Because PfSPZ Vaccine-induced protection is thought to be mediated by T cells, the T-cell data suggest PfSPZ Vaccine may be more protective in children than in adults, whereas infants may not be immunologically mature enough to respond to the PfSPZ Vaccine immunization regimen assessed.
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Areas endemic for Plasmodium falciparum, hepatitis B virus (HBV) and hepatitis C virus (HCV) overlap in many parts of sub-Saharan Africa.,HBV and HCV infections develop in the liver, where takes place the first development stage of P. falciparum before its further spread in blood.,The complex mechanisms involved in the development of hepatitis may potentially influence the development of the liver stage of malaria parasites.,Understanding the molecular mechanisms of these interactions could provide new pathophysiological insights for treatment strategies in Malaria.,We studied a cohort of 319 individuals living in a village where the three infections are prevalent.,The patients were initially given a curative antimalarial treatment and were then monitored for the emergence of asexual P. falciparum forms in blood, fortnightly for one year, by microscopy and polymerase chain reaction.,At inclusion, 65 (20.4%) subjects had detectable malaria parasites in blood, 36 (11.3%) were HBV chronic carriers, and 61 (18.9%) were HCV chronic carriers.,During follow-up, asexual P. falciparum forms were detected in the blood of 203 patients.,The median time to P. falciparum emergence in blood was respectively 140 and 120 days in HBV- and HBV+ individuals, and 135 and 224 days in HCV- and HCV+ individuals.,HCV carriage was associated with delayed emergence of asexual P. falciparum forms in blood relative to patients without HCV infection.,This pilot study represents first tentative evidence of a potential epidemiological interaction between HBV, HCV and P. falciparum infections.,Age is an important confounding factor in this setting however multivariate analysis points to an interaction between P. falciparum and HCV at the hepatic level with a slower emergence of P. falciparum in HCV chronic carriers.,More in depth analysis are necessary to unravel the basis of hepatic interactions between these two pathogens, which could help in identifying new therapeutic approaches against malaria.
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The infection dynamics between different species of Plasmodium that infect the same human host can both suppress and exacerbate disease.,This could arise from inter-parasite interactions, such as competition, from immune regulation, or both.,The occurrence of protective, cross-species (heterologous) immunity is an unlikely event, especially considering that strain-transcending immunity within a species is only partial despite lifelong exposure to that species.,Here we review the literature in humans and animal models to identify the contexts where heterologous immunity can arise, and which antigens may be involved.,From the perspective of vaccine design, understanding the mechanisms by which exposure to an antigen from one species can elicit a protective response to another species offers an alternative strategy to conventional approaches that focus on immunodominant antigens within a single species.,The underlying hypothesis is that certain epitopes are conserved across evolution, in sequence or in structure, and shared in antigens from different species.,Vaccines that focus on conserved epitopes may overcome the challenges posed by polymorphic immunodominant antigens; but to uncover these epitopes requires approaches that consider the evolutionary history of protein families across species.,The key question for vaccinologists will be whether vaccines that express these epitopes can elicit immune responses that are functional and contribute to protection against Plasmodium parasites.
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Controlled human malaria infections (CHMIs) with Plasmodium falciparum (Pf) parasites are well established.,Exposure to five Pf (NF54)-infected Anopheles mosquitoes results in 100% infection rates in malaria-naïve volunteers.,Recently Pf clones NF135.,C10 and NF166.,C8 were generated for application in CHMIs.,Here, we tested the clinical infection rates of these clones, using graded numbers of Pf-infected mosquitoes.,In a double-blind randomized trial, we exposed 24 malaria-naïve volunteers to bites from one, two, or five mosquitoes infected with NF135.,C10 or NF166.,C8.,The primary endpoint was parasitemia by quantitative polymerase chain reaction.,For both strains, bites by five infected mosquitoes resulted in parasitemia in 4/4 volunteers; 3/4 volunteers developed parasitemia after exposure to one or two infected mosquitoes infected with either clone.,The prepatent period was 7.25 ± 4.0 days (median ± range).,There were no serious adverse events and comparable clinical symptoms between all groups.,These data confirm the eligibility of NF135.,C10 and NF166.,C8 for use in CHMI studies.
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Dynamical malaria models can relate precipitation to the availability of vector breeding sites using simple models of surface hydrology.,Here, a revised scheme is developed for the VECTRI malaria model, which is evaluated alongside the default scheme using a two year simulation by HYDREMATS, a 10 metre resolution, village-scale model that explicitly simulates individual ponds.,Despite the simplicity of the two VECTRI surface hydrology parametrization schemes, they can reproduce the sub-seasonal evolution of fractional water coverage.,Calibration of the model parameters is required to simulate the mean pond fraction correctly.,The default VECTRI model tended to overestimate water fraction in periods subject to light rainfall events and underestimate it during periods of intense rainfall.,This systematic error was improved in the revised scheme by including the a parametrization for surface run-off, such that light rainfall below the initial abstraction threshold does not contribute to ponds.,After calibration of the pond model, the VECTRI model was able to simulate vector densities that compared well to the detailed agent based model contained in HYDREMATS without further parameter adjustment.,Substituting local rain-gauge data with satellite-retrieved precipitation gave a reasonable approximation, raising the prospects for regional malaria simulations even in data sparse regions.,However, further improvements could be made if a method can be derived to calibrate the key hydrology parameters of the pond model in each grid cell location, possibly also incorporating slope and soil texture.
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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.
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Filariases are diseases caused by infection with filarial nematodes and transmitted by insect vectors.,The filarial roundworm Dirofilaria immitis causes heartworm disease in dogs and other carnivores.,D. immitis is closely related to Onchocerca volvulus, Wuchereria bancrofti and Brugia malayi, which cause onchocerciasis (river blindness) and lymphatic filariasis (elephantiasis) in humans and are neglected tropical diseases.,Serum N-glycosylation is very sensitive to both pathological infections and changes in mammalian biology due to normal aging or lifestyle choices.,Here, we report significant changes in the serum N-glycosylation profiles of dogs infected with D. immitis.,Our data derive from analysis of serum from dogs with established patent infections and from a longitudinal infection study.,Overall, galactosylation and core fucosylation increase, while sialylation decreases in infected dog sera.,We also identify individual glycan structures that change significantly in their relative abundance during infection.,Notably, the abundance of the most dominant N-glycan in canine serum (biantennary, disialylated A2G2S2) decreases by over 10 percentage points during the first 6 months of infection in each dog analyzed.,This is the first longitudinal study linking changes in mammalian serum N-glycome to progression of a parasitic infection.
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Immunoglobulin G (IgG) Fc N-glycosylation affects antibody-mediated effector functions and varies with inflammation rooted in both communicable and non-communicable diseases.,Worldwide, communicable and non-communicable diseases tend to segregate geographically.,Therefore, we studied whether IgG Fc N-glycosylation varies in populations with different environmental exposures in different parts of the world.,IgG Fc N-glycosylation was analysed in serum/plasma of 700 school-age children from different communities of Gabon, Ghana, Ecuador, the Netherlands and Germany.,IgG1 galactosylation levels were generally higher in more affluent countries and in more urban communities.,High IgG1 galactosylation levels correlated with low total IgE levels, low C-reactive protein levels and low prevalence of parasitic infections.,Linear mixed modelling showed that only positivity for parasitic infections was a significant predictor of reduced IgG1 galactosylation levels.,That IgG1 galactosylation is a predictor of immune activation is supported by the observation that asthmatic children seemed to have reduced IgG1 galactosylation levels as well.,This indicates that IgG1 galactosylation levels could be used as a biomarker for immune activation of populations, providing a valuable tool for studies examining the epidemiological transition from communicable to non-communicable diseases.
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Intestinal parasites remain considerable public health problems in low-income countries where poor food hygiene practice is common.,Food handlers, people involved in preparing and serving food, working with poor personal hygiene could pose a potential threat of spreading intestinal parasites to the public in a community.,The aim of this systematic review and meta-analysis was, therefore, to synthesize the pooled prevalence estimate of intestinal parasites and associated pooled odds ratio of hygienic predictors among food handlers of food service establishments in Ethiopia that could aid to further bringing down the burden of intestinal parasites and it can also be used as a springboard for future studies.,We searched exhaustively for studies Published before 20 April 2019 using eight Databases; PubMed, Science Direct, Web of Science, Scopus, Embase, Google Scholar, ProQuest, and Ovid MEDLINE® complemented by the gray literature search.,In the final synthesis, we included twenty study reports.,We used the Cochrane Q test and I2 test to assess heterogeneity of studies, while we employed a funnel plot followed by Egger’s regression asymmetry test and Begg rank correlation methods to evaluate publication bias.,We also performed a point estimates and 95% confidence interval for each study using STATA version 14 statistical software.,The overall pooled prevalence estimate of intestinal parasites among food handlers of food service establishments in Ethiopia was 33.6% (95%CI: 27.6-39.6%).,Among ten intestinal parasites identified from food handlers, Entamoeba histolytica/ dispar (11, 95%CI: 7.9-14.1%) and Ascaris lumbricoides (8.8, 95%CI: 6.4-11.2%) were the most predominant intestinal parasites.,Food handlers who washed hands after toilet use had 54% (OR, 0.46, 95% CI: 0.23-0.94) protection from intestinal parasites compared to those who did not.,This study revealed that intestinal parasitic infections are notable among food handlers of food service establishments in Ethiopia, which may be a risk for transmitting intestinal parasites to food and drinks consumers through the food chain.,Thus, periodic stool checkup, training on intestinal parasitic infections and personal hygiene should be applied to reduce public health and socio-economic impacts of parasitic infections.
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Soil-transmitted helminth (STH) infections are among the most prevalent neglected tropical diseases (NTD) worldwide.,Since the publication of the WHO road map to combat NTD in 2012, there has been a renewed commitment to control STH.,In this study, we analysed the geographical distribution and effect of community type on prevalence of hookworm, Trichuris and Ascaris in south Asia and south east Asia.,We conducted a systematic review of open-access literature published in PubMed Central and the Global Atlas of Helminth Infection.,A total of 4182 articles were available and after applying selection criteria, 174 studies from the region were retained for analysis.,Ascaris was the commonest STH identified with an overall prevalence of 18% (95% CI, 14-23%) followed by Trichuris (14%, 9-19%) and hookworm (12%, 9-15%).,Hookworm prevalence was highest in Laos, Vietnam and Cambodia.,We found a geographical overlap in countries with high prevalence rates for Trichuris and Ascaris (Malaysia, Philippines, Myanmar, Vietnam and Bangladesh).,When the effect of community type was examined, prevalence rates of hookworm was comparable in rural (19%, 14-24%) and tribal communities (14%, 10-19%).,Tribal communities, however, showed higher prevalence of Trichuris (38%, 18-63%) and Ascaris (32%, 23-43%) than rural communities (13%, 9-20% and 14%, 9-20% respectively).,Considerable between and within country heterogeneity in the distribution of STH (I2 >90%) was also noted.,When available data from school aged children (SAC) were analysed, prevalence of Ascaris (25% 16-31%) and Trichuris (22%, 14-34%) were higher than among the general population while that of hookworm (10%, 7-16%) was comparable.,Our analysis showed significant variation in prevalence rates between and within countries in the region.,Highlighting the importance of community type in prevalence and species mix, we showed that tribal and rural communities had higher hookworm infections than urban communities and for ascariasis and trichuriasis, tribal populations had higher levels of infection than rural populations.,We also found a higher prevalence of ascariasis and trichuriasis in SAC compared to the general population but comparable levels of hookworm infections.,These key findings need to be taken into account in planning future MDA and other interventions.
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Trials of intermittent preventive treatment in infants (IPTi) and children (IPTc) have shown promising results in reducing malaria episodes but with varying efficacy and cost-effectiveness.,The effects of different intervention and setting characteristics are not well known.,We simulate the effects of the different target age groups and delivery channels, seasonal or year-round delivery, transmission intensity, seasonality, proportions of malaria fevers treated and drug characteristics.,We use a dynamic, individual-based simulation model of Plasmodium falciparum malaria epidemiology, antimalarial drug action and case management to simulate DALYs averted and the cost per DALY averted by IPTi and IPTc.,IPT cost components were estimated from economic studies alongside trials.,IPTi and IPTc were predicted to be cost-effective in most of the scenarios modelled.,The cost-effectiveness is driven by the impact on DALYs, particularly for IPTc, and the low costs, particularly for IPTi which uses the existing delivery strategy, EPI.,Cost-effectiveness was predicted to decrease with low transmission, badly timed seasonal delivery in a seasonal setting, short-acting and more expensive drugs, high frequencies of drug resistance and high levels of treatment of malaria fevers.,Seasonal delivery was more cost-effective in seasonal settings, and year-round in constant transmission settings.,The difference was more pronounced for IPTc than IPTi due to the different proportions of fixed costs and also different assumed drug spacing during the transmission season.,The number of DALYs averted was predicted to decrease as a target five-year age-band for IPTc was shifted from children under 5 years into older ages, except at low transmission intensities.,Modelling can extend the information available by predicting impact and cost-effectiveness for scenarios, for outcomes and for multiple strategies where, for practical reasons, trials cannot be carried out.,Both IPTi and IPTc are generally cost-effective but could be rendered cost-ineffective by characteristics of the setting, drug or implementation.
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A randomized trial reported by Alassane Dicko and colleagues shows that intermittent preventive treatment for malaria in children who are protected from mosquitoes by insecticide-treated bednets provides substantial protection from malaria.,Previous studies have shown that in areas of seasonal malaria transmission, intermittent preventive treatment of malaria in children (IPTc), targeting the transmission season, reduces the incidence of clinical malaria.,However, these studies were conducted in communities with low coverage with insecticide-treated nets (ITNs).,Whether IPTc provides additional protection to children sleeping under an ITN has not been established.,To assess whether IPTc provides additional protection to children sleeping under an ITN, we conducted a randomised, double-blind, placebo-controlled trial of IPTc with sulphadoxine pyrimethamine (SP) plus amodiaquine (AQ) in three localities in Kati, Mali.,After screening, eligible children aged 3-59 mo were given a long-lasting insecticide-treated net (LLIN) and randomised to receive three rounds of active drugs or placebos.,Treatments were administered under observation at monthly intervals during the high malaria transmission season in August, September, and October 2008.,Adverse events were monitored immediately after the administration of each course of IPTc and throughout the follow-up period.,The primary endpoint was clinical episodes of malaria recorded through passive surveillance by study clinicians available at all times during the follow-up.,Cross-sectional surveys were conducted in 150 randomly selected children weekly and in all children at the end of the malaria transmission season to assess usage of ITNs and the impact of IPTc on the prevalence of malaria, anaemia, and malnutrition.,Cox regression was used to compare incidence rates between intervention and control arms.,The effects of IPTc on the prevalence of malaria infection and anaemia were estimated using logistic regression. 3,065 children were screened and 3,017 (1,508 in the control and 1,509 in the intervention arm) were enrolled in the study. 1,485 children (98.5%) in the control arm and 1,481 (98.1%) in the intervention arm completed follow-up.,During the intervention period, the proportion of children reported to have slept under an ITN was 99.7% in the control and 99.3% in intervention arm (p = 0.45).,A total of 672 episodes of clinical malaria defined as fever or a history of fever and the presence of at least 5,000 asexual forms of Plasmodium falciparum per microlitre (incidence rate of 1.90; 95% confidence interval [CI] 1.76-2.05 episodes per person year) were observed in the control arm versus 126 (incidence rate of 0.34; 95% CI 0.29-0.41 episodes per person year) in the intervention arm, indicating a protective effect (PE) of 82% (95% CI 78%-85%) (p<0.001) on the primary endpoint.,There were 15 episodes of severe malaria in children in the control arm compared to two in children in the intervention group giving a PE of 87% (95% CI 42%-99%) (p = 0.001).,IPTc reduced the prevalence of malaria infection by 85% (95% CI 73%-92%) (p<0.001) during the intervention period and by 46% (95% CI 31%-68%) (p<0.001) at the end of the intervention period.,The prevalence of moderate anaemia (haemoglobin [Hb] <8 g/dl) was reduced by 47% (95% CI 15%-67%) (p<0.007) at the end of intervention period.,The frequencies of adverse events were similar between the two arms.,There was no drug-related serious adverse event.,IPTc given during the malaria transmission season provided substantial protection against clinical episodes of malaria, malaria infection, and anaemia in children using an LLIN.,SP+AQ was safe and well tolerated.,These findings indicate that IPTc could make a valuable contribution to malaria control in areas of seasonal malaria transmission alongside other interventions.,ClinicalTrials.gov NCT00738946,Please see later in the article for the Editors' Summary,Malaria accounts for one in five of all childhood deaths in Africa and of the one million annual malarial deaths world-wide, over 75% occur in African children <5 years old infected with Plasmodium falciparum.,Malaria also causes severe morbidity in children, such as anemia, low birth-weight, epilepsy, and neurological problems, which compromise the health and development of millions of children living in malaria endemic areas.,As much of the impact of malaria on African children can be effectively prevented, significant efforts have been made in recent years to improve malaria control, such as the implementation of intermittent preventive treatment (IPT) of malaria.,IPT involves administration of antimalarial drugs at defined time intervals to individuals, regardless of whether they are known to be infected with malaria, to prevent morbidity and mortality.,IPT was initially recommended for pregnant women and recently this strategy was extended to include infants (IPTi).,Now, there is also intermittent preventive treatment of malaria in children (IPTc), which is designed to protect against seasonal malaria transmission including those above one year of age.,Large clinical trials have shown that IPTc involving the administration of two to three doses of an antimalarial drug (sulphadoxine pyrimethamine [SP] and artesunate [AS] or amodiaquine [AQ]) during the high malaria transmission season effectively reduces the incidence of malaria.,However, these studies were conducted in countries where the use of insecticide-treated bednets-an intervention that provides at least 50% protection against morbidity from malaria and is the main tool used for malaria control in most of sub-Saharan Africa-was relatively low.,Therefore, it is unclear whether IPTc will be as effective in children who sleep under insecticide-treated bednets as has been previously shown in communities where insecticide-treated bednet usage is low.,So to determine the answer to this important question, the researchers conducted a randomized, placebo controlled trial of IPTc with SP+AQ (chosen because of the effectiveness of this combination in a pilot study) in children who slept under an insecticide-treated bednet in an area of seasonal malaria transmission in Mali.,The researchers enrolled 3,017 eligible children aged 3-59 months into a randomized double-blind, placebo-controlled trial during the 2008 malaria transmission season in Mali.,All children were given a long-lasting insecticide-treated bednet at the start of the study with instructions to their family on the correct use of the net.,Children were then randomized into two arms-1,509 were allocated to the intervention group and 1,508 to the control group-to receive three courses of IPTc with SP plus AQ or placebos given at monthly intervals during the peak malaria transmission season.,The researchers monitored the incidence of malaria throughout the malaria season and also monitored the use of long-lasting insecticide-treated bednets throughout the study period.,In addition, researchers conducted a cross-sectional survey in 150 randomly selected children every week and in every child enrolled in the trial 6 weeks after the last course of IPTc, to measure their temperature, height and weight, and blood hemoglobin and parasite level.,The number of children who slept under their long-lasting insecticide-treated bednet was similar in both arms.,During the intervention period, the researchers observed a total of 672 episodes of clinical malaria (defined as fever or a history of fever and the presence of at least 5,000 asexual forms of Plasmodium falciparum per microliter) in the control arm versus 126 episodes in the intervention arm, which is an incidence rate of 1.90 episodes per person year in the control arm versus 0.34 in the interventions arm-giving a protective efficacy of 87%.,IPTc reduced the prevalence of malaria infection during the intervention period by 85% and by 46% at the end of the intervention period.,The prevalence of moderate anemia was also reduced (by 47%) at the end of intervention period.,The frequencies of adverse events were similar between the two arms and there were no drug-related serious adverse events.,The results of this study show that in peak malarial transmission season in Mali, IPTc provides substantial additional protection against episodes of clinical malaria and severe malaria in children sleeping under long-lasting insecticide-treated bednets.,In addition, intermittent preventive treatment of malaria with SP plus AQ appears to be safe and well tolerated for use in children.,Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000407.,This topic is further discussed in two PLoS Medicine research articles by Konat et al. and Bojang et al., and a PLoS Medicine Perspective by Beeson,Roll Back Malaria has information about malaria in children, including intervention strategies and an information sheet on insecticide-treated bednets,UNICEF also provides comprehensive information about malaria in children,The Intermittent Preventive Treatment in Infants Consortium (ipti) provides information on intermittent preventive treatment in infants
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In 2011, Cameroon and its health partners distributed over eight million free long-lasting insecticide treated nets (LLINs) in an effort to reduce the significant morbidity and mortality burden of malaria in the country.,A national communications campaign was launched in July 2011 to ensure that as the nets were delivered, they would be used consistently to close a net use gap: only 51.6% of adults and 63.4% of their children in households with at least one net were sleeping under nets before the distribution.,Even in households with at least one net for every two people, over 35% of adults were not sleeping under a net.,Malaria No More (MNM) adapted its signature NightWatch communications programme to fit within the coordinated “KO Palu” (Knock Out Malaria) national campaign.,This study evaluates the impact of KO Palu NightWatch activities (that is, the subset of KO Palu-branded communications that were funded by MNM’s NightWatch program) on bed net use.,Using national survey data collected at baseline (in March/April 2011, before the national LLIN distribution and KO Palu NightWatch launch) and post-intervention (March/April 2012), this study evaluates the impact of exposure to KO Palu NightWatch activities on last-night net use by Cameroonian adults and their children under five.,First, a plausible case for causality was established by comparing net use in 2011 and 2012 and measuring exposure to KO Palu NightWatch; next, a propensity score matching (PSM) model was used to estimate the impact of exposure on net use by simulating a randomized control trial; finally, the model was tested for sensitivity to unmeasured factors.,The PSM model estimated that among Cameroonians with at least one net in their household, exposure to KO Palu NightWatch activities was associated with a 6.6 percentage point increase in last-night net use among respondents (65.7% vs 59.1%, p < 0.05) and a 12.0 percentage point increase in last-night net use among respondents’ children under five (79.6% vs 67.6%, p < 0.025).,Sensitivity analysis suggests only a very small risk of bias from omitted factors influencing exposure and net use.,Extrapolating the results of the PSM model to the population of Cameroonians with access to at least one mosquito net, this analysis estimates that approximately 298,000 adults and over 221,000 of their children under five slept under a bed net because of the knowledge, motivation, and/or timely reminder provided by KO Palu NightWatch activities.,The programme cost less than $0.16 per adult reached, and less than $1.62 per additional person protected by a net.,The results suggest a strong role for mass media communication interventions in support of investments in malaria control commodities such as LLINs.
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Increased control has produced remarkable reductions of malaria in some parts of sub-Saharan Africa, including Rwanda.,In the southern highlands, near the district capital of Butare (altitude, 1,768 m), a combined community-and facility-based survey on Plasmodium infection was conducted early in 2010.,A total of 749 children below five years of age were examined including 545 randomly selected from 24 villages, 103 attending the health centre in charge, and 101 at the referral district hospital.,Clinical, parasitological, haematological, and socio-economic data were collected.,Plasmodium falciparum infection (mean multiplicity, 2.08) was identified by microscopy and PCR in 11.7% and 16.7%, respectively; 5.5% of the children had malaria.,PCR-based P. falciparum prevalence ranged between 0 and 38.5% in the villages, and was 21.4% in the health centre, and 14.9% in the hospital.,Independent predictors of infection included increasing age, low mid-upper arm circumference, absence of several household assets, reported recent intake of artemether-lumefantrine, and chloroquine in plasma, measured by ELISA.,Self-reported bed net use (58%) reduced infection only in univariate analysis.,In the communities, most infections were seemingly asymptomatic but anaemia was observed in 82% and 28% of children with and without parasitaemia, respectively, the effect increasing with parasite density, and significant also for submicroscopic infections.,Plasmodium falciparum infection in the highlands surrounding Butare, Rwanda, is seen in one out of six children under five years of age.,The abundance of seemingly asymptomatic infections in the community forms a reservoir for transmission in this epidemic-prone area.,Risk factors suggestive of low socio-economic status and insufficient effectiveness of self-reported bed net use refer to areas of improvable intervention.
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Helminths represent a diverse category of parasitic organisms that can thrive within a host for years, if not decades, in the absence of treatment.,As such, they must establish mechanisms to subsist off their hosts, evade the immune system, and develop a niche among the other cohabiting microbial communities.,The complex interplay of biologically small molecules (collectively known as the metabolome) derived from, utilized by, or in response to the presence of helminths within a host is an emerging field of study.,In this Perspective, we briefly summarize the current existing literature, categorize key host-pathogen-microbiome interfaces that could be studied in the context of the metabolome, and provide background on mass spectrometry-based metabolomic methodology.,Overall, we hope to provide a comprehensive guide for utilizing metabolomics in the context of helminthic disease.
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We investigated whether the carriage of Blastocystis in IBS patients was associated with differences in the faecal microbiota.,Forty patients with diarrhoea-predominant IBS (26 Blastocystis-positive and 14 Blastocystis-negative) and 57 healthy controls (HC) (42 Blastocystis-positive and 15 Blastocystis-negative) submitted faecal samples for metataxonomic analysis of the 16S ribosomal RNA gene.,Differences in the relative abundance of bacteria in these IBS and HC groups were evaluated from phylum to genus level.,Significant changes were observed in two dominant phyla in IBS patients, regardless of Blastocystis infection status, namely a rise in Firmicutes and a statistically significant reduction in relative abundance of Bacteroidetes (with a threefold increase in the Firmicutes to Bacteoridetes ratio).,Significant differences at genus level in IBS subjects compared to HC were also observed for many bacterial species.,However, further clinical subgroup analysis of Blastocystis-positive and Blastocystis-negative subjects, regardless of symptoms, showed no significant differences at the phylum or genus level in IBS-P compared to IBS-N.,Significant differences in the faecal microbiota between diarrhoea-predominant IBS patients and healthy controls were confirmed, but the carriage of Blastocystis did not significantly alter the faecal microbiota.,If Blastocystis-positive patients represent a separate clinical subtype of IBS, this group is not identified by changes in the microbiota.,The online version of this article (doi:10.1186/s40168-016-0191-0) contains supplementary material, which is available to authorized users.
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Glucose-6-phosphate dehydrogenase deficiency (G6PDd) is widespread across malaria endemic regions.,G6PD-deficient individuals are at risk of haemolysis when exposed, among other agents, to primaquine and tafenoquine, which are capable of blocking malaria transmission by killing Plasmodium falciparum gametocytes and preventing Plasmodium vivax relapses by targeting hypnozoites.,It is evident that no measures are currently in place to ensure safe delivery of these drugs within the context of G6PDd risk.,Thus, determining G6PDd prevalence in malarious areas would contribute towards avoiding possible complications in malaria elimination using the drugs.,This study, therefore, was aimed at determining G6PDd prevalence in Gambella hospital, southwest Ethiopia, using CareStart™ G6PDd fluorescence spot test.,Venous blood samples were collected from febrile patients (n = 449) attending Gambella hospital in November-December 2013.,Malaria was diagnosed using blood films and G6PDd was screened using CareStart™ G6PDd screening test (Access Bio, New Jersey, USA).,Haematological parameters were also measured.,The association of G6PD phenotype with sex, ethnic group and malaria smear positivity was tested.,Malaria prevalence was 59.2% (96.6% of the cases being P. falciparum mono infections).,Totally 33 participants (7.3%) were G6PD-deficient with no significant difference between the sexes.,The chance of being G6PD-deficient was significantly higher for the native ethnic groups (Anuak and Nuer) compared to the ‘highlanders’/settlers (odds ratio (OD) = 3.9, 95% confidence interval (CI) 0.481-31.418 for Anuak vs ‘highlanders’; OD = 4.9, 95% CI 0.635-38.00 for Nuer vs ‘highlanders’).,G6PDd prevalence among the Nuer (14.3%) was significantly higher than that for the Anuak (12.0%).,G6PDd prevalence in the area is substantial with 30 (90.9%) of the 33 deficient individuals having malaria suggesting the non-protective role of the disorder at least from clinical malaria.,The indigenous Nilotic people tend to have a higher chance of being G6PD-deficient as 32 (96.9%) of the total 33 cases occurred among them.
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Plasmodium vivax infects a hundred million people annually and endangers 40% of the world's population.,Unlike Plasmodium falciparum, P. vivax parasites can persist as a dormant stage in the liver, known as the hypnozoite, and these dormant forms can cause malaria relapses months or years after the initial mosquito bite.,Here we analyze whole genome sequencing data from parasites in the blood of a patient who experienced consecutive P. vivax relapses over 33 months in a non-endemic country.,By analyzing patterns of identity, read coverage, and the presence or absence of minor alleles in the initial polyclonal and subsequent monoclonal infections, we show that the parasites in the three infections are likely meiotic siblings.,We infer that these siblings are descended from a single tetrad-like form that developed in the infecting mosquito midgut shortly after fertilization.,In this natural cross we find the recombination rate for P. vivax to be 10 kb per centimorgan and we further observe areas of disequilibrium surrounding major drug resistance genes.,Our data provide new strategies for studying multiclonal infections, which are common in all types of infectious diseases, and for distinguishing P. vivax relapses from reinfections in malaria endemic regions.,This work provides a theoretical foundation for studies that aim to determine if new or existing drugs can provide a radical cure of P. vivax malaria.
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Malaria presents a diagnostic challenge in areas where both Plasmodium falciparum and P.vivax are co-endemic.,Bivalent Rapid Diagnostic tests (RDTs) showed promise as diagnostic tools for P.falciparum and P.vivax.,To assist national malaria control programme in the selection of RDTs, commercially available seven malaria RDTs were evaluated in terms of their performance with special reference to heat stability.,This study was undertaken in four forested districts of central India (July, 2011- March, 2012).,All RDTs were tested simultaneously in field along with microscopy as gold standard.,These RDTs were stored in their original packing at 25°C before transport to the field or they were stored at 35°C and 45°C upto 100 days for testing the performance of RDTs at high temperature.,In all 2841 patients with fever were screened for malaria of which 26% were positive for P.falciparum, and 17% for P.vivax.,The highest sensitivity of any RDT for P.falciparum was 98% (95% CI; 95.9-98.8) and lowest sensitivity was 76% (95% CI; 71.7-79.6).,For P.vivax highest and lowest sensitivity for any RDT was 80% (95% CI; 94.9 - 83.9) and 20% (95% CI; 15.6-24.5) respectively.,Heat stability experiments showed that most RDTs for P.falciparum showed high sensitivity at 45°C upto 90 days.,While for P.vivax only two RDTs maintained good sensitivity upto day 90 when compared with RDTs kept at room temperature.,Agreement between observers was excellent for positive and negative readings for both P.falciparum and P.vivax (Kappa >0.6-0.9).,This is first field evaluation of RDTs regarding their temperature stability.,Although RDTs are useful as diagnostic tool for P.falciparum and P.vivax even at high temperature, the quality of RDTs should be regulated and monitored more closely.
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Applying the switch from presumptive treatment of malaria to new policies of anti-malarial prescriptions restricted to parasitologically-confirmed cases is a still unsolved challenge.,Pragmatic studies can provide data on consequences of such a switch.,In order to assess whether restricting anti-malarials to rapid diagnostic test (RDT)-confirmed cases in children of between five and 15 years of age is consistent with an adequate management of fevers, a school-based study was performed in Allada, Benin.,Children in the index group (with fever and a negative RDT) and the matched control group (without fever and a negative RDT) were not prescribed anti-malarials and actively followed-up during 14 days.,Blood smears were collected at each assessment.,Self-medication with chloroquine and quinine was assessed with blood spots.,Malaria attacks during the follow-up were defined by persistent or recurrent fever concomitant to a positive malaria test.,484 children were followed-up (242 in each group).,At day 3, fever had disappeared in 94% of children from the index group.,The incidence of malaria was similar (five cases in the index group and seven cases in the control group) between groups.,Self-medication with chloroquine and quinine in this cohort was uncommon.,Applying a policy of restricting anti-malarials to RDT-confirmed cases is consistent with an adequate management of fevers in this population.,Further studies on the management of fever in younger children are of upmost importance.
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Potentially untreatable Plasmodium falciparum malaria threatens the Greater Mekong subregion.,A previous series of pilot projects in Myanmar, Laos, Cambodia, and Vietnam suggested that mass drug administration was safe, and when added to provision of early diagnosis and treatment, could reduce the reservoir of P falciparum and interrupts transmission.,We examined the effects of a scaled-up programme of this strategy in four townships of eastern Myanmar on the incidence of P falciparum malaria.,The programme was implemented in the four townships of Myawaddy, Kawkareik, Hlaingbwe, and Hpapun in Kayin state, Myanmar.,Increased access to early diagnosis and treatment of malaria was provided to all villages through community-based malaria posts equipped with rapid diagnostic tests, and treatment with artemether-lumefantrine plus single low-dose primaquine.,Villages were identified as malarial hotspots (operationally defined as >40% malaria, of which 20% was P falciparum) with surveys using ultrasensitive quantitative PCR either randomly or targeted at villages where the incidence of clinical cases of P falciparum malaria remained high (ie, >100 cases per 1000 individuals per year) despite a functioning malaria post.,During each survey, a 2 mL sample of venous blood was obtained from randomly selected adults.,Hotspots received targeted mass drug administration with dihydroartemisinin-piperaquine plus single-dose primaquine once per month for 3 consecutive months in addition to the malaria posts.,The main outcome was the change in village incidence of clinical P falciparum malaria, quantified using a multivariate, generalised, additive multilevel model.,Malaria prevalence was measured in the hotspots 12 months after mass drug administration.,Between May 1, 2014, and April 30, 2017, 1222 malarial posts were opened, providing early diagnosis and treatment to an estimated 365 000 individuals.,Incidence of P falciparum malaria decreased by 60 to 98% in the four townships. 272 prevalence surveys were undertaken and 69 hotspot villages were identified.,By April 2017, 50 hotspots were treated with mass drug administration.,Hotspot villages had a three times higher incidence of P falciparum at malarial posts than neighbouring villages (adjusted incidence rate ratio [IRR] 2·7, 95% CI 1·8-4·4).,Early diagnosis and treatment was associated with a significant decrease in P falciparum incidence in hotspots (IRR 0·82, 95% CI 0·76-0·88 per quarter) and in other villages (0·75, 0·73-0·78 per quarter).,Mass drug administration was associated with a five-times decrease in P falciparum incidence within hotspot villages (IRR 0·19, 95% CI 0·13-0·26).,By April, 2017, 965 villages (79%) of 1222 corresponding to 104 village tracts were free from P falciparum malaria for at least 6 months.,The prevalence of wild-type genotype for K13 molecular markers of artemisinin resistance was stable over the three years (39%; 249/631).,Providing early diagnosis and effective treatment substantially decreased village-level incidence of artemisinin-resistant P falciparum malaria in hard-to-reach, politically sensitive regions of eastern Myanmar.,Targeted mass drug administration significantly reduced malaria incidence in hotspots.,If these activities could proceed in all contiguous endemic areas in addition to standard control programmes already implemented, there is a possibility of subnational elimination of P falciparum.,The Bill & Melinda Gates Foundation, the Regional Artemisinin Initiative (Global Fund against AIDS, Tuberculosis and Malaria), and the Wellcome Trust.
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Western Cambodia is the epicentre of Plasmodium falciparum multidrug resistance and is facing high rates of dihydroartemisinin-piperaquine treatment failures.,Genetic tools to detect the multidrug-resistant parasites are needed.,Artemisinin resistance can be tracked using the K13 molecular marker, but no marker exists for piperaquine resistance.,We aimed to identify genetic markers of piperaquine resistance and study their association with dihydroartemisinin-piperaquine treatment failures.,We obtained blood samples from Cambodian patients infected with P falciparum and treated with dihydroartemisinin-piperaquine.,Patients were followed up for 42 days during the years 2009-15.,We established in-vitro and ex-vivo susceptibility profiles for a subset using piperaquine survival assays.,We determined whole-genome sequences by Illumina paired-reads sequencing, copy number variations by qPCR, RNA concentrations by qRT-PCR, and protein concentrations by immunoblotting.,Fisher’s exact and non-parametric Wilcoxon rank-sum tests were used to identify significant differences in single-nucleotide polymorphisms or copy number variants, respectively, for differential distribution between piperaquine-resistant and piperaquine-sensitive parasite lines.,Whole-genome exon sequence analysis of 31 culture-adapted parasite lines associated amplification of the plasmepsin 2-plasmepsin 3 gene cluster with in-vitro piperaquine resistance.,Ex-vivo piperaquine survival assay profiles of 134 isolates correlated with plasmepsin 2 gene copy number.,In 725 patients treated with dihydroartemisinin-piperaquine, multicopy plasmepsin 2 in the sample collected before treatment was associated with an adjusted hazard ratio (aHR) for treatment failure of 20·4 (95% CI 9·1-45·5, p<0·0001).,Multicopy plasmepsin 2 predicted dihydroartemisinin-piperaquine failures with 0·94 (95% CI 0·88-0·98) sensitivity and 0·77 (0·74-0·81) specificity.,Analysis of samples collected across the country from 2002 to 2015 showed that the geographical and temporal increase of the proportion of multicopy plasmepsin 2 parasites was highly correlated with increasing dihydroartemisinin-piperaquine treatment failure rates (r=0·89 [95% CI 0·77-0·95], p<0·0001, Spearman’s coefficient of rank correlation).,Dihydroartemisinin-piperaquine efficacy at day 42 fell below 90% when the proportion of multicopy plasmepsin 2 parasites exceeded 22%.,Piperaquine resistance in Cambodia is strongly associated with amplification of plasmepsin 2-3, encoding haemoglobin-digesting proteases, regardless of the location.,Multicopy plasmepsin 2 constitutes a surrogate molecular marker to track piperaquine resistance.,A molecular toolkit combining plasmepsin 2 with K13 and mdr1 monitoring should provide timely information for antimalarial treatment and containment policies.,Institut Pasteur in Cambodia, Institut Pasteur Paris, National Institutes of Health, WHO, Agence Nationale de la Recherche, Investissement d’Avenir programme, Laboratoire d’Excellence Integrative “Biology of Emerging Infectious Diseases”.
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Intestinal parasitic infections (IPIs) have been major public health problems in low income countries primarily affecting school children.,Previous studies in Ethiopia have shown high burden of intestinal parasitic infections in most children.,In order to gain a deeper insight into the magnitude of the problem more information is needed from different localities where similar studies have not been conducted.,The aim of this study was to assess the prevalence of IPIs and associated risk factors among school children in Jawi Primary School, Jawi town, north -west Ethiopia.,A cross-sectional study was conducted from April to June 2017 to assess the prevalence of IPIs and associated risk factors among Jawi Primary School children, Ethiopia.,A total of 422 children were selected using age-stratified systematic random sampling technique.,Stool samples were examined microscopically using direct wet-mount and formal-ether concentration techniques.,A structured questionnaire was used to obtain information regarding the associated risk factors.,Data were analyzed using SPSS version 20 and p value < 0.05 was taken as statistically significant.,Of 406 students examined for IPIs, 235 (57.88%) were positive for one or more intestinal parasites.,Single, double and triple infections were 41.9, 6.2 and 1.2%, respectively.,Overall infection rate was slightly higher in males (51.85%) than in females (45.30%) though the difference was not significant.,Higher prevalence rate (about 51-53%) was recorded among 6 to 18 years old children.,Prevalence of Giardia lamblia was the highest (19.95%), followed by hookworm (13.8%), Schistosoma mansoni (10.3%), Entamoeba histolytica/dispar (5.9%), Hymenolepsis nana (4.2%), Taenia species (3%) and Ascaris lumbricoides (0.73%), in that order.,Among the risk factors assessed, age, hand washing habit before meals, open field defecation habit, consistency of wearing shoes, habit of eating raw and unwashed vegetables, and finger nail cleanliness and trimming habit were found to be the most important predictors associated with high risk of IPIs (p < 0.05).,High prevalence of IPIs among Jawi Primary school children demands improved health education on regular hand washing, latrine use, wearing shoes, cleaning finger nails, not crossing rivers with bare foot and avoiding eating raw vegetables.,The online version of this article (10.1186/s12879-019-3971-x) contains supplementary material, which is available to authorized users.
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Schistosomiasis, one of the most prevalent neglected tropical diseases, is a life-threatening public health problem in Yemen especially in rural communities.,This cross-sectional study aims to determine the prevalence and associated risk factors of schistosomiasis among children in rural Yemen.,Urine and faecal samples were collected from 400 children.,Urine samples were examined using filtration technique for the presence of Schistosoma haematobium eggs while faecal samples were examined using formalin-ether concentration and Kato Katz techniques for the presence of S. mansoni.,Demographic, socioeconomic and environmental information were collected via a validated questionnaire.,Overall, 31.8% of the participants were found to be positive for schistosomiasis; 23.8% were infected with S. haematobium and 9.3% were infected with S. mansoni.,Moreover, 39.5% of the participants were anaemic whereas 9.5% had hepatosplenomegaly.,The prevalence of schistosomiasis was significantly higher among children aged >10 years compared to those aged ≤10 years (P<0.05).,Multivariate analysis confirmed that presence of other infected family member (P<0.001), low household monthly income (P = 0.003), using unsafe sources for drinking water (P = 0.003), living nearby stream/spring (P = 0.006) and living nearby pool/pond (P = 0.002) were the key factors significantly associated with schistosomiasis among these children.,This study reveals that schistosomiasis is still highly prevalent in Yemen.,These findings support an urgent need to start an integrated, targeted and effective schistosomiasis control programme with a mission to move towards the elimination phase.,Besides periodic drug distribution, health education and community mobilisation, provision of clean and safe drinking water, introduction of proper sanitation are imperative among these communities in order to curtail the transmission and morbidity caused by schistosomiasis.,Screening and treating other infected family members should also be adopted by the public health authorities in combating this infection in these communities.
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Long-lasting and sterile homologous protection against malaria can be achieved by the exposure of malaria-naive volunteers under chemoprophylaxis to Plasmodium falciparum-infected mosquitoes (chemoprophylaxis and sporozoite [CPS] immunization).,While CPS-induced antibodies neutralize sporozoite infectivity in vitro and in vivo, antibody-mediated effector mechanisms are still poorly understood.,Here, we investigated whether complement contributes to CPS-induced preerythrocytic immunity.,Sera collected before and after CPS immunization in the presence of active or inactive complement were assessed for the recognition of homologous NF54 and heterologous NF135.,C10 sporozoites, complement fixation, sporozoite lysis, and possible subsequent effects on in vitro sporozoite infectivity in human hepatocytes.,CPS immunization induced sporozoite-specific IgM (P < 0.0001) and IgG (P = 0.001) antibodies with complement-fixing capacities (P < 0.0001).,Sporozoite lysis (P = 0.017), traversal (P < 0.0001), and hepatocyte invasion inhibition (P < 0.0001) by CPS-induced antibodies were strongly enhanced in the presence of active complement.,Complement-mediated invasion inhibition in the presence of CPS-induced antibodies negatively correlated with cumulative parasitemia during CPS immunizations (P = 0.013).,While IgG antibodies similarly recognized homologous and heterologous sporozoites, IgM binding to heterologous sporozoites was reduced (P = 0.023).,Although CPS-induced antibodies did not differ in their abilities to fix complement, lyse sporozoites, or inhibit the traversal of homologous and heterologous sporozoites, heterologous sporozoite invasion was more strongly inhibited in the presence of active complement (P = 0.008).,These findings demonstrate that CPS-induced antibodies have complement-fixing activity, thereby significantly further enhancing the functional inhibition of homologous and heterologous sporozoite infectivity in vitro.,The combined data highlight the importance of complement as an additional immune effector mechanism in preerythrocytic immunity after whole-parasite immunization against Plasmodium falciparum malaria.
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There is an increasing body of literature reporting treatment failure of the currently recommended radical treatment of Plasmodium vivax infections.,As P. vivax is the main malaria species outside the African continent, emerging tolerance to its radical treatment regime could have major consequences in countries like Peru, where 80% of malaria cases are due to P. vivax.,Here we describe the results of a 1-year longitudinal follow up of 51 confirmed P. vivax patients living around Iquitos, Peruvian Amazon, and treated according to the Peruvian national guidelines.,Each month a blood sample for microscopy and later genotyping was systematically collected.,Recent exposure to infection was estimated by detecting antibodies against the P. vivax circumsporozoite protein (CSP) and all PCR confirmed P. vivax infections were genotyped with 16 polymorphic microsatellites.,During a 1-year period, 84 recurrent infections, 22 positive also by microscopy, were identified, with a median survival time to first recurrent infection of 203 days.,Most of them (71%) were asymptomatic; in 13 patients the infection persisted undetected by microscopy for several consecutive months.,The genotype of mostly recurrent infections differed from that at day 0 while fewer differences were seen between the recurrent infections.,The average expected heterozygosity was 0.56.,There was strong linkage disequilibrium (IAs = 0.29, p<1.10−4) that remained also when analyzing only the unique haplotypes, suggesting common inbreeding.,In Peru, the P. vivax recurrent infections were common and displayed a high turnover of parasite genotypes compared to day 0.,Plasmodium vivax patients, even when treated according to the national guidelines, may still represent an important parasite reservoir that can maintain transmission.,Any elimination effort should consider such a hidden reservoir.
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Diagnosis of soil-transmitted helminths (STHs) in developing countries is commonly based on microscopic detection of eggs in stool samples, using the Kato-Katz (KK) method, which has a poor sensitivity for detecting light intensity infections.,We compared the performance of the KK method and real-time PCR in the framework of a randomized trial, which evaluated four novel treatments against Trichuris trichiura and concomitant STH infections.,Two stool samples obtained from 320 participants were examined at baseline and follow-up with quadruplicate KK and PCR analyses of one of the two samples using “bead-beating” for DNA extraction.,At follow-up, 80 samples were negative according to both PCR and KK and 173 were positive with both methods for any of the STHs.,Relative to PCR, the calculated sensitivity of KK at follow-up was 83.6%, 43.0% and 53.8% for T. trichiura, for hookworm and for Ascaris lumbricoides, respectively.,The sensitivity of PCR compared with KK at this time point was 89.1% for T. trichiura, 72.7% for hookworm and 87.5% for A. lumbricoides.,Cure rates (CRs) for T. trichiura and A. lumbricoides were slightly lower with the PCR method.,For hookworm CRs with KK were mostly significantly lower, namely 36.7%, 91.1%, 72.2% and 77.8% for moxidectin, moxidectin in combination with tribendimidine, moxidectin in combination with albendazole and albendazole in combination with oxantel pamoate, respectively, whereas with PCR the CRs were 8.3%, 82.6%, 37.1% and 57.1%, respectively.,In conclusion, a single real-time PCR is as sensitive as quadruplicate KK for T. trichiura and A. lumbricoides detection but more sensitive for hookworm, which has an influence on the estimated treatment efficacy.,PCR method with DNA extraction using the “bead-beating protocol” should be further promoted in endemic areas and laboratories that can afford the needed equipment.,The study is registered at ISRCTN (no.,20398469).
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It has been proposed that helminth infection may be particularly detrimental during pregnancy, through adverse effects on maternal anaemia and on birth outcomes, and that anthelminthic treatment during pregnancy will therefore be particularly beneficial.,However, the few treatment trials that have been conducted have given, but little support to this notion and further trials in settings of nutritional stress are needed.,It has also been proposed that prenatal exposure to helminth infection has an important effect on the development of the foetal immune response.,There is evidence that this may impact, long-term, upon responses to helminth and nonhelminth antigens, and to allergens.,Exposure to helminths in utero may also have nonspecific effects that may modify the offspring's susceptibility to diseases mediated by inflammation, including metabolic disorders.,The mechanisms of such effects are not known, but they deserve to be explored as current epidemiological findings suggest the possibility of primary prevention for inflammatory conditions such as allergy, through intervention during pregnancy.
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Sub-Saharan Africa still reports the highest rates of under-five mortality.,Low cost, high impact interventions exist, however poor access remains a challenge.,Integrated community case management (iCCM) was introduced to improve access to essential services for children 2-59 months through diagnosis, treatment and referral services by community health workers for malaria, pneumonia and diarrhea.,This paper presents the results of an economic analysis of iCCM implementation in regions supported by UNICEF in six countries and assesses country-level scale-up implications.,The paper focuses on costs to provider (health system and donors) to inform planning and budgeting, and does not cover cost-effectiveness.,The analysis combines annualised set-up costs and 1 year implementation costs to calculate incremental economic and financial costs per treatment from a provider perspective.,Affordability is assessed by calculating the per capita financial cost of the program as a percentage of the public health expenditure per capita.,Time and financial implications of a 30% increase in utilization were modeled.,Country scale-up is modeled for all children under 5 in rural areas.,Utilization of iCCM services varied from 0.05 treatment/y/under-five in Ethiopia to over 1 in Niger.,There were between 10 and 603 treatments/community health worker (CHW)/y.,Consultation cost represented between 93% and 22% of economic costs per treatment influenced by the level of utilization.,Weighted economic cost per treatment ranged from US$ 13 (2015 USD) in Ghana to US$ 2 in Malawi.,CHWs spent from 1 to 9 hours a week on iCCM.,A 30% increase in utilization would add up to 2 hours a week, but reduce cost per treatment (by 20% in countries with low utilization).,Country scale up would amount to under US$ 0.8 per capita total population (US$ 0.06-US$0.74), between 0.5% and 2% of public health expenditure per capita but 8% in Niger.,iCCM addresses unmet needs and impacts on under 5 mortality.,An economic cost of under US$ 1/capita/y represents a sound investment.,Utilization remains low however, and strategies must be developed as a priority to improve demand.,Continued donor support is required to sustain iCCM services and strengthen its integration within national health systems.
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Despite much success in reducing the burden of malaria in Vietnam, pockets of malaria persist and eliminating them remains an important development goal.,In central Vietnam, insecticide-treated hammocks have recently been introduced to help counter the disease in the highly forested, mountainous areas, where other measures have so far been unsuccessful.,This study assesses the cost-effectiveness of using long-lasting insecticide-treated hammocks in this area.,This cost-effectiveness study was run alongside a randomized control trial testing the efficacy of the long-lasting insecticide-treated hammocks.,Data were collected through an exit survey, a household survey, expenditure records and key informant interviews.,The study estimates that under normal (non-trial) conditions the total net societal cost per malaria episode averted in using long-lasting insecticide-treated hammocks in this area was 126 USD.,Cost per hammock, including insecticidal netting, sewing, transport, and distribution was found to be approximately 11.76 USD per hammock.,Average savings per episode averted were estimated to be $14.60 USD for the health system and 14.37 USD for households (including both direct and indirect cost savings).,The study estimates that the annual financial outlay required of government to implement this type of programme to be 3.40 USD per person covered per year.,The study finds that the use of a hammock intervention could represent good value for money to help prevent malaria in more remote areas, where traditional control measures such as insecticide-treated bednets and indoor residual spraying are insufficient or inappropriate to control malaria.,However, the life span of the hammock-the number of years over which it effectively deters mosquitoes-has a significant impact on the cost-effectiveness of the intervention and study results should be interpreted in light of the evidence on effectiveness gathered in the years to come.
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Induction of immunity that limits Toxoplasma gondii infection in mice is critically dependent on the activation of the innate immune response.,In this study, we investigated the role of cytoplasmic nucleotide-binding domain and leucine-rich repeat containing a pyrin domain (NLRP) inflammasome sensors during acute toxoplasmosis in mice.,We show that in vitro Toxoplasma infection of murine bone marrow-derived macrophages activates the NLRP3 inflammasome, resulting in the rapid production and cleavage of interleukin-1β (IL-1β), with no measurable cleavage of IL-18 and no pyroptosis.,Paradoxically, Toxoplasma-infected mice produced large quantities of IL-18 but had no measurable IL-1β in their serum.,Infection of mice deficient in NLRP3, caspase-1/11, IL-1R, or the inflammasome adaptor protein ASC led to decreased levels of circulating IL-18, increased parasite replication, and death.,Interestingly, mice deficient in NLRP1 also displayed increased parasite loads and acute mortality.,Using mice deficient in IL-18 and IL-18R, we show that this cytokine plays an important role in limiting parasite replication to promote murine survival.,Our findings reveal T. gondii as a novel activator of the NLRP1 and NLRP3 inflammasomes in vivo and establish a role for these sensors in host resistance to toxoplasmosis.,Inflammasomes are multiprotein complexes that are a major component of the innate immune system.,They contain “sensor” proteins that are responsible for detecting various microbial and environmental danger signals and function by activating caspase-1, an enzyme that mediates cleavage and release of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18.,Toxoplasma gondii is a highly successful protozoan parasite capable of infecting a wide range of host species that have variable levels of resistance.,We report here that T. gondii is a novel activator of the NLRP1 and NLRP3 inflammasomes in vivo and establish a role for these sensors in host resistance to toxoplasmosis.,Using mice deficient in IL-18 and IL-18R, we show that the IL-18 cytokine plays a pivotal role by limiting parasite replication to promote murine survival.
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Toxoplasma gondii is a ubiquitous protozoan parasite that can infect humans and animals.,The severity of toxoplasmosis varies according to the immune status of the individual, parasite strain, and host species.,In mammalian species, it has been observed that severe lesions of acute toxoplasmosis form in visceral organs such as the liver, lung, and spleen.,Some epidemiological studies have reported an association of T. gondii infection with liver cirrhosis.,Acute infection was induced in fifteen 30-day-old normal Swiss albino mice.,The mice were infected by intraperitoneal inoculation of 5000 T. gondii RH strain tachyzoites.,The mice were sacrificed in groups of 5 at 2, 4, and 6 days after inoculation.,Another group of 5 mice were used as the controls.,Anti-glial fibrillary acidic protein (GFAP) and anti-T. gondii antibodies were used to compare GFAP-immunoreactive cells and anti-T. gondii-immunopositive areas in the liver between the T. gondii-infected groups and the healthy controls, respectively.,There was a significant correlation between the numbers of GFAP-positive hepatic stellate cells (HSCs) when they were compared with T. gondii antigen immunostaining (p < 0.05).,The amount of T. gondii immunostaining increased significantly with the increase in the number of HSCs.,There is a significant relationship between the number of HSCs and T. gondii antigens, which may represent an active role of HSCs in liver pathology and the pathobiology of T. gondii-related hepatitis.
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Intestinal parasitic infection in immunodeficient patients especially those with impaired cellular immunity, like neoplasia, renal or heart transplant needs careful consideration.,The objective of this study is to evaluate the prevalence of intestinal parasites in different group of patients including cancer patients; organ transplants recipients, and primary immunodeficiency patients.,Stool samples from 190 patients including 80 patients with Primary Immunodeficiency, 85 cancer patients and 25 organ transplant recipients were collected; a direct examination with Phosphate buffered saline (PBS) and formalin ether concentration was performed.,The DNA was extracted from parasitologically confirmed patients and nested PCR and sequencing was performed and new obtained sequences of Cryptosporidium parvum and Enterocytozoon bieneusi were compared with deposited ones.,In general, the prevalence of parasites was 26/80 (32.5%) in primary immunodeficiency, 22/85(25.9%) in cancer group, and 7/25 (28%) in organ transplant.,The prevalence of intestinal parasitic infections in primary immunodeficiency patients were Blastocystis hominis 13 (16.2%), Giardia lamblia 10 (12.5%), Cryptosporidium 1(1.2%), Chilomastix mesnilii 1 (1.2%), Dientamoeba fragilis 1(1.2%).,Of 25 organ transplants, 6 (24%) Cryptosporidium sp were found, all of which were confirmed as Cryptosporidium parvum and one case of Microspora in a heart transplant recipient was confirmed as Enterocytozoon bieneusi by PCR sequencing.,The predominant intestinal parasitic infection in cancer patients was 19 (22.3%) Blastocystis hominis followed by two (2.3%) Giardia lamblia and one Dientamoeba fragilis 1 (1.1%).,The high rate of infection with Blastocystis hominis was found in cancer patients especially colorectal cancer patients, so careful consideration should be given by physicians.,Cryptosporidium sp was found to be the major cause of parasitic intestinal infection in patients with organ transplant compared to primary immunodeficiency patients; so transplant recipients undergoing immunosuppressive therapy should be considered as a risk group for acquiring microsporidiosis and Cryptosporidium infection.
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The present study was performed to analyze molecularly the phylogenetic positions of human-infecting Trichostrongylus species in Mazandaran Province, Iran, which is an endemic area for trichostrongyliasis.,DNA from 7 Trichostrongylus infected stool samples were extracted by using in-house (IH) method.,PCR amplification of ITS2-rDNA region was performed, and products were sequenced.,Phylogenetic analysis of the nucleotide sequence data was performed using MEGA 5.0 software.,Six out of 7 isolates had high similarity with Trichostrongylus colubriformis, while the other one showed high homology with Trichostrongylus axei registered in GenBank reference sequences.,Intra-specific variations within isolates of T. colubriformis and T. axei amounted to 0-1.8% and 0-0.6%, respectively.,Trichostrongylus species obtained in the present study were in a cluster with the relevant reference sequences from previous studies.,BLAST analysis indicated that there was 100% homology among all 6 ITS2 sequences of T. colubriformis in the present study and most previously registered sequences of T. colubriformis from human, sheep, and goat isolates from Iran and also human isolates from Laos, Thailand, and France.,The ITS2 sequence of T. axei exhibited 99.4% homology with the human isolate of T. axei from Thailand, sheep isolates from New Zealand and Iran, and cattle isolate from USA.
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We previously showed that thioether levels in the exhaled breath volatiles of volunteers undergoing controlled human malaria infection (CHMI) with P. falciparum increase as infection progresses.,In this study, we show that thioethers have diurnal cyclical increasing patterns and their levels are significantly higher in P. falciparum CHMI volunteers compared to those of healthy volunteers.,The synchronized cycle and elevation of thioethers were not present in P. vivax-infection, therefore it is likely that the thioethers are associated with unique factors in the pathology of P. falciparum.,Moreover, we found that time-of-day of breath collection is important to accurately predict (98%) P. falciparum-infection.,Critically, this was achieved when the disease was asymptomatic and parasitemia was below the level detectable by microscopy.,Although these findings are encouraging, they show limitations because of the limited and logistically difficult diagnostic window and its utility to P. falciparum malaria only.,We looked for new biomarkers in the breath of P. vivax CHMI volunteers and found that a set of terpenes increase significantly over the course of the malaria infection.,The accuracy of predicting P. vivax using breath terpenes was up to 91%.,Moreover, some of the terpenes were also found in the breath of P. falciparum CHMI volunteers (accuracy up to 93.5%).,The results suggest that terpenes might represent better biomarkers than thioethers to predict malaria as they were not subject to malaria pathogens diurnal changes.
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Whole malaria sporozoite vaccine regimens are promising new strategies, and some candidates have demonstrated high rates of durable clinical protection associated with memory T cell responses.,Little is known about the anatomical distribution of memory T cells following whole sporozoite vaccines, and immunization of nonhuman primates can be used as a relevant model for humans.,We conducted a chemoprophylaxis with sporozoite (CPS) immunization in P. knowlesi rhesus monkeys and challenged via mosquito bites.,Half of CPS immunized animals developed complete protection, with a marked delay in parasitemia demonstrated in the other half.,Antibody responses to whole sporozoites, CSP, and AMA1, but not CelTOS were detected.,Peripheral blood T cell responses to whole sporozoites, but not CSP and AMA1 peptides were observed.,Unlike peripheral blood, there was a high frequency of sporozoite-specific memory T cells observed in the liver and bone marrow.,Interestingly, sporozoite-specific CD4+ and CD8+ memory T cells in the liver highly expressed chemokine receptors CCR5 and CXCR6, both of which are known for liver sinusoid homing.,The majority of liver sporozoite-specific memory T cells expressed CD69, a phenotypic marker of tissue-resident memory (TRM) cells, which are well positioned to rapidly control liver-stage infection.,Vaccine strategies that aim to elicit large number of liver TRM cells may efficiently increase the efficacy and durability of response against pre-erythrocytic parasites.
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The control of malaria in schools is receiving increasing attention, but there remains currently no consensus as to the optimal intervention strategy.,This paper analyses the costs of intermittent screening and treatment (IST) of malaria in schools, implemented as part of a cluster-randomized controlled trial on the Kenyan coast.,Financial and economic costs were estimated using an ingredients approach whereby all resources required in the delivery of IST are quantified and valued.,Sensitivity analysis was conducted to investigate how programme variation affects costs and to identify potential cost savings in the future implementation of IST.,The estimated financial cost of IST per child screened is US$ 6.61 (economic cost US$ 6.24).,Key contributors to cost were salary costs (36%) and malaria rapid diagnostic tests (RDT) (22%).,Almost half (47%) of the intervention cost comprises redeployment of existing resources including health worker time and use of hospital vehicles.,Sensitivity analysis identified changes to intervention delivery that can reduce programme costs by 40%, including use of alternative RDTs and removal of supervised treatment.,Cost-effectiveness is also likely to be highly sensitive to the proportion of children found to be RDT-positive.,In the current context, school-based IST is a relatively expensive malaria intervention, but reducing the complexity of delivery can result in considerable savings in the cost of intervention.,(Costs are reported in US$ 2010).
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Asymptomatic carriers of Plasmodium falciparum serve as a reservoir of parasites for malaria transmission.,Identification and treatment of asymptomatic carriers within a region may reduce the parasite reservoir and influence malaria transmission in that area.,Using computer simulation, this analysis explored the impact of community screening campaigns (CSC) followed by systematic treatment of P. falciparum asymptomatic carriers (AC) with artemether-lumefantrine (AL) on disease transmission.,The model created by Okell et al (originally designed to explore the impact of the introduction of treatment with artemisinin-based combination therapy on malaria endemicity) was modified to represent CSC and treatment of AC with AL, with the addition of malaria vector seasonality.,The age grouping, relative distribution of age in a region, and degree of heterogeneity in disease transmission were maintained.,The number and frequency of CSC and their relative timing were explored in terms of their effect on malaria incidence.,A sensitivity analysis was conducted to determine the factors with the greatest impact on the model predictions.,The simulation showed that the intervention that had the largest effect was performed in an area with high endemicity (entomological inoculation rate, EIR > 200); however, the rate of infection returned to its normal level in the subsequent year, unless the intervention was repeated.,In areas with low disease burden (EIR < 10), the reduction was sustained for over three years after a single intervention.,Three CSC scheduled in close succession (monthly intervals) at the start of the dry season had the greatest impact on the success of the intervention.,Community screening and treatment of asymptomatic carriers with AL may reduce malaria transmission significantly.,The initial level of disease intensity has the greatest impact on the potential magnitude and duration of malaria reduction.,When combined with other interventions (e.g. long-lasting insecticide-treated nets, rapid diagnostic tests, prompt diagnosis and treatment, and, where appropriate, indoor residual spraying) the effect of this intervention can be sustained for many years, and it could become a tool to accelerate the reduction in transmission intensity to pre-elimination levels.,Repeated interventions at least every other year may help to prolong the effect.,The use of an effective diagnostic tool and a highly effective ACT, such as AL, is also vital.,The modelling supports the evaluation of this approach in a prospective clinical trial to reduce the pool of infective vectors for malaria transmission in an area with marked seasonality.
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Transmission represents a population bottleneck in the Plasmodium life cycle and a key intervention target of ongoing efforts to eradicate malaria.,Sexual differentiation is essential for this process, as only sexual parasites, called gametocytes, are infective to the mosquito vector.,Gametocyte production rates vary depending on environmental conditions, but external stimuli remain obscure.,Here, we show that the host-derived lipid lysophosphatidylcholine (LysoPC) controls P. falciparum cell fate by repressing parasite sexual differentiation.,We demonstrate that exogenous LysoPC drives biosynthesis of the essential membrane component phosphatidylcholine.,LysoPC restriction induces a compensatory response, linking parasite metabolism to the activation of sexual-stage-specific transcription and gametocyte formation.,Our results reveal that malaria parasites can sense and process host-derived physiological signals to regulate differentiation.,These data close a critical knowledge gap in parasite biology and introduce a major component of the sexual differentiation pathway in Plasmodium that may provide new approaches for blocking malaria transmission.,•P. falciparum sexual differentiation is repressed by LysoPC found in human serum•LysoPC is a major building block of parasite phospholipid metabolism•LysoPC acts upstream of the earliest known events of sexual differentiation•Parasite metabolism alters host LysoPC levels during infection,P. falciparum sexual differentiation is repressed by LysoPC found in human serum,LysoPC is a major building block of parasite phospholipid metabolism,LysoPC acts upstream of the earliest known events of sexual differentiation,Parasite metabolism alters host LysoPC levels during infection,The host-derived lipid lysophosphatidylcholine controls Plasmodium falciparum cell fate by repressing parasite sexual differentiation, a key step in malaria transmission.
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Commitment to and completion of sexual development are essential for malaria parasites (protists of the genus Plasmodium) to be transmitted through mosquitoes1.,The molecular mechanism(s) responsible for commitment have been hitherto unknown.,Here we show that PBAP2-G, a conserved member of the ApiAP2 family of transcription factors, is essential for the commitment of asexually replicating forms to sexual development in P. berghei, a malaria parasite of rodents.,PBAP2-G was identified from mutations in its encoding gene, PBANKA_143750, which account for the loss of sexual development frequently observed in parasites transmitted artificially by blood passage.,Systematic gene deletion of conserved ApiAP2 genes in Plasmodium confirmed the role of PBAP2-G and revealed a second ApiAP2 member (PBANKA_103430, termed PBAP2-G2) that significantly modulates but does not abolish gametocytogenesis indicating that a cascade of ApiAP2 proteins are involved in commitment to the production and maturation of gametocytes.,The data suggest a mechanism of commitment to gametocytogenesis in Plasmodium consistent with a positive feedback loop involving PBAP2G which might be exploited to prevent the transmission of this pernicious parasite.
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Malaria incidence is largely influenced by vector abundance.,Among the many interconnected factors relating to malaria transmission, weather conditions such as rainfall and temperature are known to create suitable environmental conditions that sustain reproduction and propagation of anopheles mosquitoes and malaria parasites.,In Ghana, climatic conditions vary across the country.,Understanding the heterogeneity of malaria morbidity using data sourced from a recently setup data repository for routine health facility data could support planning.,Monthly aggregated confirmed uncomplicated malaria cases from the District Health Information Management System and average monthly rainfall and temperature records obtained from the Ghana Meteorological Agency from 2008 to 2016 were analysed.,Univariate time series models were fitted to the malaria, rainfall and temperature data series.,After pre-whitening the morbidity data, cross correlation analyses were performed.,Subsequently, transfer function models were developed for the relationship between malaria morbidity and rainfall and temperature.,Malaria morbidity patterns vary across zones.,In the Guinea savannah, morbidity peaks once in the year and twice in both the Transitional forest and Coastal savannah, following similar patterns of rainfall at the zonal level.,While the effects of rainfall on malaria morbidity are delayed by a month in the Guinea savannah and Transitional Forest zones those of temperature are delayed by two months in the Transitional forest zone.,In the Coastal savannah however, incidence of malaria is significantly associated with two months lead in rainfall and temperature.,Data captured on the District Health Information Management System has been used to demonstrate heterogeneity in the dynamics of malaria morbidity across the country.,Timing of these variations could guide the deployment of interventions such as indoor residual spraying, Seasonal Malaria Chemoprevention or vaccines to optimise effectiveness on zonal basis.
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The effectiveness of intermittent preventive treatment of malaria in pregnancy (IPTp) may be compromised by the spread of resistance to sulphadoxine/pyrimethamine (SP) across Africa.,But little informtion exists on alternative drugs for IPTp or alternative strategies for the prevention of malaria in pregnancy.,Therefore, we have investigated whether screening with a rapid diagnostic test and treatment of those who are positive (IST) at routine antenatal clinic attendances is as effective and as safe as SP-IPTp in pregnant women.,During antenatal clinic sessions in six health facilities in Ghana held between March 2007 and September 2007, 3333 pregnant women who satisfied inclusion criteria were randomised into three intervention arms (1) standard SP-IPTp, (2) IST and treatment with SP or (3) IST and treatment with amodiaquine+artesunate (AQ+AS).,All women received a long-lasting insecticide treated net.,Study women had a maximum of three scheduled follow-up visits following enrolment.,Haemoglobin concentration and peripheral parasitaemia were assessed between 36 and 40 weeks of gestation.,Birth weight was measured at delivery or within 72 hours for babies delivered at home.,Parasite prevalence at enrolment in primigravidae and in multigravidae was 29.6% and 10.2% respectively.,At 36-40 weeks of gestation the prevalence of asymptomatic parasitaemia was 12.1% in study women overall and was very similar in all treatment groups.,The risk of third trimester severe anaemia or low birth weight did not differ significantly between the three treatment groups regardless of gravidity.,IST with AQ+AS or SP was not inferior to SP-IPTp in reducing the risk of low birth weight (RD = -1.17[95%CI; -4.39-1.02] for IST-SP vs.,SP-IPTp and RD = 0.78[95%CI; -2.11-3.68] for IST-AQAS vs.,SP-IPTp); third trimester severe anaemia (RD = 0.29[95%CI; -0.69-1.30] for IST-SP vs.,SP-IPTp and RD = -0.36[95%CI;-1.12-0.44] for IST-AQAS vs.,SP-IPTp).,The results of this study suggest that in an area of moderately high malaria transmission, IST with SP or AS+AQ may be a safe and effective strategy for the control of malaria in pregnancy.,However, it is important that these encouraging findings are confirmed in other geographical areas and that the impact of IST on placental malaria is investigated.,ClinicalTrials.gov NCT00432367 [NCT00432367]
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Two mass drug administrations (MDA) against falciparum malaria were conducted in 2015-16, one as operational research in northern Cambodia, and the other as a clinical trial in western Cambodia.,During an April 2017 workshop in Phnom Penh the field teams from Médecins Sans Frontières and the Mahidol-Oxford Tropical Medicine Research Unit discussed lessons for future MDAs.
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Background: Mass drug (antimalarial) administration (MDA) is currently under study in Southeast Asia as part of a package of interventions referred to as targeted malaria elimination (TME).,This intervention relies on effective community engagement that promotes uptake and adherence in target communities (above 80%).,Objective: Based on the experienced of designing and implementing the community engagement for TME in Laos, in this article we aim to present the elements of effective community engagement for mass antimalarial administration.,Methods: The design and implementation of community engagement, which took place from September 2015 to August 2016 was recorded as field notes, meeting minutes and photographs.,These data underwent qualitative content analysis.,Results: The community engagement strategy that accompanied TME in Laos was successful in terms of contributing to high levels of participation in mass anti-malarial administration (above 85%).,Based on the experience of designing and implementing the community engagement, five key elements were identified: (1) stakeholder and authority engagement, which proceeded from national level, to regional/district and local level; (2) local human resources, particularly the recruitment of local volunteers who were integral to the design and implementation of activities in the study villages; (3) formative research, to rapidly gain insight into the local social and economic context; (4) responsiveness whereby the approach was adapted according to the needs of the community and their responses to the various study components; and (5) sharing control/leadership with the community in terms of decisions on the organization of TME activities.,Conclusions: The community engagement that accompanied TME in Laos had to deal with challenges of implementing a complex study in remote and linguistically isolated villages.,Despite these challenges, the study recorded high population coverage.,Lessons learnt from this experience are useful for studies and intervention programs in diverse contexts.
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Sparse data on the safety of pyronaridine-artesunate after repeated treatment of malaria episodes restrict its clinical use.,We therefore compared the safety of pyronaridine-artesunate after treatment of the first episode of malaria versus re-treatment in a substudy analysis.,This planned substudy analysis of the randomised, open-label West African Network for Clinical Trials of Antimalarial Drugs (WANECAM) phase 3b/4 trial was done at six health facilities in Mali, Burkina Faso, and Guinea in patients (aged ≥6 months and bodyweight ≥5 kg) with uncomplicated microscopically confirmed Plasmodium spp malaria (parasite density <200 000 per μL blood) and fever or history of fever.,The primary safety endpoint was incidence of hepatotoxicity: alanine aminotransferase of greater than five times the upper limit of normal (ULN) or Hy's criteria (alanine aminotransferase or aspartate aminotransferase greater than three times the ULN and total bilirubin more than twice the ULN) after treatment of the first episode of malaria and re-treatment (≥28 days after first treatment) with pyronaridine-artesunate.,Pyronaridine-artesunate efficacy was compared with artemether-lumefantrine with the adequate clinical and parasitological response (ACPR) in an intention-to-treat analysis.,WANECAM is registered with PACTR.org, number PACTR201105000286876.,Following first treatment, 13 (1%) of 996 patients had hepatotoxicity (including one [<1%] possible Hy's law case) versus two (1%) of 311 patients on re-treatment (neither a Hy's law case).,No evidence was found that pyronaridine-artesunate re-treatment increased safety risk based on laboratory values, reported adverse event frequencies, or electrocardiograph findings.,For all first treatment or re-treatment episodes, pyronaridine-artesunate (n=673) day 28 crude ACPR was 92·7% (95% CI 91·0-94·3) versus 80·4% (77·8-83·0) for artemether-lumefantrine (n=671).,After exclusion of patients with PCR-confirmed new infections, ACPR was similar on treatment and re-treatment and greater than 95% at day 28 and greater than 91% at day 42 in both treatment groups.,The findings that pyronaridine-artesunate safety and efficacy were similar on first malaria treatment versus re-treatment of subsequent episodes lend support for the wider access to pyronaridine-artesunate as an alternative artemisinin-based combination treatment for malaria in sub-Saharan Africa.,European and Developing Countries Clinical Trial Partnership, Medicines for Malaria Venture (Geneva, Switzerland), UK Medical Research Council, Swedish International Development Cooperation Agency, German Ministry for Education and Research, University Claude Bernard (Lyon, France), Malaria Research and Training Centre (Bamako, Mali), Centre National de Recherche et de Formation sur le Paludisme (Burkina Faso), Institut de Recherche en Sciences de la Santé (Bobo-Dioulasso, Burkina Faso), and Centre National de Formation et de Recherche en Santé Rurale (Republic of Guinea).
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Children are most vulnerable to malaria.,A pyronaridine-artesunate pediatric granule formulation is being developed for the treatment of uncomplicated Plasmodium falciparum malaria.,This phase III, multi-center, comparative, open-label, parallel-group, controlled clinical trial included patients aged ≤12 years, bodyweight ≥5 to <25 kg, with a reported history of fever at inclusion or in the previous 24 h and microscopically-confirmed uncomplicated P. falciparum malaria.,Patients were randomized (2:1) to pyronaridine-artesunate granules (60/20 mg) once daily or artemether-lumefantrine crushed tablets (20/120 mg) twice daily, both dosed by bodyweight, orally (liquid suspension) for three days.,Of 535 patients randomized, 355 received pyronaridine-artesunate and 180 received artemether-lumefantrine.,Day-28 adequate clinical and parasitological response (ACPR), corrected for re-infection using polymerase chain reaction (PCR) genotyping (per-protocol population) was 97.1% (329/339; 95% CI 94.6, 98.6) for pyronaridine-artesunate; 98.8% (165/167; 95% CI 95.7, 99.9) for artemether-lumefantrine.,The primary endpoint was achieved: pyronaridine-artesunate PCR-corrected day-28 ACPR was statistically significantly >90% (P < .0001).,Pyronaridine-artesunate was non-inferior to artemether-lumefantrine: treatment difference -1.8% (95% CI -4.3 to 1.6).,The incidence of drug-related adverse events was 37.2% (132/355) with pyronaridine-artesunate, 44.4% (80/180) with artemether-lumefantrine.,Clinical biochemistry results showed similar mean changes versus baseline in the two treatment groups.,From day 3 until study completion, one patient in each treatment group had peak alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN) and peak total bilirubin >2xULN (i.e. within the Hy’s law definition).,The pyronaridine-artesunate pediatric granule formulation was efficacious and was non-inferior to artemether-lumefantrine.,The adverse event profile was similar for the two comparators.,Pyronaridine-artesunate should be considered for inclusion in paediatric malaria treatment programmes.,ClinicalTrials.gov: identifier NCT00541385
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Anopheles coluzzii females, important malaria vectors in Africa, mate only once in their lifetime.,Mating occurs in aerial swarms with a high male-to-female ratio, where traits underlying male mating success are largely unknown.,Here, we investigated whether cuticular hydrocarbons (CHCs) influence mating success in natural mating swarms in Burkina Faso.,As insecticides are widely used in this area for malaria control, we also determined whether CHCs affect insecticide resistance levels.,We find that mated males have higher CHC abundance than unmated controls, suggesting CHCs could be determinants of mating success.,Additionally, mated males have higher insecticide resistance under pyrethroid challenge, and we show a link between resistance intensity and CHC abundance.,Taken together, our results suggest that CHC abundance may be subject to sexual selection in addition to selection by insecticide pressure.,This has implications for insecticide resistance management, as these traits may be sustained in the population due to their benefits in mating even in the absence of insecticides.,In this study, Adams et al. investigate the effect of cuticular hydrocarbons on mating success in natural mosquito mating swarms.,These hydrocarbons confer both higher mating success and increased resistance to pyrethroid, suggesting sexual selection for insecticide resistance in this population secondary to mating success.
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Artemisinin-resistant Plasmodium falciparum parasites are rapidly spreading in Southeast Asia, yet nothing is known about their transmission.,This knowledge gap and the possibility that these parasites will spread to Africa endanger global efforts to eliminate malaria.,Here we produce gametocytes from parasite clinical isolates that displayed artemisinin resistance in patients and in vitro, and use them to infect native and non-native mosquito vectors.,We show that contemporary artemisinin-resistant isolates from Cambodia develop and produce sporozoites in two Southeast Asian vectors, Anopheles dirus and Anopheles minimus, and the major African vector, Anopheles coluzzii (formerly Anopheles gambiae M).,The ability of artemisinin-resistant parasites to infect such highly diverse Anopheles species, combined with their higher gametocyte prevalence in patients, may explain the rapid expansion of these parasites in Cambodia and neighbouring countries, and further compromise efforts to prevent their global spread.,It is unknown whether artemisinin-resistant malaria parasites from Southeast Asia can infect any African species of Anopheles mosquitoes and thus spread to Africa.,Here, St.,Laurent et al. show that artemisinin-resistant isolates from Cambodia can indeed infect the major African vector, Anopheles coluzzii.
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Background.,The epidemiology of congenital malaria was investigated in a hospital-based malaria surveillance study in Papua, Indonesia.,Methods.,From April 2005 to January 2010, 4878 delivering women and their newborns underwent prospective clinical review and malaria screening by peripheral blood microscopy.,Findings.,Congenital malaria occurred in 8 per 1000 (38/4884) live births, with Plasmodium falciparum accounting for 76.3% (29) and P. vivax for 15.8% (6) of infections.,Maternal malaria at delivery (adjusted odds ratio [AOR], 9.5; 95% confidence interval [CI], 4.2-21.5; P < .001), age ≤ 16 years (AOR, 4; 95% CI, 1.4-12.1; P = .011), and prior malaria during pregnancy (AOR, 2.2; 95% CI, 1.1-4.4, P = .022) were independent risk factors for vertical transmission.,Of 29 mothers and neonates with contemporaneous peripheral parasitemia, 17% (5) had discordant parasite species, suggesting possible antenatal malaria transmission.,Newborns with malaria were at significantly greater risk of low birth weight (AOR, 2.8; 95% CI, 1.2-6.6; P = .002).,Following introduction of dihydroartemisinin-piperaquine for uncomplicated malaria in the second and third trimesters of pregnancy, congenital malaria incidence fell from 3.2% to 0.2% (odds ratio, 0.07; 95% CI, .03-.15; P < .001).,Conclusions.,Congenital malaria is an important cause of neonatal morbidity in this region co-endemic for P. falciparum and P. vivax malaria.,The introduction of artemisinin-combination therapy was associated with a significant risk reduction in the vertical transmission of malaria.
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The World Health Organization endorses the use of artemisinin-based combination therapy for treatment of acute uncomplicated falciparum malaria in the second and third trimesters of pregnancy.,However, the effects of pregnancy on the pharmacokinetics of artemisinin derivatives, such as artesunate (AS), are poorly understood.,In this analysis, the population pharmacokinetics of oral AS, and its active metabolite dihydroartemisinin (DHA), were studied in pregnant and non-pregnant women at the Kingasani Maternity Clinic in the DRC.,Data were obtained from 26 pregnant women in the second (22 - 26 weeks) or the third (32 - 36 weeks) trimester of pregnancy and from 25 non-pregnant female controls.,All subjects received 200 mg AS.,Plasma AS and DHA were measured using a validated LC-MS method.,Estimates for pharmacokinetic and variability parameters were obtained through nonlinear mixed effects modelling.,A simultaneous parent-metabolite model was developed consisting of mixed zero-order, lagged first-order absorption of AS, a one-compartment model for AS, and a one-compartment model for DHA.,Complete conversion of AS to DHA was assumed.,The model displayed satisfactory goodness-of-fit, stability, and predictive ability.,Apparent clearance (CL/F) and volume of distribution (V/F) estimates, with 95% bootstrap confidence intervals, were as follows: 195 L (139-285 L) for AS V/F, 895 L/h (788-1045 L/h) for AS CL/F, 91.4 L (78.5-109 L) for DHA V/F, and 64.0 L/h (55.1-75.2 L/h) for DHA CL/F.,The effect of pregnancy on DHA CL/F was determined to be significant, with a pregnancy-associated increase in DHA CL/F of 42.3% (19.7 - 72.3%).,In this analysis, pharmacokinetic modelling suggests that pregnant women have accelerated DHA clearance compared to non-pregnant women receiving orally administered AS.,These findings, in conjunction with a previous non-compartmental analysis of the modelled data, provide further evidence that higher AS doses would be required to maintain similar DHA levels in pregnant women as achieved in non-pregnant controls.
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Whole malaria sporozoite vaccine regimens are promising new strategies, and some candidates have demonstrated high rates of durable clinical protection associated with memory T cell responses.,Little is known about the anatomical distribution of memory T cells following whole sporozoite vaccines, and immunization of nonhuman primates can be used as a relevant model for humans.,We conducted a chemoprophylaxis with sporozoite (CPS) immunization in P. knowlesi rhesus monkeys and challenged via mosquito bites.,Half of CPS immunized animals developed complete protection, with a marked delay in parasitemia demonstrated in the other half.,Antibody responses to whole sporozoites, CSP, and AMA1, but not CelTOS were detected.,Peripheral blood T cell responses to whole sporozoites, but not CSP and AMA1 peptides were observed.,Unlike peripheral blood, there was a high frequency of sporozoite-specific memory T cells observed in the liver and bone marrow.,Interestingly, sporozoite-specific CD4+ and CD8+ memory T cells in the liver highly expressed chemokine receptors CCR5 and CXCR6, both of which are known for liver sinusoid homing.,The majority of liver sporozoite-specific memory T cells expressed CD69, a phenotypic marker of tissue-resident memory (TRM) cells, which are well positioned to rapidly control liver-stage infection.,Vaccine strategies that aim to elicit large number of liver TRM cells may efficiently increase the efficacy and durability of response against pre-erythrocytic parasites.
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Controlled human malaria infection (CHMI) by mosquito bite is a powerful tool for evaluation of vaccines and drugs against Plasmodium falciparum malaria.,However, only a small number of research centres have the facilities required to perform such studies.,CHMI by needle and syringe could help to accelerate the development of anti-malaria interventions by enabling centres worldwide to employ CHMI.,An open-label CHMI study was performed with aseptic, purified, cryopreserved P. falciparum sporozoites (PfSPZ Challenge) in 36 malaria naïve volunteers.,In part A, the effect of the inoculation volume was assessed: 18 participants were injected intramuscularly (IM) with a dose of 2,500 PfSPZ divided into two injections of 10 µL (n = 6), 50 µL (n = 6) or 250 µL (n = 6), respectively.,In part B, the injection volume that resulted in highest infectivity rates in part A (10 µL) was used to formulate IM doses of 25,000 PfSPZ (n = 6) and 75,000 PfSPZ (n = 6) divided into two 10-µL injections.,Results from a parallel trial led to the decision to add a positive control group (n = 6), each volunteer receiving 3,200 PfSPZ in a single 500-µL injection by direct venous inoculation (DVI).,Four/six participants in the 10-µL group, 1/6 in the 50-µL group and 2/6 in the 250-µL group developed parasitaemia.,Geometric mean (GM) pre-patent periods were 13.9, 14.0 and 15.0 days, respectively.,Six/six (100%) participants developed parasitaemia in the 25,000 and 75,000 PfSPZ IM and 3,200 PfSPZ DVI groups.,GM pre-patent periods were 12.2, 11.4 and 11.4 days, respectively.,Injection of PfSPZ Challenge was well tolerated and safe in all groups.,IM injection of 75,000 PfSPZ and DVI injection of 3,200 PfSPZ resulted in infection rates and pre-patent periods comparable to the bite of five PfSPZ-infected mosquitoes.,Remarkably, it required 23.4-fold more PfSPZ administered IM than DVI to achieve the same parasite kinetics.,These results allow for translation of CHMI from research to routine use, and inoculation of PfSPZ by IM and DVI regimens.,Trial registration: ClinicalTrials.gov NCT01771848.,The online version of this article (doi:10.1186/s12936-015-0817-x) contains supplementary material, which is available to authorized users.
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In Tanzania, the first cases of schistosomiasis were reported in the early 19th century.,Since then, various studies have reported prevalences of up to 100% in some areas.,However, for many years, there have been no sustainable control programmes and systematic data from observational and control studies are very limited in the public domain.,To cover that gap, the present article reviews the epidemiology, malacology, morbidity, and the milestones the country has made in efforts to control schistosomiasis and discusses future control approaches.,The available evidence indicates that, both urinary and intestinal schistosomiasis are still highly endemic in Tanzania and cause significant morbidity.Mass drug administration using praziquantel, currently used as a key intervention measure, has not been successful in decreasing prevalence of infection.,There is therefore an urgent need to revise the current approach for the successful control of the disease.,Clearly, these need to be integrated control measures.
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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.
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Background: Malaria continues to be a major public health concern in Africa.,Approximately 3.2 billion people worldwide are still at risk of contracting malaria, and 80% of deaths caused by malaria are concentrated in only 15 countries, most of which are in Africa.,These high-burden countries have achieved a lower than average reduction of malaria incidence and mortality, and Mozambique is among these countries.,Malaria eradication is therefore one of Mozambique’s main priorities.,Few studies on malaria have been carried out in Chimoio, and there is no malaria map risk of the area.,This map is important to identify areas at risk for application of Public Precision Health approaches.,By using GIS-based spatial modelling techniques, the research goal of this article was to map and model malaria risk areas using climate, socio-demographic and clinical variables in Chimoio, Mozambique.,Methods: A 30 m × 30 m Landsat image, ArcGIS 10.2 and BioclimData were used.,A conceptual model for spatial problems was used to create the final risk map.,The risks factors used were: the mean temperature, precipitation, altitude, slope, distance to water bodies, distance to roads, NDVI, land use and land cover, malaria prevalence and population density.,Layers were created in a raster dataset.,For class value comparisons between layers, numeric values were assigned to classes within each map layer, giving them the same importance.,The input dataset were ranked, with different weights according to their suitability.,The reclassified outputs of the data were combined.,Results: Chimoio presented 96% moderate risk and 4% high-risk areas.,The map showed that the central and south-west “Residential areas”, namely, Centro Hipico, Trangapsso, Bairro 5 and 1° de Maio, had a high risk of malaria, while the rest of the residential areas had a moderate risk.,Conclusions: The entire Chimoio population is at risk of contracting malaria, and the precise estimation of malaria risk, therefore, has important precision public health implications and for the planning of effective control measures, such as the proper time and place to spray to combat vectors, distribution of bed nets and other control measures.
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Understanding the epidemiological features and metrics of malaria in endemic populations is a key component to monitoring and quantifying the impact of current and past control efforts to inform future ones.,The International Centers of Excellence for Malaria Research (ICEMR) has the opportunity to evaluate the impact of malaria control interventions across endemic regions that differ in the dominant Plasmodium species, mosquito vector species, resistance to antimalarial drugs and human genetic variants thought to confer protection from infection and clinical manifestations of plasmodia infection.,ICEMR programs are conducting field studies at multiple sites with the aim of generating standardized surveillance data to improve the understanding of malaria transmission and to monitor and evaluate the impact of interventions to inform malaria control and elimination programs.,In addition, these epidemiological studies provide a vast source of biological samples linked to clinical and environmental “meta-data” to support translational studies of interactions between the parasite, human host, and mosquito vector.,Importantly, epidemiological studies at the ICEMR field sites are integrated with entomological studies, including the measurement of the entomological inoculation rate, human biting index, and insecticide resistance, as well as studies of parasite genetic diversity and antimalarial drug resistance.
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Immunity to malaria could be categorized broadly as antiparasite or antidisease immunity.,While most vaccine research efforts have focused on antiparasite immunity, the evidence from endemic populations suggest that antidisease immunity is an important component of natural immunity to malaria.,The processes that mediate antidisease immunity have, however, attracted little to no attention, and most interests have been directed towards the antibody responses.,This review evaluates the evidence for antidisease immunity in endemic areas and discusses the possible mechanisms responsible for it.,Given the key role that inflammation plays in the pathogenesis of malaria, regulation of the inflammatory response appears to be a major mechanism for antidisease immunity in naturally exposed individuals.
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Plasmodium falciparum malaria causes 500 million clinical cases with approximately one million deaths each year.,After many years of exposure, individuals living in endemic areas develop a form of clinical immunity to disease known as premunition, which is characterised by low parasite burdens rather than sterilising immunity.,The reason why malaria parasites persist under a state of premunition is unknown but it has been suggested that suppression of protective immunity might be a mechanism leading to parasite persistence.,Although acquired immunity limits the clinical impact of infection and provides protection against parasite replication, experimental evidence indicates that cell-mediated immune responses also result in detrimental inflammation and contribute to the aetiology of severe disease.,Thus, an appropriate regulatory balance between protective immune responses and immune-mediated pathology is required for a favourable outcome of infection.,As natural regulatory T (Treg) cells are identified as an immunosuppressive lineage able to modulate the magnitude of effector responses, several studies have investigated whether this cell population plays a role in balancing protective immunity and pathogenesis during malaria.,The main findings to date are summarised in this review and the implication for the induction of pathogenesis and immunity to malaria is discussed.
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There have been many recent reports that the rate of outdoor biting by malaria vectors has increased.,This study examined the impact this might have on malaria transmission by assessing the association between exposure to outdoor bites and malaria infection on Bioko Island, Equatorial Guinea.,Responses to questions about time spent outside the previous night from a malaria indicator survey were combined with human landing catch measurements of hourly rates of outdoor and indoor biting for the whole island to estimate the number of outdoor and indoor bites received by each survey respondent.,The association between RDT measured malaria infection status of individuals and outdoor bites received was investigated.,The average number of bites received per person per night was estimated as 3.51 in total, of which 0.69 (19.7%) would occur outdoors.,Malaria infection was not significantly higher in individuals who reported spending time outside between 7 pm and 6 am the previous night compared to those not spending time outside in both adults (18.9% vs 17.4%, p = 0.20) and children (29.2% vs 27.1%, p = 0.20).,Malaria infection in neither adults (p = 0.56) nor in children (p = 0.12) was associated with exposure to outdoor bites, even after adjusting for confounders.,Malaria vector mosquitoes in Bioko do bite humans outdoors, and this has the potential to reduce the effectiveness of vector control.,However, outdoor biting is currently not a major factor influencing the malaria burden, mainly because more than 95% of the population are indoors during the middle of the night, which is the peak biting period for malaria vector mosquitoes.,The majority of resources should remain with control measures that target indoor biting and resting such as LLINs and IRS.
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Long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) interventions can reduce malaria transmission by targeting mosquitoes when they feed upon sleeping humans and/or rest inside houses, livestock shelters or other man-made structures.,However, many malaria vector species can maintain robust transmission, despite high coverage of LLINs/IRS containing insecticides to which they are physiologically fully susceptible, because they exhibit one or more behaviours that define the biological limits of achievable impact with these interventions: (1) Natural or insecticide-induced avoidance of contact with treated surfaces within houses and early exit from them, thus minimizing exposure hazard of vectors which feed indoors upon humans; (2) Feeding upon humans when they are active and unprotected outdoors, thereby attenuating personal protection and any consequent community-wide suppression of transmission; (3) Feeding upon animals, thus minimizing contact with insecticides targeted at humans or houses; (4) Resting outdoors, away from insecticide-treated surfaces of nets, walls and roofs.,Residual malaria transmission is, therefore, defined as all forms of transmission that can persist after achieving full universal coverage with effective LLINs and/or IRS containing active ingredients to which local vector populations are fully susceptible.,Residual transmission is sufficiently intense across most of the tropics to render malaria elimination infeasible without new or improved vector control methods.,Many novel or improved vector control strategies to address residual transmission are emerging that either: (1) Enhance control of adult vectors that enter houses to feed and/or rest by killing, repelling or excluding them; (2) Kill or repel adult mosquitoes when they attack people outdoors; (3) Kill adult mosquitoes when they attack livestock; (4) Kill adult mosquitoes when they feed upon sugar or; (5) Kill immature mosquitoes in aquatic habitats.,To date, none of these options has sufficient supporting evidence to justify full-scale programmatic implementation.,Concerted investment in their rigorous selection, development and evaluation is required over the coming decade to enable control and, ultimately, elimination of residual malaria transmission.,In the meantime, national programmes may assess options for addressing residual transmission under programmatic conditions through pilot studies with strong monitoring, evaluation and operational research components, similar to the Onchocerciasis Control Programme.
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Increasing evidence suggests that the infectiousness of patients for the sand fly vector of visceral leishmaniasis is linked to parasites found in the skin.,Using a murine model that supports extensive skin infection with Leishmania donovani, spatial analyses at macro-(quantitative PCR) and micro-(confocal microscopy) scales indicate that parasite distribution is markedly skewed.,Mathematical models accounting for this heterogeneity demonstrate that while a patchy distribution reduces the expected number of sand flies acquiring parasites, it increases the infection load for sand flies feeding on a patch, increasing their potential for onward transmission.,Models representing patchiness at both macro- and micro-scales provide the best fit with experimental sand fly feeding data, pointing to the importance of the skin parasite landscape as a predictor of host infectiousness.,Our analysis highlights the skin as a critical site to consider when assessing treatment efficacy, transmission competence and the impact of visceral leishmaniasis elimination campaigns.,Parasitemia has been considered the main determinant of visceral leishmaniasis transmission.,By combining imaging, qPCR and experimental xenodiagnoses with mathematical models, Doehl et al. argue that the patchy landscape of parasites in the skin is necessary to explain infectiousness.
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To support the Bangladesh National Kala-azar Elimination Programme (NKEP), we investigated the feasibility of using trained village volunteers for detecting post-kala-azar dermal leishmaniasis (PKDL) cases, using polymerase chain reaction (PCR) for confirmation of diagnosis and treatment compliance by PKDL patients in Kanthal union of Trishal sub-district, Mymensingh, Bangladesh.,In this cross-sectional study, Field Research Assistants (FRAs) conducted census in the study area, and the research team trained village volunteers on how to look for PKDL suspects.,The trained village volunteers (TVVs) visited each household in the study area for PKDL suspects and referred the suspected PKDL cases to the study clinic.,The suspected cases underwent physical examinations by a qualified doctor and rK39 strip testing by the FRAs and, if positive, slit skin examination (SSE), culture, and PCR of skin specimens and peripheral buffy coat were done.,Those with evidence of Leishmania donovani (LD) were referred for treatment.,All the cases were followed for one year.,The total population of the study area was 29,226 from 6,566 households.,The TVVs referred 52 PKDL suspects.,Probable PKDL was diagnosed in 18 of the 52 PKDL suspect cases, and PKDL was confirmed in 9 of the 18 probable PKDL cases.,The prevalence of probable PKDL was 6.2 per 10,000 people in the study area.,Thirteen PKDL suspects self-reported from outside the study area, and probable and confirmed PKDL was diagnosed in 10 of the 13 suspects and in 5 of 10 probable PKDL cases respectively.,All probable PKDL cases had hypopigmented macules.,The median time for PKDL development was 36 months (IQR, 24-48).,Evidence of the LD parasite was documented by SSE and PCR in 3.6% and 64.3% of the cases, respectively.,PCR positivity was associated with gender and severity of disease.,Those who were untreated had an increased risk (odds ratio = 3.33, 95%CI 1.29-8.59) of having persistent skin lesions compared to those who were treated.,Patients' treatment-seeking behavior and treatment compliance were poor.,Improved detection of PKDL cases by TVVs is feasible and useful.,The NKEP should promote PCR for the diagnosis of PKDL and should find ways for improving treatment compliance by patients.
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Land use and land cover changes, such as deforestation, agricultural expansion and urbanization, are one of the largest anthropogenic environmental changes globally.,Recent initiatives to evaluate the feasibility of malaria eradication have highlighted impacts of landscape changes on malaria transmission and the potential of these changes to undermine malaria control and elimination efforts.,Multisectoral approaches are needed to detect and minimize negative impacts of land use and land cover changes on malaria transmission while supporting development aiding malaria control, elimination and ultimately eradication.,Pathways through which land use and land cover changes disrupt social and ecological systems to increase or decrease malaria risks are outlined, identifying priorities and opportunities for a global malaria eradication campaign.,The impacts of land use and land cover changes on malaria transmission are complex and highly context-specific, with effects changing over time and space.,Landscape changes are only one element of a complex development process with wider economic and social dimensions affecting human health and wellbeing.,While deforestation and other landscape changes threaten to undermine malaria control efforts and have driven the emergence of zoonotic malaria, most of the malaria elimination successes have been underpinned by agricultural development and land management.,Malaria eradication is not feasible without addressing these changing risks while, conversely, consideration of malaria impacts in land management decisions has the potential to significantly accelerate progress towards eradication.,Multisectoral cooperation and approaches to linking malaria control and environmental science, such as conducting locally relevant ecological monitoring, integrating landscape data into malaria surveillance systems and designing environmental management strategies to reduce malaria burdens, are essential to achieve malaria eradication.
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Malaria rapid diagnostic tests (RDTs) have greatly improved access to diagnosis in endemic countries.,Most RDTs detect Plasmodium falciparum histidine-rich protein 2 (HRP2), but their sensitivity is seriously threatened by the emergence of pfhrp2-deleted parasites.,RDTs detecting P. falciparum or pan-lactate dehydrogenase (Pf- or pan-LDH) provide alternatives.,The objective of this study was to systematically assess the performance of malaria RDTs against well-characterized pfhrp2-deleted P. falciparum parasites.,Thirty-two RDTs were tested against 100 wild-type clinical isolates (200 parasites/µL), and 40 samples from 10 culture-adapted and clinical isolates of pfhrp2-deleted parasites.,Wild-type and pfhrp2-deleted parasites had comparable Pf-LDH concentrations.,Pf-LDH-detecting RDTs were also tested against 18 clinical isolates at higher density (2,000 parasites/µL) lacking both pfhrp2 and pfhrp3.,RDT positivity against pfhrp2-deleted parasites was highest (> 94%) for the two pan-LDH-only RDTs.,The positivity rate for the nine Pf-LDH-detecting RDTs varied widely, with similar median positivity between double-deleted (pfhrp2/3 negative; 63.9%) and single-deleted (pfhrp2-negative/pfhrp3-positive; 59.1%) parasites, both lower than against wild-type P. falciparum (93.8%).,Median positivity for HRP2-detecting RDTs against 22 single-deleted parasites was 69.9 and 35.2% for HRP2-only and HRP2-combination RDTs, respectively, compared to 96.0 and 92.5% for wild-type parasites.,Eight of nine Pf-LDH RDTs detected all clinical, double-deleted samples at 2,000 parasites/µL.,The pan-LDH-only RDTs evaluated performed well.,Performance of Pf-LDH-detecting RDTs against wild-type P. falciparum does not necessarily predict performance against pfhrp2-deleted parasites.,Furthermore, many, but not all HRP2-based RDTs, detect pfhrp2-negative/pfhrp3-positive samples, with implications for the HRP2-based RDT screening approach for detection and surveillance of HRP2-negative parasites.
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Prompt and effective malaria treatment are key in reducing transmission, disease severity and mortality.,With the current scale-up of artemisinin-based combination therapy (ACT) coverage, there is need to focus on challenges affecting implementation of the intervention.,Routine indicators focus on utilization and coverage, neglecting implementation quality.,A health system in rural Malawi was assessed for uncomplicated malaria treatment implementation in children.,A cross-sectional health facility survey was conducted in six health centres around the Majete Wildlife Reserve in Chikwawa district using a health system effectiveness approach to assess uncomplicated malaria treatment implementation.,Interviews with health facility personnel and exit interviews with guardians of 120 children under 5 years were conducted.,Health workers appropriately prescribed an ACT and did not prescribe an ACT to 73% (95% CI 63-84%) of malaria rapid diagnostic test (RDT) positive and 98% (95% CI 96-100%) RDT negative children, respectively.,However, 24% (95% CI 13-37%) of children receiving artemisinin-lumefantrine had an inappropriate dose by weight.,Health facility findings included inadequate number of personnel (average: 2.1 health workers per 10,000 population), anti-malarial drug stock-outs or not supplied, and inconsistent health information records.,Guardians of 59% (95% CI 51-69%) of children presented within 24 h of onset of child’s symptoms.,The survey presents an approach for assessing treatment effectiveness, highlighting bottlenecks which coverage indicators are incapable of detecting, and which may reduce quality and effectiveness of malaria treatment.,Health service provider practices in prescribing and dosing anti-malarial drugs, due to drug stock-outs or high patient load, risk development of drug resistance, treatment failure and exposure to adverse effects.
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Based on the recommendations of the World Health Organization in 2004, Ghana changed her antimalarial drug policy from mono-therapy to Artemisinin-based Combination Therapy (ACTs).,The country is currently using three first line drugs artesunate-amodiaquine, artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated malaria.,Despite this policy, little or no qualitative studies have been conducted to establish the factors influencing adherence to the new treatment for malaria.,This study explored factors influencing adherence to the use of ACTs in northern Ghana.,This was a qualitative study comprising forty (40) in-depth interviews with patients with malaria who visited selected public and private health facilities and received ACTs.,Systematic sampling technique was used to select participants who were given ACTs for the interviews.,Nvivo 9 software was used to code the data into themes for further analysis.,The study revealed very important differences in knowledge about ACTs.,As expected, the less or illiterates could not mention the type of ACT they would prefer to use for treating their malaria.,The educated ones had a good knowledge on ACTs and preferred artemether-lumefantrinee in treating their malaria.,The reason was that the drug was good and it had minimal or no side effects.,Individual attitudes toward the use of medications and the side effects associated with the use of these ACTs were found to be the main factors affecting adherence to the use of ACTs.,Perceived cure of illness after the initial dose greatly affected adherence.,Other factors such as forgetfulness and lack of information also influenced patient adherence to ACTs use.,Individual knowledge, attitudes and behaviors greatly influence patients’ adherence to ACTs use.,Since ACTs take a number of days to complete, continuous education by health professionals could improve on adherence to ACTs use by patients with malaria.
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Background.,The need for a highly efficacious vaccine against Plasmodium falciparum remains pressing.,In this controlled human malaria infection (CHMI) study, we assessed the safety, efficacy and immunogenicity of a schedule combining 2 distinct vaccine types in a staggered immunization regimen: one inducing high-titer antibodies to circumsporozoite protein (RTS,S/AS01B) and the other inducing potent T-cell responses to thrombospondin-related adhesion protein (TRAP) by using a viral vector.,Method.,Thirty-seven healthy malaria-naive adults were vaccinated with either a chimpanzee adenovirus 63 and modified vaccinia virus Ankara-vectored vaccine expressing a multiepitope string fused to TRAP and 3 doses of RTS,S/AS01B (group 1; n = 20) or 3 doses of RTS,S/AS01B alone (group 2; n = 17).,CHMI was delivered by mosquito bites to 33 vaccinated subjects at week 12 after the first vaccination and to 6 unvaccinated controls.,Results.,No suspected unexpected serious adverse reactions or severe adverse events related to vaccination were reported.,Protective vaccine efficacy was observed in 14 of 17 subjects (82.4%) in group 1 and 12 of 16 subjects (75%) in group 2.,All control subjects received a diagnosis of blood-stage malaria parasite infection.,Both vaccination regimens were immunogenic.,Fourteen protected subjects underwent repeat CHMI 6 months after initial CHMI; 7 of 8 (87.5%) in group 1 and 5 of 6 (83.3%) in group 2 remained protected.,Conclusions.,The high level of sterile efficacy observed in this trial is encouraging for further evaluation of combination approaches using these vaccine types.,Clinical Trials Registration.,NCT01883609.
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Malaria transmission blocking (TB) vaccines (TBVs) directed against proteins expressed on the sexual stages of Plasmodium parasites are a potentially effective means to reduce transmission.,Antibodies induced by TBVs block parasite development in the mosquito, and thus inhibit transmission to further human hosts.,The ookinete surface protein P25 is a primary target for TBV development.,Recently, transient expression in plants using hybrid viral vectors has demonstrated potential as a strategy for cost-effective and scalable production of recombinant vaccines.,Using a plant virus-based expression system, we produced recombinant P25 protein of Plasmodium vivax (Pvs25) in Nicotiana benthamiana fused to a modified lichenase carrier protein.,This candidate vaccine, Pvs25-FhCMB, was purified, characterized and evaluated for immunogenicity and efficacy using multiple adjuvants in a transgenic rodent model.,An in vivo TB effect of up to a 65% reduction in intensity and 54% reduction in prevalence was observed using Abisco-100 adjuvant.,The ability of this immunogen to induce a TB response was additionally combined with heterologous prime-boost vaccination with viral vectors expressing Pvs25.,Significant blockade was observed when combining both platforms, achieving a 74% and 68% reduction in intensity and prevalence, respectively.,This observation was confirmed by direct membrane feeding on field P. vivax samples, resulting in reductions in intensity/prevalence of 85.3% and 25.5%.,These data demonstrate the potential of this vaccine candidate and support the feasibility of expressing Plasmodium antigens in a plant-based system for the production of TBVs, while demonstrating the potential advantages of combining multiple vaccine delivery systems to maximize efficacy.
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The Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) was established in late 2008 to conduct operational research that would inform practices related to the control and elimination of schistosomiasis.,This article traces SCORE’s beginnings and underpinnings.,These include an emphasis on openness and contributing to the development of a cohesive schistosomiasis control community, building linkages between researchers and national programs, and focusing on answering questions that will help Neglected Tropical Disease program managers to better control and eliminate schistosomiasis.,It describes the development and implementation of SCORE’s multiple projects.,SCORE began by drawing on advice from a broad range of experts by holding wide-ranging meetings that informed the priorities and protocols for SCORE research.,SCORE’s major efforts included large, multicountry field studies comparing multiple strategies for mass drug administration with praziquantel, assessment of approaches to elimination, evaluation of a point-of-care assay for field mapping Schistosoma mansoni, and increasing the sensitivity of a laboratory-based diagnostic.,SCORE also supported studies on morbidity due to schistosomiasis, quantification of vector snails and the detection of schistosome infections in snails, and changes in schistosome population genetics under praziquantel drug pressure.,SCORE data and specimens are archived and will remain available for future research.,Although much remains to be carried out, our hope is that through the already published articles and SCORE results described in this supplement, we will have provided a body of evidence to assist policy makers in the development of judicious guidelines for the control and elimination of schistosomiasis.
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On 14 December 2016, Professor Alan Fenwick OBE delivered the prestigious ‘Manson Lecture’ to the Royal Society for Tropical Medicine and Hygiene at the Royal Society in London.,This paper, based on the Manson Lecture, presents the research carried out to study the epidemiology of schistosomiasis in Africa and test the various control tools as they were proposed from 1914 to date.,Subsequently the development of national control programmes against schistosomiasis in Africa from 2000 towards the full national coverage now being delivered in many countries is discussed.,In 2000 only Egypt in Africa was offering treatment to the infected and at-risk populations.,By 2016 the World Health Assembly resolutions and the WHO NTD targets for 2020 are close to being achieved in some countries where schistosomiasis appears no longer to be ‘a public health problem’.,However, in some areas in sub-Saharan Africa, continuous annual treatment is still needed because of remaining ‘hotspots’ where transmission seems to be stubbornly continuing.,The author therefore questions whether the timescales to reach eliminations are realistic and whether the tools are available to reach those targets.
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Humoral immunity consists of pre-existing antibodies expressed by long-lived plasma cells and rapidly reactive memory B cells (MBC).,Recent studies of MBC development and function after protein immunization have uncovered significant MBC heterogeneity.,To clarify functional roles for distinct MBC subsets during malaria infection, we generated tetramers that identify Plasmodium-specific MBCs in both humans and mice.,Long-lived murine Plasmodium-specific MBCs consisted of three populations: somatically hypermutated immunoglobulin M+ (IgM+) and IgG+ MBC subsets and an unmutated IgD+ MBC population.,Rechallenge experiments revealed that high affinity, somatically hypermutated Plasmodium-specific IgM+ MBCs proliferated and gave rise to antibody-secreting cells that dominated the early secondary response to parasite rechallenge.,IgM+ MBCs also gave rise to T cell-dependent IgM+ and IgG+B220+CD138+ plasmablasts or T cell-independent B220−CD138+ IgM+ plasma cells.,Thus, even in competition with IgG+ MBCs, IgM+ MBCs are rapid, plastic, early responders to a secondary Plasmodium rechallenge and should be targeted by vaccine strategies.,•Tetramers allow analyses of endogenous Plasmodium-specific B cells in mice and humans•Three phenotypically distinct MBC populations form after murine malaria infection•Plasmodium-specific IgM+ MBCs are somatically hypermutated and high affinity•Plastic IgM+ memory B cells dominate the early response to malaria rechallenge,Tetramers allow analyses of endogenous Plasmodium-specific B cells in mice and humans,Three phenotypically distinct MBC populations form after murine malaria infection,Plasmodium-specific IgM+ MBCs are somatically hypermutated and high affinity,Plastic IgM+ memory B cells dominate the early response to malaria rechallenge,Heterogeneous types of memory B cells are present in both humans and mice, yet it is unclear how different MBC subsets form or function in response to infection.,Pepper and colleagues reveal that phenotypically and functionally distinct populations of polyclonal Plasmodium-specific MBCs form in response to infection and somatically hypermutated, high-affinity, plastic IgM+ memory B cells dominate the early memory response to malaria rechallenge.
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The incidence of clinical and clinicopathological signs associated with the progression of infection was evaluated prospectively in 329 naïve young dogs exposed to Leishmania infantum transmission and examined periodically during 22 months (M).,The dogs were part of Leishmania vaccine investigations performed under natural conditions.,Vaccinated groups were considered in the evaluation when the vaccine resulted non-protective and the appearance and progression of signs did not differ statistically from controls at each time point, otherwise only control groups were included. 115 beagles were part of 3 studies (A to C) performed in the same kennel; 214 owned dogs (29 breeds, 2.3% beagles) were included in a study (D) performed in 45 endemic sites.,At M22 the prevalence of any Leishmania infection stage classified as subpatent, active asymptomatic, or symptomatic was 59.8% in studies A-C and 29.2% in study D.,Despite different breed composition and infection incidence, the relative proportion of active infections and the progression and type of clinical and clinicopathological signs have been similar in both study sets.,All asymptomatic active infections recorded have invariably progressed to full-blown disease, resulting in 56 sick dogs at M22.,In these dogs, lymph nodes enlargement and weight loss - recorded from M12 - were the most common signs.,Cutaneous signs were seen late (M18) and less frequently.,Ocular signs appeared even later, being sporadically recorded at M22.,Most clinicopathological alterations became evident from M12, although a few cases of thrombocytopenia or mild non-regenerative anemia were already observed at M6.,Albumin/globulin inversions were recorded from M12 and urea/creatinine increase appeared mostly from M18.,Altogether our findings indicate that any susceptible young dogs naturally infected by L. infantum present a common pattern of progression of signs during 2 years post infection, providing clues for medical and epidemiological applied aspects.
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Schistosomiasis is a major cause of morbidity in humans invoked by chronic infection with parasitic trematodes of the genus Schistosoma.,Schistosomes have a complex life-cycle involving infections of an aquatic snail intermediate host and a definitive mammalian host.,In humans, adult male and female worms lie within the vasculature.,Here, they propagate and eggs are laid.,These eggs must then be released from the host to continue the life cycle.,Schistosoma mansoni and Schistosoma japonicum reside in the mesenteric circulation of the intestines with egg excreted in the feces.,In contrast, S. haematobium are present in the venus plexus of the bladder, expelling eggs in the urine.,In an impressive case of exploitation of the host immune system, this process of Schistosome “eggs-iting” the host is immune dependent.,In this article, we review the formation of the egg granuloma and explore how S. mansoni eggs laid in vasculature must usurp immunity to induce regulated inflammation, to facilitate extravasation through the intestinal wall and to be expelled in the feces.,We highlight the roles of immune cell populations, stromal factors, and egg secretions in the process of egg excretion to provide a comprehensive overview of the current state of knowledge regarding a vastly unexplored mechanism.
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To further investigate the importance of insulin signaling in the growth, development, sexual maturation and egg production of adult schistosomes, we have focused attention on the insulin receptors (SjIRs) of Schistosoma japonicum, which we have previously cloned and partially characterised.,We now show, by Biolayer Interferometry, that human insulin can bind the L1 subdomain (insulin binding domain) of recombinant (r)SjIR1 and rSjIR2 (designated SjLD1 and SjLD2) produced using the Drosophila S2 protein expression system.,We have then used RNA interference (RNAi) to knock down the expression of the SjIRs in adult S. japonicum in vitro and show that, in addition to their reduced transcription, the transcript levels of other important downstream genes within the insulin pathway, associated with glucose metabolism and schistosome fecundity, were also impacted substantially.,Further, a significant decrease in glucose uptake was observed in the SjIR-knockdown worms compared with luciferase controls.,In vaccine/challenge experiments, we found that rSjLD1 and rSjLD2 depressed female growth, intestinal granuloma density and faecal egg production in S. japonicum in mice presented with a low dose challenge infection.,These data re-emphasize the potential of the SjIRs as veterinary transmission blocking vaccine candidates against zoonotic schistosomiasis japonica in China and the Philippines.
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To implement future malaria elimination strategies in French Guiana, a characterization of the infectious reservoir is recommended.,A cross-sectional survey was conducted between October and December 2017 in the French Guianese municipality of St Georges de l’Oyapock, located along the Brazilian border.,The prevalence of Plasmodium spp. was determined using a rapid diagnostic test (RDT) and a polymerase chain reaction (PCR).,Demographic, house locations, medical history, and biological data were analyzed.,Factors associated with Plasmodium spp. carriage were analyzed using logistic regression, and the carriage localization was investigated through spatial cluster analysis.,Of the 1,501 samples analyzed with PCR, positive results totaled 90 and 10 for Plasmodium vivax and Plasmodium falciparum, respectively.,The general PCR prevalence was 6.6% [5.3-7.9], among which 74% were asymptomatic.,Only 13/1,549 were positive by RDT.,In multivariate analysis, participants older than 15 years, living in a remote neighborhood, with a prior history of malaria, anemia, and thrombocytopenia were associated with an increased odds of Plasmodium spp. carriage.,High-risk clusters of P. vivax carriage were detected in the most remote neighborhoods on the village outskirts and two small foci in the village center.,We also detected a hot spot for both P. vivax and P. falciparum symptomatic carriers in the northwestern part of the village.,The present study confirms a wide-scale presence of asymptomatic P. falciparum and P. vivax carriers in this area.,Although they were more often located in remote areas, their geographic distribution was spatially heterogeneous and complex.
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In French Guiana, malaria vector control and prevention relies on indoor residual spraying and distribution of long lasting insecticidal nets.,These measures are based on solid epidemiological evidence but reveal a poor understanding of the vector.,The current study investigated the behaviour of both vectors and humans in relation to the ongoing prevention strategies.,In 2012 and 2013, Anopheles mosquitoes were sampled outdoors at different seasons and in various time slots.,The collected mosquitoes were identified and screened for Plasmodium infection.,Data on human behaviour and malaria episodes were obtained from an interview.,A total of 3,135 Anopheles mosquitoes were collected, of which Anopheles darlingi was the predominant species (96.2%).,For the December 2012-February 2013 period, the Plasmodium vivax infection rate for An. darlingi was 7.8%, and the entomological inoculation rate was 35.7 infective bites per person per three-month span.,In spite of high bednet usage (95.7%) in 2012 and 2013, 52.2% and 37.0% of the participants, respectively, had at least one malaria episode.,An. darlingi displayed heterogeneous biting behaviour that peaked between 20:30 and 22:30; however, 27.6% of the inhabitants were not yet protected by bednets by 21:30.,The use of additional individual and collective protective measures is required to limit exposure to infective mosquito bites and reduce vector densities.
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Control and elimination of zoonotic diseases requires robust information about their effect on both human and livestock health in order to enable policy formulation and the allocation of resources.,This study aimed to evaluate the cost-effectiveness of controlling Taenia solium taeniasis/cysticercosis in both humans and pigs, and soil-transmitted helminths (STH) in humans by integrating their control to on-going human and animal health control programmes in northern Lao People’s Democratic Republic.,A cross-sectional study was carried out in 49 households, focusing on the prevalence of T. solium taenias/cysticercosis and soil transmitted helminths before and after a twelve month intervention.,The village data was collected using a semi-structured questionnaire through a door-to-door survey.,The village data was then projected to the wider northern Lao PDR population using stochastic modelling and cost-effectiveness ratio (after aggregating the net cost to capture both human and animal health parameters) and GDP per capita as a threshold, to determine the cost-effectiveness of the integrated control of T. solium taeniasis/ cysticercosis and STH, assuming linear scaling out of the intervention.,The zoonotic DALY (zDALY) approach was also used as an alternative method of estimating the cost-effectiveness ratio of controlling T. solium taeniasis/cysticercosis in humans and pigs.,Using cost-effectiveness analysis after aggregating the net cost and control of T. solium taeniasis/cysticercosis alone as the base case, the study found that simultaneous control of T. solium taeniasis/cysticercosis in humans and pigs, STH in humans and Classical Swine Fever (CSF) in pigs was USD 14 per DALY averted and USD 234 per zDALY averted using zDALY method hence considered highly cost-effective whereas controlling T. solium taeniasis/cysticercosis without incorporating STH and CSF was the least cost-effective (USD 3,672 per DALY averted).,Additionally, the cost-effectiveness of controlling T. solium taeniasis/cysticercosis in people and pigs using zDALY as an alternative method was USD 3,662 per zDALY averted which was quite close to our findings using the aggregate net cost method.,The study showed that control of T. solium taeniasis/cysticercosis alone in humans and pigs is not cost-effective in northern Lao PDR whereas control of STH is.,Consequently, integrating T. solium taeniasis/cysticercosis control with other cost-effective programmes such as STH and CSF markedly improved the cost-effectiveness of the intervention.,This is especially important in low resource countries where control of zoonotic neglected tropical diseases could be integrated with the human and animal health sectors to optimize use of the limited resources.,Australia New Zealand Clinical Trials Registry (ANZCTR) ACTRN12614001067662.
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Taenia solium cysticercosis is a zoonotic neglected disease responsible for severe health disorders such as seizures and death.,Understanding the epidemiology of human cysticercosis (HCC) in endemic regions will help to expose critical information about the transmission of the disease, which could be used to design efficient control programs.,This review gathered serological data on apparent prevalence of T. solium circulating antigens and/or seroprevalence of T. solium antibodies, apparent prevalence of human taeniasis and risk factors for HCC from endemic communities in order to understand the differences in exposure to the parasite and active infections with T. solium metacestodes in endemic areas around the world.,Three databases were used to search sero-epidemiological data from community-based studies conducted between 1989 and 2014 in cysticercosis endemic communities worldwide.,The search focused on data obtained from T. solium circulating antigen detection by monoclonal antibody-based sandwich ELISA and/or T. solium antibody seroprevalence determined by Enzyme-linked Immunoelectrotransfer Blot (EITB).,A meta-analysis was performed per continent.,A total of 39,271 participants from 19 countries, described in 37 articles were studied.,The estimates for the prevalence of circulating T. solium antigens for Africa, Latin America and Asia were: 7.30% (95% CI [4.23-12.31]), 4.08% (95% CI [2.77-5.95]) and 3.98% (95% CI [2.81-5.61]), respectively.,Seroprevalence estimates of T. solium antibodies were 17.37% (95% CI [3.33-56.20]), 13.03% (95% CI [9.95-16.88]) and 15.68% (95% CI [10.25-23.24]) respectively.,Taeniasis reported prevalences ranged from 0 (95% CI [0.00-1.62]) to 17.25% (95% CI [14.55-20.23]).,A significant variation in the sero-epidemiological data was observed within each continent, with African countries reporting the highest apparent prevalences of active infections.,Intrinsic factors in the human host such as age and immunity were main determinants for the occurrence of infections, while exposure was mostly related to environmental factors which varied from community to community.
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We conducted a single-arm clinical trial in Ethiopian visceral leishmaniasis/HIV-coinfected patients using pentamidine secondary prophylaxis.,The 2-year risk of relapse was 37%.,Patients reaching a CD4 count >200 cells/µL after 12 months of prophylaxis can safely discontinue pentamidine.,We have conducted a single-arm trial evaluating monthly pentamidine secondary prophylaxis (PSP) to prevent visceral leishmaniasis (VL) relapse in Ethiopian human immunodeficiency virus-infected patients.,Outcomes at 12 months of PSP have been previously reported, supporting PSP effectiveness and safety.,However, remaining relapse-free after PSP discontinuation is vital.,We now report outcomes and associated factors for a period of up to 2.5 years after initiating PSP, including 1-year follow-up after PSP discontinuation.,The trial had 3 phases: (1) 12 months of PSP; (2) a 6-month PSP extension period if CD4 count was ≤200 cells/μL at month 12; and (3) 12-month follow-up after stopping PSP.,The probability of relapse and risk factors were calculated using Kaplan-Meier methods and Cox regression analysis.,For the 74 patients included, final study outcomes were as follows: 39 (53%) relapse-free, 20 (27%) relapsed, 5 (7%) deaths, 10 (14%) lost to follow-up.,The 2-year risk of relapse was 36.9% (95% confidence interval, 23.4%-55.0%) and was highest for those with a history of VL relapse and low baseline CD4 count.,Forty-five patients were relapse-free and in follow-up at month 12 of PSP.,This included 28 patients with month 12 CD4 counts >200 cells/µL, remaining relapse-free after PSP discontinuation.,Among the 17 with month 12 CD4 count <200 cells/µL, 1 relapsed and 3 were lost during the PSP extension period.,During 1-year post-PSP follow-up, 2 patients relapsed and 1 was lost to follow-up.,No PSP-related serious adverse events were reported during the PSP-extension/post-PSP follow-up period.,It seems safe to discontinue PSP at month 12 CD4 counts of >200 cells/µL.,The management of those failing to reach this level remains to be defined.,NCT01360762.
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Over the last 15 years, visceral leishmaniasis (VL) has emerged as a public health concern in Tbilisi, the capital of Georgia.,Seroepidemiological surveys were conducted to determine the prevalence and incidence of infection in children and dogs within the main focus of VL, and to identify risk factors associated with human infection.,Of 4,250 children investigated, 7.3% were positive by direct agglutination test in a baseline survey; an apparent incidence rate of 6.0% was estimated by one year follow-up.,None of the seropositive children progressed to VL during the survey.,Increased seropositivity at one year was predicted by presence at baseline of clustered flying insects (OR = 1.49; P = 0.001), perceived satisfactory sanitation (OR = 1.65; P<0.001), stray dogs (OR = 1.33; P = 0.023), and by persistent fever during the 6 months prior to baseline survey (OR = 14.2; P<0.001).,Overall, 18.2% (107/588) of domestic and 15.3% (110/718) of stray dogs were seropositive by the rk39 dipstick test.,Clinical VL signs were found in 1.3% of domestic and 2.9% of stray, seropositive dogs.,Parasites isolated from human and dog samples were identified by PCR and phylogenetic analysis of the Leishmania 70 kDa heat-shock protein (HSP70) gene as Leishmania infantum.,There is an active focus of L. infantum transmission in Tbilisi with a high prevalence of human and canine infections.
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Soil-transmitted helminth infections affect tens of millions of individuals in the People’s Republic of China (P.R.,China).,There is a need for high-resolution estimates of at-risk areas and number of people infected to enhance spatial targeting of control interventions.,However, such information is not yet available for P.R.,China.,A geo-referenced database compiling surveys pertaining to soil-transmitted helminthiasis, carried out from 2000 onwards in P.R.,China, was established.,Bayesian geostatistical models relating the observed survey data with potential climatic, environmental and socioeconomic predictors were developed and used to predict at-risk areas at high spatial resolution.,Predictors were extracted from remote sensing and other readily accessible open-source databases.,Advanced Bayesian variable selection methods were employed to develop a parsimonious model.,Our results indicate that the prevalence of soil-transmitted helminth infections in P.R.,China considerably decreased from 2005 onwards.,Yet, some 144 million people were estimated to be infected in 2010.,High prevalence (>20%) of the roundworm Ascaris lumbricoides infection was predicted for large areas of Guizhou province, the southern part of Hubei and Sichuan provinces, while the northern part and the south-eastern coastal-line areas of P.R.,China had low prevalence (<5%).,High infection prevalence (>20%) with hookworm was found in Hainan, the eastern part of Sichuan and the southern part of Yunnan provinces.,High infection prevalence (>20%) with the whipworm Trichuris trichiura was found in a few small areas of south P.R.,China.,Very low prevalence (<0.1%) of hookworm and whipworm infections were predicted for the northern parts of P.R.,China.,We present the first model-based estimates for soil-transmitted helminth infections throughout P.R.,China at high spatial resolution.,Our prediction maps provide useful information for the spatial targeting of soil-transmitted helminthiasis control interventions and for long-term monitoring and surveillance in the frame of enhanced efforts to control and eliminate the public health burden of these parasitic worm infections.
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The prevalence of infection with the three common soil-transmitted helminths (i.e.,Ascaris lumbricoides, Trichuris trichiura, and hookworm) in Bolivia is among the highest in Latin America.,However, the spatial distribution and burden of soil-transmitted helminthiasis are poorly documented.,We analysed historical survey data using Bayesian geostatistical models to identify determinants of the distribution of soil-transmitted helminth infections, predict the geographical distribution of infection risk, and assess treatment needs and costs in the frame of preventive chemotherapy.,Rigorous geostatistical variable selection identified the most important predictors of A. lumbricoides, T. trichiura, and hookworm transmission.,Results show that precipitation during the wettest quarter above 400 mm favours the distribution of A. lumbricoides.,Altitude has a negative effect on T. trichiura.,Hookworm is sensitive to temperature during the coldest month.,We estimate that 38.0%, 19.3%, and 11.4% of the Bolivian population is infected with A. lumbricoides, T. trichiura, and hookworm, respectively.,Assuming independence of the three infections, 48.4% of the population is infected with any soil-transmitted helminth.,Empirical-based estimates, according to treatment recommendations by the World Health Organization, suggest a total of 2.9 million annualised treatments for the control of soil-transmitted helminthiasis in Bolivia.,We provide estimates of soil-transmitted helminth infections in Bolivia based on high-resolution spatial prediction and an innovative variable selection approach.,However, the scarcity of the data suggests that a national survey is required for more accurate mapping that will govern spatial targeting of soil-transmitted helminthiasis control.
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FcεR1-expressing neutrophils accumulate in the brain of mice infected with Plasmodium berghei (PbANKA) and promote the development of experimental cerebral malaria.,The role of the IgE-FcεRI complex in malaria severity in Plasmodium falciparum-hosting patients is unknown.,We demonstrate that mice genetically deficient for the high-affinity receptor for IgE (FcεRIα-KO) or for IgE (IgE-KO) are less susceptible to experimental cerebral malaria (ECM) after infection with Plasmodium berghei (PbANKA).,Mast cells and basophils, which are the classical IgE-expressing effector cells, are not involved in disease as mast cell-deficient and basophil-depleted mice developed a disease similar to wild-type mice.,However, we show the emergence of an FcεRI+ neutrophil population, which is not observed in mice hosting a non-ECM-inducing PbNK65 parasite strain.,Depletion of this FcεRI+ neutrophil population prevents ECM, whereas transfer of this population into FcεRIα-KO mice restores ECM susceptibility.,FcεRI+ neutrophils preferentially home to the brain and induce elevated levels of proinflammatory cytokines.,These data define a new pathogenic mechanism of ECM and implicate an FcεRI-expressing neutrophil subpopulation in malaria disease severity.
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In Africa, infant susceptibility to Plasmodium falciparum malaria increases substantially as fetal hemoglobin (HbF) and maternal immune IgG disappear from circulation.,During the first few months of life, however, resistance to malaria is evidenced by extremely low parasitemias, the absence of fever, and the almost complete lack of severe disease.,This resistance has previously been attributed in part to poor parasite growth in HbF-containing red blood cells (RBCs).,A specific role for maternal immune IgG in infant resistance to malaria has been hypothesized but not yet identified.,We found that P. falciparum parasites invade and develop normally in fetal (cord blood, CB) RBCs, which contain up to 95% HbF.,However, these parasitized CB RBCs are impaired in their binding to human microvascular endothelial cells (MVECs), monocytes, and nonparasitized RBCs - cytoadherence interactions that have been implicated in the development of high parasite densities and the symptoms of malaria.,Abnormal display of the parasite's cytoadherence antigen P. falciparum erythrocyte membrane protein-1 (PfEMP-1) on CB RBCs accounts for these findings and is reminiscent of that on HbC and HbS RBCs.,IgG purified from the plasma of immune Malian adults almost completely abolishes the adherence of parasitized CB RBCs to MVECs.,Our data suggest a model of malaria protection in which HbF and maternal IgG act cooperatively to impair the cytoadherence of parasitized RBCs in the first few months of life.,In highly malarious areas of Africa, an infant's contemporaneous expression of HbC or HbS and development of an immune IgG repertoire may effectively reconstitute the waning protective effects of HbF and maternal immune IgG, thereby extending the malaria resistance of infancy into early childhood.
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A mixed methods study was conducted to look at the magnitude of residual malaria transmission (RMT) and factors contributing to low (< 1% prevalence), but sustained transmission in rural communities on the Thai-Myanmar border.,A cross-sectional behaviour and net survey, observational surveys and entomological collections in both villages and forested farm huts frequented by community members for subsistence farming practices were conducted.,Community members frequently stayed overnight at subsistence farm huts or in the forest.,Entomological collections showed higher biting rates of primary vectors in forested farm hut sites and in a more forested village setting compared to a village with clustered housing and better infrastructure.,Despite high levels of outdoor biting, biting exposure occurred predominantly indoors, particularly for non-users of long-lasting insecticidal nets (LLINs).,Risk of biting exposure was exacerbated by sub-optimal coverage of LLINs, particularly in subsistence farm huts and in the forest.,Furthermore, early waking hours when people had left the safety of their nets coincided with peaks in biting in later morning hours.,Entomological and epidemiological findings suggest drivers and modulators of sustained infection prevalence in the area to be: higher mosquito abundance in forested areas where LLINs were used less frequently or could not be used; late sleeping and waking times coinciding with peak biting hours; feeding preferences of Anopheles taking them away from contact with LLIN and indoor residual spraying (IRS), e.g. exophagy and zoophagy; non-use of LLIN and use of damaged/torn LLIN; high population movement across the border and into forested areas thereby increasing risk of exposure, decreasing use of protection and limiting access to healthcare; and, Plasmodium vivax predominance resulting in relapse(s) of previous infection.,The findings highlight gaps in current intervention coverage beyond the village setting.,The online version of this article (10.1186/s12936-019-2852-5) contains supplementary material, which is available to authorized users.
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A phase I randomised, controlled, single blind, dose escalation trial was conducted to evaluate safety and immunogenicity of JAIVAC-1, a recombinant blood stage vaccine candidate against Plasmodium falciparum malaria, composed of a physical mixture of two recombinant proteins, PfMSP-119, the 19 kD conserved, C-terminal region of PfMSP-1 and PfF2 the receptor-binding F2 domain of EBA175.,Healthy malaria naïve Indian male subjects aged 18-45 years were recruited from the volunteer database of study site.,Fifteen subjects in each cohort, randomised in a ratio of 2:1 and meeting the protocol specific eligibility criteria, were vaccinated either with three doses (10μg, 25μg and 50μg of each antigen) of JAIVAC-1 formulated with adjuvant Montanide ISA 720 or with standard dosage of Hepatitis B vaccine.,Each subject received the assigned vaccine in the deltoid muscle of the upper arms on Day 0, Day 28 and Day 180.,JAIVAC-1 was well tolerated and no serious adverse event was observed.,All JAIVAC-1 subjects sero-converted for PfF2 but elicited poor immune response to PfMSP-119.,Dose-response relationship was observed between vaccine dose of PfF2 and antibody response.,The antibodies against PfF2 were predominantly of IgG1 and IgG3 isotype.,Sera from JAIVAC-1 subjects reacted with late schizonts in a punctate pattern in immunofluorescence assays.,Purified IgG from JAIVAC-1 sera displayed significant growth inhibitory activity against Plasmodium falciparum CAMP strain.,Antigen PfF2 should be retained as a component of a recombinant malaria vaccine but PfMSP-119 construct needs to be optimised to improve its immunogenicity.,Clinical Trial Registry, India CTRI/2010/091/000301
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Bangladesh had one of the highest burdens of lymphatic filariasis (LF) at the start of the Global Programme to Eliminate Lymphatic Filariasis (GPELF) with an estimated 70 million people at risk of infection across 34 districts.,In total 19 districts required mass drug administration (MDA) to interrupt transmission, and 15 districts were considered low endemic.,Since 2001, the National LF Programme has implemented MDA, reduced prevalence, and been able to scale up the WHO standard Transmission Assessment Survey (TAS) across all endemic districts as part of its endgame surveillance strategy.,This paper presents TAS results, highlighting the momentous geographical reduction in risk of LF and its contribution to the global elimination target of 2020.,The TAS assessed primary school children for the presence of LF antigenaemia in each district (known as an evaluation unit-EU), using a defined critical cut-off threshold (or ‘pass’) that indicates interruption of transmission.,Since 2011, a total of 59 TAS have been conducted in 26 EUs across the 19 endemic MDA districts (99,148 students tested from 1,801 schools), and 22 TAS in the 15 low endemic non-MDA districts (36,932 students tested from 663 schools).,All endemic MDA districts passed TAS, except in Rangpur which required two further rounds of MDA.,In total 112 students (male n = 59; female n = 53), predominately from the northern region of the country were found to be antigenaemia positive, indicating a recent or current infection.,However, the distribution was geographically sparse, with only two small focal areas showing potential evidence of persistent transmission.,This is the largest scale up of TAS surveillance activities reported in any of the 73 LF endemic countries in the world.,Bangladesh is now considered to have very low or no risk of LF infection after 15 years of programmatic activities, and is on track to meet elimination targets.,However, it will be essential that the LF Programme continues to develop and maintain a comprehensive surveillance strategy that is integrated into the health infrastructure and ongoing programmes to ensure cost-effectiveness and sustainability.
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Lymphatic filariasis (LF) control started in Tanga Region of Tanzania in 2004, with annual ivermectin/albendazole mass drug administration (MDA).,Since then, the current project has monitored the effect in communities and schools in rural areas of Tanga District.,In 2013, after 8 rounds of MDA, spot check surveys were added in the other 7 districts of Tanga Region, to assess the regional LF status.,LF vector and transmission surveillance, and human cross sectional surveys in communities and schools, continued in Tanga District as previously reported.,In each of the other 7 districts, 2-3 spot check sites were selected and about 200 schoolchildren were examined for circulating filarial antigens (CFA).,At 1-2 of the sites in each district, additional about 200 community volunteers were examined for CFA and chronic LF disease, and the CFA positives were re-examined for microfilariae (mf).,The downward trend in LF transmission and human infection previously reported for Tanga District continued, with prevalences after MDA 8 reaching 15.5% and 3.5% for CFA and mf in communities (decrease by 75.5% and 89.6% from baseline) and 2.3% for CFA in schoolchildren (decrease by 90.9% from baseline).,Surprisingly, the prevalence of chronic LF morbidity after MDA 8 was less than half of baseline records.,No infective vector mosquitoes were detected after MDA 7.,Spot checks in the other districts after MDA 8 showed relatively high LF burdens in the coastal districts.,LF burdens gradually decreased when moving to districts further inland and with higher altitudes.,LF was still widespread in many parts of Tanga Region after MDA 8, in particular in the coastal areas.,This calls for intensified control, which should include increased MDA treatment coverage, strengthening of bed net usage, and more male focus in LF health information dissemination.,The low LF burdens observed in some inland districts suggest that MDA in these could be stepped down to provide more resources for upscale of control in the coastal areas.,Monitoring should continue to guide the programme to ensure that the current major achievements will ultimately lead to successful LF elimination.
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In India, malaria is a major public health problem in States having predominantly tribal population.,The objective of this analysis was to find out the incidence of malaria in various States/districts having varied proportions of tribal population using National Vector Borne Disease Control Programme (NVBDCP) data.,States and districts were classified into three categories based on proportions of Scheduled Tribes (ST) population as <10, 10-29.9 and 30 per cent + ST population.,Five year average (2008-2012) of all important malaria indicators collected by NVBDCP was taken to normalize the effect of annual fluctuations in malaria incidence.,State level analysis revealed that ten States/UTs with 30 per cent or more tribal population comprising only three per cent of total population, contributed 14 per cent of total malaria, 21 per cent Plasmodium falciparum and 29 per cent of deaths due to malaria.,Similarly, district level analysis showed that districts with 30 per cent or more tribal population comprising about eight per cent country's population contributed to 46 per cent of total malaria cases, 70 per cent P. falciparum and 47 per cent malarial deaths in the country.,Our analysis showed that the neglect of the ethnic communities in tribal areas would be detrimental to the overall reduction of morbidity and mortality due to malaria.,The fight against the increasing burden of malaria in tribal belt requires adoption of multiple approaches and socio-economic development of the tribal communities.
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Malaria presents a diagnostic challenge in areas where both Plasmodium falciparum and P.vivax are co-endemic.,Bivalent Rapid Diagnostic tests (RDTs) showed promise as diagnostic tools for P.falciparum and P.vivax.,To assist national malaria control programme in the selection of RDTs, commercially available seven malaria RDTs were evaluated in terms of their performance with special reference to heat stability.,This study was undertaken in four forested districts of central India (July, 2011- March, 2012).,All RDTs were tested simultaneously in field along with microscopy as gold standard.,These RDTs were stored in their original packing at 25°C before transport to the field or they were stored at 35°C and 45°C upto 100 days for testing the performance of RDTs at high temperature.,In all 2841 patients with fever were screened for malaria of which 26% were positive for P.falciparum, and 17% for P.vivax.,The highest sensitivity of any RDT for P.falciparum was 98% (95% CI; 95.9-98.8) and lowest sensitivity was 76% (95% CI; 71.7-79.6).,For P.vivax highest and lowest sensitivity for any RDT was 80% (95% CI; 94.9 - 83.9) and 20% (95% CI; 15.6-24.5) respectively.,Heat stability experiments showed that most RDTs for P.falciparum showed high sensitivity at 45°C upto 90 days.,While for P.vivax only two RDTs maintained good sensitivity upto day 90 when compared with RDTs kept at room temperature.,Agreement between observers was excellent for positive and negative readings for both P.falciparum and P.vivax (Kappa >0.6-0.9).,This is first field evaluation of RDTs regarding their temperature stability.,Although RDTs are useful as diagnostic tool for P.falciparum and P.vivax even at high temperature, the quality of RDTs should be regulated and monitored more closely.
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Parasitic helminths have evolved together with the mammalian immune system over many millennia and as such they have become remarkably efficient modulators in order to promote their own survival.,Their ability to alter and/or suppress immune responses could be beneficial to the host by helping control excessive inflammatory responses and animal models and pre-clinical trials have all suggested a beneficial effect of helminth infections on inflammatory bowel conditions, MS, asthma and atopy.,Thus, helminth therapy has been suggested as a possible treatment method for autoimmune and other inflammatory disorders in humans.
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Accumulating evidence suggests that IL-9-mediated immunity plays a fundamental role in control of intestinal nematode infection.,Here we report a different impact of Foxp3+ regulatory T cells (Treg) in nematode-induced evasion of IL-9-mediated immunity in BALB/c and C57BL/6 mice.,Infection with Strongyloides ratti induced Treg expansion with similar kinetics and phenotype in both strains.,Strikingly, Treg depletion reduced parasite burden selectively in BALB/c but not in C57BL/6 mice.,Treg function was apparent in both strains as Treg depletion increased nematode-specific humoral and cellular Th2 response in BALB/c and C57BL/6 mice to the same extent.,Improved resistance in Treg-depleted BALB/c mice was accompanied by increased production of IL-9 and accelerated degranulation of mast cells.,In contrast, IL-9 production was not significantly elevated and kinetics of mast cell degranulation were unaffected by Treg depletion in C57BL/6 mice.,By in vivo neutralization, we demonstrate that increased IL-9 production during the first days of infection caused accelerated mast cell degranulation and rapid expulsion of S. ratti adults from the small intestine of Treg-depleted BALB/c mice.,In genetically mast cell-deficient (Cpa3-Cre) BALB/c mice, Treg depletion still resulted in increased IL-9 production but resistance to S. ratti infection was lost, suggesting that IL-9-driven mast cell activation mediated accelerated expulsion of S. ratti in Treg-depleted BALB/c mice.,This IL-9-driven mast cell degranulation is a central mechanism of S. ratti expulsion in both, BALB/c and C57BL/6 mice, because IL-9 injection reduced and IL-9 neutralization increased parasite burden in the presence of Treg in both strains.,Therefore our results suggest that Foxp3+ Treg suppress sufficient IL-9 production for subsequent mast cell degranulation during S. ratti infection in a non-redundant manner in BALB/c mice, whereas additional regulatory pathways are functional in Treg-depleted C57BL/6 mice.
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The cumulative effect of co-infections between pathogen pairs on the haematological response of East African Short-horn Zebu calves is described.,Using a longitudinal study design a stratified clustered random sample of newborn calves were recruited into the Infectious Diseases of East African Livestock (IDEAL) study and monitored at 5-weekly intervals until 51 weeks of age.,At each visit samples were collected and analysed to determine the infection status of each calf as well as their haematological response.,The haematological parameters investigated included packed cell volume (PCV), white blood cell count (WBC) and platelet count (Plt).,The pathogens of interest included tick-borne protozoa and rickettsias, trypanosomes and intestinal parasites.,Generalized additive mixed-effect models were used to model the infectious status of pathogens against each haematological parameter, including significant interactions between pathogens.,These models were further used to predict the cumulative effect of co-infecting pathogen pairs on each haematological parameter.,The most significant decrease in PCV was found with co-infections of trypanosomes and strongyles.,Strongyle infections also resulted in a significant decrease in WBC at a high infectious load.,Trypanosomes were the major cause of thrombocytopenia.,Platelet counts were also affected by interactions between tick-borne pathogens.,Interactions between concomitant pathogens were found to complicate the prognosis and clinical presentation of infected calves and should be taken into consideration in any study that investigates disease under field conditions.
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In natural populations, individuals may be infected with multiple distinct pathogens at a time.,These pathogens may act independently or interact with each other and the host through various mechanisms, with resultant varying outcomes on host health and survival.,To study effects of pathogens and their interactions on host survival, we followed 548 zebu cattle during their first year of life, determining their infection and clinical status every 5 weeks.,Using a combination of clinical signs observed before death, laboratory diagnostic test results, gross-lesions on post-mortem examination, histo-pathology results and survival analysis statistical techniques, cause-specific aetiology for each death case were determined, and effect of co-infections in observed mortality patterns.,East Coast fever (ECF) caused by protozoan parasite Theileria parva and haemonchosis were the most important diseases associated with calf mortality, together accounting for over half (52%) of all deaths due to infectious diseases.,Co-infection with Trypanosoma species increased the hazard for ECF death by 6 times (1.4-25; 95% CI).,In addition, the hazard for ECF death was increased in the presence of Strongyle eggs, and this was burden dependent.,An increase by 1000 Strongyle eggs per gram of faeces count was associated with a 1.5 times (1.4-1.6; 95% CI) increase in the hazard for ECF mortality.,Deaths due to haemonchosis were burden dependent, with a 70% increase in hazard for death for every increase in strongyle eggs per gram count of 1000.,These findings have important implications for disease control strategies, suggesting a need to consider co-infections in epidemiological studies as opposed to single-pathogen focus, and benefits of an integrated approach to helminths and East Coast fever disease control.
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Traditional methods of detecting Leishmania from cutaneous lesions involve invasive diagnostic procedures, such as scrapings, which cause discomfort, require technical expertise, and carry risks of invasive procedures.,We compared the performance of 2 novel, molecular-based non-invasive methods for the diagnosis of cutaneous leishmaniasis (CL).,Consecutive patients presenting to the Leishmania Clinic at the Hospital Nacional Cayetano Heredia were enrolled.,PCR was performed on filter paper lesion impressions (FPLIs), cytology brushes, and lancets for detection of Leishmania DNA.,Smears from lesion scrapings and leishmanin skin test were also performed.,Outcome measures were sensitivity and specificity.,Composite reference standard was any 2 of 5 tests positive.,Species identification was performed by PCR assays of positive specimens.,Ninety patients with 129 lesions were enrolled, 117 of which fulfilled reference criteria for a diagnosis of CL.,Of these 117 lesions, 113 were positive by PCR of lancets used for lesion scrapings versus 116 by PCR of FPLIs (p = 0.930) or 116 by PCR of cytology brushes (p = 0.930).,Sensitivity and specificity of PCR on lancets were 96.6% [95% CI 93.3-99.9%] and 100%, respectively.,Sensitivity and specificity of FPLI PCR were 99.1% [95% CI 97.4-100%] and 100%, respectively.,Sensitivity and specificity of cytology brush PCR were 99.1% [95% CI 97.4-100%] and 100%, respectively.,Giemsa-stained lesion smear and leishmanin skin test had inferior sensitivities at 47.9% [95% CI 38.9-57.0%] and 82.3% [95% CI 73.9-90.7%], respectively, compared to PCR of invasive or non-invasive specimens (p<0.001).,Cytology brush PCR constitutes a sensitive and specific alternative to traditional diagnostic assays performed on invasive specimens such as lesion scrapings.,It performs comparatively to non-invasive FPLI PCR.,This novel, rapid, and well-tolerated method has the potential for widespread use in the field and in pediatric populations where traditional specimen collection is difficult.
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New foci of human CL caused by strains of the Leishmania donovani (L. donovani) complex have been recently described in Cyprus and the Çukurova region in Turkey (L. infantum) situated 150 km north of Cyprus.,Cypriot strains were typed by Multilocus Enzyme Electrophoresis (MLEE) using the Montpellier (MON) system as L. donovani zymodeme MON-37.,However, multilocus microsatellite typing (MLMT) has shown that this zymodeme is paraphyletic; composed of distantly related genetic subgroups of different geographical origin.,Consequently the origin of the Cypriot strains remained enigmatic.,The Cypriot strains were compared with a set of Turkish isolates obtained from a CL patient and sand fly vectors in south-east Turkey (Çukurova region; CUK strains) and from a VL patient in the south-west (Kuşadasi; EP59 strain).,These Turkish strains were initially analyzed using the K26-PCR assay that discriminates MON-1 strains by their amplicon size.,In line with previous DNA-based data, the strains were inferred to the L. donovani complex and characterized as non MON-1.,For these strains MLEE typing revealed two novel zymodemes; L. donovani MON-309 (CUK strains) and MON-308 (EP59).,A population genetic analysis of the Turkish isolates was performed using 14 hyper-variable microsatellite loci.,The genotypic profiles of 68 previously analyzed L. donovani complex strains from major endemic regions were included for comparison.,Population structures were inferred by combination of Bayesian model-based and distance-based approaches.,MLMT placed the Turkish and Cypriot strains in a subclade of a newly discovered, genetically distinct L. infantum monophyletic group, suggesting that the Cypriot strains may originate from Turkey.,The discovery of a genetically distinct L. infantum monophyletic group in the south-eastern Mediterranean stresses the importance of species genetic characterization towards better understanding, monitoring and controlling the spread of leishmaniasis in this region.
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The parasite that causes African sleeping sickness can be transmitted from mammals to tsetse flies in two stages of its lifecycle, rather than one as was previously thought.
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Kinetoplastid parasites of the Leishmania genus cause several forms of leishmaniasis.,Leishmania species pathogenic to human are separated into two subgenera, Leishmania (Leishmania) and L.,(Viannia).,Species from the Viannia subgenus cause predominantly cutaneous leishmaniasis in Central and South America, occasionally leading to more severe clinical presentations.,Although the genomes of several species of Leishmania have been sequenced to date, only one belongs to this rather different subgenus.,Here we explore the unique features of the Viannia subgenus by sequencing and analyzing the genome of L.,(Viannia) panamensis.,Against a background of conservation in gene content and synteny, we found key differences at the genomic level that may explain the occurrence of molecular processes involving nucleic acid manipulation and differential modification of surface glycoconjugates.,These differences may in part explain some phenotypic characteristics of the Viannia parasites, including their increased adaptive capacity and enhanced metastatic ability.
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Intermittent preventive treatment (IPT) is a well established malaria control intervention.,Evidence that delivering IPT to schoolchildren could provide community-level benefits is limited.,We did a cluster-randomised controlled trial to assess the effect of IPT of primary schoolchildren with dihydroartemisinin-piperaquine (DP) on indicators of malaria transmission in the community, in Jinja, Uganda.,We included 84 clusters, each comprising one primary school and the 100 closest available households.,The clusters were randomly assigned 1:1 to receive IPT with DP or standard care (control) by restricted randomisation to ensure balance by geography and school type.,Children in intervention schools received IPT monthly for up to six rounds (June to December, 2014).,We did cross-sectional community surveys in randomly selected households at baseline and in January to April, 2015, during which we measured participants' temperatures and obtained finger-prick blood smears for measurement of parasite prevalence by microscopy.,We also did entomological surveys 1 night per month in households from 20 randomly selected IPT and 20 control clusters.,The primary trial outcome was parasite prevalence in the final community survey.,The primary entomological survey outcome was the annual entomological inoculation rate (aEIR) from July, 2014, to April, 2015.,This trial is registered at ClinicalTrials.gov, number NCT02009215.,Among 23 280 students registered in the 42 intervention schools, 10 079 (43%) aged 5-20 years were enrolled and received at least one dose of DP. 9286 (92%) of 10 079 received at least one full course of DP (three doses).,Community-level parasite prevalence was lower in the intervention clusters than in the control clusters (19% vs 23%, adjusted risk ratio 0·85, 95% CI 0·73-1·00, p=0·05).,The aEIR was lower in the intervention group than in the control group, but not significantly so (10·1 vs 15·2 infective bites per person, adjusted incidence rate ratio 0·80, 95% CI 0·36-1·80, p=0·59).,IPT of schoolchildren with DP might have a positive effect on community-level malaria indicators and be operationally feasible.,Studies with greater IPT coverage are needed.,UK Medical Research Council, UK Department for International Development, and Wellcome Trust.
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Transmission intensity affects almost all aspects of malaria epidemiology and the impact of malaria on human populations.,Maps of transmission intensity are necessary to identify populations at different levels of risk and to evaluate objectively options for disease control.,To remain relevant operationally, such maps must be updated frequently.,Following the first global effort to map Plasmodium falciparum malaria endemicity in 2007, this paper describes the generation of a new world map for the year 2010.,This analysis is extended to provide the first global estimates of two other metrics of transmission intensity for P. falciparum that underpin contemporary questions in malaria control: the entomological inoculation rate (PfEIR) and the basic reproductive number (PfR).,Annual parasite incidence data for 13,449 administrative units in 43 endemic countries were sourced to define the spatial limits of P. falciparum transmission in 2010 and 22,212 P. falciparum parasite rate (PfPR) surveys were used in a model-based geostatistical (MBG) prediction to create a continuous contemporary surface of malaria endemicity within these limits.,A suite of transmission models were developed that link PfPR to PfEIR and PfR and these were fitted to field data.,These models were combined with the PfPR map to create new global predictions of PfEIR and PfR.,All output maps included measured uncertainty.,An estimated 1.13 and 1.44 billion people worldwide were at risk of unstable and stable P. falciparum malaria, respectively.,The majority of the endemic world was predicted with a median PfEIR of less than one and a median PfRc of less than two.,Values of either metric exceeding 10 were almost exclusive to Africa.,The uncertainty described in both PfEIR and PfR was substantial in regions of intense transmission.,The year 2010 has a particular significance as an evaluation milestone for malaria global health policy.,The maps presented here contribute to a rational basis for control and elimination decisions and can serve as a baseline assessment as the global health community looks ahead to the next series of milestones targeted at 2015.
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A proper identification of malaria vectors is essential for any attempt to control this disease.,Between 40 and 47 Anopheles species have been recorded in Colombia, and eight species complexes have been identified in the last decade.,An update of Anopheles species distribution and its relationship with malaria is required, particularly for newly identified members of species complexes.,A cross-sectional entomological study was conducted at 70 localities in the highest malaria transmission areas in Colombia.,In each locality, immature and adult mosquitoes were collected.,All specimens were determined using morphological characters and confirmed used restriction profiles of Internal Transcribed Spacer 2 (PCR-RFLP-ITS2), and Cytochrome c Oxidase I (COI) sequence gene.,To detect natural Plasmodium infections, enzyme-linked immunosorbent assay and nested PCR analysis were used.,Distribution of Anopheles species was spatially associated with malaria incidence.,A total of 1736 larvae and 12,052 adult mosquitoes were determined in the 70 localities.,Thirteen Anopheles species were identified.,COI sequence analysis suggested 4 new lineages for Colombia: for Anopheles albimanus (An. albimanus B), Anopheles pseudopunctipennis s.l., Anopheles neivai (An. neivai nr. neivai 4), and Anopheles apicimacula.,Two members of species complexes were identified, as: Anopheles nuneztovari C, and Anopheles albitarsis I.,Another seven species were confirmed.,Four mosquitoes were infected with Plasmodium species, An. albimanus B and An. nuneztovari C.,In Northwest of Colombia, An. nuneztovari C, An. albimanus, and Anopheles darlingi were present in the municipalities with highest annual parasitic index (API) (>35 cases/1000 inhabitants).,In the north of South Pacific coast, with a similar API, An. nuneztovari C were widely distributed inland, and the main species in coastal regions were An. albimanus B and An. neivai s.l.,In the South Pacific coast bordering with Ecuador, 3 Anopheles species were found in municipalities with high API (15-88 cases/1000 inhabitants): An. albimanus B, Anopheles calderoni and An. neivai s.l.,In the highest malaria areas of Colombia, 13 Anopheles species and four new lineages were found, which highlights the need for updating the species distribution.,A DNA barcode analysis allowed the taxonomic identification to be refined, particularly for species complexes, and to improve the further understanding of their relation with malaria transmission.,The online version of this article (doi:10.1186/s12936-016-1421-4) contains supplementary material, which is available to authorized users.
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Malaria mosquito research in Africa as elsewhere is just over a century old.,Early trials for development of mosquito control tools were driven by colonial enterprises and war efforts; they were, therefore, tested in military or colonial settings.,The failure of those tools and environmental concerns, coupled with the desperate need for integrated malaria control strategies, has necessitated the development of new malaria mosquito control tools, which are to be tested on humans, their environment and mosquito habitats.,Ethical concerns start with phase 2 trials, which pose limited ethical dilemmas.,Phase 3 trials, which are undertaken on vulnerable civilian populations, pose ethical dilemmas ranging from individual to community concerns.,It is argued that such trials must abide by established ethical principles especially safety, which is mainly enshrined in the principle of non-maleficence.,As there is total lack of experience with many of the promising candidate tools (eg genetically modified mosquitoes, entomopathogenic fungi, and biocontrol agents), great caution must be exercised before they are introduced in the field.,Since malaria vector trials, especially phase 3 are intrusive and in large populations, individual and community respect is mandatory, and must give great priority to community engagement.,It is concluded that new tools must be safe, beneficial, efficacious, effective, and acceptable to large populations in the short and long-term, and that research benefits should be equitably distributed to all who bear the brunt of the research burdens.,It is further concluded that individual and institutional capacity strengthening should be provided, in order to undertake essential research, carry out scientific and ethical review, and establish competent regulatory frameworks.
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Despite decreases in incidence and related mortality, malaria remains a major public health challenge in the Greater Mekong Sub-region (GMS).,The emergence of artemisinin resistance threatens these gains and has prompted efforts to accelerate elimination in the region.,In the GMS, transmission now clusters in hotspots along international borders and among high-risk populations, including forest-goers.,To eliminate malaria in the region, interventions must target such hard-to-reach populations.,This review provides a comprehensive overview of the qualitative research on behaviours and perceptions that influence uptake of and adherence to malaria interventions among forest-goers in the GMS.,A systematic search strategy was used to identify relevant sources, including database (OVID SP, PubMed, ISI Web of Knowledge) and bibliographic searches.,Relevant findings from qualitative research methods were extracted and thematic analysis undertaken.,Of 268 sources retrieved in searches twenty-two were reviewed.,Most reported studies were conducted in Cambodia (n = 10), and were published after 2014 (n = 16).,Four major themes emerged that are particularly relevant to the design of intervention packages targeted at forest-goers: (1) understanding of malaria and perceived risk; (2) preventive measures used when visiting the forest; (3) behaviours that put forest-goers at risk of infection; and, (4) malaria-related treatment seeking.,There were notable differences across the reviewed articles that suggest the need for a locally tailored approach.,A more detailed characterization of forest activities is needed but research on this topic raises methodological challenges.,Current vector control measures have limitations, with use of insecticidal-treated nets, hammocks and repellents influenced by the type of forest activities and the characteristics of these measures.,In contrast, anti-malarial drugs, for example, as chemoprophylaxis, hold promise but require further evaluation.,The online version of this article (10.1186/s12936-019-2666-5) contains supplementary material, which is available to authorized users.
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Mass drug administration (MDA), defined as the empiric administration of a therapeutic antimalarial regimen to an entire population at the same time, has been a historic component of many malaria control and elimination programmes, but is not currently recommended.,With renewed interest in MDA and its role in malaria elimination, this review aims to summarize the findings from existing research studies and program experiences of MDA strategies for reducing malaria burden and transmission.,To assess the impact of antimalarial MDA on population asexual parasitaemia prevalence, parasitaemia incidence, gametocytaemia prevalence, anaemia prevalence, mortality and MDA‐associated adverse events.,We searched the Cochrane Infectious Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE+, EMBASE, to February 2013.,We also searched CABS Abstracts, LILACS, reference lists, and recent conference proceedings.,Cluster‐randomized trials and non‐randomized controlled studies comparing therapeutic MDA versus placebo or no MDA, and uncontrolled before‐and‐after studies comparing post‐MDA to baseline data were selected.,Studies administering intermittent preventive treatment (IPT) to sub‐populations (for example, pregnant women, children or infants) were excluded.,Two authors independently reviewed studies for inclusion, extracted data and assessed risk of bias.,Studies were stratified by study design and then subgrouped by endemicity, by co‐administration of 8‐aminoquinoline plus schizonticide drugs and by plasmodium species.,The quality of evidence was assessed using the GRADE approach.,Two cluster‐randomized trials, eight non‐randomized controlled studies and 22 uncontrolled before‐and‐after studies are included in this review.,Twenty‐two studies (29 comparisons) compared MDA to placebo or no intervention of which two comparisons were conducted in areas of low endemicity (≤5%), 12 in areas of moderate endemicity (6‐39%) and 15 in areas of high endemicity (≥ 40%).,Ten studies evaluated MDA plus other vector control measures.,The studies used a wide variety of MDA regimens incorporating different drugs, dosages, timings and numbers of MDA rounds.,Many of the studies are now more than 30 years old.,Areas of low endemicity (≤5%),Within the first month post‐MDA, a single uncontrolled before‐and‐after study conducted in 1955 on a small Taiwanese island reported a much lower prevalence of parasitaemia following a single course of chloroquine compared to baseline (1 study, very low quality evidence).,This lower parasite prevalence was still present after more than 12 months (one study, very low quality evidence).,In addition, one cluster‐randomized trial evaluating MDA in a low endemic setting reported zero episodes of parasitaemia at baseline, and throughout five months of follow‐up in both the control and intervention arms (one study, very low quality evidence).,Areas of moderate endemicity (6‐39%),Within the first month post‐MDA, the prevalence of parasitaemia was much lower in three non‐randomized controlled studies from Kenya and India in the 1950s (RR 0.03, 95% CI 0.01 to 0.08, three studies, moderate quality evidence), and in three uncontrolled before‐and‐after studies conducted between 1954 and 1961 (RR 0.29, 95% CI 0.17 to 0.48, three studies,low quality evidence).,The longest follow‐up in these settings was four to six months.,At this time point, the prevalence of parasitaemia remained substantially lower than controls in the two non‐randomized controlled studies (RR 0.18, 95% CI 0.10 to 0.33, two studies, low quality evidence).,In contrast, the two uncontrolled before‐and‐after studies found mixed results: one found no difference and one found a substantially higher prevalence compared to baseline (not pooled, two studies, very low quality evidence).,Areas of high endemicity (≥40%),Within the first month post‐MDA, the single cluster‐randomized trial from the Gambia in 1999 found no significant difference in parasite prevalence (one study, low quality evidence).,However, prevalence was much lower during the MDA programmes in three non‐randomized controlled studies conducted in the 1960s and 1970s (RR 0.17, 95% CI 0.11 to 0.27, three studies, moderate quality evidence), and within one month of MDA in four uncontrolled before‐and‐after studies (RR 0.37, 95% CI 0.28 to 0.49, four studies,low quality evidence).,Four trials reported changes in prevalence beyond three months.,In the Gambia, the single cluster‐randomized trial found no difference at five months (one trial, moderate quality evidence).,The three uncontrolled before‐and‐after studies had mixed findings with large studies from Palestine and Cambodia showing sustained reductions at four months and 12 months, respectively, and a small study from Malaysia showing no difference after four to six months of follow‐up (three studies,low quality evidence).,8‐aminoquinolines,We found no studies directly comparing MDA regimens that included 8‐aminoquinolines with regimens that did not.,In a crude subgroup analysis with a limited number of studies, we were unable to detect any evidence of additional benefit of primaquine in moderate‐ and high‐transmission settings.,Plasmodium species,In studies that reported species‐specific outcomes, the same interventions resulted in a larger impact on Plasmodium falciparum compared to P. vivax.,MDA appears to reduce substantially the initial risk of malaria parasitaemia.,However, few studies showed sustained impact beyond six months post‐MDA, and those that did were conducted on small islands or in highland settings.,To assess whether there is an impact of MDA on malaria transmission in the longer term requires more quasi experimental studies with the intention of elimination, especially in low‐ and moderate‐transmission settings.,These studies need to address any long‐term outcomes, any potential barriers for community uptake, and contribution to the development of drug resistance.,22 March 2019,Update pending,Authors currently updating,The update is due to be published in 2019.,Administration of antimalarial drugs to whole populations,Malaria is the most important mosquito‐borne disease caused by a parasite, accounting for an estimated 660,000 deaths annually.,Fortunately, malaria is both preventable and treatable.,Several malaria control tools currently exist, and new and innovative approaches are continually under development.,The administration of drugs against malaria to whole populations, termed mass drug administration (MDA), was a component of many malaria elimination programmes in the 1950s, and is once again attracting interest as a malaria elimination tool.,As a consequence, it is important to review the currently available literature in order to assess the potential for this strategy to reduce malaria burden and transmission, and to identify gaps in our understanding.,This review assessed the impact of MDA on several malaria‐specific outcome measures.,Thirty‐two studies were included in this review, from sites in Asia, Africa, Europe and the Americas.,The review found that although MDA can reduce the initial risk of malaria‐specific outcomes, these reductions are often not sustained.,However, a few studies conducted on small islands or in highland areas did show sustained impact more than six months after MDA.,Adverse events were inadequately addressed in most studies.,Notable severe drug reactions, including haemolysis, haemoglobinuria, severe anaemia and death, were reported with 8‐aminoquinoline plus schizonticide drug co‐administration, while severe skin reactions were reported with sulphadoxine‐pyrimethamine plus artesunate plus primaquine.,Assessing the true impact of MDA programmes can be a challenge due to the heterogeneity of the study methods employed.,Nonetheless, this review can help guide future antimalarial MDA interventions and their evaluation.
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Leishmania infantum-specific antibodies are used extensively for the diagnosis and monitoring of treatment in canine leishmaniosis.,Different views have been described for the measurement of L. infantum antibody levels for the monitoring of anti-leishmanial treatment.,In addition, molecular techniques using blood are frequently employed in the clinical setting.,However, there are not enough studies to prove the usefulness of PCR in diagnosis, treatment monitoring and in assessing the prognosis of the disease.,The objectives of this study were to evaluate L. infantum-specific antibodies and blood parasitemia at the time of diagnosis and during treatment and to correlate these with the dog’s clinical status.,Thirty-seven dogs were diagnosed and followed-up during treatment (days 30, 180 and 365).,The treatment protocol consisted of a combination of meglumine antimoniate for one month and allopurinol for at least one year.,Leishmania infantum-specific antibodies and blood parasitemia were assessed by an end point sera dilution ELISA and by real-time PCR, respectively.,The majority of dogs were classified as LeishVet stage II (moderate disease) at the time of diagnosis (86 %) and the rest as stage III.,Results showed variable levels of specific antibodies at the time of diagnosis [median ± interquartile range (IQR): 1372 ± 8803 ELISA units (EU)].,Twenty-three seropositive dogs (64 %) were detected as PCR-positive at the time of diagnosis.,Interestingly, a rapid significant antibody level reduction was observed by day 30 of treatment (median ± IQR: 604 ± 2168 EU).,A continuing significant decrease of specific antibodies was also found at days 180 (median ± IQR: 201 ± 676 EU) and 365 (median ± IQR: 133 ± 329 EU) in association with clinical improvement.,A significant blood parasitemia reduction was also observed at all time points studied.,Mean parasites/ml ± SD were 19.4 ± 79.1 on day 0, 2.2 ± 11.7 on day 30, 0.9 ± 2.9 on day 180, and 0.3 ± 0.7 on day 365.,This study reports a significant reduction of L. infantum antibodies measured by an end point sera dilution ELISA method after 30 days of treatment associated with clinical improvement.,A low proportion of sick dogs with moderate disease were negative by blood real-time PCR at the time of diagnosis.
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Phlebotomine sand flies are vectors of Leishmania parasites.,During blood feeding, sand flies deposit into the host skin immunogenic salivary proteins which elicit specific antibody responses.,These anti-saliva antibodies enable an estimate of the host exposure to sand flies and, in leishmaniasis endemic areas, also the risk for Leishmania infections.,However, the use of whole salivary gland homogenates as antigen has several limitations, and therefore, recombinant salivary proteins have been tested to replace them in antibody detection assays.,In this study, we have used for the first time sand fly salivary recombinant proteins in a longitudinal field study on dogs.,Sera from dogs naturally exposed to P. perniciosus bites over two consecutive transmission seasons in a site endemic for canine leishmaniasis (CanL) were tested at different time points by ELISA for the antibodies recognizing whole saliva, single salivary 43 kDa yellow-related recombinant protein (rSP03B), and a combination of two salivary recombinant proteins, 43 kDa yellow-related protein and 35.5 kDa apyrase (rSP01).,Dogs were also tested for Leishmania infantum positivity by serology, culture, and PCR and the infection status was evaluated prospectively.,We found a significant association between active CanL infection and the amount of anti-P. perniciosus saliva antibodies.,Importantly, we detected a high correlation between IgG antibodies recognizing rSP03B protein and the whole salivary antigen.,The kinetics of antibody response showed for both a whole saliva and rSP03B a similar pattern that was clearly related to the seasonal abundance of P. perniciosus.,These results suggest that P. perniciosus rSP03B protein is a valid alternative to whole saliva and could be used in large-scale serological studies.,This novel method could be a practical and economically-sound tool to detect the host exposure to sand fly bites in CanL endemic areas.
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One of the fundamental steps toward malaria control is the use of antimalarial drugs.,The success of antimalarial treatment can be affected by the presence of drug-resistant populations of Plasmodium falciparum.,To assess resistance, we used molecular methods to examine 351 P. falciparum isolates collected from 4 sentinel sites in Mozambique for K13, pfmdr1, pfcrt, and pfdhps polymorphisms and for plasmepsin2 (pfpm2) and pfmdr1 copy numbers.,We found multiple copies of pfpm2 in 1.1% of isolates.,All isolates carried K13 wild-type alleles (3D7-like), except 4 novel polymorphisms (Leu619Leu, Phe656Ile, Val666Val, Gly690Gly).,Prevalence of isolates with pfcrt mutant (K76T) allele was low (2.3%).,Prevalence of isolates with pfdhps mutant alleles (A437G and K540E) was >80%, indicating persistence of sulfadoxine/pyrimethamine resistance; however, markers of artemisinin were absent, and markers of piperaquine resistance were low.,Piperaquine resistance isolates may spread in Mozambique as dihydroartemisinin/piperaquine drug pressure increases.
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Artemisinin resistant Plasmodium falciparum has emerged in the countries of the Greater Mekong sub-region posing a serious threat to global malaria elimination efforts.,The relationship of artemisinin resistance to treatment failure has been unclear.,In annual studies conducted in three malaria endemic provinces in the south of Vietnam (Binh Phuoc, Ninh Thuan and Gia Lai) between 2011 and 2015, 489 patients with uncomplicated P. falciparum malaria were enrolled in detailed clinical, parasitological and molecular therapeutic response assessments with 42 days follow up.,Patients received the national recommended first-line treatment dihydroartemisinin-piperaquine for three days.,Over the 5 years the proportion of patients with detectable parasitaemia on day 3 rose steadily from 38 to 57% (P < 0.001).,In Binh Phuoc province, the parasite clearance half-life increased from 3.75 h in 2011 to 6.60 h in 2015 (P < 0.001), while treatment failures rose from 0% in 2012 and 2013, to 7% in 2014 and 26% in 2015 (P < 0.001).,Recrudescence was associated with in vitro evidence of artemisinin and piperaquine resistance.,In the treatment failures cases of 2015, all 14 parasite isolates carried the C580Y Pfkelch 13 gene, marker of artemisinin resistance and 93% (13/14) of them carried exoE415G mutations, markers of piperaquine resistance.,In the south of Vietnam recent emergence of piperaquine resistant P. falciparum strains has accelerated the reduced response to artemisinin and has led to treatment failure rates of up to 26% to dihydroartemisinin-piperaquine, Vietnam’s current first-line ACT.,Alternative treatments are urgently needed.,The online version of this article (doi:10.1186/s12936-017-1680-8) contains supplementary material, which is available to authorized users.
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Intestinal parasites are a common problem in the world.,The greater proportion of infections is associated with poor water, sanitation, and hygiene (WASH).,This study was conducted to assess intestinal parasites, WASH condition, and their association in rural Dembiya, northwest Ethiopia.,A cross-sectional study was employed.,Two hundred twenty-five children aged 6-59 months were included.,Mothers were interviewed using a structured questionnaire, and the living environment was observed using checklists.,Kato-Katz technique was used to determine the intensity of parasitic infections.,Escherichia coli (E. coli) was used as a biological indicator for drinking water quality.,Multivariable binary logistic regression analysis was conducted to identify WASH predictors of parasites on the basis of adjusted odds ratio (AOR) with 95% confidence interval (CI) and p < 0.05.,The prevalence of intestinal parasites was 25.8% (95% CI = 20.3-32.0%).,Ascaris lumbricoides (78%), hookworm (12%), Hymenolepis nana (7%), Enterobius vermicularis (5%), Schistosoma mansoni (3%), Giardia lamblia (3%), and Trichuris trichiuria (2%) were identified infections.,Intestinal parasites were associated with poor child hand washing practice [AOR = 3.86, 95% CI = 1.53, 9.75], unprotected water sources [AOR = 7.79, 95% CI = 3.30, 18.40], access to water below 20 l/c/d [AOR = 3.05, 95% CI = 1.28, 7.23], poor food safety[AOR = 4.33, 95% CI = 1.62, 11.58], and poor sanitation [AOR = 5.01, 95% CI = 1.56, 16.16].,A. lumbricoides, hookworm, H. nana, E. vermicularis, S. mansoni, G. lamblia, and T. trichiuria were identified.,Child hand washing practice, service level of water supply, water sources, food safety, and sanitation were associated with intestinal parasites.,WASH promotion is needed to prevent infections.
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Intestinal parasitic infections are among the major public health problems in Sub-Saharan Africa.,Their distribution is mainly associated with poor personal hygiene, environmental sanitation and limited access to clean water.,Indeed, epidemiological information on the prevalence of various intestinal parasitic infections in different localities is a prerequisite to develop appropriate control measures.,Therefore, the aim of this study was to assess the prevalence of intestinal parasitic infections and associated risk factors among schoolchildren.,This school-based cross-sectional study was undertaken at the University of Gondar Community School from April 2012 to June 2012.,Study subjects were selected using a systematic random sampling method.,Data were gathered through direct interview by using a pretested questionnaire.,The collected stool specimens were examined microscopically for the presence of eggs, cysts and trophozoites of intestinal parasites using direct saline smear and formol-ether concentration methods.,Data entry and analysis were done using SPSS version 16 software.,Out of 304 study subjects, 104 (34.2%) were infected with one or more intestinal parasites.,The prevalence rate was 43 (32.1%) for male and 61 (35.9%) for female.,The prevalence of intestinal parasites was high in age group of 10-12 years compared to other age groups.,The predominant intestinal parasite was Hymenolepis nana, followed by Entamoeba histolytica/dispar and Ascaris lumbricoides with 42 (13.8%), 28 (9.2%), 18 (5.9%), respectively.,Hand washing practice and ways of transportation were statistically associated with intestinal parasitic infections.,Children in grades 1 to 3 had a higher prevalence of intestinal helminthic infection than those in grades 4 to 8 (p = 0.031).,Intestinal parasites were prevalent in varying magnitude among the schoolchildren.,The prevalence of infections were higher for helminths compared to protozoa.,Measures including education on personal hygiene, environmental sanitation, water supply and treatment should be taken into account to reduce the prevalence of intestinal parasites.
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Cerebral impairment and acute kidney injury (AKI) are independent predictors of mortality in both adults and children with severe falciparum malaria.,In this review, we present recent advances in understanding the pathophysiology, clinical features, and management of these complications of severe malaria, and discuss future areas of research.,Cerebral malaria and AKI are serious and well recognized complications of severe malaria.,Common pathophysiological pathways include impaired microcirculation, due to sequestration of parasitized erythrocytes, systemic inflammatory responses, and endothelial activation.,Recent MRI studies show significant brain swelling in both adults and children with evidence of posterior reversible encephalopathy syndrome-like syndrome although targeted interventions including mannitol and dexamethasone are not beneficial.,Recent work shows association of cell-free hemoglobin oxidation stress involved in the pathophysiology of AKI in both adults and children.,Paracetamol protected renal function likely by inhibiting cell-free-mediated oxidative stress.,It is unclear if heme-mediated endothelial activation or oxidative stress is involved in cerebral malaria.,The direct causes of cerebral and kidney dysfunction remain incompletely understood.,Optimal treatment involves prompt diagnosis and effective antimalarial treatment with artesunate.,Renal replacement therapy reduces mortality in AKI but delayed diagnosis is an issue.
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Differentiating cerebral malaria (CM) from other causes of serious illness in African children is problematic, owing to the non-specific nature of the clinical presentation and the high prevalence of incidental parasitaemia.,CM is associated with endothelial activation.,In this study we tested the hypothesis that endothelium-derived biomarkers are associated with the pathophysiology of severe malaria and may help identify children with CM.,Plasma samples were tested from children recruited with uncomplicated malaria (UM; n = 32), cerebral malaria with retinopathy (CM-R; n = 38), clinically defined CM without retinopathy (CM-N; n = 29), or non-malaria febrile illness with decreased consciousness (CNS; n = 24).,Admission levels of angiopoietin-2 (Ang-2), Ang-1, soluble Tie-2 (sTie-2), von Willebrand factor (VWF), its propeptide (VWFpp), vascular endothelial growth factor (VEGF), soluble ICAM-1 (sICAM-1) and interferon-inducible protein 10 (IP-10) were measured by ELISA.,Children with CM-R had significantly higher median levels of Ang-2, Ang-2:Ang-1, sTie-2, VWFpp and sICAM-1 compared to children with CM-N.,Children with CM-R had significantly lower median levels of Ang-1 and higher median concentrations of Ang-2:Ang-1, sTie-2, VWF, VWFpp, VEGF and sICAM-1 compared to UM, and significantly lower median levels of Ang-1 and higher median levels of Ang-2, Ang-2:Ang-1, VWF and VWFpp compared to children with fever and altered consciousness due to other causes.,Ang-1 was the best discriminator between UM and CM-R and between CNS and CM-R (areas under the ROC curve of 0.96 and 0.93, respectively).,A comparison of biomarker levels in CM-R between admission and recovery showed uniform increases in Ang-1 levels, suggesting this biomarker may have utility in monitoring clinical response.,These results suggest that endothelial proteins are informative biomarkers of malarial disease severity.,These results require validation in prospective studies to confirm that this group of biomarkers improves the diagnostic accuracy of CM from similar conditions causing fever and altered consciousness.
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As malaria transmission continues to decrease, an increasing number of countries will enter pre-elimination and elimination.,To interrupt transmission, changes in control strategies are likely to require more accurate identification of all carriers of Plasmodium parasites, both symptomatic and asymptomatic, using diagnostic tools that are highly sensitive, high throughput and with fast turnaround times preferably performed in local health service settings.,Currently available immunochromatographic lateral flow rapid diagnostic tests and field microscopy are unlikely to consistently detect infections at parasite densities less than 100 parasites/µL making them insufficiently sensitive for detecting all carriers.,Molecular diagnostic platforms, such as PCR and LAMP, are currently available in reference laboratories, but at a cost both financially and in turnaround time.,This review describes the recent progress in developing molecular diagnostic tools in terms of their capacity for high throughput and potential for performance in non-reference laboratories for malaria elimination.
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Malaria rapid diagnostic tests (RDTs) are now widely used for prompt on-site diagnosis in remote endemic areas where reliable microscopy is absent.,Aberrant results, whereby negative test results occur at high parasite densities, have been variously reported for over a decade and have led to questions regarding the reliability of the tests in clinical use.,In the first trial, serial dilutions of recombinant HRP2 antigen were tested on an HRP2-detectiing RDT.,In a second trial, serial dilutions of culture-derived Plasmodium falciparum parasites were tested against three HRP2-detecting RDTs.,A prozone-like effect occurred in RDTs at a high concentration of the target antigen, histidine-rich protein-2 (above 15,000 ng/ml), a level that corresponds to more than 312000 parasites per μL.,Similar results were noted on three RDT products using dilutions of cultured parasites up to a parasite density of 25%.,While reduced line intensity was observed, no false negative results occurred.,These results suggest that false-negative malaria RDT results will rarely occur due to a prozone-like effect in high-density infections, and other causes are more likely.,However, RDT line intensity is poorly indicative of parasite density in high-density infections and RDTs should, therefore, not be considered quantitative.,Immediate management of suspected severe malaria should rely on clinical assessment or microscopy.,Evaluation against high concentrations of antigen should be considered in malaria RDT product development and lot-release testing, to ensure that very weak or false negative results will not occur at antigen concentrations that might be seen clinically.
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