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Mosquitoes are arthropods of major importance to animal and human health because they are able to transmit pathogenic agents such as filarioids (Spirurida), vector-borne nematodes, which reside in the tissues of vertebrates.,In Europe, recent research has mostly focused on mosquito-borne zoonotic species, while others remain neglected.,Mosquitoes are also vectors of avian malaria, which has an almost worldwide distribution, and is caused by several Plasmodium species and lineages, the most common being P. relictum.,The Danube Delta region of Romania is one of the most important stopover sites for migratory birds.,The local mosquito fauna is diverse and well represented, while filarial infections are known to be endemic in domestic dogs in this area.,The aim of the present study was thus to assess the potential vector capacity for various filarial helminths and avian malaria of mosquitoes trapped in the Danube Delta.,In July 2015, mosquitoes were collected at seven sites located in and around a rural locality in the Danube Delta region of Romania, using CO2-baited traps and hand aspirators.,Additionally, a trap was placed next to a microfilaremic dog co-infected with Dirofilaria repens and D. immitis.,All randomly trapped mosquitoes were identified to the species level and pooled according to date, sampling site, and taxon.,Three hundred individual mosquitoes sampled next to the microfilaremic dog were processed individually and divided into abdomen and thorax/head.,Following DNA extraction, all samples were screened for the presence of DNA of filarioid helminths and avian malaria agents by PCR techniques.,All 284 pools (a total of 5855 mosquitoes) were negative for filarioid DNA.,One pool of Culex modestus mosquitoes was positive for Plasmodium sp. lineage Donana03.,In the individually extracted mosquitoes, one abdomen of Aedes vexans was positive for D. repens DNA, one thorax/head of Ae. vexans was positive for DNA of Setaria labiatopapillosa, and two thorax/head of Cx. pipiens f. pipiens were positive for P. relictum lineage pSGS1.,The present study suggests the vector competence of Cx. modestus and Cx. pipiens for avian Plasmodium including pathogenic species P. relictum and Ae. vexans for mammalian filarioids.,Moreover, it indicates the role of Cx. pipiens f. pipiens as a potential natural vector of P. relictum lineage pSGS1 in nature.

Dirofilaria immitis, or canine heartworm, is a filarial nematode parasite that infects dogs and other mammals worldwide.,Current disease control relies on regular administration of anthelmintic preventives, however, relatively poor compliance and evidence of developing drug resistance could warrant alternative measures against D. immitis and related human filarial infections be taken.,As with many other filarial nematodes, D. immitis contains Wolbachia, an obligate bacterial endosymbiont thought to be involved in providing certain critical metabolites to the nematode.,Correlations between nematode and Wolbachia transcriptomes during development have not been examined.,Therefore, we detailed the developmental transcriptome of both D. immitis and its Wolbachia (wDi) in order to gain a better understanding of parasite-endosymbiont interactions throughout the nematode life cycle.,Over 215 million single-end 50 bp reads were generated from total RNA from D. immitis adult males and females, microfilariae (mf) and third and fourth-stage larvae (L3 and L4).,We critically evaluated the transcriptomes of the various life cycle stages to reveal sex-biased transcriptional patterns, as well as transcriptional differences between larval stages that may be involved in larval maturation.,Hierarchical clustering revealed both D. immitis and wDi transcriptional activity in the L3 stage is clearly distinct from other life cycle stages.,Interestingly, a large proportion of both D. immitis and wDi genes display microfilarial-biased transcriptional patterns.,Concurrent transcriptome sequencing identified potential molecular interactions between parasite and endosymbiont that are more prominent during certain life cycle stages.,In support of metabolite provisioning between filarial nematodes and Wolbachia, the synthesis of the critical metabolite, heme, by wDi appears to be synchronized in a stage-specific manner (mf-specific) with the production of heme-binding proteins in D. immitis.,Our integrated transcriptomic study has highlighted interesting correlations between Wolbachia and D. immitis transcription throughout the life cycle and provided a resource that may be used for the development of novel intervention strategies, not only for the treatment and prevention of D. immitis infections, but of other closely related human parasites as well.,The online version of this article (doi:10.1186/1471-2164-15-1041) contains supplementary material, which is available to authorized users.

Malaria-endemic countries have to decide how much of their limited resources for vector control to allocate toward implementing long-lasting insecticidal nets (LLINs) versus indoor residual spraying (IRS).,To help the Mozambique Ministry of Health use an evidence-based approach to determine funding allocation toward various malaria control strategies, the Global Fund convened the Mozambique Modeling Working Group which then used JANUS, a software platform that includes integrated computational economic, operational, and clinical outcome models that can link with different transmission models (in this case, OpenMalaria) to determine the economic value of vector control strategies.,Any increase in LLINs (from 80% baseline coverage) or IRS (from 80% baseline coverage) would be cost-effective (incremental cost-effectiveness ratios ≤ $114/disability-adjusted life year averted).,However, LLIN coverage increases tend to be more cost-effective than similar IRS coverage increases, except where both pyrethroid resistance is high and LLIN usage is low.,In high-transmission northern regions, increasing LLIN coverage would be more cost-effective than increasing IRS coverage.,In medium-transmission central regions, changing from LLINs to IRS would be more costly and less effective.,In low-transmission southern regions, LLINs were more costly and less effective than IRS, due to low LLIN usage.,In regions where LLINs are more cost-effective than IRS, it is worth considering prioritizing LLIN coverage and use.,However, IRS may have an important role in insecticide resistance management and epidemic control.,Malaria intervention campaigns are not a one-size-fits-all solution, and tailored approaches are necessary to account for the heterogeneity of malaria epidemiology.

The most potent malaria vectors rely heavily upon human blood so they are vulnerable to attack with insecticide-treated nets (ITNs) and indoor residual spraying (IRS) within houses.,Mosquito taxa that can avoid feeding or resting indoors, or by obtaining blood from animals, mediate a growing proportion of the dwindling transmission that persists as ITNs and IRS are scaled up.,Increasing frequency of behavioural evasion traits within persisting residual vector systems usually reflect the successful suppression of the most potent and vulnerable vector taxa by IRS or ITNs, rather than their failure.,Many of the commonly observed changes in mosquito behavioural patterns following intervention scale-up may well be explained by modified taxonomic composition and expression of phenotypically plastic behavioural preferences, rather than altered innate preferences of individuals or populations.,Detailed review of the contemporary evidence base does not yet provide any clear-cut example of true behavioural resistance and is, therefore, consistent with the hypothesis presented.,Caution should be exercised before over-interpreting most existing reports of increased frequency of behavioural traits which enable mosquitoes to evade fatal contact with insecticides: this may simply be the result of suppressing the most behaviourally vulnerable of the vector taxa that constituted the original transmission system.,Mosquito taxa which have always exhibited such evasive traits may be more accurately described as behaviourally resilient, rather than resistant.,Ongoing national or regional entomological monitoring surveys of physiological susceptibility to insecticides should be supplemented with biologically and epidemiologically meaningfully estimates of malaria vector population dynamics and the behavioural phenotypes that determine intervention impact, in order to design, select, evaluate and optimize the implementation of vector control measures.

Malaria is a major public health problem, especially for children.,However, recent reports suggest a decline in the malaria burden.,The aim of this study was to assess the change in the prevalence of malaria infection among children below five years of age between 2004 and 2010 in a mesoendemic area of Uganda and to analyse the risk factors of malaria infection.,Two cross-sectional surveys were conducted in 2004 and in 2010 at the end of the rainy and dry seasons to measure the prevalence of P. falciparum infection among children less than five years of age.,Rapid diagnostic tests and blood smears were used to diagnose malaria infection.,In 2010, sampling was stratified by urban and rural areas.,In each selected household, knowledge of malaria and bed nets, and bed net ownership and use, were assessed.,In 2004 and 2010, respectively, a total of 527 and 2,320 (999 in the urban area and 1,321 in rural areas) children less than five years old were enrolled.,Prevalence of malaria infection declined from 43% (95% CI: 34-52) in 2004, to 23% (95% CI: 17-30) in rural areas in 2010 and 3% (95% CI: 2-5) in the urban area in 2010.,From the rainy to dry season in 2010, prevalence decreased from 23% to 10% (95% CI: 6-14) in rural areas (P = 0.001) and remained stable from 3% to 4% (95% CI: 1-7) in the urban area (P = 0.9).,The proportion of households reporting ownership and use of at least one bed net increased from 22.9% in 2004 to 64.7% in the urban area and 44.5% in rural areas in 2010 (P < 0.001).,In 2010, the risk of malaria infection was consistently associated with child age and household wealth.,In rural areas, malaria infection was also associated with geographic factors.,This study reports a significant drop in the prevalence of malaria infection among children below five years of age, paralleled by an uptake in bed-net use.,However, prevalence remains unacceptably high in rural areas and is strongly associated with poverty.

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.

The hypnozoite reservoir of Plasmodium vivax represents both the greatest obstacle and opportunity for ultimately eradicating this species.,It is silent and cannot be diagnosed until it awakens and provokes a clinical attack with attendant morbidity, risk of mortality, and opportunities for onward transmission.,The only licensed drug that kills hypnozoites is primaquine, which attacks the hypnozoite reservoir but imposes serious obstacles in doing so-at hypnozoitocidal doses, it invariably causes a threatening acute haemolytic anaemia in patients having an inborn deficiency in glucose-6-phosphate dehydrogenase (G6PD), affecting about 8% of people living in malaria endemic nations.,That problem excludes a large number of people from safe and effective treatment of the latent stage of vivax malaria: the G6PD deficient, pregnant or lactating women, and young infants.,These groups were estimated to comprise 14.3% of populations resident in the 95 countries with endemic vivax malaria.,Another important obstacle regarding primaquine in the business of killing hypnozoites is its apparent metabolism to an active metabolite exclusively via cytochrome P-450 isozyme 2D6 (CYP2D6).,Natural polymorphisms of this allele create genotypes expressing impaired enzymes that occur in over 20% of people living in Southeast Asia, where more than half of P. vivax infections occur globally.,Taken together, the estimated frequencies of these primaquine ineligibles due to G6PD toxicity or impaired CYP2D6 activity composed over 35% of the populations at risk of vivax malaria.,Much more detailed work is needed to refine these estimates, derive probabilities of error for them, and improve their ethnographic granularity in order to inform control and elimination strategy and tactics.

Malaria elimination will be possible only with serious attempts to address asymptomatic infection and chronic infection by both Plasmodium falciparum and Plasmodium vivax.,Currently available drugs that can completely clear a human of P. vivax (known as “radical cure”), and that can reduce transmission of malaria parasites, are those in the 8-aminoquinoline drug family, such as primaquine.,Unfortunately, people with glucose-6-phosphate dehydrogenase (G6PD) deficiency risk having severe adverse reactions if exposed to these drugs at certain doses.,G6PD deficiency is the most common human enzyme defect, affecting approximately 400 million people worldwide.,Scaling up radical cure regimens will require testing for G6PD deficiency, at two levels: 1) the individual level to ensure safe case management, and 2) the population level to understand the risk in the local population to guide Plasmodium vivax treatment policy.,Several technical and operational knowledge gaps must be addressed to expand access to G6PD deficiency testing and to ensure that a patient’s G6PD status is known before deciding to administer an 8-aminoquinoline-based drug.,In this report from a stakeholder meeting held in Thailand on October 4 and 5, 2012, G6PD testing in support of radical cure is discussed in detail.,The focus is on challenges to the development and evaluation of G6PD diagnostic tests, and on challenges related to the operational aspects of implementing G6PD testing in support of radical cure.,The report also describes recommendations for evaluation of diagnostic tests for G6PD deficiency in support of radical cure.

We tested the hypothesis that maternal worm infections in pregnancy affect infant motor and neurocognitive development, and that anthelminthic treatment during pregnancy can reverse these effects.,We used measures which examine infant motor, cognitive and executive function, including inhibition.,We assessed 983 Ugandan infants aged 15 months, using locally appropriate measures within the Entebbe Mother and Baby Study, a trial of anthelminthic treatment during pregnancy.,Key exposures were maternal worm infections and anthelminthic treatment during pregnancy.,Effects of other health and social factors were controlled for statistically.,Of the five major worm species found in the pregnant women, two had influences on the developmental measures: Maternal Mansonella perstans and Strongyloides stercoralis infections showed negative associations with the A-not B-task, and Language, respectively.,Performance on other psychomotor and cognitive measures was associated with illnesses during infancy and infants’ behavior during assessment, but not with maternal worm infections.,There were no positive effects of maternal anthelminthic treatment on infant abilities.,Mansonella perstans and Strongyloides stercoralis infection during pregnancy seem associated with impaired early executive function and language, respectively, but single-dose anthelminthic treatment during pregnancy was not beneficial.,The biological mechanisms that could underlie these neurocognitive effects are discussed.,(JINS, 2012, 18, 1019-1030)

Heligmosomoides polygyrus is a natural intestinal parasite of mice, which offers an excellent model of the immunology of gastrointestinal helminth infections of humans and livestock.,It is able to establish long-term chronic infections in many strains of mice, exerting potent immunomodulatory effects that dampen both protective immunity and bystander reactions to allergens and autoantigens.,Immunity to the parasite develops naturally in some mouse strains and can be induced in others through immunization; while the mechanisms of protective immunity are not yet fully defined, both antibodies and a host cellular component are required, with strongest evidence for a role of alternatively activated macrophages.,We discuss the balance between resistance and susceptibility in this model system and highlight new themes in innate and adaptive immunity, immunomodulation, and regulation of responsiveness in helminth infection.

Diverse enteropathogen exposures associate with childhood malnutrition.,To elucidate mechanistic pathways whereby enteric microbes interact during malnutrition, we used protein deficiency in mice to develop a new model of co-enteropathogen enteropathy.,Focusing on common enteropathogens in malnourished children, Giardia lamblia and enteroaggregative Escherichia coli (EAEC), we provide new insights into intersecting pathogen-specific mechanisms that enhance malnutrition.,We show for the first time that during protein malnutrition, the intestinal microbiota permits persistent Giardia colonization and simultaneously contributes to growth impairment.,Despite signals of intestinal injury, such as IL1α, Giardia-infected mice lack pro-inflammatory intestinal responses, similar to endemic pediatric Giardia infections.,Rather, Giardia perturbs microbial host co-metabolites of proteolysis during growth impairment, whereas host nicotinamide utilization adaptations that correspond with growth recovery increase.,EAEC promotes intestinal inflammation and markers of myeloid cell activation.,During co-infection, intestinal inflammatory signaling and cellular recruitment responses to EAEC are preserved together with a Giardia-mediated diminishment in myeloid cell activation.,Conversely, EAEC extinguishes markers of host energy expenditure regulatory responses to Giardia, as host metabolic adaptations appear exhausted.,Integrating immunologic and metabolic profiles during co-pathogen infection and malnutrition, we develop a working mechanistic model of how cumulative diet-induced and pathogen-triggered microbial perturbations result in an increasingly wasted host.

Nematode infections, in particular gastrointestinal nematodes, are widespread and co-infections with other parasites and pathogens are frequently encountered in humans and animals.,To decipher the immunological effects of a widespread protozoan infection on the anti-helminth immune response we studied a co-infection with the enteric nematode Heligmosomoides polygyrus in mice previously infected with Toxoplasma gondii.,Protective immune responses against nematodes are dependent on parasite-specific Th2 responses associated with IL-4, IL-5, IL-13, IgE, and IgG1 antibodies.,In contrast, Toxoplasma gondii infection elicits a strong and protective Th1 immune response characterized by IFN-γ, IL-12, and IgG2a antibodies.,Co-infected animals displayed significantly higher worm fecundity although worm burden remained unchanged.,In line with this, the Th2 response to H. polygyrus in co-infected animals showed a profound reduction of IL-4, IL-5, IL-13, and GATA-3 expressing T cells.,Co-infection also resulted in the lack of eosinophilia and reduced expression of the Th2 effector molecule RELM-β in intestinal tissue.,In contrast, the Th1 response to the protozoan parasite was not diminished and parasitemia of T. gondii was unaffected by concurrent helminth infection.,Importantly, H. polygyrus specific restimulation of splenocytes revealed H. polygyrus-reactive CD4+ T cells that produce a significant amount of IFN-γ in co-infected animals.,This was not observed in animals infected with the nematode alone.,Increased levels of H. polygyrus-specific IgG2a antibodies in co-infected mice mirrored this finding.,This study suggests that polarization rather than priming of naive CD4+ T cells is disturbed in mice previously infected with T. gondii.,In conclusion, a previous T. gondii infection limits a helminth-specific Th2 immune response while promoting a shift toward a Th1-type immune response.

Apicomplexan parasites, such as human malaria parasites, have complex lifecycles encompassing multiple and diverse environmental niches.,Invading, replicating, and escaping from different cell types, along with exploiting each intracellular niche, necessitate large and dynamic changes in parasite morphology and cellular architecture.,The inner membrane complex (IMC) is a unique structural element that is intricately involved with these distinct morphological changes.,The IMC is a double membrane organelle that forms de novo and is located beneath the plasma membrane of these single-celled organisms.,In Plasmodium spp. parasites it has three major purposes: it confers stability and shape to the cell, functions as an important scaffolding compartment during the formation of daughter cells, and plays a major role in motility and invasion.,Recent years have revealed greater insights into the architecture, protein composition and function of the IMC.,Here, we discuss the multiple roles of the IMC in each parasite lifecycle stage as well as insights into its sub-compartmentalization, biogenesis, disassembly and regulation during stage conversion of P. falciparum.

Cell cycle transitions are generally triggered by variation in the activity of cyclin-dependent kinases (CDKs) bound to cyclins.,Malaria-causing parasites have a life cycle with unique cell-division cycles, and a repertoire of divergent CDKs and cyclins of poorly understood function and interdependency.,We show that Plasmodium berghei CDK-related kinase 5 (CRK5), is a critical regulator of atypical mitosis in the gametogony and is required for mosquito transmission.,It phosphorylates canonical CDK motifs of components in the pre-replicative complex and is essential for DNA replication.,During a replicative cycle, CRK5 stably interacts with a single Plasmodium-specific cyclin (SOC2), although we obtained no evidence of SOC2 cycling by transcription, translation or degradation.,Our results provide evidence that during Plasmodium male gametogony, this divergent cyclin/CDK pair fills the functional space of other eukaryotic cell-cycle kinases controlling DNA replication.

Tafenoquine, a single-dose therapy for Plasmodium vivax malaria, has been associated with relapse prevention through the clearance of P. vivax parasitemia and hypnozoites, termed “radical cure.”,We performed a phase 3, prospective, double-blind, double-dummy, randomized, controlled trial to compare tafenoquine with primaquine in terms of safety and efficacy.,The trial was conducted at seven hospitals or clinics in Peru, Brazil, Colombia, Vietnam, and Thailand and involved patients with normal glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and female patients with moderate G6PD enzyme deficiency; all patients had confirmed P. vivax parasitemia.,The patients were randomly assigned, in a 2:1 ratio, to receive a single 300-mg dose of tafenoquine or 15 mg of primaquine once daily for 14 days (administered under supervision); all patients received a 3-day course of chloroquine and were followed for 180 days.,The primary safety outcome was a protocol-defined decrease in the hemoglobin level (>3.0 g per deciliter or ≥30% from baseline or to a level of <6.0 g per deciliter).,Freedom from recurrence of P. vivax parasitemia at 6 months was the primary efficacy outcome in a planned patient-level meta-analysis of the current trial and another phase 3 trial of tafenoquine and primaquine (per-protocol populations), and an odds ratio for recurrence of 1.45 (tafenoquine vs. primaquine) was used as a noninferiority margin.,A protocol-defined decrease in the hemoglobin level occurred in 4 of 166 patients (2.4%; 95% confidence interval [CI], 0.9 to 6.0) in the tafenoquine group and in 1 of 85 patients (1.2%; 95% CI, 0.2 to 6.4) in the primaquine group, for a between-group difference of 1.2 percentage points (95% CI, −4.2 to 5.0).,In the patient-level meta-analysis, the percentage of patients who were free from recurrence at 6 months was 67.0% (95% CI, 61.0 to 72.3) among the 426 patients in the tafenoquine group and 72.8% (95% CI, 65.6 to 78.8) among the 214 patients in the primaquine group.,The efficacy of tafenoquine was not shown to be noninferior to that of primaquine (odds ratio for recurrence, 1.81; 95% CI, 0.82 to 3.96).,Among patients with normal G6PD enzyme activity, the decline in hemoglobin level with tafenoquine did not differ significantly from that with primaquine.,Tafenoquine showed efficacy for the radical cure of P. vivax malaria, although tafenoquine was not shown to be noninferior to primaquine.,(Funded by GlaxoSmithKline and Medicines for Malaria Venture; GATHER ClinicalTrials.gov number, NCT02216123.)

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymatic disorder in humans and appears to be protective against falciparum severe malaria.,Controversially, it is also thought that Plasmodium vivax has driven the recent selection of G6PD alleles.,We use an experimental approach to determine whether G6PD-MahidolG487A variant, a widespread cause of severe G6PD deficiency in Southeast Asia, provides a barrier against vivax malaria.,Our results show that the immature reticulocytes (CD71+) targeted by P. vivax invasion are enzymatically normal, even in hemizygous G6PD-Mahidol G487A mutants; thus, allowing the normal growth, development, and high parasite density in severely deficient samples.

Malaria is a serious disease, caused by the parasite of the genus Plasmodium, which was responsible for 440,000 deaths in 2015.,Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is one of the main clinical complications in severe malaria.,The murine model DBA/2 reproduces the clinical signs of ALI/ARDS in humans, when infected with Plasmodium berghei ANKA.,High levels of HO-1 were reported in cases of severe malaria.,Our data indicated that the HO-1 mRNA and protein expression are increased in mice that develop malaria-associated ALI/ARDS (MA-ALI/ARDS).,Additionally, the hemin, a HO-1 inducing drug, prevented mice from developing MA-ALI/ARDS when administered prior to the development of MA-ALI/ARDS in this model.,Also, hemin treatment showed an amelioration of respiratory parameters in mice, high VEGF levels in the sera, and a decrease in vascular permeability in the lung, which are signs of ALI/ARDS.,Therefore, the induction of HO-1 before the development of MA-ALI/ARDS could be protective.,However, the increased expression of HO-1 on the onset of MA-ALI/ARDS development may represent an effort to revert the phenotype of this syndrome by the host.,We therefore confirm that HO-1 inducing drugs could be used for prevention of MA-ALI/ARDS in humans.

The mechanisms through which infection with Plasmodium spp. result in lung disease are largely unknown.,Recently a number of mouse models have been developed to research malaria-associated lung injury but no detailed ultrastructure studies of the disease in its terminal stages in a murine model have yet been published.,The goal was to perform an ultrastructural analysis of the lungs of mice that died with malaria-associated acute lung injury/acute respiratory distress syndrome to better determine the relevancy of the murine models and investigate the mechanism of disease.,DBA/2 mice were infected with Plasmodium berghei strain ANKA.,Mice had their lungs removed immediately after death, processed using standard methods and viewed by transmission electron microscopy (TEM).,Infected red blood cell:endothelium contact, swollen endothelium with distended cytoplasmic extensions and thickening of endothelium basement membrane were observed.,Septa were thick and filled with congested capillaries and leukocytes and the alveolar spaces contained blood cells, oedema and cell debris.,Results show that the lung ultrastructure of P. berghei ANKA-infected mice has similar features to what has been described in post-mortem TEM studies of lungs from individuals infected with Plasmodium falciparum.,These data support the use of murine models to study malaria-associated acute lung injury.

The mechanism of massive intravascular haemolysis occurring during the treatment of malaria infection resulting in haemoglobinuria, commonly known as blackwater fever (BWF), remains unknown.,BWF is most often seen in those with severe malaria treated with amino-alcohol drugs, including quinine, mefloquine and halofantrine.,The potential for drugs containing artemisinins, chloroquine or piperaquine to cause oxidant haemolysis is believed to be much lower, particularly during treatment of uncomplicated malaria.,Here is an unusual case of BWF, which developed on day 2 of treatment for uncomplicated Plasmodium falciparum infection with dihydroartemisinin-piperaquine (DHA-PIP) with documented evidence of concomitant seropositivity for Chikungunya infection.

The Four Artemisinin-Based Combinations (4ABC) Study Group reports a randomized, non-inferiority trial comparing the efficacy and safety of four ACTs in children with mild Plasmodium falciparum malaria from seven sub-Saharan African countries.,Artemisinin-based combination therapies (ACTs) are the mainstay for the management of uncomplicated malaria cases.,However, up-to-date data able to assist sub-Saharan African countries formulating appropriate antimalarial drug policies are scarce.,Between 9 July 2007 and 19 June 2009, a randomized, non-inferiority (10% difference threshold in efficacy at day 28) clinical trial was carried out at 12 sites in seven sub-Saharan African countries.,Each site compared three of four ACTs, namely amodiaquine-artesunate (ASAQ), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL), or chlorproguanil-dapsone-artesunate (CD+A).,Overall, 4,116 children 6-59 mo old with uncomplicated Plasmodium falciparum malaria were treated (1,226 with AL, 1,002 with ASAQ, 413 with CD+A, and 1,475 with DHAPQ), actively followed up until day 28, and then passively followed up for the next 6 mo.,At day 28, for the PCR-adjusted efficacy, non-inferiority was established for three pair-wise comparisons: DHAPQ (97.3%) versus AL (95.5%) (odds ratio [OR]: 0.59, 95% CI: 0.37-0.94); DHAPQ (97.6%) versus ASAQ (96.8%) (OR: 0.74, 95% CI: 0.41-1.34), and ASAQ (97.1%) versus AL (94.4%) (OR: 0.50, 95% CI: 0.28-0.92).,For the PCR-unadjusted efficacy, AL was significantly less efficacious than DHAPQ (72.7% versus 89.5%) (OR: 0.27, 95% CI: 0.21-0.34) and ASAQ (66.2% versus 80.4%) (OR: 0.40, 95% CI: 0.30-0.53), while DHAPQ (92.2%) had higher efficacy than ASAQ (80.8%) but non-inferiority could not be excluded (OR: 0.35, 95% CI: 0.26-0.48).,CD+A was significantly less efficacious than the other three treatments.,Day 63 results were similar to those observed at day 28.,This large head-to-head comparison of most currently available ACTs in sub-Saharan Africa showed that AL, ASAQ, and DHAPQ had excellent efficacy, up to day 63 post-treatment.,The risk of recurrent infections was significantly lower for DHAPQ, followed by ASAQ and then AL, supporting the recent recommendation of considering DHAPQ as a valid option for the treatment of uncomplicated P. falciparum malaria.,ClinicalTrials.gov NCT00393679; Pan African Clinical Trials Registry PACTR2009010000911750,Please see later in the article for the Editors' Summary,Malaria is a global public-health problem.,Half the world's population is at risk of this mosquito-borne parasitic disease, which kills a million people (mainly children living in sub-Saharan Africa) every year.,Although several parasites cause malaria, Plasmodium falciparum is responsible for most of these deaths.,During the second half of the 20th century, the main treatments for malaria were inexpensive “monotherapies” such as chloroquine and sulfadoxine-pyrimethamine.,Unfortunately, the malaria parasite quickly developed resistance to many of these monotherapies, and in the 1990 s, there was a widespread upsurge in P. falciparum malaria.,To combat this increase, the World Health Organization (WHO) now recommends artemisinin-based combination therapy (ACT) for first-line treatment of P. falciparum malaria in all regions where there is drug-resistant malaria.,In ACT, artemisinin derivatives (new, fast-acting antimalarial drugs) are used in combination with another antimalarial drug (a partner drug) to reduce the chances of P. falciparum becoming resistant to either drug.,WHO currently recommends five ACTs-amodiaquine-artesunate (ASAQ), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL), artesunate-mefloquine, and artesunate-sulfadoxine-pyrimethamine-for the treatment of malaria.,Its treatment guidelines state that the choice of ACT in a country or region should be based on the local level of resistance to the non-artemisinin-based partner drug in the combination.,However, data on resistance levels to these partner drugs are scarce or unavailable for many sub-Saharan African countries.,To help these countries make an informed choice about their national antimalarial treatment policies, in this randomized, non-inferiority trial, the researchers compare the efficacy and safety of four ACTs in African children with uncomplicated (mild) P. falciparum malaria.,In a randomized trial, groups of randomly chosen patients with a specific disease are given different treatments and then followed to compare the outcomes of these interventions.,A non-inferiority trial investigates whether one treatment is not worse than another treatment.,Each of twelve sites in seven sub-Saharan African countries compared three ACTs out of ASAQ, DHAPQ, AL, and chlorproguanil-dapsone-artesunate (CD+A).,Overall, 4,116 young children with uncomplicated malaria were treated with ACT, actively followed up for 28 days (their parents brought them back to the site for pre-arranged check-ups), and passively followed up for six months (parents brought their children back if they developed any illnesses).,At each visit, blood samples were examined for the presence of parasites, and a technique called PCR was used to determine which cases of malaria were new infections and which were recurrences of the original infection.,The researchers then calculated the percentage of patients with no infection or with a new infection (the PCR-adjusted adequate clinical and parasitological response [ACPR]) and the percentage of patients with no infection (the PCR-unadjusted ACPR).,For the PCR-adjusted efficacy, three pair-wise comparisons (DHAPQ versus AL, DHAPQ versus ASAQ, and ASAQ versus AL) showed non-inferiority at 28 days.,That is, for example, similar percentages of patients given DHAPQ or AL (97.3% and 95.5%, respectively) had either no infection or a new infection.,CD+A was less efficacious than the other three treatments.,For the PCR-unadjusted efficacy, AL was significantly less efficacious than DHAPQ and ASAQ; DHAPQ had a higher efficacy than ASAQ, but non-inferiority could not be excluded.,That is, the difference in efficacy of these two drugs might have happened by chance.,These findings suggest that AL, ASAQ, and DHAPQ are all efficacious for the treatment of uncomplicated malaria in children; CD+A was withdrawn partway through the trial because of side effects, but these findings also suggest that it was less efficacious than the other ACTs.,Importantly, the PCR-unadjusted results indicate that the risk of children becoming re-infected with malaria parasites soon after treatment was lowest for DHAPQ, followed by ASAQ, and then AL.,Because these findings are based on pooled results from seven sub-Saharan African countries, they are likely to be generalizable and thus of use in setting national antimalarial drug policies throughout the region.,AL and ASAQ are already included in the antimalarial drug policies of many sub-Saharan African countries, note the researchers, but these findings support the WHO recommendation that DHAPQ should also be considered for the treatment for uncomplicated P. falciparum malaria.,Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001119.,Information is available from WHO on malaria (in several languages); the 2010 World Malaria Report provides details of the current global malaria situation; the WHO Guidelines for the Treatment of Malaria and the report Assessment and Monitoring of Antimalarial Drug Efficacy for the Treatment of Uncomplicated Malaria are available,The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish), including a selection of personal stories about malaria,Information is available from the Roll Back Malaria Partnership on the global control of malaria including fact sheets about ACTs and about malaria in Africa,MedlinePlus provides links to additional information on malaria (in English and Spanish)

The Government of Ethiopia and its partners have deployed artemisinin-based combination therapies (ACT) since 2004 and long-lasting insecticidal nets (LLINs) since 2005.,Malaria interventions and trends in malaria cases and deaths were assessed at hospitals in malaria transmission areas during 2001-2011.,Regional LLINs distribution records were used to estimate the proportion of the population-at-risk protected by LLINs.,Hospital records were reviewed to estimate ACT availability.,Time-series analysis was applied to data from 41 hospitals in malaria risk areas to assess trends of malaria cases and deaths during pre-intervention (2001-2005) and post-interventions (2006-2011) periods.,The proportion of the population-at-risk potentially protected by LLINs increased to 51% in 2011.,The proportion of facilities with ACTs in stock exceeded 87% during 2006-2011.,Among all ages, confirmed malaria cases in 2011 declined by 66% (95% confidence interval [CI], 44-79%) and SPR by 37% (CI, 20%-51%) compared to the level predicted by pre-intervention trends.,In children under 5 years of age, malaria admissions and deaths fell by 81% (CI, 47%-94%) and 73% (CI, 48%-86%) respectively.,Optimal breakpoint of the trendlines occurred between January and June 2006, consistent with the timing of malaria interventions.,Over the same period, non-malaria cases and deaths either increased or remained unchanged, the number of malaria diagnostic tests performed reflected the decline in malaria cases, and rainfall remained at levels supportive of malaria transmission.,Malaria cases and deaths in Ethiopian hospitals decreased substantially during 2006-2011 in conjunction with scale-up of malaria interventions.,The decrease could not be accounted for by changes in hospital visits, malaria diagnostic testing or rainfall.,However, given the history of variable malaria transmission in Ethiopia, more data would be required to exclude the possibility that the decrease is due to other factors.

Health care utilization is affected by several factors including geographic accessibility.,Empirical data on utilization of health facilities is important to understanding geographic accessibility and defining health facility catchments at a national level.,Accurately defining catchment population improves the analysis of gaps in access, commodity needs and interpretation of disease incidence.,Here, empirical household survey data on treatment seeking for fever were used to model the utilisation of public health facilities and define their catchment areas and populations in northern Namibia.,This study uses data from the Malaria Indicator Survey (MIS) of 2009 on treatment seeking for fever among children under the age of five years to characterize facility utilisation.,Probability of attendance of public health facilities for fever treatment was modelled against a theoretical surface of travel times using a three parameter logistic model.,The fitted model was then applied to a population surface to predict the number of children likely to use a public health facility during an episode of fever in northern Namibia.,Overall, from the MIS survey, the prevalence of fever among children was 17.6% CI [16.0-19.1] (401 of 2,283 children) while public health facility attendance for fever was 51.1%, [95%CI: 46.2-56.0].,The coefficients of the logistic model of travel time against fever treatment at public health facilities were all significant (p < 0.001).,From this model, probability of facility attendance remained relatively high up to 180 minutes (3 hours) and thereafter decreased steadily.,Total public health facility catchment population of children under the age five was estimated to be 162,286 in northern Namibia with an estimated fever burden of 24,830 children.,Of the estimated fevers, 8,021 (32.3%) were within 30 minutes of travel time to the nearest health facility while 14,902 (60.0%) were within 1 hour.,This study demonstrates the potential of routine household surveys to empirically model health care utilisation for the treatment of childhood fever and define catchment populations enhancing the possibilities of accurate commodity needs assessment and calculation of disease incidence.,These methods could be extended to other African countries where detailed mapping of health facilities exists.

Good house construction may reduce the risk of malaria by limiting the entry of mosquito vectors.,We assessed how house design may affect mosquito house entry and malaria risk in Uganda.,100 households were enrolled in each of three sub-counties: Walukuba, Jinja district; Kihihi, Kanungu district; and Nagongera, Tororo district.,CDC light trap collections of mosquitoes were done monthly in all homes.,All children aged six months to ten years (n = 878) were followed prospectively for a total of 24 months to measure parasite prevalence every three months and malaria incidence.,Homes were classified as modern (cement, wood or metal walls; and tiled or metal roof; and closed eaves) or traditional (all other homes).,A total of 113,618 female Anopheles were collected over 6,765 nights. 6,816 routine blood smears were taken of which 1,061 (15.6%) were malaria parasite positive. 2,582 episodes of uncomplicated malaria were diagnosed after 1,569 person years of follow-up, giving an overall incidence of 1.6 episodes per person year at risk.,The human biting rate was lower in modern homes than in traditional homes (adjusted incidence rate ratio (IRR) 0.48, 95% confidence interval (CI) 0.37-0.64, p<0.001).,The odds of malaria infection were lower in modern homes across all the sub-counties (adjusted odds ratio 0.44, 95%CI 0.30-0.65, p<0.001), while malaria incidence was lower in modern homes in Kihihi (adjusted IRR 0.61, 95%CI 0.40-0.91, p = 0.02) but not in Walukuba or Nagongera.,House design is likely to explain some of the heterogeneity of malaria transmission in Uganda and represents a promising target for future interventions, even in highly endemic areas.

Philippa West and colleagues compare Plasmodium falciparum infection prevalence in children, anemia in young children, and entomological inoculation rate between study arms.,Please see later in the article for the Editors' Summary,Insecticide-treated nets (ITNs) and indoor residual spraying (IRS) of houses provide effective malaria transmission control.,There is conflicting evidence about whether it is more beneficial to provide both interventions in combination.,A cluster randomised controlled trial was conducted to investigate whether the combination provides added protection compared to ITNs alone.,In northwest Tanzania, 50 clusters (village areas) were randomly allocated to ITNs only or ITNs and IRS.,Dwellings in the ITN+IRS arm were sprayed with two rounds of bendiocarb in 2012.,Plasmodium falciparum prevalence rate (PfPR) in children 0.5-14 y old (primary outcome) and anaemia in children <5 y old (secondary outcome) were compared between study arms using three cross-sectional household surveys in 2012.,Entomological inoculation rate (secondary outcome) was compared between study arms.,IRS coverage was approximately 90%.,ITN use ranged from 36% to 50%.,In intention-to-treat analysis, mean PfPR was 13% in the ITN+IRS arm and 26% in the ITN only arm, odds ratio = 0.43 (95% CI 0.19-0.97, n = 13,146).,The strongest effect was observed in the peak transmission season, 6 mo after the first IRS.,Subgroup analysis showed that ITN users were additionally protected if their houses were sprayed.,Mean monthly entomological inoculation rate was non-significantly lower in the ITN+IRS arm than in the ITN only arm, rate ratio = 0.17 (95% CI 0.03-1.08).,This is the first randomised trial to our knowledge that reports significant added protection from combining IRS and ITNs compared to ITNs alone.,The effect is likely to be attributable to IRS providing added protection to ITN users as well as compensating for inadequate ITN use.,Policy makers should consider deploying IRS in combination with ITNs to control transmission if local ITN strategies on their own are insufficiently effective.,Given the uncertain generalisability of these findings, it would be prudent for malaria control programmes to evaluate the cost-effectiveness of deploying the combination.,www.ClinicalTrials.govNCT01697852,Please see later in the article for the Editors' Summary,Every year, more than 200 million cases of malaria occur worldwide, and more than 600,000 people, mainly children living in sub-Saharan Africa, die from this parasitic infection.,Malaria parasites, which are transmitted to people through the bites of infected night-flying mosquitoes, cause a characteristic fever that needs to be treated promptly with antimalarial drugs to prevent anaemia (a reduction in red blood cell numbers) and organ damage.,Prompt treatment also helps to reduce malaria transmission, but the mainstays of global malaria control efforts are the provision of insecticide-treated nets (ITNs) for people to sleep under to avoid mosquito bites, and indoor residual spraying (IRS) of houses with insecticides, which prevents mosquitoes from resting in houses.,Both approaches have been scaled up in the past decade.,About 54% of households in Africa now own at least one ITN, and 8% of at-risk populations are protected by IRS.,As a result of the widespread deployment of these preventative tools and the increased availability of effective antimalarial drugs, malaria-related deaths in Africa fell by 45% between 2000 and 2012.,Some countries have chosen to use ITNs and IRS in combination, reasoning that this will increase the proportion of individuals who are protected by at least one intervention and may provide additional protection to people using both interventions rather than one alone.,However, providing both interventions is costly, so it is important to know whether this rationale is correct.,In this cluster randomised controlled trial (a study that compares outcomes of groups of people randomly assigned to receive different interventions) undertaken in the Muleba District of Tanzania during 2012, the researchers investigate whether ITNs plus IRS provide more protection against malaria than ITNs alone.,Malaria transmission occurs throughout the year in Muleba District but peaks after the October-December and March-May rains.,Ninety-one percent of the district's households own at least one ITN, and 58% of households own enough ITNs to cover all their sleeping places.,Annual rounds of IRS have been conducted in the region since 2007.,The researchers allocated 50 communities to the ITN intervention or to the ITN+IRS intervention.,Dwellings allocated to ITN+IRS were sprayed with insecticide just before each of the malaria transmission peaks in 2012.,The researchers used household surveys to collect information about ITN coverage in the study population, the proportion of children aged 0.5-14 years infected with the malaria parasite Plasmodium falciparum (the prevalence of infection), and the proportion of children under five years old with anaemia.,IRS coverage in the ITN+IRS arm was approximately 90%, and 50% of the children in both intervention arms used ITNs at the start of the trial, declining to 36% at the end of the study.,In an intention-to-treat analysis (which assumed that all study participants got the planned intervention), the average prevalence of infection was 13% in the ITN+IRS arm and 26% in the ITN arm.,A per-protocol analysis (which considered data only from participants who received their allocated intervention) indicated that the combined intervention had a statistically significant protective effect on the prevalence of infection compared to ITNs alone (an effect that is unlikely to have arisen by chance).,Finally, the proportion of young children with anaemia was lower in the ITN+IRS arm than in the ITN arm, but this effect was not statistically significant.,These findings provide evidence that IRS, when used in combination with ITNs, can provide better protection against malaria infection than ITNs used alone.,This effect is likely to be the result of IRS providing added protection to ITN users as well as compensating for inadequate ITN use.,The findings also suggest that the combination of interventions may reduce the prevalence of anaemia better than ITNs alone, but this result needs to be confirmed.,Additional trials are also needed to investigate whether ITN+IRS compared to ITN reduces clinical cases of malaria, and whether similar effects are seen in other settings.,Moreover, the cost-effectiveness of ITN+IRS and ITN alone needs to be compared.,For now, though, these findings suggest that national malaria control programs should consider implementing IRS in combination with ITNs if local ITN strategies alone are insufficiently effective and cannot be improved.,Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001630.,Information is available from the World Health Organization on malaria (in several languages), including information on insecticide-treated bed nets and indoor residual spraying; the World Malaria Report 2013 provides details of the current global malaria situation,The US Centers for Disease Control and Prevention provides information on malaria, on insecticide-treated bed nets, and on indoor residual spraying; it also provides a selection of personal stories about malaria,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 nets and insecticides,MedlinePlus provides links to additional information on malaria (in English and Spanish)

Malaria elimination in Latin America is becoming an elusive goal.,Malaria cases reached a historical ~1 million in 2017 and 2018, with Venezuela contributing 53% and 51% of those cases, respectively.,Historically, malaria incidence in southern Venezuela has accounted for most of the country's total number of cases.,The efficient deployment of disease prevention measures and prediction of disease spread to new regions requires an in-depth understanding of spatial heterogeneity on malaria transmission dynamics.,Herein, we characterized the spatial epidemiology of malaria in southern Venezuela from 2007 through 2017 and described the extent to which malaria distribution has changed country-wide over the recent years.,We found that disease transmission was focal and more prevalent in the southeast region of southern Venezuela where two persistent hotspots of Plasmodium vivax (76%) and P. falciparum (18%) accounted for ~60% of the total number of cases.,Such hotspots are linked to deforestation as a consequence of illegal gold mining activities.,Incidence has increased nearly tenfold over the last decade, showing an explosive epidemic growth due to a significant lack of disease control programs.,Our findings highlight the importance of spatially oriented interventions to contain the ongoing malaria epidemic in Venezuela.,This work also provides baseline epidemiological data to assess cross-border malaria dynamics and advocates for innovative control efforts in the Latin American region.

The use of insecticide-treated bed nets (ITNs) is crucial to the prevention, control, and elimination of malaria.,Using household surveys conducted in 2014-2015 by the Health Communication Capacity Collaborative project in Madagascar, Mali, and Nigeria, we compared a model of psychosocial influence, called Ideation, to examine how malaria-related variables influence individual and household bed net use in each of these countries.,Evaluations of non-malaria programs have confirmed the value of the ideational approach, but it is infrequently used to guide malaria interventions.,The study objective was to examine how well this model could identify potentially effective malaria prevention approaches in different contexts.,Sampling and survey designs were similar across countries.,A multi-stage random sampling process selected female caregivers with at least one child under 5 years of age for interviews.,Additional data were collected from household heads about bed net use and other characteristics of household members.,The caregiver survey measured psychosocial variables that were subjected to bivariate and multivariate analysis to identify significant ideational variables related to bed net use.,In all three countries, children and adolescents over five were less likely to sleep under a net compared to children under five (OR = 0.441 in Madagascar, 0.332 in Mali, 0.502 in Nigeria).,Adults were less likely to sleep under a net compared to children under five in Mali (OR = 0.374) and Nigeria (OR = 0.448), but not Madagascar.,In all countries, the odds of bed net use were lower in larger compared to smaller households (OR = 0.452 in Madagascar and OR = 0.529 in Nigeria for households with 5 or 6 members compared to those with less than 5; and OR = 0.831 in Mali for larger compared to smaller households).,Of 14 common ideational variables examined in this study, six were significant predictors in Madagascar (all positive), three in Mali (all positive), and two in Nigeria (both negative).,This research suggests that the systematic use of this model to identify relevant ideational variables in a particular setting can guide the development of communication strategies and messaging, thereby improving the effectiveness of malaria prevention and control.

Malaria in sub-Saharan Africa has historically been almost exclusively attributed to Plasmodium falciparum (Pf).,Current diagnostic and surveillance systems in much of sub-Saharan Africa are not designed to identify or report non-Pf human malaria infections accurately, resulting in a dearth of routine epidemiological data about their significance.,The high prevalence of Duffy negativity provided a rationale for excluding the possibility of Plasmodium vivax (Pv) transmission.,However, review of varied evidence sources including traveller infections, community prevalence surveys, local clinical case reports, entomological and serological studies contradicts this viewpoint.,Here, these data reports are weighted in a unified framework to reflect the strength of evidence of indigenous Pv transmission in terms of diagnostic specificity, size of individual reports and corroboration between evidence sources.,Direct evidence was reported from 21 of the 47 malaria-endemic countries studied, while 42 countries were attributed with infections of visiting travellers.,Overall, moderate to conclusive evidence of transmission was available from 18 countries, distributed across all parts of the continent.,Approximately 86.6 million Duffy positive hosts were at risk of infection in Africa in 2015.,Analysis of the mechanisms sustaining Pv transmission across this continent of low frequency of susceptible hosts found that reports of Pv prevalence were consistent with transmission being potentially limited to Duffy positive populations.,Finally, reports of apparent Duffy-independent transmission are discussed.,While Pv is evidently not a major malaria parasite across most of sub-Saharan Africa, the evidence presented here highlights its widespread low-level endemicity.,An increased awareness of Pv as a potential malaria parasite, coupled with policy shifts towards species-specific diagnostics and reporting, will allow a robust assessment of the public health significance of Pv, as well as the other neglected non-Pf parasites, which are currently invisible to most public health authorities in Africa, but which can cause severe clinical illness and require specific control interventions.

Long-lasting insecticidal hammocks (LLIHs) are being evaluated as an additional malaria prevention tool in settings where standard control strategies have a limited impact.,This is the case among the Ra-glai ethnic minority communities of Ninh Thuan, one of the forested and mountainous provinces of Central Vietnam where malaria morbidity persist due to the sylvatic nature of the main malaria vector An. dirus and the dependence of the population on the forest for subsistence - as is the case for many impoverished ethnic minorities in Southeast Asia.,A social science study was carried out ancillary to a community-based cluster randomized trial on the effectiveness of LLIHs to control forest malaria.,The social science research strategy consisted of a mixed methods study triangulating qualitative data from focused ethnography and quantitative data collected during a malariometric cross-sectional survey on a random sample of 2,045 study participants.,To meet work requirements during the labor intensive malaria transmission and rainy season, Ra-glai slash and burn farmers combine living in government supported villages along the road with a second home at their fields located in the forest.,LLIH use was evaluated in both locations.,During daytime, LLIH use at village level was reported by 69.3% of all respondents, and in forest fields this was 73.2%.,In the evening, 54.1% used the LLIHs in the villages, while at the fields this was 20.7%.,At night, LLIH use was minimal, regardless of the location (village 4.4%; forest 6.4%).,Despite the free distribution of insecticide-treated nets (ITNs) and LLIHs, around half the local population remains largely unprotected when sleeping in their forest plot huts.,In order to tackle forest malaria more effectively, control policies should explicitly target forest fields where ethnic minority farmers are more vulnerable to malaria.

Systematic non-compliance to chemotherapeutic treatment among a portion of the eligible population is thought to be a major obstacle to the elimination of helminth infections by mass drug administration (MDA).,MDA for helminths is repeated at defined intervals such as yearly or every 2 years, as a consequence of the inability of the human host to develop fully protective immunity to reinfection.,As such, how an individual complies to these repeated rounds of MDA can have a significant impact on parasite transmission.,The importance of this factor is poorly understood at present.,Few epidemiological studies have examined longitudinal trends in compliance in the many communities in areas of endemic helminth infection that are undergoing MDA.,Reducing systematic non-compliance will obviously increase the number of individuals treated, but it may also alter the dynamics of parasite transmission.,Here we develop an individual-based stochastic model of helminth transmission and MDA treatment to investigate how different patterns of compliance influence the impact of MDA for two groups of helminths, the soil transmitted nematode infections and the schistosome parasites.,We study the effect of several alternative treatment and compliance patterns on the dynamics of transmission.,We find that the impact of different compliance patterns, ranging from random treatment at each round of chemotherapy to systematic non-compliance by a proportion of the population, is very dependent on both transmission intensity in a defined setting and the type of infection that the treatment is targeted at.,Systematic non-compliance has a greater impact on the potential for elimination of Schistosoma mansoni transmission by intensive MDA, than it does on Ascaris lumbricoides.,We discuss the implications of our findings for the prioritisation of resources in MDA programmes and for monitoring and evaluation programme design.,The key message generated by the analyses is that great care must be taken to record individual longitudinal patterns of compliance at each round of MDA as opposed to just recording overall coverage.,The online version of this article (doi:10.1186/s13071-017-2206-5) contains supplementary material, which is available to authorized users.

India has made great progress towards the elimination of lymphatic filariasis.,By 2015, most endemic districts had completed at least five annual rounds of mass drug administration (MDA).,The next challenge is to determine when MDA can be stopped.,We performed a simulation study with the individual-based model LYMFASIM to help clarify this.,We used a model-variant for Indian settings.,We considered different hypotheses on detectability of antigenaemia (Ag) in relation to underlying adult worm burden, choosing the most likely hypothesis by comparing the model predicted association between community-level microfilaraemia (Mf) and antigenaemia (Ag) prevalence levels to observed data (collated from literature).,Next, we estimated how long MDA must be continued in order to achieve elimination in different transmission settings and what Mf and Ag prevalence may still remain 1 year after the last required MDA round.,The robustness of key-outcomes was assessed in a sensitivity analysis.,Our model matched observed data qualitatively well when we assumed an Ag detection rate of 50 % for single worm infections, which increases with the number of adult worms (modelled by relating detection to the presence of female worms).,The required duration of annual MDA increased with higher baseline endemicity and lower coverage (varying between 2 and 12 rounds), while the remaining residual infection 1 year after the last required treatment declined with transmission intensity.,For low and high transmission settings, the median residual infection levels were 1.0 % and 0.4 % (Mf prevalence in the 5+ population), and 3.5 % and 2.0 % (Ag prevalence in 6-7 year-old children).,To achieve elimination in high transmission settings, MDA must be continued longer and infection levels must be reduced to lower levels than in low-endemic communities.,Although our simulations were for Indian settings, qualitatively similar patterns are also expected in other areas.,This should be taken into account in decision algorithms to define whether MDA can be interrupted.,Transmission assessment surveys should ideally be targeted to communities with the highest pre-control transmission levels, to minimize the risk of programme failure.,The online version of this article (doi:10.1186/s13071-016-1768-y) contains supplementary material, which is available to authorized users.

Reactive case detection (RCD) is a commonly used strategy for malaria surveillance and response in elimination settings.,Many approaches to RCD assume detectable infections are clustered within and around homes of passively detected cases (index households), which has been evaluated in a number of settings with disparate results.,Household questionnaires and diagnostic testing were conducted following RCD investigations in Zanzibar, Tanzania, including the index household and up to 9 additional neighboring households.,Of 12,487 participants tested by malaria rapid diagnostic test (RDT), 3·2% of those residing in index households and 0·4% of those residing in non-index households tested positive (OR = 8·4; 95%CI: 5·7, 12·5).,Of 6,281 participants tested by quantitative polymerase chain reaction (qPCR), 8·4% of those residing in index households and 1·3% of those residing in non-index households tested positive (OR = 7·1; 95%CI: 6·1, 10·9).,Within households of index cases defined as imported, odds of qPCR-positivity amongst members reporting recent travel were 1·4 times higher than among those without travel history (95%CI: 0·2, 4·4).,Amongst non-index households, odds of qPCR-detectable infection were no different between households located within 50 m of the index household as compared with those located farther away (OR = 0·8, 95%CI: 0·5, 1·4).,Sensitivity of RDT to detect qPCR-detectable infections was 34% (95%CI: 26·4, 42·3).,Malaria prevalence in index households in Zanzibar is much higher than in non-index households, in which prevalence is very low.,Travelers represent a high-risk population.,Low sensitivity of RDTs due to a high prevalence of low-density infections results in an RCD system missing a large proportion of the parasite reservoir.

Malaria continues to be a major public health problem in remote forested areas in Cambodia.,As a national strategy to strengthen community-based malaria control, the Cambodian government has been running the Village Malaria Worker (VMW) project since 2001.,This study sought to examine the nature and quality of the VMWs' services.,Data collection was carried out in February and March 2008 through interviews with one of the two VMWs who takes the lead in malaria control activities in each of the 315 VMW villages (n = 251).,The questionnaire addressed 1) the sociodemographic characteristics of VMWs, 2) service quality, 3) actions for malaria prevention and vector control, and 4) knowledge of malaria epidemiology and vector ecology.,VMWs were effective in conducting diagnosis with Rapid Diagnostic Tests (RDTs) and prescribing anti-malarials to those who had positive RDT results, skills that they had acquired through their training programmes.,However, most other services, such as active detection, explanations about compliance, and follow-up of patients, were carried out by only a small proportion of VMWs.,The variety of actions that VMWs took for malaria prevention and vector control was small (average action index score 12.8/23), and their knowledge was very limited with less than 20% of the VMWs giving correct answers to six out of seven questions on malaria epidemiology and vector ecology.,Knowledge of vector breeding places and malaria transmission were significant determinants of both the quality of VMWs' services and the variety of their actions for malaria prevention and vector control.,VMWs' services focused primarily on diagnosis and treatment.,Their focus needs to be broadened to cover other aspects of malaria control in order to further strengthen community-based malaria control.,VMWs' actions and knowledge also need substantial improvement.,Strengthening training programmes can help achieve better performance by VMWs.

The dramatic escalation of malaria control activities in Africa since the year 2000 has increased the importance of accurate measurements of impact on malaria epidemiology and burden.,This study presents a systematic review of the emerging published evidence base on trends in malaria risk in Africa and argues that more systematic, timely, and empirically-based approaches are urgently needed to track the rapidly evolving landscape of transmission.

Considerable declines in malaria have accompanied increased funding for control since the year 2000, but historical failures to maintain gains against the disease underscore the fragility of these successes.,Although malaria transmission can be suppressed by effective control measures, in the absence of active intervention malaria will return to an intrinsic equilibrium determined by factors related to ecology, efficiency of mosquito vectors, and socioeconomic characteristics.,Understanding where and why resurgence has occurred historically can help current and future malaria control programmes avoid the mistakes of the past.,A systematic review of the literature was conducted to identify historical malaria resurgence events.,All suggested causes of these events were categorized according to whether they were related to weakened malaria control programmes, increased potential for malaria transmission, or technical obstacles like resistance.,The review identified 75 resurgence events in 61 countries, occurring from the 1930s through the 2000s.,Almost all resurgence events (68/75 = 91%) were attributed at least in part to the weakening of malaria control programmes for a variety of reasons, of which resource constraints were the most common (39/68 = 57%).,Over half of the events (44/75 = 59%) were attributed in part to increases in the intrinsic potential for malaria transmission, while only 24/75 (32%) were attributed to vector or drug resistance.,Given that most malaria resurgences have been linked to weakening of control programmes, there is an urgent need to develop practical solutions to the financial and operational threats to effectively sustaining today’s successful malaria control programmes.

Progress toward reducing the malaria burden in Africa has been measured, or modeled, using datasets with relatively short time-windows.,These restricted temporal analyses may miss the wider context of longer-term cycles of malaria risk and hence may lead to incorrect inferences regarding the impact of intervention.,1147 age-corrected Plasmodium falciparum parasite prevalence (PfPR2-10) surveys among rural communities along the Kenyan coast were assembled from 1974 to 2014.,A Bayesian conditional autoregressive generalized linear mixed model was used to interpolate to 279 small areas for each of the 41 years since 1974.,Best-fit polynomial splined curves of changing PfPR2-10 were compared to a sequence of plausible explanatory variables related to rainfall, drug resistance and insecticide-treated bed net (ITN) use.,P. falciparum parasite prevalence initially rose from 1974 to 1987, dipped in 1991-92 but remained high until 1998.,From 1998 onwards prevalence began to decline until 2011, then began to rise through to 2014.,This major decline occurred before ITNs were widely distributed and variation in rainfall coincided with some, but not all, short-term transmission cycles.,Emerging resistance to chloroquine and introduction of sulfadoxine/pyrimethamine provided plausible explanations for the rise and fall of malaria transmission along the Kenyan coast.,Progress towards elimination might not be as predictable as we would like, where natural and extrinsic cycles of transmission confound evaluations of the effect of interventions.,Deciding where a country lies on an elimination pathway requires careful empiric observation of the long-term epidemiology of malaria transmission.

Whilst some populations have recently experienced dramatic declines in malaria, the majority of those most at risk of Plasmodium falciparum malaria still lack access to effective treatment with artemisinin combination therapy (ACT) and others are already facing parasites resistant to artemisinins.,In this context, there is a crucial need to improve both access to and targeting of ACT through greater availability of good quality ACT and parasitological diagnosis.,This is an issue of increasing urgency notably in the private commercial sector, which, in many countries, plays an important role in the provision of malaria treatment.,The Affordable Medicines Facility for malaria (AMFm) is a recent initiative that aims to increase the provision of affordable ACT in public, private and NGO sectors through a manufacturer-level subsidy.,However, to date, there is little documented experience in the programmatic implementation of subsidized ACT in the private sector.,Cambodia is in the unique position of having more than 10 years of experience not only in implementing subsidized ACT, but also rapid diagnostic tests (RDT) as part of a nationwide social marketing programme.,The programme includes behaviour change communication and the training of private providers as well as the sale and distribution of Malarine, the recommended ACT, and Malacheck, the RDT.,This paper describes and evaluates this experience by drawing on the results of household and provider surveys conducted since the start of the programme.,The available evidence suggests that providers' and consumers' awareness of Malarine increased rapidly, but that of Malacheck much less so.,In addition, improvements in ACT and RDT availability and uptake were relatively slow, particularly in more remote areas.,The lack of standardization in the survey methods and the gaps in the data highlight the importance of establishing a clear system for monitoring and evaluation for similar initiatives.,Despite these limitations, a number of important lessons can still be learnt.,These include the importance of a comprehensive communications strategy and of a sustained and reliable supply of products, with attention to the geographical reach of both.,Other important challenges relate to the difficulty in incentivising providers and consumers not only to choose the recommended drug, but to precede this with a confirmatory blood test and ensure that providers adhere to the test results and patients to the treatment regime.,In Cambodia, this is particularly complicated due to problems inherent to the drug itself and the emergence of artemisinin resistance.

The Plasmodium falciparum protein RH5 is an adhesin molecule essential for parasite invasion of erythrocytes.,Recent studies show that anti-PfRH5 sera have potent invasion-inhibiting activities, supporting the idea that the PfRH5 antigen could form the basis of a vaccine.,Therefore, epitopes recognized by neutralizing anti-PfRH5 antibodies could themselves be effective vaccine immunogens if presented in a sufficiently immunogenic fashion.,However, the exact regions within PfRH5 that are targets of this invasion-inhibitory activity have yet to be identified.,A battery of anti-RH5 monoclonal antibodies (mAbs) were produced and screened for their potency by inhibition of invasion assays in vitro.,Using an anti-RH5 mAb that completely inhibited invasion as the selecting mAb, affinity-selection using random sequence peptide libraries displayed on virus-like particles of bacteriophage MS2 (MS2 VLPs) was performed.,VLPs were sequenced to identify the specific peptide epitopes they encoded and used to raise specific antisera that was in turn tested for inhibition of invasion.,Three anti-RH5 monoclonals (0.1 mg/mL) were able to inhibit invasion in vitro by >95%.,Affinity-selection with one of these mAbs yielded a VLP which yielded a peptide whose sequence is identical to a portion of PfRH5 itself.,The VLP displaying the peptide binds strongly to the antibody, and in immunized animals elicits an anti-PfRH5 antibody response.,The resulting antisera against the specific VLP inhibit parasite invasion of erythrocytes more than 90% in vitro.,Here, data is presented from an anti-PfRH5 mAb that completely inhibits erythrocyte invasion by parasites in vitro, one of the few anti-malarial monoclonal antibodies reported to date that completely inhibits invasion with such potency, adding to other studies that highlight the potential of PfRH5 as a vaccine antigen.,The specific neutralization sensitive epitope within RH5 has been identified, and antibodies against this epitope also elicit high anti-invasion activity, suggesting this epitope could form the basis of an effective vaccine against malaria.

Plasmodium falciparum merozoite surface protein 5 (PfMSP5) is an attractive blood stage vaccine candidate because it is both exposed to the immune system and well conserved.,To evaluate its interest, we investigated the association of anti-PfMSP5 IgG levels, in the context of responses to two other conserved Ags PfMSP1p19 and R23, with protection from clinical episodes of malaria in cross-sectional prospective studies in two different transmission settings.,Ndiop (mesoendemic) and Dielmo (holoendemic) are two Senegalese villages participating in an on-going long-term observational study of natural immunity to malaria.,Blood samples were taken before the transmission season (Ndiop) or before peak transmission (Dielmo) and active clinical surveillance was carried out during the ensuing 5.5-month follow-up.,IgG responses to recombinant PfMSP5, PfMSP1p19 and R23 were quantified by ELISA in samples from surveys carried out in Dielmo (186 subjects) and Ndiop (221 subjects) in 2002, and Ndiop in 2000 (204 subjects).,In addition, 236 sera from the Dielmo and Ndiop-2002 surveys were analyzed for relationships between the magnitude of anti-PfMSP5 response and neutrophil antibody dependent respiratory burst (ADRB) activity.,Anti-PfMSP5 antibodies predominantly IgG1 were detected in 60-74% of villagers, with generally higher levels in older age groups.,PfMSP5 IgG responses were relatively stable for Ndiop subjects sampled both in 2000 and 2002.,ADRB activity correlated with age and anti-PfMSP5 IgG levels.,Importantly, PfMSP5 antibody levels were significantly associated with reduced incidence of clinical malaria in all three cohorts.,Inclusion of IgG to PfMSP1p19 in the poisson regression model did not substantially modify results.,These results indicate that MSP5 is recognized by naturally acquired Ab.,The large seroprevalence and association with protection against clinical malaria in two settings with differing transmission conditions and stability over time demonstrated in Ndiop argue for further evaluation of baculovirus PfMSP5 as a vaccine candidate.

In northern Papua New Guinea (PNG), most Plasmodium falciparum isolates proved resistant to chloroquine (CQ) in vitro between 2005 and 2007, and there was near-fixation of pfcrt K76T, pfdhfr C59R/S108N and pfmdr1 N86Y.,To determine whether the subsequent introduction of artemisinin combination therapy (ACT) and reduced CQ-sulphadoxine-pyrimethamine pressure had attenuated parasite drug susceptibility and resistance-associated mutations, these parameters were re-assessed between 2011 and 2013.,A validated fluorescence-based assay was used to assess growth inhibition of 52 P. falciparum isolates from children in a clinical trial in Madang Province.,Responses to CQ, lumefantrine, piperaquine, naphthoquine, pyronaridine, artesunate, dihydroartemisinin, artemether were assessed.,Molecular resistance markers were detected using a multiplex PCR ligase detection reaction fluorescent microsphere assay.,CQ resistance (in vitro concentration required for 50% parasite growth inhibition (IC50) >100 nM) was present in 19% of isolates.,All piperaquine and naphthoquine IC50s were <100 nM and those for lumefantrine, pyronaridine and the artemisinin derivatives were in low nM ranges.,Factor analysis of IC50s showed three groupings (lumefantrine; CQ, piperaquine, naphthoquine; pyronaridine, dihydroartemisinin, artemether, artesunate).,Most isolates (96%) were monoclonal pfcrt K76T (SVMNT) mutants and most (86%) contained pfmdr1 N86Y (YYSND).,No wild-type pfdhfr was found but most isolates contained wild-type (SAKAA) pfdhps.,Compared with 2005-2007, the geometric mean (95% CI) CQ IC50 was lower (87 (71-107) vs 167 (141-197) nM) and there had been no change in the prevalence of pfcrt K76T or pfmdr1 mutations.,There were fewer isolates of the pfdhps (SAKAA) wild-type (60 vs 100%) and pfdhfr mutations persisted.,Reflecting less drug pressure, in vitro CQ sensitivity appears to be improving in Madang Province despite continued near-fixation of pfcrt K76T and pfmdr1 mutations.,Temporal changes in IC50s for other anti-malarial drugs were inconsistent but susceptibility was preserved.,Retention or increases in pfdhfr and pfdhps mutations reflect continued use of sulphadoxine-pyrimethamine in the study area including through paediatric intermittent preventive treatment.,The susceptibility of local isolates to lumefantrine may be unrelated to those of other ACT partner drugs.,Australian New Zealand Clinical Trials Registry ACTRN12610000913077.

The loss of chloroquine due to selection and spread of drug resistant Plasmodium falciparum parasites has greatly impacted malaria control, especially in highly endemic areas of Africa.,Since chloroquine removal a decade ago, the guidelines to treat falciparum malaria suggest combination therapies, preferentially with an artemisinin derivative.,One of the recommended partner drugs is amodiaquine, a pro-drug that relies on its active metabolite monodesethylamodiaquine, and is still effective in areas of Africa, but not in regions of South America.,Genetic studies on P. falciparum parasites have shown that different pfcrt mutant haplotypes are linked to distinct levels of chloroquine and amodiaquine responses.,The pfcrt haplotype SVMNT (termed after the amino acids from codon positions 72-76) is stably present in several areas where amodiaquine was introduced and widely used.,Parasites with this haplotype are highly resistant to monodesethylamodiaquine and also resistant to chloroquine.,The presence of this haplotype in Africa was found for the first time in 2004 in Tanzania and a role for amodiaquine in the selection of this haplotype was suggested.,This commentary discusses the finding of a second site in Africa with high incidence of this haplotype.,The >50% SVMNT haplotype prevalence in Angola represents a threat to the rise and spread of amodiaquine resistance.,It is paramount to monitor pfcrt haplotypes in every country currently using amodiaquine and to re-evaluate current combination therapies in areas where SVMNT type parasites are prevalent.

Spillover of parasites at the domestic animal - wildlife interface is a pervasive threat to animal health.,Cat and dog fleas (Ctenocephalides felis and C. canis) are among the world’s most invasive and economically important ectoparasites.,Although both species are presumed to infest a diversity of host species across the globe, knowledge on their distributions in wildlife is poor.,We built a global dataset of wild mammal host associations for cat and dog fleas, and used Bayesian hierarchical models to identify traits that predict wildlife infestation probability.,We complemented this by calculating functional-phylogenetic host specificity to assess whether fleas are restricted to hosts with similar evolutionary histories, diet or habitat niches.,Over 130 wildlife species have been found to harbour cat fleas, representing nearly 20% of all mammal species sampled for fleas.,Phylogenetic models indicate cat fleas are capable of infesting a broad diversity of wild mammal species through ecological fitting.,Those that use anthropogenic habitats are at highest risk.,Dog fleas, by contrast, have been recorded in 31 mammal species that are primarily restricted to certain phylogenetic clades, including canids, felids and murids.,Both flea species are commonly reported infesting mammals that are feral (free-roaming cats and dogs) or introduced (red foxes, black rats and brown rats), suggesting the breakdown of barriers between wildlife and invasive reservoir species will increase spillover at the domestic animal - wildlife interface.,Our empirical evidence shows that cat fleas are incredibly host-generalist, likely exhibiting a host range that is among the broadest of all ectoparasites.,Reducing wild species’ contact rates with domestic animals across natural and anthropogenic habitats, together with mitigating impacts of invasive reservoir hosts, will be crucial for reducing invasive flea infestations in wild mammals.,The online version of this article (10.1186/s13071-017-2564-z) contains supplementary material, which is available to authorized users.

Filarioids are vector-borne parasitic nematodes of vertebrates.,In Europe, eight species of filarioids, including zoonotic species, have been reported mainly in domestic dogs, and occasionally in wild carnivores.,In Romania, infections with Dirofilaria spp. and Acanthocheilonema reconditum are endemic in domestic dogs.,Despite the abundant populations of wild carnivores in the country, their role in the epidemiology of filarioid parasites remains largely unknown.,The aim of the present study was to assess the host range, prevalence and distribution of filarioid infections in wild carnivores present in Romania.,Between May 2014 and February 2016, 432 spleen samples originating from 14 species of wild carnivores have been tested for the presence of DNA of three species of filarioids (D. immitis, D. repens and A. reconditum).,Overall 14 samples (3.24%) were molecularly positive.,The most prevalent species was D. immitis (1.62%), accounting for 50% (n = 7) of the positive animals.,The prevalence of D. repens was 1.39%, while that of A. reconditum was 0.23%.,No co-infections were detected.,Dirofilaria immitis DNA was detected in five golden jackals, Canis aureus (7.58%), one red fox, Vulpes vulpes (0.33%), and one wildcat, Felis silvestris (10%).,The presence of D. repens DNA was detected in two red foxes (0.66%), two golden jackals (3.03%), one grey wolf (7.14%), and one least weasel, Mustela nivalis (33.33%).,Acanthocheilonema reconditum DNA was found only in one red fox (0.33%).,The present study provides molecular evidence of filarial infections in wild carnivore species in Romania, suggesting their potential epidemiological role and reports a new host species for D. repens.

Recent concepts suggest that both Plasmodium falciparum factors and coagulation contribute to endothelial activation and dysfunction in pediatric cerebral malaria (CM) pathology.,However, there is still limited understanding of how these complex inflammatory stimuli are integrated by brain endothelial cells.,In this study, we examined how mature-stage P. falciparum infected erythrocytes (IE) interact with tumor necrosis factor α (TNFα) and thrombin in the activation and permeability of primary human brain microvascular endothelial cell (HBMEC) monolayers.,Whereas trophozoite-stage P. falciparum-IE have limited effect on the viability of HBMEC or the secretion of pro-inflammatory cytokines or chemokines, except at super physiological parasite-host cell ratios, schizont-stage P. falciparum-IE induced low levels of cell death.,Additionally, schizont-stage parasites were more barrier disruptive than trophozoite-stage P. falciparum-IE and prolonged thrombin-induced barrier disruption in both resting and TNFα-activated HBMEC monolayers.,These results provide evidence that parasite products and thrombin may interact to increase brain endothelial permeability.

Cerebral malaria is a deadly outcome of infection by Plasmodium falciparum, occurring when parasite-infected erythrocytes accumulate in the brain.,These erythrocytes display parasite proteins of the PfEMP1 family that bind various endothelial receptors.,Despite the importance of cerebral malaria, a binding phenotype linked to its symptoms has not been identified.,Here, we used structural biology to determine how a group of PfEMP1 proteins interacts with intercellular adhesion molecule 1 (ICAM-1), allowing us to predict binders from a specific sequence motif alone.,Analysis of multiple Plasmodium falciparum genomes showed that ICAM-1-binding PfEMP1s also interact with endothelial protein C receptor (EPCR), allowing infected erythrocytes to synergistically bind both receptors.,Expression of these PfEMP1s, predicted to bind both ICAM-1 and EPCR, is associated with increased risk of developing cerebral malaria.,This study therefore reveals an important PfEMP1-binding phenotype that could be targeted as part of a strategy to prevent cerebral malaria.,•Structural basis for P. falciparum PfEMP1 binding to endothelial receptor ICAM-1defined•A sequence motif derived from structure predicts group A PfEMP1 binding to ICAM-1•These ICAM-1-binding PfEMP1s also all bind to endothelial protein C receptor (EPCR)•Expression of dual ICAM-1- and EPCR-binding PfEMP1 is associated with cerebral malaria,Structural basis for P. falciparum PfEMP1 binding to endothelial receptor ICAM-1defined,A sequence motif derived from structure predicts group A PfEMP1 binding to ICAM-1,These ICAM-1-binding PfEMP1s also all bind to endothelial protein C receptor (EPCR),Expression of dual ICAM-1- and EPCR-binding PfEMP1 is associated with cerebral malaria,Plasmodium falciparum-infected erythrocytes display PfEMP1 proteins that bind various endothelial receptors, including ICAM-1.,Lennartz et al. structurally characterize PfEMP1 binding to ICAM-1, allowing them to identify a PfEMP1 family that simultaneously binds to both ICAM-1 and EPCR.,Dual-binding PfEMP1s display stronger endothelial adhesion and are associated with cerebral malaria.

The emergence and spread of multidrug-resistant Plasmodium falciparum in the Greater Mekong Subregion (GMS) threatens global malaria elimination efforts.,Mass drug administration (MDA), the presumptive antimalarial treatment of an entire population to clear the subclinical parasite reservoir, is a strategy to accelerate malaria elimination.,We report a cluster randomised trial to assess the effectiveness of dihydroartemisinin-piperaquine (DP) MDA in reducing falciparum malaria incidence and prevalence in 16 remote village populations in Myanmar, Vietnam, Cambodia, and the Lao People’s Democratic Republic, where artemisinin resistance is prevalent.,After establishing vector control and community-based case management and following intensive community engagement, we used restricted randomisation within village pairs to select 8 villages to receive early DP MDA and 8 villages as controls for 12 months, after which the control villages received deferred DP MDA.,The MDA comprised 3 monthly rounds of 3 daily doses of DP and, except in Cambodia, a single low dose of primaquine.,We conducted exhaustive cross-sectional surveys of the entire population of each village at quarterly intervals using ultrasensitive quantitative PCR to detect Plasmodium infections.,The study was conducted between May 2013 and July 2017.,The investigators randomised 16 villages that had a total of 8,445 residents at the start of the study.,Of these 8,445 residents, 4,135 (49%) residents living in 8 villages, plus an additional 288 newcomers to the villages, were randomised to receive early MDA; 3,790 out of the 4,423 (86%) participated in at least 1 MDA round, and 2,520 out of the 4,423 (57%) participated in all 3 rounds.,The primary outcome, P. falciparum prevalence by month 3 (M3), fell by 92% (from 5.1% [171/3,340] to 0.4% [12/2,828]) in early MDA villages and by 29% (from 7.2% [246/3,405] to 5.1% [155/3,057]) in control villages.,Over the following 9 months, the P. falciparum prevalence increased to 3.3% (96/2,881) in early MDA villages and to 6.1% (128/2,101) in control villages (adjusted incidence rate ratio 0.41 [95% CI 0.20 to 0.84]; p = 0.015).,Individual protection was proportional to the number of completed MDA rounds.,Of 221 participants with subclinical P. falciparum infections who participated in MDA and could be followed up, 207 (94%) cleared their infections, including 9 of 10 with artemisinin- and piperaquine-resistant infections.,The DP MDAs were well tolerated; 6 severe adverse events were detected during the follow-up period, but none was attributable to the intervention.,Added to community-based basic malaria control measures, 3 monthly rounds of DP MDA reduced the incidence and prevalence of falciparum malaria over a 1-year period in areas affected by artemisinin resistance.,P. falciparum infections returned during the follow-up period as the remaining infections spread and malaria was reintroduced from surrounding areas.,Limitations of this study include a relatively small sample of villages, heterogeneity between villages, and mobility of villagers that may have limited the impact of the intervention.,These results suggest that, if used as part of a comprehensive, well-organised, and well-resourced elimination programme, DP MDA can be a useful additional tool to accelerate malaria elimination.,ClinicalTrials.gov NCT01872702,In a cluster-randomized trial, Lorenz von Seidlin & colleagues investigate whether mass drug administration can accelerate malaria elimination in the Greater Mekong Subregion.

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.

Antibody responses to Plasmodium falciparum play a critical role in disease control.,Finding reliable IgG biomarkers of protection is complicated by a parasite proteome of over 5000 proteins, some with polymorphisms.,Studies of anti-malarial naturally acquired and vaccine immunity would benefit from a standard high-throughput immunoassay to measure multiple antibodies.,A multiplex quantitative suspension assay to measure antigen-specific IgGs was developed and its precision (reproducibility and repeatability), dynamic range, limits of detection and quantification, and non-specific binding to different P. falciparum proteins tested.,A set of 288 human plasma samples from a malaria-endemic region were analysed twice by two different operators.,Another set of samples from 9 malaria-naïve and 10 malaria-exposed individuals were repetitively assayed during 22 consecutive days.,Positive controls, negative controls, blanks and microspheres coated with bovine serum albumin were included in all assays.,The multiplex quantitative suspension assay demonstrated low non-specific signal and good estimates of precision and reproducibility between operators.,The overall mean of non-specific binding measured in 288 plasma samples was 32.83 to ± 44.81 median fluorescence intensity (MFI).,Repeatability was 7.66% ± 15.89 between triplicates for all antigens and samples, being lower in samples from malaria-exposed than malaria-naïve individuals.,No evidence of significantly different variance across days in MFI or arbitrary units (AU)/mL was found, assuming homogeneity of variance between days of analysis.,Intra-class correlation coefficient between 22 days of analysis was 0.98 (0.97-0.98) for MFI units and 0.9 (0.87-0.93) for AU/mL.,Reproducibility between operators for all samples and antigens had an overall adjusted correlation of 0.929 for MFI and 0.836 for AU/mL.,This high-throughput multiplex immunoassay is simple and highly reproducible.,This represents an asset for malaria vaccine studies involving CSP-specific antibodies and selected antigens for sero-epidemiological purposes.,Measuring a multiplex antigen panel in a single reaction will help to assess not only vaccine immunogenicity but also potential malaria vaccine effects on naturally acquired immune responses.,This will accelerate the identification of immune correlates of protection, down-selection of vaccine formulations, antigen discovery and guide second-generation vaccine design.,The online version of this article (10.1186/s12936-018-2365-7) contains supplementary material, which is available to authorized users.

Malaria is the major parasitic disease worldwide caused by Plasmodium infection.,The objective of integrated malaria control programs is to decrease malaria transmission, which needs specific tools to be accurately assessed.,In areas where the transmission is low or has been substantially reduced, new complementary tools have to be developed to improve surveillance.,A recent approach, based on the human antibody response to Anopheles salivary proteins, has been shown to be efficient in evaluating human exposure to Anopheles bites.,The aim of the present study was to identify new An. gambiae salivary proteins as potential candidate biomarkers of human exposure to P. falciparum-infective bites.,Experimental infections of An. gambiae by wild P. falciparum were carried out in semi-field conditions.,Then a proteomic approach, combining 2D-DIGE and mass spectrometry, was used to identify the overexpressed salivary proteins in infected salivary glands compared to uninfected An. gambiae controls.,Subsequently, a peptide design of each potential candidate was performed in silico and their antigenicity was tested by an epitope-mapping technique using blood from individuals exposed to Anopheles bites.,Five salivary proteins (gSG6, gSG1b, TRIO, SG5 and long form D7) were overexpressed in the infected salivary glands.,Eighteen peptides were designed from these proteins and were found antigenic in children exposed to the Anopheles bites.,Moreover, the results showed that the presence of wild P. falciparum in salivary glands modulates the expression of several salivary proteins and also appeared to induce post-translational modifications.,This study is, to our knowledge, the first that compares the sialome of An. gambiae both infected and not infected by wild P. falciparum, making it possible to mimic the natural conditions of infection.,This is a first step toward a better understanding of the close interactions between the parasite and the salivary gland of mosquitoes.,In addition, these results open the way to define biomarkers of infective bites of Anopheles, which could, in the future, improve the estimation of malaria transmission and the evaluation of malaria vector control tools.,The online version of this article (doi:10.1186/s13071-014-0599-y) contains supplementary material, which is available to authorized users.

Malaria infection during pregnancy is associated with adverse outcomes in sub-Saharan Africa (SSA).,For this reason, the World Health Organization currently recommends intermittent preventive treatment of malaria in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) at each scheduled antenatal care (ANC) visit.,In Tanzania, the revised IPTp policy was adopted in 2013 but the level of uptake and its association with pregnancy outcomes remains unknown.,A cross-sectional study was conducted among singleton pregnant women who delivered in two selected health facilities of Geita district, northwestern Tanzania.,Self-reported uptake of SP was verified using the ANC card and was recorded.,Placental and peripheral blood was collected for diagnosis of malaria by microscopy and rapid diagnostic tests (RDTs).,Gestational age was estimated based on last menstrual period or Ballard score.,Infant birth weights were recorded within 24 hours of delivery.,Of 431 participants, 167 (38.75%), 134 (31.09%), 104 (24.23%), and 26 (6.03%) reported taking none, one, two, and ≥ three doses of SP during pregnancy, respectively.,The uptake of ≥ three doses of IPTp-SP among delivering women at Geita hospital and Katoro health centre was 9.06% and 1.2%, respectively.,The overall prevalence of malaria in pregnancy by RDT, peripheral and placental smears was 19.5%, 29.7% and 37.6% respectively.,The prevalence of placental parasitaemia was higher for women who delivered at Katoro Health Centre (41.57%) than those who delivered at Geita hospital (35.09%).,The uptake of ≥ three doses of SP was associated with reduced odds of having placental malaria (adjusted odds ratio (AOR) = 0.31, p = 0.039) compared to < three doses.,Women with placental parasitaemia were five times more likely to have delivered pre-term (AOR = 4.67, p = 0.002) and had lower mean birth weight infants than their uninfected counterparts (mean difference = 82 g, p = 0.039).,The uptake of ≥ three doses of IPTp-SP is low in the present study area.,Placental parasitaemia is prevalent and is associated with adverse birth outcomes.,Receipt of ≥ three doses of IPTp-SP reduced the odds of placental parasitaemia.,Thus, increased efforts towards scale-up and continuous evaluation of IPTp-SP efficacy is recommended.

Jenny Hill and colleagues conduct a systematic review and meta-analysis of qualitative, quantitative, and mixed methods studies to explore the factors that affect the delivery, access, and use of interventions to prevent malaria in pregnant women in sub-Saharan Africa.,Please see later in the article for the Editors' Summary,Malaria in pregnancy has important consequences for mother and baby.,Coverage with the World Health Organization-recommended prevention strategy for pregnant women in sub-Saharan Africa of intermittent preventive treatment in pregnancy (IPTp) and insecticide-treated nets (ITNs) is low.,We conducted a systematic review to explore factors affecting delivery, access, and use of IPTp and ITNs among healthcare providers and women.,We searched the Malaria in Pregnancy Library and Global Health Database from 1 January 1990 to 23 April 2013, without language restriction.,Data extraction was performed by two investigators independently, and data was appraised for quality and content.,Data on barriers and facilitators, and the effect of interventions, were explored using content analysis and narrative synthesis.,We conducted a meta-analysis of determinants of IPTp and ITN uptake using random effects models, and performed subgroup analysis to evaluate consistency across interventions and study populations, countries, and enrolment sites.,We did not perform a meta-ethnography of qualitative data.,Ninety-eight articles were included, of which 20 were intervention studies.,Key barriers to the provision of IPTp and ITNs were unclear policy and guidance on IPTp; general healthcare system issues, such as stockouts and user fees; health facility issues stemming from poor organisation, leading to poor quality of care; poor healthcare provider performance, including confusion over the timing of each IPTp dose; and women's poor antenatal attendance, affecting IPTp uptake.,Key determinants of IPTp coverage were education, knowledge about malaria/IPTp, socio-economic status, parity, and number and timing of antenatal clinic visits.,Key determinants of ITN coverage were employment status, education, knowledge about malaria/ITNs, age, and marital status.,Predictors showed regional variations.,Delivery of ITNs through antenatal clinics presents fewer problems than delivery of IPTp.,Many obstacles to IPTp delivery are relatively simple barriers that could be resolved in the short term.,Other barriers are more entrenched within the overall healthcare system or socio-economic/cultural contexts, and will require medium- to long-term strategies.,Please see later in the article for the Editors' Summary,Half the world's population is at risk of malaria, a mosquito-borne parasite that kills a million people every year.,Most of these deaths occur among young children in sub-Saharan Africa, but pregnant women and their unborn babies are also vulnerable to malaria.,Infection with malaria during pregnancy can cause maternal death, severe maternal anemia, miscarriages, and pre-term and low-birth-weight babies.,Malaria in pregnancy is responsible for about 100,000 babies and 10,000 women dying every year but is preventable by simple, inexpensive interventions that have been available for many years.,The World Health Organization recommends a three-pronged approach to the prevention of malaria in pregnancy in areas with stable malaria transmission in Africa-delivery of the antimalarial drug sulfadoxine-pyrimethamine to pregnant women during antenatal clinic visits (intermittent preventative treatment in pregnancy; IPTp), the use of insecticide-treated bed nets (ITNs) to protect pregnant women from the bites of infected mosquitoes, and effective diagnosis and case management of pregnant women with malarial illness.,Coverage with this prevention strategy is currently very low.,Recent survey data from sub-Saharan African countries suggest that only about a quarter of pregnant women receive two doses of IPTp and only about a third use ITNs.,To improve coverage, public health experts need to understand why coverage is so low, and they need to know the factors (determinants) that are associated with the uptake of IPTp and ITNs.,In this systematic review and meta-analysis of qualitative, quantitative, and mixed methods studies, the researchers explore the factors that affect delivery, access, and use of IPTp and ITNs among pregnant women in sub-Saharan Africa.,A systematic review uses predefined criteria to identify all the research on a given topic.,Meta-analysis is a statistical method for combining the results of several studies.,Qualitative studies collect non-quantitative data such as reasons for not accepting an intervention, whereas quantitative studies collect numerical data such as the proportion of a population accepting an intervention.,The researchers' search of the Malaria in Pregnancy Library (a resource maintained by the Malaria in Pregnancy Consortium) and the Global Health Database identified 98 studies that provided data on barriers to and determinants of IPTp and ITN uptake and/or data on interventions designed to increase IPTp and ITN uptake.,The researchers explored these data using content analysis (a research methodology that examines words and phrases within texts) and narrative synthesis (a method for summarizing results drawn from several qualitative studies).,Key barriers to the provision and uptake of IPTp and ITNs included unclear policy and guidance on IPTp, general healthcare system issues such as drug shortages, healthcare facility issues such as unavailability of water for the provision of IPTp by directly observed therapy, poor healthcare provider performance such as confusion about the timing of IPTp doses, and the delayed antenatal care-seeking practices of pregnant women.,The researchers' meta-analysis identified education, knowledge about malaria, socio-economic status, number and timing of antenatal clinic visits, and number of pregnancies as key determinants of IPTp uptake, and employment status, education, knowledge, age, and marital status as key determinants of coverage of ITN use.,So, for example, highly educated women were more likely to receive IPTp or ITNs than poorly educated women.,These findings identify key interacting barriers to access, delivery, and use of IPTp and ITNs in sub-Saharan Africa and show that these barriers are relatively consistent across countries.,Moreover, they suggest that there are fewer barriers to the delivery of ITNs through antenatal clinics than to the delivery of IPTp.,Importantly, some of the barriers to IPTp uptake can be resolved in the short term (for example, simplification of country policies and guidance on IPTp might increase its uptake), but barriers to uptake that are entrenched within the overall healthcare system will only be resolved with medium- to long-term strategies that aim to improve the quality of antenatal services and to encourage antenatal clinic use among women.,Overall, this analysis provides a checklist of factors that policy-makers involved in national malaria programs may be able to use to help them decide which interventions to prioritize.,However, the researchers warn, multi-country studies are nevertheless urgently needed to evaluate targeted or multifaceted interventions designed to increase delivery and uptake of IPTp and ITNs, to reduce the adverse consequences of malaria in pregnancy.,Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001488.,Information is available from the World Health Organization on malaria (in several languages) and on IPTp; the World Malaria Report 2012 provides details of the current global malaria situation,The US Centers for Disease Control and Prevention also provides information on malaria and on IPTp; a personal story about malaria in pregnancy is available,Information is available from the Roll Back Malaria Partnership on all aspects of global malaria control, including information on malaria in pregnancy,The Malaria in Pregnancy Consortium is undertaking research into the prevention and treatment of malaria in pregnancy,MedlinePlus provides links to additional information on malaria (in English and Spanish)

Cerebral malaria (CM) is a disease of the vascular endothelium caused by Plasmodium falciparum.,It is characterized by parasite sequestration, inflammatory cytokine production, and vascular leakage.,A distinguishing feature of P. falciparum infection is parasite production and secretion of histidine-rich protein II (HRPII).,Plasma HRPII is a diagnostic and prognostic marker for falciparum malaria.,We demonstrate that disruption of a human cerebral microvascular endothelial barrier by P. falciparum-infected erythrocytes depends on expression of HRPII.,Purified recombinant or native HRPII can recapitulate these effects.,HRPII action occurs via activation of the inflammasome, resulting in decreased integrity of tight junctions and increased endothelial permeability.,We propose that HRPII is a virulence factor that may contribute to cerebral malaria by compromising endothelial barrier integrity within the central nervous system.,Cerebral malaria is a devastating disease.,Patients have high levels of the protein HRPII in their blood.,We have found that endothelial cell barriers become leaky when treated with concentrations of HRPII similar to those found in patients.,This result suggests that HRPII may be important in cerebral malaria.,Our finding that HRPII functions by causing inflammation suggests points of intervention for therapy or vaccination against this disease.

Sequestration of Plasmodium falciparum-infected erythrocytes in host blood vessels is a key triggering event in the pathogenesis of severe childhood malaria, which is responsible for about one million deaths every year1.,Sequestration is mediated by specific interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family and receptors on the endothelial lining2.,Severe malaria is associated with expression of specific PfEMP1 subtypes containing domain cassettes (DC) 8 and 133, but the endothelial receptor for parasites expressing these proteins was unknown4,5.,Here, we identify endothelial protein C receptor (EPCR), which mediates cytoprotective effects of activated protein C6, as the endothelial receptor for DC8 and DC13 PfEMP1.,We show that EPCR binding is mediated through the N-terminal cysteine-rich interdomain region (CIDRα1) of DC8 and group A PfEMP1 subfamilies and that CIDRα1 interferes with protein C binding to EPCR.,This PfEMP1 adhesive property links P. falciparum cytoadhesion to a host receptor involved in anticoagulation and endothelial cytoprotective pathways and has implications for understanding malaria pathology and the development of new malaria interventions.

Due to the rapid extension of pyrethroid resistance in malaria vectors worldwide, manufacturers are developing new vector control tools including insecticide mixtures containing at least two active ingredients with different mode of action as part of insecticide resistance management.,Olyset® Plus is a new long-lasting insecticidal net (LLIN) incorporating permethrin and a synergist, piperonyl butoxide (PBO), into its fibres in order to counteract metabolic-based pyrethroid resistance of mosquitoes.,In this study, we evaluated the efficacy of Olyset® Plus both in laboratory and field against susceptible and multi-resistant malaria vectors and compared with Olyset Net, which is a permethrin incorporated into polyethylene net.,In laboratory, Olyset® Plus performed better than Olyset® Net against susceptible Anopheles gambiae strain with a 2-day regeneration time owing to an improved permethrin bleeding rate with the new incorporation technology.,It also performed better than Olyset® Net against multiple resistant populations of An. gambiae in experimental hut trials in West Africa.,Moreover, the present study showed evidence for a benefit of incorporating a synergist, PBO, with a pyrethroid insecticide into mosquito netting.,These results need to be further validated in a large-scale field trial to assess the durability and acceptability of this new tool for malaria vector control.

Malaria pathogens are transmitted to humans by the bite of female Anopheles mosquitoes.,The juvenile stages of these mosquitoes develop in a variety of water bodies and are key targets for vector control campaigns involving the application of larvicides.,The effective operational implementation of these campaigns is difficult, time consuming, and expensive.,New evidence however, suggests that adult mosquitoes can be co-opted into disseminating larvicides in a far more targeted and efficient manner than can be achieved using conventional methods.

Scale-up of the distribution of long-lasting insecticide-treated bed nets and indoor residual spraying with insecticides over the last decade have contributed to the considerable decrease of malaria morbidity and mortality in sub-Saharan Africa.,Due to the increasing pyrethroid resistance intensity and the spread of carbamate resistance in Anopheles gambiae (s.s.) mosquitoes and the limited number of insecticides recommended by the WHO for vector control, alternative insecticide formulations for IRS with long-lasting residual activity are required to sustain the gains obtained in most malaria-endemic countries.,SumiShield 50WG (clothianidin 300 mg ai/m2) developed by Sumitomo Chemical was evaluated alongside deltamethrin 25 mg ai/m2 (K-Othrine 250 WG) against a pyrethroid resistant Anopheles gambiae (s.l.) population in experimental huts in Covè, Benin.,Residual activity was also tested in cone bioassays with the susceptible An. gambiae “Kisumu” strain and the local wild resistant population.,The results showed very low toxicity from deltamethrin (mortality rates ranged between 1-40%) against host-seeking resistant Anopheles populations.,SumiShield in contrast gave an overall mean mortality of 91.7% at the 120 h observation across the eight- month observation period following spraying.,The residual activity measured using cone tests was over the 80% WHO threshold for 24 weeks for resistant wild Anopheles population and 32 weeks for the susceptible strain “Kisumu” after the spraying.,SumiShield is a good candidate for IRS in areas of permanent malaria transmission and where Anopheles populations are resistant to other conventional insecticides such as pyrethroids.,It would be interesting to complete experimental huts studies by assessing the efficacy and residual effect of SumiShield 50WG at community level (small-scale field testing) in an area where vectors are highly resistant to insecticides.

The rapid selection of pyrethroid resistance throughout sub-Saharan Africa is a serious threat to malaria vector control.,Chlorfenapyr is a pyrrole insecticide which shows no cross resistance to insecticide classes normally used for vector control and is effective on mosquito nets under experimental hut conditions.,Unlike neurotoxic insecticides, chlorfenapyr owes its toxicity to disruption of metabolic pathways in mitochondria that enable cellular respiration.,A series of experiments explored whether standard World Health Organization (WHO) guidelines for evaluation of long-lasting insecticidal nets, developed through testing of pyrethroid insecticides, are suitable for evaluation of non-neurotoxic insecticides.,The efficacy of WHO recommended cone, cylinder and tunnel tests was compared for pyrethroids and chlorfenapyr.,To establish bioassay exposure times predictive of insecticide-treated net (ITN) efficacy in experimental hut trials, standard three-minute bioassays of pyrethroid and chlorfenapyr ITNs were compared with longer exposures.,Mosquito behaviour and response to chlorfenapyr ITN in bioassays conducted at night were compared to day and across a range of temperatures representative of highland and lowland transmission.,Standard three-minute bioassay of chlorfenapyr produced extremely low levels of mortality compared to pyrethroids.,Thirty-minute day-time bioassay produced mortality closer to hut efficacy of chlorfenapyr ITN but still fell short of the WHO threshold.,Overnight tunnel test with chlorfenapyr produced 100% mortality and exceeded the WHO threshold of 80%.,The endogenous circadian activity rhythm of anophelines results in inactivity by day and raised metabolism and flight activity by night.,A model which explains improved toxicity of chlorfenapyr ITN when tested at night, and during the day at higher ambient temperature, is that activation of chlorfenapyr and disruption of respiratory pathways is enhanced when the insect is more metabolically and behaviourally active.,Testing according to current WHO guidelines is not suitable for certain types of non-neurotoxic insecticide which, although highly effective in field trials, would be overlooked at the screening stage of evaluation through bioassay.,Testing methods must be tailored to the characteristics and mode of action of each insecticide class.,The WHO tunnel test on night-active anophelines is the most reliable bioassay for identifying the toxicity of novel insecticides.

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.

Immunization of volunteers under chloroquine prophylaxis by bites of Plasmodium falciparum sporozoite (PfSPZ)-infected mosquitoes induces > 90% protection against controlled human malaria infection (CHMI).,We studied intradermal immunization with cryopreserved, infectious PfSPZ in volunteers taking chloroquine (PfSPZ chemoprophylaxis vaccine [CVac]).,Vaccine groups 1 and 3 received 3× monthly immunizations with 7.5 × 104 PfSPZ.,Control groups 2 and 4 received normal saline.,Groups 1 and 2 underwent CHMI (#1) by mosquito bite 60 days after the third immunization.,Groups 3 and 4 were boosted 168 days after the third immunization and underwent CHMI (#2) 137 days later.,Vaccinees (11/20, 55%) and controls (6/10, 60%) had the same percentage of mild to moderate solicited adverse events.,After CHMI #1, 8/10 vaccinees (group 1) and 5/5 controls (group 2) became parasitemic by microscopy; the two negatives were positive by quantitative real-time polymerase chain reaction (qPCR).,After CHMI #2, all vaccinees in group 3 and controls in group 4 were parasitemic by qPCR.,Vaccinees showed weak antibody and no detectable cellular immune responses.,Intradermal immunization with up to 3 × 105 PfSPZ-CVac was safe, but induced only minimal immune responses and no sterile protection against Pf CHMI.

Spatio - temporal modelling of malaria has proven to be a valuable tool for forecasting as well as control and elimination activities.,This has been triggered by an increasing availability of spatially indexed data, enabling not only the characterisation of malaria at macrospatial and microspatial levels but also the development of geospatial techniques and tools that enable health policy planners to use these available data more effectively.,However, there has been little synthesis regarding the variety of spatio - temporal approaches employed, covariates employed and ‘best practice’ type recommendations to guide future modelling decisions.,This review will seek to summarise available evidence on the current state of spatio - temporal modelling approaches that have been employed in malaria modelling in low and middle-income countries within malaria transmission limits, so as to guide future modelling decisions.,A comprehensive search for articles published from January 1968 to April 2018 will be conducted using of the following electronic databases: PubMed, Web of Science, JSTOR, Cochrane CENTRAL via Wiley, Academic Search Complete via EBSCOhost, MasterFILE Premier via EBSCOhost, CINAHL via EBSCOhost, MEDLINE via EBSCOhost and Google Scholar.,Relevant grey literature sources such as unpublished reports, conference proceedings and dissertations will also be incorporated in the search.,Two reviewers will independently conduct the title screening, abstract screening and, thereafter, a full-text review of all potentially eligible articles.,Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols guidelines will be used as the standard reporting format.,A qualitative thematic analysis will be used to group and evaluate selected studies around their aim, spatio - temporal methodology employed, covariates used and model validation techniques.,Ethical approval is not applicable to this study.,The results will be disseminated through a peer-reviewed journal and presented in conferences related to malaria and spatial epidemiology.,CRD42017076427.

Over a decade ago, the Roll Back Malaria Partnership was launched, and since then there has been unprecedented investment in malaria control.,We examined the change in malaria transmission intensity during the period 2000-10 in Africa.,We assembled a geocoded and community Plasmodium falciparum parasite rate standardised to the age group 2-10 years (PfPR2-10) database from across 49 endemic countries and territories in Africa from surveys undertaken since 1980.,The data were used within a Bayesian space-time geostatistical framework to predict PfPR2-10 in 2000 and 2010 at a 1 × 1 km spatial resolution.,Population distribution maps at the same spatial resolution were used to compute populations at risk by endemicity class and estimate population-adjusted PfPR2-10 (PAPfPR2-10) for each of the 44 countries for which predictions were possible for each year.,Between 2000 and 2010, the population in hyperendemic (>50% to 75% PfPR2-10) or holoendemic (>75% PfPR2-10) areas decreased from 218·6 million (34·4%) of 635·7 million to 183·5 million (22·5%) of 815·7 million across 44 malaria-endemic countries. 280·1 million (34·3%) people lived in areas of mesoendemic transmission (>10% to 50% PfPR2-10) in 2010 compared with 178·6 million (28·1%) in 2000.,Population in areas of unstable or very low transmission (<5% PfPR2-10) increased from 131·7 million people (20·7%) in 2000 to 219·0 million (26·8%) in 2010.,An estimated 217·6 million people, or 26·7% of the 2010 population, lived in areas where transmission had reduced by at least one PfPR2-10 endemicity class. 40 countries showed a reduction in national mean PAPfPR2-10.,Only ten countries contributed 87·1% of the population living in areas of hyperendemic or holoendemic transmission in 2010.,Substantial reductions in malaria transmission have been achieved in endemic countries in Africa over the period 2000-10.,However, 57% of the population in 2010 continued to live in areas where transmission remains moderate to intense and global support to sustain and accelerate the reduction of transmission must remain a priority.,Wellcome Trust.

Plasmodium vivax remains an important cause of morbidity and mortality across the Americas, Horn of Africa, East and South East Asia.,Control of transmission has been hampered by emergence of chloroquine resistance and several intrinsic characteristics of infection including asymptomatic carriage, challenges with diagnosis, difficulty eradicating the carrier state and early gametocyte appearance.,Complex human-parasite-vector immunological interactions may facilitate onward infection of mosquitoes.,Given these challenges, new therapies are being explored including the development of transmission to mosquito blocking vaccines.,Herein, the case supporting the need for transmission-blocking vaccines to augment control of P. vivax parasite transmission and explore factors that are limiting eradication efforts is discussed.

A meeting to discuss the latest developments in the biology of sexual development of Plasmodium and transmission-control was held April 5-6, 2011, in Bethesda, MD.,The meeting was sponsored by the Bill & Melinda Gates Foundation and the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIH/NIAID) in response to the challenge issued at the Malaria Forum in October 2007 that the malaria community should re-engage with the objective of global eradication.,The consequent rebalancing of research priorities has brought to the forefront of the research agenda the essential need to reduce parasite transmission.,A key component of any transmission reduction strategy must be methods to attack the parasite as it passes from man to the mosquito (and vice versa).,Such methods must be rationally based on a secure understanding of transmission from the molecular-, cellular-, population- to the evolutionary-levels.,The meeting represented a first attempt to draw together scientists with expertise in these multiple layers of understanding to discuss the scientific foundations and resources that will be required to provide secure progress toward the design and successful implementation of effective interventions.

Reactive case detection could be a powerful tool in malaria elimination, as it selectively targets transmission pockets.,However, field operations have yet to demonstrate under which conditions, if any, reactive case detection is best poised to push a region to elimination.,This study uses mathematical modelling to assess how baseline transmission intensity and local interconnectedness affect the impact of reactive activities in the context of other possible intervention packages.,Communities in Southern Province, Zambia, where elimination operations are currently underway, were used as representatives of three archetypes of malaria transmission: low-transmission, high household density; high-transmission, low household density; and high-transmission, high household density.,Transmission at the spatially-connected household level was simulated with a dynamical model of malaria transmission, and local variation in vectorial capacity and intervention coverage were parameterized according to data collected from the area.,Various potential intervention packages were imposed on each of the archetypical settings and the resulting likelihoods of elimination by the end of 2020 were compared.,Simulations predict that success of elimination campaigns in both low- and high-transmission areas is strongly dependent on stemming the flow of imported infections, underscoring the need for regional-scale strategies capable of reducing transmission concurrently across many connected areas.,In historically low-transmission areas, treatment of clinical malaria should form the cornerstone of elimination operations, as most malaria infections in these areas are symptomatic and onward transmission would be mitigated through health system strengthening; reactive case detection has minimal impact in these settings.,In historically high-transmission areas, vector control and case management are crucial for limiting outbreak size, and the asymptomatic reservoir must be addressed through reactive case detection or mass drug campaigns.,Reactive case detection is recommended only for settings where transmission has recently been reduced rather than all low-transmission settings.,This is demonstrated in a modelling framework with strong out-of-sample accuracy across a range of transmission settings while including methodologies for understanding the most resource-effective allocations of health workers.,This approach generalizes to providing a platform for planning rational scale-up of health systems based on locally-optimized impact according to simplified stratification.,The online version of this article (doi:10.1186/s12936-017-1903-z) contains supplementary material, which is available to authorized users.

A pre-erythrocytic vaccine could provide a useful tool for burden reduction and eventual eradication of malaria.,Mathematical malaria models provide a mechanism for evaluating the effective burden reduction across a range of transmission conditions where such a vaccine might be deployed.,The EMOD model is an individual-based model of malaria transmission dynamics, including vector lifecycles and species-specific behaviour, coupled to a mechanistic intrahost model of malaria parasite and host immune system dynamics.,The present work describes the extension of the EMOD model to include diagnoses of severe malaria and iterative calibration of the immune system parameters and parasite antigenic variation to age-stratified prevalence, incidence and severe disease incidence data obtained from multiple regions with broadly varying transmission conditions in Africa.,An ensemble of calibrated model parameter sets is then employed to evaluate the potential impact of routine immunization with a pre-erythrocytic vaccine.,The reduction in severe malaria burden exhibits a broad peak at moderate transmission conditions.,Under sufficiently intense transmission, a vaccine that reduces but does not eliminate the probability of acquisition from a single challenge bite may delay infections but produces minimal or no net reduction.,Conversely, under sufficiently weak transmission conditions, a vaccine can provide a high fractional reduction but avert a relatively low absolute number of cases due to low baseline burden.,Roll-out of routine immunization with pre-erythrocytic malaria vaccines can provide substantial burden reduction across a range of transmission conditions typical to many regions in Africa.,The online version of this article (doi:10.1186/1475-2875-14-6) contains supplementary material, which is available to authorized users.

Artemisinins are the corner stone of anti-malarial drugs1.,Emergence and spread of resistance to them2-4 raises risk of wiping out recent gains achieved in reducing world-wide malaria burden and threatens future malaria control and elimination on a global level.,Genome wide association studies (GWAS) have revealed parasite genetic loci associated with artemisinin resistance5-10.,However, there is no consensus on biochemical targets of artemisinin.,Whether and how these targets interact with genes identified by GWAS, remains unknown.,Here we provide biochemical and cellular evidence that artemisinins are potent inhibitors of Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K), revealing an unexpected mechanism of action.,In resistant clinical strains, increased PfPI3K was associated with the C580Y mutation in P. falciparum Kelch13 (PfKelch13), a primary marker of artemisinin resistance.,Polyubiquitination of PfPI3K and its binding to PfKelch13 were reduced by PfKelch13 mutation, which limited proteolysis of PfPI3K and thus increased levels of the kinase as well as its lipid product phosphatidylinositol 3-phosphate (PI3P).,We find PI3P levels to be predictive of artemisinin resistance in both clinical and engineered laboratory parasites as well as across non-isogenic strains.,Elevated PI3P induced artemisinin resistance in absence of PfKelch13 mutations, but remained responsive to regulation by PfKelch13.,Evidence is presented for PI3P-dependent signaling, where transgenic expression of an additional kinase confers resistance.,Together these data present PI3P as the key mediator of artemisinin resistance and the sole PfPI3K as an important target for malaria elimination.

A significant reduction in parasite clearance rates following artesunate treatment of falciparum malaria, and increased failure rates following artemisinin combination treatments (ACT), signaled emergent artemisinin resistance in Western Cambodia.,Accurate measurement of parasite clearance is therefore essential to assess the spread of artemisinin resistance in Plasmodium falciparum.,The slope of the log-parasitaemia versus time relationship is considered to be the most robust measure of anti-malarial effect.,However, an initial lag phase of numerical instability often precedes a steady exponential decline in the parasite count after the start of anti-malarial treatment.,This lag complicates the clearance estimation, introduces observer subjectivity, and may influence the accuracy and consistency of reported results.,To address this problem, a new approach to modelling clearance of malaria parasites from parasitaemia-time profiles has been explored and validated.,The methodology detects when a lag phase is present, selects the most appropriate model (linear, quadratic or cubic) to fit log-transformed parasite data, and calculates estimates of parasite clearance adjusted for this lag phase.,Departing from previous approaches, parasite counts below the level of detection are accounted for and not excluded from the calculation.,Data from large clinical studies with frequent parasite counts were examined.,The effect of a lag phase on parasite clearance rate estimates is discussed, using individual patient data examples.,As part of the World Wide Antimalarial Resistance Network's (WWARN) efforts to make innovative approaches available to the malaria community, an automated informatics tool: the parasite clearance estimator has been developed.,The parasite clearance estimator provides a consistent, reliable and accurate method to estimate the lag phase and malaria parasite clearance rate.,It could be used to detect early signs of emerging resistance to artemisinin derivatives and other compounds which affect ring-stage clearance.

Accurate diagnosis of cutaneous leishmaniasis (CL) is important for chemotherapy and epidemiological studies.,Common approaches for Leishmania detection involve the invasive collection of specimens for direct identification of amastigotes by microscopy and the culturing of promastigotes from infected tissues.,Although these techniques are highly specific, they require highly skilled health workers and have the inherent risks of all invasive procedures, such as pain and risk of bacterial and fungal super-infection.,Therefore, it is essential to reduce discomfort, potential infection and scarring caused by invasive diagnostic approaches especially for children.,In this report, we present a novel non-invasive method, that is painless, rapid and user-friendly, using sequential tape strips for sampling and isolation of DNA from the surface of active and healed skin lesions of CL patients.,A total of 119 patients suspected of suffering from cutaneous leishmaniasis with different clinical manifestations were recruited and samples were collected both from their lesions and from uninfected areas.,In addition, 15 fungal-infected lesions and 54 areas of healthy skin were examined.,The duration of sampling is short (less than one minute) and species identification by PCR is highly specific and sensitive.,The sequential tape stripping sampling method is a sensitive, non-invasive and cost-effective alternative to traditional diagnostic assays and it is suitable for field studies as well as for use in health care centers.

The diagnosis of cutaneous leishmaniasis (CL) might be difficult, in particular in endemic areas where different species of Leishmania can cause lesions of very similar appearance and where other skin diseases with similar clinical symptoms occur.,Even today, the parasitological diagnosis of CL remains the gold standard and it is based on the direct identification of amastigotes in microscopy smears and/or culture of promastigotes from infected tissues.,Although these techniques are highly specific, they are not sensitive enough.,The objective of this study is to contribute to improving the diagnosis of CL and the identification of Leishmania species in Morocco by comparing three PCR-based assays applied directly on dermal samples.,A total of 58 patients presenting with cutaneous lesions suggestive of CL were sampled for parasitological diagnosis by direct examination (DE), culture in NNN medium, two kinetoplast DNA (kDNA) PCRs (Lmj4/Uni21 and 13A/13B primers) and one rRNA gene internal transcribed spacer 1 (ITS1) PCR (LITSR/L5.8S primers).,The techniques were statistically analyzed and compared.,According to our consensus positive, 44 out of 58 samples were true positives.,The 13A/13B-PCR and ITS1-PCR showed the highest sensitivities (100%).,Parasite microscopy and culture detected 43% and 29% of the true positives, respectively, while culture and microscopy together improved sensitivity to 52%.,PCRs 13A/13B and ITS1 were associated to four and one false positives, respectively, while the other assays were 100% specific.,Furthermore, the ITS1-PCR-RFLP assay clearly identified the Leishmania species for all the true positives (44/44), whereas Lmj4/Uni21-PCR identified 35/44 samples.,The comparison between the Leishmania molecular characterizations and the expected species according to the national data from the Ministry of Health indicate 7 discrepant results.,The PCR-based assays tested on our samples increased the speed and sensitivity of the diagnosis of CL compared to the conventional techniques.,Furthermore, we showed that we can not base the species identification on the national data from the Ministry of Health.,Finally, we suggest the use of PCR-ITS1-RFLP for diagnosis and simultaneous identification of the species in the Moroccan epidemiological context, but also in similar areas of the Mediterranean Basin.

Plasmodium is a genus of apicomplexan parasites which replicate in the liver before causing malaria.,Plasmodium vivax can also persist in the liver as dormant hypnozoites and cause clinical relapse upon activation, but the molecular mechanisms leading to activation have yet to be discovered.,In this study, we use high-resolution microscopy to characterize temporal changes of the P. vivax liver stage tubovesicular network (TVN), a parasitophorous vacuole membrane (PVM)-derived network within the host cytosol.,We observe extended membrane clusters, tubules, and TVN-derived vesicles present throughout P. vivax liver stage development.,Additionally, we demonstrate an unexpected presence of the TVN in hypnozoites and observe some association of this network to host nuclei.,We also reveal that the host water and solute channel aquaporin-3 (AQP3) associates with TVN-derived vesicles and extended membrane clusters.,AQP3 has been previously shown to localize to the PVM of P. vivax hypnozoites and liver schizonts but has not yet been shown in association to the TVN.,Our results highlight host-parasite interactions occur in both dormant and replicating liver stage P. vivax forms and implicate AQP3 function during this time.,Together, these findings enhance our understanding of P. vivax liver stage biology through characterization of the TVN with an emphasis on the presence of this network in dormant hypnozoites.

The PfEMP1 family of Plasmodium falciparum antigens play a key role in pathogenesis of severe malaria through their insertion into the surface of parasite infected erythrocytes, and adhesion to host cells.,Previous studies have suggested that parasites expressing PfEMP1 subclasses group A and DC8, associated with severe malaria, may have a growth advantage in immunologically naïve individuals.,However, this idea has not been tested in longitudinal studies.,Here we assessed expression of the var genes encoding PfEMP1, in parasites sampled from volunteers with varying prior exposure to malaria, following experimental infection by sporozoites (PfSPZ).,Using qPCR, we tested for associations between the expression of various var subgroups in surviving parasite populations from each volunteer and 1) the levels of participants’ antibodies to infected erythrocytes before challenge infection and 2) the apparent in vivo parasite multiplication rate.,We show that 1) expression of var genes encoding for group A and DC8-like PfEMP1 were associated with low levels of antibodies to infected erythrocytes (αIE) before challenge, and 2) expression of a DC8-like CIDRα1.1 domain was associated with higher apparent parasite multiplication rate in a manner that was independent of levels of prior antibodies to infected erythrocytes.,This study provides insight into the role of antibodies to infected erythrocytes surface antigens in the development of naturally acquired immunity and may help explain why specific PfEMP1 variants may be associated with severe malaria.,Pan African Clinical Trial Registry: PACTR201211000433272.,Date of registration: 10th October 2012.

The World Health Organization (WHO) has set elimination as a public health problem (EPHP) as a goal for schistosomiasis.,As the WHO treatment guidelines for schistosomiasis are currently under revision, we investigate whether school-based or community-wide treatment strategies are required for achieving the EPHP goal.,In low- to moderate-transmission settings with good school enrolment, we find that school-based treatment is sufficient for achieving EPHP.,However, community-wide treatment is projected to be necessary in certain high-transmission settings as well as settings with low school enrolment.,Hence, the optimal treatment strategy depends on setting-specific factors such as the species present, prevalence prior to treatment, and the age profile of infection.

Elimination of schistosomiasis as a public health problem and interruption of transmission in selected areas are targets set by WHO for 2025.,Our aim was to assess biannual mass drug administration (MDA) applied alone or with complementary snail control or behaviour change interventions for the reduction of Schistosoma haematobium prevalence and infection intensity in children from Zanzibar and to compare the effect between the clusters.,In a 5-year repeated cross-sectional cluster-randomised trial, 90 shehias (small administrative regions; clusters) in Zanzibar eligible owing to available natural open freshwater bodies and public primary schools were randomly allocated (ratio 1:1:1) to receive one of three interventions: biannual MDA with praziquantel alone (arm 1) or in combination with snail control (arm 2), or behaviour change activities (arm 3).,Neither participants nor field or laboratory personnel were blinded to the intervention arms.,From 2012 to 2017, annually, a single urine sample was collected from approximately 100 children aged 9-12 years in the main public primary school of each shehia.,The primary outcome was S haematobium infection prevalence and intensity in 9-12-year-old children after 5 years of follow-up.,This study is completed and was registered with the ISRCTN, number 48837681.,The trial was done from Nov 1, 2011, through to Dec 31, 2017 and recruitment took place from Nov 2, 2011, until May 17, 2017.,At baseline we enrolled 8278 participants, of whom 2899 (35%) were randomly allocated to arm 1, 2741 (33%) to arm 2, and 2638 (32%) to arm 3. 120 (4·2%) of 2853 in arm 1, 209 (7·8%) of 2688 in arm 2, and 167 (6·4%) of 2613 in arm 3 had S haematobium infections at baseline.,Heavy infections (≥50 eggs per 10 mL of urine) were found in 126 (1·6%) of 8073 children at baseline.,At the 5-year endline survey, 46 (1·4%) of 3184 in arm 1, 56 (1·7%) of 3217 (odds ratio [OR] 1·2 [95% CI 0·6-2·7] vs arm 1) in arm 2, and 58 (1·9%) of 3080 (1·3 [0·6-2·9]) in arm 3 had S haematobium infections.,Heavy infections were detected in 33 (0·3%) of 9462 children.,Biannual MDA substantially reduced the S haematobium prevalence and infection intensity but was insufficient to interrupt transmission.,Although snail control or behaviour change activities did not significantly boost the effect of MDA in our study, they might enhance interruption of transmission when tailored to focal endemicity and applied for a longer period.,It is now necessary to focus on reducing prevalence in remaining hotspot areas and to introduce new methods of surveillance and public health response so that the important gains can be maintained and advanced.,University of Georgia Research Foundation Inc and Bill & Melinda Gates Foundation.

Falciparum malaria persists in hard-to-reach areas or demographic groups that are missed by conventional healthcare systems but could be reached by trained community members in a malaria post (MP).,The main focus of a MP is to provide uninterrupted and rapid access to rapid diagnostic tests (RDTs) and artemisinin-based combination therapy (ACT) too all inhabitants of a village.,RDTs allow trained community members to perform malaria diagnosis accurately and prescribe appropriate treatment, reducing as much as possible any delay between the onset of fever and treatment.,Early treatment with ACT and with a low-dose of primaquine prevents further transmission from human to mosquito.,A functioning MP represents an essential component of any malaria elimination strategy.,Implementing large-scale, high-coverage, community-based early diagnosis and treatment through MPs requires few technological innovations but relies on a very well structured organization able to train, supervise and supply MPs, to monitor activity and to perform strict malaria surveillance.,The online version of this article (doi:10.1186/s12936-016-1399-y) contains supplementary material, which is available to authorized users.

After artemisinin resistance was reported, the Myanmar artemisinin resistance containment (MARC) project was initiated in 2011.,One of the activities of MARC is to train volunteers for early diagnosis and prompt treatment by providing rapid diagnostic tests (RDT) and artemisinin combination therapy.,This study aimed to fulfil the gap of information on the challenges faced by malaria volunteers in artemisinin-containment areas.,A cross-sectional, descriptive study was conducted in 11 townships in MARC areas to assess the challenges in early diagnosis of malaria and treatment by malaria volunteers using qualitative and quantitative approaches.,Altogether 405 volunteers participated in the study.,Although 97.5 % of volunteers can interpret a positive result for malaria, only 41.2 % correctly stated the persistence of a positive result in recently infected cases.,Over 80 % knew the effects of temperature and humidity on performance of the malaria RDT.,Unexpectedly, 15.1 % perceived that expired RDTs can still be useful for diagnosis although 98.3 % of respondents cited that the overall results of RDTs were reliable.,Although most of them knew the treatment for malaria based on RDT results, some could not give the correct answer, while a few (2 %) mentioned artesunate monotherapy for RDT-negative cases.,Training received by volunteers was also varied in study sites and 92.1 % believed that it was not sufficient.,A certain portion of them faced the problem of regular supply of RDTs (9.9 %) and drugs (47.5 %), interpretation of result of RDTs (30 %), and performing blood test (20 %).,The median RDT tested per month (25th, 75th percentile) was 6.0 (2.0, 15.0) indicating the need for prioritization based on endemicity.,Regular reporting, supervision, monitoring system, and proper refresher training using uniform content of guideline to correct misconception of the volunteers, were needed to be strengthened.,Moreover, the reliable and regular supply of materials and exchange system for expired RDTs and anti-malarials was important in the effectiveness of volunteers in MARC zones.,Adequate refresher training, monitoring, supervision, and regular reliable supply of RDTs and anti-malarials were needed for capacity strengthening of volunteers in MARC zones.

Current control strategies for soil-transmitted helminths (STH) emphasize morbidity control through mass drug administration (MDA) targeting preschool- and school-age children, women of childbearing age and adults in certain high-risk occupations such as agricultural laborers or miners.,This strategy is effective at reducing morbidity in those treated but, without massive economic development, it is unlikely it will interrupt transmission.,MDA will therefore need to continue indefinitely to maintain benefit.,Mathematical models suggest that transmission interruption may be achievable through MDA alone, provided that all age groups are targeted with high coverage.,The DeWorm3 Project will test the feasibility of interrupting STH transmission using biannual MDA targeting all age groups.,Study sites (population ≥80,000) have been identified in Benin, Malawi and India.,Each site will be divided into 40 clusters, to be randomized 1:1 to three years of twice-annual community-wide MDA or standard-of-care MDA, typically annual school-based deworming.,Community-wide MDA will be delivered door-to-door, while standard-of-care MDA will be delivered according to national guidelines.,The primary outcome is transmission interruption of the STH species present at each site, defined as weighted cluster-level prevalence ≤2% by quantitative polymerase chain reaction (qPCR), 24 months after the final round of MDA.,Secondary outcomes include the endline prevalence of STH, overall and by species, and the endline prevalence of STH among children under five as an indicator of incident infections.,Secondary analyses will identify cluster-level factors associated with transmission interruption.,Prevalence will be assessed using qPCR of stool samples collected from a random sample of cluster residents at baseline, six months after the final round of MDA and 24 months post-MDA.,A smaller number of individuals in each cluster will be followed with annual sampling to monitor trends in prevalence and reinfection throughout the trial.,ClinicalTrials.gov NCT03014167

Few drugs are available for soil-transmitted helminthiasis (STH); the benzimidazoles albendazole and mebendazole are the only drugs being used for preventive chemotherapy as they can be given in one single dose with no weight adjustment.,While generally safe and effective in reducing intensity of infection, they are contra-indicated in first-trimester pregnancy and have suboptimal efficacy against Trichuris trichiura.,In addition, drug resistance is a threat.,It is therefore important to find alternatives.,We searched the literature and the animal health marketed products and pipeline for potential drug development candidates.,Recently registered veterinary products offer advantages in that they have undergone extensive and rigorous animal testing, thus reducing the risk, cost and time to approval for human trials.,For selected compounds, we retrieved and summarised publicly available information (through US Freedom of Information (FoI) statements, European Public Assessment Reports (EPAR) and published literature).,Concomitantly, we developed a target product profile (TPP) against which the products were compared.,The paper summarizes the general findings including various classes of compounds, and more specific information on two veterinary anthelmintics (monepantel, emodepside) and nitazoxanide, an antiprotozoal drug, compiled from the EMA EPAR and FDA registration files.,Few of the compounds already approved for use in human or animal medicine qualify for development track decision.,Fast-tracking to approval for human studies may be possible for veterinary compounds like emodepside and monepantel, but additional information remains to be acquired before an informed decision can be made.

Surra, caused by Trypanosoma evansi, is a neglected disease due to frequent subclinical evolution, especially in bovines in Asia.,However, acute and chronic signs are regularly observed, with significant sanitary and economic impacts.,In this study, we evaluated and applied an indirect-ELISA test for the detection of anti-T. evansi immunoglobulin G in buffaloes using antibovine conjugate.,Based on buffalo reference sera from the Philippines, a two-graph receiver operating characteristics analysis (TG-ROC) was conducted to define an optimal cut-off value; sensitivity and specificity were estimated at 92.5% and 94.2%, respectively.,A cross-sectional serological survey was carried out in the major buffalo breeding areas of Thailand; 892 buffaloes from 8 provinces were sampled in North, Northeastern, and Southern Thailand.,Seropositive buffaloes were found in all 8 provinces, on 20.3% of farms for an overall prevalence of 12.2% (95% CI 10.2-14.5%).,Nearly one-third of the sampled population was exposed to infection.,Broader sampling would be necessary but is not possible in the southern half-wild breeding systems.,According to our results, buffaloes may constitute a large and robust reservoir for T. evansi, which is a permanent threat to other livestock such as cattle and horses as well as wild animals such as elephants in Southest Asia.

Trypanosoma evansi, the agent of “surra,” is a salivarian trypanosome, originating from Africa.,It is thought to derive from Trypanosoma brucei by deletion of the maxicircle kinetoplastic DNA (genetic material required for cyclical development in tsetse flies).,It is mostly mechanically transmitted by tabanids and stomoxes, initially to camels, in sub-Saharan area.,The disease spread from North Africa towards the Middle East, Turkey, India, up to 53° North in Russia, across all South-East Asia, down to Indonesia and the Philippines, and it was also introduced by the conquistadores into Latin America.,It can affect a very large range of domestic and wild hosts including camelids, equines, cattle, buffaloes, sheep, goats, pigs, dogs and other carnivores, deer, gazelles, and elephants.,It found a new large range of wild and domestic hosts in Latin America, including reservoirs (capybaras) and biological vectors (vampire bats).,Surra is a major disease in camels, equines, and dogs, in which it can often be fatal in the absence of treatment, and exhibits nonspecific clinical signs (anaemia, loss of weight, abortion, and death), which are variable from one host and one place to another; however, its immunosuppressive effects interfering with intercurrent diseases or vaccination campaigns might be its most significant and questionable aspect.

In spite of the extensive contribution of intestinal pathology to the pathophysiology of schistosomiasis, little is known of the impact of schistosome infection on the composition of the gut microbiota of its mammalian host.,Here, we characterised the fluctuations in the composition of the gut microbial flora of the small and large intestine, as well as the changes in abundance of individual microbial species, of mice experimentally infected with Schistosoma mansoni with the goal of identifying microbial taxa with potential roles in the pathophysiology of infection and disease.,Bioinformatic analyses of bacterial 16S rRNA gene data revealed an overall reduction in gut microbial alpha diversity, alongside a significant increase in microbial beta diversity characterised by expanded populations of Akkermansia muciniphila (phylum Verrucomicrobia) and lactobacilli, in the gut microbiota of S. mansoni-infected mice when compared to uninfected control animals.,These data support a role of the mammalian gut microbiota in the pathogenesis of hepato-intestinal schistosomiasis and serves as a foundation for the design of mechanistic studies to unravel the complex relationships amongst parasitic helminths, gut microbiota, pathophysiology of infection and host immunity.

Treatment for human African trypanosomiasis is dependent on the species of trypanosome causing the disease and the stage of the disease (stage 1 defined by parasites being present in blood and lymphatics whilst for stage 2, parasites are found beyond the blood-brain barrier in the cerebrospinal fluid (CSF)).,Currently, staging relies upon detecting the very low number of parasites or elevated white blood cell numbers in CSF.,Improved staging is desirable, as is the elimination of the need for lumbar puncture.,Here we use metabolomics to probe samples of CSF, plasma and urine from 40 Angolan patients infected with Trypanosoma brucei gambiense, at different disease stages.,Urine samples provided no robust markers indicative of infection or stage of infection due to inherent variability in urine concentrations.,Biomarkers in CSF were able to distinguish patients at stage 1 or advanced stage 2 with absolute specificity.,Eleven metabolites clearly distinguished the stage in most patients and two of these (neopterin and 5-hydroxytryptophan) showed 100% specificity and sensitivity between our stage 1 and advanced stage 2 samples.,Neopterin is an inflammatory biomarker previously shown in CSF of stage 2 but not stage 1 patients. 5-hydroxytryptophan is an important metabolite in the serotonin synthetic pathway, the key pathway in determining somnolence, thus offering a possible link to the eponymous symptoms of “sleeping sickness”.,Plasma also yielded several biomarkers clearly indicative of the presence (87% sensitivity and 95% specificity) and stage of disease (92% sensitivity and 81% specificity).,A logistic regression model including these metabolites showed clear separation of patients being either at stage 1 or advanced stage 2 or indeed diseased (both stages) versus control.

In this study, B cell function in protective TH2 immunity against N. brasiliensis infection was investigated.,Protection against secondary infection depended on IL-4Rα and IL-13; but not IL-4.,Protection did not associate with parasite specific antibody responses.,Re-infection of B cell-specific IL-4Rα−/− mice resulted in increased worm burdens compared to control mice, despite their equivalent capacity to control primary infection.,Impaired protection correlated with reduced lymphocyte IL-13 production and B cell MHC class II and CD86 surface expression.,Adoptive transfer of in vivo N. brasiliensis primed IL-4Rα expressing B cells into naïve BALB/c mice, but not IL-4Rα or IL-13 deficient B cells, conferred protection against primary N. brasiliensis infection.,This protection required MHC class II compatibility on B cells suggesting cognate interactions by B cells with CD4+ T cells were important to co-ordinate immunity.,Furthermore, the rapid nature of these protective effects by B cells suggested non-BCR mediated mechanisms, such as via Toll Like Receptors, was involved, and this was supported by transfer experiments using antigen pulsed Myd88−/− B cells.,These data suggest TLR dependent antigen processing by IL-4Rα-responsive B cells producing IL-13 contribute significantly to CD4+ T cell-mediated protective immunity against N. brasiliensis infection.

Although cognate encounters between CCR7-expressing antigen-bearing dendritic cells (DCs) and CCR7+ naïve T cells take place within the T cell zone of lymph nodes, it is unknown whether co-localization of the DCs and T cells within the T cell area is obligate for effector generation.,Here, we show that, following nematode infection, antigen-bearing DCs and CD4+ T cells upregulate CXCR5 and co-localize in a CXCL13, B cell and lymphotoxin-dependent fashion outside of the T zone.,Importantly, lymphotoxin-expressing B cells, CXCL13 and CXCR5-expressing DCs and T cells are also necessary for development of interleukin 4 (IL-4) producing TH2 cells, suggesting that TH2 differentiation can initiate outside of the T cell zone.

Major advances have been made in identifying potential vaccine molecules for the control of fasciolosis in livestock but we have yet to reach the level of efficacy required for commercialisation.,The pathogenesis of fasciolosis is associated with liver damage that is inflicted by migrating and feeding immature flukes as well as host inflammatory immune responses to parasite-secreted molecules and tissue damage alarm signals.,Immune suppression/modulation by the parasites prevents the development of protective immune responses as evidenced by the lack of immunity observed in naturally and experimentally infected animals.,In our opinion, future efforts need to focus on understanding how parasites invade and penetrate the tissues of their hosts and how they potentiate and control the ensuing immune responses, particularly in the first days of infection.,Emerging ‘omics’ data employed in an unbiased approach are helping us understand liver fluke biology and, in parallel with new immunological data, to identify molecules that are essential to parasite development and accessible to vaccine-induced immune responses.

Fascioliasis is an emerging zoonotic disease of considerable veterinary and public health importance.,Triclabendazole is the only available drug for treatment.,Laboratory studies have documented promising fasciocidal properties of the artemisinins (e.g., artemether).,We carried out two exploratory phase-2 trials to assess the efficacy and safety of oral artemether administered at (i) 6×80 mg over 3 consecutive days, and (ii) 3×200 mg within 24 h in 36 Fasciola-infected individuals in Egypt.,Efficacy was determined by cure rate (CR) and egg reduction rate (ERR) based on multiple Kato-Katz thick smears before and after drug administration.,Patients who remained Fasciola-positive following artemether dosing were treated with single 10 mg/kg oral triclabendazole.,In case of treatment failure, triclabendazole was re-administered at 20 mg/kg in two divided doses.,CRs achieved with 6×80 mg and 3×200 mg artemether were 35% and 6%, respectively.,The corresponding ERRs were 63% and nil, respectively.,Artemether was well tolerated.,A high efficacy was observed with triclabendazole administered at 10 mg/kg (16 patients; CR: 67%, ERR: 94%) and 20 mg/kg (4 patients; CR: 75%, ERR: 96%).,Artemether, administered at malaria treatment regimens, shows no or only little effect against fascioliasis, and hence does not represent an alternative to triclabendazole.,The role of artemether and other artemisinin derivatives as partner drug in combination chemotherapy remains to be elucidated.

Host-directed therapy (HDT) is gaining traction as a strategy to combat infectious diseases caused by viruses and intracellular bacteria, but its implementation in the context of parasitic diseases has received less attention.,Here, we provide a brief overview of this field and advocate HDT as a promising strategy for antimalarial intervention based on untapped targets.,HDT provides a basis from which repurposed drugs could be rapidly deployed and is likely to strongly limit the emergence of resistance.,This strategy can be applied to any intracellular pathogen and is particularly well placed in situations in which rapid identification of treatments is needed, such as emerging infections and pandemics, as starkly illustrated by the current COVID-19 crisis.,Drug resistance threatens to reverse progress achieved in malaria control.,Host-directed therapy (HDT) provides a barrier to drug resistance: since the target is not under the genetic control of the parasite, resistance-conferring mutations in the target cannot be selected under treatment.,Wei et al. review opportunities for HDT in the fight against malaria.

Malaria vaccine design and prioritization has been hindered by the lack of a mechanistic correlate of protection.,We previously demonstrated a strong association between protection and merozoite-neutralizing antibody responses following vaccination of non-human primates against Plasmodium falciparum reticulocyte binding protein homolog 5 (PfRH5).,Here, we test the mechanism of protection.,Using mutant human IgG1 Fc regions engineered not to engage complement or FcR-dependent effector mechanisms, we produce merozoite-neutralizing and non-neutralizing anti-PfRH5 chimeric monoclonal antibodies (mAbs) and perform a passive transfer-P. falciparum challenge study in Aotus nancymaae monkeys.,At the highest dose tested, 6/6 animals given the neutralizing PfRH5-binding mAb c2AC7 survive the challenge without treatment, compared to 0/6 animals given non-neutralizing PfRH5-binding mAb c4BA7 and 0/6 animals given an isotype control mAb.,Our results address the controversy regarding whether merozoite-neutralizing antibody can cause protection against P. falciparum blood-stage infections, and highlight the quantitative challenge of achieving such protection.,Proof of protection against blood-stage P. falciparum malaria by a single immunological mechanism has been elusive.,Here, using engineered anti-PfRH5 chimeric monoclonal antibodies in non-human primates, the authors show that high levels of merozoite-neutralizing antibodies can achieve protection.

An open-label, randomized controlled trial was carried out in 2011-2012 in the Democratic Republic of the Congo to test the efficacy, safety, and tolerability of the artemisinin-based combination treatments dihydroartemisinin-piperaquine, amodiaquine-artesunate, and artemether-lumefantrine.,Six hundred eighty-four children aged 3 to 59 months with uncomplicated Plasmodium falciparum malaria were randomly allocated to each study arm.,Children were hospitalized for 3 days, given supervised treatment, and followed up weekly for 42 days.,All regimens were well tolerated and rapidly effective.,The median parasitemia clearance half-life was 2.2 h, and half-lives were similar between arms (P = 0.19).,The PCR-uncorrected cure rates by day 42 were 73.0% for amodiaquine-artesunate, 70.2% for artemether-lumefantrine, and 86.3% for dihydroartemisinin-piperaquine (P = 0.001).,Early treatment failure occurred in three patients (0.5%), one in each arm.,The PCR-corrected cure rates were 93.4% for amodiaquine-artesunate, 92.7% for artemether-lumefantrine, and 94.3% for dihydroartemisinin-piperaquine (P = 0.78).,The last provided a longer posttreatment prophylactic effect than did the other two treatments.,The day 7 plasma concentration of piperaquine was below 30 ng/ml in 47% of the children treated with dihydroartemisinin-piperaquine, and the day 7 lumefantrine concentration was below 280 ng/ml in 37.0% of children who received artemether-lumefantrine.,Thus, although cure rates were all satisfactory, they could be improved by increasing the dose.,(This study has been registered with the International Standard Randomized Controlled Trial Number Register [www.isrctn.org] under registration no.,ISRCTN20984426.)

The efficacy of artemisinin-based combination therapy (ACT) has been established.,The objective of the present study was to compare the efficacy and safety in the Central African Republic (CAR) of three commercially available artemisinin-based combinations, artemether + lumefantrine (AL), artesunate + sulphamethoxypyrazine-pyrimethamine (AS-SMP) and artesunate + amodiaquine (AS-AQ), with those of sulphadoxine-pyrimethamine + amodiaquine (SP-AQ), which was the first-line reference treatment in the country from 2004, until it was replaced by ACT in 2006 in accordance with changes in international recommendations based on resistance identified in other regions.,Children aged six to 59 months with uncomplicated Plasmodium falciparum malaria were recruited in Bangui, the capital of the CAR.,The 251 patients selected were randomly assigned to receive AL (n = 60), AS-SMP (n = 58), AS-AQ (n = 68) or SP-AQ (n = 65) and were followed up for 28 days.,Clinical outcome was classified according to the standard 2003 World Health Organization protocol.,At day 28, the cure rates in a per-protocol analysis were 92% (48/52) with AL, 93% (50/54) with AS-SMP, 93% (55/59) with AS-AQ and 100% (57/57) with SP-AQ, with no statistically significant difference between the four treatments.,Defervescence was significantly faster with AS-AQ than with AL (p <0.035).,Fatigue was reported significantly more frequently by patients receiving AQ than by those treated with AS-SMP or AL (p = 0.006).,All the other adverse events reported were mild, and no significant difference was noted by treatment.,The three artemisinin-bsed combinations show similar, satisfactory results, comparable to that with SP-AQ.,This evaluation is the first conducted in CAR since the official introduction of ACT.,It should guide the National Malaria Control Programme in choosing the appropriate ACT for treatment of uncomplicated P. falciparum malaria in the future.

North East Kenya is an area of semi-arid terrain, prone to malaria epidemics.,The distribution of long-lasting insecticidal nets (LLINs) has long been a key malaria intervention, however, for nomadic populations who live and sleep outside, in harsh climates and areas with increasing reports of exophagic behaviour of mosquitoes, traditional LLINs are often inadequate.,This study investigates the acceptability of non-mesh LLINs, specifically designed to suit nomadic, outdoor sleeping communities.,In September 2011, 13,922 non-mesh LLINs were distributed to 8,511 nomadic households in Garissa County, North East Province, Kenya.,A prospective, longitudinal study design was used to assess the acceptability of this novel type of LLIN.,Cross-sectional household surveys, focus group discussions (FGDs), and key informant interviews (KIs) were used to collect data on attitudes and practices regarding the Dumuria nets.,A very high level of acceptability was reported with 95.3% of respondents stating they liked the nets.,Of the factors reportedly determining net use the most frequently mentioned was “vulnerability”.,Of those with concerns about the nets, the colour (white) was the most frequently reported.,The tailoring of LLINs to specific communities and contexts leads to increased levels of acceptability.,Large-scale, blanket net distribution campaigns, which are currently the standard practice, do not cater for the specific and nuanced needs of the differing communities they often serve.,This non-mesh LLIN offers a highly effective and desirable malaria prevention option to a typically hard to reach and underserved nomadic population at increased risk of malaria infection.

Despite recent advances in the fight against the disease, malaria remains a serious threat to the health and well-being of populations in endemic countries.,The use of long-lasting insecticidal nets (LLIN) reduces contact between the vector and humans, thereby reducing transmission of the disease.,LLINs have become an essential component of malaria control programmes worldwide.,The Culture of Net Use study used qualitative and quantitative methods in a longitudinal and iterative design over two phases, in order to capture changes in net use over a year and a half period and covering both dry and rainy seasons.,Data were collected from a total of 56 households in eight regions to understand variations due to geographical, cultural, and universal coverage differences.,At the time of the data collection, the universal coverage campaign had been completed in six of the eight regions (Dakar and Thies excluded).,Perceived barriers to use were primarily related to the characteristics of the net itself, include shape, insecticide, and a variety of minority responses, such as perceived lack of mosquito density and being unaccustomed to using nets.,Insecticide-related complaints found that insecticide did not present a significant barrier to use, but was cited as a nuisance.,Feelings of suffocation continued to be the most commonly cited nuisance.,Respondents who favoured the use of insecticide on nets appeared to be more aware of the health and malaria prevention benefits of the insecticide than those who perceived it negatively.,Despite prior evidence that barriers such as heat, shape, insecticide and perceived mosquito density contribute to non-use of LLINs in other countries, this study has shown that these factors are considered more as nuisances and that they do not consistently prevent the use of nets among respondents in Senegal.,Of those who cited inconveniences with their nets, few were moved to stop using a net.,Respondents from this study overcame these barriers and continue to value the importance of nets.

Human African trypanosomiasis (HAT) remains a major neglected tropical disease in Sub-Saharan Africa.,As clinical symptoms are usually non-specific, new diagnostic and prognostic markers are urgently needed to enhance the number of identified cases and optimise treatment.,This is particularly important for disease caused by Trypanosoma brucei rhodesiense, where indirect immunodiagnostic approaches have to date been unsuccessful.,We have conducted global metabolic profiling of plasma from T.b.rhodesiense HAT patients and endemic controls, using 1H nuclear magnetic resonance (NMR) spectroscopy and ultra-performance liquid chromatography, coupled with mass spectrometry (UPLC-MS) and identified differences in the lipid, amino acid and metabolite profiles.,Altogether 16 significantly disease discriminatory metabolite markers were found using NMR, and a further 37 lipid markers via UPLC-MS.,These included significantly higher levels of phenylalanine, formate, creatinine, N-acetylated glycoprotein and triglycerides in patients relative to controls.,HAT patients also displayed lower concentrations of histidine, sphingomyelins, lysophosphatidylcholines, and several polyunsaturated phosphatidylcholines.,While the disease metabolite profile was partially consistent with previous data published in experimental rodent infection, we also found unique lipid and amino acid profile markers highlighting subtle but important differences between the host response to trypanosome infections between animal models and natural human infections.,Our results demonstrate the potential of metabolic profiling in the identification of novel diagnostic biomarkers and the elucidation of pathogenetic mechanisms in this disease.

Schistosomiasis is one of the most widely distributed parasitic diseases in the world.,Schistosoma japonicum, a zoonotic parasite with a wide range of mammalian hosts, is one of the major pathogens of this disease.,Although numerous studies on schistosomiasis japonica have been performed using laboratory animal models, systematic comparative analysis of whole-genome expression profiles in parasites from different laboratory animals and nature mammalian hosts is lacking to date.,Adult schistosomes were obtained from laboratory animals BALB/c mice, C57BL/6 mice, New Zealand white rabbits and the natural host, water buffaloes.,The gene expression profiles of schistosomes from these animals were obtained and compared by genome-wide oligonucleotide microarray analysis.,The results revealed that the gene expression profiles of schistosomes from different laboratory animals and buffaloes were highly consistent (r>0.98) genome-wide.,Meanwhile, a total of 450 genes were identified to be differentially expressed in schistosomes which can be clustered into six groups.,Pathway analysis revealed that these genes were mainly involved in multiple signal transduction pathways, amino acid, energy, nucleotide and lipid metabolism.,We also identified a group of 1,540 abundantly and stably expressed gene products in adult worms, including a panel of 179 Schistosoma- or Platyhelminthes-specific genes that may be essential for parasitism and may be regarded as novel potential anti-parasite intervention targets for future research.,This study provides a comprehensive database of gene expression profiles of schistosomes derived from different laboratory animals and water buffaloes.,An expanded number of genes potentially affecting the development of schistosomes in different animals were identified.,These findings lay the foundation for schistosomiasis research in different laboratory animals and natural hosts at the transcriptional level and provide a valuable resource for screening anti-schistosomal intervention targets.

To complement ongoing schistosomiasis control within national control programmes (NCPs) that administer praziquantel to school-age children, assessing the risk and extent of schistosomiasis in pre-school-age children (PSAC) is important.,In June 2012, schistosomiasis in Chikhwawa district, Malawi was assessed across 12 villages examining pre-school-age children (PSAC) and their mothers by serological and parasitological diagnosis, as supplemented with urine-antigen and questionnaire-interview methods.,Urinary tract morbidity was inferred by haematuria and albuminuria assays.,In total, 49.5% (CI95 42.6-56.4) of 208 PSAC and 94.5% (CI95 90.9-98.1) of 165 mothers were seropositive for schistosomiasis, in 2 villages seroprevalence exceeded 75% in PSAC.,Egg-patent urogenital and intestinal schistosomiasis was observed; 17.7% (CI95 12.4-23.2) of PSAC and 45.1% (CI95 37.4-52.8) of mothers having active schistosomiasis by parasitological and urine-antigen testing combined.,PSAC often had extensive daily water contact and many (~25%) had haematuria and albuminuria.,As eggs with an atypical morphology of Schistosoma haematobium were observed, a general selection of schistosome eggs was characterized by DNA barcoding, finding Group I S. haematobium and Group IV and V S. mansoni.,Malacological surveys encountered several populations of Bulinus globosus but failed to find Biomphalaria.,Both PSAC and their mothers appear to be at significant risk of schistosomiasis and should be considered for treatment within the NCP of Malawi.

Schistosoma japonicum is endemic in the Philippines, China and Indonesia, and infects more than 40 mammalian host species, all of which can act as reservoirs of infection.,In China, water buffaloes have been shown to be major reservoirs of human infection.,However, in the Philippines, carabao have not been considered important reservoir hosts for S. japonicum due to the low prevalence and infection intensities reported, the only exception being a qPCR-based study indicating 51% of carabao were S. japonicum-positive.,However, the low prevalence found for the same animals when using conventional copro-parasitological techniques means that there is still confusion about the role of carabao in the transmission of schistosomiasis japonicum.,To address this inconsistency, and to shed light on the potential role of carabao in the transmission of S. japonicum in the Philippines, we undertook a pilot survey, collecting fecal samples from animals in Western Samar Province and we used a combination of molecular and copro-parasitological techniques to determine the prevalence and intensity of S. japonicum.,We found a high prevalence of S. japonicum in the carabao using a validated real-time PCR (qPCR) and a copro-parasitological tool, the formalin-ethyl acetate sedimentation (FEA-SD) technique.,A much lower prevalence of S. japonicum was recorded for the same fecal samples using conventional PCR, the Kato-Katz technique and miracidial hatching.,These results suggest that, due to their low diagnostic sensitivity, traditional copro-parasitological techniques underestimate infection in carabao.,The use of FEA-SD and qPCR provides a more accurate diagnosis.,Based on these findings, the role of bovines in the transmission of S. japonicum appears to be more important in the Philippines than previously recognized, and this may have significant implications for the future control of schistosomiasis there, particularly as, in contrast with previous surveys, we found an unprecedented high prevalence of S. japonicum in humans.

Cryptosporidium spp. are worldwide protozoan parasites which include species that can lead to cryptosporidiosis in humans.,Different animal species can serve as reservoirs and sources of dissemination of the disease, such as rodent species due their potential in transmitting zoonotic pathogens to humans and other animals.,In the Canary Islands (Spain), Cryptosporidium parvum and Cryptosporidium hominis have been identified in patients with diarrhea.,However, the occurrence of Cryptosporidium spp. in possible reservoirs in this archipelago remains unclear.,Considering the zoonotic potential of these protozoans, the aim of the present study was to determine the presence of Cryptosporidium spp. in peridomestic wild rodents and the possible role of these mammals as a source of transmission of these protozoans in Canary Islands.,A total of 179 rodents belonging to Rattus rattus and Mus musculus domesticus from four Canary Islands, La Palma, El Hierro, Tenerife and Lanzarote, were analyzed.,Feces were screened for Cryptosporidium spp. by nested PCR of the 18S ribosomal RNA fragment and the sequences used for phylogenetic analyses.,Cryptosporidium spp. were found widely distributed with an overall prevalence of 12.30% in rodents (13.86% for R. rattus and 10.25% for M. m. domesticus).,The overall prevalence by island was 19.60% for Tenerife, 7.14% for La Palma, 5.71% for El Hierro and 0% for Lanzarote.,Cryptosporidium tyzzeri, Cryptosporidium meleagridis, Cryptosporidium muris and Cryptosporidium sp. rat genotype I and II/III were successfully identified, in addition to two unidentified Cryptosporidium genotypes.,This study contributes to the knowledge of the biodiversity and distribution of Cryptosporidium spp. in wild rodents from the Canary Islands, highlighting the presence of three zoonotic species, C. tyzzeri, C. meleagridis and C. muris, being the first detection of these three species in wild rodents in the Canary Islands and the first report of C. meleagridis in R. rattus.,Given the results obtained in our study, future studies in non-sampled areas are required to better understand the epidemiology of these protozoans in wild rodents in the archipelago.

In order to examine the prevalence of Cryptosporidium infection in wild rodents and insectivores of South Korea and to assess their potential role as a source of human cryptosporidiosis, a total of 199 wild rodents and insectivore specimens were collected from 10 regions of South Korea and screened for Cryptosporidium infection over a period of 2 years (2012-2013).,A nested-PCR amplification of Cryptosporidium oocyst wall protein (COWP) gene fragment revealed an overall prevalence of 34.2% (68/199).,The sequence analysis of 18S rRNA gene locus of Cryptosporidium was performed from the fecal and cecum samples that tested positive by COWP amplification PCR.,As a result, we identified 4 species/genotypes; chipmunk genotype I, cervine genotype I, C. muris, and a new genotype which is closely related to the bear genotype.,The new genotype isolated from 12 Apodemus agrarius and 2 Apodemus chejuensis was not previously identified as known species or genotype, and therefore, it is supposed to be a novel genotype.,In addition, the host spectrum of Cryptosporidium was extended to A. agrarius and Crosidura lasiura, which had not been reported before.,In this study, we found that the Korean wild rodents and insectivores were infected with various Cryptosporidium spp. with large intra-genotypic variationa, indicating that they may function as potential reservoirs transmitting zoonotic Cryptosporidium to livestock and humans.

Post Kala-azar dermal leishmaniasis (PKDL), caused by Leishmania donovani is the dermal sequel of Visceral Leishmaniasis and importantly, is the proposed disease reservoir.,The survival of Leishmania parasites within monocytes/macrophages hinges on its ability to effectively nullify immune activation mechanisms.,Thus, delineating the disease-promoting immune mechanisms can facilitate development of immunotherapeutic strategies.,Accordingly, in the absence of an animal model, this study aimed to delineate the status of CD8+ T-cells in patients with PKDL.,At disease presentation, the absence of CD4+ T-cells at lesional sites was concomitant with an overwhelming infiltration of CD8+ T-cells that demonstrated an absence of Perforin, Granzyme and Zap-70, along with an enhanced expression of Programmed Death-1 (PD-1) and the skin-homing CCL17.,Additionally, the lesional CCR4+CD8+ population was associated with an enhanced expression of IL-10 and IL-5.,In circulation, the enhanced CD8+CCR4+ T-cell population and raised levels of CCL17/22 was associated with an increased frequency of PD-1, while CD127 was decreased.,Taken together, in PKDL, the enhanced plasma and lesional CCL17 accounted for the dermal homing of CD8+CCR4+ T-cells, that along with a concomitant upregulation of PD-1 and IL-10 mediated immune inactivation, emphasizing the need for designing immunotherapies capable of reinvigorating T-cell potency.

The high level of functional diversity and plasticity in monocytes/macrophages has been defined within in vitro systems as M1 (classically activated), M2 (alternatively activated) and deactivated macrophages, of which the latter two subtypes are associated with suppression of cell mediated immunity, that confers susceptibility to intracellular infection.,Although the Leishmania parasite modulates macrophage functions to ensure its survival, what remains an unanswered yet pertinent question is whether these macrophages are deactivated or alternatively activated.,This study aimed to characterize the functional plasticity and polarization of monocytes/macrophages and delineate their importance in the immunopathogenesis of Post kala-azar dermal leishmaniasis (PKDL), a chronic dermatosis of human leishmaniasis.,Monocytes from PKDL patients showed a decreased expression of TLR-2/4, along with an attenuated generation of reactive oxidative/nitrosative species.,At disease presentation, an increased mRNA expression of classical M2 markers CD206, ARG1 and PPARG in monocytes and lesional macrophages indicated M2 polarization of macrophages which was corroborated by increased expression of CD206 and arginase-1.,Furthermore, altered vitamin D signaling was a key feature in PKDL, as disease presentation was associated with raised plasma levels of monohydroxylated vitamin D3 and vitamin D3- associated genes, features of M2 polarization.,Taken together, in PKDL, monocyte/macrophage subsets appear to be alternatively activated, a phenotype that might sustain disease chronicity.,Importantly, repolarization of these monocytes to M1 by antileishmanial drugs suggests that switching from M2 to M1 phenotype might represent a therapeutic opportunity, worthy of future pharmacological consideration.

In epidemiological surveys and surveillance the application of molecular tools is essential in detecting submicroscopic malaria.,A genus-specific conventional cytochrome b (cytb) PCR has shown high sensitivity in field studies, detecting 70% submicroscopic malaria.,The main objective of this study was to assess the conversion from conventional to real-time PCR testing both SYBR and probe protocols, and including quantitative (q) PCR.,The protocols were assessed applying well-defined clinical patient material consisting of 33 positive and 80 negative samples.,Sequencing of positive PCR products was performed.,In addition, a sensitivity comparison of real-time PCR methods was done by including five relevant assays investigating the effect of amplification target and platform.,Sensitivity was further examined using field material consisting of 111 P.falciparum positive samples from Tanzanian children (< 5 years), as well as using related patient data to assess the application of q-PCR with focus on low-level parasitaemia.,Both the cytb SYBR and probe PCR protocols showed as high sensitivity and specificity as their conventional counterpart, except missing one P. malariae sample.,The SYBR protocol was more sensitive and specific than using probe.,Overall, choice of amplification target applied is relevant for achieving ultra-sensitivity, and using intercalating fluorescence dye rather than labelled hydrolysis probes is favourable.,Application of q-PCR analysis in field projects is important for the awareness and understanding of low-level parasitaemia.,For use in clinical diagnosis and epidemiological studies the highly sensitive and user-friendly cytb SYBR q-PCR method is a relevant tool.,The genus-specific method has the advantage that species identification by sequencing can be performed as an alternative to species-specific PCR.

Plasmodium ovale is comprised of two genetically distinct subspecies, P. ovale curtisi and P. ovale wallikeri.,Although P. ovale subspecies are similar based on morphology and geographical distribution, allelic differences indicate that P. ovale curtisi and P. ovale wallikeri are genetically divergent.,Additionally, potential clinical and latency duration differences between P. ovale curtisi and P. ovale wallikeri demonstrate the need for investigation into the contribution of this neglected malaria parasite to the global malaria burden.,In order to detect all P. ovale subspecies simultaneously, we developed an inclusive P. ovale-specific real-time PCR assay based on conserved regions between P. ovale curtisi and P. ovale wallikeri in the reticulocyte binding protein 2 (rbp2) gene.,Additionally, we characterized the P. ovale subspecies prevalence from 22 asymptomatic malaria infections using multilocus genotyping to discriminate P. ovale curtisi and P. ovale wallikeri.,Our P. ovale rbp2 qPCR assay validation experiments demonstrated a linear dynamic range from 6.25 rbp2 plasmid copies/microliter to 100,000 rbp2 plasmid copies/microliter and a limit of detection of 1.5 rbp2 plasmid copies/microliter.,Specificity experiments showed the ability of the rbp2 qPCR assay to detect low-levels of P. ovale in the presence of additional malaria parasite species, including P. falciparum, P. vivax, and P. malariae.,We identified P. ovale curtisi and P. ovale wallikeri in Western Kenya by DNA sequencing of the tryptophan-rich antigen gene, the small subunit ribosomal RNA gene, and the rbp2 gene.,Our novel P. ovale rbp2 qPCR assay detects P. ovale curtisi and P. ovale wallikeri simultaneously and can be utilized to characterize the prevalence, distribution, and burden of P. ovale in malaria endemic regions.,Using multilocus genotyping, we also provided the first description of the prevalence of P. ovale curtisi and P. ovale wallikeri in Western Kenya, a region holoendemic for malaria transmission.

To compare the performance of the Paracheck™ rapid diagnostic test (RDT) with microscopy for diagnosing malaria in hospitalised children.,Children aged between 2 months and 13 years with fever were enrolled in the study over 1 year.,A standard clinical history and examination were recorded and blood drawn for culture, complete blood count, Paracheck™ RDT and double-read blood slide.,Of 3639 children enrolled, 2195 (60.3%) were slide positive.,The sensitivity and specificity of Paracheck were 97.5% (95% CI 96.9-98.0) and 65.3% (95% CI 63.8-66.9), respectively.,There was an inverse relationship between age-specific prevalence of parasitaemia and Paracheck specificity.,In logistic regression model, false-positive Paracheck results were significantly associated with pre-admission use of antimalarial drug (OR 1.44, 95% CI 1.16-1.78), absence of current fever (OR 0.64, 95% CI 0.52-0.79) and non-typhi Salmonella bacteraemia (OR 3.89.,95% CI 2.27-6.63).,In spite of high sensitivity, 56/2195 (2.6%) of true infections were Paracheck negative and 8/56 (14.3%) were in patients with >50 000 parasites/μl.,Paracheck had poor specificity in diagnosing malaria in severely ill children; this was likely to be due to HRP2 persistence following recent parasite clearance.,The combination of positive Paracheck and negative blood slide results identified a group of children at high risk of non-typhi Salmonella infection.,While Paracheck was highly sensitive, some high-density infections were missed.,For children with severe febrile illness, at least two reliable negative parasitological test results should be available to justify withholding antimalarial treatment; the optimal choice of these has yet to be identified.

Poor access to prompt and effective treatment for malaria contributes to high mortality and severe morbidity.,In Kenya, it is estimated that only 12% of children receive anti-malarials for their fever within 24 hours.,The first point of care for many fevers is a local medicine retailer, such as a pharmacy or chemist.,The role of the medicine retailer as an important distribution point for malaria medicines has been recognized and several different strategies have been used to improve the services that these retailers provide.,Despite these efforts, many mothers still purchase ineffective drugs because they are less expensive than effective artemisinin combination therapy (ACT).,One strategy that is being piloted in several countries is an international subsidy targeted at anti-malarials supplied through the retail sector.,The goal of this strategy is to make ACT as affordable as ineffective alternatives.,The programme, called the Affordable Medicines Facility - malaria was rolled out in Kenya in August 2010.,In December 2010, the affordability and accessibility of malaria medicines in a rural district in Kenya were evaluated using a complete census of all public and private facilities, chemists, pharmacists, and other malaria medicine retailers within the Webuye Demographic Surveillance Area.,Availability, types, and prices of anti-malarials were assessed.,There are 13 public or mission facilities and 97 medicine retailers (registered and unregistered).,The average distance from a home to the nearest public health facility is 2 km, but the average distance to the nearest medicine retailer is half that.,Quinine is the most frequently stocked anti-malarial (61% of retailers).,More medicine retailers stocked sulphadoxine-pyramethamine (SP; 57%) than ACT (44%).,Eleven percent of retailers stocked AMFm subsidized artemether-lumefantrine (AL).,No retailers had chloroquine in stock and only five were selling artemisinin monotherapy.,The mean price of any brand of AL, the recommended first-line drug in Kenya, was $2.7 USD.,Brands purchased under the AMFm programme cost 40% less than non-AMFm brands.,Artemisinin monotherapies cost on average more than twice as much as AMFm-brand AL.,SP cost only $0.5, a fraction of the price of ACT.,AMFm-subsidized anti-malarials are considerably less expensive than unsubsidized AL, but the price difference between effective and ineffective therapies is still large.

Mosquitoes, which evade contact with long-lasting insecticidal nets and indoor residual sprays, by feeding outdoors or upon animals, are primary malaria vectors in many tropical countries.,They can also dominate residual transmission where high coverage of these front-line vector control measures is achieved.,Complementary strategies, which extend insecticide coverage beyond houses and humans, are required to eliminate malaria transmission in most settings.,The overwhelming diversity of the world's malaria transmission systems and optimal strategies for controlling them can be simply conceptualized and mapped across two-dimensional scenario space defined by the proportion of blood meals that vectors obtain from humans and the proportion of human exposure to them which occurs indoors.

The most common pesticide products for controlling malaria-transmitting mosquitoes combine two distinct modes of action: 1) conventional insecticidal activity which kills mosquitoes exposed to the pesticide and 2) deterrence of mosquitoes away from protected humans.,While deterrence enhances personal or household protection of long-lasting insecticidal nets and indoor residual sprays, it may also attenuate or even reverse communal protection if it diverts mosquitoes to non-users rather than killing them outright.,A process-explicit model of malaria transmission is described which captures the sequential interaction between deterrent and toxic actions of vector control pesticides and accounts for the distinctive impacts of toxic activities which kill mosquitoes before or after they have fed upon the occupant of a covered house or sleeping space.,Increasing deterrency increases personal protection but consistently reduces communal protection because deterrent sub-lethal exposure inevitably reduces the proportion subsequently exposed to higher lethal doses.,If the high coverage targets of the World Health Organization are achieved, purely toxic products with no deterrence are predicted to generally provide superior protection to non-users and even users, especially where vectors feed exclusively on humans and a substantial amount of transmission occurs outdoors.,Remarkably, this is even the case if that product confers no personal protection and only kills mosquitoes after they have fed.,Products with purely mosquito-toxic profiles may, therefore, be preferable for programmes with universal coverage targets, rather than those with equivalent toxicity but which also have higher deterrence.,However, if purely mosquito-toxic products confer little personal protection because they do not deter mosquitoes and only kill them after they have fed, then they will require aggressive "catch up" campaigns, with behaviour change communication strategies that emphasize the communal nature of protection, to achieve high coverage rapidly.

African trypanosomiases are infectious diseases caused by trypanosomes.,African animal trypanosomiasis (AAT) remains an important threat for livestock production in some affected areas whereas human African trypanosomiasis (HAT) is targeted for elimination in 2020.,In West and Central Africa, it has been shown that the parasites causing these diseases can coexist in the same tsetse fly or the same animal.,In such complex settings, the control of these diseases must be put in the general context of trypanosomiasis control or “one health” concept where the coordination of control operations will be beneficial for both diseases.,In this context, implementing control activities on AAT will help to sustain HAT control.,It will also have a positive impact on animal health and economic development of the regions.,The training of inhabitants on how to implement and sustain vector control tools will enable a long-term sustainability of control operations that will lead to the elimination of HAT and AAT.

This review deals with transmission of Trypanosoma cruzi by the most important domestic vectors, blood transfusion and oral intake.,Among the vectors, Triatoma infestans, Panstrongylus megistus, Rhodnius prolixus, Triatoma dimidiata, Triatoma brasiliensis, Triatoma pseudomaculata, Triatoma sordida, Triatoma maculata, Panstrongylus geniculatus, Rhodnius ecuadoriensis and Rhodnius pallescens can be highlighted.,Transmission of Chagas infection, which has been brought under control in some countries in South and Central America, remains a great challenge, particularly considering that many endemic countries do not have control over blood donors.,Even more concerning is the case of non-endemic countries that receive thousands of migrants from endemic areas that carry Chagas disease, such as the United States of America, in North America, Spain, in Europe, Japan, in Asia, and Australia, in Oceania.,In the Brazilian Amazon Region, since Shaw et al. (1969) described the first acute cases of the disease caused by oral transmission, hundreds of acute cases of the disease due to oral transmission have been described in that region, which is today considered to be endemic for oral transmission.,Several other outbreaks of acute Chagas disease by oral transmission have been described in different states of Brazil and in other South American countries.

Trypanosomes are important disease agents of humans, livestock and cold-blooded species, including fish.,The cellular morphology of trypanosomes is central to their motility, adaptation to the host’s environments and pathogenesis.,However, visualizing the behaviour of trypanosomes resident in a live vertebrate host has remained unexplored.,In this study, we describe an infection model of zebrafish (Danio rerio) with Trypanosoma carassii.,By combining high spatio-temporal resolution microscopy with the transparency of live zebrafish, we describe in detail the swimming behaviour of trypanosomes in blood and tissues of a vertebrate host.,Besides the conventional tumbling and directional swimming, T. carassii can change direction through a ‘whip-like’ motion or by swimming backward.,Further, the posterior end can act as an anchoring site in vivo.,To our knowledge, this is the first report of a vertebrate infection model that allows detailed imaging of trypanosome swimming behaviour in vivo in a natural host environment.,Trypanosomes are one-celled parasites that cause the disease trypanosomiasis, which is also known as sleeping sickness.,Trypanosomiasis is transmitted to humans and animals by a type of fly, known as tse-tse, which is commonly found in sub-Saharan Africa.,A bite from the tse-tse fly transfers the trypanosome cells into the host’s bloodstream, where they spread from the blood to the internal organs and brain.,This leads to a long-term illness, which can sometimes result in a coma and eventually death.,Once in the blood trypanosomes move around using a structure similar to an underwater propeller called the flagellum.,How the trypanosomes move and behave in the blood determines how the infection will progress.,Until now it has only been possible to observe trypanosomes in plastic dishes or in blood drawn from infected patients.,However, neither of these settings mimic the conditions of the bloodstream, and it is currently impossible to look inside human hosts to watch how trypanosomes move.,To overcome this hurdle, Doro et al. infected zebrafish with Trypanosoma carassii, a close relative of the sub-Saharan trypanosomes that specifically infects fish.,Zebrafish are transparent when young, making it possible to observe the parasite in the blood and tissues of live fish using a microscope.,Doro et al. noticed that Trypanosoma carassii cells adapt to different environments in the host by using different swimming techniques.,For example, in small capillaries trypanosomes were dragged along with the blood flow, whilst in larger vessels, when blood flow was slow or there were fewer red blood cells, trypanosomes actively swam against the current.,The parasites were also able to change direction by using their flagella in a ‘whip-like’ motion.,Lastly, it was discovered that Trypanosoma carassii could rapidly attach to blood vessel walls using one end of its cell body, even when blood flow was strong.,This behaviour may help the parasites escape from the bloodstream into the surrounding tissues, making the infection more dangerous.,Studying how trypanosomes infect zebrafish at this high level of detail provides new insights into how these parasites move and behave inside a host.,An important question that remains to be answered, is how exactly the trypanosomes leave the bloodstream.,A better understanding of the whole infection process may hint at new ways of fighting these deadly infections in future.

Transmitted by blood-sucking insects, the unicellular parasite Trypanosoma cruzi is the causative agent of Chagas' disease, a malady manifested in a variety of symptoms from heart disease to digestive and urinary tract dysfunctions.,The reasons for such organ preference have been a matter of great interest in the field, particularly because the parasite can invade nearly every cell line and it can be found in most tissues following an infection.,Among the molecular factors that contribute to virulence is a large multigene family of proteins known as gp85/trans-sialidase, which participates in cell attachment and invasion.,But whether these proteins also contribute to tissue homing had not yet been investigated.,Here, a combination of endothelial cell immortalization and phage display techniques has been used to investigate the role of gp85/trans-sialidase in binding to the vasculature.,Bacteriophage expressing an important peptide motif (denominated FLY) common to all gp85/trans-sialidase proteins was used as a surrogate to investigate the interaction of this motif with the endothelium compartment.,For that purpose phage particles were incubated with endothelial cells obtained from different organs or injected into mice intravenously and the number of phage particles bound to cells or tissues was determined.,Binding of phages to intermediate filament proteins has also been studied.,Our data indicate that FLY interacts with the endothelium in an organ-dependent manner with significantly higher avidity for the heart vasculature.,Phage display results also show that FLY interaction with intermediate filament proteins is not limited to cytokeratin 18 (CK18), which may explain the wide variety of cells infected by the parasite.,This is the first time that members of the intermediate filaments in general, constituted by a large group of ubiquitously expressed proteins, have been implicated in T. cruzi cell invasion and tissue homing.

Different methods and data sources have been utilized to determine the relationship between malaria and mortality in endemic countries.,Most of these efforts have focused on deaths directly attributed to malaria, while they overlooked causes of mortality that might be indirectly related to the disease, for instance anemia.,We estimated the association of malaria parasitaemia, anemia, and malaria-anemia comorbidity with all-cause under-five mortality and evaluated the potential of malaria-anemia comorbidity prevalence to quantify malaria-related deaths in sub-Saharan Africa.,We analysed data from Demographic and Health Surveys (DHS) and employed Bayesian geostatistical models.,Mortality hazard obtained from malaria-anemia comorbidity prevalence was up to 3·5 times higher compared to the hazard related to Plasmodium parasitaemia only.,Malaria parasite prevalence alone could not always capture a statistically important association with under-five mortality.,Geographical variation of the malaria-anemia comorbidity effect was observed in most, but not all, countries.,We concluded that the malaria burden in sub-Saharan Africa is considerably underestimated when anemia in not taken into account and that the malaria-anemia comorbidity prevalence provides a useful measure of the malaria-related deaths.

Severe malaria is a rare life threatening illness.,Only a small proportion of patients with clinical malaria progress to this medical emergency.,On reviewing 61 malaria death investigation forms submitted to the provincial office in 2014, 22(36%) were children below ten years who succumbed to severe malaria.,Mutasa and Nyanga Districts reported 73% of these deaths.,This study was conducted to determine factors associated with severe malaria so as to come up with evidence based interventions to prevent severe malaria and associated mortality.,A 1:2 unmatched case control study was conducted.,A case was defined as a child 10 years and below, who was admitted at Hauna (Mutasa) or Nyanga District Hospitals between September 2014 and May 2015 with a primary diagnosis of severe malaria.,Controls were children of similar age with uncomplicated malaria.,Permission to conduct the study was sought and granted by the Medical Research Council of Zimbabwe (Approval number B/874), Joint Research Ethics Committee, Health Studies Office and the Manicaland Directorate Institutional Review Board.,Written informed consent was sought from all caregivers of enrolled children.,Interviewer administered questionnaires were used to ascertain exposures.,A total of 52 cases and 104 controls were enrolled into the study.,The median age of cases was 4 years (Q1=3, Q3=9) and 6 years for controls (Q1=3, Q3=8).,The Case Fatality Rate among cases was 28.8%.,The independent risk factors for severe malaria were; distance >10km to the nearest health facility [Adjusted Odds Ratio (aOR)=14.35, 95% CI=1.30, 158.81], duration of symptoms before seeking medical care >2 days [aOR=9.03, 95% CI=2.21, 36.93], having comorbidities [aOR=5.38, 95% CI=1.90, 15.19], staying in a house under construction [aOR=4.51, 95%CI=1.80, 11.32] and duration of illness before receiving antimalarial medicines >24 hours [aOR=3.82, 95% CI=1.44, 10.12].,Owning at least one ITN in the household [aOR=0.32, 95% CI=0.11, 0.95] and having a mother as a caregiver [aOR=0.23, 95% CI=0.09, 0.76] were independently protective of severe malaria.,Being undernourished [Odds Ratio (OR)=10.13, 95% CI=1.04, 98.49] and being female [OR=0.27, 95% CI=0.08, 0.96] were associated with mortality owing to severe malaria.,Factors associated with severe malaria and mortality owing to severe malaria identified in this study are consistent with other studies.,Caregiver healthcare seeking behaviours, patient related factors and health system related factors are important determinants of severe malaria among children.,There is need for regular health education campaigns emphasizing on malaria prevention, signs and symptoms and benefits of seeking medical care immediately for sick children.

Malaria continues to be a major health threat in Africa, mainly in rural areas.,Recently, the urban malaria vector Anopheles stephensi invaded Djibouti and Ethiopia, potentially spreading to other areas of Africa.,Urgent action is needed to prevent urban malaria epidemics from emerging and causing a public health disaster.

It was in Freetown, Sierra Leone, that the malaria mosquito Anopheles coastalis, now known as Anopheles gambiae, was first discovered as the vector of malaria, in 1899.,That discovery led to a pioneering vector research in Sierra Leone and neighbouring Liberia, where mosquito species were extensively characterized.,Unfortunately, the decade long civil conflicts of the 1990s, in both countries, resulted in a stagnation of the once vibrant research on disease vectors.,This paper attempts to fill in some of the gaps on what is now known of the distribution of the sibling species of the An. gambiae complex, and especially the An. coluzzii and An. gambiae s.s, formerly known as the An. gambiae molecular M and S forms respectively, in the cities of Freetown and Monrovia.

Treating Mansonella perstans is challenged by the low efficacy of registered antihelminthics.,Wolbachia endobacteria provide an alternative treatment target because depletion results in amicrofilaremia in filarial infections with Wuchereria bancrofti and Onchocerca volvulus infections.,This open-label, randomized study sought to confirm that i) Wolbachia are present in M. perstans in Ghana and ii) doxycycline treatment will deplete Wolbachia and cause a slow, sustained decline in microfilariae (MF).,Two hundred and two Ghanaians with M. perstans infection were randomized into early (immediate) and delayed (6 months deferred) treatment groups, given doxycycline 200 mg/day for 6 weeks, and monitored for MF and Wolbachia levels at baseline, 4, 12, and 24 months after the study onset (= time of randomization and start of treatment for the early group).,Per protocol analysis revealed that the median MF/mL in the early group declined from 138 at baseline to 64 at month 4 and further to 0 at month 12.,In the delayed group, MF load did not change from a baseline median of 97 to 102 at month 4 but declined to 42 at month 12, that is, 6 months after receiving treatment, trailing the early group as expected.,By month 24, both treatment groups had reached a median MF level of 0.,After treatment, Wolbachia were depleted from MF by ≥ 1-log drop compared with baseline levels.,We conclude that M. perstans in Ghana harbor Wolbachia that are effectively depleted by doxycycline with subsequent reduction in MF loads, most likely because of interruption of fertility of adult worms.

Filarial (and other helminth) infections are known to modulate mycobacteria-specific pro-inflammatory cytokine responses necessary for maintaining latency in tuberculosis (TB).,We sought to address whether helminth co-infection alters progression to active pulmonary TB in a co-endemic area of South India.,Incidence of active pulmonary TB was assessed in 5096 subjects from five villages among helminth-infected (hel+) and -uninfected (hel−) groups.,Baseline stool examinations, circulating filarial antigen, and tuberculin skin testing (PPD) were performed along with chest radiographs, sputum microscopy, and culture.,During three follow-up visits each 2.5 years, patients were assessed using PPD tests and questionnaires and-for those with potential symptoms of TB-sputum microscopy and culture.,Of the 5096 subjects, 1923 were found to be hel+ and 3173 were hel−.,Follow up interval stool examination could not be performed.,In each group, 21 developed active TB over the course of the study.,After adjusting for sex, age, BCG vaccination status, and PPD positivity, no difference was seen in active TB incidence between hel+ and hel− groups either at baseline (relative risk (RR) 1.60; 95% confidence interval (CI): 0.69, 3.71, P = 0·27), or when followed prospectively (RR 1.24; 95% CI: 0.48, 3.18, P = 0·66).,Our findings suggest that, despite the immunomodulatory effects of helminth infection, baseline co-morbid infection with these parasites had little effect on the clinical progression from latent to active pulmonary TB.

Plasmodium vivax is responsible for most of the malaria infections outside Africa and is currently the predominant malaria parasite in countries under elimination programs.,P. vivax preferentially enters young red cells called reticulocytes.,Advances in understanding the molecular and cellular mechanisms of entry are hampered by the inability to grow large numbers of P. vivax parasites in a long‐term in vitro culture.,Recent progress in understanding the biology of the P. vivax Reticulocyte Binding Protein (PvRBPs) family of invasion ligands has led to the identification of a new invasion pathway into reticulocytes, an understanding of their structural architecture and PvRBPs as targets of the protective immune response to P. vivax infection.,This review summarises current knowledge on the role of reticulocytes in P. vivax infection, the function of the PvRBP family of proteins in generating an immune response in human populations, and the characterization of anti‐PvRBP antibodies in blocking parasite invasion.

Malaria in sub-Saharan Africa has historically been almost exclusively attributed to Plasmodium falciparum (Pf).,Current diagnostic and surveillance systems in much of sub-Saharan Africa are not designed to identify or report non-Pf human malaria infections accurately, resulting in a dearth of routine epidemiological data about their significance.,The high prevalence of Duffy negativity provided a rationale for excluding the possibility of Plasmodium vivax (Pv) transmission.,However, review of varied evidence sources including traveller infections, community prevalence surveys, local clinical case reports, entomological and serological studies contradicts this viewpoint.,Here, these data reports are weighted in a unified framework to reflect the strength of evidence of indigenous Pv transmission in terms of diagnostic specificity, size of individual reports and corroboration between evidence sources.,Direct evidence was reported from 21 of the 47 malaria-endemic countries studied, while 42 countries were attributed with infections of visiting travellers.,Overall, moderate to conclusive evidence of transmission was available from 18 countries, distributed across all parts of the continent.,Approximately 86.6 million Duffy positive hosts were at risk of infection in Africa in 2015.,Analysis of the mechanisms sustaining Pv transmission across this continent of low frequency of susceptible hosts found that reports of Pv prevalence were consistent with transmission being potentially limited to Duffy positive populations.,Finally, reports of apparent Duffy-independent transmission are discussed.,While Pv is evidently not a major malaria parasite across most of sub-Saharan Africa, the evidence presented here highlights its widespread low-level endemicity.,An increased awareness of Pv as a potential malaria parasite, coupled with policy shifts towards species-specific diagnostics and reporting, will allow a robust assessment of the public health significance of Pv, as well as the other neglected non-Pf parasites, which are currently invisible to most public health authorities in Africa, but which can cause severe clinical illness and require specific control interventions.

Chagas disease is an anthropozoonosis caused by the protozoan parasite Trypanosoma cruzi that represents a major public health problem in Latin America.,Although the United States is defined as non-endemic for Chagas disease due to the rarity of human cases, the presence of T. cruzi has now been amply demonstrated as enzootic in different regions of the south of the country from Georgia to California.,In southeastern Louisiana, a high T. cruzi infection rate has been demonstrated in Triatoma sanguisuga, the local vector in this area.,However, little is known about the role of small mammals in the wild and peridomestic transmission cycles.,This study focused on the molecular identification and genotyping of T. cruzi in both small rodents and T. sanguisuga from a rural area of New Orleans, Louisiana.,DNA extractions were prepared from rodent heart, liver, spleen and skeletal muscle tissues and from cultures established from vector feces.,T. cruzi infection was determined by standard PCR using primers specific for the minicircle variable region of the kinetoplastid DNA (kDNA) and the highly repetitive genomic satellite DNA (satDNA).,Genotyping of discrete typing units (DTUs) was performed by amplification of mini-exon and 18S and 24Sα rRNA genes and subsequent sequence analysis.,The DTUs TcI, TcIV and, for the first time, TcII, were identified in tissues of mice and rats naturally infected with T. cruzi captured in an area of New Orleans, close to the house where the first human case of Chagas disease was reported in Louisiana.,The T. cruzi infection rate in 59 captured rodents was 76%.,The frequencies of the detected DTUs in such mammals were TcI 82%, TcII 22% and TcIV 9%; 13% of all infections contained more than one DTU.,Our results indicate a probable presence of a considerably greater diversity in T. cruzi DTUs circulating in the southeastern United States than previously reported.,Understanding T. cruzi transmission dynamics in sylvatic and peridomestic cycles in mammals and insect vectors will be crucial to estimating the risk of local, vector-borne transmission of T. cruzi to humans in the United States.

Traditional methods for Chagas disease prevention are targeted at domestic vector reduction, as well as control of transfusion and maternal-fetal transmission.,Population connectivity of Trypanosoma cruzi-infected vectors and hosts, among sylvatic, ecotone and domestic habitats could jeopardize targeted efforts to reduce human exposure.,This connectivity was evaluated in a Mexican community with reports of high vector infestation, human infection, and Chagas disease, surrounded by agricultural and natural areas.,We surveyed bats, rodents, and triatomines in dry and rainy seasons in three adjacent habitats (domestic, ecotone, sylvatic), and measured T. cruzi prevalence, and host feeding sources of triatomines.,Of 12 bat and 7 rodent species, no bat tested positive for T. cruzi, but all rodent species tested positive in at least one season or habitat.,Highest T. cruzi infection prevalence was found in the rodents, Baiomys musculus and Neotoma mexicana.,In general, parasite prevalence was not related to habitat or season, although the sylvatic habitat had higher infection prevalence than by chance, during the dry season.,Wild and domestic mammals were identified as bloodmeals of T. pallidipennis, with 9% of individuals having mixed human (4.8% single human) and other mammal species in bloodmeals, especially in the dry season; these vectors tested >50% positive for T. cruzi.,Overall, ecological connectivity is broad across this matrix, based on high rodent community similarity, vector and T. cruzi presence.,Cost-effective T. cruzi, vector control strategies and Chagas disease transmission prevention will need to consider continuous potential for parasite movement over the entire landscape.,This study provides clear evidence that these strategies will need to include reservoir/host species in at least ecotones, in addition to domestic habitats.

Infection with the intestinal helminth parasite Heligmosomoides polygyrus exacerbates the colitis caused by the bacterial enteropathogen Citrobacter rodentium.,To clarify the underlying mechanism, we analyzed fecal microbiota composition of control and helminth-infected mice and evaluated the functional role of compositional differences by microbiota transplantation experiments.,Our results showed that infection of Balb/c mice with H. polygyrus resulted in significant changes in the composition of the gut microbiota, characterized by a marked increase in the abundance of Bacteroidetes and decreases in Firmicutes and Lactobacillales.,Recipients of the gut microbiota from helminth-infected wide-type, but not STAT 6-deficient, Balb/c donors had increased fecal pathogen shedding and significant worsening of Citrobacter-induced colitis compared to recipients of microbiota from control donors.,Recipients of helminth-altered microbiota also displayed increased regulatory T cells and IL-10 expression.,Depletion of CD4+CD25+ T cells and neutralization of IL-10 in recipients of helminth-altered microbiota led to reduced stool C. rodentium numbers and attenuated colitis.,These results indicate that alteration of the gut microbiota is a significant contributor to the H. polygyrus-induced exacerbation of C. rodentium colitis.,The helminth-induced alteration of the microbiota is Th2-dependent and acts by promoting regulatory T cells that suppress protective responses to bacterial enteropathogens.

Urogenital schistosomiasis is caused by the helminth parasite Schistosoma haematobium.,In high transmission areas, children acquire schistosome infection early in life with infection levels peaking in early childhood and subsequently declining in late childhood.,This age-related infection profile is thought to result from the gradual development of protective acquired immunity.,Age-related differences in schistosome-specific humoral and cellular responses have been reported from several field studies.,However there has not yet been a systematic study of the age-related changes in human dendritic cells, the drivers of T cell polarisation.,Peripheral blood mononuclear cells were obtained from a cohort of 61 Zimbabwean aged 5-45 years with a S. haematobium prevalence of 47.5%.,Two subsets of dendritic cells, myeloid and plasmacytoid dentritic cells (mDCs and pDCs), were analyzed by flow cytometry.,In this population, schistosome infection levels peaked in the youngest age group (5-9 years), and declined in late childhood and adulthood (10+ years).,The proportions of both mDCs and pDCs varied with age.,However, for mDCs the age profile depended on host infection status.,In the youngest age group infected people had enhanced proportions of mDCs as well as lower levels of HLA-DR on mDCs than un-infected people.,In the older age groups (10-13 and 14-45 years) infected people had lower proportions of mDCs compared to un-infected individuals, but no infection status-related differences were observed in their levels of HLA-DR.,Moreover mDC proportions correlated with levels of schistosome-specific IgG, which can be associated with protective immunity.,In contrast proportions of pDCs varied with host age, but not with infection status.,Our results show that dendritic cell proportions and activation in a human population living in schistosome-endemic areas vary with host age reflecting differences in cumulative history of exposure to schistosome infection.

Extraction of natural resources through mining and logging activities provides revenue and employment across sub-Saharan Africa, a region with the highest burden of malaria globally.,The extent to which mining and logging influence malaria transmission in Africa remains poorly understood.,Here, we evaluate associations between mining, logging, and malaria in the high transmission setting of the Democratic Republic of the Congo using population-representative malaria survey results and geographic data for environmental features and mining and logging concessions.,We find elevated malaria prevalence among individuals in rural areas exposed to mining; however, we also detect significant spatial confounding among locations.,Upon correction, effect estimates for mining and logging shifted toward the null and we did not find sufficient evidence to detect an association with malaria.,Our findings reveal a complex interplay between mining, logging, space, and malaria prevalence.,While mining concessions alone may not drive the high prevalence, unobserved features of mining-exposed areas, such as human migration, changing vector populations, or parasite genetics, may instead be responsible.

In Africa, most rapid diagnostic tests (RDTs) for falciparum malaria recognize histidine-rich protein 2 antigen.,Plasmodium falciparum parasites lacking histidine-rich protein 2 (pfhrp2) and 3 (pfhrp3) genes escape detection by these RDTs, but it is not known whether these deletions confer sufficient selective advantage to drive rapid population expansion.,By studying blood samples from a cohort of 12,572 participants enroled in a prospective, cross-sectional survey along Ethiopia’s borders with Eritrea, Sudan and South Sudan using RDTs, PCR, an ultrasensitive bead-based immunoassay for antigen detection and next-generation sequencing, we estimate that histidine-rich protein 2-based RDTs would miss 9.7% (95% confidence interval 8.5-11.1) of P. falciparum malaria cases owing to pfhrp2 deletion.,We applied a molecular inversion probe-targeted deep sequencing approach to identify distinct subtelomeric deletion patterns and well-established pfhrp3 deletions and to uncover recent expansion of a singular pfhrp2 deletion in all regions sampled.,We propose a model in which pfhrp3 deletions have arisen independently multiple times, followed by strong positive selection for pfhrp2 deletion owing to RDT-based test-and-treatment.,Existing diagnostic strategies need to be urgently reconsidered in Ethiopia, and improved surveillance for pfhrp2 deletion is needed throughout the Horn of Africa.,A prospective, cross-sectional survey of 12,572 participants in Ethiopia reveals that malaria diagnostics miss almost 10% of cases owing to a gene deletion in Plasmodium falciparum that is under positive selection.

Larviciding refers to the regular application of chemical or microbial insecticides to water bodies or water containers to kill the aquatic immature forms of the mosquito (the larvae and pupae).,To summarize research evidence evaluating whether larviciding with chemical or microbial insecticides prevents malaria transmission.,We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; Embase; CAB Abstracts; LILACS; the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP); ClinicalTrials.gov; and the ISRCTN registry up to 6 June 2019.,We included cluster‐randomized controlled trials (cRCTs), interrupted time series (ITS), randomized cross‐over studies, non‐randomized cross‐over studies, and controlled before‐and‐after studies (CBAs) that compared larviciding with no larviciding.,We independently assessed trials for eligibility and risk of bias, and extracted data.,We assessed the certainty of evidence using the GRADE approach.,Four studies (one cRCT, two CBAs, and one non‐randomized cross‐over design) met the inclusion criteria.,All used ground application of larvicides (people hand‐delivering larvicides); one evaluated chemical and three evaluated microbial agents.,Studies were carried out in The Gambia, Tanzania, Kenya, and Sri Lanka.,Three studies were conducted in areas where mosquito aquatic habitats were less extensive (< 1 km²), and one where habitats were more extensive (> 1 km²; a cross‐over study from The Gambia).,For aquatic habitats of less than 1 km², one cRCT randomized eight villages in Sri Lanka to evaluate chemical larviciding using insect growth regulator; and two CBA studies undertaken in Kenya and Tanzania evaluated microbial larvicides.,In the cRCT, larviciding across all villages was associated with lower malaria incidence (rate ratio 0.24, 4649 participants, low‐certainty evidence) and parasite prevalence (risk ratio (RR) 0.26, 5897 participants, low‐certainty evidence) compared to no larviciding.,The two CBA studies reported lower malaria prevalence during the intervention period (parasite prevalence RR 0.79, 95% confidence interval (CI) 0.71 to 0.89; 70,902 participants; low‐certainty evidence).,The Kenyan study also reported a reduction in the incidence of new malaria cases (RR 0.62, 95% CI 0.38 to 1.01; 720 participants; very low‐certainty evidence).,For aquatic habitats of more than 1 km², the non‐randomized cross‐over trial using microbial larvicides did not detect an effect for malaria incidence (RR 1.58, 95% CI 0.94 to 2.65; 4226 participants), or parasite prevalence (RR 1.15, 95% CI 0.41 to 3.20; 3547 participants); both were very low‐certainty evidence.,The Gambia trial also reported the mean haemoglobin level, and there was no difference across the four comparisons (mean difference -0.13, 95% CI -0.40 to 0.13; 3586 participants).,We were unable to summarize or pool entomological outcomes due to unreported and missing data.,Most controlled studies on larviciding have been performed with microbial agents.,Ground larviciding for non‐extensive larval habitats may have an effect on malaria transmission, and we do not know if there is an effect in large‐scale aquatic habitats.,We found no studies using larviciding application techniques that could cover large aquatic habitats, such as aerial spraying using aircraft.,16 September 2019,Up to date,All studies incorporated from most recent search,All published trials found in the last search (6 Jun, 2019) were included, and we did not identify any ongoing trials.,Larviciding to control malaria,What was the aim of this review?,Larviciding is the regular application of microbial or chemical insecticides to water bodies or water containers.,The aim of larviciding is to reduce the adult population of mosquitoes by killing the aquatic immature forms, so that fewer will develop into adults.,This should reduce the number of mosquitoes that bite and infect humans with malaria.,Key messages,All four studies included in this review distributed larvicides manually.,Hand larviciding of small mosquito habitats may be effective in preventing malaria.,Only one study was conducted in an area where larval habitats spanned a large area and this study found no effect of larviciding.,What was studied in the review?,We searched for trials that evaluated the impact of larviciding, using a microbial agent or chemical insecticide on malaria transmission.,We considered effects on both human health outcomes and on mosquito populations.,What were the main results of the review?,Evidence from three studies shows that larviciding may decrease at least one malaria disease outcome in some studies, and this was in areas where the mosquito aquatic habitats were less than 1 km2 (low‐certainty evidence).,We do not know if larviciding in large water bodies shows an impact on malaria based on results from one study in The Gambia (very low‐certainty evidence).,How up to date is the review?,We searched for relevant trials up to 6 June 2019.

Scale-up of insecticide-based interventions has averted more than 500 million malaria cases since 2000.,Increasing insecticide resistance could herald a rebound in disease and mortality.,We aimed to investigate whether insecticide resistance was associated with loss of effectiveness of long-lasting insecticidal nets and increased malaria disease burden.,This WHO-coordinated, prospective, observational cohort study was done at 279 clusters (villages or groups of villages in which phenotypic resistance was measurable) in Benin, Cameroon, India, Kenya, and Sudan.,Pyrethroid long-lasting insecticidal nets were the principal form of malaria vector control in all study areas; in Sudan this approach was supplemented by indoor residual spraying.,Cohorts of children from randomly selected households in each cluster were recruited and followed up by community health workers to measure incidence of clinical malaria and prevalence of infection.,Mosquitoes were assessed for susceptibility to pyrethroids using the standard WHO bioassay test.,Country-specific results were combined using meta-analysis.,Between June 2, 2012, and Nov 4, 2016, 40 000 children were enrolled and assessed for clinical incidence during 1·4 million follow-up visits. 80 000 mosquitoes were assessed for insecticide resistance.,Long-lasting insecticidal net users had lower infection prevalence (adjusted odds ratio [OR] 0·63, 95% CI 0·51-0·78) and disease incidence (adjusted rate ratio [RR] 0·62, 0·41-0·94) than did non-users across a range of resistance levels.,We found no evidence of an association between insecticide resistance and infection prevalence (adjusted OR 0·86, 0·70-1·06) or incidence (adjusted RR 0·89, 0·72-1·10).,Users of nets, although significantly better protected than non-users, were nevertheless subject to high malaria infection risk (ranging from an average incidence in net users of 0·023, [95% CI 0·016-0·033] per person-year in India, to 0·80 [0·65-0·97] per person year in Kenya; and an average infection prevalence in net users of 0·8% [0·5-1·3] in India to an average infection prevalence of 50·8% [43·4-58·2] in Benin).,Irrespective of resistance, populations in malaria endemic areas should continue to use long-lasting insecticidal nets to reduce their risk of infection.,As nets provide only partial protection, the development of additional vector control tools should be prioritised to reduce the unacceptably high malaria burden.,Bill & Melinda Gates Foundation, UK Medical Research Council, and UK Department for International Development.

Malaria is spread by mosquitoes that are increasingly recognised to have diverse biting behaviours.,How a mosquito in a specific environment responds to differing availability of blood-host species is largely unknown and yet critical to vector control efficacy.,A parsimonious mathematical model is proposed that accounts for a diverse range of host-biting behaviours and assesses their impact on combining long-lasting insecticidal nets (LLINs) with a novel approach to malaria control: livestock treated with insecticidal compounds (‘endectocides’) that kill biting mosquitoes.,Simulations of a malaria control programme showed marked differences across biting ecologies in the efficacy of both LLINs as a stand-alone tool and the combination of LLINs with endectocide-treated cattle.,During the intervals between LLIN mass campaigns, concordant use of endectocides is projected to reduce the bounce-back in malaria prevalence that can occur as LLIN efficacy decays over time, especially if replacement campaigns are delayed.,Integrating these approaches can also dramatically improve the attainability of local elimination; endectocidal treatment schedules required to achieve this aim are provided for malaria vectors with different biting ecologies.,Targeting blood-feeding mosquitoes by treating livestock with endectocides offers a potentially useful complement to existing malaria control programmes centred on LLIN distribution.,This approach is likely to be effective against vectors with a wide range of host-preferences and biting behaviours, with the exception of species that are so strictly anthropophilic that most blood meals are taken on humans even when humans are much less available than non-human hosts.,Identifying this functional relationship in wild mosquito populations and ascertaining the extent to which it differs, within as well as between species, is a critical next step before targets can be set for employing this novel approach and combination.,The online version of this article (doi:10.1186/s12936-017-1748-5) contains supplementary material, which is available to authorized users.

Philippa West and colleagues compare Plasmodium falciparum infection prevalence in children, anemia in young children, and entomological inoculation rate between study arms.,Please see later in the article for the Editors' Summary,Insecticide-treated nets (ITNs) and indoor residual spraying (IRS) of houses provide effective malaria transmission control.,There is conflicting evidence about whether it is more beneficial to provide both interventions in combination.,A cluster randomised controlled trial was conducted to investigate whether the combination provides added protection compared to ITNs alone.,In northwest Tanzania, 50 clusters (village areas) were randomly allocated to ITNs only or ITNs and IRS.,Dwellings in the ITN+IRS arm were sprayed with two rounds of bendiocarb in 2012.,Plasmodium falciparum prevalence rate (PfPR) in children 0.5-14 y old (primary outcome) and anaemia in children <5 y old (secondary outcome) were compared between study arms using three cross-sectional household surveys in 2012.,Entomological inoculation rate (secondary outcome) was compared between study arms.,IRS coverage was approximately 90%.,ITN use ranged from 36% to 50%.,In intention-to-treat analysis, mean PfPR was 13% in the ITN+IRS arm and 26% in the ITN only arm, odds ratio = 0.43 (95% CI 0.19-0.97, n = 13,146).,The strongest effect was observed in the peak transmission season, 6 mo after the first IRS.,Subgroup analysis showed that ITN users were additionally protected if their houses were sprayed.,Mean monthly entomological inoculation rate was non-significantly lower in the ITN+IRS arm than in the ITN only arm, rate ratio = 0.17 (95% CI 0.03-1.08).,This is the first randomised trial to our knowledge that reports significant added protection from combining IRS and ITNs compared to ITNs alone.,The effect is likely to be attributable to IRS providing added protection to ITN users as well as compensating for inadequate ITN use.,Policy makers should consider deploying IRS in combination with ITNs to control transmission if local ITN strategies on their own are insufficiently effective.,Given the uncertain generalisability of these findings, it would be prudent for malaria control programmes to evaluate the cost-effectiveness of deploying the combination.,www.ClinicalTrials.govNCT01697852,Please see later in the article for the Editors' Summary,Every year, more than 200 million cases of malaria occur worldwide, and more than 600,000 people, mainly children living in sub-Saharan Africa, die from this parasitic infection.,Malaria parasites, which are transmitted to people through the bites of infected night-flying mosquitoes, cause a characteristic fever that needs to be treated promptly with antimalarial drugs to prevent anaemia (a reduction in red blood cell numbers) and organ damage.,Prompt treatment also helps to reduce malaria transmission, but the mainstays of global malaria control efforts are the provision of insecticide-treated nets (ITNs) for people to sleep under to avoid mosquito bites, and indoor residual spraying (IRS) of houses with insecticides, which prevents mosquitoes from resting in houses.,Both approaches have been scaled up in the past decade.,About 54% of households in Africa now own at least one ITN, and 8% of at-risk populations are protected by IRS.,As a result of the widespread deployment of these preventative tools and the increased availability of effective antimalarial drugs, malaria-related deaths in Africa fell by 45% between 2000 and 2012.,Some countries have chosen to use ITNs and IRS in combination, reasoning that this will increase the proportion of individuals who are protected by at least one intervention and may provide additional protection to people using both interventions rather than one alone.,However, providing both interventions is costly, so it is important to know whether this rationale is correct.,In this cluster randomised controlled trial (a study that compares outcomes of groups of people randomly assigned to receive different interventions) undertaken in the Muleba District of Tanzania during 2012, the researchers investigate whether ITNs plus IRS provide more protection against malaria than ITNs alone.,Malaria transmission occurs throughout the year in Muleba District but peaks after the October-December and March-May rains.,Ninety-one percent of the district's households own at least one ITN, and 58% of households own enough ITNs to cover all their sleeping places.,Annual rounds of IRS have been conducted in the region since 2007.,The researchers allocated 50 communities to the ITN intervention or to the ITN+IRS intervention.,Dwellings allocated to ITN+IRS were sprayed with insecticide just before each of the malaria transmission peaks in 2012.,The researchers used household surveys to collect information about ITN coverage in the study population, the proportion of children aged 0.5-14 years infected with the malaria parasite Plasmodium falciparum (the prevalence of infection), and the proportion of children under five years old with anaemia.,IRS coverage in the ITN+IRS arm was approximately 90%, and 50% of the children in both intervention arms used ITNs at the start of the trial, declining to 36% at the end of the study.,In an intention-to-treat analysis (which assumed that all study participants got the planned intervention), the average prevalence of infection was 13% in the ITN+IRS arm and 26% in the ITN arm.,A per-protocol analysis (which considered data only from participants who received their allocated intervention) indicated that the combined intervention had a statistically significant protective effect on the prevalence of infection compared to ITNs alone (an effect that is unlikely to have arisen by chance).,Finally, the proportion of young children with anaemia was lower in the ITN+IRS arm than in the ITN arm, but this effect was not statistically significant.,These findings provide evidence that IRS, when used in combination with ITNs, can provide better protection against malaria infection than ITNs used alone.,This effect is likely to be the result of IRS providing added protection to ITN users as well as compensating for inadequate ITN use.,The findings also suggest that the combination of interventions may reduce the prevalence of anaemia better than ITNs alone, but this result needs to be confirmed.,Additional trials are also needed to investigate whether ITN+IRS compared to ITN reduces clinical cases of malaria, and whether similar effects are seen in other settings.,Moreover, the cost-effectiveness of ITN+IRS and ITN alone needs to be compared.,For now, though, these findings suggest that national malaria control programs should consider implementing IRS in combination with ITNs if local ITN strategies alone are insufficiently effective and cannot be improved.,Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001630.,Information is available from the World Health Organization on malaria (in several languages), including information on insecticide-treated bed nets and indoor residual spraying; the World Malaria Report 2013 provides details of the current global malaria situation,The US Centers for Disease Control and Prevention provides information on malaria, on insecticide-treated bed nets, and on indoor residual spraying; it also provides a selection of personal stories about malaria,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 nets and insecticides,MedlinePlus provides links to additional information on malaria (in English and Spanish)

Strongyloidiasis is a much-neglected soil born helminthiasis caused by the nematode Strongyloides stercoralis.,Human derived S. stercoralis can be maintained in dogs in the laboratory and this parasite has been reported to also occur in dogs in the wild.,Some authors have considered strongyloidiasis a zoonotic disease while others have argued that the two hosts carry host specialized populations of S. stercoralis and that dogs play a minor role, if any, as a reservoir for zoonotic S. stercoralis infections of humans.,We isolated S. stercoralis from humans and their dogs in rural villages in northern Cambodia, a region with a high incidence of strongyloidiasis, and compared the worms derived from these two host species using nuclear and mitochondrial DNA sequence polymorphisms.,We found that in dogs there exist two populations of S. stercoralis, which are clearly separated from each other genetically based on the nuclear 18S rDNA, the mitochondrial cox1 locus and whole genome sequence.,One population, to which the majority of the worms belong, appears to be restricted to dogs.,The other population is indistinguishable from the population of S. stercoralis isolated from humans.,Consistent with earlier studies, we found multiple sequence variants of the hypervariable region I of the 18 S rDNA in S. stercoralis from humans.,However, comparison of mitochondrial sequences and whole genome analysis suggest that these different 18S variants do not represent multiple genetically isolated subpopulations among the worms isolated from humans.,We also investigated the mode of reproduction of the free-living generations of laboratory and wild isolates of S. stercoralis.,Contrary to earlier literature on S. stercoralis but similar to other species of Strongyloides, we found clear evidence of sexual reproduction.,Overall, our results show that dogs carry two populations, possibly different species of Strongyloides.,One population appears to be dog specific but the other one is shared with humans.,This argues for the strong potential of dogs as reservoirs for zoonotic transmission of S. stercoralis to humans and suggests that in order to reduce the exposure of humans to infective S. stercoralis larvae, dogs should be treated for the infection along with their owners.

Humans and dogs are the two major hosts of Strongyloides stercoralis, an intestinal parasitic nematode.,To better understand the phylogenetic relationships among S. stercoralis isolates infecting humans and dogs and to assess the zoonotic potential of this parasite, we analyzed mitochondrial Cox1, nuclear 18S rDNA, 28S rDNA, and a major sperm protein domain-containing protein genes.,Overall, our analyses indicated the presence of two distinct lineages of S. stercoralis (referred to as type A and type B).,While type A parasites were isolated both from humans and dogs in different countries, type B parasites were found exclusively in dogs, indicating that the type B has not adapted to infect humans.,These epidemiological data, together with the close phylogenetic relationship of S. stercoralis with S. procyonis, a Strongyloides parasite of raccoons, possibly indicates that S. stercoralis originally evolved as a canid parasite, and later spread into humans.,The inability to infect humans might be an ancestral character of this species and the type B might be surmised to be an origin population from which human-infecting strains are derived.

STING is an innate immune cytosolic adaptor for DNA sensors that engage malaria parasite (Plasmodium falciparum) or other pathogen DNA.,As P. falciparum infects red blood cells and not leukocytes, how parasite DNA reaches such host cytosolic DNA sensors in immune cells is unclear.,Here we show that malaria parasites inside red blood cells can engage host cytosolic innate immune cell receptors from a distance by secreting extracellular vesicles (EV) containing parasitic small RNA and genomic DNA.,Upon internalization of DNA-harboring EVs by human monocytes, P. falciparum DNA is released within the host cell cytosol, leading to STING-dependent DNA sensing.,STING subsequently activates the kinase TBK1, which phosphorylates the transcription factor IRF3, causing IRF3 to translocate to the nucleus and induce STING-dependent gene expression.,This DNA-sensing pathway may be an important decoy mechanism to promote P. falciparum virulence and thereby may affect future strategies to treat malaria.,STING is an intracellular DNA sensor that can alter response to infection, but in the case of malaria it is unclear how parasite DNA in red blood cells (RBCs) reaches DNA sensors in immune cells.,Here the authors show that STING in human monocytes can sense P. falciparum nucleic acids transported from infected RBCs via parasite extracellular vesicles.

The FMP2.1/AS02A candidate malaria vaccine was tested in a Phase 2 study in Mali.,Based on results from the first eight months of follow-up, the vaccine appeared well-tolerated and immunogenic.,It had no significant efficacy based on the primary endpoint, clinical malaria, but marginal efficacy against clinical malaria in secondary analyses, and high allele-specific efficacy.,Extended follow-up was conducted to evaluate extended safety, immunogenicity and efficacy.,A randomized, double-blinded trial of safety, immunogenicity and efficacy of the candidate Plasmodium falciparum apical membrane antigen 1 (AMA1) vaccine FMP2.1/AS02A was conducted in Bandiagara, Mali.,Children aged 1-6 years were randomized in a 1∶1 ratio to receive FMP2.1/AS02A or control rabies vaccine on days 0, 30 and 60.,Using active and passive surveillance, clinical malaria and adverse events as well as antibodies against P. falciparum AMA1 were monitored for 24 months after the first vaccination, spanning two malaria seasons.,400 children were enrolled.,Serious adverse events occurred in nine participants in the FMP2.1/AS02A group and three in the control group; none was considered related to study vaccination.,After two years, anti-AMA1 immune responses remained significantly higher in the FMP2.1/AS02A group than in the control group.,For the entire 24-month follow-up period, vaccine efficacy was 7.6% (p = 0.51) against first clinical malaria episodes and 9.9% (p = 0.19) against all malaria episodes.,For the final 16-month follow-up period, vaccine efficacy was 0.9% (p = 0.98) against all malaria episodes.,Allele-specific efficacy seen in the first malaria season did not extend into the second season of follow-up.,Allele-specific vaccine efficacy was not sustained in the second malaria season, despite continued high levels of anti-AMA1 antibodies.,This study presents an opportunity to evaluate correlates of partial protection against clinical malaria that waned during the second malaria season.,Clinicaltrials.gov NCT00460525 NCT00460525

Concerted efforts from national and international partners have scaled up malaria control interventions, including insecticide-treated nets, indoor residual spraying, diagnostics, prompt and effective treatment of malaria cases, and intermittent preventive treatment during pregnancy in sub-Saharan Africa (SSA).,This scale-up warrants an assessment of its health impact to guide future efforts and investments; however, measuring malaria-specific mortality and the overall impact of malaria control interventions remains challenging.,In 2007, Roll Back Malaria's Monitoring and Evaluation Reference Group proposed a theoretical framework for evaluating the impact of full-coverage malaria control interventions on morbidity and mortality in high-burden SSA countries.,Recently, several evaluations have contributed new ideas and lessons to strengthen this plausibility design.,This paper harnesses that new evaluation experience to expand the framework, with additional features, such as stratification, to examine subgroups most likely to experience improvement if control programs are working; the use of a national platform framework; and analysis of complete birth histories from national household surveys.,The refined framework has shown that, despite persisting data challenges, combining multiple sources of data, considering potential contributions from both fundamental and proximate contextual factors, and conducting subnational analyses allows identification of the plausible contributions of malaria control interventions on malaria morbidity and mortality.

Background: Climate change may affect Plasmodium vivax malaria transmission in a wide region including both subtropical and temperate areas.,Objectives: We aimed to estimate the effects of climatic variables on the transmission of P. vivax in temperate regions.,Methods: We estimated the effects of climatic factors on P. vivax malaria transmission using data on weekly numbers of malaria cases for the years 2001-2009 in the Republic of Korea.,Generalized linear Poisson models and distributed lag nonlinear models (DLNM) were adopted to estimate the effects of temperature, relative humidity, temperature fluctuation, duration of sunshine, and rainfall on malaria transmission while adjusting for seasonal variation, between-year variation, and other climatic factors.,Results: A 1°C increase in temperature was associated with a 17.7% [95% confidence interval (CI): 16.9, 18.6%] increase in malaria incidence after a 3-week lag, a 10% rise in relative humidity was associated with 40.7% (95% CI: -44.3, -36.9%) decrease in malaria after a 7-week lag, a 1°C increase in the diurnal temperature range was associated with a 24.1% (95% CI: -26.7, -21.4%) decrease in malaria after a 7-week lag, and a 10-hr increase in sunshine per week was associated with a 5.1% (95% CI: -8.4, -1.7%) decrease in malaria after a 2-week lag.,The cumulative relative risk for a 10-mm increase in rainfall (≤ 350 mm) on P. vivax malaria was 3.61 (95% CI: 1.69, 7.72) based on a DLNM with a 10-week maximum lag.,Conclusions: Our findings suggest that malaria transmission in temperate areas is highly dependent on climate factors.,In addition, lagged estimates of the effect of rainfall on malaria are consistent with the time necessary for mosquito development and P. vivax incubation.

Introduction: Relapses are important contributors to illness and morbidity in Plasmodium vivax and P. ovale infections.,Relapse prevention (radical cure) with primaquine is required for optimal management, control and ultimately elimination of Plasmodium vivax malaria.,A review was conducted with publications in English, French, Portuguese and Spanish using the search terms ‘P. vivax’ and ‘relapse’.,Areas covered: Hypnozoites causing relapses may be activated weeks or months after initial infection.,Incidence and temporal patterns of relapse varies geographically.,Relapses derive from parasites either genetically similar or different from the primary infection indicating that some derive from previous infections.,Malaria illness itself may activate relapse.,Primaquine is the only widely available treatment for radical cure.,However, it is often not given because of uncertainty over the risks of primaquine induced haemolysis when G6PD deficiency testing is unavailable.,Recommended dosing of primaquine for radical cure in East Asia and Oceania is 0.5 mg base/kg/day and elsewhere is 0.25 mg base/kg/day.,Alternative treatments are under investigation.,Expert commentary: Geographic heterogeneity in relapse patterns and chloroquine susceptibility of P. vivax, and G6PD deficiency epidemiology mean that radical treatment should be given much more than it is today.,G6PD testing should be made widely available so primaquine can be given more safely.

Plasmodium vivax malaria is widespread, and the persistent liver stage causes relapse of the disease which contributes to continued P. vivax transmission.,Primaquine is currently the only drug that cures the parasite liver stage, but requires 14 days to be effective and can cause haemolysis in people with glucose‐6‐phosphate dehydrogenase (G6PD) deficiency.,In addition, there is some evidence of parasite resistance to the drug.,Tafenoquine is a new alternative with a longer half‐life.,To assess the effects of tafenoquine in people with P. vivax infection.,We searched the following databases up to 13 April 2015: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; CINAHL; SCOPUS; and LILACS.,We also searched the World Health Organization (WHO) International Clinical Trial Registry Platform and the metaRegister of Controlled Trials (mRCT) for ongoing trials using "tafenoquine" and "malaria" as search terms up to 13 April 2015.,Randomized controlled trials (RCTs) in people with P. vivax malaria.,Adverse effects of tafenoquine are assessed in populations where people with G6PD deficiency have been excluded, and in populations without screening for G6PD deficiency.,All review authors independently extracted data and assessed trial quality.,Meta‐analysis was carried out where appropriate, and estimates given as relative risk with 95% confidence intervals.,We assessed the quality of the evidence using the GRADE approach.,Three RCTs met our inclusion criteria, with the asexual infection in both the tafenoquine and comparator arm treated with chloroquine, and in all trials G6PD deficiency patients were excluded.,Tafenoquine dose comparisons,Three of the included trials compared eight different dosing regimens.,Tafenoquine doses of 300 mg and above resulted in fewer relapses than no hypnozoite treatment over six months follow‐up in adults (300 mg single dose: RR 0.19, 95% CI 0.08 to 0.41, one trial, 110 participants, moderate quality evidence; 500 to 600 mg single dose: RR 0.14, 95%CI 0.06 to 0.34, two trials, 122 participants, moderate quality evidence; 1800 mg to 3000 mg in divided doses: RR 0.05, 95% CI 0.01 to 0.23, two trials, 63 participants, low quality evidence).,In people with normal G6PD status, there may be little or no difference in serious adverse events (three trials, 358 participants, low quality evidence); or any adverse event (one trial, 272 participants, low quality evidence).,Tafenoquine versus primaquine,Two of the included trials compared four different dosing regimens of tafenoquine against the standard primaquine regimen of 15 mg/day for 14 days.,A single tafenoquine dose of 600 mg may be more effective than primaquine in relation to relapses at six months follow‐up (RR 0.29, 95% CI 0.10 to 0.84, two trials, 98 participants, low quality evidence),In people with normal G6PD status, there may be little or no difference for serious adverse events (two trials, 323 participants, low quality evidence) or any adverse event (two trials, 323 participants, low quality evidence) between tafenoquine and primaquine.,Tafenoquine prevents relapses after clinically and parasitologically confirmed P. vivax malaria.,The drug is untested in pregnancy, children and in G6PD‐deficient people.,The shorter treatment course is an important practical advantage in people who do not have G6PD deficiency, but the longer half‐life may have more substantive consequences if given inadvertently to people with G6PD deficiency.,Background,Vivax malaria is caused by the parasite Plasmodium vivax.,The disease includes a stage of liver infection and this can cause relapse unless treated.,The only drug available until recently was primaquine, but this requires a 14‐day course of treatment.,Alternatives have been tried, one of which is tafenoquine, which does not need such a long course of treatment.,Both primaquine and tafenoquine can cause haemolysis in people with glucose‐6‐phosphate dehydrogenase (G6PD) enzyme deficiency, which is a common genetic defect.,We conducted a Cochrane Review on the effect of the drug tafenoquine on clearing the dormant P. vivax parasites in infected patients to prevent a relapse.,Review findings,Researchers in the Cochrane Collaboration examined the research published up to 13 April 2015.,We identified three trials conducted in Thailand, India, Peru and Brazil on adults with confirmedP. vivax malaria that randomized 453 participants.,All adults received chloroquine (to clear the parasites in the blood) and some groups received either tafenoquine, primaquine or no further treatment.,All were observed for recurrences of P. vivax malaria (up to six months) and all trials tested people for G6PD enzyme, and excluded patients who were deficient.,Adults receiving tafenoquine at doses greater than 300 mg had fewer relapses than adults who had no further treatment (moderate quality evidence).,Tafenoquine 600 mg may be better in relapse prevention than standard primaquine doses (low quality evidence).,In patients who do not have G6PD deficiency, there may be little or no difference in adverse effects (low quality evidence).,The drug is untested in children and pregnant women.,The shorter treatment course is a practical advantage, but the longer half‐life could may have more substantive consequences if given inadvertently to people with G6PD deficiency.

In the past decade, national malaria control efforts in Papua New Guinea (PNG) have received renewed support, facilitating nationwide distribution of free long-lasting insecticidal nets (LLINs), as well as improvements in access to parasite-confirmed diagnosis and effective artemisinin-combination therapy in 2011-2012.,To study the effects of these intensified control efforts on the epidemiology and transmission of Plasmodium falciparum and Plasmodium vivax infections and investigate risk factors at the individual and household level, two cross-sectional surveys were conducted in the East Sepik Province of PNG; one in 2005, before the scale-up of national campaigns and one in late 2012-early 2013, after 2 rounds of LLIN distribution (2008 and 2011-2012).,Differences between studies were investigated using Chi square (χ2), Fischer’s exact tests and Student’s t-test.,Multivariable logistic regression models were built to investigate factors associated with infection at the individual and household level.,The prevalence of P. falciparum and P. vivax in surveyed communities decreased from 55% (2005) to 9% (2013) and 36% to 6%, respectively.,The mean multiplicity of infection (MOI) decreased from 1.8 to 1.6 for P. falciparum (p = 0.08) and from 2.2 to 1.4 for P. vivax (p < 0.001).,Alongside these reductions, a shift towards a more uniform distribution of infections and illness across age groups was observed but there was greater heterogeneity across the study area and within the study villages.,Microscopy positive infections and clinical cases in the household were associated with high rate infection households (> 50% of household members with Plasmodium infection).,After the scale-up of malaria control interventions in PNG between 2008 and 2012, there was a substantial reduction in P. falciparum and P. vivax infection rates in the studies villages in East Sepik Province.,Understanding the extent of local heterogeneity in malaria transmission and the driving factors is critical to identify and implement targeted control strategies to ensure the ongoing success of malaria control in PNG and inform the development of tools required to achieve elimination.,In household-based interventions, diagnostics with a sensitivity similar to (expert) microscopy could be used to identify and target high rate households.

Chloroquine is the first-line treatment for Plasmodium vivax malaria in most endemic countries, but resistance is increasing.,Monitoring of antimalarial efficacy is essential, but in P vivax infections the assessment of treatment efficacy is confounded by relapse from the dormant liver stages.,We systematically reviewed P vivax malaria treatment efficacy studies to establish the global extent of chloroquine resistance.,We searched Medline, Web of Science, Embase, and the Cochrane Database of Systematic Reviews to identify studies published in English between Jan 1, 1960, and April 30, 2014, which investigated antimalarial treatment efficacy in P vivax malaria.,We excluded studies that did not include supervised schizonticidal treatment without primaquine.,We determined rates of chloroquine resistance according to P vivax malaria recurrence rates by day 28 whole-blood chloroquine concentrations at the time of recurrence and study enrolment criteria.,We identified 129 eligible clinical trials involving 21 694 patients at 179 study sites and 26 case reports describing 54 patients.,Chloroquine resistance was present in 58 (53%) of 113 assessable study sites, spread across most countries that are endemic for P vivax.,Clearance of parasitaemia assessed by microscopy in 95% of patients by day 2, or all patients by day 3, was 100% predictive of chloroquine sensitivity.,Heterogeneity of study design and analysis has confounded global surveillance of chloroquine-resistant P vivax, which is now present across most countries endemic for P vivax.,Improved methods for monitoring of drug resistance are needed to inform antimalarial policy in these regions.,Wellcome Trust (UK).

Mosquito-borne diseases pose some of the greatest challenges in public health, especially in tropical and sub-tropical regions of the world.,Efforts to control these diseases have been underpinned by a theoretical framework developed for malaria by Ross and Macdonald, including models, metrics for measuring transmission, and theory of control that identifies key vulnerabilities in the transmission cycle.,That framework, especially Macdonald's formula for R0 and its entomological derivative, vectorial capacity, are now used to study dynamics and design interventions for many mosquito-borne diseases.,A systematic review of 388 models published between 1970 and 2010 found that the vast majority adopted the Ross-Macdonald assumption of homogeneous transmission in a well-mixed population.,Studies comparing models and data question these assumptions and point to the capacity to model heterogeneous, focal transmission as the most important but relatively unexplored component in current theory.,Fine-scale heterogeneity causes transmission dynamics to be nonlinear, and poses problems for modeling, epidemiology and measurement.,Novel mathematical approaches show how heterogeneity arises from the biology and the landscape on which the processes of mosquito biting and pathogen transmission unfold.,Emerging theory focuses attention on the ecological and social context for mosquito blood feeding, the movement of both hosts and mosquitoes, and the relevant spatial scales for measuring transmission and for modeling dynamics and control.

Sustaining elimination of malaria in areas with high receptivity and vulnerability will require effective strategies to prevent reestablishment of local transmission, yet there is a dearth of evidence about this phase.,Mauritius offers a uniquely informative history, with elimination of local transmission in 1969, re-emergence in 1975, and second elimination in 1998.,Towards this end, Mauritius's elimination and prevention of reintroduction (POR) programs were analyzed via a comprehensive review of literature and government documents, supplemented by program observation and interviews with policy makers and program personnel.,The impact of the country's most costly intervention, a passenger screening program, was assessed quantitatively using simulation modeling.,On average, Mauritius spent $4.43 per capita per year (pcpy) during its second elimination campaign from 1982 to 1988.,The country currently spends $2.06 pcpy on its POR program that includes robust surveillance, routine vector control, and prompt and effective treatment and response.,Thirty-five percent of POR costs are for a passenger screening program.,Modeling suggests that the estimated 14% of imported malaria infections identified by this program reduces the annual risk of indigenous transmission by approximately 2%.,Of cases missed by the initial passenger screening program, 49% were estimated to be identified by passive or reactive case detection, leaving an estimated 3.1 unidentified imported infections per 100,000 inhabitants per year.,The Mauritius experience indicates that ongoing intervention, strong leadership, and substantial predictable funding are critical to consistently prevent the reestablishment of malaria.,Sustained vigilance is critical considering Mauritius's enabling conditions.,Although the cost of POR is below that of elimination, annual per capita spending remains at levels that are likely infeasible for countries with lower overall health spending.,Countries currently embarking on elimination should quantify and plan for potentially similar POR operations and costs.

Despite growing evidence that infants and very young children can be infected with schistosomes, the epidemiological features and risk factors are not well described in this age group.,We aimed to assess the prevalence of S. mansoni infection in children under two years of age from a population with a known high burden of infection in school-aged children and adults and thus inform the need for interventions in this potentially vulnerable age group.,In a cross-sectional study in Mbita Sub-county, along the east coast of Lake Victoria, Western Kenya, we enrolled 361 children aged 6-23 months.,The prevalence of S. mansoni infection was detected using the Kato-Katz stool examination and a point-of-care test for urinary circulating cathodic antigen (POC-CCA) (Rapid Medical Diagnostics, Pretoria, South Africa).,Three-hundred and five (305) children had complete data of whom 276 (90.5%, 95%CI: 86.6-93.5) children were positive for S. mansoni by the POC-CCA test, while 11 (3.6%, 95%CI: 1.8-6.4) were positive by the Kato-Katz method.,All Kato-Katz positive cases were also positive by the POC-CCA test.,In multivariable analysis, only geographical area, Rusinga West (AOR = 7.1, 95%CI: 1.4-35.2, P = 0.02), was associated with S. mansoni infection using Kato-Katz test.,Independent associations for POC-CCA positivity included age, (12-17 months vs 6-11 months; AOR = 7.8, 95%CI: 1.8-32.6, P = 0.002) and breastfeeding in the previous 24 hours (AOR = 3.4, 95%CI: 1.3-9.0, P = 0.009).,We found a potentially very high prevalence of S. mansoni infection among children under two years of age based on POC-CCA test results in Mbita Sub-county, Kenya, which if confirmed strongly supports the need to include infants in public health strategies providing universal prophylactic treatment in high burden settings.,Further research is required to determine the accuracy of diagnostic tools to detect light infection among very young children and possible long-term health impacts.

Prevalence of schistosomiasis is high among children under five years in Uganda.,Schistosomiasis control efforts over time have included periodic mass treatments in endemic areas for adults and school going children aged 5 years and above.,This study explores behaviour practices of children age 2-4 years that increase the risk of schistosomiasis infection in this age group.,A qualitative descriptive study was conducted using in-depth interviews with 30 caregivers of children aged 2-4 years who tested positive for schistosomiasis in a national prevalence survey in 2017.,Observations were done at water bodies where young children go with caretakers or other older children.,The study was conducted in three Ugandan sub-regions of West Nile and East-central, and South-western with high, and low prevalence of schistosomiasis, respectively.,Data were thematically analysed.,Anonymised supporting photos from observations are also presented.,Knowledge about schistosomiasis transmission was poor among caregivers, who concurrently had mixed right and wrong information.,Reported avenues for contracting schistosomiasis included both correct: contact activities with infested water, and incorrect modes: contact with dirty water, sharing bathrooms, witchcraft, polluted air and contaminated food.,The children in this study could have contracted schistosomiasis through the contact with infested water during activities such as bathing and playing, while their caregivers washed clothes, collected snail shells for poultry feeds, fetched water at the water bodies.,These activities were reported by caregivers and observed in all study areas.,Evidence of open defecation and urination in and near water bodies by adults and children was also observed.,Pre-school children age 2-4 years are at a high risk of exposure to schistosomiasis while caretakers conduct activities in infested water bodies.,There is need for prevention interventions to target children in their early stages of life to control schistosomiasis in this vulnerable population.

Light microscopy and antigen-based rapid diagnostic tests are the primary diagnostic tools for detecting malaria, although being labour-intensive and frequently challenged by lack of personnel’s experience and low levels of parasite density.,The latter being especially important in non-endemic settings.,Novel molecular techniques aim to overcome this drawback.,The objective of this study was to assess the diagnostic performance of the illumigene malaria assay® (Meridian Bioscience) compared to microscopy, RDT and real-time PCR.,This loop-mediated isothermal amplification (LAMP) assay is a qualitative in vitro diagnostic test for the direct detection of Plasmodium spp.,DNA in human venous whole blood samples.,The illumigene assay was assessed on a retrospective panel of stored blood samples (n = 103) from returned travellers and external quality control samples (n = 12).,Additionally the assay was prospectively assessed on 30 fresh routine samples with a request for malaria diagnosis.,The illumigene assay was compared to microscopy, RDT and Plasmodium species specific real-time PCR.,In the retrospective evaluation, the illumigene assay showed 100% agreement with the real-time PCR, RDT and microscopy yielding a sensitivity and specificity of 100% (95% CI 95.1-100% and 89.7-100%, respectively).,Seven samples from patients recently treated for Plasmodium falciparum infection that were RDT positive and microscopy negative yielded positive test results.,The performance of the illumigene assay equals that of microscopy combined with RDT in the prospective panel with three false negative RDT results and one false negative microscopy result.,Excellent concordance with PCR was observed.,The limit of detection of the assay approached 0.5 parasites/µL for both P. falciparum and Plasmodium vivax.,In non-endemic regions where the diagnostic process for malaria infections is questioned by lack of experience and low levels of parasite densities, the illumigene assay can be of value.,Due to its high sensitivity, the LAMP assay may be considered as primary diagnostic test.,The results of this study indicate that negative screen results do not need further confirmation.,However, before implementation, this approach needs to be confirmed in larger, prospective studies.,A shortcoming of this assay is that no species identification nor determination of parasite density are possible.

The literature data on malaria in Western Kasai, DRC, are limited and inadequate.,A recent molecular survey there has detected Plasmodium ovale and Plasmodium malariae as mixed infections with Plasmodium falciparum.,In Tshimbulu, Western Kasai, during a humanitarian initiative designed to provide children with free preventive screening and to reduce the local high malaria death rate, accurate species identification was performed, in order to collect unambiguous epidemiological data and to evaluate the reliability of locally applied diagnostics.,Finger pricks provided fresh blood for microscopic analysis (MA), for rapid diagnostic test (RDT) and for molecular diagnostics (MD).,MA and RDT were first performed by the local team and then a re-interpretation of the results (on the same slides and on RDT’s taken pictures) was conducted in Italy, where MD were performed.,The analysis was conducted on 306 children; RDT found 80.9 % as P. falciparum-positive (37.4 % as two-band positive, P. falciparum single infection).,MA identified a further four children as positive to P. falciparum and six co-infections with P. ovale.,The second RDT evaluation confirmed a similar infection rate (78.2 %) but interpreted as two-band positive a significantly higher share of tests (56.8 %).,MA confirmed 80.0 % of the children as malaria positive and, in addition to P. falciparum, identified P. malariae (13.8 %), P. vivax (3.4 %) and P. ovale (2.4 %), and detected Babesia microti in 19 smears.,MD confirmed all of the species found (Babesia microti included), classified as mono-infection with P. falciparum a rate of spots comparable to MA revision, and identified all P. ovale as Plasmodium ovale wallikeri.,The RDT used locally proved 93.1 % sensitive and 92.1 % specific for P. falciparum.,The malaria prevalence among the children and the presence of four Plasmodium species, highlighted in this study, identified a sanitary issue which proved to be more alarming than expected, as it was worsened by the unpredictable presence of P. vivax and Babesia microti (never before reported in DRC).,Each diagnostic tool showed its point of weakness.,Therefore, the most correct approach is by the combined use of different, locally available, diagnostic tools.

In rural areas in Morocco, diagnosing cutaneous leishmaniasis (CL) can be challenging.,We evaluated the accuracy of a rapid diagnostic test (RDT) based on antigen detection, CL Detect Rapid Test™ (Inbios International Inc., Seattle, WA), in this setting.,We consecutively recruited patients with new skin ulcers in nine primary health centers.,We took a dental broach sample for the RDT and two other tissue samples by scraping the border and center of the lesion with a scalpel and smearing it on a slide.,We duplicated each smear by pressing a clean slide against it and processed the slides by microscopy, polymerase chain reaction (PCR) internal transcribed spacer 1, and kDNA minicircle PCR.,In a subgroup with positive PCR, the Leishmania species was identified using PCR-restriction fragment length polymorphism and PCR-sequencing of hsp70 genes.,A participant with positive microscopy and/or PCR was considered a confirmed CL case.,We computed sensitivity (Se) and specificity (Sp) of the RDT compared with this reference standard (ClinicalTrials.gov registration: NCT02979002).,Between December 2016 and July 2017, we included 219 patients, 50% of them were under 18 years old.,Rapid diagnostic test Se was 68% [95% confidence interval (CI): 61-74], Sp 94% [95% CI: 91-97], positive predictive value 95% [95% CI: 92-98], and negative predictive value 64% [95% CI: 58-70].,Despite its low Se, this novel RDT is a useful addition to clinical management of CL in Morocco, especially in isolated localities.,Rapid diagnostic test-positive lesions can be treated as CL; but when RDT negative, microscopy should be done in a second step.,The Se of the RDT can probably be optimized by improving the sampling procedure.

The diagnosis of the leishmaniases poses enormous challenges in Argentina.,The Polymorphism-Specific PCR (PS-PCR) designed and validated in our laboratories has been proven effective for typifying the Leishmania genus from cultured material.,Here we evaluated the performance of this method in the diagnosis of American tegumentary leishmaniasis (ATL) and the rapid identification of Leishmania spp. directly from clinical specimens.,A total of 63 patients from northwestern Argentina, with cutaneous or mucocutaneous lesions, underwent an ATL diagnosis protocol which included clinical examination, Leishmanin skin test, and microscopic examination of dermal smears.,In addition, we performed PS-PCR on DNA directly extracted from the specimens scraped from the lesions.,Out of the 63 patients, 44 were classified as ATL cases and 19 as non-ATL cases.,The diagnostic sensitivity of the microscopic analysis of dermal smears and PS-PCR individually were 70.5% and 81%, respectively.,When performing both tests in parallel, this parameter increased significantly to 97.6% (p = 0.0018).,The specificities, on the other hand, were 100%, 84.2%, and 83.3% for the combination, respectively (p > 0.05).,Using the PS-PCR analysis we successfully identified the Leishmania spp. in 31 out of the 44 ATL cases.,Twenty-eight (90.3%) cases were caused by L.,(V.) braziliensis, two (6.5%) by L.,(V.) guyanensis, and one (3.2%) by L.,(V.) panamensis.,The efficacy of the ATL diagnosis was significantly improved by combining the dermal smear examination with a PS-PCR analysis.,Our strategy allowed us to reach the diagnosis of ATL with high accuracy regarding the species of the etiological agent in 70.5% of the cases.,Moreover, we diagnosed two cases of the disseminated cutaneous form caused by L.,(V.) braziliensis and a cutaneous case due to L.,(V.) panamensis infection, both findings reported for the first time in Argentina.

Malaria has affected human health globally with a significant burden of disease, and also has impeded social and economic development in the areas where it is present.,In Africa, many countries have faced serious challenges in controlling malaria, in part due to major limitations in public health systems and primary health care infrastructure.,Although China is a developing country, a set of control strategies and measures in different local settings have been implemented successfully by the National Malaria Control Programme over the last 60 years, with a low cost of investment.,It is expected that Chinese experience may benefit malaria control in Africa.,This review will address the importance and possibility of China-Africa collaboration in control of malaria in targeted African countries, as well as how to proceed toward the goal of elimination where this is technically feasible.

Since several malaria parasite species are usually present in a particular area, co-infections with more than one species of Plasmodium are more likely to occur in humans infected in these areas.,In many mixed infections, parasite densities of the cryptic species may be low and often not recognized in clinical practice.,Two children (3 and 6 years old) adopted recently from Central African Republic were admitted to hospital because of intermittent fever.,Thin blood smears stained with Giemsa showed Plasmodium falciparum and Plasmodium malariae co-infection for both children at admission.,They were both treated with atovaquone-proguanil combination for 3 days.,At day 7, both thin blood smears examination remained negative but at day 28, thin blood smear was positive for P. malariae trophozoites and for Plasmodium ovale for the girl and her brother, respectively.,Samples collected at day 1 and day 28 were submitted to real-time PCR showing the presence of the three parasite species (P. falciparum, P malariae and P. ovale) in admission blood samples from the two children and only P. ovale at day 28.,Twenty-eight days follow-up after treatment led to detection of a third parasite species in the blood of these two patients suggesting covert co-infection and a delayed appearance of one cryptic species following treatment.,Concurrently infecting malaria species could be mutually suppressive, with P. falciparum tending to dominate other species.,These observations provide more evidence that recommendations for treatment of imported malaria should take into account the risk of concurrent or cryptic infection with Plasmodium species.,Clinicians and biologists should be aware of the underestimated frequency of mixed infections with cryptic species and of the importance of patient follow-up at day 28.,Future guidelines should shed more light on the treatment of mixed infection and on the interest of using artemisinin-based combinations for falciparum and non-falciparum species.

Rapid population growth in Africa requires an urgent expansion and improvement of housing options.,Improving housing presents a promising opportunity for malaria control by reducing indoor exposure to mosquitoes.,We measured recent changes in house design in rural Uganda and evaluated their association with malaria in relation to a mass scale-up of control efforts.,This analysis was part of a cohort study designed to compare temporal changes in malaria incidence from a cohort of children and adults with temporal changes in malaria test positivity rate from health facility surveillance.,All children aged 6 months to 10 years (n=384) living in 107 households in Nagongera sub-country, Tororo, Uganda, were given long-lasting insecticide-treated nets and followed between Aug 19, 2011, and June 30, 2017.,Repeat rounds of indoor residual spraying of insecticide were initiated on Dec 5, 2014.,Socioeconomic data were collected at two timepoints (Sept 25-Oct 9, 2013 and June 21-July 11, 2016) and houses were classified as modern (cement, wood, or metal walls, tiled or metal roof, and closed eaves) or traditional (all other homes).,Associations between house design and three outcomes were evaluated before and after the introduction of indoor residual spraying: human biting rate estimated monthly in each household using US Centers for Disease Control and Prevention light traps; parasite prevalence measured routinely by microscopy every 3 months before indoor residual spraying and monthly after indoor residual spraying; and malaria incidence measured by passive surveillance.,The implementation of indoor residual spraying was associated with significant declines in human biting rate (33·5 vs 2·7 Anopheles per house per night after indoor residual spraying, p<0·0001), parasite prevalence (32·0% vs 14·0%, p<0·0001), and malaria incidence (3·0 vs 0·5 episodes per person-year at risk, p<0·0001).,The prevalence of modern housing increased from 23·4% in 2013 to 45·4% in 2016 (p=0·001).,Compared with traditional houses, modern houses were associated with a 48% reduction in human biting rate before indoor residual spraying (adjusted incidence rate ratio [aIRR] 0·52, 95% CI 0·36-0·73, p=0·0002), and a 73% reduction after indoor residual spraying (aIRR 0·27, 0·17-0·42, p<0·0001).,Before indoor residual spraying, there was no association between house type and parasite prevalence, but after indoor residual spraying there was a 57% reduction in the odds of parasitaemia in modern houses compared with traditional houses, controlling for age, sex, and socioeconomic position (adjusted odds ratio 0·43, 95% CI 0·24-0·77, p=0·004).,House type was not associated with malaria incidence before or after indoor residual spraying.,House design improved rapidly in rural Uganda and was associated with additional reductions in mosquito density and parasite prevalence following the introduction of indoor residual spraying.,Changes to house design in endemic Africa, including closing eaves and the replacement of traditional building materials, might help further the gains achieved with more widely accepted malaria control interventions.,US National Institutes of Health, Bill & Melinda Gates Foundation, and Medical Research Council UK.

Improvements to housing may contribute to malaria control and elimination by reducing house entry by malaria vectors and thus exposure to biting.,We tested the hypothesis that the odds of malaria infection are lower in modern, improved housing compared to traditional housing in sub-Saharan Africa (SSA).,We analysed 15 Demographic and Health Surveys (DHS) and 14 Malaria Indicator Surveys (MIS) conducted in 21 countries in SSA between 2008 and 2015 that measured malaria infection by microscopy or rapid diagnostic test (RDT).,DHS/MIS surveys record whether houses are built with finished materials (e.g., metal) or rudimentary materials (e.g., thatch).,This information was used to develop a binary housing quality variable where houses built using finished wall, roof, and floor materials were classified as “modern”, and all other houses were classified as “traditional”.,Conditional logistic regression was used to determine the association between housing quality and prevalence of malaria infection in children aged 0-5 y, adjusting for age, gender, insecticide-treated net (ITN) use, indoor residual spraying, household wealth, and geographic cluster.,Individual survey odds ratios (ORs) were combined to determine a summary OR using a random effects meta-analysis.,Of 284,532 total children surveyed, 139,318 were tested for malaria infection using microscopy (n = 131,652) or RDT (n = 138,540).,Within individual surveys, malaria prevalence measured by microscopy ranged from 0.4% (Madagascar 2011) to 45.5% (Burkina Faso 2010) among children living in modern houses and from 0.4% (The Gambia 2013) to 70.6% (Burkina Faso 2010) in traditional houses, and malaria prevalence measured by RDT ranged from 0.3% (Senegal 2013-2014) to 61.2% (Burkina Faso 2010) in modern houses and from 1.5% (The Gambia 2013) to 79.8% (Burkina Faso 2010) in traditional houses.,Across all surveys, modern housing was associated with a 9% to 14% reduction in the odds of malaria infection (microscopy: adjusted OR 0.91, 95% CI 0.85-0.97, p = 0.003; RDT: adjusted OR 0.86, 95% CI 0.80-0.92, p < 0.001).,This association was consistent regardless of ITN usage.,As a comparison, the odds of malaria infection were 15% to 16% lower among ITN users versus non-users (microscopy: adjusted OR 0.84, 95% CI 0.79-0.90, p < 0.001; RDT: adjusted OR 0.85, 95% CI 0.80-0.90, p < 0.001).,The main limitation of this study is that residual confounding by household wealth of the observed association between housing quality and malaria prevalence is possible, since the wealth index may not have fully captured differences in socioeconomic position; however, the use of multiple national surveys offers the advantage of a large sample size and the elimination of many biases typically associated with pooling observational data.,Housing quality is an important risk factor for malaria infection across the spectrum of malaria endemicity in SSA, with a strength of association between housing quality and malaria similar to that observed between ITN use and malaria.,Improved housing should be considered a promising intervention for malaria control and elimination and long-term prevention of reintroduction.,Lucy Tusting and colleagues investigate the association between housing quality and malaria infection in children under 5 living in sub-Saharan Africa.

Soil transmitted nematodes, including Strongyloides, cause one of the most prevalent Neglected Tropical Diseases.,Here we compare the genomes of four Strongyloides spp., including the human pathogen S. stercoralis, and their close relatives that are facultatively parasitic (Parastrongyloides trichosuri) and free-living (Rhabditophanes sp).,A significant paralogous expansion of key gene families - astacin-like and SCP/TAPS coding gene families - is associated with the evolution of parasitism in this clade.,Exploiting the unique Strongyloides life cycle we compare the transcriptome of its parasitic and free-living stages and find that these same genes are upregulated in the parasitic stages, underscoring their role in nematode parasitism.

Insulin resistance is a strong predictor of the development of type 2 diabetes mellitus.,Chronic helminth infections might protect against insulin resistance via a caloric restriction state and indirectly via T-helper-2 polarization of the immune system.,Therefore the elimination of helminths might remove this beneficial effect on insulin resistance.,To determine whether soil-transmitted helminth infections are associated with a better whole-body insulin sensitivity and whether this protection is reversible by anthelmintic treatment, a household-based cluster-randomized, double blind, placebo-controlled trial was conducted in the area of Nangapanda on Flores Island, Indonesia, an area endemic for soil-transmitted helminth infections.,The trial incorporates three monthly treatment with albendazole or matching placebo for one year, whereby each treatment round consists of three consecutive days of supervised drug intake.,The presence of soil-transmitted helminths will be evaluated in faeces using microscopy and/or PCR.,The primary outcome of the study will be changes in insulin resistance as assessed by HOMA-IR, while the secondary outcomes will be changes in body mass index, waist circumference, fasting blood glucose, 2 h-glucose levels after oral glucose tolerance test, HbA1c, serum lipid levels, immunological parameters, and efficacy of anthelmintic treatment.,The study will provide data on the effect of helminth infections on insulin resistance.,It will assess the relationship between helminth infection status and immune responses as well as metabolic parameters, allowing the establishment of a link between inflammation and whole-body metabolic homeostasis.,In addition, it will give information on anthelmintic treatment efficacy and effectiveness.,This study has been approved by the ethical committee of Faculty of Medicine Universitas Indonesia (ref: 549/H2.,F1/ETIK/2013), and has been filed by the ethics committee of Leiden University Medical Center, clinical trial number: ISRCTN75636394.,The study is reported in accordance with the CONSORT guidelines for cluster-randomised trials.

Amplicon deep sequencing permits sensitive detection of minority clones and improves discriminatory power for genotyping multi-clone Plasmodium falciparum infections.,New amplicon sequencing and data analysis protocols are needed for genotyping in epidemiological studies and drug efficacy trials of P. falciparum.,Targeted sequencing of molecular marker csp and novel marker cpmp was conducted in duplicate on mixtures of parasite culture strains and 37 field samples.,A protocol allowing to multiplex up to 384 samples in a single sequencing run was applied.,Software “HaplotypR” was developed for data analysis.,Cpmp was highly diverse (He = 0.96) in contrast to csp (He = 0.57).,Minority clones were robustly detected if their frequency was >1%.,False haplotype calls owing to sequencing errors were observed below that threshold.,To reliably detect haplotypes at very low frequencies, experiments are best performed in duplicate and should aim for coverage of >10′000 reads/amplicon.,When compared to length polymorphic marker msp2, highly multiplexed amplicon sequencing displayed greater sensitivity in detecting minority clones.,The online version of this article (10.1186/s12864-017-4260-y) contains supplementary material, which is available to authorized users.

A major challenge to global malaria control and elimination is early detection and containment of emerging drug resistance.,Next-generation sequencing (NGS) methods provide the resolution, scalability, and sensitivity required for high-throughput surveillance of molecular markers of drug resistance.,We have developed an amplicon sequencing method on the Ion Torrent PGM platform for targeted resequencing of a panel of six Plasmodium falciparum genes implicated in resistance to first-line antimalarial therapy, including artemisinin combination therapy, chloroquine, and sulfadoxine-pyrimethamine.,The protocol was optimized using 12 geographically diverse P. falciparum reference strains and successfully applied to multiplexed sequencing of 16 clinical isolates from India.,The sequencing results from the reference strains showed 100% concordance with previously reported drug resistance-associated mutations.,Single-nucleotide polymorphisms (SNPs) in clinical isolates revealed a number of known resistance-associated mutations and other nonsynonymous mutations that have not been implicated in drug resistance.,SNP positions containing multiple allelic variants were used to identify three clinical samples containing mixed genotypes indicative of multiclonal infections.,The amplicon sequencing protocol has been designed for the benchtop Ion Torrent PGM platform and can be operated with minimal bioinformatics infrastructure, making it ideal for use in countries that are endemic for the disease to facilitate routine large-scale surveillance of the emergence of drug resistance and to ensure continued success of the malaria treatment policy.

Veterinarians and farmers must contend with the development of drug resistance and climate variability, which threaten the sustainability of current parasite control practices.,Field trials evaluating competing strategies for controlling parasites while simultaneously slowing the development of resistance are time consuming and expensive.,In contrast, modelling studies can rapidly explore a wide range of scenarios and have generated an array of decision support tools for veterinarians and farmers such as real-time weather-dependent infection risk alerts.,Models have also been valuable for predicting the development of anthelmintic resistance, evaluating the sustainability of current parasite control practices and promoting the responsible use of novel anthelmintics.

This study examines the prevalence of drug resistance in gastrointestinal nematodes to macrocyclic lactones (ML) and benzimidazoles (BZ) in Lithuanian sheep using sensitive and precise in vitro methods.,The survey was conducted from August 2013 to November 2014.,Thirty-three farms with sheep previously treated with BZ and ivermectin (IVM) were included in the study.,On 12 farms where only BZ were used, egg hatch discrimination dose testing (EHDDT) was conducted to detect anthelmintic resistance (AR) to BZ.,On eight farms where only ML were used, micro agar larval development testing (MALDT) was conducted to detect AR to ivermectin (IVM).,On the remaining 13 farms, where both classes of drugs were used, EHDDT and MALDT were both applied to detect multidrug resistance to BZ and IVM.,BZ-resistant gastrointestinal nematodes were found on all 25 farms with a previous history of BZ use.,High levels of resistance (>40 % of hatching) were recorded on 36 % of these farms, and low levels (<20 % of hatching) on 40 % of farms.,IVM-resistant populations were found on 13 out of 21 sheep farms using this drug.,Of these 13 farms with AR to IVM, low levels of resistance (<30 % development) were recorded on 84.6 % of farms and high levels (>30 % development) on 15.4 % of farms.,No resistance to IVM was recorded on 38.1 % of farms.,Multi-drug resistance was detected on five farms out of 13 (38.5 %) using both classes of drugs.,The present study demonstrates the existence of AR to BZ and ML on Lithuanian sheep farms thus confirming results in a previous in vivo study.,Cases of multi-drug resistance were recorded in the present study and require further consideration.,An appropriate strategy for anthelmintic treatment, measures to prevent gastrointestinal nematode infection and a better understanding of the management practices associated with resistance may slow down further development of AR.

While the combination of nifurtimox and eflornithine (NECT) is currently recommended for the treatment of the late stage human African trypansomiasis (HAT), single-agent eflornithine was still the treatment of choice when this trial commenced.,This study intended to provide supportive evidence to complement previous trials.,A multi-centre randomised, open-label, non-inferiority trial was carried out in the Trypanosoma brucei gambiense endemic districts of North-Western Uganda to compare the efficacy and safety of NECT (200 mg/kg eflornithine infusions every 12 h for 7 days and 8 hourly oral nifurtimox at 5 mg/kg for 10 days) to the standard eflornithine regimen (6 hourly at 100 mg/kg for 14 days).,The primary endpoint was the cure rate, determined as the proportion of patients alive and without laboratory signs of infection at 18 months post-treatment, with no demonstrated trypanosomes in the cerebrospinal fluid (CSF), blood or lymph node aspirates, and CSF white blood cell count < 20 /μl.,The non-inferiority margin was set at 10%.,One hundred and nine patients were enrolled; all contributed to the intent-to-treat (ITT), modified intent-to-treat (mITT) and safety populations, while 105 constituted the per-protocol population (PP).,The cure rate was 90.9% for NECT and 88.9% for eflornithine in the ITT and mITT populations; the same was 90.6 and 88.5%, respectively in the PP population.,Non-inferiority was demonstrated for NECT in all populations: differences in cure rates were 0.02 (95% CI: -0.07-0.11) and 0.02 (95% CI: -0.08-0.12) respectively.,Two patients died while on treatment (1 in each arm), and 3 more during follow-up in the NECT arm.,No difference was found between the two arms for the secondary efficacy and safety parameters.,A meta-analysis involving several studies demonstrated non-inferiority of NECT to eflornithine monotherapy.,These results confirm findings of earlier trials and support implementation of NECT as first-line treatment for late stage T. b. gambiense HAT.,The overall risk difference for cure between NECT and eflornithine between this and two previous randomised controlled trials is 0.03 (95% CI: -0.02-0.08).,The NECT regimen is simpler, safer, shorter and less expensive than single-agent DFMO.,ISRCTN ISRCTN03148609 (registered 18 April 2008).,The online version of this article (10.1186/s13071-018-2634-x) contains supplementary material, which is available to authorized users.

Leishmania braziliensis is the most prevalent species isolated from patients displaying cutaneous and muco-cutaneous leishmaniasis in South America.,However, there are difficulties for studying L. braziliensis pathogenesis or response to chemotherapy in vivo due to the natural resistance of most mouse strains to infection with these parasites.,The aim of this work was to develop an experimental set up that could be used to assess drug efficacy against L. braziliensis.,The model was tested using miltefosine.,A L. braziliensis line, originally isolated from a cutaneous leishmaniasis patient, was passaged repeatedly in laboratory rodents and further genetically manipulated to express luciferase.,Once collected from a culture of parasites freshly transformed from amastigotes, 106 wild type or luciferase-expressing stationary phase promastigotes were inoculated subcutaneously in young BALB/c mice or golden hamsters.,In both groups, sustained cutaneous lesions developed at the site of inoculation, no spontaneous self- healing being observed 4 months post-inoculation, if left untreated.,Compared to the wild type line features, no difference was noted for the luciferase-transgenic line.,Infected animals were treated with 5 or 15 mg/kg/day miltefosine orally for 15 days.,At the end of treatment, lesions had regressed and parasites were not detected.,However, relapses were observed in animals treated with both doses of miltefosine.,Here we described experimental settings for a late-healing model of cutaneous leishmaniasis upon inoculation of a luciferase-expressing L. braziliensis line that can be applied to drug development projects.,These settings allowed the monitoring of the transient efficacy of a short-term miltefosine administration.

Myocardium damage during Chagas' disease results from the immunological imbalance between pro- and production of anti-inflammatory cytokines and has been explained based on the Th1-Th2 dichotomy and regulatory T cell activity.,Recently, we demonstrated that IL-17 produced during experimental T. cruzi infection regulates Th1 cells differentiation and parasite induced myocarditis.,Here, we investigated the role of IL-17 and regulatory T cell during human Chagas' disease.,First, we observed CD4+IL-17+ T cells in culture of peripheral blood mononuclear cells (PBMC) from Chagas' disease patients and we evaluated Th1, Th2, Th17 cytokine profile production in the PBMC cells from Chagas' disease patients (cardiomyopathy-free, and with mild, moderate or severe cardiomyopathy) cultured with T. cruzi antigen.,Cultures of PBMC from patients with moderate and severe cardiomyopathy produced high levels of TNF-α, IFN-γ and low levels of IL-10, when compared to mild cardiomyopathy or cardiomyopathy-free patients.,Flow cytometry analysis showed higher CD4+IL-17+ cells in PBMC cultured from patients without or with mild cardiomyopathy, in comparison to patients with moderate or severe cardiomyopathy.,We then analyzed the presence and function of regulatory T cells in all patients.,All groups of Chagas' disease patients presented the same frequency of CD4+CD25+ regulatory T cells.,However, CD4+CD25+ T cells from patients with mild cardiomyopathy or cardiomyopathy-free showed higher suppressive activity than those with moderate and severe cardiomyopathy.,IFN-γ levels during chronic Chagas' disease are inversely correlated to the LVEF (P = 0.007, r = −0.614), while regulatory T cell activity is directly correlated with LVEF (P = 0.022, r = 0.500).,These results indicate that reduced production of the cytokines IL-10 and IL-17 in association with high levels of IFN-γ and TNF-α is correlated with the severity of the Chagas' disease cardiomyopathy, and the immunological imbalance observed may be causally related with deficient suppressor activity of regulatory T cells that controls myocardial inflammation.

TNF-alpha plays an important role in trypanocidal mechanisms and is related to tissue injury.,This cytokine has been detected in the heart of human chagasic patients where it is associated with tissue damage.,This study investigated whether TNF-alpha levels and the presence of genetic polymorphisms are associated with the presence of T. cruzi infection and/or with the development of the cardiac form in chronic chagasic patients.,Genomic DNA of 300 subjects from an endemic area was extracted and analyzed by PCR using specific primers.,TNF-alpha was assayed in culture supernatants by ELISA.,An association was observed between the absence of the TNF-238A allele and negative serology.,Furthermore, seropositive individuals carrying the TNF-238A allele produced significantly higher TNF-alpha levels without stimulation (p = 0.04) and after stimulation with LPS (p = 0.007) and T. cruzi antigens (p = 0.004).,The present results suggest that the polymorphism at position -238 influences susceptibility to infection and that this allele is associated with higher TNF-alpha production in seropositive individuals.

The different components of the mouthparts of hard ticks (Ixodidae) enable these parasites to penetrate host skin, secrete saliva, embed, and suck blood.,Moreover, the tick’s mouthparts represent a key route for saliva-assisted pathogen transmission as well as pathogen acquisition from blood meal during the tick feeding process.,Much has been learned about the basic anatomy of the tick’s mouthparts and in the broad outlines of how they function in previous studies.,However, the precise mechanics of these functions are little understood.,Here, we propose for the first time an animated model of the orchestration of the tick mouthparts and associated structures during blood meal acquisition and salivation.,These two actions are known to alternate during tick engorgement.,Specifically, our attention has been paid to the mechanism underlining the blood meal uptake into the pharynx through the mouth and how ticks prevent mixing the uptaken blood with secreted saliva.,We animated function of muscles attached to the salivarium and their possible opening /closing of the salivarium, with a plausible explanation of the movement of saliva within the salivarium and massive outpouring of saliva.

Infestations with the cattle tick, Rhipicephalus microplus, constitute the most important ectoparasite problem for cattle production in tropical and subtropical regions worldwide, resulting in major economic losses.,The control of R. microplus is mostly based on the use of conventional acaricides and macrocyclic lactones.,However, the intensive use of such compounds has resulted in tick populations that exhibit resistance to all major acaricide chemical classes.,Consequently, there is a need for the development of alternative approaches, possibly including the use of animal husbandry practices, synergized pesticides, rotation of acaricides, pesticide mixture formulations, manual removal of ticks, selection for host resistance, nutritional management, release of sterile male hybrids, environmental management, plant species that are unfavourable to ticks, pasture management, plant extracts, essential oils and vaccination.,Integrated tick management consists of the systematic combination of at least two control technologies aiming to reduce selection pressure in favour of acaricide-resistant individuals, while maintaining adequate levels of animal production.,The purpose of this paper is to present a current review on conventional acaricide and macrocyclic lactone resistance for better understanding and control of resistant ticks with particular emphasis on R. microplus on cattle.

The ability of mosquitoes to evade fatal exposure to insecticidal nets and sprays represents the primary obstacle to eliminating malaria.,However, it remains unclear which behaviours are most important for buffering mosquito and parasite populations against vector control.,Simulated life histories were used to compare the impact of alternative feeding behaviour strategies upon overall lifetime feeding success, and upon temporal distributions of successful feeds and biting rates experienced by unprotected humans, in the presence and absence of insecticidal nets.,Strictly nocturnal preferred feeding times were contrasted with 1) a wider preference window extending to dawn and dusk, and 2) crepuscular preferences wherein foraging is suppressed when humans sleep and can use nets but is maximal immediately before and after.,Simulations with diversion and mortality parameters typical of endophagic, endophilic African vectors, such as Anopheles gambiae and Anopheles funestus, were compared with those for endophagic but exophilic species, such as Anopheles arabiensis, that also enter houses but leave earlier before lethal exposure to insecticide-treated surfaces occurs.,Insecticidal nets were predicted to redistribute successful feeding events to dawn and dusk where these were included in the profile of innately preferred feeding times.,However, predicted distributions of biting unprotected humans were unaffected because extended host-seeking activity was redistributed to innately preferred feeding times.,Recently observed alterations of biting activity distributions therefore reflect processes not captured in this model, such as evolutionary selection of heritably modified feeding time preferences or phenotypically plastic expression of feeding time preference caused by associative learning.,Surprisingly, endophagy combined with exophily, among mosquitoes that enter houses but then feed and/or rest briefly before rapidly exiting, consistently attenuated predicted insecticide impact more than any feeding time preference trait.,Regardless of underlying cause, recent redistributions of host-biting activity to dawn and dusk necessitate new outdoor control strategies.,However, persistently indoor-feeding vectors, that evade intradomiciliary insecticide exposure, are at least equally important.,Fortunately, recent evaluations of occupied houses or odour-baited stations, with baffled entrances that retain An. arabiensis within insecticide-treated structures, illustrate how endophagic but exophilic vectors may be more effectively tackled using existing insecticides.

Background: Climate change is expected to affect the distribution of environmental suitability for malaria transmission by altering temperature and rainfall patterns; however, the local and global impacts of climate change on malaria transmission are uncertain.,Objective: We assessed the effect of climate change on malaria transmission in West Africa.,Methods: We coupled a detailed mechanistic hydrology and entomology model with climate projections from general circulation models (GCMs) to predict changes in vectorial capacity, an indication of the risk of human malaria infections, resulting from changes in the availability of mosquito breeding sites and temperature-dependent development rates.,Because there is strong disagreement in climate predictions from different GCMs, we focused on the GCM projections that produced the best and worst conditions for malaria transmission in each zone of the study area.,Results: Simulation-based estimates suggest that in the desert fringes of the Sahara, vectorial capacity would increase under the worst-case scenario, but not enough to sustain transmission.,In the transitional zone of the Sahel, climate change is predicted to decrease vectorial capacity.,In the wetter regions to the south, our estimates suggest an increase in vectorial capacity under all scenarios.,However, because malaria is already highly endemic among human populations in these regions, we expect that changes in malaria incidence would be small.,Conclusion: Our findings highlight the importance of rainfall in shaping the impact of climate change on malaria transmission in future climates.,Even under the GCM predictions most conducive to malaria transmission, we do not expect to see a significant increase in malaria prevalence in this region.,Citation: Yamana TK, Eltahir EA.,2013.,Projected impacts of climate change on environmental suitability for malaria transmission in West Africa.,Environ Health Perspect 121:1179-1186; http://dx.doi.org/10.1289/ehp.1206174

Previous analyses have suggested that immunity to non-cerebral severe malaria due to Plasmodium falciparum is acquired after only a few infections, whereas longitudinal studies show that some children experience multiple episodes of severe disease, suggesting that immunity may not be acquired so quickly.,We fitted a mathematical model for the acquisition and loss of immunity to severe disease to the age distribution of severe malaria cases stratified by symptoms from a range of transmission settings in Tanzania, combined with data from several African countries on the age distribution and overall incidence of severe malaria.,We found that immunity to severe disease was acquired more gradually with exposure than previously thought.,The model also suggests that physiological changes, rather than exposure, may alter the symptoms of disease with increasing age, suggesting that a later age at infection would be associated with a higher proportion of cases presenting with cerebral malaria regardless of exposure.,This has consequences for the expected pattern of severe disease as transmission changes.,Careful monitoring of the decline in immunity associated with reduced transmission will therefore be needed to ensure rebound epidemics of severe and fatal malaria are avoided.

These markers can identify spatial variations in transmission patterns.,Areas in which malaria is not highly endemic are suitable for malaria elimination, but assessing transmission is difficult because of lack of sensitivity of commonly used methods.,We evaluated serologic markers for detecting variation in malaria exposure in Somalia.,Plasmodium falciparum or P. vivax was not detected by microscopy in cross-sectional surveys of samples from persons during the dry (0/1,178) and wet (0/1,128) seasons.,Antibody responses against P. falciparum or P. vivax were detected in 17.9% (179/1,001) and 19.3% (202/1,044) of persons tested.,Reactivity against P. falciparum was significantly different between 3 villages (p<0.001); clusters of seroreactivity were present.,Distance to the nearest seasonal river was negatively associated with P. falciparum (p = 0.028) and P. vivax seroreactivity (p = 0.016).,Serologic markers are a promising tool for detecting spatial variation in malaria exposure and evaluating malaria control efforts in areas where transmission has decreased to levels below the detection limit of microscopy.

Cholangiocarcinoma (CCA) is an aggressive cancer arising from epithelial cells of the bile duct.,Most patients with CCA have an unresectable tumor at the time of diagnosis.,In Western countries, the risk of CCA increases in patients with primary sclerosing cholangitis, whereas liver fluke infection appears to be the major risk factor for CCA in Asian countries.,A diagnosis of liver fluke infection often relies on stool samples, including microscopic examination, polymerase chain reaction-based assays, and fluke antigen detection.,Tests of serum, saliva and urine samples are also potentially diagnostic.,The presence of liver fluke along with exogenous carcinogens magnifies the risk of CCA in people living in endemic areas.,The “liver fluke-cholangiocarcinoma” carcinogenesis pathways consist of mechanical damage to the bile duct epithelium, immunopathologic and cellular reactions to the liver fluke’s antigens and excretory/secretory products, liver fluke-induced changes in the biliary tract microbiome and the effects of repeated treatment for liver fluke.,A vaccine and novel biomarkers are needed for the primary and secondary prevention of CCA in endemic areas.,Importantly, climate change exerts an effect on vector-borne parasitic diseases, and awareness of liver fluke should be enhanced in potentially migrated habitat areas.

Soil transmitted nematodes, including Strongyloides, cause one of the most prevalent Neglected Tropical Diseases.,Here we compare the genomes of four Strongyloides spp., including the human pathogen S. stercoralis, and their close relatives that are facultatively parasitic (Parastrongyloides trichosuri) and free-living (Rhabditophanes sp).,A significant paralogous expansion of key gene families - astacin-like and SCP/TAPS coding gene families - is associated with the evolution of parasitism in this clade.,Exploiting the unique Strongyloides life cycle we compare the transcriptome of its parasitic and free-living stages and find that these same genes are upregulated in the parasitic stages, underscoring their role in nematode parasitism.

The host immune response plays a critical role not only in protection from human leishmaniasis, but also in promoting disease severity.,Although candidate gene approaches in mouse models of leishmaniasis have been extremely informative, a global understanding of the immune pathways active in lesions from human patients is lacking.,To address this issue, genome-wide transcriptional profiling of Leishmania braziliensis-infected cutaneous lesions and normal skin controls was carried out.,A signature of the L. braziliensis skin lesion was defined that includes over 2,000 differentially regulated genes.,Pathway-level analysis of this transcriptional response revealed key biological pathways present in cutaneous lesions, generating a testable ‘metapathway’ model of immunopathology, and providing new insights for treatment of human leishmaniasis.

Leishmania infection triggers the recruitment of Gr1+ monocytes to the site of infection via platelet-derived PDGF and subsequent CCL2 production.,Leishmania species trigger a brisk inflammatory response and efficiently induce cell-mediated immunity.,We examined the mechanisms whereby leukocytes were recruited into lesions after Leishmania major infection of mice.,We found that a subpopulation of effector monocytes expressing the granulocyte marker GR1 (Ly6C) is rapidly recruited into lesions, and these monocytes efficiently kill L. major parasites.,The recruitment of this subpopulation of monocytes depends on the chemokine receptor CCR2 and the activation of platelets.,Activated platelets secrete platelet-derived growth factor, which induces the rapid release of CCL2 from leukocytes and mesenchymal cells.,This work points to a new role for platelets in host defense involving the selective recruitment of a subpopulation of effector monocytes from the blood to efficiently kill this intracellular parasite.

Malaria treatment efforts are hindered by the rapid emergence and spread of drug resistant parasites.,Simple assays to monitor parasite drug response in direct patient samples (ex vivo) can detect drug resistance before it becomes clinically apparent, and can inform changes in treatment policy to prevent the spread of resistance.,Parasite drug responses to amodiaquine, artemisinin, chloroquine and mefloquine were tested in approximately 400 Plasmodium falciparum malaria infections in Thiès, Senegal between 2008 and 2011 using a DAPI-based ex vivo drug resistance assay.,Drug resistance-associated mutations were also genotyped in pfcrt and pfmdr1.,Parasite drug responses changed between 2008 and 2011, as parasites became less sensitive to amodiaquine, artemisinin and chloroquine over time.,The prevalence of known resistance-associated mutations also changed over time.,Decreased amodiaquine sensitivity was associated with sustained, highly prevalent mutations in pfcrt, and one mutation in pfmdr1 - Y184F - was associated with decreased parasite sensitivity to artemisinin.,Directly measuring ex vivo parasite drug response and resistance mutation genotyping over time are useful tools for monitoring parasite drug responses in field samples.,Furthermore, these data suggest that the use of amodiaquine and artemisinin derivatives in combination therapies is selecting for increased drug tolerance within this population.

The treatment of falciparum malaria poses unique challenges in settings where malaria transmission intensity is high because recurrent infections are common.,These could be new infections, recrudescences, or a combination of the two.,Though several African countries continue to use quinine as the second line treatment for patients with recurrent infections, there is little information on its efficacy when used for rescue therapy.,Moreover, such practice goes against the World Health Organisation (WHO) recommendation to use combination therapy for uncomplicated malaria.,We conducted a nested, randomized, open label, three-arm clinical trial of rescue therapy in children 6-59 months old with recurrent malaria infection during 28 days post treatment with artemisinin combination treatment (ACT).,Patients were randomly assigned to receive either quinine, artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DHAPQ), and actively followed up for 28 days.,Among 220 patients enrolled, 217 (98.6 %) were assigned an efficacy outcome and 218 (99.1 %) were assessed for safety.,The risk of recurrent infection was significantly higher in patients treated with quinine (70 %, 74/110, HR = 3.9; 95 % CI: 2.4-6.7, p<0.0001) and AL (60%, 21/35, HR = 3.3; 95 % CI: 1.8-6.3, p<0.0002), compared to DHAPQ (25%, 18/72).,Recrudescence tended to be lower in the DHAPQ (1%, 1/72) than in the quinine (7%, 8/110) or AL (6 %, 2/35) group, though it was not statistically significant.,No serious adverse events were reported.,Recurrent infections observed after the administration of an ACT can be successfully treated with an alternative ACT rather than with quinine.,Current Controlled Trials ISRCTN99046537

Methods to diagnose malaria are of paramount interest to eradicate the disease.,Current methods have severe limitations, as they are either costly or not sensitive enough to detect low levels of parasitemia.,Here we report an ultrasensitive, yet low-resource chemical assay for the detection and quantification of hemozoin, a biomarker of all Plasmodium species.,Solubilized hemozoin catalyzes the atom transfer radical polymerization of N-isopropylacrylamide above the lower critical solution temperature of poly(N-isopropylacrylamide).,The solution becomes turbid, which can be observed by naked eye and quantified by UV-visible spectroscopy.,The rate of turbidity increase is proportional to the concentration of hemozoin, with a detection limit of 0.85 ng mL−1.,Malaria parasites in human blood can be detected down to 10 infected red blood cells μL−1.,The assay could potentially be applied as a point-of-care test.,The signal-amplification of an analyte by biocatalytic precipitation polymerization represents a powerful approach in biosensing.,Methods to diagnose malaria are of interest but can be costly or not sensitive enough to detect low levels of parasitemia.,Here the authors report an ultrasensitive method by using hemozoin (a biomarker of all Plasmodium species) to catalyse the polymerization of N-isopropylacrylamide.

Rapid diagnostic tests (RDTs) are today the most widely used method for malaria diagnosis and are recommended, alongside microscopy, for the confirmation of suspected cases before the administration of anti-malarial treatment.,The diagnostic performance of RDTs, as compared to microscopy or PCR is well described but the actual analytical sensitivity of current best-in-class tests is poorly documented.,This value is however a key performance indicator and a benchmark value needed to developed new RDTs of improved sensitivity.,Thirteen RDTs detecting either the Plasmodium falciparum histidine rich protein 2 (HRP2) or the plasmodial lactate dehydrogenase (pLDH) antigens were selected from the best performing RDTs according to the WHO-FIND product testing programme.,The analytical sensitivity of these products was evaluated using a range of reference materials including P. falciparum and Plasmodium vivax whole parasite samples as well as recombinant proteins.,The best performing HRP2-based RDTs could detect all P. falciparum cultured samples at concentrations as low as 0.8 ng/mL of HRP2.,The limit of detection of the best performing pLDH-based RDT specifically detecting P. vivax was 25 ng/mL of pLDH.,The analytical sensitivity of P. vivax and Pan pLDH-based RDTs appears to vary considerably from product to product, and improvement of the limit-of-detection for P. vivax detecting RDTs is needed to match the performance of HRP2 and Pf pLDH-based RDTs for P. falciparum.,Different assays using different reference materials produce different values for antigen concentration in a given specimen, highlighting the need to establish universal reference assays.,The online version of this article (doi:10.1186/s12936-017-1780-5) contains supplementary material, which is available to authorized users.

An increasing number of countries in Africa and elsewhere are developing national plans for the control of neglected tropical diseases.,A key component of such plans is school-based deworming (SBD) for the control of soil-transmitted helminths (STHs) and schistosomiasis.,Monitoring and evaluation (M&E) of national programmes is essential to ensure they are achieving their stated aims and to evaluate when to reduce the frequency of treatment or when to halt it altogether.,The article describes the M&E design of the Kenya national SBD programme and presents results from the baseline survey conducted in early 2012.,The M&E design involves a stratified series of pre- and post-intervention, repeat cross-sectional surveys in a representative sample of 200 schools (over 20,000 children) across Kenya.,Schools were sampled based on previous knowledge of STH endemicity and were proportional to population size.,Stool (and where relevant urine) samples were obtained for microscopic examination and in a subset of schools; finger-prick blood samples were collected to estimate haemoglobin concentration.,Descriptive and spatial analyses were conducted.,The evaluation measured both prevalence and intensity of infection.,Overall, 32.4% of children were infected with at least one STH species, with Ascaris lumbricoides as the most common species detected.,The overall prevalence of Schistosoma mansoni was 2.1%, while in the Coast Province the prevalence of S. haematobium was 14.8%.,There was marked geographical variation in the prevalence of species infection at school, district and province levels.,The prevalence of hookworm infection was highest in Western Province (25.1%), while A. lumbricoides and T. trichiura prevalence was highest in the Rift Valley (27.1% and 11.9%).,The lowest prevalence was observed in the Rift Valley for hookworm (3.5%), in the Coast for A. lumbricoides (1.0%), and in Nyanza for T. trichiura (3.6%).,The prevalence of S. mansoni was most common in Western Province (4.1%).,The current findings are consistent with the known spatial ecology of STH and schistosome infections and provide an important empirical basis on which to evaluate the impact of regular mass treatment through the school system in Kenya.

Mass treatment with ivermectin controls onchocerciasis as a public health problem, but it was not known if it could also interrupt transmission and eliminate the parasite in endemic foci in Africa where vectors are highly efficient.,A longitudinal study was undertaken in three hyperendemic foci in Mali and Senegal with 15 to 17 years of annual or six-monthly ivermectin treatment in order to assess residual levels of infection and transmission, and test whether treatment could be safely stopped.,This article reports the results of the final evaluations up to 5 years after the last treatment.,Skin snip surveys were undertaken in 131 villages where 29,753 people were examined and 492,600 blackflies were analyzed for the presence of Onchocerca volvulus larva using a specific DNA probe.,There was a declining trend in infection and transmission levels after the last treatment.,In two sites the prevalence of microfilaria and vector infectivity rate were zero 3 to 4 years after the last treatment.,In the third site, where infection levels were comparatively high before stopping treatment, there was also a consistent decline in infection and transmission to very low levels 3 to 5 years after stopping treatment.,All infection and transmission indicators were below postulated thresholds for elimination.,The study has established the proof of principle that onchocerciasis elimination with ivermectin treatment is feasible in at least some endemic foci in Africa.,The study results have been instrumental for the current evolution from onchocerciasis control to elimination in Africa.

The China’s 1-3-7 strategy was initiated and extensively adopted in different types of counties (geographic regions) for reporting of malaria cases within 1 day, their confirmation and investigation within 3 days, and the appropriate public health response to prevent further transmission within 7 days.,Assessing the level of compliance to the 1-3-7 strategy at the county level is a first step towards determining whether the surveillance and response strategy is happening according to plan.,This study assessed if the time-bound targets of the 1-3-7 strategy were being sustained over time.,Such information would be useful to improve implementation of the 1-3-7 strategy in China.,This cross-sectional study involved country-wide programmatic data for the period January 1st 2013 to June 30th 2014.,Data variables were extracted from the national malaria information system and included socio-demographic information, type of county, date of diagnosis, date of reporting, date of case investigation, case classification (indigenous, or imported, or unknown), focus investigation, date of reactive case detection (RACD), and date of indoor residual spraying (IRS).,Summary statistics and proportions were used and comparisons between groups were assessed using the chi-square test.,Level of significance was set at a P-value ≤ 0.05.,Of a total of 5,688 malaria cases from 731 counties, there were 55 (1 %) indigenous cases (only in Type 1 and Type 2 counties) and 5,633 (99 %) imported cases from all types of counties.,There was no delay in reporting malaria cases by type of county.,In terms of case investigation, 97.5 % cases were investigated within 3 days with the proportion of delays (1.5 %) in type 2 counties, being significantly lower than type 1 counties (4.1 %).,Regarding active foci, 96.4 % were treated by RACD and/or IRS.,The performance of 1-3-7 strategy was encouraging but identified some challenges that if addressed can further improve implementation.,The online version of this article (doi:10.1186/s40249-015-0089-2) contains supplementary material, which is available to authorized users.

Mosquito-borne diseases pose some of the greatest challenges in public health, especially in tropical and sub-tropical regions of the world.,Efforts to control these diseases have been underpinned by a theoretical framework developed for malaria by Ross and Macdonald, including models, metrics for measuring transmission, and theory of control that identifies key vulnerabilities in the transmission cycle.,That framework, especially Macdonald's formula for R0 and its entomological derivative, vectorial capacity, are now used to study dynamics and design interventions for many mosquito-borne diseases.,A systematic review of 388 models published between 1970 and 2010 found that the vast majority adopted the Ross-Macdonald assumption of homogeneous transmission in a well-mixed population.,Studies comparing models and data question these assumptions and point to the capacity to model heterogeneous, focal transmission as the most important but relatively unexplored component in current theory.,Fine-scale heterogeneity causes transmission dynamics to be nonlinear, and poses problems for modeling, epidemiology and measurement.,Novel mathematical approaches show how heterogeneity arises from the biology and the landscape on which the processes of mosquito biting and pathogen transmission unfold.,Emerging theory focuses attention on the ecological and social context for mosquito blood feeding, the movement of both hosts and mosquitoes, and the relevant spatial scales for measuring transmission and for modeling dynamics and control.

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.

Information on the growth rate and metabolism of microbial pathogens that cause long-term chronic infections is limited, reflecting the absence of suitable tools for measuring these parameters in vivo.,Here, we have measured the replication and physiological state of Leishmania mexicana parasites in murine inflammatory lesions using 2H2O labeling.,Infected BALB/c mice were labeled with 2H2O for up to 4 months, and the turnover of parasite DNA, RNA, protein and membrane lipids estimated from the rate of deuterium enrichment in constituent pentose sugars, amino acids, and fatty acids, respectively.,We show that the replication rate of parasite stages in these tissues is very slow (doubling time of ~12 days), but remarkably constant throughout lesion development.,Lesion parasites also exhibit markedly lower rates of RNA synthesis, protein turnover and membrane lipid synthesis than parasite stages isolated from ex vivo infected macrophages or cultured in vitro, suggesting that formation of lesions induces parasites to enter a semi-quiescent physiological state.,Significantly, the determined parasite growth rate accounts for the overall increase in parasite burden indicating that parasite death and turnover of infected host cells in these lesions is minimal.,We propose that the Leishmania response to lesion formation is an important adaptive strategy that minimizes macrophage activation, providing a permissive environment that supports progressive expansion of parasite burden.,This labeling approach can be used to measure the dynamics of other host-microbe interactions in situ.

India, a persistently significant contributor to the global malaria burden, rolled out several anti-malaria interventions at the national and state level to control and recently, to eliminate the disease.,Odisha, the eastern Indian state with the highest malaria burden experienced substantial gains shown by various anti-malaria initiatives implemented under the National Vector-borne Disease Control Programme (NVBDCP).,However, recalcitrant high-transmission “pockets” of malaria persist in hard-to-reach stretches of the state, characterised by limited access to routine malaria surveillance and the forested hilly topography favouring unbridled vector breeding.,The prevalence of asymptomatic malaria in such pockets serves as perpetual malaria reservoir, thus hindering its elimination.,Therefore, a project with the acronym DAMaN was initiated since 2017 by state NVBDCP, targeting locally identified high endemic ‘pockets’ in 23 districts.,DAMaN comprised biennial mass screening and treatment, provisioning of long-lasting insecticidal net (LLIN) and behavioural change communication.,Subsequently, to inform policy, assessment of DAMaN was conceived that aims to estimate the coverage of the various components of the project; the prevalence of malaria, even at sub-patent level especially among pregnant/lactating women and children; and its impact on malaria incidence.,A survey of DAMaN beneficiaries will measure coverage; and knowledge and practices related to LLIN; along with collection of blood specimens from a probability sample.,A multi-stage stratified clustered sample of 2228 households (~33% having pregnant/lactating women) will be selected from 6 DAMaN districts.,Routine DAMaN project data (2017-2018) and NVBDCP data (2013-2018) will be extracted.,Rapid Diagnostic Test, Polymerase Chain Reaction and blood smear microscopy will be conducted to detect malarial parasitemia.,In addition to measuring DAMaN’s coverage and malarial prevalence in DAMaN pockets, its impact will be estimated using pre-post differences and Interrupted Time Series analysis using 2017 as the “inflection” point.,The assessment may help to validate the unique strategies employed by DAMaN.

In malaria elimination settings, all malaria cases must be identified, documented and investigated.,To facilitate complete and timely reporting of all malaria cases and effective case management and follow-up, engagement with private providers is essential, particularly in settings where the private sector is a major source of healthcare.,However, research on the role and performance of the private sector in malaria diagnosis, case management and reporting in malaria elimination settings is limited.,Moreover, the most effective strategies for private sector engagement in malaria elimination settings remain unclear.,Twenty-five experts in malaria elimination, disease surveillance and private sector engagement were purposively sampled and interviewed.,An extensive review of grey and peer-reviewed literature on private sector testing, treatment, and reporting for malaria was performed.,Additional in-depth literature review was conducted for six case studies on eliminating and neighbouring countries in Southeast Asia and Southern Africa.,The private health sector can be categorized based on their commercial orientation or business model (for-profit versus nonprofit) and their regulation status within a country (formal vs informal).,A number of potentially effective strategies exist for engaging the private sector.,Conducting a baseline assessment of the private sector is critical to understanding its composition, size, geographical distribution and quality of services provided.,Facilitating reporting, referral and training linkages between the public and private sectors and making malaria a notifiable disease are important strategies to improve private sector involvement in malaria surveillance.,Financial incentives for uptake of rapid diagnostic tests and artemisinin-based combination therapy should be combined with training and community awareness campaigns for improving uptake.,Private sector providers can also be organized and better engaged through social franchising, effective regulation, professional organizations and government outreach.,This review highlights the importance of engaging private sector stakeholders early and often in the development of malaria elimination strategies.,The online version of this article (doi:10.1186/s12936-017-1901-1) contains supplementary material, which is available to authorized users.

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.

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.

Long-lasting insecticidal nets (LLINs) have successfully reduced malaria in sub-Saharan Africa, but their effectiveness is now partly compromised by widespread resistance to insecticides among vectors.,We evaluated new classes of LLINs with two active ingredients with differing modes of action against resistant malaria vectors.,We did a four-arm, cluster-randomised trial in Misungwi, Tanzania.,Clusters were villages, or groups of hamlets, with at least 119 households containing children aged 6 months to 14 years living in the cluster's core area.,Constrained randomisation was used to allocate clusters (1:1:1:1) to receive one of four types of LLIN treated with the following: α-cypermethrin only (pyrethroid-only [reference] group); pyriproxyfen and α-cypermethrin (pyriproxyfen group); chlorfenapyr and α-cypermethrin (chlorfenapyr group); or the synergist piperonyl butoxide and permethrin (piperonyl butoxide group).,At least one LLIN was distributed for every two people.,Community members and the field team were masked to group allocation.,Malaria prevalence data were collected through cross-sectional surveys of randomly selected households from each cluster, in which children aged 6 months to 14 years were assessed for Plasmodium falciparum malaria infection by rapid diagnostic tests.,The primary outcome was malaria infection prevalence at 24 months after LLIN distribution, comparing each of the dual-active-ingredient LLINs to the standard pyrethroid-only LLINs in the intention-to-treat population.,The primary economic outcome was cost-effectiveness of dual-active-ingredient LLINs, based on incremental cost per disability-adjusted life-year (DALY) averted compared with pyrethroid-only LLINs, modelled over a 2-year period; we included costs of net procurement and malaria diagnosis and treatment, and estimated DALYs in all age groups.,This study is registered with ClinicalTrials.gov (NCT03554616), and is ongoing but no longer recruiting.,84 clusters comprising 39 307 households were included in the study between May 11 and July 2, 2018.,147 230 LLINs were distributed among households between Jan 26 and Jan 28, 2019.,Use of study LLINs was reported in 3155 (72·1%) of 4378 participants surveyed at 3 months post-distribution and decreased to 8694 (40·9%) of 21 246 at 24 months, with varying rates of decline between groups.,Malaria infection prevalence at 24 months was 549 (45·8%) of 1199 children in the pyrethroid-only reference group, 472 (37·5%) of 1258 in the pyriproxyfen group (adjusted odds ratio 0·79 [95% CI 0·54-1·17], p=0·2354), 512 (40·7%) of 1259 in the piperonyl butoxide group (0·99 [0·67-1·45], p=0·9607), and 326 [25·6%] of 1272 in the chlorfenapyr group (0·45 [0·30-0·67], p=0·0001).,Skin irritation or paraesthesia was the most commonly reported side-effect in all groups.,Chlorfenapyr LLINs were the most cost-effective LLINs, costing only US$19 (95% uncertainty interval 1-105) more to public providers or $28 (11-120) more to donors per DALY averted over a 2-year period compared with pyrethroid-only LLINs, and saving costs from societal and household perspectives.,After 2 years, chlorfenapyr LLINs provided significantly better protection than pyrethroid-only LLINs against malaria in an area with pyrethroid-resistant mosquitoes, and the additional cost of these nets would be considerably below plausible cost-effectiveness thresholds ($292-393 per DALY averted).,Before scale-up of chlorfenapyr LLINs, resistance management strategies are needed to preserve their effectiveness.,Poor textile and active ingredient durability in the piperonyl butoxide and pyriproxyfen LLINs might have contributed to their relative lack of effectiveness compared with standard LLINs.,Joint Global Health Trials scheme (UK Foreign, Commonwealth and Development Office; UK Medical Research Council; Wellcome; UK Department of Health and Social Care), US Agency for International Development, President's Malaria Initiative.

Progress in malaria control is under threat by wide-scale insecticide resistance in malaria vectors.,Two recent vector control products have been developed: a long-lasting insecticidal net that incorporates a synergist piperonyl butoxide (PBO) and a long-lasting indoor residual spraying formulation of the insecticide pirimiphos-methyl.,We evaluated the effectiveness of PBO long-lasting insecticidal nets versus standard long-lasting insecticidal nets as single interventions and in combination with the indoor residual spraying of pirimiphos-methyl.,We did a four-group cluster randomised controlled trial using a two-by-two factorial design of 48 clusters derived from 40 villages in Muleba (Kagera, Tanzania).,We randomly assigned these clusters using restricted randomisation to four groups: standard long-lasting insecticidal nets, PBO long-lasting insecticidal nets, standard long-lasting insecticidal nets plus indoor residual spraying, or PBO long-lasting insecticidal nets plus indoor residual spraying.,Both standard and PBO nets were distributed in 2015.,Indoor residual spraying was applied only once in 2015.,We masked the inhabitants of each cluster to the type of nets received, as well as field staff who took blood samples.,Neither the investigators nor the participants were masked to indoor residual spraying.,The primary outcome was the prevalence of malaria infection in children aged 6 months to 14 years assessed by cross-sectional surveys at 4, 9, 16, and 21 months after intervention.,The endpoint for assessment of indoor residual spraying was 9 months and PBO long-lasting insecticidal nets was 21 months.,This trial is registered with ClinicalTrials.gov, number NCT02288637.,7184 (68·0%) of 10 560 households were selected for post-intervention survey, and 15 469 (89·0%) of 17 377 eligible children from the four surveys were included in the intention-to-treat analysis.,Of the 878 households visited in the two indoor residual spraying groups, 827 (94%) had been sprayed.,Reported use of long-lasting insecticidal nets, across all groups, was 15 341 (77·3%) of 19 852 residents after 1 year, decreasing to 12 503 (59·2%) of 21 105 in the second year.,Malaria infection prevalence after 9 months was lower in the two groups that received PBO long-lasting insecticidal nets than in the two groups that received standard long-lasting insecticidal nets (531 [29%] of 1852 children vs 767 [42%] of 1809; odds ratio [OR] 0·37, 95% CI 0·21-0·65; p=0·0011).,At the same timepoint, malaria prevalence in the two groups that received indoor residual spraying was lower than in groups that did not receive indoor residual spraying (508 [28%] of 1846 children vs 790 [44%] of 1815; OR 0·33, 95% CI 0·19-0·55; p<0·0001) and there was evidence of an interaction between PBO long-lasting insecticidal nets and indoor residual spraying (OR 2·43, 95% CI 1·19-4·97; p=0·0158), indicating redundancy when combined.,The PBO long-lasting insecticidal net effect was sustained after 21 months with a lower malaria prevalence than the standard long-lasting insecticidal net (865 [45%] of 1930 children vs 1255 [62%] of 2034; OR 0·40, 0·20-0·81; p=0·0122).,The PBO long-lasting insecticidal net and non-pyrethroid indoor residual spraying interventions showed improved control of malaria transmission compared with standard long-lasting insecticidal nets where pyrethroid resistance is prevalent and either intervention could be deployed to good effect.,As a result, WHO has since recommended to increase coverage of PBO long-lasting insecticidal nets.,Combining indoor residual spraying with pirimiphos-methyl and PBO long-lasting insecticidal nets provided no additional benefit compared with PBO long-lasting insecticidal nets alone or standard long-lasting insecticidal nets plus indoor residual spraying.,UK Department for International Development, Medical Research Council, and Wellcome Trust.

The aim is to compare the cost-effectiveness of two long-lasting insecticidal nets (LLINs) delivery models (standard vs. new) in universal coverage (UC) campaigns in rural Mozambique.,The total financial cost of delivering LLINs was US$ 231,237.30 and US$ 174,790.14 in the intervention (302,648 LLINs were delivered) and control districts (219,613 LLINs were delivered), respectively.,The average cost-effectiveness ratio (ACER) per LLIN delivered and ACER per household (HH) achieving UC was lower in the intervention districts.,The incremental cost-effectiveness ratio (ICER) per LLIN and ICER per HH reaching UC were US$ 0.68 and US$ 2.24, respectively.,Both incremental net benefit (for delivered LLIN and for HHs reaching UC) were positive (intervention deemed cost-effective).,Overall, the newer delivery model was the more cost-effective intervention.,However, the long-term sustainability of either delivery models is far from guaranteed in Mozambique’s current economic context.

Malaria control remains a challenge in sub-Saharan Africa.,In 2006, the World Health Organization (WHO) reinforced the recommendation of indoor residual spraying (IRS) with dichlorodiphenyltrichloroethane (DDT) to reduce malaria transmission.,The National Malaria Control Programme has been reporting high coverage rates of IRS in Mozambique.,It is important to establish to what extent these rates are a reflection of community acceptability, and to explore the factors associated with adherence, in order to recommend suitable approaches for interventions of this nature.,To understand the implementation process, reception and acceptability of the IRS program in Manhiça district, Southern Mozambique.,Qualitative data was collected through in-depth interviews, participant observation of IRS activities, informal interviews, and focus group discussions.,Study participants comprised householders, community leaders, health care providers, sprayers, and community members.,Qualitative data analysis was based on grounded theory.,Secondary data from the Manhiça Demographic Surveillance System was used to complement the qualitative data.,IRS was well received in most neighbourhoods.,The overall coverage rates varied between 29% and 41% throughout the study period.,The factors related to adherence to IRS were: immediate impact on insects in general, trust and obedience in the health authority, community leaders' influence, and acquaintance with the sprayers.,Fighting malaria was not an important motivation for IRS adherence.,There was a perception of limited efficacy of IRS against mosquitoes, but this did not affect adherence.,Non-adherence to the intervention was mainly due to the unavailability of key householders, disagreement with the procedures, and the perception that spraying increased the burden of insects.,Most respondents strongly favoured bed nets over IRS.,The study suggests that the contribution of IRS to malaria and mosquito control is not entirely perceived by the beneficiaries, and that other as cost effective interventions such as insecticide-treated nets are favoured over IRS.,Adherence to IRS was found to be influenced by socio-political factors.,There is a need to redefine the community sensitization approaches in order to make IRS a genuinely participative, acceptable, and sustainable programme.

Leishmaniasis is a vector-borne neglected tropical disease that affects more than 700,000 people annually.,Leishmania parasites cause the disease, and different species trigger a distinct immune response and clinical manifestations.,Macrophages are the final host cells for the proliferation of Leishmania parasites, and these cells are the key to a controlled or exacerbated response that culminates in clinical manifestations.,M1 and M2 are the two main macrophage phenotypes.,M1 is a pro-inflammatory subtype with microbicidal properties, and M2, or alternatively activated, is an anti-inflammatory/regulatory subtype that is related to inflammation resolution and tissue repair.,The present review elucidates the roles of M1 and M2 polarization in leishmaniasis and highlights the role of the salivary components of the vector and the action of the parasite in the macrophage plasticity.

Leishmania, the causative agent of vector-borne diseases, known as leishmaniases, is an obligate intracellular parasite within mammalian hosts.,The outcome of infection depends largely on the activation status of macrophages, the first line of mammalian defense and the major target cells for parasite replication.,Understanding the strategies developed by the parasite to circumvent macrophage defense mechanisms and to survive within those cells help defining novel therapeutic approaches for leishmaniasis.,We previously showed the formation of lipid droplets (LDs) in L. major infected macrophages.,Here, we provide novel insights on the origin of the formed LDs by determining their cellular distribution and to what extent these high-energy sources are directed to the proximity of Leishmania parasites.,We show that the ability of L. major to trigger macrophage LD accumulation is independent of parasite viability and uptake and can also be observed in non-infected cells through paracrine stimuli suggesting that LD formation is from cellular origin.,The accumulation of LDs is demonstrated using confocal microscopy and live-cell imagin in parasite-free cytoplasmic region of the host cell, but also promptly recruited to the proximity of Leishmania parasites.,Indeed LDs are observed inside parasitophorous vacuole and in parasite cytoplasm suggesting that Leishmania parasites besides producing their own LDs, may take advantage of these high energy sources.,Otherwise, these LDs may help cells defending against parasitic infection.,These metabolic changes, rising as common features during the last years, occur in host cells infected by a large number of pathogens and seem to play an important role in pathogenesis.,Understanding how Leishmania parasites and different pathogens exploit this LD accumulation will help us define the common mechanism used by these different pathogens to manipulate and/or take advantage of this high-energy source.

Estimates of Plasmodium falciparum migration may inform strategies for malaria elimination.,Here we elucidate fine-scale parasite population structure and infer recent migration across Southeast Asia using identity-by-descent (IBD) approaches based on genome-wide single nucleotide polymorphisms called in 1722 samples from 54 districts.,IBD estimates are consistent with isolation-by-distance.,We observe greater sharing of larger IBD segments between artemisinin-resistant parasites versus sensitive parasites, which is consistent with the recent spread of drug resistance.,Our IBD analyses reveal actionable patterns, including isolated parasite populations, which may be prioritized for malaria elimination, as well as asymmetrical migration identifying potential sources and sinks of migrating parasites.,Understanding genomic variation in Plasmodium falciparum parasites and inferring migration patterns can guide malaria elimination strategies.,Using genome-wide data for 1722 parasites collected from 54 districts, the authors use identity-by-descent approaches to estimate regional parasite migration and spread of artemisinin drug resistance.

The efficacy of the 8-aminoquinoline (8AQ) drug primaquine (PQ) has been historically linked to CYP-mediated metabolism.,Although to date no clear evidence exists in the literature that unambiguously assigns the metabolic pathway or specific metabolites necessary for activity, recent literature suggests a role for CYP 2D6 in the generation of redox active metabolites.,In the present study, the specific CYP 2D6 inhibitor paroxetine was used to assess its effects on the production of specific phenolic metabolites thought to be involved in PQ efficacy.,Further, PQ causal prophylactic (developing liver stage) efficacy against Plasmodium berghei in CYP 2D knockout mice was assessed in comparison with a normal C57 background and with humanized CYP 2D6 mice to determine the direct effects of CYP 2D6 metabolism on PQ activity.,PQ exhibited no activity at 20 or 40 mg/kg in CYP 2D knockout mice, compared to 5/5 cures in normal mice at 20 mg/kg.,The activity against developing liver stages was partially restored in humanized CYP 2D6 mice.,These results unambiguously demonstrate that metabolism of PQ by CYP 2D6 is essential for anti-malarial causal prophylaxis efficacy.

In areas with ongoing malaria transmission, strategies to clear parasites from populations can reduce infection and transmission.,The objective of this paper was to describe a malaria mass testing and treatment (MTAT) intervention implemented in six kebeles (villages) in Amhara Region, Ethiopia, at the beginning of the 2014 transmission season.,Intervention kebeles were selected based on incidence of passively detected Plasmodium falciparum and mixed (P. falciparum and P. vivax) malaria cases during the 2013 malaria transmission season.,All households in intervention kebeles were targeted; consenting residents received a rapid diagnostic test (RDT) and RDT-positive individuals received artemether-lumefantrine for P. falciparum/mixed infections or chloroquine for P. vivax.,Data were collected on MTAT participation, sociodemographic characteristics, malaria risk factors, and RDT positivity.,Of 9162 households targeted, 7974 (87.0 %) participated in the MTAT.,Among the 35,389 residents of these households, 30,712 (86.8 %) received an RDT.,RDT-positivity was 1.4 % (0.3 % P. vivax, 0.7 % P. falciparum, 0.3 % mixed), ranging from 0.3 to 5.1 % by kebele; 39.4 % of RDT-positive individuals were febrile, 28.5 % resided in the same household with another RDT-positive individual, 23.0 % were not protected by vector control interventions [mosquito net or indoor residual spray (IRS)], and 7.1 % had travel history.,For individuals under 10 years of age, the odds of being RDT-positive was significantly higher for those with fever, recent use of anti-malarial drugs or residing in the same household with another RDT-positive individual; 59.0 % of RDT-positive individuals had at least one of these risk factors.,For individuals 10 years of age and older, the odds of being RDT positive was significantly higher for those with reported travel, fever, recent use of anti-malarial drugs, no use of vector control, and those residing in the same household as another RDT-positive individual; 71.2 % of RDT-positive individuals had at least one of these risk factors.,In the Ethiopia setting, an MTAT intervention is operationally feasible and can be conducted with high coverage.,RDT-positivity is low and varies widely by kebele.,While several risk factors are significantly associated with RDT-positivity, there are still many RDT-positive individuals who do not have any of these risk factors.,Strategies that target populations for testing and treatment based on these risk factors alone are likely to leave many infections undetected.,The online version of this article (doi:10.1186/s12936-016-1333-3) contains supplementary material, which is available to authorized users.

Malaria parasite prevalence in endemic populations is an essential indicator for monitoring the progress of malaria control, and has traditionally been assessed by microscopy.,However, surveys increasingly use sensitive molecular methods that detect higher numbers of infected individuals, questioning our understanding of the true infection burden and resources required to reduce it.,Here we analyse a series of data sets to characterize the distribution and epidemiological factors associated with low-density, submicroscopic infections.,We show that submicroscopic parasite carriage is common in adults, in low-endemic settings and in chronic infections.,We find a strong, non-linear relationship between microscopy and PCR prevalence in population surveys (n=106), and provide a tool to relate these measures.,When transmission reaches very low levels, submicroscopic carriers are estimated to be the source of 20-50% of all human-to-mosquito transmissions.,Our findings challenge the idea that individuals with little previous malaria exposure have insufficient immunity to control parasitaemia and suggest a role for molecular screening.,Malaria can persist at levels that escape detection by standard microscopy, but can be detected by PCR.,Okell et al. now show that rates of submicroscopic infection can be predicted using more widely available microscopy data, and are most epidemiologically significant in areas with low malaria transmission.

Visceral leishmaniasis (VL) is a life-threatening infection caused by Leishmania species.,In Sudan, VL is caused by L donovani.,Most drugs used to treat VL, especially pentavalent antimony compounds (sodium stibogluconate, SSG), are potentially hepatotoxic.,A number of fatal catastrophes happened because patients with VL-hepatitis B/C coinfection were indiscriminately treated with SSG in settings where VL and viral hepatitis coexist.,This study aimed to study biochemical and hematological parameters of patients with VL-hepatitis B/C coinfections with the aim to modify treatment protocols to reduce coinfection-added morbidity and mortality.,This was a prospective analytical, hospital-based, and case-controlled study.,The study was done at Kassab Hospital and Professor Elhassan Centre for tropical medicine during the period of February 2008 to April 2013.,Following informed consent by the participants, 78 parasitologically confirmed VL patients with either hepatitis B or C or both and 528 sex- and age-unmatched VL patients without hepatitis B/C coinfection (control group) were enrolled sequentially.,Diagnosis of hepatitis B or C was made using immunochromatographic test kits and confirmed by an enzyme-linked immunosorbent assay.,VL patients with hepatitis B/C coinfections had significantly increased levels of AST, ALT, and total bilirubin compared to the control group (P=.0001 for all), with significantly decreased levels of albumin and platelets counts (P=.0029 for both).,VL-hepatitis B/C coinfections are an emerging entity that needs anti-leishmanial treatment modification.,Alternative treatments like paromomycin and amphotericin B (AmBisome) could be reserved for these patients.

The World Health Organization (WHO) has targeted the elimination of Human African trypanosomiasis (HAT) ‘as a public health problem’ by 2020.,The selected indicators of elimination should be monitored every two years, and we provide here a comprehensive update to 2014.,The monitoring system is underpinned by the Atlas of HAT.,With 3,797 reported cases in 2014, the corresponding milestone (5,000 cases) was surpassed, and the 2020 global target of ‘fewer than 2,000 reported cases per year’ seems within reach.,The areas where HAT is still a public health problem (i.e.,> 1 HAT reported case per 10,000 people per year) have halved in less than a decade, and in 2014 they corresponded to 350 thousand km2.,The number and potential coverage of fixed health facilities offering diagnosis and treatment for HAT has expanded, and approximately 1,000 are now operating in 23 endemic countries.,The observed trends are supported by sustained surveillance and improved reporting.,HAT elimination appears to be on track.,For gambiense HAT, still accounting for the vast majority of reported cases, progress continues unabated in a context of sustained intensity of screening activities.,For rhodesiense HAT, a slow-down was observed in the last few years.,Looking beyond the 2020 target, innovative tools and approaches will be increasingly needed.,Coordination, through the WHO network for HAT elimination, will remain crucial to overcome the foreseeable and unforeseeable challenges that an elimination process will inevitably pose.

Danube Delta Biosphere Reserve is one of the most interesting regions in Europe from an epidemiological point of view due to its great biodiversity, local climatic conditions and various types of habitats.,Moreover, there is no data regarding the ectoparasite communities of dogs from this area.,In this frame, the aims of our study were to establish the tick communities parasitizing dogs and to provide new data regarding seasonal dynamics of a neglected tick species, Rhipicephalus rossicus.,A survey was carried out in order to gather information regarding tick species attaching to domestic dogs from a steppic region of southeastern Romania and to establish their seasonal dynamics.,The research was conducted from 1 December 2012 to 30 November 2013, on 8 dogs from Iazurile, a locality from the west-central part of the Danube Delta Biosphere Reserve.,In total, 384 examinations were made, each dog being checked for tick infestation 4 times per month, for one year.,The 893 ticks found belonged to six species: R. rossicus (95.6%), Dermacentor reticulatus (3.2%), Ixodes ricinus (0.5%), Hyalomma marginatum (0.3%), Rhipicephalus sanguineus sensu lato (s.l.),(0.2%) and Ixodes crenulatus (0.1%).,From the 91 positive examinations, R. rossicus was found in 80 (87.9%).,Single species infestation occurred in 84 examinations.,In 7 out of 91 positive examinations mixed infestation were found.,No ticks were found in December, January and September.,For R. rossicus, high frequency and intensity were observed in May, June and July.,The activity peaks for D. reticulatus were in spring and autumn.,Our results highlight that within the range of R. sanguineus s.l., the most common dog tick worldwide, selected dog populations may be predominantly infested by closely related species, like in our case, R. rossicus.

This study investigated the transmission and prevalence of Leishmania parasite infection of humans in two foci of Visceral Leishmaniasis (VL) in Georgia, the well known focus in Tbilisi in the East, and in Kutaisi, a new focus in the West of the country.,The seroprevalence of canine leishmaniasis was investigated in order to understand the zoonotic transmission.,Blood samples of 1575 dogs (stray and pet) and 77 wild canids were tested for VL by Kalazar Detect rK39 rapid diagnostic tests.,Three districts were investigated in Tbilisi and one in Kutaisi.,The highest proportions of seropositive pet dogs were present in District #2 (28.1%, 82/292) and District #1 (26.9%, 24/89) in Tbilisi, compared to 17.3% (26/150) of pet dogs in Kutaisi.,The percentage of seropositive stray dogs was also twice as high in Tbilisi (16.1%, n = 670) than in Kutaisi (8%, n = 50); only 2/58 wild animals screened were seropositive (2.,6%).,A total of 873 Phlebotomine sand flies were collected, with 5 different species identified in Tbilisi and 3 species in Kutaisi; 2.3% of the females were positive for Leishmania parasites.,The Leishmanin Skin Test (LST) was performed on 981 human subjects in VL foci in urban areas in Tbilisi and Kutaisi.,A particularly high prevalence of LST positives was observed in Tbilisi District #1 (22.2%, 37.5% and 19.5% for ages 5-9, 15-24 and 25-59, respectively); lower prevalence was observed in Kutaisi (0%, 3.2% and 5.2%, respectively; P<0.05).,This study shows that Tbilisi is an active focus for leishmaniasis and that the infection prevalence is very high in dogs and in humans.,Although exposure is as yet not as high in Kutaisi, this is a new VL focus.,The overall situation in the country is alarming and new control measures are urgently needed.

Jenny Hill and colleagues conduct a systematic review and meta-analysis of qualitative, quantitative, and mixed methods studies to explore the factors that affect the delivery, access, and use of interventions to prevent malaria in pregnant women in sub-Saharan Africa.,Please see later in the article for the Editors' Summary,Malaria in pregnancy has important consequences for mother and baby.,Coverage with the World Health Organization-recommended prevention strategy for pregnant women in sub-Saharan Africa of intermittent preventive treatment in pregnancy (IPTp) and insecticide-treated nets (ITNs) is low.,We conducted a systematic review to explore factors affecting delivery, access, and use of IPTp and ITNs among healthcare providers and women.,We searched the Malaria in Pregnancy Library and Global Health Database from 1 January 1990 to 23 April 2013, without language restriction.,Data extraction was performed by two investigators independently, and data was appraised for quality and content.,Data on barriers and facilitators, and the effect of interventions, were explored using content analysis and narrative synthesis.,We conducted a meta-analysis of determinants of IPTp and ITN uptake using random effects models, and performed subgroup analysis to evaluate consistency across interventions and study populations, countries, and enrolment sites.,We did not perform a meta-ethnography of qualitative data.,Ninety-eight articles were included, of which 20 were intervention studies.,Key barriers to the provision of IPTp and ITNs were unclear policy and guidance on IPTp; general healthcare system issues, such as stockouts and user fees; health facility issues stemming from poor organisation, leading to poor quality of care; poor healthcare provider performance, including confusion over the timing of each IPTp dose; and women's poor antenatal attendance, affecting IPTp uptake.,Key determinants of IPTp coverage were education, knowledge about malaria/IPTp, socio-economic status, parity, and number and timing of antenatal clinic visits.,Key determinants of ITN coverage were employment status, education, knowledge about malaria/ITNs, age, and marital status.,Predictors showed regional variations.,Delivery of ITNs through antenatal clinics presents fewer problems than delivery of IPTp.,Many obstacles to IPTp delivery are relatively simple barriers that could be resolved in the short term.,Other barriers are more entrenched within the overall healthcare system or socio-economic/cultural contexts, and will require medium- to long-term strategies.,Please see later in the article for the Editors' Summary,Half the world's population is at risk of malaria, a mosquito-borne parasite that kills a million people every year.,Most of these deaths occur among young children in sub-Saharan Africa, but pregnant women and their unborn babies are also vulnerable to malaria.,Infection with malaria during pregnancy can cause maternal death, severe maternal anemia, miscarriages, and pre-term and low-birth-weight babies.,Malaria in pregnancy is responsible for about 100,000 babies and 10,000 women dying every year but is preventable by simple, inexpensive interventions that have been available for many years.,The World Health Organization recommends a three-pronged approach to the prevention of malaria in pregnancy in areas with stable malaria transmission in Africa-delivery of the antimalarial drug sulfadoxine-pyrimethamine to pregnant women during antenatal clinic visits (intermittent preventative treatment in pregnancy; IPTp), the use of insecticide-treated bed nets (ITNs) to protect pregnant women from the bites of infected mosquitoes, and effective diagnosis and case management of pregnant women with malarial illness.,Coverage with this prevention strategy is currently very low.,Recent survey data from sub-Saharan African countries suggest that only about a quarter of pregnant women receive two doses of IPTp and only about a third use ITNs.,To improve coverage, public health experts need to understand why coverage is so low, and they need to know the factors (determinants) that are associated with the uptake of IPTp and ITNs.,In this systematic review and meta-analysis of qualitative, quantitative, and mixed methods studies, the researchers explore the factors that affect delivery, access, and use of IPTp and ITNs among pregnant women in sub-Saharan Africa.,A systematic review uses predefined criteria to identify all the research on a given topic.,Meta-analysis is a statistical method for combining the results of several studies.,Qualitative studies collect non-quantitative data such as reasons for not accepting an intervention, whereas quantitative studies collect numerical data such as the proportion of a population accepting an intervention.,The researchers' search of the Malaria in Pregnancy Library (a resource maintained by the Malaria in Pregnancy Consortium) and the Global Health Database identified 98 studies that provided data on barriers to and determinants of IPTp and ITN uptake and/or data on interventions designed to increase IPTp and ITN uptake.,The researchers explored these data using content analysis (a research methodology that examines words and phrases within texts) and narrative synthesis (a method for summarizing results drawn from several qualitative studies).,Key barriers to the provision and uptake of IPTp and ITNs included unclear policy and guidance on IPTp, general healthcare system issues such as drug shortages, healthcare facility issues such as unavailability of water for the provision of IPTp by directly observed therapy, poor healthcare provider performance such as confusion about the timing of IPTp doses, and the delayed antenatal care-seeking practices of pregnant women.,The researchers' meta-analysis identified education, knowledge about malaria, socio-economic status, number and timing of antenatal clinic visits, and number of pregnancies as key determinants of IPTp uptake, and employment status, education, knowledge, age, and marital status as key determinants of coverage of ITN use.,So, for example, highly educated women were more likely to receive IPTp or ITNs than poorly educated women.,These findings identify key interacting barriers to access, delivery, and use of IPTp and ITNs in sub-Saharan Africa and show that these barriers are relatively consistent across countries.,Moreover, they suggest that there are fewer barriers to the delivery of ITNs through antenatal clinics than to the delivery of IPTp.,Importantly, some of the barriers to IPTp uptake can be resolved in the short term (for example, simplification of country policies and guidance on IPTp might increase its uptake), but barriers to uptake that are entrenched within the overall healthcare system will only be resolved with medium- to long-term strategies that aim to improve the quality of antenatal services and to encourage antenatal clinic use among women.,Overall, this analysis provides a checklist of factors that policy-makers involved in national malaria programs may be able to use to help them decide which interventions to prioritize.,However, the researchers warn, multi-country studies are nevertheless urgently needed to evaluate targeted or multifaceted interventions designed to increase delivery and uptake of IPTp and ITNs, to reduce the adverse consequences of malaria in pregnancy.,Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001488.,Information is available from the World Health Organization on malaria (in several languages) and on IPTp; the World Malaria Report 2012 provides details of the current global malaria situation,The US Centers for Disease Control and Prevention also provides information on malaria and on IPTp; a personal story about malaria in pregnancy is available,Information is available from the Roll Back Malaria Partnership on all aspects of global malaria control, including information on malaria in pregnancy,The Malaria in Pregnancy Consortium is undertaking research into the prevention and treatment of malaria in pregnancy,MedlinePlus provides links to additional information on malaria (in English and Spanish)

The World Health Organization recommends insecticidal bednets and intermittent preventive treatment to reduce malaria in pregnancy.,Longitudinal data of malaria prevalence and pregnancy outcomes are valuable in gauging the impact of these antimalarial interventions.,We recruited 8,131 women delivering in a single Malawian hospital over 9 years.,We recorded demographic data, antenatal prescription of intermittent preventive therapy during pregnancy with sulfadoxine-pyrimethamine and bed net use, and examined finger-prick blood for malaria parasites and hemoglobin concentration.,In 4,712 women, we examined placental blood for malaria parasites and recorded the infant's birth weight.,Peripheral and placental parasitemia prevalence declined from 23.5% to 5.0% and from 25.2% to 6.8% respectively.,Smaller declines in prevalence of low birth weight and anemia were observed.,Coverage of intermittent preventive treatment and bednets increased.,Number of sulfadoxine-pyrimethamine doses received correlated inversely with placental parasitemia (Odds Ratio (95% CI): 0.79 (0.68, 0.91)), maternal anemia (0.81, (0.73, 0.90)) and low birth weight from 1997-2001 (0.63 (0.53, 0.75)), but not from 2002-2006.,Bednet use protected from peripheral parasitemia (0.47, (0.37, 0.60)) and placental parasitemia (0.41, (0.31, 0.54)) and low birth weight (0.75 (0.59, 0.95)) but not anemia throughout the study.,Compared to women without nets who did not receive 2-dose sulfadoxine-pyrimethamine, women using nets and receiving 2-dose sulfadoxine-pyrimethamine were less likely to have parasitemia or low birth weight babies.,Women receiving 2-dose sulfadoxine-pyrimethamine alone had little evidence of protection whereas bednets alone gave intermediate protection.,Increased bednet coverage explains changes in parasitemia and birth weight among pregnant women better than sulfadoxine-pyrimethamine use.,High bed net coverage, and sulfadoxine-pyrimethamine resistance, may be contributing to its apparent loss of effectiveness.

Handheld light microscopy using compact optics and mobile phones may improve the quality of health care in resource-constrained settings by enabling access to prompt and accurate diagnosis.,Laboratory technicians were trained to operate two handheld diagnostic devices (Newton Nm1 microscope and a clip-on version of the mobile phone-based CellScope).,The accuracy of these devices was compared to conventional light microscopy for the diagnosis of Schistosoma haematobium, S. mansoni, and intestinal protozoa infection in a community-based survey in rural Côte d’Ivoire.,One slide of 10 ml filtered urine and a single Kato-Katz thick smear from 226 individuals were subjected to the Newton Nm1 microscope and CellScope for detection of Schistosoma eggs and compared to conventional microscopy.,Additionally, 121 sodium acetate-acetic acid-formalin (SAF)-fixed stool samples were examined by the Newton Nm1 microscope and compared to conventional microscopy for the diagnosis of intestinal protozoa.,The prevalence of S. haematobium, S. mansoni, Giardia intestinalis, and Entamoeba histolytica/E. dispar, as determined by conventional microscopy, was 39.8%, 5.3%, 20.7%, and 4.9%, respectively.,The Newton Nm1 microscope had diagnostic sensitivities for S. mansoni and S. haematobium infection of 91.7% (95% confidence interval (CI) 59.8-99.6%) and 81.1% (95% CI 71.2-88.3%), respectively, and specificities of 99.5% (95% CI 97.0-100%) and 97.1% (95% CI 92.2-99.1%), respectively.,The CellScope demonstrated sensitivities for S. mansoni and S. haematobium of 50.0% (95% CI 25.4-74.6%) and 35.6% (95% CI 25.9-46.4%), respectively, and specificities of 99.5% (95% CI 97.0-100%) and 100% (95% CI 86.7-100%), respectively.,For G. intestinalis and E. histolytica/E. dispar, the Newton Nm1 microscope had sensitivity of 84.0% (95% CI 63.1-94.7%) and 83.3% (95% CI 36.5-99.1%), respectively, and 100% specificity.,Handheld diagnostic devices can be employed in community-based surveys in resource-constrained settings after minimal training of laboratory technicians to diagnose intestinal parasites.

Although seasonality is a defining characteristic of many infectious diseases, few studies have described and compared seasonal patterns across diseases globally, impeding our understanding of putative mechanisms.,Here, we review seasonal patterns across five enteric zoonotic diseases: campylobacteriosis, salmonellosis, vero-cytotoxigenic Escherichia coli (VTEC), cryptosporidiosis and giardiasis in the context of two primary drivers of seasonality: (i) environmental effects on pathogen occurrence and pathogen-host associations and (ii) population characteristics/behaviour.,We systematically reviewed published literature from 1960-2010, resulting in the review of 86 studies across the five diseases.,The Gini coefficient compared temporal variations in incidence across diseases and the monthly seasonality index characterised timing of seasonal peaks.,Consistent seasonal patterns across transnational boundaries, albeit with regional variations was observed.,The bacterial diseases all had a distinct summer peak, with identical Gini values for campylobacteriosis and salmonellosis (0.22) and a higher index for VTEC (Gini = 0.36).,Cryptosporidiosis displayed a bi-modal peak with spring and summer highs and the most marked temporal variation (Gini = 0.39).,Giardiasis showed a relatively small summer increase and was the least variable (Gini = 0.18).,Seasonal variation in enteric zoonotic diseases is ubiquitous, with regional variations highlighting complex environment-pathogen-host interactions.,Results suggest that proximal environmental influences and host population dynamics, together with distal, longer-term climatic variability could have important direct and indirect consequences for future enteric disease risk.,Additional understanding of the concerted influence of these factors on disease patterns may improve assessment and prediction of enteric disease burden in temperate, developed countries.