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Malaria control programmes currently face the challenge of maintaining, as well as accelerating, the progress made against malaria with fewer resources and uncertain funding.,There is a critical need to determine what combination of malaria interventions confers the greatest protection against malaria morbidity and child mortality under routine conditions.,This study assesses intervention effectiveness experienced by children under the age of five exposed to both insecticide-treated nets (ITNs) and indoor residual spraying (IRS), as compared to each intervention alone, based on nationally representative survey data collected from 17 countries in sub-Saharan Africa.,Living in households with both ITNs and IRS was associated with a significant risk reduction against parasitaemia in medium and high transmission areas, 53% (95% CI 37% to 67%) and 31% (95% CI 11% to 47%) respectively.,For medium transmission areas, an additional 36% (95% CI 7% to 53%) protection was garnered by having both interventions compared with exposure to only ITNs or only IRS.,Having both ITNs and IRS was not significantly more protective against parasitaemia than either intervention alone in low and high malaria transmission areas.,In rural and urban areas, exposure to both interventions provided significant protection against parasitaemia, 57% (95% CI 48% to 65%) and 39% (95% CI 10% to 61%) respectively; however, this effect was not significantly greater than having a singular intervention.,Statistically, risk for all-cause child mortality was not significantly reduced by having both ITNs and IRS, and no additional protectiveness was detected for having dual intervention coverage over a singular intervention.,These findings suggest that greater reductions in malaria morbidity and health gains for children may be achieved with ITNs and IRS combined beyond the protection offered by IRS or ITNs alone.

Scaling up of long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) with support from the Global Fund and President's Malaria Initiative is providing increased opportunities for malaria control in Africa.,The most cost-effective and longest-lasting residual insecticide DDT is also the most environmentally persistent.,Alternative residual insecticides exist, but are too short-lived or too expensive to sustain.,Dow Agrosciences have developed a microencapsulated formulation (CS) of the organophosphate chlorpyrifos methyl as a cost-effective, long-lasting alternative to DDT.,Chlorpyrifos methyl CS was tested as an IRS or ITN treatment in experimental huts in an area of Benin where Anopheles gambiae and Culex quinquefasiactus are resistant to pyrethroids, but susceptible to organophosphates.,Efficacy and residual activity was compared to that of DDT and the pyrethroid lambdacyalothrin.,IRS with chlorpyrifos methyl killed 95% of An. gambiae that entered the hut as compared to 31% with lambdacyhalothrin and 50% with DDT.,Control of Cx. quinquefasciatus showed a similar trend; although the level of mortality with chlorpyrifos methyl was lower (66%) it was still much higher than for DDT (14%) or pyrethroid (15%) treatments.,Nets impregnated with lambdacyhalothrin were compromized by resistance, killing only 30% of An. gambiae and 8% of Cx. quinquefasciatus.,Nets impregnated with chlorpyrifos methyl killed more (45% of An gambiae and 15% of Cx. quinquefasciatus), but its activity on netting was of short duration.,Contact bioassays on the sprayed cement-sand walls over the nine months of monitoring showed no loss of activity of chlorpyrifos methyl, whereas lambdacyhalothrin and DDT lost activity within a few months of spraying.,As an IRS treatment against pyrethroid resistant mosquitoes chlorpyrifos methyl CS outperformed DDT and lambdacyhalothrin.,In IRS campaigns, chlorpyrifos methyl CS should show higher, more-sustained levels of malaria transmission control than conventional formulations of DDT or pyrethroids.,The remarkable residual activity indicates that cost-effective alternatives to DDT are feasible through modern formulation technology.

Human to vector transmission of malaria requires that some blood stage parasites abandon asexual growth and convert into non-replicating sexual forms called gametocytes.,The initial steps of gametocytogenesis remain largely uncharacterized.,Here we studied this part of the malaria life cycle in Plasmodium falciparum using PfAP2-G, the master regulator of sexual conversion, as a marker of commitment.,We demonstrate the existence of PfAP2-G-positive sexually-committed parasite stages preceding the previously known committed schizont stage.,We also found that sexual conversion can occur by two different routes: the previously described route where PfAP2-G-expressing parasites complete a replicative cycle as committed forms before converting into gametocytes upon reinvasion, or a direct route with conversion within the same cycle as initial PfAP2-G expression.,The latter route is linked to early PfAP2-G expression in ring stages.,Re-analysis of published single-cell RNA-seq data confirmed the presence of both routes.,Consistent with these results, using plaque assays we observed that, in contrast to the prevailing model, many schizonts produced mixed plaques containing both asexual parasites and gametocytes.,Altogether, our results reveal unexpected features of the initial steps of sexual development and extend the current view of this part of the malaria life cycle.

2015 was the target year for malaria goals set by the World Health Assembly and other international institutions to reduce malaria incidence and mortality.,A review of progress indicates that malaria programme financing and coverage have been transformed since the beginning of the millennium, and have contributed to substantial reductions in the burden of disease.,Investments in malaria programmes increased by more than 2.5 times between 2005 and 2014 from US$ 960 million to US$ 2.5 billion, allowing an expansion in malaria prevention, diagnostic testing and treatment programmes.,In 2015 more than half of the population of sub-Saharan Africa slept under insecticide-treated mosquito nets, compared to just 2 % in 2000.,Increased availability of rapid diagnostic tests and antimalarial medicines has allowed many more people to access timely and appropriate treatment.,Malaria incidence rates have decreased by 37 % globally and mortality rates by 60 % since 2000.,It is estimated that 70 % of the reductions in numbers of cases in sub-Saharan Africa can be attributed to malaria interventions.,Reductions in malaria incidence and mortality rates have been made in every WHO region and almost every country.,However, decreases in malaria case incidence and mortality rates were slowest in countries that had the largest numbers of malaria cases and deaths in 2000; reductions in incidence need to be greatly accelerated in these countries to achieve future malaria targets.,Progress is made challenging because malaria is concentrated in countries and areas with the least resourced health systems and the least ability to pay for system improvements.,Malaria interventions are nevertheless highly cost-effective and have not only led to significant reductions in the incidence of the disease but are estimated to have saved about US$ 900 million in malaria case management costs to public providers in sub-Saharan Africa between 2000 and 2014.,Investments in malaria programmes can not only reduce malaria morbidity and mortality, thereby contributing to the health targets of the Sustainable Development Goals, but they can also transform the well-being and livelihood of some of the poorest communities across the globe.,The online version of this article (doi:10.1186/s40249-016-0151-8) contains supplementary material, which is available to authorized users.

The emergence of resistance to artemisinin derivatives in Southeast Asia, manifested as delayed clearance of Plasmodium falciparum following treatment with artemisinins, is a major concern.,Recently, the artemisinin resistance phenotype was attributed to mutations in portions of a P. falciparum gene (PF3D7_1343700) encoding kelch (K13) propeller domains, providing a molecular marker to monitor the spread of resistance.,The P. falciparum cysteine protease falcipain-2 (FP2; PF3D7_1115700) has been shown to contribute to artemisinin action, as hemoglobin degradation is required for potent drug activity, and a stop mutation in the FP2 gene was identified in parasites selected for artemisinin resistance.,Although delayed parasite clearance after artemisinin-based combination therapy (ACT) has not yet been noted in Uganda and ACTs remain highly efficacious, characterizing the diversity of these genes is important to assess the potential for resistance selection and to provide a baseline for future surveillance.,We therefore sequenced the K13-propeller domain and FP2 gene in P. falciparum isolates from children previously treated with ACT in Uganda, including samples from 2006-7 (n = 49) and from 2010-12 (n = 175).,Using 3D7 as the reference genome, we identified 5 non-synonymous polymorphisms in the K13-propeller domain (133 isolates) and 35 in FP2 (160 isolates); these did not include the polymorphisms recently associated with resistance after in vitro selection or identified in isolates from Asia.,The prevalence of K13-propeller and FP2 polymorphisms did not increase over time, and was not associated with either time since prior receipt of an ACT or the persistence of parasites ≥2 days following treatment with an ACT.,Thus, the K13-propeller and FP2 polymorphisms associated with artemisinin resistance are not prevalent in Uganda, and we did not see evidence for selection of polymorphisms in these genes.

Plasmodium falciparum resistance to artemisinins, the first line treatment for malaria worldwide, has been reported in western Cambodia.,Resistance is characterized by significantly delayed clearance of parasites following artemisinin treatment.,Artemisinin resistance has not previously been reported in Myanmar, which has the highest falciparum malaria burden among Southeast Asian countries.,A non-randomized, single-arm, open-label clinical trial of artesunate monotherapy (4 mg/kg daily for seven days) was conducted in adults with acute blood-smear positive P. falciparum malaria in Kawthaung, southern Myanmar.,Parasite density was measured every 12 hours until two consecutive negative smears were obtained.,Participants were followed weekly at the study clinic for three additional weeks.,Co-primary endpoints included parasite clearance time (the time required for complete clearance of initial parasitemia), parasite clearance half-life (the time required for parasitemia to decrease by 50% based on the linear portion of the parasite clearance slope), and detectable parasitemia 72 hours after commencement of artesunate treatment.,Drug pharmacokinetics were measured to rule out delayed clearance due to suboptimal drug levels.,The median (range) parasite clearance half-life and time were 4.8 (2.1-9.7) and 60 (24-96) hours, respectively.,The frequency distributions of parasite clearance half-life and time were bimodal, with very slow parasite clearance characteristic of the slowest-clearing Cambodian parasites (half-life longer than 6.2 hours) in approximately 1/3 of infections.,Fourteen of 52 participants (26.9%) had a measurable parasitemia 72 hours after initiating artesunate treatment.,Parasite clearance was not associated with drug pharmacokinetics.,A subset of P. falciparum infections in southern Myanmar displayed markedly delayed clearance following artemisinin treatment, suggesting either emergence of artemisinin resistance in southern Myanmar or spread to this location from its site of origin in western Cambodia.,Resistance containment efforts are underway in Myanmar.,Australian New Zealand Clinical Trials Registry ACTRN12610000896077

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.

Long lasting pyrethroid treated bednets are the most important tool for preventing malaria.,Pyrethroid resistant Anopheline mosquitoes are now ubiquitous in Africa, though the public health impact remains unclear, impeding the deployment of more expensive nets.,Meta-analyses of bioassay studies and experimental hut trials are used to characterise how pyrethroid resistance changes the efficacy of standard bednets, and those containing the synergist piperonyl butoxide (PBO), and assess its impact on malaria control.,New bednets provide substantial personal protection until high levels of resistance, though protection may wane faster against more resistant mosquito populations as nets age.,Transmission dynamics models indicate that even low levels of resistance would increase the incidence of malaria due to reduced mosquito mortality and lower overall community protection over the life-time of the net.,Switching to PBO bednets could avert up to 0.5 clinical cases per person per year in some resistance scenarios.,DOI:http://dx.doi.org/10.7554/eLife.16090.001,In recent years, widespread use of insecticide-treated bednets has prevented hundreds of thousands cases of malaria in Africa.,Insecticide-treated bednets protect people in two ways: they provide a physical barrier that prevents the insects from biting and the insecticide kills mosquitos that come into contact with the net while trying to bite.,Unfortunately, some mosquitoes in Africa are evolving so that they can survive contact with the insecticide currently used on bednets.,How this emerging insecticide resistance is changing the number of malaria infections in Africa is not yet clear and it is difficult for scientists to study.,To help mitigate the effects of insecticide resistance, scientists are testing new strategies to boost the effects of bednets, such as adding a second chemical that makes the insecticide on bednets more deadly to mosquitoes.,In some places, adding this second chemical makes the nets more effective, but in others it does not.,Moreover, these doubly treated, or “combination”, nets are more expensive and so it can be hard for health officials to decide whether and where to use them.,Now, Churcher et al. have used computer modeling to help predict how insecticide resistance might change malaria infection rates and help determine when it makes sense to switch to the combination net.,Insecticide-treated bednets provide good protection for individuals sleeping under them until relatively high levels of resistance are achieved, as measured using a simple test.,As more resistant mosquitos survive encounters with the nets, the likelihood of being bitten before bed or while sleeping unprotected by a net increases.,This is expected to increase malaria infections.,As bednets age and are washed multiple times, they lose some of their insecticide and this problem becomes worse.,Churcher et al. also show that the combination bednets may provide some additional protection against resistant mosquitos and reduce the number of malaria infections in some cases.,The experiments show a simple test could help health officials determine which type of net would be most beneficial.,The experiments and the model Churcher et al. created also may help scientists studying how to prevent increased spread of malaria in communities where mosquitos are becoming resistant to insecticide-treated nets.,DOI:http://dx.doi.org/10.7554/eLife.16090.002

Lymphatic filariasis is a neglected tropical disease that can cause permanent disability through disruption of the lymphatic system.,This disease is caused by parasitic filarial worms that are transmitted by mosquitos.,Mass drug administration (MDA) of antihelmintics is recommended by WHO to eliminate lymphatic filariasis as a public health problem.,This study aims to produce the first geospatial estimates of the global prevalence of lymphatic filariasis infection over time, to quantify progress towards elimination, and to identify geographical variation in distribution of infection.,A global dataset of georeferenced surveyed locations was used to model annual 2000-18 lymphatic filariasis prevalence for 73 current or previously endemic countries.,We applied Bayesian model-based geostatistics and time series methods to generate spatially continuous estimates of global all-age 2000-18 prevalence of lymphatic filariasis infection mapped at a resolution of 5 km2 and aggregated to estimate total number of individuals infected.,We used 14 927 datapoints to fit the geospatial models.,An estimated 199 million total individuals (95% uncertainty interval 174-234 million) worldwide were infected with lymphatic filariasis in 2000, with totals for WHO regions ranging from 3·1 million (1·6-5·7 million) in the region of the Americas to 107 million (91-134 million) in the South-East Asia region.,By 2018, an estimated 51 million individuals (43-63 million) were infected.,Broad declines in prevalence are observed globally, but focal areas in Africa and southeast Asia remain less likely to have attained infection prevalence thresholds proposed to achieve local elimination.,Although the prevalence of lymphatic filariasis infection has declined since 2000, MDA is still necessary across large populations in Africa and Asia.,Our mapped estimates can be used to identify areas where the probability of meeting infection thresholds is low, and when coupled with large uncertainty in the predictions, indicate additional data collection or intervention might be warranted before MDA programmes cease.,Bill & Melinda Gates Foundation.

Mosquitoes in the Culex pipiens complex thrive in temperate and tropical regions worldwide, and serve as efficient vectors of Bancroftian lymphatic filariasis (LF) caused by Wuchereria bancrofti in Asia, Africa, the West Indies, South America, and Micronesia.,However, members of this mosquito complex do not act as natural vectors for Brugian LF caused by Brugia malayi, or for the cat parasite B. pahangi, despite their presence in South Asia where these parasites are endemic.,Previous work with the Iowa strain of Culex pipiens pipiens demonstrates that it is equally susceptible to W. bancrofti as is the natural Cx. p. pipiens vector in the Nile Delta, however it is refractory to infection with Brugia spp.,Here we report that the infectivity barrier for Brugia spp. in Cx. p. pipiens is the mosquito midgut, which inflicts internal and lethal damage to ingested microfilariae.,Following per os Brugia exposures, the prevalence of infection is significantly lower in Cx. p. pipiens compared to susceptible mosquito controls, and differs between parasite species with <50% and <5% of Cx. p. pipiens becoming infected with B. pahangi and B. malayi, respectively.,When Brugia spp. mf were inoculated intrathoracically to bypass the midgut, larvae developed equally well as in controls, indicating that, beyond the midgut, Cx. p. pipiens is physiologically compatible with Brugia spp.,Mf isolated from Cx. p. pipiens midguts exhibited compromised motility, and unlike mf derived from blood or isolated from the midguts of Ae. aegypti, failed to develop when inoculated intrathoracically into susceptible mosquitoes.,Together these data strongly support the role of the midgut as the primary infection barrier for Brugia spp. in Cx. p. pipiens.,Examination of parasites recovered from the Cx. p. pipiens midgut by vital staining, and those exsheathed with papain, suggest that the damage inflicted by the midgut is subcuticular and disrupts internal tissues.,Microscopic studies of these worms reveal compromised motility and sharp bends in the body; and ultrastructurally the presence of many fluid or carbohydrate-filled vacuoles in the hypodermis, body wall, and nuclear column.,Incubation of Brugia mf with Cx. p. pipiens midgut extracts produces similar internal damage phenotypes; indicating that the Cx. p. pipiens midgut factor(s) that damage mf in vivo are soluble and stable in physiological buffer, and inflict damage on mf in vitro.

With visceral leishmaniasis (VL) incidence at its lowest level since the 1960s, increasing attention has turned to early detection and investigation of outbreaks.,Outbreak investigations were triggered by recognition of case clusters in the VL surveillance system established for the elimination program.,Investigations included ascertainment of all VL cases by date of fever onset, household mapping and structured collection of risk factor data.,VL outbreaks were investigated in 13 villages in 10 blocks of 7 districts.,Data were collected for 20,670 individuals, of whom 272 were diagnosed with VL between 2012 and 2019.,Risk was significantly higher among 10-19 year-olds and adults 35 or older compared to children younger than 10 years.,Outbreak confirmation triggered vector control activities and heightened surveillance.,VL cases strongly clustered in tolas (hamlets within villages) in which > 66% of residents self-identified as scheduled caste or scheduled tribe (SC/ST); 79.8% of VL cases occurred in SC/ST tolas whereas only 24.2% of the population resided in them.,Other significant risk factors included being an unskilled non-agricultural laborer, migration for work in a brick kiln, living in a kuccha (mud brick) house, household crowding, habitually sleeping outside or on the ground, and open defecation.,Our data highlight the importance of sensitive surveillance with triggers for case cluster detection and rapid, careful outbreak investigations to better respond to ongoing and new transmission.,The strong association with SC/ST tolas suggests that efforts should focus on enhanced surveillance in these disadvantaged communities.

Visceral leishmaniasis (VL) control in the Indian subcontinent is currently based on case detection and treatment, and on vector control using indoor residual spraying (IRS).,The use of long-lasting insecticidal nets (LN) has been postulated as an alternative or complement to IRS.,Here we tested the impact of comprehensive distribution of LN on the density of Phlebotomus argentipes in VL-endemic villages.,A cluster-randomized controlled trial with household P. argentipes density as outcome was designed.,Twelve clusters from an ongoing LN clinical trial-three intervention and three control clusters in both India and Nepal-were selected on the basis of accessibility and VL incidence.,Ten houses per cluster selected on the basis of high pre-intervention P. argentipes density were monitored monthly for 12 months after distribution of LN using CDC light traps (LT) and mouth aspiration methods.,Ten cattle sheds per cluster were also monitored by aspiration.,A random effect linear regression model showed that the cluster-wide distribution of LNs significantly reduced the P. argentipes density/house by 24.9% (95% CI 1.80%-42.5%) as measured by means of LTs.,The ongoing clinical trial, designed to measure the impact of LNs on VL incidence, will confirm whether LNs should be adopted as a control strategy in the regional VL elimination programs.,The entomological evidence described here provides some evidence that LNs could be usefully deployed as part of the VL control program.,ClinicalTrials.gov CT-2005-015374

Over 60 % of human emerging infectious diseases are zoonotic, and there is growing evidence of the zooanthroponotic transmission of diseases from humans to livestock and wildlife species, with major implications for public health, economics, and conservation.,Zooanthroponoses are of relevance to critically endangered species; amongst these is the mountain gorilla (Gorilla beringei beringei) of Uganda.,Here, we assess the occurrence of Cryptosporidium, Cyclospora, Giardia, and Entamoeba infecting mountain gorillas in the Bwindi Impenetrable National Park (BINP), Uganda, using molecular methods.,We also assess the occurrence of these parasites in humans and livestock species living in overlapping/adjacent geographical regions.,Diagnostic PCR detected Cryptosporidium parvum in one sample from a mountain gorilla (IIdA23G2) and one from a goat (based on SSU).,Cryptosporidium was not detected in humans or cattle.,Cyclospora was not detected in any of the samples analysed.,Giardia was identified in three human and two cattle samples, which were linked to assemblage A, B and E of G. duodenalis.,Sequences defined as belonging to the genus Entamoeba were identified in all host groups.,Of the 86 sequence types characterised, one, seven and two have been recorded previously to represent genotypes of Cryptosporidium, Giardia, and Entamoeba, respectively, from humans, other mammals, and water sources globally.,This study provides a snapshot of the occurrence and genetic make-up of selected protists in mammals in and around BINP.,The genetic analyses indicated that 54.6% of the 203 samples analysed contained parasites that matched species, genotypes, or genetic assemblages found globally.,Seventy-six new sequence records were identified here for the first time.,As nothing is known about the zoonotic/zooanthroponotic potential of the corresponding parasites, future work should focus on wider epidemiological investigations together with continued surveillance of all parasites in humans, other mammals, the environment, and water in this highly impoverished area.,The online version of this article (doi:10.1186/s13071-017-2283-5) contains supplementary material, which is available to authorized users.

Giardia duodenalis and Entamoeba spp. are among the most common intestinal human protozoan parasites worldwide and they are frequently reported in captive non-human primates (NHP).,From a public health point of view, infected animals in zoos constitute a risk for animal caretakers and visitors.,In this study we carried out the molecular identification of G. duodenalis and Entamoeba spp. from nine species of primates housed in the zoological garden of Rome, to better ascertain their occurrence and zoonotic potential.,G. duodenalis was found only in Lemur catta (47.0%).,Entamoeba spp. were detected in all species studied, with the exception of Eulemur macaco and Varecia rubra.,The number of positive pools ranged from 5.9% in L. catta to 81.2% in Mandrillus sphinx; in Pan troglodytes the observed prevalence was 53.6%.,A mixed Entamoeba-Giardia infection was recorded only in one sample of L. catta.,All G. duodenalis isolates belonged to the zoonotic assemblage B, sub assemblage BIV.,Three Entamoeba species were identified: E. hartmanni, E. coli and E. dispar.,Our results highlight the importance of regularly testing animals kept in zoos for the diagnosis of zoonotic parasites, in order to evaluate their pathogenic role in the housed animals and the zoonotic risk linked to their presence.,A quick detection of the arrival of pathogens into the enclosures could also be a prerequisite to limit their spread into the structure via the introduction of specific control strategies.,The need for molecular identification of some parasite species/genotype in order to better define the zoonotic risk is also highlighted.

Plasmodium vivax and Plasmodium ovale are often considered the malaria parasites best adapted to long-term survival in the human host because of their latent exo-erythrocytic forms.,The prevailing opinion until the middle of the last century was that the maximum duration of Plasmodium falciparum infections was less than two years.,Case reports and series investigating blood donors following accidental malaria infection of blood transfusion recipients and other sporadic malaria cases in non-endemic countries have shown clearly that asymptomatic P. falciparum infections may persist for up to a decade or longer (maximum confirmed 13 years).,Current policies in malaria-free countries of excluding blood donors who have lived in malarious areas are justified.,Vigilance for longer than three years after declaring elimination in an area may be needed.

Clinical malaria incidence was determined over 18 months in a cohort of 553 children living in a peri-urban area near Cotonou.,Three cross-sectional surveys were also carried out.,Malaria incidence showed a marked seasonal distribution with two peaks: the first corresponding to the long rainy season, and the second corresponding to the overflowing of Lake Nokoue.,The overall Plasmodium falciparum incidence rate was estimated at 84/1,000 person-months, and its prevalence was estimated at over 40% in the two first surveys and 68.9% in the third survey.,Multivariate analysis showed that girls and people living in closed houses had a lower risk of clinical malaria.,Bed net use was associated with a lower risk of malaria infection.,Conversely, children of families owing a pirogue were at higher risk of clinical malaria.,Considering the high pyrethroids resistance, indoor residual spraying with either a carbamate or an organophospate insecticide may have a major impact on the malaria burden.

Onchocerca volvulus infection can result in blindness, itching and skin lesions.,Previous research concentrated on blindness.,A clinical classification system of the cutaneous changes in onchocerciasis was used for the first time in this study within the context of an early ivermectin drug trial in the savanna region of Kaduna State, northern Nigeria.,Skin examinations were performed in 6,790 individuals aged 5+ years in endemic communities and 1,343 individuals in nonendemic communities.,There was increased risk for all forms of onchocercal skin disease in endemic communities with the most common finding being the presence of nodules (1,438 individuals, 21.2%), followed by atrophy (367, 6.1% of those < 50 years), acute papular onchodermatitis, APOD (233, 3.4%), depigmentation (216, 3.2%) and chronic papular onchodermatitis, CPOD (155, 2.3%).,A further 645 individuals (9.5%) complained of pruritus but had completely normal skin.,APOD was more common in males whereas atrophy, hanging groin and nodules were more common in females.,After controlling for age and sex, microfilarial positivity was a risk factor for CPOD, depigmentation, hanging groin and nodules (OR 1.54, p = 0.046; OR 2.29, p = 0.002; OR 2.18, p = 0.002 and OR 3.80, p <0.001 respectively).,Comparable results were found using presence of nodules as the marker for infection.,Microfilarial load showed similar, though weaker, results.,A total of 2621(38.6%) endemic residents had itching with normal skin, or had one or more types of onchocercal skin disease including nodules, which may be considered as a composite index of the overall prevalence of onchocercal skin disease.,Significant levels of onchocercal skin disease were documented in this savanna area, which subsequently resulted in a reassessment of the true burden of skin disease in onchocerciasis.,This paper represents the first detailed report of the association of onchocercal skin disease with markers for onchocercal infection.

River blindness (onchocerciasis) causes severe itching, skin lesions, and vision impairment including blindness.,More than 99% of all current cases are found in sub-Saharan Africa.,Fortunately, vector control and community-directed treatment with ivermectin have significantly reduced morbidity.,Studies in Mali and Senegal proved the feasibility of elimination with ivermectin administration.,The treatment goal is shifting from control to elimination in endemic African regions.,Given limited resources, national and global policymakers need a rigorous analysis comparing investment options.,For this, we developed scenarios for alternative treatment goals and compared treatment timelines and drug needs between the scenarios.,Control, elimination, and eradication scenarios were developed with reference to current standard practices, large-scale studies, and historical data.,For each scenario, the timeline when treatment is expected to stop at country level was predicted using a dynamical transmission model, and ivermectin treatment needs were predicted based on population in endemic areas, treatment coverage data, and the frequency of community-directed treatment.,The control scenario requires community-directed treatment with ivermectin beyond 2045 with around 2.63 billion treatments over 2013-2045; the elimination scenario, until 2028 in areas where feasible, but beyond 2045 in countries with operational challenges, around 1.15 billion treatments; and the eradication scenario, lasting until 2040, around 1.30 billion treatments.,The eradication scenario is the most favorable in terms of the timeline of the intervention phase and treatment needs.,For its realization, strong health systems and political will are required to overcome epidemiological and political challenges.

There is little information on the social perception of malaria and the use of preventative measures in Gabon, especially in rural areas.,Adequate knowledge of malaria prevention and control can help in reducing the burden of malaria among vulnerable groups, particularly pregnant women and children under 5 years old living in malaria-endemic settings.,This study was designed to assess the prevalence of malaria and the knowledge and attitude towards this disease in households in Nyanga Province.,A cross-sectional study was conducted to assess malaria knowledge, prevention practices and prevalence of the malaria infection in five departments of Nyanga Province.,Plasmodial infection was diagnosed in children ≤ 5 years of age and women aged 15-49 years using rapid diagnostic tests.,A questionnaire was administered randomly to women aged 15-49 years and to the parents or guardians of children aged ≤ 5 years in 535 households during a 2-week period in March 2018.,Overall, the respondents’ socio-demographic characteristics, knowledge of malaria, malaria prevention practices and malaria prevalence were evaluated and compared across the five departments.,Data from a total of 1,307 participants were included in this study, including 631 women of childbearing age (61 of them pregnant) and 676 children.,Practically the entire (97.7%) interviewed population had heard about malaria and attributed the cause of malaria to a mosquito bite (95.7%).,This survey revealed that the reported rate of reported bed-net use was 73.3%.,The study observed an average malaria parasite prevalence of 13.9%.,All departmental capitals of Nyanga Province had a significant level of malaria infection except for Mayumba where no plasmodial infection was found.,High malaria prevalence is found in the departmental capital cities of Nyanga Province.,This study reveals that respondents have a high knowledge of the malaria symptoms, its mode of transmission and preventive measures.,Despite this high level of knowledge of the disease and its preventive measures, the incidence of malaria remains relatively high in this rural community highlighting the need for other types of interventions.

Gaps remain in understanding the role of caregiver responses on time to seek appropriate care.,The objective of this study was to describe caregiver responses to illness and the impact of these responses on time to seek appropriate care among children with malaria.,A case-control study of 325 children with severe (cases) and 325 children with uncomplicated (controls) malaria was conducted in Jinja, Uganda.,Caregivers’ responses to their children’s illnesses and time to seek appropriate care were documented.,Responses included staying at home, seeking care at drug shops, and seeking care at public health facilities classified into two types: (1) health facilities where caregiver initially sought care before enrollment, and (2) health facilities where children were provided appropriate care and enrolled in the study.,Weighted Cox regression was used to determine risk factors for delays in time to seek appropriate care within 24 h of illness onset.,Children staying home on self-medication was the most common initial response to illness among caregivers of controls (57.5%) and cases (42.4%, p < 0.001), followed by staying at home without medication (25.2%) and seeking care at drug shops (32.0%) for caregivers of controls and cases, respectively.,Seeking care at drug shops was more common among caregivers of cases than of controls (32.0% vs.,12.3%; p < 0.001).,However, compared to public health facilities, drug shops offered sub-optimal services with children less likely to have been examined (50.0% vs.,82.9%; p < 0.001) or referred to another facility (12.5% vs.,61.4%; p < 0.001).,Upon adjustment for known risk factors for delay, initially seeking care at a drug shop (HR 0.37, p = 0.036) was associated with delay in seeking care at a health facility where appropriate care was provided.,In contrast, those initially seeking care at public health facility before enrollment were more likely to subsequently seek care at another public health facility where appropriate care was provided (HR 5.55, p < 0.001).,Caregivers should be educated on the importance of promptly seeking care at a health facility where appropriate care can be provided.,The role of drug shops in providing appropriate care to children with malaria needs to be reviewed.,The online version of this article (10.1186/s12936-018-2630-9) contains supplementary material, which is available to authorized users.

Mapping and diagnosis of infections by the three major schistosome species (Schistosoma haematobium, S. mansoni and S. japonicum) has been done with assays that are known to be specific but increasingly insensitive as prevalence declines or in areas with already low prevalence of infection.,This becomes a true challenge to achieving the goal of elimination of schistosomiasis because the multiplicative portion of the life-cycle of schistosomes, in the snail vector, favors continued transmission as long as even a few people maintain low numbers of worms that pass eggs in their excreta.,New mapping tools based on detection of worm antigens (circulating cathodic antigen - CCA; circulating anodic antigen - CAA) in urine of those infected are highly sensitive and the CAA assay is reported to be highly specific.,Using these tools in areas of low prevalence of all three of these species of schistosomes has demonstrated that more people harbor adult worms than are regularly excreting eggs at a level detectable by the usual stool assay (Kato-Katz) or by urine filtration.,In very low prevalence areas this is sometimes 6- to10-fold more.,Faced with what appears to be a sizable population of “egg-negative/worm-positive schistosomiasis” especially in areas of very low prevalence, national NTD programs are confounded about what guidelines and strategies they should enact if they are to proceed toward a goal of elimination.,There is a critical need for continued evaluation of the assays involved and to understand the contribution of this “egg-negative/worm-positive schistosomiasis” condition to both individual morbidity and community transmission.,There is also a critical need for new guidelines based on the use of these more sensitive assays for those national NTD programs that wish to move forward to strategies designed for elimination.,The online version of this article (doi:10.1186/s40249-017-0275-5) contains supplementary material, which is available to authorized users.

In Tanzania, the first cases of schistosomiasis were reported in the early 19th century.,Since then, various studies have reported prevalences of up to 100% in some areas.,However, for many years, there have been no sustainable control programmes and systematic data from observational and control studies are very limited in the public domain.,To cover that gap, the present article reviews the epidemiology, malacology, morbidity, and the milestones the country has made in efforts to control schistosomiasis and discusses future control approaches.,The available evidence indicates that, both urinary and intestinal schistosomiasis are still highly endemic in Tanzania and cause significant morbidity.Mass drug administration using praziquantel, currently used as a key intervention measure, has not been successful in decreasing prevalence of infection.,There is therefore an urgent need to revise the current approach for the successful control of the disease.,Clearly, these need to be integrated control measures.

Novel transgenic mosquito control methods require progressively more realistic evaluation.,The goal of this study was to determine the effect of a transgene that causes a male-bias sex ratio on Anopheles gambiae target populations in large insectary cages.,Life history characteristics of Anopheles gambiae wild type and Ag(PMB)1 (aka gfp124L-2) transgenic mosquitoes, whose progeny are 95% male, were measured in order to parameterize predictive population models.,Ag(PMB)1 males were then introduced at two ratios into large insectary cages containing target wild type populations with stable age distributions and densities.,The predicted proportion of females and those observed in the large cages were compared.,A related model was then used to predict effects of male releases on wild mosquitoes in a west African village.,The frequency of transgenic mosquitoes in target populations reached an average of 0.44 ± 0.02 and 0.56 ± 0.02 after 6 weeks in the 1:1 and in the 3:1 release ratio treatments (transgenic male:wild male) respectively.,Transgenic males caused sex-ratio distortion of 73% and 80% males in the 1:1 and 3:1 treatments, respectively.,The number of eggs laid in the transgenic treatments declined as the experiment progressed, with a steeper decline in the 3:1 than in the 1:1 releases.,The results of the experiment are partially consistent with predictions of the model; effect size and variability did not conform to the model in two out of three trials, effect size was over-estimated by the model and variability was greater than anticipated, possibly because of sampling effects in restocking.,The model estimating the effects of hypothetical releases on the mosquito population of a West African village demonstrated that releases could significantly reduce the number of females in the wild population.,The interval of releases is not expected to have a strong effect.,The biological data produced to parameterize the model, the model itself, and the results of the experiments are components of a system to evaluate and predict the performance of transgenic mosquitoes.,Together these suggest that the Ag(PMB)1 strain has the potential to be useful for reversible population suppression while this novel field develops.

Anopheles gambiae sensu stricto, the main vector of malaria in Africa, is characterized by its vast geographical range and complex population structure.,Assortative mating amongst the reproductively isolated cryptic forms that co-occur in many areas poses unique challenges for programs aiming to decrease malaria incidence via the release of sterile or genetically-modified mosquitoes.,Importantly, whether laboratory-rearing affects the ability of An. gambiae individuals of a given cryptic taxa to successfully mate with individuals of their own form in field conditions is still unknown and yet crucial for mosquito-releases.,Here, the independent effects of genetic and environmental factors associated with laboratory rearing on male and female survival, mating success and assortative mating were evaluated in the Mopti form of An. gambiae over 2010 and 2011.,In semi-field enclosures experiments and despite strong variation between years, the overall survival and mating success of male and female progeny from a laboratory strain was not found to be significantly lower than those of the progeny of field females from the same population.,Adult progeny from field-caught females reared at the larval stage in the laboratory and from laboratory females reared outdoors exhibited a significant decrease in survival but not in mating success.,Importantly, laboratory individuals reared as larvae indoors were unable to mate assortatively as adults, whilst field progeny reared either outdoors or in the laboratory, as well as laboratory progeny reared outdoors all mated significantly assortatively.,These results highlight the importance of genetic and environment interactions for the development of An. gambiae's full mating behavioral repertoire and the challenges this creates for mosquito rearing and release-based control strategies.

Humoral immunity is a critical effector arm for protection against malaria but develops only slowly after repeated infections.,T cell-mediated regulatory dynamics affect the development of antibody responses to Plasmodium parasites.,Here, we hypothesize that T follicular helper cell (TFH) polarization generated by repeated Plasmodium asexual blood-stage infections delays the onset of protective humoral responses.,IFN-γ production promotes polarization toward TFH1 and increased generation of regulatory follicular helper cells (TFR).,Delineating the mechanisms that drive TH1 polarization will provide clues for appropriate induction of lasting, protective immunity against malaria.

Cerebral malaria is among the major causes of malaria-associated mortality and effective adjunctive therapeutic strategies are currently lacking.,Central pathophysiological processes involved in the development of cerebral malaria include an imbalance of pro- and anti-inflammatory responses to Plasmodium infection, endothelial cell activation, and loss of blood-brain barrier integrity.,However, the sequence of events, which initiates these pathophysiological processes as well as the contribution of their complex interplay to the development of cerebral malaria remain incompletely understood.,Several cytokines and chemokines have repeatedly been associated with cerebral malaria severity.,Increased levels of these inflammatory mediators could account for the sequestration of leukocytes in the cerebral microvasculature present during cerebral malaria, thereby contributing to an amplification of local inflammation and promoting cerebral malaria pathogenesis.,Herein, we highlight the current knowledge on the contribution of cytokines and chemokines to the pathogenesis of cerebral malaria with particular emphasis on their roles in endothelial activation and leukocyte recruitment, as well as their implication in the progression to blood-brain barrier permeability and neuroinflammation, in both human cerebral malaria and in the murine experimental cerebral malaria model.,A better molecular understanding of these processes could provide the basis for evidence-based development of adjunct therapies and the definition of diagnostic markers of disease progression.

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.

In Southeast Asia, Plasmodium knowlesi, a parasite of long-tailed macaques (Macaca fascicularis), is an important cause of human malaria.,Plasmodium cynomolgi also commonly infects these monkeys, but only one naturally acquired symptomatic human case has been reported previously.,Malariometric studies involving 5422 subjects (aged 6 months to 65 years) were conducted in 23 villages in Pailin and Battambang, western Cambodia.,Parasite detection and genotyping was conducted on blood samples, using high-volume quantitative PCR (uPCR).,Asymptomatic malaria parasite infections were detected in 1361 of 14732 samples (9.2%).,Asymptomatic infections with nonhuman primate malaria parasites were found in 21 individuals living close to forested areas; P. cynomolgi was found in 11, P. knowlesi was found in 8, and P. vivax and P. cynomolgi were both found in 2.,Only 2 subjects were female, and 14 were men aged 20-40 years.,Geometric mean parasite densities were 3604 parasites/mL in P. cynomolgi infections and 52488 parasites/mL in P. knowlesi infections.,All P. cynomolgi isolates had wild-type dihydrofolate reductase genes, in contrast to the very high prevalence of mutations in the human malaria parasites.,Asymptomatic reappearance of P. cynomolgi occurred in 2 subjects 3 months after the first infection.,Asymptomatic naturally acquired P. cynomolgi and P. knowlesi infections can both occur in humans.,NCT01872702.,Epidemiological studies in western Cambodia identified 21 subjects with asymptomatic monkey malaria parasite infections (8 with P. knowlesi infection and 13 with P. cynomolgi infection).,These parasites represented 1.9% of all identified malaria parasites.

Recent studies have demonstrated the deletion of the histidine-rich protein 2 (PfHRP2) gene (pfhrp2) in field isolates of Plasmodium falciparum, which could result in false negative test results when PfHRP2-based rapid diagnostic tests (RDTs) are used for malaria diagnosis.,Although primary diagnosis of malaria in Honduras is determined based on microscopy, RDTs may be useful in remote areas.,In this study, it was investigated whether there are deletions of the pfhrp2, pfhrp3 and their respective flanking genes in 68 P. falciparum parasite isolates collected from the city of Puerto Lempira, Honduras.,In addition, further investigation considered the possible correlation between parasite population structure and the distribution of these gene deletions by genotyping seven neutral microsatellites.,Sixty-eight samples used in this study, which were obtained from a previous chloroquine efficacy study, were utilized in the analysis.,All samples were genotyped for pfhrp2, pfhrp3 and flanking genes by PCR.,The samples were then genotyped for seven neutral microsatellites in order to determine the parasite population structure in Puerto Lempira at the time of sample collection.,It was found that all samples were positive for pfhrp2 and its flanking genes on chromosome 8.,However, only 50% of the samples were positive for pfhrp3 and its neighboring genes while the rest were either pfhrp3-negative only or had deleted a combination of pfhrp3 and its neighbouring genes on chromosome 13.,Population structure analysis predicted that there are at least two distinct parasite population clusters in this sample population.,It was also determined that a greater proportion of parasites with pfhrp3-(and flanking gene) deletions belonged to one cluster compared to the other.,The findings indicate that the P. falciparum parasite population in the municipality of Puerto Lempira maintains the pfhrp2 gene and that PfHRP2-based RDTs could be considered for use in this region; however continued monitoring of parasite population will be useful to detect any parasites with deletions of pfhrp2.

Recently, a real-time PCR assay known as photo-induced electron transfer (PET)-PCR which relies on self-quenching primers for the detection of Plasmodium spp. and Plasmodium falciparum was described.,PET-PCR assay was found to be robust, and easier to use when compared to currently available real-time PCR methods.,The potential of PET-PCR for molecular detection of malaria parasites in a nationwide malaria community survey in Haiti was investigated.,DNA from the dried blood spots was extracted using QIAGEN methodology.,All 2,989 samples were screened using the PET-PCR assay in duplicate.,Samples with a cycle threshold (CT) of 40 or less were scored as positive.,A subset of the total samples (534) was retested using a nested PCR assay for confirmation.,In addition, these same samples were also tested using a TaqMan-based real-time PCR assay.,A total of 12 out of the 2,989 samples screened (0.4%) were found to be positive by PET-PCR (mean CT value of 35.7).,These same samples were also found to be positive by the nested and TaqMan-based methods.,The nested PCR detected an additional positive sample in a subset of 534 samples that was not detected by either PET-PCR or TaqMan-based PCR method.,While the nested PCR was found to be slightly more sensitive than the PET-PCR, it is not ideal for high throughput screening of samples.,Given the ease of use and lower cost than the nested PCR, the PET-PCR provides an alternative assay for the rapid screening of a large number of samples in laboratory settings.

Chagas disease is a complex illness caused by the protozoan Trypanosoma cruzi displaying highly diverse clinical outcomes.,In this sense, the genome sequence elucidation and comparison between strains may lead to disease understanding.,Here, two new T. cruzi strains, have been sequenced, Y using Illumina and Bug2148 using PacBio, assembled, analyzed and compared with the T. cruzi annotated genomes available to date.,The assembly stats from the new sequences show effective improvement of T. cruzi genome over the actual ones.,Such as, the largest contig assembled (1.3 Mb in Bug2148) in de novo attempts and the highest mean assembly coverage (71X for Y).,Our analysis reveals a new genomic expansion and greater complexity for those multi-copy gene families related to infection process and disease development, such as Trans-sialidases, Mucins and Mucin Associated Surface Proteins, among others.,On one side, we demonstrate that multi-copy gene families are located near telomeric regions of the “chromosome-like” 1.3 Mb contig assembled of Bug2148, where they likely suffer high evolutive pressure.,On the other hand, we identified several strain-specific single copy genes that might help to understand the differences in infectivity and physiology among strains.,In summary, our results indicate that T. cruzi has a complex genomic architecture that may have promoted its evolution.

Trypanosoma cruzi, the causative agent of Chagas disease, presents wide genetic diversity.,Currently, six discrete typing units (DTUs), named TcI to TcVI, and a seventh one called TcBat are used for strain typing.,Beyond the debate concerning this classification, this systematic review has attempted to provide an inventory by compiling the results of 137 articles that have used it.,A total of 6,343 DTU identifications were analyzed according to the geographical and host origins.,Ninety-one percent of the data available is linked to South America.,This sample, although not free of potential bias, nevertheless provides today’s picture of T. cruzi genetic diversity that is closest to reality.,DTUs were genotyped from 158 species, including 42 vector species.,Remarkably, TcI predominated in the overall sample (around 60%), in both sylvatic and domestic cycles.,This DTU known to present a high genetic diversity, is very widely distributed geographically, compatible with a long-term evolution.,The marsupial is thought to be its most ancestral host and the Gran Chaco region the place of its putative origin.,TcII was rarely sampled (9.6%), absent, or extremely rare in North and Central America, and more frequently identified in domestic cycles than in sylvatic cycles.,It has a low genetic diversity and has probably found refuge in some mammal species.,It is thought to originate in the south-Amazon area.,TcIII and TcIV were also rarely sampled.,They showed substantial genetic diversity and are thought to be composed of possible polyphyletic subgroups.,Even if they are mostly associated with sylvatic transmission cycles, a total of 150 human infections with these DTUs have been reported.,TcV and TcVI are clearly associated with domestic transmission cycles.,Less than 10% of these DTUs were identified together in sylvatic hosts.,They are thought to originate in the Gran Chaco region, where they are predominant and where putative parents exist (TcII and TcIII).,Trends in host-DTU specificities exist, but generally it seems that the complexity of the cycles and the participation of numerous vectors and mammal hosts in a shared area, maintains DTU diversity.

Visceral leishmaniasis (VL) is considered a major public health concern in Brazil and several regions of the world.,A recent advance in the diagnosis of infectious diseases was the development of loop-mediated isothermal amplification (LAMP).,The aim of this study was to develop and evaluate a new LAMP assay for detection of K26 antigen-coding gene of L. donovani complex.,A total of 219 blood samples of immunocompetent patients, including 114 VL cases and 105 non-VL cases, were analyzed for the diagnosis of VL in the present study.,Diagnostic accuracy was calculated against a combination of parasitological and/or serological tests as a reference standard.,The results were compared to those of kDNA Leishmania-PCR.,The detection limit for the K26-Lamp assay was 1fg L. infantum purified DNA and 100 parasites/mL within 60 min of amplification time with visual detection for turbidity.,The assay was specific for L. donovani complex.,Sensitivity, specificity, and accuracy were 98.2%, 98.1%, and 98.2%, respectively, for K26-LAMP and 100%, 100%, and 100%, respectively, for kDNA Leishmania-PCR.,Excellent agreement was observed between K26-LAMP and kDNA Leishmania-PCR assays (K = 0.96).,A highly sensitive and specific LAMP assay targeting K26 antigen-coding gene of L. donovani complex was developed for diagnosis in peripheral blood samples of VL patients.

Leishmania is an obligate intracellular pathogen that invades phagocytic host cells.,Approximately 30 different species of Phlebotomine sand flies can transmit this parasite either anthroponotically or zoonotically through their bites.,Leishmaniasis affects poor people living around the Mediterranean Basin, East Africa, the Americas, and Southeast Asia.,Affected regions are often remote and unstable, with limited resources for treating this disease.,Leishmaniasis has been reported as one of the most dangerous neglected tropical diseases, second only to malaria in parasitic causes of death.,People can carry some species of Leishmania for long periods without becoming ill, and symptoms depend on the form of the disease.,There are many drugs and candidate vaccines available to treat leishmaniasis.,For instance, antiparasitic drugs, such as amphotericin B (AmBisome), are a treatment of choice for leishmaniasis depending on the type of the disease.,Despite the availability of different treatment approaches to treat leishmaniasis, therapeutic tools are not adequate to eradicate this infection.,In the meantime, drug therapy has been limited because of adverse side effects and unsuccessful vaccine preparation.,However, it can immediately make infections inactive.,According to other studies, vaccination cannot eradicate leishmaniasis.,There is no perfect vaccine or suitable drug to eradicate leishmaniasis completely.,So far, no vaccine or drug has been provided to induce long-term protection and ensure effective immunity against leishmaniasis.,Therefore, it is necessary that intensive research should be performed in drug and vaccine fields to achieve certain results.

Gut microbiota were recently shown to impact malaria disease progression and outcome, and prior studies have shown that Plasmodium infections increase the likelihood of enteric bacteria causing systemic infections.,Currently, it is not known whether Plasmodium infection impacts human gut microbiota as a prelude to bacteremia or whether antimalarials affect gut microbiota.,Our goal was to determine to what degree Plasmodium infections and antimalarial treatment affect human gut microbiota.,One hundred Kenyan infants underwent active surveillance for malaria from birth to 10 months of age.,Each malaria episode was treated with artemether-lumefantrine (AL).,Any other treatments, including antibiotics, were recorded.,Stool samples were collected on an approximately biweekly basis.,Ten children were selected on the basis of stool samples having been collected before (n = 27) or after (n = 17) a malaria episode and without antibiotics having been administered between collections.,These samples were subjected to 16S ribosomal ribonucleic acid gene (V3-V4 region) sequencing.,Bacterial community network analysis revealed no obvious differences in the before and after malaria/AL samples, which was consistent with no difference in alpha and beta diversity and taxonomic analysis at the family and genus level with one exception.,At the sequence variant (SV) level, akin to bacterial species, only 1 of the top 100 SVs was significantly different.,In addition, predicted metagenome analysis revealed no significant difference in metagenomic capacity between before and after malaria/AL samples.,The number of malaria episodes, 1 versus 2, explained significant variation in gut microbiota composition of the infants.,In-depth bioinformatics analysis of stool bacteria has revealed for the first time that human malaria episode/AL treatment have minimal effects on gut microbiota in Kenyan infants.,Although malaria-induced dysbiosis of gut microbiota has been postulated to contribute towards increased susceptibility to Non-typhoid Salmonella infections, this report demonstrates that Plasmodium infections and oral treatment with antimalarial drugs do not alter stool bacteria populations in Kenyan infants.

Although thrombocytopenia is a hematological disorder commonly reported in malarial patients, its mechanisms are still poorly understood, with only a few studies focusing on the role of platelets phagocytosis.,Thirty-five malaria vivax patients and eight healthy volunteers (HV) were enrolled in the study.,Among vivax malaria patients, thrombocytopenia (<150,000 platelets/µL) was found in 62.9% (22/35).,Mean platelet volume (MPV) was higher in thrombocytopenic patients as compared to non- thrombocytopenic patients (p = 0.017) and a negative correlation was found between platelet count and MPV (r = −0.483; p = 0.003).,Platelets from HV or patients were labeled with 5-chloromethyl fluorescein diacetate (CMFDA), incubated with human monocytic cell line (THP-1) and platelet phagocytosis index was analyzed by flow cytometry.,The phagocytosis index was higher in thrombocytopenic patients compared to non-thrombocytopenic patients (p = 0.042) and HV (p = 0.048).,A negative correlation was observed between platelet count and phagocytosis index (r = −0.402; p = 0.016).,Platelet activation was assessed measuring the expression of P-selectin (CD62-P) in platelets’ surface by flow cytometry.,No significant difference was found in the expression of P-selectin between thrombocytopenic patients and HV (p = 0.092).,After evaluating the cytokine profile (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ and IL-17) in the patients’ sera, levels of IL-6, IL-10 and IFN-γ were elevated in malaria patients compared to HV.,Moreover, IL-6 and IL-10 values were higher in thrombocytopenic patients than non-thrombocytopenic ones (p = 0.044 and p = 0.017, respectively.,In contrast, TNF-α levels were not different between the three groups, but a positive correlation was found between TNF-α and phagocytosis index (r = −0.305; p = 0.037).,Collectively, our findings indicate that platelet phagocytosis may contribute to thrombocytopenia found in vivax malaria.,Finally, we believe that this study opens new avenues to explore the mechanisms involved in platelet dysfunction, commonly found in vivax malaria patients.

To achieve malaria elimination, it is important to determine the role of human mobility in parasite transmission maintenance.,The Alto Juruá basin (Brazil) exhibits one of the largest vivax and falciparum malaria prevalence in the Amazon.,The goal of this study was to estimate the contribution of human commutes to malaria persistence in this region, using data from an origin-destination survey.,Data from an origin-destination survey were used to describe the intensity and motivation for commutations between rural and urban areas in two Alto Juruá basin (Brazil) municipalities, Mâncio Lima and Rodrigues Alves.,The relative time-person spent in each locality per household was estimated.,A logistic model was developed to estimate the effect of commuting on the probability of contracting malaria for a certain residence zone inhabitant commuting to another zone.,The main results suggest that the assessed population is not very mobile.,A total of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$96\%$$\end{document}96% households reported spending over \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$90\%$$\end{document}90% of their annual person-hour in areas within the same residence zone.,Study and work were the most prevalent commuting motivations, calculated at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$40.5\%$$\end{document}40.5% and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$29.5\%$$\end{document}29.5% respectively.,Spending person-hours in urban Rodrigues Alves conferred relative protection to urban Mâncio Lima residents.,The opposite effect was observed for those spending time in rural areas of both municipalities.,Residence area is a stronger determinant for contracting malaria than commuting zones in the Alto Juruá region.,As these municipalities are a hotspot for Plasmodium transmission, understanding the main local human fluxes is essential for planning control strategies, since the probability of contracting malaria is dependent on the transmission intensity of both the origin and the displacement area.,The natural conditions for the circulation of certain pathogens, such as Plasmodium spp., combined with the Amazon human mobility pattern indicate the need for disease control perspective changes.,Therefore, intersectoral public policies should become the basis for health mitigation actions.

In recent years, considerable success in reducing its incidence has been achieved in Brazil, leading to a relative increase in the proportion of cases caused by Plasmodium vivax, considered a harder-to-eliminate parasite.,This study aim is to describe the transmission dynamics and associated risk factors in a rural settlement area in the Western Brazilian Amazon.,A prospective cohort was established in a rural settlement area for 3 years.,Follow-up included continuous passive case detection and monthly active case detection for a period of 6 months.,Demographic, clinical and transmission control practices data were collected.,Malaria diagnosis was performed through thick blood smear.,Univariable and multivariable analyses of factors associated with malaria incidence were performed using negative binomial regression models.,Factors associated with recurrence of P. vivax and Plasmodium falciparum malaria within 90 days of a previous episode were analysed using univariable and multivariable Cox-Proportional Hazard models.,Malaria prevalence decreased from 7 % at the study beginning to 0.6 % at month 24, with P. vivax predominating and P. falciparum disappearing after 1 year of follow-up.,Malaria incidence was significantly higher in the dry season [IRR (95 % CI) 1.4 (1.1-1.6); p < 0.001)].,Use of ITN was associated to malaria protection in the localities [IRR (95 % CI) 0.7 (0.6-0.8); p = 0.001)].,A recurrent P. vivax episode within 90 days was observed in 29.4 % of individuals after an initial diagnosis.,A previous P. vivax [IRR (95 % CI) 2.3 (1.3-4.0); p = 0.006)] or mixed P. vivax + P. falciparum [IRR (95 % CI) 2.9 (1.5-5.7); p = 0.002)] infections were significantly associated to a vivax malaria episode within 90 days of follow-up.,In an area of P. falciparum and P. vivax co-endemicity, a virtual disappearance of P. falciparum was observed with P. vivax increasing its relative contribution, with a large proportion of recurring episodes.,This finding reinforces the perception of P. falciparum being more responsive to early diagnosis and treatment and ITN use and the contribution of relapsing P. vivax to maintain this species’ transmission.,In areas of P. vivax endemicity, antihypnozoite treatment effectiveness assessment in different transmission intensity may be a fundamental activity for malaria control and elimination.,The online version of this article (doi:10.1186/s12936-016-1326-2) contains supplementary material, which is available to authorized users.

Reactive case detection (RCD) for malaria is a strategy to identify additional malaria infections in areas of low malaria transmission and can complement passive surveillance.,This study describes experiences with RCD in two Indian sites, and aimed to synthesize experiences with RCD across endemic countries.,RCD programmes were piloted in two urban areas of India with a low prevalence of mainly Plasmodium vivax malaria in 2014.,Cases were identified in a clinic by microscopy and contacts were screened within 2 weeks; PCR, in addition to microscopy, was used to detect Plasmodium parasites.,A systematic review was conducted to identify RCD experiences in the literature.,In Chennai, 868 contacts were enrolled for 18 index cases of clinical malaria; in Nadiad, 131 contacts were enrolled for 20 index cases.,No new malaria infections were detected in Nadiad among contacts, and four new infections were detected in Chennai (three P. vivax and one Plasmodium falciparum), of which two were among household members of index cases.,An additional five studies describing results from an RCD strategy were identified in the literature: four in Africa and one in Thailand.,Including the results from India, the average number of contacts screened per index case in a total of seven studies ranged from four to 50, and 126 in a case study in Thailand with one index case.,Malaria was detected in 0-45 % of the contacted persons.,The average number of index cases needed to be traced to find one new case of malaria ranged from one to five, and could not be assessed in one study in India (no contacts positive for 20 cases).,Sharing the household with an index case was associated with a five-fold increased risk of malaria compared to contacts from households without an index case (pooled risk ratio 5.29, 95 % CI 3.31-8.47, I2 0 %, four studies).,RCD in areas of low malaria transmission is a labour-intensive strategy, and its benefit is not clear.,Studies are needed to assess how RCD can be optimized or into alternatives where interventions are targeted to family members or hotspots.

Asymptomatic reservoirs of malaria parasites are common yet are difficult to detect, posing a problem for malaria control.,If control programmes focus on mosquito control and treatment of symptomatic individuals only, malaria can quickly resurge if interventions are scaled back.,Foci of parasite populations must be identified and treated.,Therefore, an active case detection system that facilitates detection of asymptomatic parasitaemia and gametocyte carriers was developed and tested in the Macha region in southern Zambia.,Each week, nurses at participating rural health centres (RHC) communicated the number of rapid diagnostic test (RDT) positive malaria cases to a central research team.,During the dry season when malaria transmission was lowest, the research team followed up each positive case reported by the RHC by a visit to the homestead.,The coordinates of the location were obtained by GPS and all consenting residents completed a questionnaire and were screened for malaria using thick blood film, RDT, nested-PCR, and RT-PCR for asexual and sexual stage parasites.,Persons who tested positive by RDT were treated with artemether/lumefantrine (Coartem®).,Data were compared with a community-based study of randomly selected households to assess the prevalence of asymptomatic parasitaemia in the same localities in September 2009.,In total, 186 and 141 participants residing in 23 case and 24 control homesteads, respectively, were screened.,In the case homesteads for which a control population was available (10 of the 23), household members of clinically diagnosed cases had a 8.0% prevalence of malaria using PCR compared to 0.7% PCR positive individuals in the control group (p = 0.006).,The case and control groups had a gametocyte prevalence of 2.3% and 0%, respectively but the difference was not significant (p = 0.145).,This pilot project showed that active case detection is feasible and can identify reservoirs of asymptomatic infection.,A larger sample size, data over multiple low transmission seasons, and in areas with different transmission dynamics are needed to further validate this approach.

Sleeping sickness is a fatal disease caused by Trypanosoma brucei, a unicellular parasite that lives in the bloodstream and interstitial spaces of peripheral tissues and the brain.,Patients have altered sleep/wake cycles, body temperature, and endocrine profiles, but the underlying causes are unknown.,Here, we show that the robust circadian rhythms of mice become phase advanced upon infection, with abnormal activity occurring during the rest phase.,This advanced phase is caused by shortening of the circadian period both at the behavioral level as well as at the tissue and cell level.,Period shortening is T. brucei specific and independent of the host immune response, as co-culturing parasites with explants or fibroblasts also shortens the clock period, whereas malaria infection does not.,We propose that T. brucei causes an advanced circadian rhythm disorder, previously associated only with mutations in clock genes, which leads to changes in the timing of sleep.,African sleeping sickness is well known for the alterations of sleeping patterns, but it is not known how circadian biology is altered by the causative pathogen Trypanosoma brucei.,Here the authors show T. brucei causes a disorder of the cellular circadian clock that is unrelated to the immune response to the parasite.

Control of human African sleeping sickness, caused by subspecies of the protozoan parasite Trypanosoma brucei, is based on preventing transmission by elimination of the tsetse vector and by active diagnostic screening and treatment of infected patients.,To identify trypanosome proteins that have potential as biomarkers for detection and monitoring of African sleeping sickness, we have used a ‘deep-mining” proteomics approach to identify trypanosome proteins in human plasma.,Abundant human plasma proteins were removed by immunodepletion.,Depleted plasma samples were then digested to peptides with trypsin, fractionated by basic reversed phase and each fraction analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS).,This sample processing and analysis method enabled identification of low levels of trypanosome proteins in pooled plasma from late stage sleeping sickness patients infected with Trypanosoma brucei rhodesiense.,A total of 254 trypanosome proteins were confidently identified.,Many of the parasite proteins identified were of unknown function, although metabolic enzymes, chaperones, proteases and ubiquitin-related/acting proteins were found.,This approach to the identification of conserved, soluble trypanosome proteins in human plasma offers a possible route to improved disease diagnosis and monitoring, since these molecules are potential biomarkers for the development of a new generation of antigen-detection assays.,The combined immuno-depletion/mass spectrometric approach can be applied to a variety of infectious diseases for unbiased biomarker identification.

Plasmodium vivax sporozoites reside in the salivary glands of a mosquito before infecting a human host and causing malaria.,Previous transcriptome-wide studies in populations of these parasite forms were limited in their ability to elucidate cell-to-cell variation, thereby masking cellular states potentially important in understanding malaria transmission outcomes.,In this study, we performed transcription profiling on 9,947 P. vivax sporozoites to assess the extent to which they differ at single-cell resolution.,We show that sporozoites residing in the mosquito’s salivary glands exist in distinct developmental states, as defined by their transcriptomic signatures.,Additionally, relative to P. falciparum, P. vivax displays overlapping and unique gene usage patterns, highlighting conserved and species-specific gene programs.,Notably, distinguishing P. vivax from P. falciparum were a subset of P. vivax sporozoites expressing genes associated with translational regulation and repression.,Finally, our comparison of single-cell transcriptomic data from P. vivax sporozoite and erythrocytic forms reveals gene usage patterns unique to sporozoites.,In defining the transcriptomic signatures of individual P. vivax sporozoites, our work provides new insights into the factors driving their developmental trajectory and lays the groundwork for a more comprehensive P. vivax cell atlas.

Malaria is a major mosquito transmitted, blood-borne parasitic disease that afflicts humans.,The disease causes anaemia and other clinical complications, which can lead to death.,Plasmodium vivax is known for its reticulocyte host cell specificity, but many gaps in disease details remain.,Much less is known about the closely related species, Plasmodium cynomolgi, although it is naturally acquired and causes zoonotic malaria.,Here, a computational model is developed based on longitudinal analyses of P. cynomolgi infections in nonhuman primates to investigate the erythrocyte dynamics that is pertinent to understanding both P. cynomolgi and P. vivax malaria in humans.,A cohort of five P. cynomolgi infected Rhesus macaques (Macaca mulatta) is studied, with individuals exhibiting a plethora of clinical outcomes, including varying levels of anaemia.,A discrete recursive model with age structure is developed to replicate the dynamics of P. cynomolgi blood-stage infections.,The model allows for parasitic reticulocyte preference and assumes an age preference among the mature RBCs.,RBC senescence is modelled using a hazard function, according to which RBCs have a mean lifespan of 98 ± 21 days.,Based on in vivo data from three cohorts of macaques, the computational model is used to characterize the reticulocyte lifespan in circulation as 24 ± 5 h (n = 15) and the rate of RBC production as 2727 ± 209 cells/h/µL (n = 15).,Analysis of the host responses reveals a pre-patency increase in the number of reticulocytes.,It also allows the quantification of RBC removal through the bystander effect.,The evident pre-patency increase in reticulocytes is due to a shift towards the release of younger reticulocytes, which could result from a parasite-induced factor meant to increase reticulocyte availability and satisfy the parasite’s tropism, which has an average value of 32:1 in this cohort.,The number of RBCs lost due to the bystander effect relative to infection-induced RBC losses is 62% for P. cynomolgi infections, which is substantially lower than the value of 95% previously determined for another simian species, Plasmodium coatneyi.,The online version of this article (10.1186/s12936-018-2560-6) contains supplementary material, which is available to authorized users.

In Vietnam, malaria persists in remote forested regions where infections are spatially heterogeneous, mostly asymptomatic and with low parasite density.,Previous studies in Vietnam have investigated broad behavioural concepts such as ‘engaging in forest activities’ as risk factors for malaria infection, which may not explain heterogeneity in malaria risk, especially in malaria elimination settings.,A mixed methods study combining ethnographic research and a cross-sectional survey was embedded in a 1-year malariometric cohort study in three ethnic minority villages in South Tra My district, Quang Nam Province in Central Vietnam.,Qualitative data collection included in-depth interviews, informal conversations and participant observations over a 2-month period, and the findings were used to develop the questionnaire used in the cross-sectional survey.,The latter collected data on evening activities, mobility patterns and household characteristics.,The primary outcome, recent exposure to malaria, was defined using the classification and regression tree method to determine significant changes in antibody titres during the year preceding the survey.,Risk factor analyses for recent exposure to malaria were conducted using logistic regression.,22 in-depth interviews and numerous participant observations were recorded during the ethnographic research (April to June 2015), and 160 adults (86% response rate) responded to the cross-sectional survey (November to December 2015).,Recent exposure to Plasmodium falciparum malaria was estimated at 22.9 and at 17.1% for Plasmodium vivax.,Ongoing malaria transmission appears to be maintained by activities that delay or disrupt sleeping in a permanent structure in which a bed net could be hung, including evening drinking gatherings, fishing, logging in the forest and outdoor TV watching.,Vector control tools for outdoor evening activities in villages as well as at farms, forest and river locations should be incorporated into current malaria elimination efforts in Central Vietnam.,Micro-epidemiology studies using mixed-methods designs can provide a comprehensive understanding of the malaria risk at fine spatial scales and better inform the implementation of targeted interventions for malaria elimination.,The online version of this article (10.1186/s12936-018-2262-0) contains supplementary material, which is available to authorized users.

Malaria transmission is spatially heterogeneous.,This reduces the efficacy of control strategies, but focusing control strategies on clusters or ‘hotspots’ of transmission may be highly effective.,Among 1500 homesteads in coastal Kenya we calculated (a) the fraction of febrile children with positive malaria smears per homestead, and (b) the mean age of children with malaria per homestead.,These two measures were inversely correlated, indicating that children in homesteads at higher transmission acquire immunity more rapidly.,This inverse correlation increased gradually with increasing spatial scale of analysis, and hotspots of febrile malaria were identified at every scale.,We found hotspots within hotspots, down to the level of an individual homestead.,Febrile malaria hotspots were temporally unstable, but 4 km radius hotspots could be targeted for 1 month following 1 month periods of surveillance.,DOI:http://dx.doi.org/10.7554/eLife.02130.001,Malaria remains a formidable threat to public health in tropical regions.,The parasite that causes the disease is transmitted to humans by bites from infected mosquitoes, and the complicated lifecycle of the parasite makes developing vaccines difficult.,However, preventive strategies are effective at reducing the spread of malaria.,The two most widely used and effective strategies are the use of pesticide-treated bed nets to create a barrier between sleeping families and biting mosquitoes, and indoor residual spraying to reduce the numbers of mosquitoes biting sleeping families in homesteads.,Other potential preventive strategies include killing mosquito larvae in breeding sites and mass anti-malarial drug treatment for infected humans.,Targeting preventive efforts to malaria hotspots-the areas where the risk of malaria transmission is greatest-may help to eliminate malaria more efficiently.,Unfortunately, identifying hotspots is complicated as there are many different factors that affect how malaria spreads.,These factors range from ecological conditions such as rainfall and soil type, to human effects like population density and migration.,Bejon et al. have examined the patterns of malaria transmission in Kenya over 9 years.,Over this period, 54% of children who went to health clinics with a fever tested positive for the parasite that causes malaria.,Infected children from areas with the highest rate of malaria infection were, on average, younger than those from less infected regions.,This makes sense as in highly affected areas children have a greater chance of encountering the parasite at an early age.,They are therefore more likely to get malaria when younger and, as exposure to the parasite can provide some immunity to a child, they are also less likely to get infected again when older.,In addition, mapping the spread of malaria reveals hotspots at different geographical scales.,Bejon et al. could see hotspots within hotspots, and in some cases could go as far as identifying the individual homesteads most at risk of malaria.,Public health workers could potentially use these analyses to identify areas that are likely to be hotspots and then target preventive measures there for the next month.,However, the constantly changing locations of the hotspots means workers would have to reanalyse the data and retarget their interventions at the end of each month.,DOI:http://dx.doi.org/10.7554/eLife.02130.002

Latent toxoplasmosis, a lifelong infection with the protozoan Toxoplasma gondii, has cumulative effects on the behaviour of hosts, including humans.,The most impressive effect of toxoplasmosis is the “fatal attraction phenomenon,” the conversion of innate fear of cat odour into attraction to cat odour in infected rodents.,While most behavioural effects of toxoplasmosis were confirmed also in humans, neither the fatal attraction phenomenon nor any toxoplasmosis-associated changes in olfactory functions have been searched for in them.,Thirty-four Toxoplasma-infected and 134 noninfected students rated the odour of urine samples from cat, horse, tiger, brown hyena and dog for intensity and pleasantness.,The raters were blind to their infection status and identity of the samples.,No signs of changed sensitivity of olfaction were observed.,However, we found a strong, gender dependent effect of toxoplasmosis on the pleasantness attributed to cat urine odour (p = 0.0025).,Infected men rated this odour as more pleasant than did the noninfected men, while infected women rated the same odour as less pleasant than did noninfected women.,Toxoplasmosis did not affect how subjects rated the pleasantness of any other animal species' urine odour; however, a non-significant trend in the same directions was observed for hyena urine.,The absence of the effects of toxoplasmosis on the odour pleasantness score attributed to large cats would suggest that the amino acid felinine could be responsible for the fatal attraction phenomenon.,Our results also raise the possibility that the odour-specific threshold deficits observed in schizophrenia patients could be caused by increased prevalence of Toxoplasma-infected subjects in this population rather than by schizophrenia itself.,The trend observed with the hyena urine sample suggests that this carnivore, and other representatives of the Feliformia suborder, should be studied for their possible role as definitive hosts in the life cycle of Toxoplasma.

Inflammatory bowel diseases (IBDs) appear to be modulated by the interaction of pathogen-associated molecular patterns (PAMPs) derived from intestinal bacteria with their respective innate immune receptors, including Toll-like receptors (TLRs).,We aimed to establish if intestinal concentrations of proinflammatory bacterial ligands of TLR2, TLR4, or TLR5 may be altered in murine IBD models, and to characterize which of the major bacterial groups may contribute to each signal.,PAMPs specific for TLR2 (lipopeptide equivalents), TLR4 (lipopolysaccharide equivalents), and TLR5 (flagellin equivalents) in human and murine fecal and intestinal samples were quantified using HEK-293 cells transfected with respective TLRs and calibrated with defined standard PAMPs.,The induction of colitis in mice by dextran-sodium-sulphate treatment significantly increased colonic lipopeptide (fourfold) and LPS equivalent (550-fold) concentrations, while flagellin equivalent concentrations remained similar.,The induction of ileitis by oral infection with Toxoplasma gondii dramatically increased ileal concentrations of lipopeptide (370-fold), LPS (3,300-fold), and flagellin equivalents (38-fold), all P<0.01.,Analysis of representative strains of the major bacterial groups of the human intestine revealed that enterobacterial species are likely to be more significant contributors of soluble TLR2 and TLR4 stimulants to the intestinal milieu than Bacteroides species or Gram-positive Firmicutes.,We conclude that the induction of colitis or ileitis in mice is associated with significant disease-specific alterations to the PAMP profile of the gut microbiota.

Onchocerciasis is a parasitic, vector borne disease caused by the filarial nematode Onchocerca volvulus.,More than 99% of the population at risk of infection live in Africa.,Onchocerciasis control was initiated in West Africa in 1974 with vector control, later complemented by ivermectin mass drug administration and in the other African endemic countries in 1995 with annual community directed treatment with ivermectin (CDTI.),This has significantly reduced infection prevalence.,Together with proof-of-concept for onchocerciasis elimination with annual CDTI from foci in Senegal and Mali, this has resulted in targeting onchocerciasis elimination in selected African countries by 2020 and in 80% of African countries by 2025.,The challenges for meeting these targets include the number of endemic countries where conflict has delayed or interrupted control programmes, cross-border foci, potential emergence of parasite strains with low susceptibility to ivermectin and co-endemicity of loiasis, another parasitic vector borne disease, which slows down or prohibits CDTI implementation.,Some of these challenges could be addressed with new drugs or drug combinations with a higher effect on Onchocerca volvulus than ivermectin.,This paper reviews the path from discovery of new compounds to their qualification for large scale use and the support regulatory authorities provide for development of drugs for neglected tropical diseases.,The status of research for new drugs or treatment regimens for onchocerciasis along the path to regulatory approval and qualification for large scale use is reviewed.,This research includes new regimens and combinations of ivermectin and albendazole, antibiotics targeting the O. volvulus endosymbiont Wolbachia, flubendazole, moxidectin and emodepside and discovery of new compounds.,•Challenges for onchocerciasis elimination requiring new drugs.,•Summary of path from discovery to qualification of drugs for human use.,•Regulatory support and incentives for development of drugs for neglected diseases.,•Development of new dose regimens, drug combinations and new drugs against O. volvulus.,Challenges for onchocerciasis elimination requiring new drugs.,Summary of path from discovery to qualification of drugs for human use.,Regulatory support and incentives for development of drugs for neglected diseases.,Development of new dose regimens, drug combinations and new drugs against O. volvulus.

River blindness (onchocerciasis) causes severe itching, skin lesions, and vision impairment including blindness.,More than 99% of all current cases are found in sub-Saharan Africa.,Fortunately, vector control and community-directed treatment with ivermectin have significantly reduced morbidity.,Studies in Mali and Senegal proved the feasibility of elimination with ivermectin administration.,The treatment goal is shifting from control to elimination in endemic African regions.,Given limited resources, national and global policymakers need a rigorous analysis comparing investment options.,For this, we developed scenarios for alternative treatment goals and compared treatment timelines and drug needs between the scenarios.,Control, elimination, and eradication scenarios were developed with reference to current standard practices, large-scale studies, and historical data.,For each scenario, the timeline when treatment is expected to stop at country level was predicted using a dynamical transmission model, and ivermectin treatment needs were predicted based on population in endemic areas, treatment coverage data, and the frequency of community-directed treatment.,The control scenario requires community-directed treatment with ivermectin beyond 2045 with around 2.63 billion treatments over 2013-2045; the elimination scenario, until 2028 in areas where feasible, but beyond 2045 in countries with operational challenges, around 1.15 billion treatments; and the eradication scenario, lasting until 2040, around 1.30 billion treatments.,The eradication scenario is the most favorable in terms of the timeline of the intervention phase and treatment needs.,For its realization, strong health systems and political will are required to overcome epidemiological and political challenges.

Malaria morbidity and mortality has declined in recent years in a number of settings.,The ability to describe changes in malaria transmission associated with these declines is important in terms of assessing the potential effects of control interventions, and for monitoring and evaluation purposes.,Data from five cross-sectional surveys conducted in Farafenni and surrounding villages on the north bank of River Gambia between 1988 and 2011 were compiled.,Antibody responses to MSP-119 were measured in samples from all surveys, data were normalized and expressed as seroprevalence and seroconversion rates (SCR) using different mathematical models.,Results showed declines in serological metrics with seroprevalence in children aged one to 5 years dropping from 19 % (95 % CI 15-23 %) in 1988 to 1 % (0-2 %) in 2011 (p value for trend in proportions < 0.001) and the SCR dropping from 0.069 year−1 (0.059-0.080) to 0.022 year−1 (0.017-0.028; p = 0.004).,The serological data were consistent with previously described drops in both parasite prevalence in children aged 1-5 years (62 %, 57-66 %, in 1988 to 2 %, 0-4 %, in 2011; p < 0.001), and all-cause under five mortality rates (37 per 1000 person-years, 34-41, in 1990 to 17, 15-19, in 2006; p = 0.059).,This analysis shows accurate reconstruction of historical malaria transmission patterns in the Farafenni area using anti-malarial antibody responses.,Demonstrating congruence between serological measures, and conventional clinical and parasitological measures suggests broader utility for serology in monitoring and evaluation of malaria transmission.,The online version of this article (doi:10.1186/s12936-015-0939-1) contains supplementary material, which is available to authorized users.

To optimize malaria control, WHO has prioritised the need for new indicators to evaluate the efficacy of malaria vector control strategies.,The gSG6-P1 peptide from gSG6 protein of Anopheles gambiae salivary glands was previously designed as a specific salivary sequence of malaria vector species.,It was shown that the quantification of human antibody (Ab) responses to Anopheles salivary proteins in general and especially to the gSG6-P1 peptide was a pertinent biomarker of human exposure to Anopheles.,The present objective was to validate this indicator in the evaluation of the efficacy of Insecticide Treated Nets (ITNs).,A longitudinal evaluation, including parasitological, entomological and immunological assessments, was conducted on children and adults from a malaria-endemic area before and after the introduction of ITNs.,Significant decrease of anti-gSG6-P1 IgG response was observed just after the efficient ITNs use.,Interestingly, specific IgG Ab level was especially pertinent to evaluate a short-time period of ITNs efficacy and at individual level.,However, specific IgG rose back up within four months as correct ITN use waned.,IgG responses to one salivary peptide could constitute a reliable biomarker for the evaluation of ITN efficacy, at short- and long-term use, and provide a valuable tool in malaria vector control based on a real measurement of human-vector contact.

The potential use of ivermectin as an additional vector control tool is receiving increased attention from the malaria elimination community, driven by the increased importance of outdoor/residual malaria transmission and the threat of insecticide resistance where vector tools have been scaled-up.,This report summarizes the emerging evidence presented at a side meeting on “Ivermectin for malaria elimination: current status and future directions” at the annual meeting of the American Society of Tropical Medicine and Hygiene in New Orleans on November 4, 2014.,One outcome was the creation of the “Ivermectin Research for Malaria Elimination Network” whose main goal is to establish a common research agenda to generate the evidence base on whether ivermectin-based strategies should be added to the emerging arsenal to interrupt malaria transmission.

The heterogeneity of malaria transmission makes widespread elimination a difficult goal to achieve.,Most of the current vector control measures insufficiently target outdoor transmission.,Also, insecticide resistance threatens to diminish the efficacy of the most prevalent measures, indoor residual spray and insecticide treated nets.,Innovative approaches are needed.,The use of endectocides, such as ivermectin, could be an important new addition to the toolbox of anti-malarial measures.,Ivermectin effectively targets outdoor transmission, has a novel mechanism of action that could circumvent resistance and might be distributed over the channels already in place for the control of onchocerciasis and lymphatic filariasis.,The previous works involving ivermectin and Anopheles vectors are reviewed and summarized.,A review of ivermectin’s safety profile is also provided.,Finally three definitive clinical trials are described in detail and proposed as the evidence needed for implementation.,Several smaller and specific supportive studies are also proposed.,The use of ivermectin solves many challenges identified for future vector control strategies.,It is an effective and safe endectocide that was approved for human use more than 25 years ago.,Recent studies suggest it might become an effective and complementary strategy in malaria elimination and eradication efforts; however, intensive research will be needed to make this a reality.

The Lubombo Spatial Development Initiative (LSDI) was a tri-country project between South Africa, Swaziland and Mozambique with the aim of accelerating socio-economic development in the region.,The malaria component of the project was introduced to decrease the transmission of malaria in the region.,This goal was met but with termination of this project resulted in an upsurge of malaria cases in the sub-region mainly as a result of migration from high transmission areas to low transmission ones.,The movement of people across borders in southern Africa remains a challenge in sustaining malaria control and elimination.,Malaria case data for Swaziland and South Africa were obtained from their respective national Malaria Information Systems.,Data for Mozambique was obtained from the Mozambican Ministry of Health.,Data obtained during the course of the LSDI project was compared to the case data post the termination of the LSDI.,The 12-year period of the LSDI showed a substantial decrease in disease burden amongst the three countries involved when compared to the baseline year of 2000.,The decrease in malaria cases was 99 % in South Africa and 98 % in Swaziland.,Malaria prevalence in Mozambique decreased by 85 % over the same period.,However, after the LSDI ended, between 2012 and 2014, there was an upward trend in case data that was counter to the goal of elimination.,South Africa and Swaziland benefitted from the LSDI and were able to sustain malaria control and progress to the stage of elimination.,Mozambique could not sustain the gains made during the LSDI and case numbers increased.,Technical and financial resources are key challenges for malaria control and elimination interventions.

Malaria is a major public health problem in Ghana.,We present a site-specific entomological study of malaria vectors and transmission indices as part of an effort to develop a site for the testing of improved control strategies including possible vaccine trials.,Pyrethrum spray catches (PSC), and indoor and outdoor human landing collections of adult female anopheline mosquitoes were carried out over a six-month period (November 2005 - April 2006) at Kpone-on-Sea, a fishing village in southern Ghana.,These were morphologically identified to species level and sibling species of the Anopheles gambiae complex further characterized by the polymerase chain reaction (PCR).,Enzyme-linked immunosorbent assay was used to detect Plasmodium falciparum mosquito infectivity and host blood meal sources.,Parity rate was examined based on dilatation of ovarian tracheoles following dissection.,Of the 1233 Anopheles mosquitoes collected, An. gambiae s.l. was predominant (99.5%), followed by An. funestus (0.4%) and An. pharoensis (0.1%).,All An. gambiae s.l. examined (480) were identified as An. gambiae s.s. with a majority of M molecular form (98.2%) and only 1.8% S form with no record of M/S hybrid.,A significantly higher proportion of anophelines were observed outdoors relative to indoors (χ2 = 159.34, df = 1, p < 0.0000).,Only An. gambiae M molecular form contributed to transmission with a high degree of anthropophily, parity rate and an estimated entomological inoculation rate (EIR) of 62.1 infective bites/person/year.,The Majority of the infective bites occurred outdoors after 09.00 pm reaching peaks between 12.00-01.00 am and 03.00-04.00 am.,Anopheles gambiae M molecular form is responsible for maintaining the status quo of malaria in the surveyed site during the study period.,The findings provide a baseline for evidence-based planning and implementation of improved malaria interventions.,The plasticity observed in biting patterns especially the combined outdoor and early biting behavior of the vector may undermine the success of insecticide-based strategies using insecticide treated nets (ITN) and indoor residual spray (IRS).,As such, novel or improved vector interventions should be informed by the local malaria epidemiology data as it relates to vector behavior.

It has become increasingly clear that the functions of eosinophils extend beyond host defense and allergy to metabolism and tissue regeneration.,These influences have strong potential to be relevant in worm infections in which eosinophils are prominent and parasites rely on the host for nutrients to support growth or reproduction.,The aim of this study was to investigate the mechanism underlying the observation that eosinophils promote growth of Trichinella spiralis larvae in skeletal muscle.,Our results indicate that IL-4 and eosinophils are necessary for normal larval growth and that eosinophils from IL-4 competent mice are sufficient to support growth.,The eosinophil-mediated effect operates in the absence of adaptive immunity.,Following invasion by newborn larvae, host gene expression in skeletal muscle was compatible with a regenerative response and a shift in the source of energy in infected tissue.,The presence of eosinophils suppressed local inflammation while also influencing nutrient homeostasis in muscle.,Redistribution of glucose transporter 4 (GLUT4) and phosphorylation of Akt were observed in nurse cells, consistent with enhancement of glucose uptake and glycogen storage by larvae that is known to occur.,The data are consistent with a mechanism in which eosinophils promote larval growth by an IL-4 dependent mechanism that limits local interferon-driven responses that otherwise alter nutrient metabolism in infected muscle.,Our findings document a novel interaction between parasite and host in which worms have evolved a strategy to co-opt an innate host cell response in a way that facilitates their growth.

Soil-transmitted helminths colonize more than 1.5 billion people worldwide, yet little is known about how they interact with bacterial communities in the gut microbiota.,Differences in the gut microbiota between individuals living in developed and developing countries may be partly due to the presence of helminths, since they predominantly infect individuals from developing countries, such as the indigenous communities in Malaysia we examine in this work.,We compared the composition and diversity of bacterial communities from the fecal microbiota of 51 people from two villages in Malaysia, of which 36 (70.6%) were infected by helminths.,The 16S rRNA V4 region was sequenced at an average of nineteen thousand sequences per samples.,Helminth-colonized individuals had greater species richness and number of observed OTUs with enrichment of Paraprevotellaceae, especially with Trichuris infection.,We developed a new approach of combining centered log-ratio (clr) transformation for OTU relative abundances with sparse Partial Least Squares Discriminant Analysis (sPLS-DA) to enable more robust predictions of OTU interrelationships.,These results suggest that helminths may have an impact on the diversity, bacterial community structure and function of the gut microbiota.

Cutaneous leishmaniasis (CL) is caused by Leishmania (Viannia) braziliensis, which infects dermal macrophages and dendritic cells, causing an intense immune-mediated-tissue inflammation and a skin ulcer with elevated borders that can heal spontaneously or after antimonial therapy.,The resolution of lesions depends on an adaptive immune response, and cytotoxic cells seem to have a fundamental role in this process.,The aim of this study is to better understand the role of cytotoxicity mediated mechanisms that occur during the immune response in the CL lesion milieu, considering distinct cytotoxic-related CD107a+ cells, such as CD8+, CD4+, CD4neg CD8neg (double-negative, DN) and CD4+CD8+ (double-positive, DP) T lymphocytes, as well as NK and NKT cells.,Lesion derived cells were assessed for T cell subpopulations and NK cells, as well as CD107a expression by flow cytometry.,In addition, cytometric bead array (CBA) was used to quantify cytokines and granzyme B concentrations in supernatants from macerated lesions.,Flow cytometry analyses revealed that NKT cells are the major CD107a-expressing cell population committed to cytotoxicity in CL lesion, although we also observed high frequencies of CD4+ and DN T cells expressing CD107a.,Analysing the pool of CD107a+-cell populations, we found a higher distribution of DN T cells (44%), followed by approximately 25% of NKT cells.,Interestingly, NK and CD8+ T cells represented only 3 and 4% of the total-CD107a+-cell pool, respectively.,The cytotoxicity activity that occurs in the lesion milieu of CL patients seems to be dominated by DN T and NKT cells.,These findings suggest the need for a reevaluation of the role of classical-cytotoxic NK and CD8+ T cells in the pathogenesis of CL, implicating an important role for other T cell subpopulations.

Infection with different Leishmania spp. protozoa can lead to a variety of clinical syndromes associated in many cases with inflammatory responses in the skin.,Although macrophages harbor the majority of parasites throughout chronic infection, neutrophils are the first inflammatory cells to migrate to the site of infection.,Whether neutrophils promote parasite clearance or exacerbate disease in murine models varies depending on the susceptible or resistant status of the host.,Based on the hypothesis that neutrophils contribute to a systemic inflammatory state in humans with symptomatic L. braziliensis infection, we evaluated the phenotype of neutrophils from patients with cutaneous leishmaniasis (CL) during the course of L. braziliensis infection.,After in vitro infection with L. braziliensis, CL patient neutrophils produced more reactive oxygen species (ROS) and higher levels of CXCL8 and CXCL9, chemokines associated with recruitment of neutrophils and Th1-type cells, than neutrophils from control healthy subjects (HS).,Despite this, CL patient and HS neutrophils were equally capable of phagocytosis of L. braziliensis.,There was no difference between the degree of activation of neutrophils from CL versus healthy subjects, assessed by CD66b and CD62L expression using flow cytometry.,Of interest, these studies revealed that both parasite-infected and bystander neutrophils became activated during incubation with L. braziliensis.,The enhanced ROS and chemokine production in neutrophils from CL patients reverted to baseline after treatment of disease.,These data suggest that the circulating neutrophils during CL are not necessarily more microbicidal, but they have a more pro-inflammatory profile after parasite restimulation than neutrophils from healthy subjects.

An influx of immigrants is contributing to the reemergence of Plasmodium vivax malaria in Greece; 1 persistent focus of transmission is in Laconia, Pelopónnese.,We genotyped archived blood samples from a substantial proportion of malaria cases recorded in Greece in 2009-2013 using 8 microsatellite markers and a PvMSP-3α gene fragment and plotted their spatiotemporal distribution.,High parasite genetic diversity with low multiplicity of infection was observed.,A subset of genetically identical/related parasites was restricted to 3 areas in migrants and Greek residents, with some persisting over 2 consecutive transmission periods.,We identified 2 hitherto unsuspected additional foci of local transmission: Kardhítsa and Attica.,Furthermore, this analysis indicates that several cases in migrants initially classified as imported malaria were actually locally acquired.,This study shows the potential for P. vivax to reestablish transmission and counsels public health authorities about the need for vigilance to achieve or maintain sustainable malaria elimination.

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.

Historically, malaria had been a widespread disease in China.,A national plan was launched in China in 2010, aiming to eliminate malaria by 2020.,In 2017, no indigenous cases of malaria were detected in China for the first time.,To provide evidence for precise surveillance and response to achieve elimination goal, a comprehensive study is needed to determine the changing epidemiology of malaria and the challenges towards elimination.,Using malaria surveillance data from 2011 to 2016, an integrated series of analyses was conducted to elucidate the changing epidemiological features of autochthonous and imported malaria, and the spatiotemporal patterns of malaria importation from endemic countries.,From 2011 to 2016, a total of 21,062 malaria cases with 138 deaths were reported, including 91% were imported and 9% were autochthonous.,The geographic distribution of local transmission have shrunk dramatically, but there were still more than 10 counties reporting autochthonous cases in 2013-2016, particularly in counties bordering with countries in South-East Asia.,The importation from 68 origins countries had an increasing annual trend from Africa but decreasing importation from Southeast Asia.,Four distinct communities have been identified in the importation networks with the destinations in China varied by origin and species.,China is on the verge of malaria elimination, but the residual transmission in border regions and the threats of importation from Africa and Southeast Asia are the key challenges to achieve and maintain malaria elimination.,Efforts from China are also needed to help malaria control in origin countries and reduce the risk of introduced transmission.,The online version of this article (10.1186/s12936-019-2736-8) contains supplementary material, which is available to authorized users.

Implementing effective interventions remain a lot of difficulties along all border regions.,The emergence of artemisinin resistance of Plasmodium falciparum strains in the Greater Mekong Subregion is a matter of great concern.,China has effectively controlled cross-border transmission of malaria and artemisinin resistance of P. falciparum along the China-Myanmar border.,A combined quantitative and qualitative study was used to collect data, and then an integrated impact evaluation was conducted to malaria control along the China-Myanmar border during 2007-2013.,The parasite prevalence rate (PPR) in the five special regions of Myanmar was decreased from 13.6 % in March 2008 to 1.5 % in November 2013.,Compared with the baseline (PPR in March 2008), the risk ratio was only 0.11 [95 % confidence interval (CI), 0.09-0. 14) in November 2013, which is equal to an 89 % reduction in the malaria burden.,Annual parasite incidence (API) across 19 Chinese border counties was reduced from 19.6 per 10 000 person-years in 2006 to 0.9 per 10 000 person-years in 2013.,Compared with the baseline (API in 2006), the API rate ratio was only 0.05(95 % CI, 0.04-0.05) in 2013, which equates to a reduction of the malaria burden by 95.0 %.,Meanwhile, the health service system was strengthened and health inequity of marginalized populations reduced along the international border.,The effective collaboration between China, Myanmar and the international non-governmental organization promptly carried out the core interventions through simplified processes.,The integrated approaches dramatically decreased malaria burden of Chinese-Myanmar border.,The online version of this article (doi:10.1186/s40249-016-0171-4) contains supplementary material, which is available to authorized users.

Mass distribution of insecticide-treated nets (ITNs) is a cost-effective way to achieve universal coverage, but maintaining this coverage is more difficult.,In addition to commonly used indicators, evaluation of universal coverage should include coverage of effective nets and changes in coverage over time.,Longitudinal and cross-sectional household ITN surveys were carried out from 2010 to 2013 in six locations representing a variety of settings across western Kenya.,Five indicators were used to evaluate the current status of universal coverage: 1) ITN ownership - proportion of households that own at least one ITN, 2) access index - ratio of the number of family members over the number of ITNs owned by that household, 3) operational coverage - proportion of the at-risk population potentially covered by ITNs, assuming one ITN for every two people, 4) effective coverage - population coverage of effective ITNs, and 5) usage - proportion of the population that used ITNs the previous night.,ITN ownership and operational coverage increased substantially from 2010 to 2013, but this increase was mostly due to the 2011 mass distribution campaign.,In 2013, household ITN ownership was on average 84.4% (95% CI [78.4, 90.5]) across the six study areas, and operational coverage was 83.2% (95% CI [72.5, 93.8]).,The ITN access rate was 59.1% (95% CI [56.6, 61.7]), and 40.8% (95% CI [38.3, 43.4]) of the people at risk needed more nets to achieve universal coverage.,About 88.5% (95% CI [86.1, 90.9]) of the ITNs were below three years old and 16.5% (95% CI [12.1, 20.9]) of the ITNs had hole(s).,The estimated effective long-lasting insecticide-treated net (LLIN) coverage was 70.5% (95 CI [58.7, 82.3]).,Approximately 18.4% (95% CI [15.5, 21.4]) of the ITNs were shared by more than three persons, and the population ITN usage rate was about 75-87%.,The reason for not using ITNs was almost exclusively “net not available”.,Current methods of delivering ITNs, i.e., one mass campaign every five years and regular distribution of ITNs from health center can barely maintain the current effective coverage.,Inaccessibility and loss of physical integrity of ITNs are major hindrances to achieving and maintaining universal coverage.,The online version of this article (doi:10.1186/1475-2875-13-351) contains supplementary material, which is available to authorized users.

Until recently only two indicators were used to evaluate malaria prevention with insecticide-treated nets (ITN): “proportion of households with any ITN” and “proportion of the population using an ITN last night”.,This study explores the potential of the expanded set of indicators recommended by the Roll Back Malaria Monitoring and Evaluation Reference Group (MERG) for comprehensive analysis of universal coverage with ITN by applying them to the Nigeria 2010 Malaria Indicator Survey data.,The two additional indicators of “proportion of households with at least one ITN for every two people” and “proportion of population with access to an ITN within the household” were calculated as recommended by MERG.,Based on the estimates for each of the four ITN indicators three gaps were calculated: i) households with no ITN, ii) households with any but not enough ITN, iii) population with access to ITN not using it.,In addition, coverage with at least one ITN at community level was explored by applying Lot Quality Assurance Sampling (LQAS) decision rules to the cluster level of the data.,All outcomes were analysed by household background characteristics and whether an ITN campaign had recently been done.,While the proportion of households with any ITN was only 42% overall, it was 75% in areas with a recent mass campaign and in these areas 66% of communities had coverage of 80% or better.,However, the campaigns left a considerable intra-household ownership gap with 66% of households with any ITN not having enough for every family member.,In contrast, the analysis comparing actual against potential use showed that ITN utilization was good overall with only 19% of people with access not using the ITN, but with a significant difference between the North, where use was excellent (use gap 11%), and the South (use gap 36%) indicating the need for enhanced behaviour change communication.,The expanded ITN indicators to assess universal coverage provide strong tools for a comprehensive system effectiveness analysis that produces clear, actionable evidence of progress as well as the need for specific additional interventions clearly differentiating between gaps in ownership and use.

In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria.,We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa.,Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia, and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectively defined therapeutic-dose ranges of 0.15-0.4 mg PQ base/kg for children aged 1-5 years and 0.15-0.5 mg PQ base/kg for individuals aged ≥6 years (therapeutic indices 2.7 and 3.3, respectively).,We chose 1.25 mg PQ base for infants aged 6-11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA.,We modelled an anthropometric database of 661,979 African individuals aged ≥6 months (549,127 healthy individuals, 28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box-Cox transformation power exponential and tested PQ doses of 1-15 mg base, selecting dosing groups based on calculated mg/kg PQ doses.,From the Box-Cox transformation power exponential model, five age categories were selected: (i) 6-11 months (n = 39,886, 6.03%), (ii) 1-5 years (n = 261,036, 45.46%), (iii) 6-9 years (n = 20,770, 3.14%), (iv) 10-14 years (n = 12,155, 1.84%) and (v) ≥15 years (n = 328,132, 49.57%) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and 99th centiles) mg/kg PQ base of: (i) 0.16 (0.12-0.25), (ii) 0.21 (0.13-0.37), (iii) 0.25 (0.16-0.38), (iv) 0.26 (0.15-0.38) and (v) 0.27 (0.17-0.40).,The proportions of individuals predicted to receive optimal therapeutic PQ doses were: 73.2 (29,180/39,886), 93.7 (244,537/261,036), 99.6 (20,690/20,770), 99.4 (12,086/12,155) and 99.8% (327,620/328,132), respectively.,We plan to test the safety of this age-based dosing regimen in a large randomised placebo-controlled trial (ISRCTN11594437) of uncomplicated falciparum malaria in G6PDd African children aged 0.5 − 11 years.,If the regimen is safe and demonstrates adequate pharmacokinetics, it should be used to support malaria elimination.,The online version of this article (doi:10.1186/s12916-017-0990-6) contains supplementary material, which is available to authorized users.

Plasmodium vivax parasites are the predominant cause of malaria infections in the Brazilian Amazon.,Infected individuals are treated with primaquine, which can induce haemolytic anaemia in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals and may lead to severe and fatal complications.,This X-linked disorder is distributed globally and is caused by allelic variants with a geographical distribution that closely reflects populations exposed historically to endemic malaria.,In Brazil, few studies have reported the frequency of G6PD deficiency (G6PDd) present in malaria-endemic areas.,This is particularly important, as G6PDd screening is not currently performed before primaquine treatment.,The aim of this study was to determine the prevalence of G6PDd in the region of Alto do Juruá, in the Western Brazilian Amazon, an area characterized by a high prevalence of P. vivax infection.,Five-hundred and sixteen male volunteers were screened for G6PDd using the fluorescence spot test (Beutler test) and CareStart™ G6PD Biosensor system.,Demographic and clinical-epidemiological data were acquired through an individual interview.,To assess the genetic basis of G6PDd, 24 SNPs were genotyped using the Kompetitive Allele Specific PCR assay.,Twenty-three (4.5%) individuals were G6PDd.,No association was found between G6PDd and the number of malaria cases.,An increased risk of reported haemolysis symptoms and blood transfusions was evident among the G6PDd individuals.,Twenty-two individuals had the G6PDd A(−) variant and one the G6PD A(+) variant.,The Mediterranean variant was not present.,Apart from one polymorphism, almost all SNPs were monomorphic or with low frequencies (0-0.04%).,No differences were detected among ethnic groups.,The data indicates that ~1/23 males from the Alto do Juruá could be G6PD deficient and at risk of haemolytic anaemia if treated with primaquine.,G6PD A(−) is the most frequent deficiency allele in this population.,These results concur with reported G6PDd in other regions in Brazil.,Routine G6PDd screening to personalize primaquine administration should be considered, particularly as complete treatment of patients with vivax malaria using chloroquine and primaquine, is crucial for malaria elimination.,The online version of this article (doi:10.1186/s12936-017-1889-6) contains supplementary material, which is available to authorized users.

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.

Although global efforts in the past decade have halved the number of deaths due to malaria, there are still an estimated 219 million cases of malaria a year, causing more than half a million deaths.,In this forum article, we asked experts working in malaria research and control to discuss the ways in which malaria might eventually be eradicated.,Their collective views highlight the challenges and opportunities, and explain how multi-factorial and integrated processes could eventually make malaria eradication a reality.

Many control programmes against neglected tropical diseases have been interrupted due to the coronavirus disease 2019 (COVID-19) pandemic, including those that rely on active case finding.,In this study we focus on gambiense human African trypanosomiasis (gHAT), where active screening was suspended in the Democratic Republic of Congo (DRC) due to the pandemic.,We use two independent mathematical models to predict the impact of COVID-19 interruptions on transmission and reporting and achievement of the 2030 elimination of transmission (EOT) goal for gHAT in two moderate-risk regions of the DRC.,We consider different interruption scenarios, including reduced passive surveillance in fixed health facilities, and whether this suspension lasts until the end of 2020 or 2021.,Our models predict an increase in the number of new infections in the interruption period only if both active screening and passive surveillance were suspended, and with a slowed reduction-but no increase-if passive surveillance remains fully functional.,In all scenarios, the EOT may be slightly pushed back if no mitigation, such as increased screening coverage, is put in place.,However, we emphasise that the biggest challenge will remain in the higher-prevalence regions where EOT is already predicted to be behind schedule without interruptions unless interventions are bolstered.

Human African trypanosomiasis (HAT), or African sleeping sickness, is a fatal disease found throughout sub-Saharan Africa.,The disease is close to elimination in many areas, although it was similarly close to elimination once before and subsequently reemerged, despite seemingly low rates of transmission.,Determining how these foci persisted and overcame an apparent transmission paradox is key to finally eliminating HAT.,By assessing clinical, laboratory, and mathematical data, we propose that asymptomatic infections contribute to transmission through the presence of an overlooked reservoir of skin-dwelling parasites.,Our assessment suggests that a combination of asymptomatic and parasitaemic cases is sufficient to maintain transmission at foci without animal reservoirs, and we argue that the current policy not to treat asymptomatic HAT should be reconsidered.,African sleeping sickness is an important disease of sub-Saharan Africa that is approaching elimination, but this Essay maintains that an overlooked anatomical reservoir - human skin - may impact control efforts.

The geographic distribution of cutaneous leishmaniasis (CL) makes it a disease of major clinical importance in Brazil, where it is endemic in the state of Paraná.,The objective of this study was to analyze the spatial distribution of CL in Paraná between 2001 and 2015, based on data from the Sistema de Informação de Agravos de Notificação (Information System for Notifiable Diseases) regarding autochthonous CL cases.,Spatial autocorrelation was performed using Moran’s Global Index and the Local Indicator of Spatial Association (LISA).,The construction of maps was based on categories of association (high-high, low-low, high-low, and low-high).,A total of 4,557 autochthonous cases of CL were registered in the state of Paraná, with an annual average of 303.8 (± 135.2) and a detection coefficient of 2.91.,No correlation was found between global indices and their respective significance in 2001 (I = -0.456, p = 0.676), but evidence of spatial autocorrelation was found in other years (p< 0.05).,In the construction and analysis of the cluster maps, areas with a high-high positive association were found in the Ivaí-Pirapó, Tibagi, Cinzas-Laranjinha, and Ribeira areas.,The state of Paraná should keep a constant surveillance over CL due to the prominent presence of socioeconomic and environmental factors such as the favorable circumstances for the vectors present in peri-urban and agriculture áreas.

Acre has reported the highest incidence of American cutaneous leishmaniasis (ACL) in Brazil in recent years.,The present study seeks to identify high and low risk agglomerations of ACL in space and space-time during the period from 2007 to 2013 in Acre, and also to characterize the occurrence of the disease in time and according to sociodemographic variables.,This is an ecological study, the study population of which consisted of autochthonous ACL cases notified in the municipalities of Acre by an epidemiological surveillance system.,Scan statistics of SaTScan™ software were used to identify spatial and space-time clusters.,In addition, the cases were characterized by sex, age, home situation (in a rural or urban area), and temporal tendency.,Acre reported an incidence rate of 12.4 cases per 10 000 inhabitant-years in the study period, with the rates varied greatly (standard deviation of 21.8) among their 22 municipalities.,One agglomeration of high risk and three of low risk were detected in space and space-time.,Four of the five micro-regions of Acre presented a stationary temporal tendency.,The profile of transmission varied according to the micro-region.,Generally speaking, the disease occurred more often among young people, those of male gender, and those living in rural areas.,Acre has stood out within the Brazilian national context due to its high rates of ACL incidence in the central region of the Acre Valley.,The high rates in the micro-region of Brasiléia are related to the disease’s intra/peridomiciliary occurrence, and it would seem that the municipality of Sena Madureira is approaching a transmission pattern similar to that of Brasiléia.,In other micro-regions, the profile of the disease’s transmission is mainly related to the forest/sylvatic cycle of ACL.,The online version of this article (doi:10.1186/s40249-017-0311-5) contains supplementary material, which is available to authorized users.

Schistosomiasis is a major cause of morbidity in humans invoked by chronic infection with parasitic trematodes of the genus Schistosoma.,Schistosomes have a complex life-cycle involving infections of an aquatic snail intermediate host and a definitive mammalian host.,In humans, adult male and female worms lie within the vasculature.,Here, they propagate and eggs are laid.,These eggs must then be released from the host to continue the life cycle.,Schistosoma mansoni and Schistosoma japonicum reside in the mesenteric circulation of the intestines with egg excreted in the feces.,In contrast, S. haematobium are present in the venus plexus of the bladder, expelling eggs in the urine.,In an impressive case of exploitation of the host immune system, this process of Schistosome “eggs-iting” the host is immune dependent.,In this article, we review the formation of the egg granuloma and explore how S. mansoni eggs laid in vasculature must usurp immunity to induce regulated inflammation, to facilitate extravasation through the intestinal wall and to be expelled in the feces.,We highlight the roles of immune cell populations, stromal factors, and egg secretions in the process of egg excretion to provide a comprehensive overview of the current state of knowledge regarding a vastly unexplored mechanism.

Cancer may be induced by many environmental and physiological conditions.,Infections with viruses, bacteria and parasites have been recognized for years to be associated with human carcinogenicity.,Here we review current concepts of carcinogenicity and its associations with parasitic infections.,The helminth diseases schistosomiasis, opisthorchiasis, and clonorchiasis are highly carcinogenic while the protozoan Trypanosoma cruzi, the causing agent of Chagas disease, has a dual role in the development of cancer, including both carcinogenic and anticancer properties.,Although malaria per se does not appear to be causative in carcinogenesis, it is strongly associated with the occurrence of endemic Burkitt lymphoma in areas holoendemic for malaria.,The initiation of Plasmodium falciparum related endemic Burkitt lymphoma requires additional transforming events induced by the Epstein-Barr virus.,Observations suggest that Strongyloides stercoralis may be a relevant co-factor in HTLV-1-related T cell lymphomas.,This review provides an overview of the mechanisms of parasitic infection-induced carcinogenicity.,•The helminth diseases schistosomiasis, opisthorchiasis, and clonorchiasis are highly carcinogenic.,•Trypanosoma cruzi has a dual role in cancer development including both carcinogenic and anticancer properties.,•Initiation of Plasmodium falciparum related endemic Burkitt lymphoma requires additional transforming events induced by EBV.,•Strongyloides stercoralis may be a relevant co-factor in HTLV-1-related T cell lymphomas.,The helminth diseases schistosomiasis, opisthorchiasis, and clonorchiasis are highly carcinogenic.,Trypanosoma cruzi has a dual role in cancer development including both carcinogenic and anticancer properties.,Initiation of Plasmodium falciparum related endemic Burkitt lymphoma requires additional transforming events induced by EBV.,Strongyloides stercoralis may be a relevant co-factor in HTLV-1-related T cell lymphomas.,We searched MEDLINE database and PubMed for articles from 1970 through June 30, 2016.,Search terms used in various combinations were “parasite infection”, “carcinogenesis”, “cancer”, “human malignancy”, “parasite and cancer”, “infection-associated cancer”, “parasite-associated cancer” “schistosomiasis”, “opisthorchiasis”, “malaria”, “Chagas disease”, and “strongyloidiasis”.,Articles resulting from these searches and relevant references cited in those articles were selected based on their related topics and were reviewed.,Abstracts and reports from meetings were also included.,Articles published in English were included.

Genome and transcriptome studies of Plasmodium nucleic acids obtained from parasitized whole blood are greatly improved by depletion of human DNA or enrichment of parasite DNA prior to next-generation sequencing and microarray hybridization.,The most effective method currently used is a two-step procedure to deplete leukocytes: centrifugation using density gradient media followed by filtration through expensive, commercially available columns.,This method is not easily implemented in field studies that collect hundreds of samples and simultaneously process samples for multiple laboratory analyses.,Inexpensive syringes, hand-packed with CF11 cellulose powder, were recently shown to improve ex vivo cultivation of Plasmodium vivax obtained from parasitized whole blood.,This study was undertaken to determine whether CF11 columns could be adapted to isolate Plasmodium falciparum DNA from parasitized whole blood and achieve current quantity and purity requirements for Illumina sequencing.,The CF11 procedure was compared with the current two-step standard of leukocyte depletion using parasitized red blood cells cultured in vitro and parasitized blood obtained ex vivo from Cambodian patients with malaria.,Procedural variations in centrifugation and column size were tested, along with a range of blood volumes and parasite densities.,CF11 filtration reliably produces 500 nanograms of DNA with less than 50% human DNA contamination, which is comparable to that obtained by the two-step method and falls within the current quality control requirements for Illumina sequencing.,In addition, a centrifuge-free version of the CF11 filtration method to isolate P. falciparum DNA at remote and minimally equipped field sites in malaria-endemic areas was validated.,CF11 filtration is a cost-effective, scalable, one-step approach to remove human DNA from P. falciparum-infected whole blood samples.

Resistance of the malaria parasite Plasmodium falciparum to sulfadoxine-pyrimethamine (SP) has evolved worldwide.,In the archipelago of São Tomé and Principe (STP), West Africa, although SP resistance is highly prevalent the drug is still in use in particular circumstances.,To address the evolutionary origins of SP resistance in these islands, we genotyped point mutations at P. falciparum dhfr and dhps genes and analysed microsatellites flanking those genes.,Blood samples were collected in July and December 2004 in three localities of São Tomé Island and one in Principe Island.,Species-specific nested-PCR was used to identify P. falciparum infected samples.,Subsequently, SNPs at the dhfr and dhps genes were identified through PCR-RFLP.,Isolates were also analysed for three microsatellite loci flanking the dhfr gene, three loci flanking dhps and four loci located at putative neutral genomic regions.,An increase of resistance-associated mutations at dhfr and dhps was observed, in particular for the dhfr/dhps quintuple mutant, associated with clinical SP failure.,Analysis of flanking microsatellites suggests multiple independent introductions for dhfr and dhps mutant haplotypes, possibly from West Africa.,A reduced genetic diversity and increased differentiation at flanking microsatellites when compared to neutral loci is consistent with a selective sweep for resistant alleles at both loci.,This study provides additional evidence for the crucial role of gene flow and drug selective pressures in the rapid spread of SP resistance in P. falciparum populations, from only a few mutation events giving rise to resistance-associated mutants.,It also highlights the importance of human migration in the spread of drug resistant malaria parasites, as the distance between the islands and mainland is not consistent with mosquito-mediated parasite dispersal.

The Kato-Katz (KK) stool smear is the standard test for the diagnosis of Schistosoma mansoni infection, but suffers from low sensitivity when infections intensities are moderate to low.,Thus, misdiagnosed individuals remain untreated and contribute to the disease transmission, thereby forestalling public health efforts to move from a modality of disease control to one of elimination.,As an alternative, the urine-based diagnosis of schistosomiasis mansoni via the circulating cathodic antigen immuno-chromatographic test (CCA-ICT) has been extensively evaluated in Africa with the conclusion that it may replace the KK test in areas where prevalences are moderate or high.,The objective was to measure the performance of the CCA-ICT in a sample study population composed of residents from non-endemic and endemic areas for schistosomiasis mansoni in two municipalities of Minas Gerais state, Brazil.,Volunteers (130) were classified into three infection status groups based on duplicate Kato-Katz thick smears from one stool sample (2KK test): 41 negative individuals from non-endemic areas, 41 negative individuals from endemic areas and 48 infected individuals from endemic areas.,Infection status was also determined by the CCA-ICT and infection exposure by antibody ELISA (enzyme-linked immunosorbent assay) to S. mansoni soluble egg antigen (SEA) and soluble (adult) worm antigen preparation (SWAP).,Sensitivity and specificity were influenced by whether the trace score visually adjudicated in the CCA-ICT was characterized as positive or negative for S. mansoni infection.,An analysis of a two-graph receiver operating characteristic was performed to change the cutoff point.,When the trace score was interpreted as a positive rather than as a negative result, the specificity decreased from 97.6% to 78.0% whereas sensitivity increased from 68.7% to 85.4%.,A significantly positive correlation between the CCA-ICT scores and egg counts was identified (r = 0.6252, p = 0.0001).,However, the CCA-ICT misdiagnosed as negative 14.6% of 2KK positive individuals, predominantly those with light infections (fewer than 100 eggs/g feces).,Considering 2KK as reference test, the discriminating power of the CCA-ICT (the area under the curve [AUC] = 0.817) was greater than the SEA-ELISA (AUC = 0.744) and SWAP-ELISA (AUC = 0.704).,Our data for the performance of the CCA-ICT in the Brazilian communities endemic for schistosomiasis mansoni support those from Africa, i.e., in areas with greater infection prevalence and intensities, the CCA-ICT may be useful as a tool to indicate community-based preventative chemotherapy without individual diagnosis.,However, because of the Brazilian Ministry of Health’s recommendation for individual diagnosis in areas where prevalence is less than 15%, i.e., those areas in which infection intensities are likely to be lowest, the CCA-ICT lacks the sensitivity to be used as standalone diagnostic tool.

Regular treatment with praziquantel (PZQ) is the strategy for human schistosomiasis control aiming to prevent morbidity in later life.,With the recent resolution on schistosomiasis elimination by the 65th World Health Assembly, appropriate diagnostic tools to inform interventions are keys to their success.,We present a discrete Markov chains modelling framework that deals with the longitudinal study design and the measurement error in the diagnostic methods under study.,A longitudinal detailed dataset from Uganda, in which one or two doses of PZQ treatment were provided, was analyzed through Latent Markov Models (LMMs).,The aim was to evaluate the diagnostic accuracy of Circulating Cathodic Antigen (CCA) and of double Kato-Katz (KK) faecal slides over three consecutive days for Schistosoma mansoni infection simultaneously by age group at baseline and at two follow-up times post treatment.,Diagnostic test sensitivities and specificities and the true underlying infection prevalence over time as well as the probabilities of transitions between infected and uninfected states are provided.,The estimated transition probability matrices provide parsimonious yet important insights into the re-infection and cure rates in the two age groups.,We show that the CCA diagnostic performance remained constant after PZQ treatment and that this test was overall more sensitive but less specific than single-day double KK for the diagnosis of S. mansoni infection.,The probability of clearing infection from baseline to 9 weeks was higher among those who received two PZQ doses compared to one PZQ dose for both age groups, with much higher re-infection rates among children compared to adolescents and adults.,We recommend LMMs as a useful methodology for monitoring and evaluation and treatment decision research as well as CCA for mapping surveys of S. mansoni infection, although additional diagnostic tools should be incorporated in schistosomiasis elimination programs.

Asymptomatic low-density gametocyte carriers represent the majority of malaria-infected individuals.,However, the impact of recommended treatment with single low dose of primaquine and an artemisinin-based combination therapy to reduce transmission in this group is unknown.,This was a four-arm, open label, randomized controlled trial comparing the effect of dihydroartemisinin-piperaquine (DHAP) alone or combined with single dose of primaquine (PQ) at 0.20 mg/kg, 0.40 mg/kg, or 0.75 mg/kg on Plasmodium falciparum gametocytaemia, infectiousness to mosquitoes and hemoglobin change in asymptomatic, malaria-infected, glucose-6-phosphate dehydrogenase (G6PD) normal individuals.,Randomization was done using a computer-generated sequence of uneven block sizes with codes concealed in sequentially numbered opaque envelopes.,The primary endpoint was the prevalence of P. falciparum gametocytemia at day 7 of follow-up determined by quantitative nucleic acid sequence based assay and analysis was by intention to treat.,The trial has been concluded (registration number: NCT01838902; https://clinicaltrials.gov/ct2/show/NCT01838902).,A total of 694 asymptomatic, malaria-infected individuals were enrolled.,Gametocyte prevalence at day 7 was 37.0% (54/146; 95% CI 29.2-45.4), 19.0% (27/142; 95% CI 12.9-26.4), 17.2% (25/145; 95% CI 11.0-23.5) and 10.6% (15/141; 95% CI 6.1-16.9) in the DHAP alone, 0.20 mg/kg, 0.40 mg/kg, and 0.75 mg/kg PQ arms, respectively.,The main adverse events reported include headache (130/471, 27.6%), cough (73/471, 15.5%), history of fever (61/471, 13.0%) and abdominal pain (57/471, 12.1%).,There were five serious adverse events however, none was related to the interventions.,A single course of PQ significantly reduces gametocyte carriage in malaria-infected asymptomatic, G6PD-normal individuals without increasing the risk of clinical anemia.,The limited number of successful mosquito infections suggests that post-treatment transmission potential in this asymptomatic population is low.,•Treatment with primaquine and an artemisinin-based combination therapy is part of malaria elimination strategies.,•Its slow uptake, despite specific recommendations highlights the need for evidence on primaquine's efficacy and safety.,•About 50% of asymptomatic P. falciparum-infected individuals carry gametocytes detectable by sensitive molecular methods.,•Primaquine reduced gametocyte prevalence at day 7 and carriage time in the study population at all doses tested.,Treatment with primaquine and an artemisinin-based combination therapy is part of malaria elimination strategies.,Its slow uptake, despite specific recommendations highlights the need for evidence on primaquine's efficacy and safety.,About 50% of asymptomatic P. falciparum-infected individuals carry gametocytes detectable by sensitive molecular methods.,Primaquine reduced gametocyte prevalence at day 7 and carriage time in the study population at all doses tested.,Adding a single dose (0.75 mg/kg) of primaquine to the treatment of uncomplicated falciparum malaria was recommended in 2010 on the basis of weak evidence.,Primaquine, at doses as low as 0.20 mg/kg, can reduce substantially gametocyte carriage in asymptomatic, malaria-infected individuals, representing the majority of the human reservoir of infection.,Post-treatment transmission potential is low with artemisinin-based combination alone or with the 0.20 mg/kg dose but may occur despite reductions in gametocyte carriage.

Appropriate case management of suspected malaria in Cambodia is critical given anti-malarial drug resistance in the region.,Improving diagnosis and the use of recommended malarial treatments is a challenge in Cambodia where self-treatment and usage of drug cocktails is widespread, a notable difference from malaria treatment seeking in other countries.,This qualitative study adds to the limited evidence base on Cambodian practices, aiming to understand the demand-side factors influencing treatment-seeking behaviour, including the types of home treatments, perceptions of cocktail medicines and reasons for diagnostic testing.,The findings may help guide intervention design.,The study used in-depth interviews (IDIs) (N = 16) and focus group discussions (FGDs) (N = 12) with Cambodian adults from malaria-endemic areas who had experienced malaria fever in the previous two weeks.,Data were analysed using NVivo software.,Findings suggest that Cambodians initially treat suspected malaria at home with home remedies and traditional medicines.,When seeking treatment outside the home, respondents frequently reported receiving a cocktail of medicines from trusted providers.,Cocktails are perceived as less expensive and more effective than full-course, pre-packaged medicines.,Barriers to diagnostic testing include a belief in the ability to self-diagnose based on symptoms, cost and reliance on providers to recommend a test.,Factors that facilitate testing include recommendation by trusted providers and a belief that anti-malarial treatment for illnesses other than malaria can be harmful.,Treatment-seeking behaviour for malaria in Cambodia is complex, driven by cultural norms, practicalities and episode-related factors.,Effective malaria treatment programmes will benefit from interventions and communication materials that leverage these demand-side factors, promoting prompt visits to facilities for suspected malaria and challenging patients’ misconceptions about the effectiveness of cocktails.,Given the importance of the patient-provider interaction and the pivotal role that providers play in ensuring the delivery of appropriate malaria care, future research and interventions should also focus on the supply side factors influencing provider behaviour.

Seasonal malaria chemoprevention, previously known as intermittent preventive treatment in children, is highly effective in areas with a short malaria transmission season.,Here we assess seasonality in malaria incidence data and define a predictor of seasonality based on rainfall.,We then use spatial rainfall, malaria endemicity and population data to identify areas likely to have highly seasonal malaria incidence, and estimate the population at risk and malaria burden in areas where seasonal malaria chemoprevention would be appropriate.,We estimate that in areas suitable for seasonal malaria chemoprevention, there are 39 million children under 5 years of age, who experience 33.7 million malaria episodes and 152,000 childhood deaths from malaria each year.,The majority of this burden occurs in the Sahelian or sub-Sahelian regions of Africa.,Our data suggest that seasonal malaria chemoprevention has the potential to avert several million malaria cases and tens of thousands of childhood deaths each year if successfully delivered to the populations at risk.,Seasonal malaria chemoprevention can lower the incidence of malaria in areas where transmission is highly periodical.,Combining data on rainfall, population and malaria endemicity, Cairns et al. identify geographical areas in sub-Saharan Africa where this intervention is likely to be effective and cost-effective.

Michael Delves and colleagues compare the activity of 50 current and experimental antimalarials against liver, sexual blood, and mosquito stages of selected human and nonhuman parasite species, including Plasmodium falciparum, Plasmodium berghei, and Plasmodium yoelii.,Malaria remains a disease of devastating global impact, killing more than 800,000 people every year-the vast majority being children under the age of 5.,While effective therapies are available, if malaria is to be eradicated a broader range of small molecule therapeutics that are able to target the liver and the transmissible sexual stages are required.,These new medicines are needed both to meet the challenge of malaria eradication and to circumvent resistance.,Little is known about the wider stage-specific activities of current antimalarials that were primarily designed to alleviate symptoms of malaria in the blood stage.,To overcome this critical gap, we developed assays to measure activity of antimalarials against all life stages of malaria parasites, using a diverse set of human and nonhuman parasite species, including male gamete production (exflagellation) in Plasmodium falciparum, ookinete development in P. berghei, oocyst development in P. berghei and P. falciparum, and the liver stage of P. yoelii.,We then compared 50 current and experimental antimalarials in these assays.,We show that endoperoxides such as OZ439, a stable synthetic molecule currently in clinical phase IIa trials, are strong inhibitors of gametocyte maturation/gamete formation and impact sporogony; lumefantrine impairs development in the vector; and NPC-1161B, a new 8-aminoquinoline, inhibits sporogony.,These data enable objective comparisons of the strengths and weaknesses of each chemical class at targeting each stage of the lifecycle.,Noting that the activities of many compounds lie within achievable blood concentrations, these results offer an invaluable guide to decisions regarding which drugs to combine in the next-generation of antimalarial drugs.,This study might reveal the potential of life-cycle-wide analyses of drugs for other pathogens with complex life cycles.,Please see later in the article for the Editors' Summary,Malaria is a life-threatening disease caused by the Plasmodium parasite, which is transmitted to people through the bites of infected mosquitoes.,According to latest global estimates, about 250 million people are infected with malaria every year with roughly 800,000 deaths-most occurring among young children living in Africa.,Malaria also causes severe morbidity in children, such as anemia, low birth weight, and neurological problems, which compromise the health and development of millions of children living in malaria endemic areas.,In addition to strategies that scale up and roll out the prevention of malaria, such as country-wide programs to provide insecticide-treating bednets, in the goal to eradicate malaria, the global health community has refocused efforts on the treatment of malaria, including finding new compounds that target different stages of the parasite life cycle as it passes from vector to host and back.,The interruption of malaria transmission worldwide is one of the greatest challenges for the global health community.,In January 2011, this journal published a series on The Malaria Eradication Research Agenda (malERA), which described a set of research and development priorities, identified key knowledge gaps and the necessary tools needed, and introduced a draft research and development agenda for the worldwide eradication of malaria.,Most currently available antimalarial drugs primarily target the disease-causing parasites' stages in the human blood system.,But to eradicate malaria, new drugs that block transmission of the parasite between the human host and the mosquito vector, and eliminate the various stages of the parasite during its cycle in the human body, are needed.,In this laboratory study, the researchers compared the profiles of all available and experimental antimalarials and analyzed each drug for activity against each specific stage in the malaria parasite's life cycle to provide a reference set of methods and data, that might serve as a benchmark to help guide the malaria research community in assessing the potential of newly discovered antimalarials.,Furthermore, this analysis could provide insights into which chemical drug classes might provide transmission-blocking capabilities-an essential component of malaria eradication.,The researchers used novel laboratory techniques under standardized conditions to develop a series of novel assays to analyze the activities of 50 antimalarial compounds (current drugs and those under development) against three Plasmodium species encompassing every major cellular strategy of the malarial life cycle including drug resistant parasite strains.,In their comparative analysis, the researchers undertook a chemical profiling approach to identify the drugs that block transmission from the host to the mosquito vector and additionally suppress transmission from the mosquito to the human host.,The researchers highlighted some encouraging results; for example, the potencies of some antimalarials against the asexual blood stage of cultivated P. falciparum and P. vivax isolates show a very good correlation, suggesting that most of the pathways inhibited by antimalarials in P. falciparum may also be valid targets in P. vivax.,The researchers also have shown that approved drugs, such as pyronaridine and atovaquone, can target liver and sexual stages in addition to asexual blood stages.,Furthermore, the researchers found promising results for new compounds currently in clinical trials, such as the endoperoxide OZ439, a stable synthetic molecule currently being studied in a phase IIa clinical trial, which seemed to be a strong inhibitor of gametocyte maturation and gamete formation.,The new 8-aminoquinoline, NPC-1161B, also inhibited sporogony.,The results of this analysis provide a valuable guide to help researchers decide which drugs and compounds show most promise as potential future antimalarial drugs for blocking the transmission of malaria.,This study could also help researchers make decisions about which molecules could be best combined to provide the next generation of drugs that will succeed artemisinin compound therapy and support the eradication of malaria.,Furthermore, this comprehensive approach to drug discovery could be applied to test drugs against other pathogens with complex life cycles.,Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001169.,The malERA a research agenda for malaria eradication sponsored collection, published by PLoS in January 2011, comprises 12 Review articles that discuss agendas in malaria research and development

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

Plasmodium vivax and Plasmodium falciparum cause a significant illness burden in Peru.,Anopheline indices for populated communities in the peri-Iquitos region of Loreto have been reported to be remarkably low, with entomological inoculation rates (EIR) estimated at one to 30 infective bites per year based on a few studies in close proximity to the urban centre of Iquitos and surrounding deforested areas.,Local reports suggest that a large number of the reported cases are contracted outside of populated communities in undeveloped riverine areas frequented by loggers and fishermen.,To better understand vectorial capacity in suspected high malaria transmission zones in a rural district near Iquitos, Peru, mosquito collections were conducted at different points in the seasonality of malaria transmission in 21 sites frequented by occupational labourers.,Prevalence of Plasmodium spp in vectors was determined by circumsporozoite protein ELISA on individual mosquitoes.,Slide surveillance was performed for humans encountered in the zone.,In total, of 8,365 adult female mosquitoes examined, 98.5% were identified as Anopheles darlingi and 117 (1.4%) tested positive for sporozoites (P. falciparum, P. vivax VK210 or P. vivax VK247).,Measured human biting rates at these sites ranged from 0.102 to 41.13 bites per person per hour, with EIR values as high as 5.3 infective bites per person per night.,Six percent of the 284 blood films were positive for P. vivax or P. falciparum; however, 88% of the individuals found to be positive were asymptomatic at the time of sampling.,The results of this study provide key missing indices of prominent spatial and temporal heterogeneity of vectorial capacity in the Amazon Basin of Peru.,The identification of a target human subpopulation as a principal reservoir and dispersion source of Plasmodium species has important implications for vaccine development and the delivery of effective targeted malaria control strategies.

Malaria has been the pre-eminent cause of early mortality in many parts of the world throughout much of the last five thousand years and, as a result, it is the strongest force for selective pressure on the human genome yet described.,Around one third of the variability in the risk of severe and complicated malaria is now explained by additive host genetic effects.,Many individual variants have been identified that are associated with malaria protection, but the most important all relate to the structure or function of red blood cells.,They include the classical polymorphisms that cause sickle cell trait, α-thalassaemia, G6PD deficiency, and the major red cell blood group variants.,More recently however, with improving technology and experimental design, others have been identified that include the Dantu blood group variant, polymorphisms in the red cell membrane protein ATP2B4, and several variants related to the immune response.,Characterising how these genes confer their effects could eventually inform novel therapeutic approaches to combat malaria.,Nevertheless, all together, only a small proportion of the heritable component of malaria resistance can be explained by the variants described so far, underscoring its complex genetic architecture and the need for continued research.

Avian malaria parasites are prevalent around the world and infect a wide diversity of bird species.,Here, we report the sequencing and analysis of high-quality draft genome sequences for two avian malaria species, Plasmodium relictum and Plasmodium gallinaceum.,We identify 50 genes that are specific to avian malaria, located in an otherwise conserved core of the genome that shares gene synteny with all other sequenced malaria genomes.,Phylogenetic analysis suggests that the avian malaria species form an outgroup to the mammalian Plasmodium species, and using amino acid divergence between species, we estimate the avian- and mammalian-infective lineages diverged in the order of 10 million years ago.,Consistent with their phylogenetic position, we identify orthologs of genes that had previously appeared to be restricted to the clades of parasites containing Plasmodium falciparum and Plasmodium vivax, the species with the greatest impact on human health.,From these orthologs, we explore differential diversifying selection across the genus and show that the avian lineage is remarkable in the extent to which invasion-related genes are evolving.,The subtelomeres of the P. relictum and P. gallinaceum genomes contain several novel gene families, including an expanded surf multigene family.,We also identify an expansion of reticulocyte binding protein homologs in P. relictum, and within these proteins, we detect distinct regions that are specific to nonhuman primate, humans, rodent, and avian hosts.,For the first time in the Plasmodium lineage, we find evidence of transposable elements, including several hundred fragments of LTR-retrotransposons in both species and an apparently complete LTR-retrotransposon in the genome of P. gallinaceum.

Because the success of deworming programs targeting soil-transmitted helminths (STHs) is evaluated through the periodically assessment of prevalence and infection intensities, the use of the correct diagnostic method is of utmost importance.,The STH community has recently published for each phase of a deworming program the minimal criteria that a potential diagnostic method needs to meet, the so-called target product profiles (TPPs).,We compared the diagnostic performance of a single Kato-Katz (reference method) with that of other microscopy-based methods (duplicate Kato-Katz, Mini-FLOTAC and FECPAKG2) and one DNA-based method (qPCR) for the detection and quantification of STH infections in three drug efficacy trials in Ethiopia, Lao PDR, and Tanzania.,Furthermore, we evaluated a selection of minimal diagnostic criteria of the TPPs.,All diagnostic methods showed a clinical sensitivity of ≥90% for all STH infections of moderate-to-heavy intensities.,For infections of very low intensity, only qPCR resulted in a sensitivity that was superior to a single Kato-Katz for all STHs.,Compared to the reference method, both Mini-FLOTAC and FECPAKG2 resulted in significantly lower fecal egg counts for some STHs, leading to a substantial underestimation of the infection intensity.,For qPCR, there was a positive significant correlation between the egg counts of a single Kato-Katz and the DNA concentration.,Our results indicate that the diagnostic performance of a single Kato-Katz is underestimated by the community and that diagnostic specific thresholds to classify intensity of infection are warranted for Mini-FLOTAC, FECPAKG2 and qPCR.,When we strictly apply the TPPs, Kato-Katz is the only microscopy-based method that meets the minimal diagnostic criteria for application in the planning, monitoring and evaluation phase of an STH program. qPCR is the only method that could be considered in the phase that aims to seek confirmation for cessation of program.,ClinicalTrials.gov NCT03465488

Intestinal nematodes affecting dogs, i.e. roundworms, hookworms and whipworms, have a relevant health-risk impact for animals and, for most of them, for human beings.,Both dogs and humans are typically infected by ingesting infective stages, (i.e. larvated eggs or larvae) present in the environment.,The existence of a high rate of soil and grass contamination with infective parasitic elements has been demonstrated worldwide in leisure, recreational, public and urban areas, i.e. parks, green areas, bicycle paths, city squares, playgrounds, sandpits, beaches.,This review discusses the epidemiological and sanitary importance of faecal pollution with canine intestinal parasites in urban environments and the integrated approaches useful to minimize the risk of infection in different settings.

Tanzania’s Zanzibar archipelago has made significant gains in malaria control over the last decade and is a target for malaria elimination.,Despite consistent implementation of effective tools since 2002, elimination has not been achieved.,Importation of parasites from outside of the archipelago is thought to be an important cause of malaria’s persistence, but this paradigm has not been studied using modern genetic tools.,Whole-genome sequencing (WGS) was used to investigate the impact of importation, employing population genetic analyses of Plasmodium falciparum isolates from both the archipelago and mainland Tanzania.,Ancestry, levels of genetic diversity and differentiation, patterns of relatedness, and patterns of selection between these two populations were assessed by leveraging recent advances in deconvolution of genomes from polyclonal malaria infections.,Significant decreases in the effective population sizes were inferred in both populations that coincide with a period of decreasing malaria transmission in Tanzania.,Identity by descent analysis showed that parasites in the two populations shared long segments of their genomes, on the order of 5 cM, suggesting shared ancestry within the last 10 generations.,Even with limited sampling, two of isolates between the mainland and Zanzibar were identified that are related at the expected level of half-siblings, consistent with recent importation.,These findings suggest that importation plays an important role for malaria incidence on Zanzibar and demonstrate the value of genomic approaches for identifying corridors of parasite movement to the island.

Malaysia has a national goal to eliminate malaria by 2020.,Understanding the genetic diversity of malaria parasites in residual transmission foci can provide invaluable information which may inform the intervention strategies used to reach elimination targets.,This study was conducted to determine the genetic diversity level of P. falciparum isolates in malaria residual foci areas of Sabah.,Malaria active case detection was conducted in Kalabakan and Kota Marudu.,All individuals in the study sites were screened for malaria infection by rapid diagnostic test.,Blood from P. falciparum-infected individuals were collected on filter paper prior to DNA extraction.,Genotyping was performed using merozoite surface protein-1 (MSP-1), merozoite surface protein-2 (MSP-2), glutamate rich protein (GLURP) and 10 neutral microsatellite loci markers.,The size of alleles, multiplicity of infection (MOI), mean number of alleles (Na), expected heterozygosity (He), linkage disequilibrium (LD) and genetic differentiation (FST) were determined.,In Kalabakan, the MSP-1 and MSP-2 alleles were predominantly K1 and FC27 family types, respectively.,The GLURP genotype VI (751-800 bp) was predominant.,The MOI for MSP-1 and MSP-2 were 1.65 and 1.20, respectively.,The Na per microsatellite locus was 1.70.,The He values for MSP-1, MSP-2, GLURP and neutral microsatellites were 0.17, 0.37, 0.70 and 0.33, respectively.,In Kota Marudu, the MSP-1 and MSP-2 alleles were predominantly MAD20 and 3D7 family types, respectively.,The GLURP genotype IV (651-700 bp) was predominant.,The MOI for both MSP-1 and MSP-2 was 1.05.,The Na per microsatellite locus was 3.60.,The He values for MSP-1, MSP-2, GLURP and neutral microsatellites were 0.24, 0.25, 0.69 and 0.30, respectively.,A significant LD was observed in Kalabakan (0.495, p<0.01) and Kota Marudu P. falciparum populations (0.601, p<0.01).,High genetic differentiation between Kalabakan and Kota Marudu P. falciparum populations was observed (FST = 0.532).,The genetic data from the present study highlighted the limited diversity and contrasting genetic pattern of P. falciparum populations in the malaria declining areas of Sabah.

More than ever, it is crucial to make the best use of existing country data, and analytical tools for developing malaria control strategies as the heterogeneity in malaria risk within countries is increasing, and the available malaria control tools are expanding while large funding gaps exist.,Global and local policymakers, as well as funders, increasingly recognize the value of mathematical modelling as a strategic tool to support decision making.,This case study article describes the long-term use of modelling in close collaboration with the National Malaria Control Programme (NMCP) in Tanzania, the challenges encountered and lessons learned.,In Tanzania, a recent rebound in prevalence led to the revision of the national malaria strategic plan with interventions targeted to the malaria risk at the sub-regional level.,As part of the revision, a mathematical malaria modelling framework for setting specific predictions was developed and used between 2016 and 2019 to (1) reproduce setting specific historical malaria trends, and (2) to simulate in silico the impact of future interventions.,Throughout the project, multiple stakeholder workshops were attended and the use of mathematical modelling interactively discussed.,In Tanzania, the model application created an interdisciplinary and multisectoral dialogue platform between modellers, NMCP and partners and contributed to the revision of the national malaria strategic plan by simulating strategies suggested by the NMCP.,The uptake of the modelling outputs and sustained interest by the NMCP were critically associated with following factors: (1) effective sensitization to the NMCP, (2) regular and intense communication, (3) invitation for the modellers to participate in the strategic plan process, and (4) model application tailored to the local context.,Empirical data analysis and its use for strategic thinking remain the cornerstone for evidence-based decision-making.,Mathematical impact modelling can support the process both by unifying all stakeholders in one strategic process and by adding new key evidence required for optimized decision-making.,However, without a long-standing partnership, it will be much more challenging to sensibilize programmes to the usefulness and sustained use of modelling and local resources within the programme or collaborating research institutions need to be mobilized.

Scale-up of malaria prevention and treatment needs to continue but national strategies and budget allocations are not always evidence-based.,This article presents a new modelling tool projecting malaria infection, cases and deaths to support impact evaluation, target setting and strategic planning.,Nested in the Spectrum suite of programme planning tools, the model includes historic estimates of case incidence and deaths in groups aged up to 4, 5-14, and 15+ years, and prevalence of Plasmodium falciparum infection (PfPR) among children 2-9 years, for 43 sub-Saharan African countries and their 602 provinces, from the WHO and malaria atlas project.,Impacts over 2016-2030 are projected for insecticide-treated nets (ITNs), indoor residual spraying (IRS), seasonal malaria chemoprevention (SMC), and effective management of uncomplicated cases (CMU) and severe cases (CMS), using statistical functions fitted to proportional burden reductions simulated in the P. falciparum dynamic transmission model OpenMalaria.,In projections for Nigeria, ITNs, IRS, CMU, and CMS scale-up reduced health burdens in all age groups, with largest proportional and especially absolute reductions in children up to 4 years old.,Impacts increased from 8 to 10 years following scale-up, reflecting dynamic effects.,For scale-up of each intervention to 80% effective coverage, CMU had the largest impacts across all health outcomes, followed by ITNs and IRS; CMS and SMC conferred additional small but rapid mortality impacts.,Spectrum-Malaria’s user-friendly interface and intuitive display of baseline data and scenario projections holds promise to facilitate capacity building and policy dialogue in malaria programme prioritization.,The module’s linking to the OneHealth Tool for costing will support use of the software for strategic budget allocation.,In settings with moderately low coverage levels, such as Nigeria, improving case management and achieving universal coverage with ITNs could achieve considerable burden reductions.,Projections remain to be refined and validated with local expert input data and actual policy scenarios.,The online version of this article (doi:10.1186/s12936-017-1705-3) contains supplementary material, which is available to authorized users.

Using an ensemble modeling approach, Thomas Smith and colleagues find that targeted mass vaccination with a pre-erythrocytic malaria vaccine RTS,S in low-transmission settings might have better health effects than vaccination through national EPI programs.,The RTS,S malaria vaccine may soon be licensed.,Models of impact of such vaccines have mainly considered deployment via the World Health Organization's Expanded Programme on Immunization (EPI) in areas of stable endemic transmission of Plasmodium falciparum, and have been calibrated for such settings.,Their applicability to low transmission settings is unclear.,Evaluations of the efficiency of different deployment strategies in diverse settings should consider uncertainties in model structure.,An ensemble of 14 individual-based stochastic simulation models of P. falciparum dynamics, with differing assumptions about immune decay, transmission heterogeneity, and treatment access, was constructed.,After fitting to an extensive library of field data, each model was used to predict the likely health benefits of RTS,S deployment, via EPI (with or without catch-up vaccinations), supplementary vaccination of school-age children, or mass vaccination every 5 y.,Settings with seasonally varying transmission, with overall pre-intervention entomological inoculation rates (EIRs) of two, 11, and 20 infectious bites per person per annum, were considered.,Predicted benefits of EPI vaccination programs over the simulated 14-y time horizon were dependent on duration of protection.,Nevertheless, EPI strategies (with an initial catch-up phase) averted the most deaths per dose at the higher EIRs, although model uncertainty increased with EIR.,At two infectious bites per person per annum, mass vaccination strategies substantially reduced transmission, leading to much greater health effects per dose, even at modest coverage.,In higher transmission settings, EPI strategies will be most efficient, but vaccination additional to the EPI in targeted low transmission settings, even at modest coverage, might be more efficient than national-level vaccination of infants.,The feasibility and economics of mass vaccination, and the circumstances under which vaccination will avert epidemics, remain unclear.,The approach of using an ensemble of models provides more secure conclusions than a single-model approach, and suggests greater confidence in predictions of health effects for lower transmission settings than for higher ones.,Please see later in the article for the Editors' Summary,The World Health Organization estimates that there are over 200 million cases of malaria each year, and that more than three-quarters of a million people (mostly children living in sub-Saharan Africa) die as a result.,Several Plasmodium parasites cause malaria, the most deadly being Plasmodium falciparum.,Plasmodium parasites, which are transmitted to people through the bites of infected night-flying mosquitoes, cause recurring fever and can cause life-threatening organ damage.,Malaria transmission can be prevented by using insecticides to control the mosquitoes that spread the parasite and by sleeping under insecticide-treated bed nets to avoid mosquito bites.,Treatment with antimalarial drugs also reduces transmission.,Together, these preventative measures have greatly reduced the global burden of malaria over recent years, but a malaria vaccine could be a valuable additional tool against the disease.,At present there is no licensed malaria vaccine, but one promising vaccine-RTS,S-is currently undergoing phase III clinical trials (the last stage of testing before licensing) in infants and children in seven African countries.,If the RTS,S vaccine fulfills its promise and is licensed, how should it be used to maximize its effect on the global malaria burden?,Should it be given through the World Health Organization's Expanded Programme on Immunization (EPI), which aims to provide universal access to immunization against several infectious diseases during the first three months of life, for example, or through mass vaccination campaigns?,Individual mathematical models have been used to investigate this type of question, but the predictions made by these models may be inaccurate because malaria immunity is poorly understood, because little is known about the levels of variability (heterogeneity) in host responses to malaria infection and in malaria transmission, and because it is unclear what the structure of models used to predict vaccine efficacy should be.,In this study, the researchers use an “ensemble” approach to model the likely public health impact of the RTS,S malaria vaccine.,That is, they simultaneously consider the effect of the vaccine in multiple models of P. falciparum dynamics.,Ensemble modeling is widely used in weather forecasting and has been used to investigate several other infectious diseases.,The researchers constructed an ensemble of 14 individual-based stochastic simulation models of P. falciparum dynamics that included different assumptions about immune decay, transmission heterogeneity, and access to treatment.,Such models simulate the passage of thousands of hypothetical individuals through different stages of malaria infection; movement between stages occurs stochastically (by chance) at a probability based on field data.,Each model was used to predict the health benefits over 14 years of RTS,S deployment through EPI (with and without catch-up vaccination for infants who were not immunized during their first three months of life), through EPI and supplementary vaccination of school children, and through mass vaccination campaigns every five years at malaria transmission levels of 2, 11, and 20 infectious bites per person per annum (low, medium, and high entomological inoculation rates [EIRs], respectively).,The predicted benefits of EPI vaccination programs over the 14-year period were modest and similar over a wide range of settings.,However, EPI with an initial catch-up phase averted the most deaths per vaccine dose at higher EIRs.,At the lowest EIR, mass vaccination strategies substantially reduced transmission, leading to much greater health effects per dose than other strategies, even at modest coverage.,The ensemble approach taken here suggests that targeted mass vaccination with RTS,S in low transmission settings may have greater health benefits than vaccination through national EPI programs.,Importantly, this computer-intensive approach, which used computers made available over the internet by volunteers, provides more secure predictions than can be obtained using single models.,In addition, it suggests that predictions made about the health effects of RTS,S vaccination for low transmission settings are more likely to be accurate than those made for higher transmission settings.,However, this study only reports the first stages of using ensemble modeling to predict the health effects of RTS,S vaccination.,Future studies will need to combine the outputs of multiple models with economic analyses to provide a rational basis for the design of vaccine-containing malaria control and elimination programs.,Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001157.,Information is available from the World Health Organization on malaria and on malaria immunization; the 2010 World Malaria Report provides details on the current global malaria situation; WHO also provides information on its Expanded Programme on Immunization (EPI), and its Global Immunization Vision and Strategy (some information is available in several languages),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 and on malaria in Africa,The latest results from the phase III trial of RTS,S are available on the website of the PATH Malaria Vaccine Initiative, a global program of the international nonprofit organization PATH that aims to accelerate the development of malaria vaccines and ensure their availability and accessibility in the developing world,Wikipedia has a page on ensemble forecasting (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages),OpenMalaria is the open source simulator of malaria epidemiology and control used in this study; BOINC is the open source software for volunteer computing and grid computing that was used to run the simulations,MedlinePlus provides links to additional information on malaria and on immunization (in English and Spanish)

Roll Back Malaria set the goal of 100% of households in malaria endemic countries in Africa owning an insecticide-treated mosquito net (ITN) by 2010.,Zambia has used mass free distribution campaigns and distribution through antenatal care (ANC) clinics to achieve high coverage.,We conducted a probability survey of 801 households in 2008 to assess factors associated with households that lacked an ITN after mass distribution.,Community perceptions of barriers to ITN access were also obtained from in-depth interviews with household heads that reported not owning an ITN.,Nearly 74% of households in Luangwa district reported owning ≥1 ITN.,Logistic regression showed households without a child <5 years old during the ITN distribution campaigns were twice as likely to not have an ITN as those with a child <5 during distribution (Adjusted odds ratio (AOR) = 2.43; 95% confidence interval (CI): 1.67-3.55).,Households without a woman who attended an ANC in the past 2 years were more likely to be without ITNs compared to households with a woman who attended an ANC in the past 2 years (AOR = 1.52; 95% CI: 1.04-2.21).,In-depth interviews with heads of households without an ITN revealed that old age was a perceived barrier to receiving an ITN during distribution, and that ITNs wore out before they could be replaced.,Delivery of a large number of ITNs does not translate directly into 100% household coverage.,Due to their design, current ITN distribution strategies may miss households occupied by the elderly and those without children or ANC access.,ITN distribution strategies targeting the elderly, those with limited access to distribution points, and others most likely to be missed are necessary if 100% ITN coverage of households is to be achieved.

Scale-up of malaria preventive and control interventions over the last decade resulted in substantial declines in mortality and morbidity from the disease in sub-Saharan Africa and many other parts of the world.,Sustaining these gains will depend on the health system performance.,Treatment provides individual benefits by curing infection and preventing progression to severe disease as well as community-level benefits by reducing the infectious reservoir and averting emergence and spread of drug resistance.,However many patients with malaria do not access care, providers do not comply with treatment guidelines, and hence, patients do not necessarily receive the correct regimen.,Even when the correct regimen is administered some patients will not adhere and others will be treated with counterfeit or substandard medication leading to treatment failures and spread of drug resistance.,We apply systems effectiveness concepts that explicitly consider implications of health system factors such as treatment seeking, provider compliance, adherence, and quality of medication to estimate treatment outcomes for malaria case management.,We compile data for these indicators to derive estimates of effective coverage for 43 high-burden Sub-Saharan African countries.,Parameters are populated from the Demographic and Health Surveys and other published sources.,We assess the relative importance of these factors on the level of effective coverage and consider variation in these health systems indicators across countries.,Our findings suggest that effective coverage for malaria case management ranges from 8% to 72% in the region.,Different factors account for health system inefficiencies in different countries.,Significant losses in effectiveness of treatment are estimated in all countries.,The patterns of inter-country variation suggest that these are system failures that are amenable to change.,Identifying the reasons for the poor health system performance and intervening to tackle them become key priority areas for malaria control and elimination policies in the region.

Health facility stock-outs of artemether-lumefantrine (AL), the common first-line therapy for uncomplicated malaria across Africa, adversely affect effective malaria case-management.,They have been previously reported on various scales in time and space, however the magnitude of the problem and trends over time are less clear.,Here, 2010-2011 data are reported from public facilities in Kenya where alarming stock-outs were revealed in 2008.,Data were collected between January 2010 and June 2011 as part of 18 monthly cross-sectional surveys undertaken at nationally representative samples of public health facilities.,The primary monitoring indicator was total stock-out of all four weight-specific AL packs.,The secondary indicators were stock-outs of at least one AL pack and individual stock-outs for each AL pack.,Monthly proportions and summary means of the proportions over the monitoring period were measured for each indicator.,Stock-out trends were assessed using linear regression.,The number of surveyed facilities across 18 time points ranged between 162 and 176 facilities.,The stock-out means of the proportion of health facilities were 11.6% for total AL stock-out, 40.6% for stock-out of at least one AL pack, and between 20.5% and 27.4% for stock-outs of individual AL packs.,Monthly decrease of the total AL stock-out was 0.005% (95% CI: -0.5 to +0.5; p = 0.983).,Monthly decrease in the stock-out of at least one AL pack was 0.7% (95% CI: -1.5 to +0.3; p = 0.058) while stock-outs of individual AL packs decreased monthly between 0.2% for AL 24-pack and 0.7% for AL six-pack without statistical significance for any of the weight-specific packs.,Despite lower levels of AL stock-outs compared to the reports in 2008, the stock-outs at Kenyan facilities during 2010-2011 are still substantial and of particular worry for the most detrimental:- simultaneous absence of any AL pack.,Only minor decrease was observed in the stock-outs of individual AL packs.,Recently launched interventions to eliminate AL stock-outs in Kenya are fully justified.

Zoonotic leishmaniosis, caused by the protozoan Leishmania infantum, is a public and animal health problem in Asia, Central and South America, the Middle East and the Mediterranean Basin.,Several phlebotomine sand fly species from the subgenus Larroussius are vectors of L. infantum.,Data from dogs living in endemic areas of leishmaniosis advocate the use of antibody response to phlebotomine sand fly saliva as an epidemiological biomarker for monitoring vector exposure.,The aim of this study was to analyse the exposure of cats to phlebotomine sand flies using detection of IgG antibodies to Phlebotomus perniciosus saliva.,The association between phlebotomine sand fly exposure and the presence of Leishmania infection was also investigated.,IgG antibodies to P. perniciosus saliva were detected in 167 (47.7%) out of 350 cats; higher antibody levels were present in sera collected during the period of phlebotomine sand fly seasonal activity (OR = 19.44, 95% CI: 9.84-38.41).,Cats of 12-35 months had higher antibody levels than younger ones (OR = 3.56, 95% CI: 1.39-9.16); this difference was also significant with older cats (for 36-95 months-old, OR = 9.43, 95% CI: 3.62-24.48; for older than 95 months, OR = 9.68, 95% CI: 3.92-23.91).,Leishmania spp.,DNA was detected in the blood of 24 (6.9%) cats, while antibodies to L. infantum were detected in three (0.9%).,Only one cat was positive to Leishmania by both techniques.,Cats presenting IgG antibodies to P. perniciosus had a significantly higher risk of being positive for Leishmania infection.,To our knowledge, this is the first study demonstrating anti-sand fly saliva antibodies in cats.,The evaluation of the contact of this animal species with the vector is important to the development of prophylactic measures directed to cats, with the aim of reducing the prevalence of infection in an endemic area.,Therefore, studies evaluating whether the use of imidacloprid/flumethrin collars reduces the frequency of P. perniciosus bites in cats are needed.,It is also important to evaluate if there is a correlation between the number of phlebotomine sand fly bites and IgG antibody levels.

Antibody responses to sand fly saliva have been suggested to be a useful marker of exposure to sand fly bites and Leishmania infection and a potential tool to monitor the effectiveness of entomological interventions.,Exposure to sand fly bites before infection has also been suggested to modulate the severity of the infection.,Here, we test these hypotheses by quantifying the anti-saliva IgG response in a cohort study of dogs exposed to natural infection with Leishmania infantum in Brazil.,IgG responses to crude salivary antigens of the sand fly Lutzomyia longipalpis were measured by ELISA in longitudinal serum samples from 47 previously unexposed sentinel dogs and 11 initially uninfected resident dogs for up to 2 years.,Antibody responses were compared to the intensity of transmission, assessed by variation in the incidence of infection between seasons and between dogs.,Antibody responses before patent infection were then compared with the severity of infection, assessed using tissue parasite loads and clinical symptoms.,Previously unexposed dogs acquired anti-saliva antibody responses within 2 months, and the rate of acquisition increased with the intensity of seasonal transmission.,Over the following 2 years, antibody responses varied with seasonal transmission and sand fly numbers, declining rapidly in periods of low transmission.,Antibody responses varied greatly between dogs and correlated with the intensity of transmission experienced by individual dogs, measured by the number of days in the field before patent infection.,After infection, anti-saliva antibody responses were positively correlated with anti-parasite antibody responses.,However, there was no evidence that the degree of exposure to sand fly bites before infection affected the severity of the infection.,Anti-saliva antibody responses are a marker of current transmission intensity in dogs exposed to natural infection with Leishmania infantum, but are not associated with the outcome of infection.

Infants are thought to be protected against malaria during the first months of life mainly due to passage of maternal antibodies.,However, in high transmission settings, malaria in early infancy is not uncommon and susceptibility to the infections varies between individuals.,This study aimed to determine malaria morbidity and infection during early childhood in rural Burkina Faso.,Malariometric indices were determined over 1-year follow-up in a birth cohort of 734 infants living in Nanoro health district.,Clinical malaria episodes were determined by passive case detection at peripheral health centres while asymptomatic malaria infections were identified during 4 cross-sectional surveys at 3, 6, 9 and 12 months of age.,Plasmodium falciparum infections were detected by rapid diagnostic test and/or light microscopy (LM) and quantitative PCR (qPCR).,In total, 717 clinical episodes were diagnosed by qPCR over 8335.18 person-months at risk.,The overall malaria incidence was 1.03 per child-year and increased from 0.27 per child-year at 0-3 months of age to 1.92 per child-year at 9-12 months of age.,Some 59% of children experienced at least one clinical episode with a median survival time estimated at 9.9 months, while 20% of infants experienced the first episode before 6 months of age.,The majority of the clinical episodes were attributable to microscopic parasitaemia (84.2%), and there was a positive correlation between parasite density and age (Spearman’s rho = 0.30; P < 0.0001).,Prevalence of asymptomatic infections was similar at 3, 6 and 9 months of age (17.7-20.1%) and nearly 1.6 times higher at 12 months (31.3%).,Importantly, gametocyte prevalence among the LM-positive study population was 6.7%, but increased to 10% among asymptomatic infections.,In addition, 46% of asymptomatic infections were only detected by qPCR suggesting that infants below 1 year are a potential reservoir for sustaining malaria transmission.,Both symptomatic and asymptomatic infections showed marked seasonal distribution with the highest transmission period (July to December) accounting for about 89 and 77% of those infections, respectively.,These findings indicate high and marked age and seasonal-dependency of malaria infections and disease during the first year of life in Nanoro, calling for intensified efforts to control malaria in rural Burkina Faso.

Congenital malaria diagnosis is challenging due to frequently observed low parasite density infections, while their clinical relevance during early infancy is not well characterized.,In Nanoro health district (Burkina Faso), we determined the prevalence of congenital malaria by real-time quantitative PCR and we assessed the performance of rapid diagnosis test (RDT) and light microscopy (LM) to detect Plasmodium falciparum infections in cord-blood samples.,In addition, we examined the usefulness of P. falciparum Histidine Rich Protein2 (PfHRP2) as surrogate biomarker of infection and explored association between congenital malaria and clinical outcomes.,A prevalence of congenital malaria by qPCR of 4% (16/400) was found, which increased to 10% among newborns from mothers infected at delivery.,RDT and LM showed poor performances indicating limited utility for congenital malaria screening in cord blood.,Because PfHRP2 detection in cord blood could be affected by transplacental passage of parasite antigens, PfHRP2 might not be used as a surrogate biomarker of congenital malaria infections.,There was no evidence of a significant clinical impact of congenital malaria on infant’s health from birth to 59 days of life.,Case control studies including long-term follow up may provide additional understanding on the relevance of neonatal malaria infections.

Malaria remains one of the leading communicable diseases in Ethiopia.,Early diagnosis combined with prompt treatment is one of the main strategies for malaria prevention and control.,Despite its limitation, Giemsa microscopy is still considered to be the gold standard for malaria diagnosis.,This study aimed to compare the performance of Giemsa microscopy with nested polymerase chain reaction (nPCR) for the diagnosis of malaria in north-west Ethiopia.,A cross sectional study was conducted in public health facilities in North Gondar, from March 2013 to April 2013.,A total number of 297 subjects with suspected malaria were enrolled in the study.,Finger-prick blood samples were collected and examined for Plasmodium parasites using Giemsa microscopy and standard nPCR.,Among the study participants, 61.6% (183/297) patients tested positive for malaria by Giemsa microscopy of which, 72.1% (132/183) and 27.9% (51/183) were diagnosed as Plasmodium falciparum and Plasmodium vivax, respectively.,By nPCR, 73.1% (217/297) were malaria-positive.,Among microscopy-negative samples, 13.1% (39/297) samples turned malaria-positive in nPCR.,In nPCR, the rate of mixed Plasmodium infections was 4.7% (14/297) and 3.03% (9/297) were positive for Plasmodium ovale.,Using nPCR as reference the sensitivity, specificity, positive predictive and negative predictive values of Giemsa microscopy were 82.0%, 93.8%, 97.3% and 65.8%, respectively, with a good agreement (κ = 0.668) to nested PCR.,The sensitivity and specificity of Giemsa microscopy in identifying,P. falciparium infections were 74.0% and 87.4% and 63.2% and 96.5% for P. vivax infections, respectively.,Although Giemsa microscopy remains the gold standard for malaria diagnosis in resource-limited environments, its sensitivity and specificity as compared to nPCR is limited suggesting exploration of novel rapid and simplified molecular techniques for malaria-endemic countries.,A high rate of misclassification and misidentification highlights the importance of adequate training for staff involved in malaria diagnosis.

Malaria remains a serious disease in the developing world.,There is a growing consensus that new diagnostics are needed in low-resource settings.,The ideal malaria diagnostic should be able to speciate; measure parasitemia; low-cost, quick, and simple to use; and capable of detecting low-level infections.,A promising development are nucleic acid tests (NATs) for the diagnosis of malaria, which are well suited for point-of-care use because of their ability to detect low-level infections and speciate, and because they have high sensitivity and specificity.,The greatest barrier to NAT use in the past has been its relatively high cost, and the amount of infrastructure required in the form of equipment, stable power, and reagent storage.,This review describes recent developments to decrease the cost and run time, and increase the ease of use of NAT while maintaining their high sensitivity and specificity and low limit of detection at the point-of-care.

Progress made in malaria control during the past decade has prompted increasing global dialogue on malaria elimination and eradication.,The product development pipeline for malaria has never been stronger, with promising new tools to detect, treat, and prevent malaria, including innovative diagnostics, medicines, vaccines, vector control products, and improved mechanisms for surveillance and response.,There are at least 25 projects in the global malaria vaccine pipeline, as well as 47 medicines and 13 vector control products.,In addition, there are several next-generation diagnostic tools and reference methods currently in development, with many expected to be introduced in the next decade.,The development and adoption of these tools, bolstered by strategies that ensure rapid uptake in target populations, intensified mechanisms for information management, surveillance, and response, and continued financial and political commitment are all essential to achieving global eradication.,Malaria elimination in many settings will not be possible without new vaccines, drugs, and vector control products.,Although a healthy pipeline of new products in each of these areas has been developed over the past decade, significant work is required to bring these products to market and deploy optimal strategies for their use.

Malaria vector control relies on toxicity of insecticides used in long lasting insecticide treated nets and indoor residual spraying.,This is despite evidence that sub-lethal insecticides reduce human-vector contact and malaria transmission.,The impact of sub-lethal insecticides on host seeking and blood feeding of mosquitoes was measured.,Taxis boxes distinguished between repellency and attraction inhibition of mosquitoes by measuring response of mosquitoes towards or away from Transfluthrin coils and humans.,Protective effective distance of coils and long-term effects on blood feeding were measured in the semi-field tunnel and in a Peet Grady chamber.,Laboratory reared pyrethroid susceptible Anopheles gambiae sensu stricto mosquitoes were used.,In the taxis boxes, a higher proportion of mosquitoes (67%-82%) were activated and flew towards the human in the presence of Transfluthrin coils.,Coils did not hinder attraction of mosquitoes to the human.,In the semi-field Tunnel, coils placed 0.3 m from the human reduced feeding by 86% (95% CI [0.66; 0.95]) when used as a “bubble” compared to 65% (95% CI [0.51; 0.76]) when used as a “point source”.,Mosquitoes exposed to coils inside a Peet Grady chamber were delayed from feeding normally for 12 hours but there was no effect on free flying and caged mosquitoes exposed in the semi-field tunnel.,These findings indicate that airborne pyrethroids minimize human-vector contact through reduced and delayed blood feeding.,This information is useful for the development of target product profiles of spatial repellent products that can be used to complement mainstream malaria vector control tools.

Urinary schistosomiasis is caused by an intravascular infection with parasitic Schistosoma haematobium worms.,The adult worms typically migrate to the venous plexus of the human bladder and excrete eggs which the infected person passes in their urine.,Chronic infection can cause substantial morbidity and long‐term complications as the eggs become trapped in human tissues causing inflammation and fibrosis.,We summarised evidence of drugs active against the infection.,This is new edition of a review first published in 1997.,To evaluate the efficacy and safety of drugs for treating urinary schistosomiasis.,We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, CENTRAL, EMBASE and LILACS and reference lists of articles up to 23 May 2014.,Randomized controlled trials (RCTs) of antischistosomal drugs and drug combinations compared to placebo, no intervention, or each other.,Two researchers independently screened the records, extracted the data and assessed risk of bias.,The primary efficacy outcomes were parasitological failure (defined as the continued presence of S. haematobium eggs in the urine at time points greater than one month after treatment), and percent reduction of egg counts from baseline.,We presented dichotomous data as risk ratios (RR), and continuous data as mean difference (MD), alongside their 95% confidence intervals (CIs).,Where appropriate we combined trials in meta analyses or tables.,We assessed the quality of evidence using the GRADE approach.,We included 30 RCTs enrolling 8165 participants in this review.,Twenty‐four trials were conducted in children in sub‐Saharan Africa, and 21 trials were over 20 years old.,Many studies were assessed as being at unclear risk of bias due to inadequate descriptions of study methods.,Praziquantel,On average, a single 40 mg/kg dose of praziquantel reduced the proportion of people still excreting eggs in their urine by around 60% compared to placebo at one to two months after treatment (treatment failure: RR 0.42, 95% CI 0.29 to 0.59, 864 participants, seven trials, high quality evidence).,The proportion of people cured with praziquantel varied substantially between trials, from 22.5% to 83.3%, but was higher than 60% in five of the seven trials.,At one to two months following praziquantel treatment at 40 mg/kg, the mean number of schistosome eggs in the urine was reduced by over 95% in five out of six trials (678 participants, six trials, high quality evidence).,Splitting praziquantel 40 mg/kg into two doses over 12 hours probably has no benefits over a single dose, and in a single trial of 220 participants the split dose caused more vomiting (RR 0.5, 95% CI 0.29 to 0.86) and dizziness (RR 0.39, 95% CI 0.16 to 0.94).,Metrifonate,A single dose of metrifonate 10 mg/kg reduced egg excretion (210 participants, one trial, at eight months), but was only marginally better than placebo at achieving cure at one month (RR 0.83, 95% CI 0.74 to 0.94, 142 participants, one trial).,In a single trial comparing one, two and three doses, the absolute number of participants cured improved from 47% after one dose to 81% after three doses (93 participants, one trial, low quality evidence).,Two small trials compared 40 mg/kg single dose praziquantel with two or three doses of 10 mg/kg metrifonate and found no clear evidence of differences in cure (metrifonate 2 x 10 mg/kg at one month: RR 1.03, 95% CI 0.8 to 1.34, 72 participants, one trial; metrifonate 3 x 10 mg/kg at three months: RR 0.33, 95% CI 0.07 to 1.57, 100 participants, one trial.,In one trial both drugs performed badly and in one trial both performed well.,Other drugs,Three trials have evaluated the antimalarial artesunate; with inconsistent results.,Substantial antischistosomal effects were only seen in one of the three trials, which was at unclear risk of bias due to poor reporting of the trial methods.,Similarly, another anti‐malarial mefloquine has been evaluated in two small trials with inconsistent effects.,Adverse events were described as mild for all evaluated drugs, but adverse event monitoring and reporting was generally of low quality.,Praziquantel 40 mg/kg is the most studied drug for treating urinary schistosomiasis, and has the strongest evidence base.,Potential strategies to improve future treatments for schistosomiasis include the combination of praziquantel with metrifonate, or with antimalarial drugs with antischistosomal properties such as artesunate and mefloquine.,Evaluation of these combinations requires rigorous, adequately powered trials using standardized outcome measures.,15 April 2019,Update pending,Studies awaiting assessment,The CIDG is currently examining a new search conducted in April 2019 for potentially relevant studies.,These studies have not yet been incorporated into this Cochrane Review.,Drugs for treating urinary schistosomiasis,What is urinary schistosomiasis and how is it treated?,Urinary schistosomiasis is a disease caused by infection of people with the parasitic worm Schistosoma haematobium.,These worms live in blood vessels around the infected person's bladder and the worm releases eggs which are released in the person's urine.,If the urine is passed into ponds or lakes, the eggs can hatch and infect people that are washing or swimming there.,Infection can cause blood in the urine and if left untreated can eventually lead to anaemia, malnutrition, kidney failure, or bladder cancer.,Urinary schistosomiasis is diagnosed by looking for worm eggs in the urine.,The disease occurs mainly in school‐aged children and young adults in sub‐Saharan Africa.,The drug currently recommended for treatment is praziquantel, which can be given as a single dose, but other drugs such as metrifonate, artesunate, and mefloquine have also been evaluated.,After examining the research published up to 23th May 2014, we included 30 randomized controlled trials, enrolling 8165 children and adults.,What does the research say?,On average, the standard dose of praziquantel cures around 60% of people at one to two months after treatment (high quality evidence), and reduces the number of schistosome eggs in the urine by over 95% (high quality evidence).,Metrifonate, an older drug no longer in use, had little effect when given as a single dose but an improved effect when given as multiple doses two weeks apart.,Two trials compared three doses of metrifonate with the single dose of praziquantel and found similar effects.,Two more recent trials evaluated a combination of artesunate and praziquantel compared to praziquantel alone.,In one trial artesunate improved cure and in one it made no difference.,Authors conclusions,Future treatments for schistosomiasis could include combining praziquantel with metrifonate, or with artesunate, but these need to be evaluated in high quality trials.

Schistosomes are parasitic flatworms that infect >200 million people worldwide, causing the chronic, debilitating disease schistosomiasis.,Unusual among parasitic helminths, the long-lived adult worms, continuously bathed in blood, take up nutrients directly across the body surface and also by ingestion of blood into the gut.,Recent proteomic analyses of the body surface revealed the presence of hydrolytic enzymes, solute, and ion transporters, thus emphasising its metabolic credentials.,Furthermore, definition of the molecular mechanisms for the uptake of selected metabolites (glucose, certain amino acids, and water) establishes it as a vital site of nutrient acquisition.,Nevertheless, the amount of blood ingested into the gut per day is considerable: for males ∼100 nl; for the more actively feeding females ∼900 nl, >4 times body volume.,Ingested erythrocytes are lysed as they pass through the specialized esophagus, while leucocytes become tethered and disabled there.,Proteomics and transcriptomics have revealed, in addition to gut proteases, an amino acid transporter in gut tissue and other hydrolases, ion, and lipid transporters in the lumen, implicating the gut as the site for acquisition of essential lipids and inorganic ions.,The surface is the principal entry route for glucose, whereas the gut dominates amino acid acquisition, especially in females.,Heme, a potentially toxic hemoglobin degradation product, accumulates in the gut and, since schistosomes lack an anus, must be expelled by the poorly understood process of regurgitation.,Here we place the new observations on the proteome of body surface and gut, and the entry of different nutrient classes into schistosomes, into the context of older studies on worm composition and metabolism.,We suggest that the balance between surface and gut in nutrition is determined by the constraints of solute diffusion imposed by differences in male and female worm morphology.,Our conclusions have major implications for worm survival under immunological or pharmacological pressure.

•Transmission dynamics of schistosomiasis presents multiple heterogeneity sources.,•A comprehensive framework for heterogeneous disease transmission is proposed.,•Heterogeneous multigroup communities can be more prone to parasite transmission.,•Presence of multiple water sources can hinder parasite transmission.,•Spatial and temporal heterogeneities can have nontrivial implications for endemicity.,Transmission dynamics of schistosomiasis presents multiple heterogeneity sources.,A comprehensive framework for heterogeneous disease transmission is proposed.,Heterogeneous multigroup communities can be more prone to parasite transmission.,Presence of multiple water sources can hinder parasite transmission.,Spatial and temporal heterogeneities can have nontrivial implications for endemicity.,Simple models of disease propagation often disregard the effects of transmission heterogeneity on the ecological and epidemiological dynamics associated with host-parasite interactions.,However, for some diseases like schistosomiasis, a widespread parasitic infection caused by Schistosoma worms, accounting for heterogeneity is crucial to both characterize long-term dynamics and evaluate opportunities for disease control.,Elaborating on the classic Macdonald model for macroparasite transmission, we analyze families of models including explicit descriptions of heterogeneity related to differential transmission risk within a community, water contact patterns, the distribution of the snail host population, human mobility, and the seasonal fluctuations of the environment.,Through simple numerical examples, we show that heterogeneous multigroup communities may be more prone to schistosomiasis than homogeneous ones, that the availability of multiple water sources can hinder parasite transmission, and that both spatial and temporal heterogeneities may have nontrivial implications for disease endemicity.,Finally, we discuss the implications of heterogeneity for disease control.,Although focused on schistosomiasis, results from this study may apply as well to other parasitic infections with complex transmission cycles, such as cysticercosis, dracunculiasis and fasciolosis.

Schistosomiasis is a water borne parasitic disease of global importance and with ongoing control the disease endemic landscape is changing.,In sub-Saharan Africa, for example, the landscape is becoming ever more heterogeneous as there are several species of Schistosoma that respond in different ways to ongoing preventive chemotherapy and the inter-sectoral interventions currently applied.,The major focus of preventive chemotherapy is delivery of praziquantel by mass drug administration to those shown to be, or presumed to be, at-risk of infection and disease.,In some countries, regional progress may be uneven but in certain locations there are very real prospects to transition from control into interruption of transmission, and ultimately elimination.,To manage this transition requires reconsideration of some of the currently deployed diagnostic tools used in surveillance and downward realignment of existing prevalence thresholds to trigger mass treatment.,A key challenge will be maintaining and if possible, expanding the current donation of praziquantel to currently overlooked groups, then judging when appropriate to move from mass drug administration to selective treatment.,In so doing, this will ensure the health system is adapted, primed and shown to be cost-effective to respond to these changing disease dynamics as we move forward to 2020 targets and beyond.,The online version of this article (doi:10.1186/s40249-017-0256-8) contains supplementary material, which is available to authorized users.

The levels of insecticide-treated net use among pregnant women and uptake of intermittent preventive treatment in pregnancy, have been sub-optimal in Nigeria.,Previous studies have reported positive correlations between knowledge, attitude and practice of malaria preventive measures.,It has also been reported that information and motivation, act through a mediator (behavioural skills), to cause a health behaviour change.,The aim of this study was as such to develop, implement, and assess the effects of a health educational intervention based on the information-motivation-behavioural skills (IMB) model on the levels of knowledge, motivation, and behavioural skills for ITN use and IPTp uptake among pregnant women in a hospital in north-eastern Nigeria.,This was a randomized controlled parallel-group trial in which 372 antenatal care attendees were randomly assigned to either an intervention or control group after collecting baseline data using a structured questionnaire.,The intervention group received a 4-h health education on malaria, guided by a module developed based on the IMB theory, while the control group received health education on breastfeeding for a similar duration and by the same facilitator.,Follow-up data were subsequently collected at 2 months and at 4 months post-intervention using the same questionnaire.,The generalized linear mixed models analysis was used to determine the between-group and within-group effects of the intervention.,The intention-to-treat analysis was used after missing data had been replaced.,This was followed by a sensitivity analysis, where the analyses were repeated without replacing the missing values.,The intervention was significant in achieving a 12.75% (p < 0.001), 8.55% (p < 0.001), and 6.350% (p < 0.001) higher total knowledge, motivation, and behavioural skills scores respectively, for the intervention group over the control group.,The sensitivity analysis revealed no great differences in the effect sizes, even when missing data were not replaced.,The intervention module was effective in improving knowledge, motivation and behavioural skills.,It is as such recommended to be adopted and incorporated into the routine antenatal health education schedules.,It is also recommended that booster doses of the module be given say 2 months after the first dose to sustain levels of motivation and behavioural skills.,Trial registration Pan African Clinical Trial Registry, PACTR201610001823405.,Registered 26 October 2016, http://www.pactr.org,The online version of this article (10.1186/s12936-019-2676-3) contains supplementary material, which is available to authorized users.

Uganda is conducting a second mass LLIN distribution campaign and Katakwi district recently received LLINs as part of this activity.,This study was conducted to measure the success of the campaign in this setting, an area of high transmission, with the objectives to estimate LLIN ownership, access and use pre and post campaign implementation.,Two identical cross sectional surveys, based on the Malaria Indicator Survey methodology, were conducted in three sub-counties in this district (Kapujan, Magoro and Toroma), six months apart, one before and another after the mass distribution campaign.,Data on three main LLIN indicators including; household LLIN ownership, population with access to an LLIN and use were collected using a household and a women’s questionnaire identical to the Malaria Indicator Survey.,A total of 601 and 607 households were randomly selected in survey one and two respectively.,At baseline, 60.57% (56.53-64.50) of households owned at least one net for every two persons who stayed in the household the night before the survey which significantly increased to 70.35% (66.54-73.96) after the campaign (p = 0.001).,Similarly, the percentage of the household population with access to an LLIN significantly increased from 84.76% (82.99-86.52) to 91.57% (90.33-92.81), p = 0.001 and the percentage of household population that slept under an LLIN the night before the survey also significantly increased from 56.85% (55.06-58.82) to 81.72% (76.75-83.21), p = 0.001.,The LLIN mass campaign successfully achieved the national target of over eighty-five percent of the population with access to an LLIN in this setting, however, universal household coverage and use were fourteen and three percent points less than the national target respectively.,This is useful for malaria programs to consider during the planning of future campaigns by tailoring efforts around deficient areas like mechanisms to increase universal coverage and behavior change communication.

The objective of this study was to evaluate the influence of different infant feeding habits on the occurrence of malnutrition, Plasmodium falciparum parasitaemia and anaemia in children ≤5 years in the Mount Cameroon area.,A total of 1227 children ≤5 years of age were recruited in a descriptive cross-sectional study.,Socio demographic data and information on the different infant feeding habits was obtained by the use of semi-structured questionnaire.,Nutritional status was assessed by the use of anthropometric measurements.,Plasmodium was detected by light microscopy and haemoglobin was measured by use of an auto-haematology analyser.,Anaemia as well as its severity was classified based on WHO standards.,The associations between variables were assessed using logistic regression analysis.,The prevalence of exclusive breast feeding (EBF) was 22.6%, mixed feeding (MF) was 60.1% and those not breastfed (NBF) at all was 17.3%.,The prevalence of malnutrition, P. falciparum parasitaemia and anaemia was 32.6%, 30.4% and 77.3% respectively.,Children who had EBF had significantly lower (P <0.001) prevalence of malaria parasite (16.2%) than those NBF at all (61.3%).,The prevalence of anaemia was significantly higher (P <0.001) in children who had MF (80.5%) while, severe and moderate anaemia was highest in those NBF at all (6.6%, 67.1% respectively; P = 0.029) than their counterparts.,The significant predictors of anaemia were age group (P <0.001), marital status (P <0.001) and educational level of parent (P <0.001), that for malaria parasitaemia was infant feeding habit (MF: P< 0.001 and NBF: P <0.001) and malnutrition was age group (≤2 years: P <0.008 and 2.1-4.0 years: P = 0.028).,The infant feeding habit significantly influenced the occurrence of malaria parasite infection and not malnutrition and anaemia, hence EBF should be encouraged in malaria endemic zones.

In 2011, Cameroon and its health partners distributed over eight million free long-lasting insecticide treated nets (LLINs) in an effort to reduce the significant morbidity and mortality burden of malaria in the country.,A national communications campaign was launched in July 2011 to ensure that as the nets were delivered, they would be used consistently to close a net use gap: only 51.6% of adults and 63.4% of their children in households with at least one net were sleeping under nets before the distribution.,Even in households with at least one net for every two people, over 35% of adults were not sleeping under a net.,Malaria No More (MNM) adapted its signature NightWatch communications programme to fit within the coordinated “KO Palu” (Knock Out Malaria) national campaign.,This study evaluates the impact of KO Palu NightWatch activities (that is, the subset of KO Palu-branded communications that were funded by MNM’s NightWatch program) on bed net use.,Using national survey data collected at baseline (in March/April 2011, before the national LLIN distribution and KO Palu NightWatch launch) and post-intervention (March/April 2012), this study evaluates the impact of exposure to KO Palu NightWatch activities on last-night net use by Cameroonian adults and their children under five.,First, a plausible case for causality was established by comparing net use in 2011 and 2012 and measuring exposure to KO Palu NightWatch; next, a propensity score matching (PSM) model was used to estimate the impact of exposure on net use by simulating a randomized control trial; finally, the model was tested for sensitivity to unmeasured factors.,The PSM model estimated that among Cameroonians with at least one net in their household, exposure to KO Palu NightWatch activities was associated with a 6.6 percentage point increase in last-night net use among respondents (65.7% vs 59.1%, p < 0.05) and a 12.0 percentage point increase in last-night net use among respondents’ children under five (79.6% vs 67.6%, p < 0.025).,Sensitivity analysis suggests only a very small risk of bias from omitted factors influencing exposure and net use.,Extrapolating the results of the PSM model to the population of Cameroonians with access to at least one mosquito net, this analysis estimates that approximately 298,000 adults and over 221,000 of their children under five slept under a bed net because of the knowledge, motivation, and/or timely reminder provided by KO Palu NightWatch activities.,The programme cost less than $0.16 per adult reached, and less than $1.62 per additional person protected by a net.,The results suggest a strong role for mass media communication interventions in support of investments in malaria control commodities such as LLINs.

Since 2004, the national schistosomiasis control strategy in China has shifted from the morbidity control strategy (conventional strategy) to an integrated strategy (new strategy).,We investigated the effectiveness of the new strategy and compared it against the conventional strategy.,We retrieved from electronic databases the literature regarding the new strategy published from 2000 to 2017.,The effect of the new or conventional strategy on infection by Schistosoma japonicum of humans and snails (Oncomelania hupensis) was evaluated with pooled log relative risk (logRR).,A total of only eight eligible publications were included in the final meta-analysis.,The results showed that implementation of the new strategy reduced the infection risk by 3-4 times relative to the conventional strategy.,More specifically, the conventional strategy caused a reduction in both human (logRR = 0.56, 95% CI: 0.12-0.99) and snail infections (logRR = 0.34, 95% CI: −0.69-1.37), while the new strategy also significantly reduced both human (logRR = 1.89, 95% CI: 1.33-2.46) and snail infections (logRR = 1.61, 95% CI: 1.06-2.15).,In contrast to the conventional strategy, the new strategy appeared more effective to control both human (logRR difference = 1.32, 95% CI: 0.78-1.86) and snail infections (logRR difference = 1.53, 95% CI: 0.76-2.31).,Our data demonstrate that the new integrated strategy is highly effective to control the transmission of S. japonicum in China, and this strategy is recommended for schistosomiasis elimination in other affected regions across the world, with adaptation to local conditions.

The prevalence of schistosomiasis japonica has decreased significantly, and the responses changing from control to elimination in Jiangsu Province, P.R.,China.,How to estimate the change in prevalence of schistosomiasis using only serological data will be important and useful.,We collected serum samples from 2011 to 2015 to build a serum bank from Dantu County of Jiangsu, China.,Serum samples were detected by enzyme-linked immunosorbent assay (ELISA), the positive rate and optical density (OD) value were obtained.,The Bayesian model including the prior information of sensitivity and specificity of ELISA was established, and the estimated infection rates were obtained for different years, genders and age groups.,There was no significant difference in the mean OD between different years and genders, but there was a significant difference between the different age groups.,There were statistically significant differences in the positive rate for different years and age groups, but no significant difference at different genders.,The estimated infection rate for the five years was 1.288, 1.456, 1.032, 1.485 and 1.358%, respectively.,There was no significant difference between different years and between genders, but a significant difference between different age groups.,The risk of schistosomiasis transmission in this area still exists, and risk monitoring of schistosomiasis should be strengthened.,The online version of this article (10.1186/s40249-018-0443-2) contains supplementary material, which is available to authorized users.

We present three transmission models of visceral leishmaniasis (VL) in the Indian subcontinent (ISC) with structural differences regarding the disease stage that provides the main contribution to transmission, including models with a prominent role of asymptomatic infection, and fit them to recent case data from 8 endemic districts in Bihar, India.,Following a geographical cross-validation of the models, we compare their predictions for achieving the WHO VL elimination targets with ongoing treatment and vector control strategies.,All the transmission models suggest that the WHO elimination target (<1 new VL case per 10,000 capita per year at sub-district level) is likely to be met in Bihar, India, before or close to 2020 in sub-districts with a pre-control incidence of 10 VL cases per 10,000 people per year or less, when current intervention levels (60% coverage of indoor residual spraying (IRS) of insecticide and a delay of 40 days from onset of symptoms to treatment (OT)) are maintained, given the accuracy and generalizability of the existing data regarding incidence and IRS coverage.,In settings with a pre-control endemicity level of 5/10,000, increasing the effective IRS coverage from 60 to 80% is predicted to lead to elimination of VL 1-3 years earlier (depending on the particular model), and decreasing OT from 40 to 20 days to bring elimination forward by approximately 1 year.,However, in all instances the models suggest that L. donovani transmission will continue after 2020 and thus that surveillance and control measures need to remain in place until the longer-term aim of breaking transmission is achieved.

Visceral Leishmaniasis (VL) is a neglected vector-borne disease.,In India, it is transmitted to humans by Leishmania donovani-infected Phlebotomus argentipes sand flies.,In 2005, VL was targeted for elimination by the governments of India, Nepal and Bangladesh by 2015.,The elimination strategy consists of rapid case detection, treatment of VL cases and vector control using indoor residual spraying (IRS).,However, to achieve sustained elimination of VL, an appropriate post elimination surveillance programme should be designed, and crucial knowledge gaps in vector bionomics, human infection and transmission need to be addressed.,This review examines the outstanding knowledge gaps, specifically in the context of Bihar State, India.,The knowledge gaps in vector bionomics that will be of immediate benefit to current control operations include better estimates of human biting rates and natural infection rates of P. argentipes, with L. donovani, and how these vary spatially, temporally and in response to IRS.,The relative importance of indoor and outdoor transmission, and how P. argentipes disperse, are also unknown.,With respect to human transmission it is important to use a range of diagnostic tools to distinguish individuals in endemic communities into those who: 1) are to going to progress to clinical VL, 2) are immune/refractory to infection and 3) have had past exposure to sand flies.,It is crucial to keep in mind that close to elimination, and post-elimination, VL cases will become infrequent, so it is vital to define what the surveillance programme should target and how it should be designed to prevent resurgence.,Therefore, a better understanding of the transmission dynamics of VL, in particular of how rates of infection in humans and sand flies vary as functions of each other, is required to guide VL elimination efforts and ensure sustained elimination in the Indian subcontinent.,By collecting contemporary entomological and human data in the same geographical locations, more precise epidemiological models can be produced.,The suite of data collected can also be used to inform the national programme if supplementary vector control tools, in addition to IRS, are required to address the issues of people sleeping outside.

Rapid reprogramming of the macrophage activation phenotype is considered important in the defense against consecutive infection with diverse infectious agents.,However, in the setting of persistent, chronic infection the functional importance of macrophage-intrinsic adaptation to changing environments vs. recruitment of new macrophages remains unclear.,Here we show that resident peritoneal macrophages expanded by infection with the nematode Heligmosomoides polygyrus bakeri altered their activation phenotype in response to infection with Salmonella enterica ser.,Typhimurium in vitro and in vivo.,The nematode-expanded resident F4/80high macrophages efficiently upregulated bacterial induced effector molecules (e.g.,MHC-II, NOS2) similarly to newly recruited monocyte-derived macrophages.,Nonetheless, recruitment of blood monocyte-derived macrophages to Salmonella infection occurred with equal magnitude in co-infected animals and caused displacement of the nematode-expanded, tissue resident-derived macrophages from the peritoneal cavity.,Global gene expression analysis revealed that although nematode-expanded resident F4/80high macrophages made an anti-bacterial response, this was muted as compared to newly recruited F4/80low macrophages.,However, the F4/80high macrophages adopted unique functional characteristics that included enhanced neutrophil-stimulating chemokine production.,Thus, our data provide important evidence that plastic adaptation of MΦ activation does occur in vivo, but that cellular plasticity is outweighed by functional capabilities specific to the tissue origin of the cell.

Interactions of the Th2 cytokine IL-33 with its receptor ST2 lead to amplified Type 2 immune responses.,As Type 2 immune responses are known to mediate protection against helminth infections we hypothesized that the lack of ST2 would lead to an increased susceptibility to filarial infections.,ST2 deficient and immunocompetent BALB/c mice were infected with the filarial nematode Litomosoides sigmodontis.,At different time points after infection mice were analyzed for worm burden and their immune responses were examined within the thoracic cavity, the site of infection, and systemically using spleen cells and plasma.,Absence of ST2 led to significantly increased levels of peripheral blood microfilariae, the filarial progeny, whereas L. sigmodontis adult worm burden was not affected.,Development of local and systemic Type 2 immune responses were not impaired in ST2 deficient mice after the onset of microfilaremia, but L. sigmodontis infected ST2-ko mice had significantly reduced total numbers of cells within the thoracic cavity and spleen compared to infected immunocompetent controls.,Pronounced microfilaremia in ST2-ko mice did not result from an increased microfilariae release by adult female worms, but an impaired splenic clearance of microfilariae.,Our findings suggest that the absence of ST2 does not impair the establishment of adult L. sigmodontis worms, but is important for the splenic clearance of microfilariae from peripheral blood.,Thus, ST2 interactions may be important for therapies that intend to block the transmission of filarial disease.

Despite the highest global burden of malaria, information on bionomics and insecticide resistance status of malaria vectors is grossly lacking in the densely populated Sahelo-Sudanian region of Nigeria.,To support evidence-based vector control we characterised transmission and resistance profiles of Anopheles coluzzii populations from three sites in northern Nigeria.,High sporozoite infection (~19.51%) was found in the An. coluzzii populations.,A high pyrethroid resistance was observed with only 1% mortality against deltamethrin, a high LD50 (96.57 µg/ml), and a high LT50 (170.27 min, resistance ratio of ~51 compared with the fully susceptible Ngoussou colony).,Moderate carbamate resistance was observed.,Synergist bioassays significantly recovered deltamethrin susceptibility implicating CYP450s (mortality = 85%, χ2 = 134.04, p < 0.0001) and esterases (mortality = 56%, χ2 = 47.31, p < 0.0001).,Reduced bed net efficacy was also observed, with mortalities on exposure to the roof of PermaNet3.0 (PBO + deltamethrin) more than 22 times compared to the side panel (deltamethrin).,TaqMan genotyping revealed a high frequency of 1014F kdr mutation (82%) with significant difference in genotype distribution associated with permethrin resistance [OR = 4.69 (CI:1.53-14.35, χ2 = 8.22 p = 0.004].,Sequencing of exons 18-21 of the VGSC led to detection of two additional nonsynonymous mutations, Ile10148Asn and Ser1156Gly.,These findings highlight the threats posed by the highly resistant An. coluzzii to malaria control in Nigeria.

Constant and extensive use of chemical insecticides has created a selection pressure and favored resistance development in many insect species worldwide.,One of the most important pyrethroid resistance mechanisms is classified as target site insensitivity, due to conformational changes in the target site that impair a proper binding of the insecticide molecule.,The voltage-gated sodium channel (NaV) is the target of pyrethroids and DDT insecticides, used to control insects of medical, agricultural and veterinary importance, such as anophelines.,It has been reported that the presence of a few non-silent point mutations in the NaV gene are associated with pyrethroid resistance, termed as ‘kdr’ (knockdown resistance) for preventing the knockdown effect of these insecticides.,The presence of these mutations, as well as their effects, has been thoroughly studied in Anopheles mosquitoes.,So far, kdr mutations have already been detected in at least 13 species (Anopheles gambiae, Anopheles arabiensis, Anopheles sinensis, Anopheles stephensi, Anopheles subpictus, Anopheles sacharovi, Anopheles culicifacies, Anopheles sundaicus, Anopheles aconitus, Anopheles vagus, Anopheles paraliae, Anopheles peditaeniatus and Anopheles albimanus) from populations of African, Asian and, more recently, American continents.,Seven mutational variants (L1014F, L1014S, L1014C, L1014W, N1013S, N1575Y and V1010L) were described, with the highest prevalence of L1014F, which occurs at the 1014 site in NaV IIS6 domain.,The increase of frequency and distribution of kdr mutations clearly shows the importance of this mechanism in the process of pyrethroid resistance.,In this sense, several species-specific and highly sensitive methods have been designed in order to genotype individual mosquitoes for kdr in large scale, which may serve as important tolls for monitoring the dynamics of pyrethroid resistance in natural populations.,We also briefly discuss investigations concerning the course of Plasmodium infection in kdr individuals.,Considering the limitation of insecticides available for employment in public health campaigns and the absence of a vaccine able to brake the life cycle of the malaria parasites, the use of pyrethroids is likely to remain as the main strategy against mosquitoes by either indoor residual spraying (IR) and insecticide treated nets (ITN).,Therefore, monitoring insecticide resistance programs is a crucial need in malaria endemic countries.,The online version of this article (doi:10.1186/1756-3305-7-450) contains supplementary material, which is available to authorized users.

The complicated interactions between Leishmania and the host antigen-presenting cells (APCs) have fundamental effects on the final outcome of the disease.,Two major APCs, macrophages and dendritic cells (DCs), play critical roles in mediating resistance and susceptibility during Leishmania infection.,Macrophages are the primary resident cell for Leishmania: they phagocytose and permit parasite proliferation.,However, these cells are also the major effector cells to eliminate infection.,The effective clearance of parasites by macrophages depends on activation of appropriate immune response, which is usually initiated by DCs.,Here, we review the early interaction of APCs with Leishmania parasites and how these interactions profoundly impact on the ensuing adaptive immune response.,We also discuss how the current knowledge will allow further refinement of our understanding of the interplay between Leishmania and its hosts that leads to resistance or susceptibility.

Leishmania transmission occurs in the presence of insect saliva.,Immunity to Phlebotomus papatasi or Lutzomyia longipalpis saliva or salivary components confers protection against an infection by Leishmania in the presence of the homologous saliva.,However, immunization with Lutzomyia intermedia saliva did not protect mice against Leishmania braziliensis plus Lu. intermedia saliva.,In the present study, we have studied whether the immunization with Lu. longipalpis saliva or a DNA plasmid coding for LJM19 salivary protein would be protective against L. braziliensis infection in the presence of Lu. intermedia saliva, the natural vector for L. braziliensis.,Immunization with Lu. longipalpis saliva or with LJM19 DNA plasmid induced a Delayed-Type Hypersensitivity (DTH) response against Lu. longipalpis as well as against a Lu. intermedia saliva challenge.,Immunized and unimmunized control hamsters were then intradermally infected in the ears with L. braziliensis in the presence of Lu. longipalpis or Lu. intermedia saliva.,Animals immunized with Lu. longipalpis saliva exhibited smaller lesion sizes as well as reduced disease burdens both at lesion site and in the draining lymph nodes.,These alterations were associated with a significant decrease in the expression levels of IL-10 and TGF-β.,Animals immunized with LJM19 DNA plasmid presented similar findings in protection and immune response and additionally increased IFN-γ expression.,Immunization with Lu. longipalpis saliva or with a DNA plasmid coding LJM19 salivary protein induced protection in hamsters challenged with L. braziliensis plus Lu. intermedia saliva.,These findings point out an important role of immune response against saliva components, suggesting the possibility to develop a vaccine using a single component of Lu. longipalpis saliva to generate protection against different species of Leishmania, even those transmitted by a different vector.

Indoor residual spraying (IRS) is known to reduce malaria transmission.,In northern Uganda, a high endemic area, IRS has been implemented since 2006.,Limited data however, exists on the effect of IRS on the malaria burden.,This study sought to assess the effect of IRS on malaria morbidity in the high intensity area of northern Uganda.,Retrospective routine data from ten health facilities in three districts which had received at least five rounds of IRS in northern Uganda was analysed.,The primary outcome of interest was malaria morbidity, measured by the slide positivity rate (SPR).,Descriptive statistics were used to describe the malaria morbidity stratified by age and sex.,The average change in the malaria morbidity, measured by the SPR was assessed according to time, measured as calendar months.,A fixed-effects linear regression model was used which included a polynomial function of time and controlled for malaria seasonality and variations between districts/facilities.,The total out-patient department attendance in the ten health facilities for the study period was 2,779,246, of which 736,034 (26.5%) malaria cases were diagnosed with 374,826 (50.9%) cases of under 5 years and an overall SPR of 37.5%.,The percentage point (p.p.) changes in SPR according to time measured as calendar months following IRS, revealed a decreasing trend in malaria morbidity in the first 3 months following each round of IRS.,The highest percentage point decrease in the SPR was observed in the second month following IRS (9.5 p.p., CI −17.85 to −1.16, p = 0.026), among patients above 5 years.,The SPR decline however waned by the fourth month following IRS, with an increase in the SPR of 8.4 p.p. at district level by the sixth month, p = 0.510.,The study results show that IRS was associated with a significant reduction in malaria morbidity in northern Uganda in the first 3 months following IRS.,The malaria reduction however waned by the fourth month following IRS.,The online version of this article (doi:10.1186/s12936-016-1652-4) contains supplementary material, which is available to authorized users.

Malaria is still a major public health problem in Brazil, with approximately 306 000 registered cases in 2009, but it is estimated that in the early 1940s, around six million cases of malaria occurred each year.,As a result of the fight against the disease, the number of malaria cases decreased over the years and the smallest numbers of cases to-date were recorded in the 1960s.,From the mid-1960s onwards, Brazil underwent a rapid and disorganized settlement process in the Amazon and this migratory movement led to a progressive increase in the number of reported cases.,Although the main mosquito vector (Anopheles darlingi) is present in about 80% of the country, currently the incidence of malaria in Brazil is almost exclusively (99,8% of the cases) restricted to the region of the Amazon Basin, where a number of combined factors favors disease transmission and impair the use of standard control procedures.,Plasmodium vivax accounts for 83,7% of registered cases, while Plasmodium falciparum is responsible for 16,3% and Plasmodium malariae is seldom observed.,Although vivax malaria is thought to cause little mortality, compared to falciparum malaria, it accounts for much of the morbidity and for huge burdens on the prosperity of endemic communities.,However, in the last few years a pattern of unusual clinical complications with fatal cases associated with P. vivax have been reported in Brazil and this is a matter of concern for Brazilian malariologists.,In addition, the emergence of P. vivax strains resistant to chloroquine in some reports needs to be further investigated.,In contrast, asymptomatic infection by P. falciparum and P. vivax has been detected in epidemiological studies in the states of Rondonia and Amazonas, indicating probably a pattern of clinical immunity in both autochthonous and migrant populations.,Seropidemiological studies investigating the type of immune responses elicited in naturally-exposed populations to several malaria vaccine candidates in Brazilian populations have also been providing important information on whether immune responses specific to these antigens are generated in natural infections and their immunogenic potential as vaccine candidates.,The present difficulties in reducing economic and social risk factors that determine the incidence of malaria in the Amazon Region render impracticable its elimination in the region.,As a result, a malaria-integrated control effort - as a joint action on the part of the government and the population - directed towards the elimination or reduction of the risks of death or illness, is the direction adopted by the Brazilian government in the fight against the disease.

Parasites from the genus Plasmodium, the aetiological agent of malaria in humans, can also infect non-human primates (NHP), increasing the potential risk of zoonotic transmission with its associated global public health concerns.,In Colombia, there are no recent studies on Plasmodium spp. infecting free-ranging NHP.,Thus, this study aimed to determine the diversity of Plasmodium species circulating in fragmented forests in central Colombia, both in Anopheles mosquitoes and in the four sympatric NHP in the region (Ateles hybridus, Cebus versicolor, Alouatta seniculus and Aotus griseimembra), in order to evaluate the risk of infection to humans associated with the presence of sylvatic hosts and vectors infected with Plasmodium spp.,Overall, there were collected 166 fecal samples and 25 blood samples from NHP, and 442 individuals of Anopheles spp.,DNA extraction, nested PCR using mitochondrial (cox3 gene) and ribosomal (18S rDNA) primers, electrophoresis and sequencing were conducted in order to identify Plasmodium spp. from the samples.,Plasmodium falciparum was detected in two fecal samples of Alouatta seniculus, while Plasmodium vivax/simium infected Ateles hybridus, Cebus versicolor and Alouatta seniculus.,Co-infections with P. vivax/simium and Plasmodium malariae/brasilianum were found in three individuals.,The highest prevalence from blood samples was found for Plasmodium malariae/brasilianum in two Alouatta seniculus while Plasmodium vivax/simium was most prevalent in fecal samples, infecting four individuals of Alouatta seniculus.,Seven Anopheles species were identified in the study site: Anopheles (Anopheles) punctimacula, Anopheles (An.) malefactor, Anopheles (Nyssorhynchus) oswaldoi, Anopheles (Nys.) triannulatus, Anopheles (An.) neomaculipalpus, Anopheles (Nys.) braziliensis and Anopheles (Nys.) nuneztovari.,Infection with P. vivax/simium was found in An. nuneztovari, An. neomaculipalpus, and An. triannulatus.,Furthermore, An. oswaldoi and An. triannulatus were found infected with P. malariae/brasilianum.,The effect of fragmentation and distance to the nearest town measured in five forests with different degrees of fragmentation was not statistically significant on the prevalence of Plasmodium in NHP, but forest fragmentation did have an effect on the Minimum Infection Rate (MIR) in Anopheles mosquitoes.,The presence of Plasmodium spp. in NHP and Anopheles spp. in fragmented forests in Colombia has important epidemiological implications in the human-NHP interface and the associated risk of malaria transmission.

Botswana is one of eight SADC countries targeting malaria elimination by 2018.,Through spirited upscaling of control activities and passive surveillance, significant reductions in case incidence of Plasmodium falciparum (0.96 - 0.01) was achieved between 2008 and 2012.,As part of the elimination campaign, active detection of asymptomatic Plasmodium species by a highly sensitive method was deemed necessary.,This study was carried out to determine asymptomatic Plasmodium species carriage by nested PCR in the country, in 2012.,A cross-sectional study involving 3924 apparently healthy participants were screened for Plasmodium species in 14 districts (5 endemic: Okavango, Ngami, Tutume, Boteti and Bobirwa; and 9 epidemic: North East, Francistown, Serowe-Palapye, Ghanzi, Kweneng West, Kweneng East, Kgatleng, South East, and Good Hope).,Venous blood was taken from each participant for a nested PCR detection of Plasmodium species.,The parasite rates of asymptomatic Plasmodium species detected were as follows: Plasmodium falciparum, 0.16 %; Plasmodium vivax, 4.66 %; Plasmodium malariae, (Pm) 0.16 %; Plasmodium ovale, 0 %, mixed infections (P. falciparum and P. vivax), 0.055 %; and (P. vivax and P. malariae), 0.027 %, (total: 5.062 %).,The high proportion of asymptomatic reservoir of P. vivax was clustered in the East, South Eastern and Central districts of the country.,There appeared to be a correlation between the occurrence of P. malariae infection with P. vivax infection, with the former only occurring in districts that had substantial P. vivax circulation.,The median age among 2-12 year olds for P. vivax infection was 5 years (Mean 5.13 years, interquartile range 3-7 years).,The odds of being infected with P. vivax decreased by 7 % for each year increase in age (OR 0.93, 95 % CI 0.87-1.00, p = 0.056).,We have confirmed low parasite rate of asymptomatic Plasmodium species in Botswana, with the exception of P.vivax which was unexpectedly high.,This has implication for the elimination campaign so a follow up study is warranted to inform decisions on new strategies that take this evidence into account in the elimination campaign.

In spite of low peripheral blood parasitemia, vivax malaria causes severe disease.,This conundrum finds an explanation from reports suggesting that the spleen is a place for parasite sequestration.,We performed a global transcriptional analysis of parasites that grew in the presence or absence of the spleen in a nonhuman primate model.,We identified 67 spleen-dependent genes, including multigene variant families, and functionally demonstrated specific adherence to human spleen fibroblasts by a member of such families.,Moreover, we further demonstrated that spleen-dependent Plasmodium vivax genes code for immunogenic proteins during natural infections.,Our results indicate that this organ plays an important function in P. vivax malaria and call for deeper studies of the role of spleen in P. vivax infections.,Plasmodium vivax, the most widely distributed human malaria parasite, causes severe clinical syndromes despite low peripheral blood parasitemia.,This conundrum is further complicated as cytoadherence in the microvasculature is still a matter of investigations.,Previous reports in Plasmodium knowlesi, another parasite species shown to infect humans, demonstrated that variant genes involved in cytoadherence were dependent on the spleen for their expression.,Hence, using a global transcriptional analysis of parasites obtained from spleen-intact and splenectomized monkeys, we identified 67 P. vivax genes whose expression was spleen dependent.,To determine their role in cytoadherence, two Plasmodium falciparum transgenic lines expressing two variant proteins pertaining to VIR and Pv-FAM-D multigene families were used.,Cytoadherence assays demonstrated specific binding to human spleen but not lung fibroblasts of the transgenic line expressing the VIR14 protein.,To gain more insights, we expressed five P. vivax spleen-dependent genes as recombinant proteins, including members of three different multigene families (VIR, Pv-FAM-A, Pv-FAM-D), one membrane transporter (SECY), and one hypothetical protein (HYP1), and determined their immunogenicity and association with clinical protection in a prospective study of 383 children in Papua New Guinea.,Results demonstrated that spleen-dependent antigens are immunogenic in natural infections and that antibodies to HYP1 are associated with clinical protection.,These results suggest that the spleen plays a major role in expression of parasite proteins involved in cytoadherence and can reveal antigens associated with clinical protection, thus prompting a paradigm shift in P. vivax biology toward deeper studies of the spleen during infections.

Antigenic diversity has posed a critical barrier to vaccine development against the pathogenic blood-stage infection of the human malaria parasite Plasmodium falciparum.,To date, only strain-specific protection has been reported by trials of such vaccines in nonhuman primates.,We recently showed that P. falciparum reticulocyte binding protein homolog 5 (PfRH5), a merozoite adhesin required for erythrocyte invasion, is highly susceptible to vaccine-inducible strain-transcending parasite-neutralizing antibody.,In vivo efficacy of PfRH5-based vaccines has not previously been evaluated.,Here, we demonstrate that PfRH5-based vaccines can protect Aotus monkeys against a virulent vaccine-heterologous P. falciparum challenge and show that such protection can be achieved by a human-compatible vaccine formulation.,Protection was associated with anti-PfRH5 antibody concentration and in vitro parasite-neutralizing activity, supporting the use of this in vitro assay to predict the in vivo efficacy of future vaccine candidates.,These data suggest that PfRH5-based vaccines have potential to achieve strain-transcending efficacy in humans.,•Vaccines based on the P. falciparum merozoite antigen PfRH5 were tested in Aotus monkeys•PfRH5-based vaccines afforded protection against heterologous strains of P. falciparum•Protection correlated with anti-PfRH5 IgG concentration and in vivo neutralization,Vaccines based on the P. falciparum merozoite antigen PfRH5 were tested in Aotus monkeys,PfRH5-based vaccines afforded protection against heterologous strains of P. falciparum,Protection correlated with anti-PfRH5 IgG concentration and in vivo neutralization,Antigenic diversity has hindered development of vaccines against the pathogenic blood-stage of Plasmodium falciparum.,Douglas et al. demonstrate that human-compatible PfRH5-based vaccines can protect Aotus monkeys against vaccine-heterologous P. falciparum challenge.,Protection correlated with anti-PfRH5 antibody concentration and parasite-neutralizing activity.,PfRH5-based vaccines have potential to achieve strain-transcending efficacy in humans.

Many studies have reported a relationship between climate factors and malaria.,However, results were inconsistent across the areas.,We examined associations between climate factors and malaria in two geographically different areas: lowland (lakeside area) and highland in Western Kenya.,Associations between climate factors (rainfall, land surface temperature (LST), and lake water level (LWL)) and monthly malaria cases from 2000 to 2013 in six hospitals (two in lowland and four in highland) were analyzed using time-series regression analysis with a distributed lag nonlinear model (DLNM) and multivariate meta-analysis.,We found positive rainfall-malaria overall associations in lowland with a peak at 120 mm of monthly rainfall with a relative risk (RR) of 7.32 (95% CI: 2.74, 19.56) (reference 0 mm), whereas similar associations were not found in highland.,Positive associations were observed at lags of 2 to 4 months at rainfall around 100-200 mm in both lowland and highland.,The RRs at 150 mm rainfall were 1.42 (95% CI: 1.18, 1.71) in lowland and 1.20 (95% CI: 1.07, 1.33) in highland (at a lag of 3 months).,LST and LWL did not show significant association with malaria.,The results suggest that geographical characteristics can influence climate-malaria relationships.

Malaria surveillance and interventions in endemic countries often target young children at highest risk of malaria morbidity and mortality.,We aimed to determine whether school-age children and adults not captured in surveillance serve as a reservoir for malaria infection and may contribute to malaria transmission.,Cross-sectional surveys were conducted in one rainy and one dry season in southern Malawi.,Demographic and health information was collected for all household members.,Blood samples were obtained for microscopic and PCR identification of Plasmodium falciparum.,Among 5796 individuals aged greater than six months, PCR prevalence of malaria infection was 5%, 10%, and 20% in dry, and 9%, 15%, and 32% in rainy seasons in Blantyre, Thyolo, and Chikhwawa, respectively.,Over 88% of those infected were asymptomatic.,Participants aged 6-15 years were at higher risk of infection (OR=4.8; 95%CI, 4.0-5.8) and asymptomatic infection (OR=4.2; 95%CI, 2.7-6.6) than younger children in all settings.,School-age children used bednets less frequently than other age groups.,Compared to young children, school-age children were brought less often for treatment and more often to unreliable treatment sources.,Conclusion: School-age children represent an underappreciated reservoir of malaria infection and have less exposure to antimalarial interventions.,Malaria control and elimination strategies may need to expand to include this age group.

Areas with dynamic population movements are likely to be associated with higher levels of drug-resistant malaria.,Myanmar Artemisinin Resistance Containment (MARC) Project has been launching since 2012.,One of its components includes enhancing strategic approaches for mobile/migrant populations.,We aimed to ascertain the estimated population of mobile migrant workers and their families in terms of stability in work setting in townships classified as tier II (areas with significant inflows of people from areas with credible evidence of artemisinin resistance) for Artemisinin resistance; to identify knowledge, attitudes and practices related to prevention and control of malaria and to recommend cost-effective strategies in planning for prevention and control of malaria.,A prospective cross-sectional study conducted between June to December 2013 that covered 1,899 migrant groups from 16 tier II townships of Bago Region, and Kayin and Kayah States.,Trained data collectors used a pre-tested and subsequently modified questionnaire and interviewed 2,381 respondents.,Data of migrant groups were analyzed and compared by category depending upon the stability of their work setting.,The estimated population of the 1,899 migrant groups categorized into three on the nature of their work setting was 56,030.,Bago region was the commonest reported source of origin of migrant groups as well as their transit.,Malaria volunteers were mostly within the reach of category 1 migrant groups (43/66, 65.2 %).,Less stable migrant groups in category 3 had limited access to malaria information (14.7 %) and malaria care providers (22.1 %), low level of awareness and use of long-lasting insecticide-treated nets (46.6 and 38.8 %).,Also, they had poor knowledge on malaria prevention on confirming suspected malaria and on using artemisinin combined therapy (ACT).,Within two weeks prior to the survey, only 16.5 % of respondents in all categories combined reported acute undifferentiated fever.,Mobility dynamics of migrant groups was complex and increased their vulnerability to malaria.,This phenomenon was accentuated in less stable areas.,Even though migrant workers were familiar with rapid diagnostic tests for malaria, ACT still needed wide recognition to improve practices supportive of MARC including the use of appropriate personal protection.,High mobility calls for re-designation of tier II townships to optimize ACT resistance containment.,The online version of this article (doi:10.1186/s12889-015-2241-0) contains supplementary material, which is available to authorized users.

Mobile populations are at a high risk of malaria infection and suspected to carry and spread resistant parasites.,The Myanmar National Malaria Control Programme focuses on preventive interventions and vector control measures for the temporary mobile/migrant workers in Myanmar Artemisinin Resistance Containment Zones.,A prospective cross-sectional study was conducted in 2012 in Kawthaung and Bokepyin townships of Tanintharyi Region, Myanmar, covering 192 mobile/migrant aggregates.,The objectives were to identify the spatial distribution of the mobile/migrant populations, and to assess knowledge, attitudes, perceptions, and practices concerning malaria prevention and control, and their preferred methods of interventions.,The structure of the192 migrant aggregates was investigated using a migrant mapping tool.,Individual and household information was collected by structured interviews of 408 respondents from 39 aggregates, supplemented by 12 in-depth interviews of health care providers, authorities, volunteers, and employers.,Data were analyzed by triangulating quantitative and qualitative data.,The primary reasons for the limitation in access to formal health services for suspected malaria within 24 hours were identified to be scattered distribution of migrant aggregates, variable working hours and the lack of transportation.,Only 19.6% of respondents reported working at night from dusk to dawn.,Among study populations, 73% reported a perceived risk of contracting malaria and 60% reported to know how to confirm a suspected case of malaria.,Moreover, only 15% was able to cite correct antimalarial drugs, and less than 10% believed that non-compliance with antimalarial treatment may be related to the risk of drug resistance.,About 50% of study population reported to seeking health care from the public sector, and to sleep under ITNs/LLINs the night before the survey.,There was a gap in willingness to buy ITNs/LLINs and affordability (88.5% vs.,60.2%) which may affect their sustained and consistent use.,Only 32.4% across all aggregates realized the importance of community participation in effective malaria prevention and control.,Community-based innovative approaches through strong collaboration and coordination of multi-stakeholders are desirable for relaying information on ITNs/LLINs, rapid diagnostic test, and artemisinin combination therapy and drug resistance successfully across the social and economic diversity of mobile/migrant aggregates in Myanmar.

Mosquito-borne diseases, such as malaria, dengue and chikungunya, cause morbidity and mortality around the world.,Recent advances in gene drives have produced control methods that could theoretically modify all populations of a disease vector, from a single release, making whole species less able to transmit pathogens.,This ability has caused both excitement, at the prospect of global eradication of mosquito-borne diseases, and concern around safeguards.,Drive mechanisms that require individuals to be released at high frequency before genes will spread can therefore be desirable as they are potentially localised and reversible.,These include underdominance-based strategies and use of the reproductive parasite Wolbachia.,Here, we review recent advances in practical applications and mathematical analyses of these threshold-dependent gene drives with a focus on implementation in Aedes aegypti, highlighting their mechanisms and the role of fitness costs on introduction frequencies.,Drawing on the parallels between these systems offers useful insights into practical, controlled application of localised drives, and allows us to assess the requirements needed for gene drive reversal.

Malaria (Plasmodium spp.) kills nearly one million people annually and this number will likely increase as drug and insecticide resistance reduces the effectiveness of current control strategies.,The most important human malaria parasite, Plasmodium falciparum, undergoes a complex developmental cycle in the mosquito that takes approximately two weeks and begins with the invasion of the mosquito midgut.,Here, we demonstrate that increased Akt signaling in the mosquito midgut disrupts parasite development and concurrently reduces the duration that mosquitoes are infective to humans.,Specifically, we found that increased Akt signaling in the midgut of heterozygous Anopheles stephensi reduced the number of infected mosquitoes by 60-99%.,Of those mosquitoes that were infected, we observed a 75-99% reduction in parasite load.,In homozygous mosquitoes with increased Akt signaling parasite infection was completely blocked.,The increase in midgut-specific Akt signaling also led to an 18-20% reduction in the average mosquito lifespan.,Thus, activation of Akt signaling reduced the number of infected mosquitoes, the number of malaria parasites per infected mosquito, and the duration of mosquito infectivity.

Malaria still kills hundreds of thousands of children each year.,Malaria vaccine development is complicated by high levels of parasite genetic diversity, which makes single target vaccines vulnerable to the development of variant-specific immunity.,To overcome this hurdle, we systematically screened a panel of 29 blood-stage antigens from the most deadly human malaria parasite, Plasmodium falciparum.,We identified several targets that were able to inhibit erythrocyte invasion in two genetically diverse strains.,Testing these targets in combination identified several pairs that blocked invasion more effectively in combination than in isolation.,Video microscopy and studies of natural immune responses to malaria in patients suggest that targeting multiple steps in invasion is more likely to produce a synergistic vaccine response.,A highly effective vaccine would be a valuable weapon in the drive toward malaria elimination.,No such vaccine currently exists, and only a handful of the hundreds of potential candidates in the parasite genome have been evaluated.,In this study, we systematically evaluated 29 antigens likely to be involved in erythrocyte invasion, an essential developmental stage during which the malaria parasite is vulnerable to antibody-mediated inhibition.,Testing antigens alone and in combination identified several strain-transcending targets that had synergistic combinatorial effects in vitro, while studies in an endemic population revealed that combinations of the same antigens were associated with protection from febrile malaria.,Video microscopy established that the most effective combinations targeted multiple discrete stages of invasion, suggesting a mechanistic explanation for synergy.,Overall, this study both identifies specific antigen combinations for high-priority clinical testing and establishes a generalizable approach that is more likely to produce effective vaccines.

Preventing malaria infection through vaccination requires preventing every sporozoite inoculated by mosquito bite: a major challenge for Plasmodium falciparum.,Plasmodium vivax sporozoites consist of tachysporozoites causing primary infection and bradysporozoites leading to relapses.,We hypothesise that a candidate P. vivax vaccine with low efficacy against primary infection may substantially reduce transmission by preventing relapses.

As malaria transmission declines, understanding the differential impact of intensified control on Plasmodium falciparum relative to Plasmodium vivax and identifying key drivers of ongoing transmission is essential to guide future interventions.,Three longitudinal child cohorts were conducted in Papua New Guinea before (2006/2007), during (2008) and after scale-up of control interventions (2013).,In each cohort, children aged 1-5 years were actively monitored for infection and illness.,Incidence of malaria episodes, molecular force of blood-stage infections (molFOB) and population-averaged prevalence of infections were compared across the cohorts to investigate the impact of intensified control in young children and the key risk factors for malaria infection and illness in 2013.,Between 2006 and 2008, P. falciparum infection prevalence, molFOB, and clinical malaria episodes reduced by 47%, 59% and 69%, respectively, and a further 49%, 29% and 75% from 2008 to 2013 (prevalence 41.6% to 22.1% to 11.2%; molFOB: 3.4 to 1.4 to 1.0 clones/child/year; clinical episodes incidence rate (IR) 2.6 to 0.8 to IR 0.2 episodes/child/year).,P. vivax clinical episodes declined at rates comparable to P. falciparum between 2006, 2008 and 2013 (IR 2.5 to 1.1 to 0.2), while P. vivax molFOB (2006, 9.8; 2008, 12.1) and prevalence (2006, 59.6%; 2008, 65.0%) remained high in 2008.,However, in 2013, P. vivax molFOB (1.2) and prevalence (19.7%) had also substantially declined.,In 2013, 89% of P. falciparum and 93% of P. vivax infections were asymptomatic, 62% and 47%, respectively, were sub-microscopic.,Area of residence was the major determinant of malaria infection and illness.,Intensified vector control and routine case management had a differential impact on rates of P. falciparum and P. vivax infections but not clinical malaria episodes in young children.,This suggests comparable reductions in new mosquito-derived infections but a delayed impact on P. vivax relapsing infections due to a previously acquired reservoir of hypnozoites.,This demonstrates the need to strengthen implementation of P. vivax radical cure to maximise impact of control in co-endemic areas.,The high heterogeneity of malaria in 2013 highlights the importance of surveillance and targeted interventions to accelerate towards elimination.

The delivery of safe and effective radical cure for Plasmodium vivax is one of the greatest challenges for achieving malaria elimination from the Asia-Pacific by 2030.,During the annual meeting of the Asia Pacific Malaria Elimination Network Vivax Working Group in October 2016, a round table discussion was held to discuss the programmatic issues hindering the widespread use of primaquine (PQ) radical cure.,Participants included 73 representatives from 16 partner countries and 33 institutional partners and other research institutes.,In this meeting report, the key discussion points are presented and grouped into five themes: (i) current barriers for glucose-6-phosphate deficiency (G6PD) testing prior to PQ radical cure, (ii) necessary properties of G6PD tests for wide scale deployment, (iii) the promotion of G6PD testing, (iv) improving adherence to PQ regimens and (v) the challenges for future tafenoquine (TQ) roll out.,Robust point of care (PoC) G6PD tests are needed, which are suitable and cost-effective for clinical settings with limited infrastructure.,An affordable and competitive test price is needed, accompanied by sustainable funding for the product with appropriate training of healthcare staff, and robust quality control and assurance processes.,In the absence of quantitative PoC G6PD tests, G6PD status can be gauged with qualitative diagnostics, however none of the available tests is currently sensitive enough to guide TQ treatment.,TQ introduction will require overcoming additional challenges including the management of severely and intermediately G6PD deficient individuals.,Robust strategies are needed to ensure that effective treatment practices can be deployed widely, and these should ensure that the caveats are outweighed by the benefits of radical cure for both the patients and the community.,Widespread access to quality controlled G6PD testing will be critical.

In March 2020, the government of Uganda implemented a strict lockdown policy in response to the COVID-19 pandemic.,Interrupted time series analysis (ITSA) was performed to assess whether major changes in outpatient attendance, malaria burden, and case management occurred after the onset of the COVID-19 epidemic in rural Uganda.,Individual level data from all outpatient visits collected from April 2017 to March 2021 at 17 facilities were analysed.,Outcomes included total outpatient visits, malaria cases, non-malarial visits, proportion of patients with suspected malaria, proportion of patients tested using rapid diagnostic tests (RDTs), and proportion of malaria cases prescribed artemether-lumefantrine (AL).,Poisson regression with generalized estimating equations and fractional regression was used to model count and proportion outcomes, respectively.,Pre-COVID trends (April 2017-March 2020) were used to predict the’expected’ trend in the absence of COVID-19 introduction.,Effects of COVID-19 were estimated over two six-month COVID-19 time periods (April 2020-September 2020 and October 2020-March 2021) by dividing observed values by expected values, and expressed as ratios.,A total of 1,442,737 outpatient visits were recorded.,Malaria was suspected in 55.3% of visits and 98.8% of these had a malaria diagnostic test performed.,ITSA showed no differences between observed and expected total outpatient visits, malaria cases, non-malarial visits, or proportion of visits with suspected malaria after COVID-19 onset.,However, in the second six months of the COVID-19 time period, there was a smaller mean proportion of patients tested with RDTs compared to expected (relative prevalence ratio (RPR) = 0.87, CI (0.78-0.97)) and a smaller mean proportion of malaria cases prescribed AL (RPR = 0.94, CI (0.90-0.99)).,In the first year after the COVID-19 pandemic arrived in Uganda, there were no major effects on malaria disease burden and indicators of case management at these 17 rural health facilities, except for a modest decrease in the proportion of RDTs used for malaria diagnosis and the mean proportion of malaria cases prescribed AL in the second half of the COVID-19 pandemic year.,Continued surveillance will be essential to monitor for changes in trends in malaria indicators so that Uganda can quickly and flexibly respond to challenges imposed by COVID-19.,The online version contains supplementary material available at 10.1186/s12936-021-04018-0.

Malaria has declined in recent years in countries of the American continents.,In 2011, 12 of 21 endemic countries had already met their 2015 Millennium Development Goal.,However, this declining trend has not been adequately evaluated.,An analysis of the number of cases per 100,000 people (annual parasite index [API]) and the percentage of positive blood slides (slide positivity rate [SPR]) during the period of 1959-2011 in 21 endemic countries was done using the joinpoint regression methodology.,During 1960-1979, API and SPR increased significantly and peaked in the 1980s.,Since the 1990s, there have been significant declining trends in both API and SPR.,Additionally, both Plasmodium vivax and P. falciparum species-specific incidence have declined.,With the exception of two countries, such a collectively declining malaria trend was not observed in previous decades.,This presents a unique opportunity for the Americas to seriously consider malaria elimination as a final goal.

Achieving a malaria-free world presents exciting scientific challenges as well as overwhelming health, equity, and economic benefits.,WHO and countries are setting ambitious goals for reducing the burden and eliminating malaria through the “Global Technical Strategy” and 21 countries are aiming to eliminate malaria by 2020.,The commitment to achieve these targets should be celebrated.,However, the need for innovation to achieve these goals, sustain elimination, and free the world of malaria is greater than ever.,Over 180 experts across multiple disciplines are engaged in the Malaria Eradication Research Agenda (malERA) Refresh process to address problems that need to be solved.,The result is a research and development agenda to accelerate malaria elimination and, in the longer term, transform the malaria community’s ability to eradicate it globally.,The malERA Refresh Consultative Panel on Health Systems and Policy Research summarize a research and development agenda to accelerate malaria elimination and eradicate globally.

In malaria-endemic countries, large proportions of infected individuals are asymptomatic, constituting a reservoir of parasites for infection of newly hatched mosquitoes.,This study evaluated the impact of screening and treatment of asymptomatic carriers of Plasmodium falciparum.,Eighteen villages were randomized (1:1) to study arms and inhabitants participated in four community screening campaigns: three before the rainy season ~1 month apart, and the fourth after the rains at ~12 months.,On day 1 of campaigns 1-3, asymptomatic carriers in the intervention arm were identified by rapid diagnostic test and treated with artemether-lumefantrine.,Outcomes were symptomatic malaria with parasite density >5,000/μL per person-year in children < 5 years and change in haemoglobin between days 1 and 28 of campaign 1.,At 12 months, the number of symptomatic malaria episodes with a parasite density >5,000/μL per person-year in children < 5 years was not significantly different between arms (1.69 vs 1.60, p = 0.3482).,Mean haemoglobin change in asymptomatic carriers during campaign 1 was greater in the intervention vs control arm (+0.53 g/dL vs -0.21 g/dL, p < 0.0001).,ANCOVA demonstrated that mean asymptomatic carriage at the cluster level was lower in the intervention vs control arm at day 1 of campaigns 2 (5.0% vs 34.9%, p < 0.0001) and 3 (3.5% vs 31.5%, p < 0.0001), but showed only a small difference at day 1 of campaign 4 (34.6% vs 37.6%, p = 0.2982).,Mean gametocyte carriage was lower in the intervention vs control arm at day 1 of campaigns 2 and 3 (0.7% vs 5.4%, p < 0.0001; 0.5% vs 5.8%, p < 0.0001), but was similar at day 1 of campaign 4 (4.9% vs 5.1%, p = 0.7208).,Systematic screening and treatment of asymptomatic carriers at the community level did not reduce clinical malaria incidence in the subsequent transmission season, indicating greater levels of parasite clearance are required to achieve a sustained impact in this setting.

Malaria vectors which predominantly feed indoors upon humans have been locally eliminated from several settings with insecticide treated nets (ITNs), indoor residual spraying or larval source management.,Recent dramatic declines of An. gambiae in east Africa with imperfect ITN coverage suggest mosquito populations can rapidly collapse when forced below realistically achievable, non-zero thresholds of density and supporting resource availability.,Here we explain why insecticide-based mosquito elimination strategies are feasible, desirable and can be extended to a wider variety of species by expanding the vector control arsenal to cover a broader spectrum of the resources they need to survive.,The greatest advantage of eliminating mosquitoes, rather than merely controlling them, is that this precludes local selection for behavioural or physiological resistance traits.,The greatest challenges are therefore to achieve high biological coverage of targeted resources rapidly enough to prevent local emergence of resistance and to then continually exclude, monitor for and respond to re-invasion from external populations.

Overnight stays in farming huts are known to pose a risk of malaria infection.,However, studies reporting the risk were conducted in the settings of poor net coverage.,This study sought to assess whether an overnight stay in a farming hut is associated with an increased risk of malaria infection if insecticide-treated bed nets (ITNs) are properly used.,A pair of cross-sectional surveys was carried out in the Lamarm district of Sekong province, Laos, in March (dry season) and August (rainy season) in 2008.,Questionnaire-based interviews and blood examinations were conducted with farmers and their household members from three randomly selected villages in March (127 households, 891 people) and August (128 households, 919 people).,Logistic regression analysis, adjusted for potential confounding factors, was used to assess the association between malaria infection status and frequency of overnight stays for the two weeks prior to the study in both the seasons.,In March, 13.7% of participants reported staying overnight in a farming hut at least once in the previous two weeks.,The percentage increased to 74.6% in August.,Not only adults but also young children stayed overnight as often as adults.,The use of an ITN the preceding night was common both in farming huts (66.3% in March, 95.2% in August), and in main residences (85.8% in March, 92.5% in August).,Logistic regression analysis showed no statistical association between malaria infection status and frequency of overnight stays in farming huts in either study period.,However, people sharing one family type net with five people or more were significantly more likely to have malaria than those sharing a net with up to two people in the dry season.,This study showed that staying overnight in farming huts was not associated with an increased risk of malaria infection in the setting where ITNs were widely used in farming huts.,It suggests that malaria infection during overnight stays in farming huts might be preventable if ITNs are properly used in rural Laos.

Malaria around the China-Myanmar border is a serious health problem in the countries of South-East Asia.,An. minimus is a principle malaria vector with a wide geographic distribution in this area.,Malaria is endemic along the boundary between Yunnan province in China and the Kachin State of Myanmar where the local Anopheles community (species composition) and the malaria transmission vectors have never been clarified.,Adult Anopheles specimens were collected using CDC light traps in four villages along the border of China and Myanmar from May 2012 to April 2013.,Morphological and molecular identification of mosquito adults confirmed the species of Anopheles.,Blood-meal identification using the female abdomens was conducted using multiplex PCR.,For sporozoite detection in An. minimus, sets of 10 female salivary glands were pooled and identified with SSU rDNA using nested PCR.,Monthly abundance of An. minimus populations during the year was documented.,The diversity of Anopheles and the role of An. minimus on malaria transmission in this border area were analyzed.,4,833 adult mosquitoes in the genus Anopheles were collected and morphologically identified to species or species complex.,The Anopheles community is comprised of 13 species, and 78.83% of our total specimens belonged to An. minimus s.l., followed by An. maculatus (5.55%) and the An. culicifacies complex (4.03%).,The quantity of trapped An. minimus in the rainy season of malaria transmission was greater than during the non-malarial dry season, and a peak was found in May 2012.,An. minimus fed on the blood of four animals: humans (79.8%), cattle (10.6%), pigs (5.8%) and dogs (3.8%). 1,500 females of An. minimus were pooled into 150 samples and tested for sporozoites: only 1 pooled sample was found to have sporozoites of Plasmodium vivax.,Anopheles is abundant with An. minimus being the dominant species and having a high human blood index along the China-Myanmar border.,The sporozoites in An. minimus were determined to be Plasmodium vivax with a 0.07-0.7% infection rate.

Over the past decade the use of long-lasting insecticidal nets (LLINs), in combination with improved drug therapies, indoor residual spraying (IRS), and better health infrastructure, has helped reduce malaria in many African countries for the first time in a generation.,However, insecticide resistance in the vector is an evolving threat to these gains.,We review emerging and historical data on behavioral resistance in response to LLINs and IRS.,Overall the current literature suggests behavioral and species changes may be emerging, but the data are sparse and, at times unconvincing.,However, preliminary modeling has demonstrated that behavioral resistance could have significant impacts on the effectiveness of malaria control.,We propose seven recommendations to improve understanding of resistance in malaria vectors.,Determining the public health impact of physiological and behavioral insecticide resistance is an urgent priority if we are to maintain the significant gains made in reducing malaria morbidity and mortality.

Gametocytes are the only form of the malaria parasite that is transmissible to the mosquito vector.,They are present at low levels in blood circulation and significant knowledge gaps exist in their biology.,Recent reductions in the global malaria burden have brought the possibility of elimination and eradication, with renewed focus on malaria transmission biology as a basis for interventions.,This review discusses recent insights into gametocyte biology in the major human malaria parasite, Plasmodium falciparum and related species.,This review provides an update on our current understanding of the only parasite stage that can transmit malaria from man to mosquito, the gametocyte.

The pivotal factor leading to the declining efficacy of the artemisinin-based combination on the Thailand-Myanmar border (mefloquine-artesunate) to a clinically unacceptable level is the increasing local prevalence of K13 mutations superimposed onto a long-standing background of Pfmdr1 amplification.,Background.,Deployment of mefloquine-artesunate (MAS3) on the Thailand-Myanmar border has led to a sustained reduction in falciparum malaria, although antimalarial efficacy has declined substantially in recent years.,The role of Plasmodium falciparum K13 mutations (a marker of artemisinin resistance) in reducing treatment efficacy remains controversial.,Methods.,Between 2003 and 2013, we studied the efficacy of MAS3 in 1005 patients with uncomplicated P. falciparum malaria in relation to molecular markers of resistance.,Results.,Polymerase chain reaction (PCR)-adjusted cure rates declined from 100% in 2003 to 81.1% in 2013 as the proportions of isolates with multiple Pfmdr1 copies doubled from 32.4% to 64.7% and those with K13 mutations increased from 6.7% to 83.4%.,K13 mutations conferring moderate artemisinin resistance (notably E252Q) predominated initially but were later overtaken by propeller mutations associated with slower parasite clearance (notably C580Y).,Those infected with both multiple Pfmdr1 copy number and a K13 propeller mutation were 14 times more likely to fail treatment.,The PCR-adjusted cure rate was 57.8% (95% confidence interval [CI], 45.4, 68.3) compared with 97.8% (95% CI, 93.3, 99.3) in patients with K13 wild type and Pfmdr1 single copy.,K13 propeller mutation alone was a strong risk factor for recrudescence (P = .009).,The combined population attributable fraction of recrudescence associated with K13 mutation and Pfmdr1 amplification was 82%.,Conclusions.,The increasing prevalence of K13 mutations was the decisive factor for the recent and rapid decline in efficacy of artemisinin-based combination (MAS3) on the Thailand-Myanmar border.

Malaria and iron-deficient anemia during pregnancy pose considerable risks for the mother and newborn.,Intermittent Preventive Treatment during pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) and iron supplement to prevent anemia to all pregnant women receiving antenatal care (ANC) services is highly recommended.,However, their compliance remains low.,This study aimed at identifying factors influencing non-compliance of medications among pregnant women.,A descriptive cross-sectional study was conducted in Simiyu region in northwest Tanzania using a structured questionnaire to collect data from 430 women who were pregnant or gave birth 12 months prior to data collection.,Data were analyzed using non-parametric statistical analysis with STATA 10.,Overall, 284 (66%) and 195 (45%) of interviewed women received IPTp-SP and iron supplementation during their ANC visits, respectively.,The majority (85%) of women whom received medications were aware if they had received IPTp-SP or iron supplementation.,Of those received IPTp-SP, only 11% took all the three doses, while the remaining 89% took only two doses or one dose.,For women who received iron supplementation, 29% reported that they did not take any dose at all.,Reasons given for not complying with regiments included not liking the medications and disapproval from male partners.,Our findings suggest that IPTp-SP and iron supplement compliance among pregnant women in Simiyu region is low.,Intensification of community education, further qualitative research and administration of medication through directly-observed therapy (DOT) are recommended to address the problem.

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.

Numerous population-based studies have documented high prevalence of scabies in overcrowded settings, particularly among children and in tropical regions.,We provide an estimate of the global burden of scabies using data from the Global Burden of Disease (GBD) Study 2015.,We identified scabies epidemiological data sources from an extensive literature search and hospital insurance data and analysed data sources with a Bayesian meta-regression modelling tool, DisMod-MR 2·1, to yield prevalence estimates.,We combined prevalence estimates with a disability weight, measuring disfigurement, itch, and pain caused by scabies, to produce years lived with disability (YLDs).,With an assumed zero mortality from scabies, YLDs were equivalent to disability-adjusted life-years (DALYs).,We estimated DALYs for 195 countries divided into 21 world regions, in both sexes and 20 age groups, between 1990 and 2015.,Scabies was responsible for 0·21% of DALYs from all conditions studied by GBD 2015 worldwide.,The world regions of east Asia (age-standardised DALYs 136·32), southeast Asia (134·57), Oceania (120·34), tropical Latin America (99·94), and south Asia (69·41) had the greatest burden of DALYs from scabies.,Mean percent change of DALY rate from 1990 to 2015 was less than 8% in all world regions, except North America, which had a 23·9% increase.,The five individual countries with greatest scabies burden were Indonesia (age-standardised DALYs 153·86), China (138·25), Timor-Leste (136·67), Vanuatu (131·59), and Fiji (130·91).,The largest standard deviations of age-standardised DALYs between the 20 age groups were observed in southeast Asia (60·1), Oceania (58·3), and east Asia (56·5), with the greatest DALY burdens in children, adolescents, and the elderly.,The burden of scabies is greater in tropical regions, especially in children, adolescents, and elderly people.,As a worldwide epidemiological assessment, GBD 2015 provides broad and frequently updated measures of scabies burden in terms of skin effects.,These global data might help guide research protocols and prioritisation efforts and focus scabies treatment and control measures.,Bill & Melinda Gates Foundation.

This study was undertaken in five onchocerciasis/lymphatic filariasis (LF) co-endemic local government areas (LGAs) in Plateau and Nasarawa, Nigeria.,Annual MDA with ivermectin had been given for 17 years, 8 of which were in combination with albendazole.,In 2008, assessments indicated that LF transmission was interrupted, but that the MDA had to continue due to the uncertain status of onchocerciasis transmission.,Accordingly, assessments to determine if ivermectin MDA for onchocerciasis could be stopped were conducted in 2009.,We evaluated nodule, microfilarial (mf) skin snip, and antibody (IgG4 response to OV16) prevalence in adults and children in six sentinel sites where baseline data from the 1990s were available.,We applied the 2001 WHO criteria for elimination of onchocerciasis that defined transmission interruption as an infection rate of <0.1% in children (using both skin snip and OV16 antibody) and a rate of infective (L3) blackflies of <0.05%.,Among adult residents in sentinel sites, mean mf prevalence decreased by 99.37% from the 1991-1993 baseline of 42.95% (64/149) to 0.27% (2/739) in 2009 (p<0.001).,The OV16 seropositivity of 3.52% (26/739) among this same group was over ten times the mf rate.,No mf or nodules were detected in 4,451 children in sentinel sites and ‘spot check’ villages, allowing the exclusion of 0.1% infection rate with 95% confidence.,Seven OV16 seropositives were detected, yielding a seroprevalence of 0.16% (0.32% upper 95%CI).,No infections were detected in PCR testing of 1,568 Simulium damnosum s.l. flies obtained from capture sites around the six sentinel sites.,Interruption of transmission of onchocerciasis in these five LGAs is highly likely, although the number of flies caught was insufficient to exclude 0.05% with 95% confidence (upper CI 0.23%).,We suggest that ivermectin MDA could be stopped in these LGAs if similar results are seen in neighboring districts.

Bravecto™ Chewable Tablets for Dogs, containing fluralaner as active ingredient, is an innovative treatment for flea and tick infestations that provides safe, rapid and long acting efficacy after a single oral administration in dogs.,Topically applied fluralaner provides similar safe, rapid and long acting efficacy, both in dogs and in cats.,The pharmacokinetic profile of fluralaner was evaluated in dogs and in cats following either topical or intravenous administration.,Twenty four dogs and 24 cats received three different topical doses, with the mid-dose based on the respective minimum recommended dose, and one intravenous dose.,Plasma samples were collected for 112 days and fluralaner concentrations were quantified using a validated high performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) method.,Pharmacokinetic parameters were calculated using non-compartmental methods.,In dogs, fluralaner was readily absorbed from the topical administration site into the skin, subjacent tissues and blood.,Fluralaner plasma concentrations showed an apparent plateau between ~ day 7 and 63, with individual tmax seen within this time period.,After the plasma plateau, concentrations declined slowly and were quantifiable for more than 12 weeks.,In cats, fluralaner was readily systemically absorbed from the topical administration site, reaching maximum concentrations (Cmax) in plasma between 3 and 21 days post administration, after which concentrations declined slowly, and were also quantifiable for more than 12 weeks.,Systemic exposure, as shown by Cmax and the area under the concentration versus time curve from time 0 to the last measurable concentration (AUC(0→t)) increased proportionally with dose in both species.,Following intravenous administration fluralaner showed a relatively high apparent volume of distribution (Vz), a low plasma clearance (Cl), a long terminal half-life (t1/2) and a long mean residence time (MRT); thereby demonstrating a long persistence of fluralaner in both species.,The pharmacokinetic characteristics of fluralaner explain its prolonged activity against fleas and ticks on both dogs and cats after a single topical administration.

Pathogens that are transmitted by ticks to dogs, such as Anaplasma phagocytophilum, Babesia spp., Borrelia burgdorferi sensu latu, and Ehrlichia canis, are an increasing problem in the world.,One method to prevent pathogen transmission to dogs is to kill the ticks before transmission occurs.,Fluralaner (Bravecto™) is a novel isoxazoline insecticide and acaricide that provides long persistent antiparasitic activity following systemic administration.,This study investigated the speed of kill of fluralaner against Ixodes ricinus ticks on dogs.,A total of 48 dogs were randomized to 8 groups of 6 dogs and each dog was infested with 50 female and 10 male I. ricinus ticks.,Two days later (day 0), 4 groups received a single treatment of 25 mg fluralaner/kg body weight as Bravecto™ chewable tablets; the dogs in the other 4 groups were left untreated.,Separate control and treatment groups were paired at each time point (4, 8, 12, or 24 hours after treatment) for assessment of tick-killing efficacy.,At 4, 8, and 12 weeks after treatment, all dogs were re-infested with 50 female I. ricinus ticks and subsequently assessed for live or dead ticks at either 4, 8, 12, or 24 hours after re-infestation.,Efficacy was calculated for each assessment time point by comparison of the treatment group with the respective control group.,Tick-killing efficacy was 89.6% at 4 hours, 97.9% at 8 hours, and 100% at 12 and 24 hours after treatment.,Eight hours after re-infestation, efficacy was 96.8%, 83.5%, and 45.8% at 4, 8, and 12 weeks after treatment, respectively.,At least 98.1% tick-killing efficacy was demonstrated 12 and 24 hours after re-infestation over the entire 12 week study period.,Fluralaner kills ticks rapidly after treatment at 4 hours, and over its entire 12-week period of efficacy, it achieves an almost complete killing effect within 12 hours after tick infestation.,The rapid tick-killing effect together with the long duration of efficacy enables fluralaner to aid in the prevention of tick borne diseases.

We are using controlled human malaria infection (CHMI) by direct venous inoculation (DVI) of cryopreserved, infectious Plasmodium falciparum (Pf) sporozoites (SPZ) (PfSPZ Challenge) to try to reduce time and costs of developing PfSPZ Vaccine to prevent malaria in Africa.,Immunization with five doses at 0, 4, 8, 12, and 20 weeks of 2.7 × 105 PfSPZ of PfSPZ Vaccine gave 65% vaccine efficacy (VE) at 24 weeks against mosquito bite CHMI in U.S. adults and 52% (time to event) or 29% (proportional) VE over 24 weeks against naturally transmitted Pf in Malian adults.,We assessed the identical regimen in Tanzanians for VE against PfSPZ Challenge.,Twenty- to thirty-year-old men were randomized to receive five doses normal saline or PfSPZ Vaccine in a double-blind trial.,Vaccine efficacy was assessed 3 and 24 weeks later.,Adverse events were similar in vaccinees and controls.,Antibody responses to Pf circumsporozoite protein were significantly lower than in malaria-naïve Americans, but significantly higher than in Malians.,All 18 controls developed Pf parasitemia after CHMI.,Four of 20 (20%) vaccinees remained uninfected after 3 week CHMI (P = 0.015 by time to event, P = 0.543 by proportional analysis) and all four (100%) were uninfected after repeat 24 week CHMI (P = 0.005 by proportional, P = 0.004 by time to event analysis).,Plasmodium falciparum SPZ Vaccine was safe, well tolerated, and induced durable VE in four subjects.,Controlled human malaria infection by DVI of PfSPZ Challenge appeared more stringent over 24 weeks than mosquito bite CHMI in United States or natural exposure in Malian adults, thereby providing a rigorous test of VE in Africa.

Cyclic paroxysm and high fever are hallmarks of malaria and are associated with high levels of pyrogenic cytokines, including IL-1β.,In this report, we describe a signature for the expression of inflammasome-related genes and caspase-1 activation in malaria.,Indeed, when we infected mice, Plasmodium infection was sufficient to promote MyD88-mediated caspase-1 activation, dependent on IFN-γ-priming and the expression of inflammasome components ASC, P2X7R, NLRP3 and/or NLRP12.,Pro-IL-1β expression required a second stimulation with LPS and was also dependent on IFN-γ-priming and functional TNFR1.,As a consequence of Plasmodium-induced caspase-1 activation, mice produced extremely high levels of IL-1β upon a second microbial stimulus, and became hypersensitive to septic shock.,Therapeutic intervention with IL-1 receptor antagonist prevented bacterial-induced lethality in rodents.,Similar to mice, we observed a significantly increased frequency of circulating CD14+CD16−Caspase-1+ and CD14dimCD16+Caspase-1+ monocytes in peripheral blood mononuclear cells from febrile malaria patients.,These cells readily produced large amounts of IL-1β after stimulation with LPS.,Furthermore, we observed the presence of inflammasome complexes in monocytes from malaria patients containing either NLRP3 or NLRP12 pyroptosomes.,We conclude that NLRP12/NLRP3-dependent activation of caspase-1 is likely to be a key event in mediating systemic production of IL-1β and hypersensitivity to secondary bacterial infection during malaria.

In the Greater Mekong Sub-region (GMS), malaria elimination efforts are targeting the asymptomatic parasite reservoirs.,Understanding community perceptions about asymptomatic malaria infections and interventions that target this reservoir is critical to the design of community engagement.,This article examines knowledge, attitudes, perceptions and practices related to asymptomatic malaria infections and mass drug administration (MDA) in malaria-endemic villages in southern Savannakhet Province, Laos.,A questionnaire consisting of questions on socio-demographic characteristics, knowledge, attitudes, perceptions and practices on malaria and MDA was administered to each household head or representative (n = 281) in four villages.,These topics were also further discussed in 12 single-gender focus group discussions (FGDs).,The FGDs were conducted in all four villages and consisted of eight to 10 participants.,A minority (14.2%; 40/281) of respondents agreed that a seemingly healthy person could have malaria parasite in his or her blood.,Half (52%; 146/281) disagreed and one third (33.8%, 95/281) were unsure.,Respondents who responded that “MDA aims to cure everyone” [AOR = 4.6; CI: 1.6-13.1], “MDA is to make our community malaria free” [AOR = 3.3; CI: 1.3-8.1] and “I will take part in future MDA” [AOR = 9.9; CI: 1.2-78.8] were more likely to accept the idea of asymptomatic malaria.,During FGDs, respondents recalled signs and symptoms of malaria (fever, chills and headache), and described malaria as a major health problem.,Symptomatic and asymptomatic malaria infections were associated with their work in the forest and living conditions.,Measures described to eliminate malaria included using mosquito nets, wearing long-sleeved clothes and taking medicine when symptomatic.,Most respondents were unaware of MDA as a tool to eliminate malaria.,Awareness of asymptomatic malaria infections, and MDA as a tool to eliminate malaria, was low.,With the need to target asymptomatic malaria carriers for elimination efforts in the GMS, as well as informing target groups about asymptomatic infection, accompanying community engagement must build trust in interventions through the active collaboration of government stakeholders, key local persons and community members.,This entails training and devolving responsibilities to the community members to implement and sustain the control and elimination efforts.

Targeted malaria elimination (TME) in Lao PDR (Laos) included three rounds of mass drug administrations (MDA) against malaria followed by quarterly blood surveys in two villages in Nong District at Savannakhet Province.,The success of MDA largely depends upon the efficacy of the anti-malarial drug regimen, local malaria epidemiology and the population coverage.,In order to explore the reasons for participation in TME, a quantitative survey was conducted after the completion of the three rounds of MDA.,The survey was conducted in two villages with a total of 158 households in July and August 2016.,Among the 973 villagers eligible for participation in the MDA, 158 (16.2%) adults (> 18 years) were selected, one each from every household for the interviews using a quantitative questionnaire.,150/158 (94.9%) respondents participated at least in one activity (taking medicine or testing their blood) of TME.,141/150 (94.0%) respondents took part in the MDA and tested their blood in all three rounds.,17/158 (10.7%) were partial or non-participants in three rounds of MDA.,Characteristics of respondents which were independently associated with completion of three rounds of MDA included: attending TME meetings [AOR = 12.0 (95% CI 1.1-20.5) (p = 0.03)], knowing that malaria can be diagnosed through blood tests [AOR = 5.6 (95% CI 1.0-32.3) (p = 0.05)], all members from household participated [AOR = 4.2 (95% CI 1.3-14.0) (p = 0.02)], liking all aspects of TME [AOR = 17.2 (95% CI 1.6-177.9) (p = 0.02)] and the perception that TME was important [AOR = 14.9 (95% CI 1.3-171.2) (p = 0.03)].,Complete participation in TME was significantly associated with participation in community engagement activities, knowledge that the blood tests were for malaria diagnosis, family members’ participation at TME and perceptions that TME was worthwhile.,A responsive approach to community engagement that includes formative research and the involvement of community members may increase the uptake of the intervention.,The online version of this article (doi:10.1186/s12936-017-2070-y) contains supplementary material, which is available to authorized users.

With visceral leishmaniasis (VL) incidence at its lowest level since the 1960s, increasing attention has turned to early detection and investigation of outbreaks.,Outbreak investigations were triggered by recognition of case clusters in the VL surveillance system established for the elimination program.,Investigations included ascertainment of all VL cases by date of fever onset, household mapping and structured collection of risk factor data.,VL outbreaks were investigated in 13 villages in 10 blocks of 7 districts.,Data were collected for 20,670 individuals, of whom 272 were diagnosed with VL between 2012 and 2019.,Risk was significantly higher among 10-19 year-olds and adults 35 or older compared to children younger than 10 years.,Outbreak confirmation triggered vector control activities and heightened surveillance.,VL cases strongly clustered in tolas (hamlets within villages) in which > 66% of residents self-identified as scheduled caste or scheduled tribe (SC/ST); 79.8% of VL cases occurred in SC/ST tolas whereas only 24.2% of the population resided in them.,Other significant risk factors included being an unskilled non-agricultural laborer, migration for work in a brick kiln, living in a kuccha (mud brick) house, household crowding, habitually sleeping outside or on the ground, and open defecation.,Our data highlight the importance of sensitive surveillance with triggers for case cluster detection and rapid, careful outbreak investigations to better respond to ongoing and new transmission.,The strong association with SC/ST tolas suggests that efforts should focus on enhanced surveillance in these disadvantaged communities.

Visceral leishmaniasis (VL) is highly prevalent in the Indian state of Bihar and, without proper diagnosis and treatment, is associated with high fatality.,However, lack of efficient reporting mechanism had been an impediment in estimating the burden of mortality and its antecedents among symptomatic VL cases.,The objectives of the current study were to generate a reliable estimate of symptomatic VL caseload and mortality in Bihar, as well as to identify the epidemiologic and health infrastructure-related predictors of VL mortality.,Using an elaborate index case tracing method, we attempted to locate all symptomatic VL patients in eight districts of Bihar.,Interviews and medical-record-reviews were conducted with cases (or next-of-kin for the dead) meeting the eligibility criteria.,The information collected during the interviews included socio-demographic characteristics, onset of disease symptoms, place of diagnosis, pre- and post-diagnosis treatment history, type and duration of drugs received.,In total, we analyzed data on 4925 VL patients-59% were male and 68% were less than 30 years old.,There were 158 (3.2%) deaths and the incidence rate of mortality was 3.2/100 person-years.,In the adjusted Cox-proportional-hazards analysis, treatment at public facility [Adjusted Hazard Ratio (AHR) = 0.61; 95% CI = 0.43-0.86], shorter (≤30 days) diagnostic delay [AHR = 0.62, 95% CI = 0.43-0.92], and treatment completion [AHR = 0.03, 95% CI = 0.02-0.05] emerged as significant negative predictors of mortality.,Mortality reduction efforts in Bihar should focus on improving access to early diagnosis, quality treatment and treatment-adherence measures, with special emphasis on marginalized communities.

Current Uganda National Malaria treatment guidelines recommend parasitological confirmation either by microscopy or rapid diagnostic test (RDT) before treatment with artemether-lumefantrine (AL).,However, the cost-effectiveness of these strategies has not been assessed at rural operational primary care centres.,Three health centres (HCs) were randomized to three diagnostic arms (microscopy, RDT and presumptive diagnosis) in a district of low and another of high malaria transmission intensities in Uganda.,Some 22,052 patients presenting with fever at outpatients departments were enrolled from March 2010 to February 2011.,Of these, a random sample of 1,627 was selected to measure additional socio-economic characteristics.,Costing was performed following the standard step-down cost allocation and the ingredients approach.,Effectiveness was measured as the number and proportion of patients correctly diagnosed and treated.,Incremental Cost-Effectiveness Ratios (ICERs) were estimated from the societal perspective (http://Clinicaltrials.gov, NCT00565071).,Overall RDT was most cost-effective with lowest ICER US$5.0 compared to microscopy US$9.61 per case correctly diagnosed and treated.,In the high transmission setting, ICER was US$4.38 for RDT and US$12.98 for microscopy.,The corresponding ICERs in the low transmission setting were US$5.85 and US$7.63 respectively.,The difference in ICERs between RDT and microscopy was greater in the high transmission area (US$8.9) than in low transmission setting (US$1.78).,At a willingness to pay of US$2.8, RDT remained cost effective up to a threshold value of the cost of treatment of US$4.7.,RDT was cost effective in both low and high transmission settings.,With a global campaign to reduce the costs of AL and RDT, the Malaria Control Programme and stakeholders need a strategy for malaria diagnosis because as the cost of AL decreases, presumptive treatment is likely to become more attractive.

Recent WHO guidelines recommend a universal "test and treat" strategy for malaria, mainly by use of rapid diagnostic test (RDT) in all areas.,The evidence for this approach is questioned here as there is a risk of over-reliance on parasitological diagnosis in high transmission situations, which still exist.,In such areas, when a patient has fever or other malaria symptoms, the presence of Plasmodium spp neither reliably confirms malaria as the cause of the fever, nor excludes the possibility of other diseases.,This is because the patient may be an asymptomatic carrier of malaria parasites and suffer from another disease.,To allow clinicians to perform their work adequately, local epidemiologic data are necessary.,One size does not fit all.,If parasite prevalence in the population is low, a diagnostic test is relevant; if the prevalence is high, the test does not provide information of any clinical usefulness, as happens with any test in medicine when the prevalence of the tested characteristic is high in the healthy population.,It should also be remembered that, if in some cases anti-malarials are prescribed to parasite-negative patients, this will not increase selection pressure for drug resistance, because the parasite is not there.,In high transmission situations at least, other diagnoses should be sought in all patients, irrespective of the presence of malaria parasites.,For this, clinical skills (but not necessarily physicians) are irreplaceable, in order to differentiate malaria from other causes of acute fever, such as benign viral infection or potentially dangerous conditions, which can all be present with the parasite co-existing only as a "commensal" or silent undesirable guest.

It has been speculated that widespread and sustained use of insecticide treated bed nets (ITNs) for over 10 years in Asembo, western Kenya, may have selected for changes in the location (indoor versus outdoor) and time (from late night to earlier in the evening) of biting of the predominant species of human malaria vectors (Anopheles funestus, Anopheles gambiae sensu stricto, and Anopheles arabiensis).,Mosquitoes were collected by human landing catches over a six week period in June and July, 2011, indoors and outdoors from 17 h to 07 h, in 75 villages in Asembo, western Kenya.,Collections were separated by hour of the night, and mosquitoes were identified to species and tested for sporozoite infection with Plasmodium falciparum.,A subset was dissected to determine parity.,Human behavior (time going to bed and rising, time spent indoors and outdoors) was quantified by cross-sectional survey.,Data from past studies of a similar design and in nearby settings, but conducted before the ITN scale up commenced in the early 2000s, were compared with those from the present study.,Of 1,960 Anopheles mosquitoes collected in 2011, 1,267 (64.6%) were morphologically identified as An. funestus, 663 (33.8%) as An. gambiae sensu lato (An. gambiae s.s. and An. arabiensis combined), and 30 (1.5%) as other anophelines.,Of the 663 An. gambiae s.l. collected, 385 were successfully tested by PCR among which 235 (61.0%) were identified as An. gambiae s.s. while 150 (39.0%) were identified as An. arabiensis.,Compared with data collected before the scale-up of ITNs, daily entomological inoculation rates (EIRs) were consistently lower for An. gambiae s.l. (indoor EIR = 0.432 in 1985-1988, 0.458 in 1989-1990, 0.023 in 2011), and An. arabiensis specifically (indoor EIR = 0.532 in 1989-1990, 0.039 in 2009, 0.006 in 2011) but not An. funestus (indoor EIR = 0.029 in 1985-1988, 0.147 in 1989-1990, 0.010 in 2009 and 0.103 in 2011).,Sporozoite rates were lowest in 2009 but rose again in 2011.,Compared with data collected before the scale-up of ITNs, An. arabiensis and An. funestus were more likely to bite outdoors and/or early in the evening (p < 0.001 for all comparisons).,However, when estimates of human exposure that would occur indoors (πi) or while asleep (πs) in the absence of an ITN were generated based on human behavioral patterns, the changes were modest with >90% of exposure of non-ITN users to mosquito bites occurring while people were indoors in all years.,The proportion of bites occurring among non-ITN users while they were asleep was ≥90% for all species except for An. arabiensis.,For this species, 97% of bites occurred while people were asleep in 1989-1990 while in 2009 and 2011, 80% and 84% of bites occurred while people were asleep for those not using ITNs.,Assuming ITNs prevent a theoretical maximum of 93.7% of bites, it was estimated that 64-77% of bites would have occurred among persons using nets while they were asleep in 1989-1990, while 20-52% of bites would have occurred among persons using nets while they were asleep in 2009 and 2011.,This study found no evidence to support the contention that populations of Anopheles vectors of malaria in Asembo, western Kenya, are exhibiting departures from the well-known pattern of late night, indoor biting characteristic of these typically highly anthropophilic species.,While outdoor, early evening transmission likely does occur in western Kenya, the majority of transmission still occurs indoors, late at night.,Therefore, malaria control interventions such as ITNs that aim to reduce indoor biting by mosquitoes should continue to be prioritized.

Over the past 20 years, numerous studies have investigated the ecology and behaviour of malaria vectors and Plasmodium falciparum malaria transmission on the coast of Kenya.,Substantial progress has been made to control vector populations and reduce high malaria prevalence and severe disease.,The goal of this paper was to examine trends over the past 20 years in Anopheles species composition, density, blood-feeding behaviour, and P. falciparum sporozoite transmission along the coast of Kenya.,Using data collected from 1990 to 2010, vector density, species composition, blood-feeding patterns, and malaria transmission intensity was examined along the Kenyan coast.,Mosquitoes were identified to species, based on morphological characteristics and DNA extracted from Anopheles gambiae for amplification.,Using negative binomial generalized estimating equations, mosquito abundance over the period were modelled while adjusting for season.,A multiple logistic regression model was used to analyse the sporozoite rates.,Results show that in some areas along the Kenyan coast, Anopheles arabiensis and Anopheles merus have replaced An. gambiae sensu stricto (s.s.) and Anopheles funestus as the major mosquito species.,Further, there has been a shift from human to animal feeding for both An. gambiae sensu lato (s.l.) (99% to 16%) and An. funestus (100% to 3%), and P. falciparum sporozoite rates have significantly declined over the last 20 years, with the lowest sporozoite rates being observed in 2007 (0.19%) and 2008 (0.34%).,There has been, on average, a significant reduction in the abundance of An. gambiae s.l. over the years (IRR = 0.94, 95% CI 0.90-0.98), with the density standing at low levels of an average 0.006 mosquitoes/house in the year 2010.,Reductions in the densities of the major malaria vectors and a shift from human to animal feeding have contributed to the decreased burden of malaria along the Kenyan coast.,Vector species composition remains heterogeneous but in many areas An. arabiensis has replaced An. gambiae as the major malaria vector.,This has important implications for malaria epidemiology and control given that this vector predominately rests and feeds on humans outdoors.,Strategies for vector control need to continue focusing on tools for protecting residents inside houses but additionally employ outdoor control tools because these are essential for further reducing the levels of malaria transmission.

Toxoplasma gondii secretes a novel dense granule protein, GRA24, that traffics from the vacuole to the host cell nucleus where it prolongs p38a activation and correlates with proinflammatory cytokine production.,Toxoplasma gondii, the causative agent of toxoplasmosis, is an obligate intracellular protozoan parasite that resides inside a parasitophorous vacuole.,During infection, Toxoplasma actively remodels the transcriptome of its hosting cells with profound and coupled impact on the host immune response.,We report that Toxoplasma secretes GRA24, a novel dense granule protein which traffics from the vacuole to the host cell nucleus.,Once released into the host cell, GRA24 has the unique ability to trigger prolonged autophosphorylation and nuclear translocation of the host cell p38α MAP kinase.,This noncanonical kinetics of p38α activation correlates with the up-regulation of the transcription factors Egr-1 and c-Fos and the correlated synthesis of key proinflammatory cytokines, including interleukin-12 and the chemokine MCP-1, both known to control early parasite replication in vivo.,Remarkably, the GRA24-p38α complex is defined by peculiar structural features and uncovers a new regulatory signaling path distinct from the MAPK signaling cascade and otherwise commonly activated by stress-related stimuli or various intracellular microbes.

Tissue-encysting coccidia, including Toxoplasma gondii and Sarcocystis neurona, are heterogamous parasites with sexual and asexual life stages in definitive and intermediate hosts, respectively.,During its sexual life stage, T. gondii reproduces either by genetic out-crossing or via clonal amplification of a single strain through self-mating.,Out-crossing has been experimentally verified as a potent mechanism capable of producing offspring possessing a range of adaptive and virulence potentials.,In contrast, selfing and other life history traits, such as asexual expansion of tissue-cysts by oral transmission among intermediate hosts, have been proposed to explain the genetic basis for the clonal population structure of T. gondii.,In this study, we investigated the contributing roles self-mating and sexual recombination play in nature to maintain clonal population structures and produce or expand parasite clones capable of causing disease epidemics for two tissue encysting parasites.,We applied high-resolution genotyping against strains isolated from a T. gondii waterborne outbreak that caused symptomatic disease in 155 immune-competent people in Brazil and a S. neurona outbreak that resulted in a mass mortality event in Southern sea otters.,In both cases, a single, genetically distinct clone was found infecting outbreak-exposed individuals.,Furthermore, the T. gondii outbreak clone was one of several apparently recombinant progeny recovered from the local environment.,Since oocysts or sporocysts were the infectious form implicated in each outbreak, the expansion of the epidemic clone can be explained by self-mating.,The results also show that out-crossing preceded selfing to produce the virulent T. gondii clone.,For the tissue encysting coccidia, self-mating exists as a key adaptation potentiating the epidemic expansion and transmission of newly emerged parasite clones that can profoundly shape parasite population genetic structures or cause devastating disease outbreaks.

Reactive malaria strategies are predicated on the assumption that individuals infected with malaria are clustered within households or neighbourhoods.,Despite the widespread programmatic implementation of reactive strategies, little empirical evidence exists as to whether such strategies are appropriate and, if so, how they should be most effectively implemented.,We collated 2 different datasets to assess clustering of malaria infections within households: (i) demographic health survey (DHS) data, integrating household information and patent malaria infection, recent fever, and recent treatment status in children; and (ii) data from cross-sectional and reactive detection studies containing information on the household and malaria infection status (patent and subpatent) of all-aged individuals.,Both datasets were used to assess the odds of infections clustering within index households, where index households were defined based on whether they contained infections detectable through one of 3 programmatic strategies: (a) Reactive Case Detection (RACD) classifed by confirmed clinical cases, (b) Mass Screen and Treat (MSAT) classifed by febrile, symptomatic infections, and (c) Mass Test and Treat (MTAT) classifed by infections detectable using routine diagnostics.,Data included 59,050 infections in 208,140 children under 7 years old (median age = 2 years, minimum = 2, maximum = 7) by microscopy/rapid diagnostic test (RDT) from 57 DHSs conducted between November 2006 and December 2018 from 23 African countries.,Data representing 11,349 infections across all ages (median age = 22 years, minimum = 0.5, maximum = 100) detected by molecular tools in 132,590 individuals in 43 studies published between April 2006 and May 2019 in 20 African, American, Asian, and Middle Eastern countries were obtained from the published literature.,Extensive clustering was observed-overall, there was a 20.40 greater (95% credible interval [CrI] 0.35-20.45; P < 0.001) odds of patent infections (according to the DHS data) and 5.13 greater odds (95% CI 3.85-6.84; P < 0.001) of molecularly detected infections (from the published literature) detected within households in which a programmatically detectable infection resides.,The strongest degree of clustering identified by polymerase chain reaction (PCR)/ loop mediated isothermal amplification (LAMP) was observed using the MTAT strategy (odds ratio [OR] = 6.79, 95% CI 4.42-10.43) but was not significantly different when compared to MSAT (OR = 5.2, 95% CI 3.22-8.37; P-difference = 0.883) and RACD (OR = 4.08, 95% CI 2.55-6.53; P-difference = 0.29).,Across both datasets, clustering became more prominent when transmission was low.,However, limitations to our analysis include not accounting for any malaria control interventions in place, malaria seasonality, or the likely heterogeneity of transmission within study sites.,Clustering may thus have been underestimated.,In areas where malaria transmission is peri-domestic, there are programmatic options for identifying households where residual infections are likely to be found.,Combining these detection strategies with presumptively treating residents of index households over a sustained time period could contribute to malaria elimination efforts.,Gillian Stresman and co-workers report on clustering of malaria infections within households to further approaches to disease prevention and treatment.

Decreasing malaria transmission leads to increasing heterogeneity with increased risk in both hot spots (locations) and hot pops (certain demographics).,In Southern Province, Zambia, reactive case detection has formed a part of malaria surveillance and elimination efforts since 2011.,Various factors may be associated with finding malaria infections during case investigations, including the demographics of the incident case and environmental characteristics of the location of the incident case.,Community health worker registries were used to determine what factors were associated with finding a malaria infection during reactive case detection.,Location was a more powerful predictor of finding malaria infections during case investigations than the demographics of the incident case.,After accounting for environmental characteristics, no demographics around the incident case were associated with finding malaria infections during case investigations.,Various time-invariant measures of the environment, such as median enhanced vegetation index, the topographic position index, the convergence index, and the topographical wetness index, were all associated as expected with increased probability of finding a malaria infection during case investigations.,These results suggest that targeting the locations highly at risk of malaria transmission is of importance in elimination settings.

In a systematic review and meta-analysis, Eric Strunz and colleagues examine whether improvements in water, sanitation, and hygiene (WASH) practices are associated with reduced risk of infections with soil-transmitted helminths.,Please see later in the article for the Editors' Summary,Preventive chemotherapy represents a powerful but short-term control strategy for soil-transmitted helminthiasis.,Since humans are often re-infected rapidly, long-term solutions require improvements in water, sanitation, and hygiene (WASH).,The purpose of this study was to quantitatively summarize the relationship between WASH access or practices and soil-transmitted helminth (STH) infection.,We conducted a systematic review and meta-analysis to examine the associations of improved WASH on infection with STH (Ascaris lumbricoides, Trichuris trichiura, hookworm [Ancylostoma duodenale and Necator americanus], and Strongyloides stercoralis).,PubMed, Embase, Web of Science, and LILACS were searched from inception to October 28, 2013 with no language restrictions.,Studies were eligible for inclusion if they provided an estimate for the effect of WASH access or practices on STH infection.,We assessed the quality of published studies with the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach.,A total of 94 studies met our eligibility criteria; five were randomized controlled trials, whilst most others were cross-sectional studies.,We used random-effects meta-analyses and analyzed only adjusted estimates to help account for heterogeneity and potential confounding respectively.,Use of treated water was associated with lower odds of STH infection (odds ratio [OR] 0.46, 95% CI 0.36-0.60).,Piped water access was associated with lower odds of A. lumbricoides (OR 0.40, 95% CI 0.39-0.41) and T. trichiura infection (OR 0.57, 95% CI 0.45-0.72), but not any STH infection (OR 0.93, 95% CI 0.28-3.11).,Access to sanitation was associated with decreased likelihood of infection with any STH (OR 0.66, 95% CI 0.57-0.76), T. trichiura (OR 0.61, 95% CI 0.50-0.74), and A. lumbricoides (OR 0.62, 95% CI 0.44-0.88), but not with hookworm infection (OR 0.80, 95% CI 0.61-1.06).,Wearing shoes was associated with reduced odds of hookworm infection (OR 0.29, 95% CI 0.18-0.47) and infection with any STH (OR 0.30, 95% CI 0.11-0.83).,Handwashing, both before eating (OR 0.38, 95% CI 0.26-0.55) and after defecating (OR 0.45, 95% CI 0.35-0.58), was associated with lower odds of A. lumbricoides infection.,Soap use or availability was significantly associated with lower infection with any STH (OR 0.53, 95% CI 0.29-0.98), as was handwashing after defecation (OR 0.47, 95% CI 0.24-0.90).,Observational evidence constituted the majority of included literature, which limits any attempt to make causal inferences.,Due to underlying heterogeneity across observational studies, the meta-analysis results reflect an average of many potentially distinct effects, not an average of one specific exposure-outcome relationship.,WASH access and practices are generally associated with reduced odds of STH infection.,Pooled estimates from all meta-analyses, except for two, indicated at least a 33% reduction in odds of infection associated with individual WASH practices or access.,Although most WASH interventions for STH have focused on sanitation, access to water and hygiene also appear to significantly reduce odds of infection.,Overall quality of evidence was low due to the preponderance of observational studies, though recent randomized controlled trials have further underscored the benefit of handwashing interventions.,Limited use of the Joint Monitoring Program's standardized water and sanitation definitions in the literature restricted efforts to generalize across studies.,While further research is warranted to determine the magnitude of benefit from WASH interventions for STH control, these results call for multi-sectoral, integrated intervention packages that are tailored to social-ecological contexts.,Please see later in the article for the Editors' Summary,Worldwide, more than a billion people are infected with soil-transmitted helminths (STHs), parasitic worms that live in the human intestine (gut).,These intestinal worms, including roundworm, hookworm, and whipworm, mainly occur in tropical and subtropical regions and are most common in developing countries, where personal hygiene is poor, there is insufficient access to clean water, and sanitation (disposal of human feces and urine) is inadequate or absent.,STHs colonize the human intestine and their eggs are shed in feces and enter the soil.,Humans ingest the eggs, either by touching contaminated ground or eating unwashed fruit and vegetables grown in such soil.,Hookworm may enter the body by burrowing through the skin, most commonly when bare-footed individuals walk on infected soil.,Repeated infection with STHs leads to a heavy parasite infestation of the gut, causing chronic diarrhea, intestinal bleeding, and abdominal pain.,In addition the parasites compete with their human host for nutrients, leading to malnutrition, anemia, and, in heavily infected children, stunting of physical growth and slowing of mental development.,While STH infections can be treated in the short-term with deworming medication, rapid re-infection is common, therefore a more comprehensive program of improved water, sanitation, and hygiene (WASH) is needed.,WASH strategies include improvements in water access (e.g., water quality, water quantity, and distance to water), sanitation access (e.g., access to improved latrines, latrine maintenance, and fecal sludge management), and hygiene practices (e.g., handwashing before eating and/or after defecation, water treatment, soap use, wearing shoes, and water storage practices).,WASH strategies have been shown to be effective for reducing rates of diarrhea and other neglected tropical diseases, such as trachoma; however, there is limited evidence linking specific WASH access or practices to STH infection rates.,In this systematic review and meta-analysis, the researchers investigate whether WASH access or practices lower the risk of STH infections.,A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical method that combines the results of several studies.,The researchers identified 94 studies that included measurements of the relationship between WASH access and practices with one or more types of STHs.,Meta-analyses of the data from 35 of these studies indicated that overall people with access to WASH strategies or practices were about half as likely to be infected with any STH.,Specifically, a lower odds of infection with any STH was observed for those people who use treated water (odd ratio [OR] of 0.46), have access to sanitation (OR of 0.66), wear shoes (OR of 0.30), and use soap or have soap availability (OR of 0.53) compared to those without access to these practices or strategies.,In addition, infection with roundworm was less than half as likely in those who practiced handwashing both before eating and after defecating than those who did not practice handwashing (OR of 0.38 and 0.45, respectively).,The studies included in this systematic review and meta-analysis have several shortcomings.,For example, most were cross-sectional surveys-studies that examined the effect of WASH strategies on STH infections in a population at a single time point.,Given this study design, people with access to WASH strategies may have shared other characteristics that were actually responsible for the observed reductions in the risk of STH infections.,Consequently, the overall quality of the included studies was low and there was some evidence for publication bias (studies showing a positive association are more likely to be published than those that do not).,Nevertheless, these findings confirm that WASH access and practices provide an effective control measure for STH.,Controlling STHs in developing countries would have a huge positive impact on the physical and mental health of the population, especially children, therefore there should be more emphasis on expanding access to WASH as part of development guidelines and targets, in addition to short-term preventative chemotherapy currently used.,Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001620.,The US Centers for Disease Control and Prevention also provides detailed information on roundworm, whipworm, and hookworm infections,The World Health Organization provides information on soil-transmitted helminths, including a description of the current control strategy,Children Without Worms (CWW) partners with Johnson & Johnson, GlaxoSmithKline, the World Health Organization, national ministries of health and education, non-governmental organizations, and others to promote treatment and prevention of soil-transmitted helminthiasis.,CWW advocates a four-pronged, comprehensive control strategy-Water, Sanitation, Hygiene Education, and Deworming (WASHED) to break the cycle of reinfection,The Global Network for Neglected Tropical Diseases, an advocacy initiative dedicated to raising the awareness, political will, and funding necessary to control and eliminate the most common neglected tropical diseases, provides information on infections with roundworm (ascariasis), whipworm (trichuriasis), and hookworm,WASH for the Neglected Tropical Diseases is a repository of information on WASH and the neglected tropical diseases (NTDs) such as soil-transmitted helminthiasis, and features a resource titled “WASH and the NTDs: A Manual for WASH Implementers.”,Two international programs promoting water sanitation are the World Health Organization Water Sanitation and Health program and the World Health Organization/United Nations Childrens Fund Joint Monitoring Programme for Water Supply and Sanitation

Quantifying the burden of parasitic diseases in relation to other diseases and injuries requires reliable estimates of prevalence for each disease and an analytic framework within which to estimate attributable morbidity and mortality.,Here we use data included in the Global Atlas of Helminth Infection to derive new global estimates of numbers infected with intestinal nematodes (soil-transmitted helminths, STH: Ascaris lumbricoides, Trichuris trichiura and the hookworms) and use disability-adjusted life years (DALYs) to estimate disease burden.,Prevalence data for 6,091 locations in 118 countries were sourced and used to estimate age-stratified mean prevalence for sub-national administrative units via a combination of model-based geostatistics (for sub-Saharan Africa) and empirical approaches (for all other regions).,Geographical variation in infection prevalence within these units was approximated using modelled logit-normal distributions, and numbers of individuals with infection intensities above given thresholds estimated for each species using negative binomial distributions and age-specific worm/egg burden thresholds.,Finally, age-stratified prevalence estimates for each level of infection intensity were incorporated into the Global Burden of Disease Study 2010 analytic framework to estimate the global burden of morbidity and mortality associated with each STH infection.,Globally, an estimated 438.9 million people (95% Credible Interval (CI), 406.3 - 480.2 million) were infected with hookworm in 2010, 819.0 million (95% CI, 771.7 - 891.6 million) with A. lumbricoides and 464.6 million (95% CI, 429.6 - 508.0 million) with T. trichiura.,Of the 4.98 million years lived with disability (YLDs) attributable to STH, 65% were attributable to hookworm, 22% to A. lumbricoides and the remaining 13% to T. trichiura.,The vast majority of STH infections (67%) and YLDs (68%) occurred in Asia.,When considering YLDs relative to total populations at risk however, the burden distribution varied more considerably within major global regions than between them.,Improvements in the cartography of helminth infection, combined with mathematical modelling approaches, have resulted in the most comprehensive contemporary estimates for the public health burden of STH.,These numbers form an important benchmark upon which to evaluate future scale-up of major control efforts.

The host hormone melatonin is known to modulate the asexual cell-cycle of the human malaria parasite Plasmodium falciparum and the kinase PfPK7 is fundamental in the downstream signaling pathways.,The nuclear protein PfMORC displays a histidine kinase domain and is involved in parasite cell cycle control.,By using a real-time assay, we show a 24 h (h) rhythmic expression of PfMORC at the parasite asexual cycle and the expression is dramatically changed when parasites were treated with 100 nM melatonin for 17 h.,Moreover, PfMORC expression was severely affected in PfPK7 knockout (PfPK7−) parasites following melatonin treatment.,Parasites expressing 3D7morc-GFP shows nuclear localization of the protein during the asexual stage of parasite development.,Although the PfMORC knockdown had no significant impact on the parasite proliferation in vitro it significantly changed the ratio of the different asexual intraerythrocytic stages of the parasites upon the addition of melatonin.,Our data reveal that in addition to the upstream melatonin signaling pathways such as IP3 generation, calcium, and cAMP rise, a nuclear protein, PfMORC is essential for the hormone response in parasite synchronization.

Neutrophils are abundant in the circulation and are one of the immune system's first lines of defense against infection.,There has been substantial work carried out investigating the role of neutrophils in malaria and it is clear that during infection neutrophils are activated and are capable of clearing malaria parasites by a number of mechanisms.,This review focuses on neutrophil responses to human malarias, summarizing evidence which helps us understand where neutrophils are, what they are doing, how they interact with parasites as well as their potential role in vaccine mediated immunity.,We also outline future research priorities for these, the most abundant of leukocytes.

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.

Insecticide-treated nets (ITNs) and indoor residual spraying (IRS) represent the front-line tools for malaria vector control globally, but are optimally effective where the majority of baseline transmission occurs indoors.,In the surveyed area of rural southern Tanzania, bed net use steadily increased over the last decade, reducing malaria transmission intensity by 94%.,Starting before bed nets were introduced (1997), and then after two milestones of net use had been reached-75% community-wide use of untreated nets (2004) and then 47% use of ITNs (2009)-hourly biting rates of malaria vectors from the Anopheles gambiae complex and Anopheles funestus group were surveyed.,In 1997, An. gambiae s.l. and An. funestus mosquitoes exhibited a tendency to bite humans inside houses late at night.,For An. gambiae s.l., by 2009, nocturnal activity was less (p = 0.0018).,At this time, the sibling species composition of the complex had shifted from predominantly An. gambiae s.s. to predominantly An. arabiensis.,For An. funestus, by 2009, nocturnal activity was less (p = 0.0054) as well as the proportion biting indoors (p < 0.0001).,At this time, An. funestus s.s. remained the predominant species within this group.,As a consequence of these altered feeding patterns, the proportion (mean ± standard error) of human contact with mosquitoes (bites per person per night) occurring indoors dropped from 0.99 ± 0.002 in 1997 to 0.82 ± 0.008 in 2009 for the An. gambiae complex (p = 0.0143) and from 1.00 ± <0.001 to only 0.50 ± 0.048 for the An. funestus complex (p = 0.0004) over the same time period.,High usage of ITNs can dramatically alter African vector populations so that intense, predominantly indoor transmission is replaced by greatly lowered residual transmission, a greater proportion of which occurs outdoors.,Regardless of the underlying mechanism, the residual, self-sustaining transmission will respond poorly to further insecticidal measures within houses.,Additional vector control tools which target outdoor biting mosquitoes at the adult or immature stages are required to complement ITNs and IRS.

Visceral leishmaniasis, commonly known as kala-azar in India, is a global public health problem.,In Southeast Asia, Bangladesh, Bhutan, India, Nepal, Sri Lanka and Thailand are endemic for visceral leishmaniasis.,The role of sandflies as the vector of kala-azar was first confirmed in 1942 in India.,Insecticide resistance in Phlebotomus argentipes Annandale and Brunetti, the vector of kala-azar in the Indian subcontinent, was first reported in 1987 in Bihar, India.,This article provides a scoping review of the studies undertaken from 1959 to 2015 on insecticide resistance in P. argentipes and P. papatasi (Scopoli), the vectors of visceral and cutaneous leishmaniasis respectively, in Southeast Asia, mainly in Bangladesh, India, Nepal and Sri Lanka.,Studies undertaken in areas of Bihar and West Bengal in India where kala-azar is endemic have reported resistance of P. argentipes to DDT, while in non-endemic areas it has been reported to be susceptible.,In areas of Nepal bordering India, there are indications of resistance to DDT; biochemical resistance has been reported in Sri Lanka.,No laboratory studies have been undertaken in Bangladesh; however, the sandfly vector is reported to be still susceptible to pyrethroids in all kala-azar endemic areas in the aforementioned countries.,Studies are needed to determine the resistance of sandfly vectors to all available classes of potential insecticides in kala-azar endemic areas.,There is a need to assess the impact of indoor residual spraying with DDT and pyrethroids on the incidence of kala-azar in India where 54 districts remain endemic for the disease, strengthen entomological surveillance capacity, and develop and implement an insecticide management plan.,Alpha-cypermethrin indoor residual spraying has been introduced in 33 kala-azar endemic districts in Bihar State of India in a pilot trial; the outcomes should be used to inform decisions on expanding coverage with alpha-cypermethrin in all remaining endemic districts to achieve the revised goal of elimination of visceral leishmaniasis by 2020.,The online version of this article (doi:10.1186/s40249-016-0200-3) contains supplementary material, which is available to authorized users.

Visceral leishmaniasis (VL), also known as kala-azar in the Indian sub-continent (ISC), is a major public health concern in Bangladesh, India, and Nepal, where it is caused by Leishmania donovani transmitted by the sand fly Phlebotomus argentipes.,Various ecological parameters including air temperature, rainfall, wind speed, relative humidity, soil moisture, pH, and organic carbon are known to influence the oviposition of female sand flies, as well as the survival and development of larvae.,However, more detailed knowledge on vector behavior, such as biting times, breeding places, and preferred hosts are needed to design optimal evidence-based vector control interventions.,In order to facilitate rational decisions regarding VL vector control, a systematic review was conducted to identify the prevailing practice and knowledge gaps in relation to vector bionomics and behavior.,Search terms included ‘sand fly bionomics’, ‘habitat’, and ‘visceral leishmaniasis/kala-azar vector control’ using the Boolean operator AND to identify the country of interest, namely: Bangladesh, India, and Nepal.,Both PubMed and Google search engines were used.,Additional unpublished documents in the three countries were also analyzed.,Information on the life cycle of VL vectors, their breeding behavior, infection rate with L. donovani, feeding behavior, and seasonal variation are useful for designing vector control operations.,Unfortunately, none of the studies on the life cycle of P. argentipes was conducted in field settings of the ISC, so the publications from other locations had to be used for determining the duration of life cycle and development from egg to adult.,However, information about breeding places, seasonal variation of vector densities, and 47 out of the selected 51 papers are available from the ISC and can be used for intelligent design of control operations.,Vector control services should undertake routine insecticide resistance monitoring and adapt indoor residual spraying rounds to the seasonality of vector densities.,Further research is needed on potential animal reservoirs for L. donovani, on the breeding habitat, and life cycle of sand flies in the ISC.

Plasmodium knowlesi, a simian malaria parasite, has become the main cause of malaria in Sarawak, Malaysian Borneo.,Epidemiological data on malaria for Sarawak has been derived solely from hospitalized patients, and more accurate epidemiological data on malaria is necessary.,Therefore, a longitudinal study of communities affected by knowlesi malaria was undertaken.,A total of 3002 blood samples on filter paper were collected from 555 inhabitants of 8 longhouses with recently reported knowlesi malaria cases in the Betong Division of Sarawak, Malaysian Borneo.,Each longhouse was visited bimonthly for a total of 10 times during a 21-month study period (Jan 2014-Oct 2015).,DNA extracted from blood spots were examined by a nested PCR assay for Plasmodium and positive samples were then examined by nested PCR assays for Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, Plasmodium knowlesi, Plasmodium cynomolgi and Plasmodium inui.,Blood films of samples positive by PCR were also examined by microscopy.,Genus-specific PCR assay detected Plasmodium DNA in 9 out of 3002 samples.,Species-specific PCR identified 7 P. knowlesi and one P. vivax.,Malaria parasites were observed in 5 thick blood films of the PCR positive samples.,No parasites were observed in blood films from one knowlesi-, one vivax- and the genus-positive samples.,Only one of 7 P. knowlesi-infected individual was febrile and had sought medical treatment at Betong Hospital the day after sampling.,The 6 knowlesi-, one vivax- and one Plasmodium-infected individuals were afebrile and did not seek any medical treatment.,Asymptomatic human P. knowlesi and P. vivax malaria infections, but not P. cynomolgi and P. inui infections, are occurring within communities affected with malaria.

The Indonesian archipelago is endemic for malaria.,Although Plasmodium falciparum and P. vivax are the most common causes for malaria cases, P. malariae and P. ovale are also present in certain regions.,Zoonotic case of malaria had just became the attention of public health communities after the Serawak study in 2004.,However, zoonotic case in Indonesia is still under reported; only one published report of knowlesi malaria in South Kalimantan in 2010.,A case of Plasmodium knowlesi infection in a worker from a charcoal mining company in Central Kalimantan, Indonesia was described.,The worker suffered from fever following his visit to a lowland forest being cut and converted into a new mining location.,This study confirmed a zoonotic infection using polymerase chain reaction amplification and Sanger sequencing of plasmodial DNA encoding the mitochondrial cytochrome c oxidase subunit I (mtCOI).

The carbon metabolism of the blood stages of Plasmodium falciparum, comprising rapidly dividing asexual stages and non-dividing gametocytes, is thought to be highly streamlined, with glycolysis providing most of the cellular ATP.,However, these parasitic stages express all the enzymes needed for a canonical mitochondrial tricarboxylic acid (TCA) cycle, and it was recently proposed that they may catabolize glutamine via an atypical branched TCA cycle.,Whether these stages catabolize glucose in the TCA cycle and what is the functional significance of mitochondrial metabolism remains unresolved.,We reassessed the central carbon metabolism of P. falciparum asexual and sexual blood stages, by metabolically labeling each stage with 13C-glucose and 13C-glutamine, and analyzing isotopic enrichment in key pathways using mass spectrometry.,In contrast to previous findings, we found that carbon skeletons derived from both glucose and glutamine are catabolized in a canonical oxidative TCA cycle in both the asexual and sexual blood stages.,Flux of glucose carbon skeletons into the TCA cycle is low in the asexual blood stages, with glutamine providing most of the carbon skeletons, but increases dramatically in the gametocyte stages.,Increased glucose catabolism in the gametocyte TCA cycle was associated with increased glucose uptake, suggesting that the energy requirements of this stage are high.,Significantly, whereas chemical inhibition of the TCA cycle had little effect on the growth or viability of asexual stages, inhibition of the gametocyte TCA cycle led to arrested development and death.,Our metabolomics approach has allowed us to revise current models of P. falciparum carbon metabolism.,In particular, we found that both asexual and sexual blood stages utilize a conventional TCA cycle to catabolize glucose and glutamine.,Gametocyte differentiation is associated with a programmed remodeling of central carbon metabolism that may be required for parasite survival either before or after uptake by the mosquito vector.,The increased sensitivity of gametocyte stages to TCA-cycle inhibitors provides a potential target for transmission-blocking drugs.

Malaria, caused by the apicomplexan parasite Plasmodium, threatens 40% of the world's population.,Transmission between vertebrate and insect hosts depends on the sexual stages of the life-cycle.,The male gamete of Plasmodium parasite is the only developmental stage that possesses a flagellum.,Very little is known about the identity or function of proteins in the parasite's flagellar biology.,Here, we characterise a Plasmodium PF16 homologue using reverse genetics in the mouse malaria parasite Plasmodium berghei.,PF16 is a conserved Armadillo-repeat protein that regulates flagellar structure and motility in organisms as diverse as green algae and mice.,We show that P. berghei PF16 is expressed in the male gamete flagellum, where it plays a crucial role maintaining the correct microtubule structure in the central apparatus of the axoneme as studied by electron microscopy.,Disruption of the PF16 gene results in abnormal flagellar movement and reduced fertility, but does not lead to complete sterility, unlike pf16 mutations in other organisms.,Using homology modelling, bioinformatics analysis and complementation studies in Chlamydomonas, we show that some regions of the PF16 protein are highly conserved across all eukaryotes, whereas other regions may have species-specific functions.,PF16 is the first ARM-repeat protein characterised in the malaria parasite genus Plasmodium and this study opens up a novel model for analysis of Plasmodium flagellar biology that may provide unique insights into an ancient organelle and suggest novel intervention strategies to control the malaria parasite.

Recent efforts to reduce malaria incidence have had some successes.,Nevertheless, malaria persists as a significant public health problem in the Brazilian Amazon.,The objective of this study was to describe changes in malaria case characteristics and to identify trends in malaria incidence in the Brazilian Amazon.,This study used data from the Malaria Epidemiological Surveillance and Case Notification Information System from 2004 to 2013.,The annual parasite incidence (API) was calculated and joinpoint regression was used to assess the trends in API over time.,There was a sharp increase in API in the state of Acre, followed by two periods of decrease.,Pará also presented inconsistent decreases over the study period.,Amapá, Amazonas, Rondônia, and Roraima showed statistically significant decreases over the period.,The sharpest decrease occurred in Rondônia, with a reduction of 21.7% in the average annual percent change (AAPC) (AAPC: -21.7%; 95% confidence interval: -25.4%, -17.8%; p < 0.05).,This panorama of malaria incidence highlights the importance of integrating evidence-based malaria surveillance and control.,Malaria is highly preventable, and eliminating its transmission should be a goal in coming decades.

Gold-mining may play an important role in the maintenance of malaria worldwide.,Gold-mining, mostly illegal, has significantly expanded in Colombia during the last decade in areas with limited health care and disease prevention.,We report a descriptive study that was carried out to determine the malaria prevalence in gold-mining areas of Colombia, using data from the public health surveillance system (National Health Institute) during the period 2010-2013.,Gold-mining was more prevalent in the departments of Antioquia, Córdoba, Bolívar, Chocó, Nariño, Cauca, and Valle, which contributed 89.3% (270,753 cases) of the national malaria incidence from 2010-2013 and 31.6% of malaria cases were from mining areas.,Mining regions, such as El Bagre, Zaragoza, and Segovia, in Antioquia, Puerto Libertador and Montelíbano, in Córdoba, and Buenaventura, in Valle del Cauca, were the most endemic areas.,The annual parasite index (API) correlated with gold production (R2 0.82, p < 0.0001); for every 100 kg of gold produced, the API increased by 0.54 cases per 1,000 inhabitants.,Lack of malaria control activities, together with high migration and proliferation of mosquito breeding sites, contribute to malaria in gold-mining regions.,Specific control activities must be introduced to control this significant source of malaria in Colombia.

Plasma Plasmodium falciparum histidine-rich protein-2 (PfHRP2) is the most accurate biomarker for severe malaria, but its measurement by ELISA has been considered too unwieldy to incorporate into clinical management.,Plasma samples covering a wide range of PfHRP2 concentrations were applied to rapid diagnostic tests (RDTs).,RDTs were read by eye and digital capture, and PfHRP2 concentrations were measured via serial dilution with results compared to ELISA readings.,The Paracheck® brand showed the strongest correlation (r2 = 0.963) as well as the lowest inter-observer variability (combined kappa across band intensities for three observers = 0.938).,Plasma PfHRP2 measurement via serial dilution showed minimal bias compared to ELISA and acceptable limits of agreement.,Three different dilutions of a well characterized set of admission samples from uncomplicated and severe malaria patients studied in a low transmission setting gave an area under the receiver operator characteristic curve of 0.844 in terms of identifying severe malaria.,These studies show that plasma PfHRP2 can be assessed via a single RDT, with application of a plasma dilution of 1:5 or 1:10 providing useful diagnostic information to assist in patient management or clinical trial inclusion.

Background.,In malaria-endemic settings, asymptomatic parasitemia complicates the diagnosis of malaria.,Histidine-rich protein 2 (HRP2) is produced by Plasmodium falciparum, and its plasma concentration reflects the total body parasite burden.,We aimed to define the malaria-attributable fraction of severe febrile illness, using the distributions of plasma P. falciparum HRP2 (PfHRP2) concentrations from parasitemic children with different clinical presentations.,Methods.,Plasma samples were collected from and peripheral blood slides prepared for 1435 children aged 6−60 months in communities and a nearby hospital in northeastern Tanzania.,The study population included children with severe or uncomplicated malaria, asymptomatic carriers, and healthy control subjects who had negative results of rapid diagnostic tests.,The distributions of plasma PfHRP2 concentrations among the different groups were used to model severe malaria-attributable disease.,Results.,The plasma PfHRP2 concentration showed a close correlation with the severity of infection.,PfHRP2 concentrations of >1000 ng/mL denoted a malaria-attributable fraction of severe disease of 99% (95% credible interval [CI], 96%-100%), with a sensitivity of 74% (95% CI, 72%-77%), whereas a concentration of <200 ng/mL denoted severe febrile illness of an alternative diagnosis in >10% (95% CI, 3%-27%) of patients.,Bacteremia was more common among patients in the lowest and highest PfHRP2 concentration quintiles.,Conclusions.,The plasma PfHRP2 concentration defines malaria-attributable disease and distinguishes severe malaria from coincidental parasitemia in African children in a moderate-to-high transmission setting.

The post-translational addition of C-16 long chain fatty acids to protein cysteine residues is catalysed by palmitoyl-S-acyl-transferases (PAT) and affects the affinity of a modified protein for membranes and therefore its subcellular localisation.,In apicomplexan parasites this reversible protein modification regulates numerous biological processes and specifically affects cell motility, and invasion of host cells by Plasmodium falciparum merozoites and Toxoplasma gondii tachyzoites.,Using inhibitor studies we show here that palmitoylation is key to transformation of zygotes into ookinetes during initial mosquito infection with P. berghei.,We identify DHHC2 as a unique PAT mediating ookinete formation and morphogenesis.,Essential for life cycle progression in asexual blood stage parasites and thus refractory to gene deletion analyses, we used promoter swap (ps) methodology to maintain dhhc2 expression in asexual blood stages but down regulate expression in sexual stage parasites and during post-fertilization development of the zygote.,The ps mutant showed normal gamete formation, fertilisation and DNA replication to tetraploid cells, but was characterised by a complete block in post-fertilisation development and ookinete formation.,Our report highlights the crucial nature of the DHHC2 palmitoyl-S-acyltransferase for transmission of the malaria parasite to the mosquito vector through its essential role for ookinete morphogenesis.

The passage through the mosquito is a major bottleneck for malaria parasite populations and a target of interventions aiming to block disease transmission.,Here, we used DNA microarrays to profile the developmental transcriptomes of the rodent malaria parasite Plasmodium berghei in vivo, in the midgut of Anopheles gambiae mosquitoes, from parasite stages in the midgut blood bolus to sporulating oocysts on the basal gut wall.,Data analysis identified several distinct transcriptional programmes encompassing genes putatively involved in developmental processes or in interactions with the mosquito.,At least two of these programmes are associated with the ookinete development that is linked to mosquito midgut invasion and establishment of infection.,Targeted disruption by homologous recombination of two of these genes resulted in mutant parasites exhibiting notable infection phenotypes.,GAMER encodes a short polypeptide with granular localization in the gametocyte cytoplasm and shows a highly penetrant loss-of-function phenotype manifested as greatly reduced ookinete numbers, linked to impaired male gamete release.,HADO encodes a putative magnesium phosphatase with distinctive cortical localization along the concave ookinete periphery.,Disruption of HADO compromises ookinete development leading to significant reduction of oocyst numbers.,Our data provide important insights into the molecular framework underpinning Plasmodium development in the mosquito and identifies two genes with important functions at initial stages of parasite development in the mosquito midgut.

Background: Malaria is one of the infectious diseases of greatest interest to the scientific community and of greatest concern to international health authorities.,Traditionally, the focus has been on Plasmodium falciparum, the parasite that causes the most severe form of the disease in Africa.,However, in the last twenty years, the Plasmodium vivax parasite, responsible for a large number of cases in Latin America, the Middle East, South and Southeast Asia, the Horn of Africa, and Oceania, has also generated enormous interest due, among other things, to the published evidence that it can cause severe malaria.,Methods: In this paper, the international scientific publication on malaria and P. vivax has been analyzed using the Scopus database to try to define global trends in this field of study.,Results: It has been shown that events such as the emergence of resistance to certain drugs can break a trend.,The important role of non-malaria-endemic countries such as the USA or Switzerland in malaria research is also evident.,Conclusions: International cooperation will be essential for the eradication of the disease.,Moreover, in this sense, the general vision given by the bibliometric analysis of malaria caused by P. vivax is fundamental to paint the picture regarding the current situation and encourage international cooperation and control efforts.

We describe a case series of 17 patients hospitalized in Manaus (western Brazilian Amazon) with PCR-confirmed Plasmodium vivax infection who were treated with chloroquine and primaquine.,The major complications were jaundice and severe anemia.,No in vivo chloroquine resistance was detected.,These data help characterize the clinical profile of severe P. vivax malaria in Latin America.

Plasmodium ovale curtisi and wallikeri are perceived as relapsing malarial parasites.,Contrary to Plasmodium vivax, direct evidence for this hypothesis is scarce.,The aim of this prospective study was to characterize the reappearance patterns of ovale parasites.,P. ovale spp. infected patients were treated with artemether-lumefantrine and followed biweekly for up to 1 year for the detection of reappearing parasitemia.,Molecular analysis of reappearing isolates was performed to identify homologous isolates by genotyping and to define cases of relapse following predefined criteria.,At inclusion, 26 participants were positive for P. ovale curtisi and/or P. ovale wallikeri.,The median duration of follow-up was 35 weeks.,Reappearance of the same P. ovale species was observed in 46% of participants; 61% of P. ovale curtisi and 19% of P. ovale wallikeri infection-free intervals were estimated to end with reappearance by week 32.,Based on the predefined criteria, 23% of participants were identified with 1 or 2 relapses, all induced by P. ovale curtisi.,These findings are in line with the currently accepted relapse theory inasmuch as the reappearance of P. ovale curtisi strains following initial blood clearance was conclusively demonstrated.,Interestingly, no relapse of P. ovale wallikeri was observed.,The formation of hypnozoites and consequential relapse of tertian malaria is a widely accepted theory that lacks, however, confirmation for Plasmodium ovale spp.,This study clinically and molecularly evaluates reappearing P. ovale spp. parasites to provide new evidence.

Sequencing data from Plasmodium ovale genotypes co-circulating in multiple countries support the hypothesis that P. ovale curtisi and P. ovale wallikeri are 2 separate species.,We conducted a multicenter, retrospective, comparative study in Spain of 21 patients who had imported P. ovale curtisi infections and 14 who had imported P. ovale wallikeri infections confirmed by PCR and gene sequencing during June 2005-December 2011.,The only significant finding was more severe thrombocytopenia among patients with P. ovale wallikeri infection than among those with P. ovale curtisi infection (p = 0.031).,However, we also found nonsignificant trends showing that patients with P. ovale wallikeri infection had shorter time from arrival in Spain to onset of symptoms, lower level of albumin, higher median maximum core temperature, and more markers of hemolysis than did those with P. ovale curtisi infection.,Larger, prospective studies are needed to confirm these findings.

There is substantial variation in the relapse frequency of Plasmodium vivax malaria, with fast-relapsing strains in tropical areas, and slow-relapsing strains in temperate areas with seasonal transmission.,We hypothesize that much of the phenotypic diversity in P. vivax relapses arises from selection of relapse frequency to optimize transmission potential in a given environment, in a process similar to the virulence trade-off hypothesis.,We develop mathematical models of P. vivax transmission and calculate the basic reproduction number R0 to investigate how transmission potential varies with relapse frequency and seasonality.,In tropical zones with year-round transmission, transmission potential is optimized at intermediate relapse frequencies of two to three months: slower-relapsing strains increase the opportunity for onward transmission to mosquitoes, but also increase the risk of being outcompeted by faster-relapsing strains.,Seasonality is an important driver of relapse frequency for temperate strains, with the time to first relapse predicted to be six to nine months, coinciding with the duration between seasonal transmission peaks.,We predict that there is a threshold degree of seasonality, below which fast-relapsing tropical strains are selected for, and above which slow-relapsing temperate strains dominate, providing an explanation for the observed global distribution of relapse phenotypes.

As successful malaria control programmes re-orientate towards elimination, the identification of transmission foci, targeting of attack measures to high-risk areas and management of importation risk become high priorities.,When resources are limited and transmission is varying seasonally, approaches that can rapidly prioritize areas for surveillance and control can be valuable, and the most appropriate attack measure for a particular location is likely to differ depending on whether it exports or imports malaria infections.,Here, using the example of Namibia, a method for targeting of interventions using surveillance data, satellite imagery, and mobile phone call records to support elimination planning is described.,One year of aggregated movement patterns for over a million people across Namibia are analyzed, and linked with case-based risk maps built on satellite imagery.,By combining case-data and movement, the way human population movements connect transmission risk areas is demonstrated.,Communities that were strongly connected by relatively higher levels of movement were then identified, and net export and import of travellers and infection risks by region were quantified.,These maps can aid the design of targeted interventions to maximally reduce the number of cases exported to other regions while employing appropriate interventions to manage risk in places that import them.,The approaches presented can be rapidly updated and used to identify where active surveillance for both local and imported cases should be increased, which regions would benefit from coordinating efforts, and how spatially progressive elimination plans can be designed.,With improvements in surveillance systems linked to improved diagnosis of malaria, detailed satellite imagery being readily available and mobile phone usage data continually being collected by network providers, the potential exists to make operational use of such valuable, complimentary and contemporary datasets on an ongoing basis in infectious disease control and elimination.

Distribution campaigns for insecticide-treated nets (ITN) have increased the use of ITNs in Malawi, but malaria prevalence remains high even among those using the nets.,Previous studies have addressed ITN ownership, insecticide resistance, and frequency of ITN use as possible contributing factors to the high prevalence of malaria infection despite high ITN coverage, but have rarely considered whether the condition of the ITN, or how many people use it, impacts efficacy.,This study assessed how ITN integrity, ITN age, and the number of persons sharing a net might mitigate or reduce protective efficacy among self-identified ITN users in Malawi.,From 2012 to 2014, six cross-sectional surveys were conducted in both the rainy and dry seasons in southern Malawi.,Data were collected on ITN use, integrity (number and size of holes), and age.,Blood samples for detecting Plasmodium falciparum infection were obtained from reported ITN users over 6 months of age.,Generalized linear mixed models were used to account for clustering at the household and community level.,The final model controlled for gender, household eaves, and community-level infection prevalence during the rainy season.,There were 9646 ITN users with blood samples across six surveys, 15% of whom tested positive for P. falciparum infection.,Among children under 5 years old, there was a 50% increased odds of P. falciparum infection among those sleeping under an ITN older than two years, compared to those using an ITN less than 2 years old (OR = 1.50; 95% CI 1.07-2.08).,ITN integrity and number of individuals sharing an ITN were not associated with P. falciparum infection.,Older ITNs were associated with higher rates of P. falciparum in young children, which may indicate that insecticide concentrations play a larger role in infection prevention than the physical barrier of an ITN.,ITN use was self-reported and the integrity measures lacked the precision of newer methods, suggesting a need for objective measures of ITN use and more precise assessment of ITN integrity.

Pyrethroid resistance in the major malaria vector Anopheles funestus is rapidly expanding across Southern Africa.,It remains unknown whether this resistance has a unique origin with the same molecular basis or is multifactorial.,Knowledge of the origin, mechanisms and evolution of resistance are crucial to designing successful resistance management strategies.,Here, we established the resistance profile of a Zambian An. funestus population at the northern range of the resistance front.,Similar to other Southern African populations, Zambian An. funestus mosquitoes are resistant to pyrethroids and carbamate, but in contrast to populations in Mozambique and Malawi, these insects are also DDT resistant.,Genome-wide microarray-based transcriptional profiling and qRT-PCR revealed that the cytochrome P450 gene CYP6M7 is responsible for extending pyrethroid resistance northwards.,Indeed, CYP6M7 is more over-expressed in Zambia [fold-change (FC) 37.7; 13.2 for qRT-PCR] than CYP6P9a (FC15.6; 8.9 for qRT-PCR) and CYP6P9b (FC11.9; 6.5 for qRT-PCR), whereas CYP6P9a and CYP6P9b are more highly over-expressed in Malawi and Mozambique.,Transgenic expression of CYP6M7 in Drosophila melanogaster coupled with in vitro assays using recombinant enzymes and assessments of kinetic properties demonstrated that CYP6M7 is as efficient as CYP6P9a and CYP6P9b in conferring pyrethroid resistance.,Polymorphism patterns demonstrate that these genes are under contrasting selection forces: the exceptionally diverse CYP6M7 likely evolves neutrally, whereas CYP6P9a and CYP6P9b are directionally selected.,The higher variability of CYP6P9a and CYP6P9b observed in Zambia supports their lesser role in resistance in this country.,Pyrethroid resistance in Southern Africa probably has multiple origins under different evolutionary forces, which may necessitate the design of different resistance management strategies.,The online version of this article (doi:10.1186/1471-2164-15-817) contains supplementary material, which is available to authorized users.

Botswana is one of eight SADC countries targeting malaria elimination by 2018.,Through spirited upscaling of control activities and passive surveillance, significant reductions in case incidence of Plasmodium falciparum (0.96 - 0.01) was achieved between 2008 and 2012.,As part of the elimination campaign, active detection of asymptomatic Plasmodium species by a highly sensitive method was deemed necessary.,This study was carried out to determine asymptomatic Plasmodium species carriage by nested PCR in the country, in 2012.,A cross-sectional study involving 3924 apparently healthy participants were screened for Plasmodium species in 14 districts (5 endemic: Okavango, Ngami, Tutume, Boteti and Bobirwa; and 9 epidemic: North East, Francistown, Serowe-Palapye, Ghanzi, Kweneng West, Kweneng East, Kgatleng, South East, and Good Hope).,Venous blood was taken from each participant for a nested PCR detection of Plasmodium species.,The parasite rates of asymptomatic Plasmodium species detected were as follows: Plasmodium falciparum, 0.16 %; Plasmodium vivax, 4.66 %; Plasmodium malariae, (Pm) 0.16 %; Plasmodium ovale, 0 %, mixed infections (P. falciparum and P. vivax), 0.055 %; and (P. vivax and P. malariae), 0.027 %, (total: 5.062 %).,The high proportion of asymptomatic reservoir of P. vivax was clustered in the East, South Eastern and Central districts of the country.,There appeared to be a correlation between the occurrence of P. malariae infection with P. vivax infection, with the former only occurring in districts that had substantial P. vivax circulation.,The median age among 2-12 year olds for P. vivax infection was 5 years (Mean 5.13 years, interquartile range 3-7 years).,The odds of being infected with P. vivax decreased by 7 % for each year increase in age (OR 0.93, 95 % CI 0.87-1.00, p = 0.056).,We have confirmed low parasite rate of asymptomatic Plasmodium species in Botswana, with the exception of P.vivax which was unexpectedly high.,This has implication for the elimination campaign so a follow up study is warranted to inform decisions on new strategies that take this evidence into account in the elimination campaign.

Plasmodium knowlesi is a potentially life-threatening zoonotic malaria parasite due to its relatively short erythrocytic cycle.,Microscopic identification of P. knowlesi is difficult, with “compacted parasite cytoplasm” being one of the important identifying keys.,This report is about a case of hyperparasitaemic human P. knowlesi infection (27% parasitaemia) with atypical amoeboid morphology.,A peninsular Malaysian was admitted to the hospital with malaria.,He suffered anaemia and acute kidney function impairment.,Microscopic examination, assisted by nested PCR and sequencing confirmed as P. knowlesi infection.,With anti-malarial treatment and several medical interventions, patient survived and recovered.,One-month medical follow-up was performed after recovery and no recrudescence was noted.,This case report highlights the extreme hyperparasitaemic setting, the atypical morphology of P. knowlesi in the patient’s erythrocytes, as well as the medical interventions involved in this successfully treated case.

Leishmaniasis is endemic in southern Europe, and in other European countries cases are diagnosed in travellers who have visited affected areas both within the continent and beyond.,Prompt and accurate diagnosis poses a challenge in clinical practice in Europe.,Different methods exist for identification of the infecting Leishmania species.,Sixteen clinical laboratories in 10 European countries, plus Israel and Turkey, conducted a study to assess their genotyping performance.,DNA from 21 promastigote cultures of 13 species was analysed blindly by the routinely used typing method.,Five different molecular targets were used, which were analysed with PCR-based methods.,Different levels of identification were achieved, and either the Leishmania subgenus, species complex, or actual species were reported.,The overall error rate of strains placed in the wrong complex or species was 8.5%.,Various reasons for incorrect typing were identified.,The study shows there is considerable room for improvement and standardisation of Leishmania typing.,The use of well validated standard operating procedures is recommended, covering testing, interpretation, and reporting guidelines.,Application of the internal transcribed spacer 1 of the rDNA array should be restricted to Old World samples, while the heat-shock protein 70 gene and the mini-exon can be applied globally.

Leishmaniases are tropical zoonotic diseases, caused by kinetoplastid parasites from the genus Leishmania.,New World (NW) species are related to sylvatic cycles although urbanization processes have been reported in some South American Countries such as Colombia.,Currently, few studies show the relative distribution of Leishmania species related to cutaneous Leishmaniasis (CL) in South America due to the lack of accurate surveillance and public health systems.,Herein, we conducted a systematic estimation of the Leishmania species causing CL in Colombia from 1980 to 2001 via molecular typing and isoenzymes.,A total of 327 Leishmania isolates from humans, sandflies and reservoirs were typed as L. panamensis 61.3% (201), L. braziliensis 27.1% (88), L. lainsoni 0.6% (2), L. guyanensis 0.9% (3), L. infantum chagasi 4% (12), L. equatoriensis 0.6% (2), L. mexicana 2.1% (8), L. amazonensis 2.8% (9) and L. colombiensis 0.6% (2).,This is the first report of two new Leishmania species circulating in Colombia and suggests the need to convince the Colombian government about the need to deploy and standardize tools for the species identification to provide adequate management to individuals suffering this pathology.