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There is an increased focus on whether mass drug administration (MDA) programmes alone can interrupt the transmission of soil-transmitted helminths (STH).,Mathematical models can be used to model these interventions and are increasingly being implemented to inform investigators about expected trial outcome and the choice of optimum study design.,One key factor is the choice of threshold for detecting elimination.,However, there are currently no thresholds defined for STH regarding breaking transmission.,We develop a simulation of an elimination study, based on the DeWorm3 project, using an individual-based stochastic disease transmission model in conjunction with models of MDA, sampling, diagnostics and the construction of study clusters.,The simulation is then used to analyse the relationship between the study end-point elimination threshold and whether elimination is achieved in the long term within the model.,We analyse the quality of a range of statistics in terms of the positive predictive values (PPV) and how they depend on a range of covariates, including threshold values, baseline prevalence, measurement time point and how clusters are constructed.,End-point infection prevalence performs well in discriminating between villages that achieve interruption of transmission and those that do not, although the quality of the threshold is sensitive to baseline prevalence and threshold value.,Optimal post-treatment prevalence threshold value for determining elimination is in the range 2% or less when the baseline prevalence range is broad.,For multiple clusters of communities, both the probability of elimination and the ability of thresholds to detect it are strongly dependent on the size of the cluster and the size distribution of the constituent communities.,Number of communities in a cluster is a key indicator of probability of elimination and PPV.,Extending the time, post-study endpoint, at which the threshold statistic is measured improves PPV value in discriminating between eliminating clusters and those that bounce back.,The probability of elimination and PPV are very sensitive to baseline prevalence for individual communities.,However, most studies and programmes are constructed on the basis of clusters.,Since elimination occurs within smaller population sub-units, the construction of clusters introduces new sensitivities for elimination threshold values to cluster size and the underlying population structure.,Study simulation offers an opportunity to investigate key sources of sensitivity for elimination studies and programme designs in advance and to tailor interventions to prevailing local or national conditions.

Lymphatic filariasis (LF) and soil-transmitted-helminths (STH) are co-endemic in 58 countries which are mostly in Africa and Asia.,Worldwide, 486 million school-age children are considered at risk of both diseases.,In 2000, the World Health Organization (WHO) established the global programme to eliminate LF by 2020.,Since then, the LF elimination programme has distributed ivermectin or diethylcarbamazine citrate (DEC) in combination with albendazole, thereby also treating STH.,Consequently, many school-age children have been treated for STH through the LF programme.,As treatment targets towards the 2020 LF elimination goal are achieved, many countries are implementing the transmission assessment survey (TAS) and, if the LF prevalence is estimated to be less than 1%, scaling down mass drug administration (MDA).,We analysed the 2014 data on preventive chemotherapy (PC) reported from LF STH co-endemic countries and projected the year and location of TAS expected to be conducted between 2016 and 2020 to assess the impact of this scaling down on STH PC.,Eighty percent of all co-endemic countries that have already stopped LF MDA nationally were able to establish STH PC through schools.,It is estimated that 14% of the total number of children presently covered by the LF programme is at risk of not continuing to receive PC for STH.,In order to achieve and maintain the WHO 2020 goal for STH control, there is an urgent need to establish and reinforce school-based deworming programmes in countries scaling-down national LF elimination programmes.

Antibodies to P. falciparum apical membrane protein 1 (AMA1) may contribute to protective immunity against clinical malaria by inhibiting blood stage growth of P. falciparum, and AMA1 is a leading malaria vaccine candidate.,Currently, there is limited knowledge of the acquisition of strain-specific and cross-reactive antibodies to AMA1 in humans, or the acquisition of invasion-inhibitory antibodies to AMA1.,We examined the acquisition of human antibodies to specific polymorphic invasion-inhibitory and non-inhibitory AMA1 epitopes, defined by the monoclonal antibodies 1F9 and 2C5, respectively.,Naturally acquired antibodies were measured in cohorts of Kenyan children and adults.,Antibodies to the invasion-inhibitory 1F9 epitope and non-inhibitory 2C5 epitope were measured indirectly by competition ELISA.,Antibodies to the 1F9 and 2C5 epitopes were acquired by children and correlated with exposure, and higher antibody levels and prevalence were observed with increasing age and with active P. falciparum infection.,Of note, the prevalence of antibodies to the inhibitory 1F9 epitope was lower than antibodies to AMA1 or the 2C5 epitope.,Antibodies to AMA1 ectodomain, the 1F9 or 2C5 epitopes, or a combination of responses, showed some association with protection from P. falciparum malaria in a prospective longitudinal study.,Furthermore, antibodies to the invasion-inhibitory 1F9 epitope were positively correlated with parasite growth-inhibitory activity of serum antibodies.,Individuals acquire antibodies to functional, polymorphic epitopes of AMA1 that may contribute to protective immunity, and these findings have implications for AMA1 vaccine development.,Measuring antibodies to the 1F9 epitope by competition ELISA may be a valuable approach to assessing human antibodies with invasion-inhibitory activity in studies of acquired immunity and vaccine trials of AMA1.

Acquired immunity in vertebrates maintains polymorphisms in endemic pathogens, leading to identifiable signatures of balancing selection.,To comprehensively survey for genes under such selection in the human malaria parasite Plasmodium falciparum, we generated paired-end short-read sequences of parasites in clinical isolates from an endemic Gambian population, which were mapped to the 3D7 strain reference genome to yield high-quality genome-wide coding sequence data for 65 isolates.,A minority of genes did not map reliably, including the hypervariable var, rifin, and stevor families, but 5,056 genes (90.9% of all in the genome) had >70% sequence coverage with minimum read depth of 5 for at least 50 isolates, of which 2,853 genes contained 3 or more single nucleotide polymorphisms (SNPs) for analysis of polymorphic site frequency spectra.,Against an overall background of negatively skewed frequencies, as expected from historical population expansion combined with purifying selection, the outlying minority of genes with signatures indicating exceptionally intermediate frequencies were identified.,Comparing genes with different stage-specificity, such signatures were most common in those with peak expression at the merozoite stage that invades erythrocytes.,Members of clag, PfMC-2TM, surfin, and msp3-like gene families were highly represented, the strongest signature being in the msp3-like gene PF10_0355.,Analysis of msp3-like transcripts in 45 clinical and 11 laboratory adapted isolates grown to merozoite-containing schizont stages revealed surprisingly low expression of PF10_0355.,In diverse clonal parasite lines the protein product was expressed in a minority of mature schizonts (<1% in most lines and ∼10% in clone HB3), and eight sub-clones of HB3 cultured separately had an intermediate spectrum of positive frequencies (0.9 to 7.5%), indicating phase variable expression of this polymorphic antigen.,This and other identified targets of balancing selection are now prioritized for functional study.

Insecticide-based interventions have averted more than 500 million malaria cases since 2000, but insecticide resistance in mosquitoes could bring about a rebound in disease and mortality.,This study investigated whether insecticide resistance was associated with increased incidence of clinical malaria.,In an area of southern Benin with insecticide resistance and high use of insecticide-treated nets (ITNs), malaria morbidity and insecticide resistance were measured simultaneously in 30 clusters (villages or collections of villages) multiple times over the course of 2 years.,Insecticide resistance frequencies were measured using the standard World Health Organization bioassay test.,Malaria morbidity was measured by cases recorded at health facilities both in the whole population using routinely collected data and in a passively followed cohort of children under 5 years old.,There was no evidence that incidence of malaria from routinely collected data was higher in clusters with resistance frequencies above the median, either in children aged under 5 (RR = 1.27 (95% CI 0.81-2.00) p = 0.276) or in individuals aged 5 or over (RR = 1.74 (95% CI 0.91-3.34) p = 0.093).,There was also no evidence that incidence was higher in clusters with resistance frequencies above the median in the passively followed cohort (RR = 1.11 (0.52-2.35) p = 0.777).,This study found no association between frequency of resistance and incidence of clinical malaria in an area where ITNs are the principal form of vector control.,This may be because, as other studies have shown, ITNs continue to offer some protection from malaria even in the presence of insecticide resistance.,Irrespective of resistance, nets provide only partial protection so the development of improved or supplementary vector control tools is required to reduce Africa’s unacceptably high malaria burden.

Indoor residual spraying (IRS) is an important part of malaria control.,There is a growing list of insecticide classes; pyrethroids remain the principal insecticide used in bednets but recently, novel non-pyrethroid IRS products, with contrasting impacts, have been introduced.,There is an urgent need to better assess product efficacy to help decision makers choose effective and relevant tools for mosquito control.,Here we use experimental hut trial data to characterise the entomological efficacy of widely-used, novel IRS insecticides.,We quantify their impact against pyrethroid-resistant mosquitoes and use a Plasmodium falciparum transmission model to predict the public health impact of different IRS insecticides.,We report that long-lasting IRS formulations substantially reduce malaria, though their benefit over cheaper, shorter-lived formulations depends on local factors including bednet use, seasonality, endemicity and pyrethroid resistance status of local mosquito populations.,We provide a framework to help decision makers evaluate IRS product effectiveness.,Indoor residual spraying is a commonly used method for mosquito, and malaria, control and there are a number of available insecticides that are available for this.,Here, the authors evaluate the efficacy of widely-used and novel insecticides against pyrethroid-resistant mosquitoes.

This new resistance will have serious effects on malaria control.,Malaria control is dependent on insecticides.,Increases in prevalence of insecticide resistance in malaria vectors across Africa are well-documented.,However, few attempts have been made to quantify the strength of this resistance and link it to the effectiveness of control tools.,Using quantitative bioassays, we show that in Burkina Faso pyrethroid resistance in Anopheles gambiae mosquitoes has increased in intensity in recent years and now exceeds 1,000-fold.,In laboratory assays, this level of resistance renders insecticides used to impregnate bed nets ineffective.,Thus, the level of personal and community protection afforded by long-lasting insecticide-treated net campaigns will probably be reduced.,Standardized methods are needed to quantify resistance levels in malaria vectors and link these levels to failure of vector control methods.

Traps baited with synthetic human odors have been proposed as suitable technologies for controlling malaria and other mosquito-borne diseases.,We investigated the potential benefits of such traps for preventing malaria transmission in Africa and the essential characteristics that they should possess so as to be effective.,An existing mathematical model was reformulated to distinguish availability of hosts for attack by mosquitoes from availability of blood per se.,This adaptation allowed the effects of pseudo-hosts such as odor-baited mosquito traps, which do not yield blood but which can nonetheless be attacked by the mosquitoes, to be simulated considering communities consisting of users and non-users of insecticide-treated nets (ITNs), currently the primary malaria prevention method.,We determined that malaria transmission declines as trap coverage (proportion of total availability of all hosts and pseudo hosts that traps constitute) increases.,If the traps are more attractive than humans and are located in areas where mosquitoes are most abundant, 20-130 traps per 1000 people would be sufficient to match the impact of 50% community-wide ITN coverage.,If such traps are used to complement ITNs, malaria transmission can be reduced by 99% or more in most scenarios representative of Africa.,However, to match cost-effectiveness of ITNs, the traps delivery, operation and maintenance would have to cost a maximum of US$4.25 to 27.61 per unit per year.,Odor-baited mosquito traps might potentially be effective and affordable tools for malaria control in Africa, particularly if they are used to complement, rather than replace, existing methods.,We recommend that developers should focus on super-attractive baits and cheaper traps to enhance cost-effectiveness, and that the most appropriate way to deploy such technologies is through vertical delivery mechanisms.

Restoring protection requires innovation combining pyrethroids and novel insecticides.,Pyrethroid resistance is becoming widespread in Anopheles gambiae mosquitoes, coinciding with expanded use of insecticide-treated nets (ITNs) throughout Africa.,To investigate whether nets in use are still protective, we conducted household trials in northern and southern Benin, where An. gambiae mosquitoes are susceptible and resistant, respectively, to pyrethroids.,Rooms were fitted with window traps and monitored for mosquito biting and survival rates before and after the nets were treated with pyrethroid.,Sleeping under an ITN in the location with resistant mosquitoes was no more protective than sleeping under an untreated net, regardless of its physical condition.,By contrast, sleeping under an ITN in the location with susceptible mosquitoes decreased the odds of biting by 66%.,ITNs provide little or no protection once the mosquitoes become resistant and the netting acquires holes.,Resistance seriously threatens malaria control strategies based on ITN.

There is little information on the social perception of malaria and the use of prevention methods in Cameroon.,This study was designed to assess knowledge, attitude and management of malaria in households living in the cities of Douala and Yaoundé.,Over 82% of people interviewed associated malaria transmission to mosquito bites.,Methods used for malaria prevention were: environmental sanitation 1645 (76.1%), use of bed nets 1491 (69%), insecticide spray/coils 265 (12.3%) and netting of doors or windows 42 (1.9%).,Bed net ownership was significantly high in Yaoundé (73.8%) (P < 0.0001), whereas the use of insecticide spray or coils was significantly important in Douala (16.3%) (P < 0.0001).,Some of the problems experienced by families using ITN were the difficulty in finding chemicals for the retreatment of nets 702 (47%), insufficient financial means to buy new bed nets to replace old ones 366 (24.5%) or, to provide bed nets to everybody in the household 289 (19.4%) and the sensation of feeling excessive heat when sleeping under a bed net 74 (5%).,The amount spent monthly by a household for vector control and malaria treatment was estimated at 2377 fcfa (3.6 euros) and 4562 fcfa (6.95 euros) respectively.,These amounts were not significantly different between households of Douala and Yaoundé.,Concerning management of malaria cases, 18.6% of people declare going to the hospital when suffering from malaria.,The majority of people (81.4%) do self medication - they either buy drugs from the pharmacists, street sellers or they use plants to cure malaria.,The study revealed a high awareness of populations on malaria and ITNs.,However some attitudes hindering the use of ITN or related to the management of clinical cases need further attention.

To investigate the effectiveness of seasonal malaria chemoprevention (SMC) and community case management with long‐acting artemisinin‐based combination therapies (ACTs) for the control of malaria in areas of extended seasonal malaria transmission.,Individually randomised, placebo‐controlled trial in the Ashanti Region of Ghana.,A total of 2400 children aged 3-59 months received either: (i) a short‐acting ACT for case management of malaria (artemether‐lumefantrine, AL) plus placebo SMC, or (ii) a long‐acting ACT (dihydroartemisinin‐piperaquine, DP) for case management plus placebo SMC or (iii) AL for case management plus active SMC with sulphadoxine‐pyrimethamine and amodiaquine.,SMC or placebo was delivered on five occasions during the rainy season.,Malaria cases were managed by community health workers, who used rapid diagnostic tests to confirm infection prior to treatment.,The incidence of malaria was lower in children given SMC during the rainy season.,Compared to those given placebo SMC and AL for case management, the adjusted hazard ratio (aHR) was 0.62 (95% CI: 0.41, 0.93), P = 0.020 by intention to treat and 0.53 (95% CI: 0.29, 0.95), P = 0.033 among children given five SMC courses.,There were no major differences between groups given different ACTs for case management (aHR DP vs.,AL 1.18 (95% CI 0.83, 1.67), P = 0.356).,SMC may have an important public health impact in areas with a longer transmission season, but further optimisation of SMC schedules is needed to maximise its impact in such settings.

Results from trials of intermittent preventive treatment (IPT) in infants and children have shown that IPT provides significant protection against clinical malaria.,Sulfadoxine-pyrimethamine (SP) given alone or in combination with other drugs has been used for most IPT programmes.,However, SP resistance is increasing in many parts of Africa.,Thus, we have investigated whether SP plus AQ, SP plus piperaquine (PQ) and dihydroartemisinin (DHA) plus PQ might be equally safe and effective when used for IPT in children in an area of seasonal transmission.,During the 2007 malaria transmission season, 1008 Gambian children were individually randomized to receive SP plus amodiaquine (AQ), SP plus piperaquine (PQ) or dihydroartemisinin (DHA) plus PQ at monthly intervals on three occasions during the peak malaria transmission season.,To determine the risk of side effects following drug administration, participants in each treatment group were visited at home three days after the start of each round of drug administration and a side effects questionnaire completed.,To help establish whether adverse events were drug related, the same questionnaire was administered to 286 age matched control children recruited from adjacent villages.,Morbidity was monitored throughout the malaria transmission season and study children were seen at the end of the malaria transmission season.,All three treatment regimens showed good safety profiles.,No severe adverse event related to IPT was reported.,The most frequent adverse events reported were coughing, diarrhoea, vomiting, abdominal pain and loss of appetite.,Cough was present in 15.2%, 15.4% and 18.7% of study subjects who received SP plus AQ, DHA plus PQ or SP plus PQ respectively, compared to 19.2% in a control group.,The incidence of malaria in the DHA plus PQ, SP plus AQ and SP plus PQ groups were 0.10 cases per child year (95% CI: 0.05, 0.22), 0.06 (95% CI: 0.022, 0.16) and 0.06 (95% CI: 0.02, 0.15) respectively.,The incidence of malaria in the control group was 0.79 cases per child year (0.58, 1.08).,All the three regimens of IPT in children were safe and highly efficacious,ClinicalTrials.gov NCT00561899

The filarial nematode Brugia malayi is an etiological agent of Lymphatic Filariasis.,The capability of B. malayi and other parasitic nematodes to modulate host biology is recognized but the mechanisms by which such manipulation occurs are obscure.,An emerging paradigm is the release of parasite-derived extracellular vesicles (EV) containing bioactive proteins and small RNA species that allow secretion of parasite effector molecules and their potential trafficking to host tissues.,We have previously described EV release from the infectious L3 stage B. malayi and here we profile vesicle release across all intra-mammalian life cycle stages (microfilariae, L3, L4, adult male and female worms).,Nanoparticle Tracking Analysis was used to quantify and size EVs revealing discrete vesicle populations and indicating a secretory process that is conserved across the life cycle.,Brugia EVs are internalized by murine macrophages with no preference for life stage suggesting a uniform mechanism for effector molecule trafficking.,Further, the use of chemical uptake inhibitors suggests all life stage EVs are internalized by phagocytosis.,Proteomic profiling of adult male and female EVs using nano-scale LC-MS/MS described quantitative and qualitative differences in the adult EV proteome, helping define the biogenesis of Brugia EVs and revealing sexual dimorphic characteristics in immunomodulatory cargo.,Finally, ivermectin was found to rapidly inhibit EV release by all Brugia life stages.,Further this drug effect was also observed in the related filarial nematode, the canine heartworm Dirofilaria immitis but not in an ivermectin-unresponsive field isolate of that parasite, highlighting a potential mechanism of action for this drug and suggesting new screening platforms for anti-filarial drug development.

Investigations of the relationships between the gut microbiota and gastrointestinal parasitic nematodes are attracting growing interest by the scientific community, driven by the need to better understand the contribution of parasite-associated changes in the composition of the gut flora to both host malnutrition and immune modulation.,These studies have however been carried out mainly in humans and experimental animals, while knowledge of the make-up of the gut commensal flora in presence or absence of infection by parasitic nematodes in domestic animals is limited.,In this study, we investigate the qualitative and quantitative impact that infections by a widespread parasite of cats (i.e.,Toxocara cati) exert on the gut microbiota of feline hosts.,The faecal microbiota of cats with patent infection by T. cati (= Tc+), as well as that of negative controls (= Tc-) was examined via high-throughput sequencing of the V3-V4 hypervariable region of the bacterial 16S rRNA gene, followed by bioinformatics and biostatistical analyses of sequence data.,A total of 2,325,366 useable high-quality sequences were generated from the faecal samples analysed in this study and subjected to further bioinformatics analyses, which led to the identification of 128 OTUs and nine bacterial phyla, respectively.,The phylum Firmicutes was predominant in all samples analysed (mean of 53.0%), followed by the phyla Proteobacteria (13.8%), Actinobacteria (13.7%) and Bacteroidetes (10.1%).,Among others, bacteria of the order Lactobacillales, the family Enterococcaceae and genera Enterococcus and Dorea showed a trend towards increased abundance in Tc+ compared with Tc- samples, while no significant differences in OTU richness and diversity were recorded between Tc+ and Tc- samples (P = 0.485 and P = 0.581, respectively).,However, Canonical Correlation and Redundancy Analyses were able to separate samples by infection status (P = 0.030 and P = 0.015, respectively), which suggests a correlation between the latter and the composition of the feline faecal microbiota.,In spite of the relatively small number of samples analysed, subtle differences in the composition of the gut microbiota of Tc+ vs Tc- cats could be identified, some of which in accordance with current data from humans and laboratory animal hosts.,Nevertheless, the findings from this study contribute valuable knowledge to the yet little explored area of parasite-microbiota interactions in domestic animals.,The online version of this article (doi:10.1186/s13071-016-1908-4) contains supplementary material, which is available to authorized users.

Insecticide-treated nets (ITNs) for malaria control are widespread but coverage remains inadequate.,We developed a Bayesian model using data from 102 national surveys, triangulated against delivery data and distribution reports, to generate year-by-year estimates of four ITN coverage indicators.,We explored the impact of two potential 'inefficiencies': uneven net distribution among households and rapid rates of net loss from households.,We estimated that, in 2013, 21% (17%-26%) of ITNs were over-allocated and this has worsened over time as overall net provision has increased.,We estimated that rates of ITN loss from households are more rapid than previously thought, with 50% lost after 23 (20-28) months.,We predict that the current estimate of 920 million additional ITNs required to achieve universal coverage would in reality yield a lower level of coverage (77% population access).,By improving efficiency, however, the 920 million ITNs could yield population access as high as 95%.,DOI:http://dx.doi.org/10.7554/eLife.09672.001,Malaria is a major cause of death in many parts of the world, especially in sub-Saharan Africa.,Recently, there has been a renewed emphasis on using preventive measures to reduce the deaths and illnesses caused by malaria.,Insecticide-treated nets are the most prominent preventive measure used in areas where malaria is particularly common.,However, despite huge international efforts to send enough nets to the regions that need them, the processes of delivering and distributing the nets are inefficient.,This problem is compounded by the fact that little information is available on how many nets people actually own and use within each country.,`,Bhatt et al. have now created a mathematical model that describes the use and distribution of nets across Africa since 2000.,This is based on data collected from national surveys and reports on the delivery and distribution of the nets.,The model estimates that in 2013, only 43% of people at risk of malaria slept under a net.,Furthermore, 21% of new nets were allocated to households that already had enough nets, an inefficiency that has worsened over the years.,Nets are also lost from households much more rapidly than previously thought.,It’s currently estimated that 920 million additional nets are required to ensure that everyone at risk from malaria in Africa is adequately protected.,However, Bhatt et al.’s model suggests that given the current inefficiencies in net distribution, the extra nets would in reality protect a much smaller proportion of the population.,Taking measures to more effectively target the nets to the households that need them could improve this coverage level to 95% of the population.,The next challenge is to devise distribution strategies to send nets to where they are most needed.,DOI:http://dx.doi.org/10.7554/eLife.09672.002

Elimination of malaria can only be achieved through removal of all vectors or complete depletion of the infectious reservoir in humans.,Mechanistic models can be built to synthesize diverse observations from the field collected under a variety of conditions and subsequently used to query the infectious reservoir in great detail.,The EMOD model of malaria transmission was calibrated to prevalence, incidence, asexual parasite density, gametocyte density, infection duration, and infectiousness data from nine study sites.,The infectious reservoir was characterized by age and parasite detectability with diagnostics of varying sensitivity over a range of transmission intensities with and without case management and vector control.,Mass screen-and-treat drug campaigns were tested for likelihood of achieving elimination.,The composition of the infectious reservoir is similar over a range of transmission intensities, and higher intensity settings are biased towards infections in children.,Recent ramp-ups in case management and use of insecticide-treated bed nets (ITNs) reduce the infectious reservoir and shift the composition towards sub-microscopic infections.,Mass campaigns with anti-malarial drugs are highly effective at interrupting transmission if deployed shortly after ITN campaigns.,Low-density infections comprise a substantial portion of the infectious reservoir.,Proper timing of vector control, seasonal variation in transmission intensity and mass drug campaigns allows lingering population immunity to help drive a region towards elimination.,The online version of this article (doi:10.1186/s12936-015-0751-y) contains supplementary material, which is available to authorized users.

Schistosomiasis is an important zoonotic parasitic disease that causes serious harms to humans and animals.,Surveillance and diagnosis play key roles in schistosomiasis control, however, current techniques for surveillance and diagnosis of the disease have limitations.,As genome data for parasites are increasing, novel techniques for detection incorporating nucleotide sequences are receiving widespread attention.,These sensitive, specific, and rapid detection methods are particularly important in the diagnosis of low-grade and early infections, and may prove to have clinical significance.,This paper reviews the progress of nucleic acid detection in the diagnosis and prevention of schistosomiasis, including such aspects as the selection of target genes, and development and application of nucleic acid detection methods.,The online version of this article (doi:10.1186/s40249-016-0116-y) contains supplementary material, which is available to authorized users.

In an effort to enhance accuracy of diagnosis of Schistosoma haematobium, this study explores day-to-day variability and diagnostic performance of real-time PCR for detection and quantification of Schistosoma DNA compared to other diagnostic tools in an endemic area before and after treatment.,Previously collected urine samples (N = 390) from 114 preselected proven parasitological and/or clinical S. haematobium positive Kenyan schoolchildren were analyzed by a Schistosoma internal transcribed spacer-based real-time PCR after 14 years of storage.,Pre-treatment day-to-day fluctuations of PCR and microscopy over three consecutive days were measured for 24 children using intra-class correlation coefficient.,A combined ‘gold standard’ (PCR and/or microscopy positive) was used to measure sensitivity and negative predictive value (NPV) of several diagnostic tools at baseline, two and 18 months post-treatment with praziquantel.,All 24 repeatedly tested children were PCR-positive over three days with little daily variation in median Ct-values, while 83.3% were found to be egg-positive for S. haematobium at day 1 and 75.0% at day 2 and 3 pre-treatment, signifying daily fluctuations in microscopy diagnosis.,Of all 114 preselected schoolchildren, repeated microscopic measurements were required to detect 96.5% versus 100% of positive pre-treatment cases by single PCR.,At two months post-treatment, microscopy and PCR detected 22.8% versus 69.3% positive children, respectively.,Based on the ‘gold standard’, PCR showed high sensitivity (>92%) as compared to >31% sensitivity for microscopy, both pre- and post-treatment.,Detection and quantification of Schistosoma DNA in urine by real-time PCR was shown to be a powerful and specific diagnostic tool for detection of S. haematobium infections, with less day-to-day variation and higher sensitivity compared to microscopy.,The superior performance of PCR before, and two and 18 months post-treatment provides a compelling argument for PCR as an accurate and reproducible tool for monitoring treatment efficacy.

Trypanosoma equiperdum causes dourine via sexual transmission in Equidae.,T. equiperdum is classified under the subgenus Trypanozoon along with the T. brucei sspp. and T. evansi; however, the species classification of Trypanozoon remains a controversial topic due to the limited number of T. equiperdum reference strains.,In addition, it is possible that some were misclassified T. evansi strains.,Thus, there is a strong need for a new T. equiperdum strain directly isolated from the genital mucosa of a horse with a clinically- and parasitologically-confirmed dourine infection.,Trypanosomes isolated from the urethral tract of a stallion with suspected dourine, were directly cultivated using soft agarose media at 37 °C in 5 % CO2.,For molecular characterization, 18S ribosomal RNA (rRNA) gene, the internal transcribed spacer (ITS) and 8 maxicircle DNA regions were amplified by a PCR and their sequences were determined.,To analyze the ratio of the kinetoplastic/akinetoplastic population, the kinetoplasts and the nuclei of trypanosomes were subjected to Hoechst staining and observed by fluorescence microscopy.,In addition to the clinical symptoms and the molecular diagnosis, this stallion was definitively diagnosed with dourine by the detection of trypanosomes in the urethral mucosa.,These results strongly suggested that the isolated trypanosome was true T. equiperdum.,T. equiperdum isolated from the urethral tract was adapted in vitro using soft agarose media.,Based on the results of a phylogenetic analysis of 18S rRNA and ITS, this T. equiperdum isolate was classified into the Trypanozoon clade.,In a PCR of the maxicircle DNA region, only NADH-dehydrogenase subunits 4 and 5 was amplified.,Clear kinetoplasts were observed in most of the T. equiperdum isolates.,In contrast, most culture-adapted T. equiperdum were of the akinetoplastic form.,We concluded that our isolated trypanosome was the first confirmed case of T. equiperdum in Mongolia and named it “T. equiperdum IVM-t1”.,T. equiperdum IVM-t1 was well adapted and propagated in soft agarose media, which indicates that this culture method is useful for isolation of T. equiperdum from horses with dourine.,The online version of this article (doi:10.1186/s13071-016-1755-3) contains supplementary material, which is available to authorized users.

Incidence of Leishmania donovani infection and Visceral Leishmaniasis (VL) was assessed in a prospective study in Indian and Nepalese high-endemic villages.,DAT-seroconversion was used as marker of incident infection in 3 yearly surveys.,The study population was followed up to month 30 to identify incident clinical cases.,In a cohort of 9034 DAT-negative individuals with neither active signs nor history of VL at baseline, 42 VL cases and 375 asymptomatic seroconversions were recorded in the first year, giving an infection∶disease ratio of 8.9 to 1.,In the 18 months' follow-up, 7 extra cases of VL were observed in the seroconverters group (N = 375), against 14 VL cases among the individuals who had not seroconverted in the first year (N = 8570) (RR = 11.5(4.5<RR<28.3)).,Incident asymptomatic L. donovani infection in VL high-endemic foci in India and Nepal is nine times more frequent than incident VL disease.,About 1 in 50 of these new but latent infections led to VL within the next 18 months.

Immunity to malaria is widely believed to wane in the absence of reinfection, but direct evidence for the presence or absence of durable immunological memory to malaria is limited.,Here, we analysed malaria-specific CD4+ T cell responses of individuals living in an area of low malaria transmission in northern Thailand, who had had a documented clinical attack of P. falciparum and/or P. vivax in the past 6 years.,CD4+ T cell effector memory (CD45RO+) IFN-γ (24 hours ex vivo restimulation) and cultured IL-10 (6 day secretion into culture supernatant) responses to malaria schizont antigens were detected only in malaria-exposed subjects and were more prominent in subjects with long-lived antibodies or memory B cells specific to malaria antigens.,The number of IFN-γ-producing effector memory T cells declined significantly over the 12 months of the study, and with time since last documented malaria infection, with an estimated half life of the response of 3.3 (95% CI 1.9-10.3) years.,In sharp contrast, IL-10 responses were sustained for many years after last known malaria infection with no significant decline over at least 6 years.,The observations have clear implications for understanding the immunoepidemiology of naturally acquired malaria infections and for malaria vaccine development.

Antibodies constitute a critical component of the naturally acquired immunity that develops following frequent exposure to malaria.,However, specific antibody titres have been reported to decline rapidly in the absence of reinfection, supporting the widely perceived notion that malaria infections fail to induce durable immunological memory responses.,Currently, direct evidence for the presence or absence of immune memory to malaria is limited.,In this study, we analysed the longevity of both antibody and B cell memory responses to malaria antigens among individuals who were living in an area of extremely low malaria transmission in northern Thailand, and who were known either to be malaria naïve or to have had a documented clinical attack of P. falciparum and/or P. vivax in the past 6 years.,We found that exposure to malaria results in the generation of relatively avid antigen-specific antibodies and the establishment of populations of antigen-specific memory B cells in a significant proportion of malaria-exposed individuals.,Both antibody and memory B cell responses to malaria antigens were stably maintained over time in the absence of reinfection.,In a number of cases where antigen-specific antibodies were not detected in plasma, stable frequencies of antigen-specific memory B cells were nonetheless observed, suggesting that circulating memory B cells may be maintained independently of long-lived plasma cells.,We conclude that infrequent malaria infections are capable of inducing long-lived antibody and memory B cell responses.

Regulatory T cells (Tregs) are a subset of T cells that play an important role in modulating T effector responses during infectious challenges.,The aim of this study was to evaluate possible associations between regulatory gene polymorphisms and the risk of uncomplicated malaria and the control of Plasmodium falciparum parasite density levels.,Twelve regulatory single nucleotide polymorphisms (SNPs) in the promoter regions of FOXP3 (ss270137548, rs11091253), IL10RA (rs56356146, rs7925112), IL10RB (rs8178433, rs8178435, rs999788), STAT6 (rs3024941, rs3024943, rs3024944) and TNFRSF18 (ss2080581728, rs3753344) were genotyped in a cohort of Congolese children.,Studied subjects were followed up (passively) during one year.,The children who experienced one or several clinical episodes were genotyped as “uncomplicated malaria” group (n=179) and those children who did not experience any episode were genotyped as “asymptomatic children” group (n=138).,The prevalence of rs3024944CC genotype of STAT6 was significantly higher in the group of asymptomatic children compared to that of uncomplicated malaria (P=0.003).,Similarly, the minor allele rs3024944C was more prevalent in the group of asymptomatic children (P=0.019).,Two novel SNPs were observed including -163T/G (ss491228441) in IL10RA gene and -163C/T (ss491228440) in TNFRSF18 gene.,The genotype ss491228441TT and the minor allele ss491228441G of the IL10RA were more frequent in the group of asymptomatic children (P=0.006 and P=0.007, respectively).,The genotype rs11091253CT of the FOXP3 was associated with high parasite density levels.,In addition, a new promoter IL10RA variant (ss491228441) contributes to shield against mild malaria.,The study indicated that the STAT6 promoter polymorphism rs3024944 was associated with uncomplicated malaria, whereas the FOXP3 promoter variant rs11091253 was associated with significant P. falciparum parasitaemia levels.,These genetic data may contribute to the understanding of molecular mechanisms that regulate immune response to P. falciparum infections.

RTS,S/AS01E is the lead candidate pre-erythrocytic malaria vaccine.,In Phase IIb field trials the safety profile was acceptable and the efficacy was 53% (95%CI 31%-72%) for protecting children against clinical malaria caused by P. falciparum.,We studied CS-specific T cell responses in order to identify correlates of protection.,We used intracellular cytokine staining (for IL2, IFNγ, and TNFα), ex-vivo ELISPOTs (IFNγ and IL2) and IFNγ cultured ELISPOT assays to characterize the CS-specific cellular responses in 407 children (5-17 months of age) in a phase IIb randomized controlled trial of RTS,S/AS01E (NCT00380393).,RTS,S/ AS01E vaccinees had higher frequencies of CS-specific CD4+ T cells producing IFNγ, TNFα or IL2 compared to control vaccinees.,In a multivariable analysis TNFα+ CD4+ T cells were independently associated with a reduced risk for clinical malaria among RTS,S/AS01E vaccinees (HR = 0.64, 95%CI 0.49-0.86, p = 0.002).,There was a non-significant tendency towards reduced risk among control vaccinees (HR = 0.80, 95%CI 0.62-1.03, p = 0.084), albeit with lower CS-specific T cell frequencies and higher rates of clinical malaria.,When data from both RTS,S/AS01E vaccinees and control vaccinees were combined (with adjusting for vaccination group), the HR was 0.74 (95%CI 0.62-0.89, p = 0.001).,After a Bonferroni correction for multiple comparisons (n-18), the finding was still significant at p = 0.018.,There was no significant correlation between cultured or ex vivo ELISPOT data and protection from clinical malaria.,The combination of TNFα+ CD4+ T cells and anti-CS antibody statistically accounted for the protective effect of vaccination in a Cox regression model.,RTS,S/AS01E induces CS-specific Th1 T cell responses in young children living in a malaria endemic area.,The combination of anti-CS antibody concentrations titers and CS-specific TNFα+ CD4+ T cells could account for the level of protection conferred by RTS,S/AS01E.,The correlation between CS-specific TNFα+ CD4+ T cells and protection needs confirmation in other datasets.

Fascioliasis is a zoonotic infection caused by a liver trematode: fasciola hepatica; which commonly affects cattle and sheep, humans are accidental hosts.,Several cases have been reported in the literature worldwide with a large geographical distribution.,We present a case of bile duct obstruction due to a hepatic fascioliasis, successfully treated with both a combined surgical and medical approaches.,A high index of suspicion should be kept in mind for all cases of obstructive jaundice, especially in areas in which human fascioliasis infection is repeatedly reported.

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

Glucose-6-phosphate dehydrogenase (G6PD) deficiency exhibits considerable allelic heterogeneity which manifests with variable biochemical and clinical penetrance.,It has long been thought that G6PD deficiency confers partial protection against severe malaria, however prior genetic association studies have disagreed with regard to the strength and specificity of a protective effect, which might reflect differences in the host genetic background, environmental influences, or in the specific clinical phenotypes considered.,A case-control association study of severe malaria was conducted in The Gambia, a region in West Africa where there is considerable allelic heterogeneity underlying expression of G6PD deficiency trait, evaluating the three major nonsynonymous polymorphisms known to be associated with enzyme deficiency (A968G, T542A, and C202T) in a cohort of 3836 controls and 2379 severe malaria cases.,Each deficiency allele exhibited a similar trend toward protection against severe malaria overall (15-26 % reduced risk); however, in stratifying severe malaria to two of its constituent clinical subphenotypes, severe malarial anaemia (SMA) and cerebral malaria (CM), the three deficiency alleles exhibited trends of opposing effect, with risk conferred to SMA and protection with respect to CM.,To assess the overall effect of G6PD deficiency trait, deficiency alleles found across all three loci were pooled.,G6PD deficiency trait was found to be significantly associated with protection from severe malaria overall (OR 0.83 [0.75-0.92], \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$P = 0.0006$$\end{document}P=0.0006), but this was limited to CM (OR 0.73 [0.61-0.87], \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$P = 0.0005$$\end{document}P=0.0005), with a trend toward increased risk for SMA, especially in fully-deficient individuals (OR 1.43 [0.99-2.08], \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$P = 0.056$$\end{document}P=0.056).,Sex-stratified testing largely comported with these results, with evidence suggesting that protection by G6PD deficiency trait is conferred to both males and females, though susceptibility to SMA may be restricted to fully-deficient male hemizygotes.,In a part of Africa where multiple alleles contribute to expression of G6PD deficiency trait, these findings clarify and extend previous work done in populations where a single variant predominates, and taken together suggest a causal role for G6PD deficiency trait itself with respect to severe malaria, with opposing effects seen on two major clinical subphenotypes.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is common in populations living in malaria endemic areas.,G6PD genotype and phenotype were determined for malaria patients enrolled in the chlorproguanil-dapsone-artesunate (CDA) phase III clinical trial programme.,Study participants, aged > 1 year, with microscopically confirmed uncomplicated Plasmodium falciparum malaria, and haemoglobin ≥ 70 g/L or haematocrit ≥ 25%, were recruited into two clinical trials conducted in six African countries (Burkina Faso, Ghana, Kenya, Nigeria, Tanzania, Mali).,G6PD genotype of the three most common African forms, G6PD*B, G6PD*A (A376G), and G6PD*A- (G202A, A542T, G680T and T968C), were determined and used for frequency estimation.,G6PD phenotype was assessed qualitatively using the NADPH fluorescence test.,Exploratory analyses investigated the effect of G6PD status on baseline haemoglobin concentration, temperature, asexual parasitaemia and anti-malarial efficacy after treatment with CDA 2/2.5/4 mg/kg or chlorproguanil-dapsone 2/2.5 mg/kg (both given once daily for three days) or six-dose artemether-lumefantrine.,Of 2264 malaria patients enrolled, 2045 had G6PD genotype available and comprised the primary analysis population (1018 males, 1027 females).,G6PD deficiency prevalence was 9.0% (184/2045; 7.2% [N = 147] male hemizygous plus 1.8% [N = 37] female homozygous), 13.3% (273/2045) of patients were heterozygous females, 77.7% (1588/2045) were G6PD normal.,All deficient G6PD*A- genotypes were A376G/G202A.,G6PD phenotype was available for 64.5% (1319/2045) of patients: 10.2% (134/1319) were G6PD deficient, 9.6% (127/1319) intermediate, and 80.2% (1058/1319) normal.,Phenotype test specificity in detecting hemizygous males was 70.7% (70/99) and 48.0% (12/25) for homozygous females.,Logistic regression found no significant effect of G6PD genotype on adjusted mean baseline haemoglobin (p = 0.154), adjusted mean baseline temperature (p = 0.9617), or adjusted log mean baseline parasitaemia (p = 0.365).,There was no effect of G6PD genotype (p = 0.490) or phenotype (p = 0.391) on the rate of malaria recrudescence, or reinfection (p = 0.134 and p = 0.354, respectively).,G6PD deficiency is common in African patients with malaria and until a reliable and simple G6PD test is available, the use of 8-aminoquinolines will remain problematic.,G6PD status did not impact baseline haemoglobin, parasitaemia or temperature or the outcomes of anti-malarial therapy.,Clinicaltrials.gov: NCT00344006 and NCT00371735.

Blood-sucking phlebotomine sand flies are the vectors of the protozoan parasites Leishmania spp.,Different Phlebotomus species transmit different Leishmania species causing leishmaniases which are neglected diseases emerging/reemerging in new regions.,Thirteen sand fly species, ten belonging to the medically important genus Phlebotomus and three belonging to Sergentomyia are known in Greece.,An increasing number of human and dog cases are reported each year from all parts of the country including the Aegean Islands.,However, no previous study has been conducted on the sand fly fauna on the islands, except for Rhodes and Samos.,The aim of this study was to investigate sand fly species in eleven small Aegean islands; to understand species-specific relationships with environmental and climatic factors and to compare sand fly community parameters among islands.,A risk analysis was carried out for each species using climatic and environmental variables.,Nine sand fly species: Phlebotomus neglectus, P. tobbi, P. similis, P. simici, P. perfiliewi, P. alexandri, P. papatasi, Sergentomyia minuta and S. dentata, were collected from the islands studied.,Phlebotomus (Adlerius) sp. and Sergentomyia sp. specimens were also collected but not identified to the species level.,There was a positive effect of distance from the sea on the abundance of P. neglectus, S. minuta and S. dentata, and a negative effect on the abundance of P. tobbi, P. simici and P. similis.,In general, temperature preferences of sand fly populations were between 21 and 29 °C.,Nevertheless, there were significant differences in terms of temperature and relative humidity preference ranges among species.,The most important species found, P. neglectus, was indisputably the most adapted species in the study area with a very high reaction norm, favoring even the lower temperature and humidity ranges.,Overall, the sand fly fauna in the islands was very rich but there were differences in species diversity, as indicated by the values of the Shannon-Wiener index, along with evenness and richness of the sand fly fauna between the islands and altitude ranges in the islands.,The study indicated that the Greek Aegean Islands, however small, maintain a rich sand fly fauna.,This includes important vectors of Leishmania spp. representing a risk for parasite transmission to humans and dogs along with the danger of maintaining new Leishmania spp. if introduced to the area.,The online version of this article (10.1186/s13071-018-2680-4) contains supplementary material, which is available to authorized users.

Leishmaniasis in Serbia was an endemic disease, and is considered to be eradicated for more than 40 years.,In the past decade sporadic cases of canine leishmaniasis started to emerge for the first time in Vojvodina Province (previously non-endemic region of Serbia).,Reports of introduced, and later on autochthonous cases of leishmaniasis alerted the possibility of disease emergence.,The aim of this study was to bridge more than a half a century wide gap in entomological surveillance of sand fly vectors in Vojvodina, as well as to verify the presence of the vector species that could support Leishmania spp. circulation.,During the period 2013-2015, a total of 136 sand flies were collected from 48 of 80 surveyed locations.,Four sand fly species of the genus Phlebotomus were detected: P. papatasi, P. perfiliewi, P. mascittii and P. neglectus.,Detection of P. mascittii represents the first record of this species for the sand fly fauna in Vojvodina and in Serbia.,All female specimens (n = 80) were tested for Leishmania spp.,DNA, and three blood-fed P. papatasi specimens were positive (4%).,One positive DNA sample was successfully amplified by ITS1 nPCR.,The RFLP analysis of the resulting 350 bp fragment showed a typical pattern of L. infantum, and the ITS1 partial sequence blasted in GenBank confirmed 100% identity with L. infantum and L. donovani complex sequences.,This result represents the first record of both Leishmania spp. and L. infantum DNA from sand flies in Vojvodina, and in Serbia.,Presence of autochthonous canine leishmaniasis cases, records of Phlebotomus (Larroussius) species proven vectors of L. infantum (P. perfiliewi and P. neglectus) and detection of L. infantum DNA from wild caught (non-competent) vectors, prove that L. infantum is present in Vojvodina and indicates a probable circulation in the region.

The lifestyle of intracellular pathogens, such as malaria parasites, is intimately connected to that of their host(s), primarily for nutrient supply.,Nutrients act not only as primary sources of energy but also as regulators of gene expression, metabolism and growth, through various signaling networks that confer to cells the ability to sense and adapt to varying environmental conditions1,2.,Canonical nutrient-sensing pathways are presumably absent in the causing agent of malaria Plasmodium3-5, thus raising the question of whether these parasites possess the capacity to sense and cope with host nutrient fluctuations.,Here, we show that Plasmodium blood-stage parasites actively respond to host dietary calorie alterations through a rearrangement of their transcriptome accompanied by a significant adjustment of their multiplication rate.,A kinome analysis combined with chemical and genetic approaches identified KIN as a critical regulator that mediates sensing of nutrients and controls a transcriptional response to the host nutritional status.,KIN shares homology to SNF1/AMPKα and yeast complementation studies suggest functional conservation of an ancient cellular energy sensing pathway.,Overall, these findings reveal a key parasite nutrient-sensing mechanism that is critical to modulate parasite replication and virulence.

The genome sequence available for different Plasmodium species is a valuable resource for understanding malaria parasite biology.,However, comparative genomics on its own cannot fully explain all the species-specific differences which suggests that other genomic aspects such as regulation of gene expression play an important role in defining species-specific characteristics.,Here, we developed a comprehensive approach to measure transcriptional changes of the evolutionary conserved syntenic orthologs during the intraerythrocytic developmental cycle across six Plasmodium species.,We show significant transcriptional constraint at the mid-developmental stage of Plasmodium species while the earliest stages of parasite development display the greatest transcriptional variation associated with critical functional processes.,Modeling of the evolutionary relationship based on changes in transcriptional profile reveal a phylogeny pattern of the Plasmodium species that strictly follows its mammalian hosts.,In addition, the work shows that transcriptional conserved orthologs represent potential future targets for anti-malaria intervention as they would be expected to carry out key essential functions within the parasites.,This work provides an integrated analysis of orthologous transcriptome, which aims to provide insights into the Plasmodium evolution thereby establishing a framework to explore complex pathways and drug discovery in Plasmodium species with broad host range.,•Comparison of variations in mRNA abundance across six different Plasmodium species.,•Transcriptional conservation and divergence of Plasmodium syntenic orthologs.,•Pattern of Plasmodium transcriptome evolution are established.,•Transcriptionally conserved orthologs represent attractive intervention targets.,Comparison of variations in mRNA abundance across six different Plasmodium species.,Transcriptional conservation and divergence of Plasmodium syntenic orthologs.,Pattern of Plasmodium transcriptome evolution are established.,Transcriptionally conserved orthologs represent attractive intervention targets.,Malaria remains a major public health concern despite global efforts in the fight against this disease.,The intraerythrocytic stage of the malaria parasites is currently in the spotlight for anti-malarial intervention and vaccine targets.,The primary goal of this study is to generate a comprehensive and directly comparable transcriptome dataset across multiple Plasmodium species originating from different hosts.,We establish that specific pathways and intraerythrocytic stages are more transcriptionally diverged than others, reflecting transcriptional evolutionary diversity.,We further propose a panel of transcriptionally conserved genes as potential drug targets.

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.

Following the development of resistance to anti-malarial mono-therapies, malaria endemic countries in Africa now use artemisinin-based combination therapy (ACT) as recommended first-line treatment for uncomplicated malaria.,Patients' adherence to ACT is an important factor to ensure treatment efficacy, as well as to reduce the likelihood of parasite resistance to these drugs.,This study reports adherence to a specific ACT, artemether-lumefantrine (AL), under conditions of routine clinical practice in Kenya.,The study was undertaken in Garissa and Bunyala districts among outpatients of five government health facilities.,Patients treated with AL were visited at home four days after having been prescribed the drug.,Respondents (patients ≥ 15 years and caregivers of patients < 15 years) were interviewed using a standardized questionnaire, AL blister packs were physically inspected and the adherence status of patients was then recorded.,Multivariate logistic regression modelling was used to determine predictors of adherence.,Of the 918 patients included in the study, 588 (64.1%) were 'probably adherent', 291 (31.7%) were 'definitely non-adherent' and 39 (4.2%) were 'probably non-adherent'.,Six factors were found to be significant predictors of adherence: patient knowledge of the ACT dosing regimen (odds ratio (OR) = 1.76; 95% CI = 1.32-2.35), patient age (OR = 1.65; 95% CI = 1.02-1.85), respondent age (OR = 1.37; 95% CI = 1.10-2.48), whether a respondent had seen AL before (OR = 1.46; 95% CI = 1.08-1.98), whether a patient had reported dislikes to AL (OR = 0.62 95% CI = 0.47-0.82) and whether a respondent had waited more than 24 hours to seek treatment (OR = 0.73; 95% CI = 0.54-0.99).,Overall, adherence to AL was found to be low in both Garissa and Bunyala districts, with patient knowledge of the AL dosing regimen found to be the strongest predictor of adherence.,Interventions aimed at increasing community awareness of the AL dosing regimen, use of child friendly formulations and improving health workers' prescribing practices are likely to ensure higher adherence to AL and eventual treatment success.

The current treatments for human African trypanosomiasis (HAT), Chagas disease and leishmaniasis (collectively referred to as the kinetoplastid diseases) are far from ideal but, for some, there has been significant recent progress.,For HAT the only advances in treatment over the past two decades have been the introduction of an eflornithine/nifurtimox co-administration and a shorter regime of the old standard melarsoprol.,PubMed.,There is a need for new safe, oral drugs for cost-effective treatment of patients and use in control programmes for all the trypanosomatid diseases.,Cutaneous leishmaniasis is not on the agenda and treatments are lagging behind.,There are three compounds in development for the treatment of the CNS stage of HAT: fexinidazole, currently due to entry into phase II clinical studies, a benzoxaborole (SCYX-7158) in phase I trials and a diamidine derivative (CPD-0802), in advanced pre-clinical development.,For Chagas disease, two anti-fungal triazoles are now in clinical trial.,In addition, clinical studies with benznidazole, a drug previously recommended only for acute stage treatment, are close to completion to determine the effectiveness in the treatment of early chronic and indeterminate Chagas disease.,For visceral leishmaniasis new formulations, therapeutic switching, in particular AmBisome, and the potential for combinations of established drugs have significantly improved the opportunities for the treatment in the Indian subcontinent, but not in East Africa.,Improved diagnostic tools are needed to support treatment, for test of cure in clinical trials and for monitoring/surveillance of populations in control programmes.

Pentavalent antimonials have been the mainstay of antileishmanial therapy for decades, but increasing failure rates under antimonial treatment have challenged further use of these drugs in the Indian subcontinent.,Experimental evidence has suggested that parasites which are resistant against antimonials have superior survival skills than sensitive ones even in the absence of antimonial treatment.,We use simulation studies based on a mathematical L. donovani transmission model to identify parameters which can explain why treatment failure rates under antimonial treatment increased up to 65% in Bihar between 1980 and 1997.,Model analyses suggest that resistance to treatment alone cannot explain the observed treatment failure rates.,We explore two hypotheses referring to an increased fitness of antimony-resistant parasites: the additional fitness is (i) disease-related, by causing more clinical cases (higher pathogenicity) or more severe disease (higher virulence), or (ii) is transmission-related, by increasing the transmissibility from sand flies to humans or vice versa.,Both hypotheses can potentially explain the Bihar observations.,However, increased transmissibility as an explanation appears more plausible because it can occur in the background of asymptomatically transmitted infection whereas disease-related factors would most probably be observable.,Irrespective of the cause of fitness, parasites with a higher fitness will finally replace sensitive parasites, even if antimonials are replaced by another drug.

Severe chronic hepatic schistosomiasis is a common cause of episodes upper gastrointestinal bleeding (UGIB) in sub-Saharan Africa (SSA).,However, there is paucity of data on clinical epidemiology of episodes of UGIB from rural Africa despite on going public health interventions to control and eliminate schistosomiasis.,Through a cross sectional study we profiled lifetime episodes of upper gastrointestinal bleeding and associated factors at a rural primary health facility in sub-Saharan Africa were schistosomiasis is endemic.,The main outcome was number of lifetime episodes of UGIB analyzed as count data.,From 107 enrolled participants, 323 lifetime episodes of UGIB were reported.,Fifty-seven percent experienced ≥ 2 lifetime episodes of UGIB.,Ninety-four percent had severe chronic hepatic schistosomiasis and 80% esophageal varices.,Alcohol use and viral hepatitis was infrequent.,Eighty-eight percent were previously treated with praziquantel and 70% had a history of blood transfusion.,No patient had ever had an endoscopy or treatment for prevention of recurrent variceal bleeding.,Multivariable analysis identified a cluster of eight clinical factor variables (age ≥ 40, female sex, history of blood transfusion, abdominal collaterals, esophageal varices, pattern x periportal fibrosis, anemia, and thrombocytopenia) significantly associated (P-value < 0.05) with increased probability of experiencing two or more lifetime episodes of UGIB in our study.,Upper gastrointestinal bleeding is a common health problem in this part of rural SSA where schistosomiasis is endemic.,The clinical profile described is unique and is important for improved case management, and for future research.

Schistosoma (S.) haematobium is a neglected tropical disease which may affect any part of the genital tract in women.,Female genital schistosomiasis (FGS) may cause abnormal vaginal discharge, contact bleeding, genital tumours, ectopic pregnancies and increased susceptibility to HIV.,Symptoms may mimic those typical of sexually transmitted infections (STIs) and women with genital schistosomiasis may be incorrectly diagnosed.,An expert consensus meeting suggested that the following findings by visual inspection should serve as proxy indicators for the diagnosis of schistosomiasis of the lower genital tract in women from S. haematobium endemic areas: sandy patches appearing as (1) single or clustered grains or (2) sandy patches appearing as homogenous, yellow areas, or (3) rubbery papules.,In this atlas we aim to provide an overview of the genital mucosal manifestations of schistosomiasis in women.,Photocolposcopic images were captured from women, between 1994 and 2012 in four different study sites endemic for S. haematobium in Malawi, Zimbabwe, South Africa and Madagascar.,Images and specimens were sampled from sexually active women between 15 and 49 years of age.,Colposcopic images of other diseases are included for differential diagnostic purposes.,This is the first atlas to present the clinical manifestations of schistosomiasis in the lower female genital tract.,It will be freely available for online use, downloadable as a presentation and for print.,It could be used for training purposes, further research, and in clinical practice.

Transmission intensity affects almost all aspects of malaria epidemiology and the impact of malaria on human populations.,Maps of transmission intensity are necessary to identify populations at different levels of risk and to evaluate objectively options for disease control.,To remain relevant operationally, such maps must be updated frequently.,Following the first global effort to map Plasmodium falciparum malaria endemicity in 2007, this paper describes the generation of a new world map for the year 2010.,This analysis is extended to provide the first global estimates of two other metrics of transmission intensity for P. falciparum that underpin contemporary questions in malaria control: the entomological inoculation rate (PfEIR) and the basic reproductive number (PfR).,Annual parasite incidence data for 13,449 administrative units in 43 endemic countries were sourced to define the spatial limits of P. falciparum transmission in 2010 and 22,212 P. falciparum parasite rate (PfPR) surveys were used in a model-based geostatistical (MBG) prediction to create a continuous contemporary surface of malaria endemicity within these limits.,A suite of transmission models were developed that link PfPR to PfEIR and PfR and these were fitted to field data.,These models were combined with the PfPR map to create new global predictions of PfEIR and PfR.,All output maps included measured uncertainty.,An estimated 1.13 and 1.44 billion people worldwide were at risk of unstable and stable P. falciparum malaria, respectively.,The majority of the endemic world was predicted with a median PfEIR of less than one and a median PfRc of less than two.,Values of either metric exceeding 10 were almost exclusive to Africa.,The uncertainty described in both PfEIR and PfR was substantial in regions of intense transmission.,The year 2010 has a particular significance as an evaluation milestone for malaria global health policy.,The maps presented here contribute to a rational basis for control and elimination decisions and can serve as a baseline assessment as the global health community looks ahead to the next series of milestones targeted at 2015.

Many countries are scaling up malaria interventions towards elimination.,This transition changes demands on malaria diagnostics from diagnosing ill patients to detecting parasites in all carriers including asymptomatic infections and infections with low parasite densities.,Detection methods suitable to local malaria epidemiology must be selected prior to transitioning a malaria control programme to elimination.,A baseline malaria survey conducted in Temotu Province, Solomon Islands in late 2008, as the first step in a provincial malaria elimination programme, provided malaria epidemiology data and an opportunity to assess how well different diagnostic methods performed in this setting.,During the survey, 9,491 blood samples were collected and examined by microscopy for Plasmodium species and density, with a subset also examined by polymerase chain reaction (PCR) and rapid diagnostic tests (RDTs).,The performances of these diagnostic methods were compared.,A total of 256 samples were positive by microscopy, giving a point prevalence of 2.7%.,The species distribution was 17.5% Plasmodium falciparum and 82.4% Plasmodium vivax.,In this low transmission setting, only 17.8% of the P. falciparum and 2.9% of P. vivax infected subjects were febrile (≥38°C) at the time of the survey.,A significant proportion of infections detected by microscopy, 40% and 65.6% for P. falciparum and P. vivax respectively, had parasite density below 100/μL.,There was an age correlation for the proportion of parasite density below 100/μL for P. vivax infections, but not for P. falciparum infections.,PCR detected substantially more infections than microscopy (point prevalence of 8.71%), indicating a large number of subjects had sub-microscopic parasitemia.,The concordance between PCR and microscopy in detecting single species was greater for P. vivax (135/162) compared to P. falciparum (36/118).,The malaria RDT detected the 12 microscopy and PCR positive P. falciparum, but failed to detect 12/13 microscopy and PCR positive P. vivax infections.,Asymptomatic malaria infections and infections with low and sub-microscopic parasite densities are highly prevalent in Temotu province where malaria transmission is low.,This presents a challenge for elimination since the large proportion of the parasite reservoir will not be detected by standard active and passive case detection.,Therefore effective mass screening and treatment campaigns will most likely need more sensitive assays such as a field deployable molecular based assay.

Single-cell genomics is a powerful tool for determining the genetic architecture of complex communities of unicellular organisms.,In areas of high transmission, malaria patients are often challenged by the activities of multiple Plasmodium falciparum lineages, which can potentiate pathology, spread drug resistance loci, and also complicate most genetic analysis.,Single-cell sequencing of P. falciparum would be key to understanding infection complexity, though efforts are hampered by the extreme nucleotide composition of its genome (∼80% AT-rich).,To counter the low coverage achieved in previous studies, we targeted DNA-rich late-stage parasites by Fluorescence-Activated Cell Sorting and whole genome sequencing.,Our method routinely generates accurate, near-complete capture of the 23 Mb P. falciparum genome (mean breadth of coverage 90.7%) at high efficiency.,Data from 48 single-cell genomes derived from a polyclonal infection sampled in Chikhwawa, Malawi allowed for unambiguous determination of haplotype diversity and recent meiotic events, information that will aid public health efforts.

Cerebral malaria, a severe form of Plasmodium falciparum infection, is an important cause of mortality in sub-Saharan African children.,A Taqman 24 Single Nucleotide Polymorphisms (SNP) molecular barcode assay was developed for use in laboratory parasites which estimates genotype number and identifies the predominant genotype.,The 24 SNP assay was used to determine predominant genotypes in blood and tissues from autopsy and clinical patients with cerebral malaria.,Single genotypes were shared between the peripheral blood, the brain, and other tissues of cerebral malaria patients, while malaria-infected patients who died of non-malarial causes had mixed genetic signatures in tissues examined.,Children with retinopathy-positive cerebral malaria had significantly less complex infections than those without retinopathy (OR = 3.7, 95% CI [1.51-9.10]).,The complexity of infections significantly decreased over the malaria season in retinopathy-positive patients compared to retinopathy-negative patients.,Cerebral malaria patients harbour a single or small set of predominant parasites; patients with incidental parasitaemia sustain infections involving diverse genotypes.,Limited diversity in the peripheral blood of cerebral malaria patients and correlation with tissues supports peripheral blood samples as appropriate for genome-wide association studies of parasite determinants of pathogenicity.

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

In Brazil, case-fatality rates attributable to visceral leishmaniasis (VL) are high and knowledge of the risk factors associated with death may help reduce mortality.,The aim of this study was to construct and validate a scoring system for prognosis of death from VL by using all cases reported in Brazil from 2007 to 2011.,In this historical cohort study, 18,501 VL cases were analyzed; of these, 17,345 cases were cured and 1,156 cases caused death.,The database was divided into two series: primary (two-thirds of cases), to develop the model score, and secondary (one-third of cases), to validate the scoring system.,Multivariate logistic regression models were performed to identify factors associated with death from VL, and these were included in the scoring system.,The factors associated with death from VL were: bleeding (score 3); splenomegaly (score 1); edema (score 1); weakness (score 1); jaundice (score 1); Leishmania-HIV co-infection (score 1); bacterial infection (score 1); and age (≤0.5 years [score 5]; >0.5 and ≤1 [score 2]; >19 and ≤50 [score 2]; >50 and <65 [score 3]; ≥65 [score 5]).,It was observed that patients with a score of 4 had a probability of death of approximately 4.5% and had a worse prognosis.,The sensitivity, specificity, and accuracy of this score were 89.4, 51.2, and 53.5, respectively.,The scoring system based on risk factors for death showed good performance in identifying patients with signs of severity at the time of clinical suspicion of VL and can contribute to improving the surveillance system for reducing case fatalities.,The classification of patients according to their prognosis for death may assist decision-making regarding the transfer of the patients to hospitals more capable of handling their condition, admission to the intensive care unit, and adequate support and specific treatment.

The aim of this study was to provide information on trypanosome species infecting trypanotolerant cattle from southern Gabon.,The study was conducted on 224 trypanotolerant cattle from three regions located in southern Gabon, using ITS1 primer-based PCR.,Seventy-two (32%) N’dama cattle were found polymerase chain reaction (PCR) positive with trypanosomes.,The overall prevalence of trypanosomosis was 57% (63/110), 4% (4/100), and 36% (5/14) in the Gala section of the Nyanga ranch, the Miyama ranch, and Ossiele, respectively.,Trypanosoma congolense and Trypanosoma vivax were identified.,In Gala section and Ossiele, T. congolense and T. vivax were found.,In the Miyama ranch, only T. vivax was identified.,Mixed infections were also found.,The forest (9%) and savannah (63%) subgroups of T. congolense were identified.,The presence of the two subgroups was detected in 16 out of 56 cattle (29%).,T. congolense and T. vivax would appear to be the main agents responsible for bovine trypanosomosis in southern Gabon.,Although trypanotolerant, N’dama cattle may serve as a reservoir, and this should be further studied.,On the other hand, these trypanotolerant cattle can be reared in such tsetse infested areas, which gives them an advantage compared to other trypanosensitive breeds, and this shows that they represent a key factor in biodiversity which has to be promoted.

This study was conducted to (i) determine the prevalence of African Animal Trypanosomosis (AAT) in tsetse challenged areas, (ii) compare conventional with qPCR detection systems and (iii) evaluate the host genetic background and biology as risk factors.,AAT prevalence studies are often confronted with low levels of parasitaemia.,Hence, we designed a novel qPCR assay using primers and species specific probes amplifying the Internal Transcribed Spacer 1 (ITS1) gene.,Thereby all three AAT species could be detected simultaneously. 368 individuals from three cattle types (Baoulé, Zebu and hybrids) originating from 72 farms in Burkina Faso were analysed.,Farmers were interviewed and morphometric measurements of the cattle taken.,A chi-squared test and a logistic regression model were calculated to detect associations with infection.,In our study, the overall rate of prevalence detected with the novel qPCR assay was 11.14%.,Compared to conventional PCR we identified a concordance of 91.30%.,We tested 41 animals positive for trypanosome DNA, five animals showed multiple infections.,Zebus were twice as often infected (21.74%) compared to Baoulé (9.70%) and hybrids (9.57%).,Trypanosoma vivax is the dominant species (9.24%), as compared to T. congolense (2.44%) and T. brucei (0.82%).,The chi-squared tests linking the infection events to the breeds (Zebu vs.,Baoulé and Zebu vs. hybrids) were on the border of significance.,No significant association with other tested parameters could be detected.,We introduce a novel qPCR technique for the fast, sensitive and simultaneous detection of the three AAT species.,Our results suggest that associations with breed and infection exist since Zebu cattle are more likely to be infected compared to Baoulé and hybrids.,Indigenous taurine cattle breeds, like the Baoulé, therefore provide a unique and valuable genetic resource.

Malaysia aims to eliminate malaria by 2020.,However, while cases of Plasmodium falciparum and Plasmodium vivax have decreased substantially, the incidence of zoonotic malaria from Plasmodium knowlesi continues to increase, presenting a major challenge to regional malaria control efforts.,Here we report incidence of all Plasmodium species in Sabah, including zoonotic P. knowlesi, during 2015-2017.,Microscopy-based malaria notification data and polymerase chain reaction (PCR) results were obtained from the Sabah Department of Health and State Public Health Laboratory, respectively, from January 2015 to December 2017.,From January 2016 this was complemented by a statewide prospective hospital surveillance study.,Databases were matched, and species was determined by PCR, or microscopy if PCR was not available.,A total of 3867 malaria cases were recorded between 2015 and 2017, with PCR performed in 93%.,Using PCR results, and microscopy if PCR was unavailable, P. knowlesi accounted for 817 (80%), 677 (88%), and 2030 (98%) malaria cases in 2015, 2016, and 2017, respectively.,P. falciparum accounted for 110 (11%), 45 (6%), and 23 (1%) cases and P. vivax accounted for 61 (6%), 17 (2%), and 8 (0.4%) cases, respectively.,Of those with P. knowlesi, the median age was 35 (interquartile range: 24-47) years, and 85% were male.,Malaysia is approaching elimination of the human-only Plasmodium species.,However, the ongoing increase in P. knowlesi incidence presents a major challenge to malaria control and warrants increased focus on knowlesi-specific prevention activities.,Wider molecular surveillance in surrounding countries is required.,Despite near-elimination of Plasmodium falciparum and Plasmodium vivax malaria in Malaysia, more than 2000 cases of Plasmodium knowlesi occurred in the state of Sabah in 2017, accounting for 98% of malaria diagnoses and representing a major challenge to malaria control.

Plasmodium knowlesi is a significant cause of human malaria in Sarawak, Malaysian Borneo.,Only one study has been previously undertaken in Sarawak to identify vectors of P. knowlesi, where Anopheles latens was incriminated as the vector in Kapit, central Sarawak.,A study was therefore undertaken to identify malaria vectors in a different location in Sarawak.,Mosquitoes found landing on humans and resting on leaves over a 5-day period at two sites in the Lawas District of northern Sarawak were collected and identified.,DNA samples extracted from salivary glands of Anopheles mosquitoes were subjected to nested PCR malaria-detection assays.,The small subunit ribosomal RNA (SSU rRNA) gene of Plasmodium was sequenced, and the internal transcribed spacer 2 (ITS2) and mitochondrial cytochrome c oxidase subunit 1 (cox1) gene of the mosquitoes were sequenced from the Plasmodium-positive samples for phylogenetic analysis.,Totals of 65 anophelines and 127 culicines were collected.,By PCR, 6 An. balabacensis and 5 An. donaldi were found to have single P. knowlesi infections while 3 other An. balabacensis had either single, double or triple infections with P. inui, P. fieldi, P. cynomolgi and P. knowlesi.,Phylogenetic analysis of the Plasmodium SSU rRNA gene confirmed 3 An. donaldi and 3 An. balabacensis with single P. knowlesi infections, while 3 other An. balabacensis had two or more Plasmodium species of P. inui, P. knowlesi, P. cynomolgi and some species of Plasmodium that could not be conclusively identified.,Phylogenies inferred from the ITS2 and/or cox1 sequences of An. balabacensis and An. donaldi indicate that they are genetically indistinguishable from An. balabacensis and An. donaldi, respectively, found in Sabah, Malaysian Borneo.,Previously An. latens was identified as the vector for P. knowlesi in Kapit, central Sarawak, Malaysian Borneo, and now An. balabacensis and An. donaldi have been incriminated as vectors for zoonotic malaria in Lawas, northern Sarawak.

Analyses of the population genetic structure of schistosomes under the “Schistosomiasis Consortium for Operational Research and Evaluation” (SCORE) contrasting treatment pressure scenarios in Tanzania, Niger, and Zanzibar were performed to provide supplementary critical information with which to evaluate the impact of these large-scale control activities and guide how activities could be adjusted.,We predicted that population genetic analyses would reveal information on a range of important parameters including, but not exclusive to, recruitment and transmission of genotypes, occurrence of hybridization events, differences in reproductive mode, and degrees of inbreeding, and hence, the evolutionary potential, and responses of parasite populations under contrasting treatment pressures.,Key findings revealed that naturally high levels of gene flow and mixing of the parasite populations between neighboring sites were likely to dilute any effects imposed by the SCORE treatment arms.,Furthermore, significant inherent differences in parasite fecundity were observed, independent of current treatment arm, but potentially of major impact in terms of maintaining high levels of ongoing transmission in persistent “biological hotspot” sites.,Within Niger, naturally occurring Schistosoma haematobium/Schistosoma bovis viable hybrids were found to be abundant, often occurring in significantly higher proportions than that of single-species S. haematobium infections.,By examining parasite population genetic structures across hosts, treatment regimens, and the spatial landscape, our results to date illustrate key transmission processes over and above that which could be achieved through standard parasitological monitoring of prevalence and intensity alone, as well as adding to our understanding of Schistosoma spp. life history strategies in general.

Following implementation of the national control program, a reassessment of Schistosoma mansoni prevalence was conducted in Burundi to determine the feasibility of moving toward elimination.,A countrywide cluster-randomized cross-sectional study was performed in May 2014.,At least 25 schools were sampled from each of five eco-epidemiological risk zones for schistosomiasis.,Fifty randomly selected children 13-14 years of age per school were included for a single urine-circulating cathodic antigen (CCA) rapid test and, in a subset of schools, for duplicate Kato-Katz slide preparation from a single stool sample.,A total of 17,331 children from 347 schools were tested using CCA.,The overall prevalence of S. mansoni infection, when CCA trace results were considered negative, was 13.5% (zone range [zr] = 4.6-17.8%), and when CCA trace results were considered positive, it was 42.8% (zr = 34.3-49.9%).,In 170 schools, prevalence of this infection determined using Kato-Katz method was 1.5% (zr ==0-2.7%).,The overall mean intensity of S. mansoni infection determined using Kato-Katz was 0.85 eggs per gram (standard deviation = 10.86).,A majority of schools (84%) were classified as non-endemic (prevalence = 0) using Kato-Katz; however, a similar proportion of schools were classified as endemic when CCA trace results were considered negative (85%) and nearly all (98%) were endemic when CCA trace results were considered positive.,The findings of this nationwide reassessment using a CCA rapid test indicate that Schistosoma infection is still widespread in Burundi, although its average intensity is probably low.,Further evidence is now needed to determine the association between CCA rapid test positivity and low-intensity disease transmission.

Due to their remarkable parasitocidal activity, artemisinins represent the key components of first-line therapies against Plasmodium falciparum malaria.,However, the decline in efficacy of artemisinin-based drugs jeopardizes global efforts to control and ultimately eradicate the disease.,To better understand the resistance phenotype, artemisinin-resistant parasite lines were derived from two clones of the 3D7 strain of P. falciparum using a selection regimen that mimics how parasites interact with the drug within patients.,This long term in vitro selection induced profound stage-specific resistance to artemisinin and its relative compounds.,Chemosensitivity and transcriptional profiling of artemisinin-resistant parasites indicate that enhanced adaptive responses against oxidative stress and protein damage are associated with decreased artemisinin susceptibility.,This corroborates our previous findings implicating these cellular functions in artemisinin resistance in natural infections.,Genomic characterization of the two derived parasite lines revealed a spectrum of sequence and copy number polymorphisms that could play a role in regulating artemisinin response, but did not include mutations in pfk13, the main marker of artemisinin resistance in Southeast Asia.,Taken together, here we present a functional in vitro model of artemisinin resistance that is underlined by a new set of genetic polymorphisms as potential genetic markers.

The phist gene family has members identified across the Plasmodium genus, defined by the presence of a domain of roughly 150 amino acids having conserved aromatic residues and an all alpha-helical structure.,The family is highly amplified in P. falciparum, with 65 predicted genes in the genome of the 3D7 isolate.,In contrast, in the rodent malaria parasite P. berghei 3 genes are identified, one of which is an apparent pseudogene.,Transcripts of the P. berghei phist genes are predominant in schizonts, whereas in P. falciparum transcript profiles span different asexual blood stages and gametocytes.,We pursued targeted disruption of P. berghei phist genes in order to characterize a simplistic model for the expanded phist gene repertoire in P. falciparum.,Unsuccessful attempts to disrupt P. berghei PBANKA_114540 suggest that this phist gene is essential, while knockout of phist PBANKA_122900 shows an apparent normal progression and non-essential function throughout the life cycle.,Epitope-tagging of P. falciparum and P. berghei phist genes confirmed protein export to the erythrocyte cytoplasm and localization with a punctate pattern.,Three P. berghei PEXEL/HT-positive exported proteins exhibit at least partial co-localization, in support of a common vesicular compartment in the cytoplasm of erythrocytes infected with rodent malaria parasites.

The development of highly effective and durable vaccines against the human malaria parasites Plasmodium falciparum and P. vivax remains a key priority.,Decades of endeavor have taught that achieving this goal will be challenging; however, recent innovation in malaria vaccine research and a diverse pipeline of novel vaccine candidates for clinical assessment provides optimism.,With first-generation pre-erythrocytic vaccines aiming for licensure in the coming years, it is important to reflect on how next-generation approaches can improve on their success.,Here we review the latest vaccine approaches that seek to prevent malaria infection, disease, and transmission and highlight some of the major underlying immunological and molecular mechanisms of protection.,The synthesis of rational antigen selection, immunogen design, and immunization strategies to induce quantitatively and qualitatively improved immune effector mechanisms offers promise for achieving sustained high-level protection.,Development of highly effective vaccines against human malaria remains a public health priority.,In this Review, Draper et al. describe the latest vaccine approaches to prevent malaria alongside immunological and molecular mechanisms of protection.,Rational antigen selection, immunogen design, and novel immunization strategies offer promise for achieving high-level protection.

Transmission-blocking vaccines (TBVs) that target sexual stage parasite development could be an integral part of measures for malaria elimination.,Pfs25 is a leading TBV candidate, and previous studies conducted in animals demonstrated an improvement of its functional immunogenicity after conjugation to EPA, a recombinant, detoxified ExoProtein A from Pseudomonas aeruginosa.,In this report, we describe results of an open-label, dose-escalating Phase 1 trial to assess the safety and immunogenicity of Pfs25-EPA conjugates formulated with Alhydrogel®.,Thirty malaria-naïve healthy adults received up to four doses of the conjugate vaccine, with 8, 16, or 47 μg of conjugated Pfs25 mass, at 0, 2, 4, and 10 months.,Vaccinations were generally well tolerated.,The majority of solicited adverse events were mild in severity with pain at the injection site the most common complaint.,Anemia was the most common laboratory abnormality, but was considered possibly related to the study in only a minority of cases.,No vaccine-related serious adverse events occurred.,The peak geometric mean anti-Pfs25 antibody level in the highest dose group was 88 (95% CI 53, 147) μg/mL two weeks after the 4th vaccination, and declined to near baseline one year later.,Antibody avidity increased over successive vaccinations.,Transmission blocking activity demonstrated in a standard membrane feeding assay (SMFA) also increased from the second to the third dose, and correlated with antibody titer and, after the final dose, with antibody avidity.,These results support the further evaluation of Pfs25-EPA/Alhydrogel® in a malaria-endemic population.

•Self-fertilisation does occur but is rare in field populations of Fasciola hepatica.,•Some hosts harboured genotypically identical parasites (clones).,•The presence of clones is consistent with clonal expansion and clumped transmission.•84% of 1579 F. hepatica had unique genotypes, indicating high genetic diversity.,•We found high gene flow, no population structure and low self-fertilisation rate.,Self-fertilisation does occur but is rare in field populations of Fasciola hepatica.,Some hosts harboured genotypically identical parasites (clones).,The presence of clones is consistent with clonal expansion and clumped transmission.,84% of 1579 F. hepatica had unique genotypes, indicating high genetic diversity.,We found high gene flow, no population structure and low self-fertilisation rate.,Fasciola hepatica, the liver fluke, is a trematode parasite of considerable economic importance to the livestock industry and is a re-emerging zoonosis that poses a risk to human health in F. hepatica-endemic areas worldwide.,Drug resistance is a substantial threat to the current and future control of F. hepatica, yet little is known about how the biology of the parasite influences the development and spread of resistance.,Given that F. hepatica can self-fertilise and therefore inbreed, there is the potential for greater population differentiation and an increased likelihood of recessive alleles, such as drug resistance genes, coming together.,This could be compounded by clonal expansion within the snail intermediate host and aggregation of parasites of the same genotype on pasture.,Alternatively, widespread movement of animals that typically occurs in the UK could promote high levels of gene flow and prevent population differentiation.,We identified clonal parasites with identical multilocus genotypes in 61% of hosts.,Despite this, 84% of 1579 adult parasites had unique multilocus genotypes, which supports high levels of genotypic diversity within F. hepatica populations.,Our analyses indicate a selfing rate no greater than 2%, suggesting that this diversity is in part due to the propensity for F. hepatica to cross-fertilise.,Finally, although we identified high genetic diversity within a given host, there was little evidence for differentiation between populations from different hosts, indicating a single panmictic population.,This implies that, once those emerge, anthelmintic resistance genes have the potential to spread rapidly through liver fluke populations.

Anthelmintic resistance has been increasingly reported in cattle worldwide over the last decade, although reports from Europe are more limited.,The objective of the present study was to evaluate the efficacy of injectable formulations of ivermectin and moxidectin at 0.2 mg per kg bodyweight against naturally acquired gastro-intestinal nematodes in cattle.,A total of 753 animals on 40 farms were enrolled in Germany (12 farms), the UK (10 farms), Italy (10 farms), and France (8 farms).,Animals were selected based on pre-treatment faecal egg counts and were allocated to one of the two treatment groups.,Each treatment group consisted of between 7 and 10 animals.,A post-treatment faecal egg count was performed 14 days (±2 days) after treatment.,The observed percentage reduction was calculated for each treatment group based on the arithmetic mean faecal egg count before and after treatment.,The resistance status was evaluated based on the reduction in arithmetic mean faecal egg count and both the lower and upper 95% confidence limits.,A decreased efficacy was observed in half or more of the farms in Germany, France and the UK.,For moxidectin, resistance was confirmed on 3 farms in France, and on 1 farm in Germany and the UK.,For ivermectin, resistance was confirmed on 3 farms in the UK, and on 1 farm in Germany and France.,The remaining farms with decreased efficacy were classified as having an inconclusive resistance status based on the available data.,After treatment Cooperia spp. larvae were most frequently identified, though Ostertagia ostertagi was also found, in particular within the UK and Germany.,The present study reports lower than expected efficacy for ivermectin and moxidectin (based on the reduction in egg excretion after treatment) on European cattle farms, with confirmed anthelmintic resistance on 12.5% of the farms.,•Multi-centre study in four major cattle markets in Europe.,•Decreased efficacy in more than half of the farms in three out of four countries.,•12.5% of farms with confirmed anthelmintic resistance to ivermectin and moxidectin.,•Mainly Cooperia larvae found in post-treatment copro-cultures.,•Also Ostertagia ostertagi larvae found in post-treatment copro-cultures.,Multi-centre study in four major cattle markets in Europe.,Decreased efficacy in more than half of the farms in three out of four countries.,12.5% of farms with confirmed anthelmintic resistance to ivermectin and moxidectin.,Mainly Cooperia larvae found in post-treatment copro-cultures.,Also Ostertagia ostertagi larvae found in post-treatment copro-cultures.

The soil transmitted helminths are a group of parasitic worms responsible for extensive morbidity in many of the world’s most economically depressed locations.,With growing emphasis on disease mapping and eradication, the availability of accurate and cost-effective diagnostic measures is of paramount importance to global control and elimination efforts.,While real-time PCR-based molecular detection assays have shown great promise, to date, these assays have utilized sub-optimal targets.,By performing next-generation sequencing-based repeat analyses, we have identified high copy-number, non-coding DNA sequences from a series of soil transmitted pathogens.,We have used these repetitive DNA elements as targets in the development of novel, multi-parallel, PCR-based diagnostic assays.,Utilizing next-generation sequencing and the Galaxy-based RepeatExplorer web server, we performed repeat DNA analysis on five species of soil transmitted helminths (Necator americanus, Ancylostoma duodenale, Trichuris trichiura, Ascaris lumbricoides, and Strongyloides stercoralis).,Employing high copy-number, non-coding repeat DNA sequences as targets, novel real-time PCR assays were designed, and assays were tested against established molecular detection methods.,Each assay provided consistent detection of genomic DNA at quantities of 2 fg or less, demonstrated species-specificity, and showed an improved limit of detection over the existing, proven PCR-based assay.,The utilization of next-generation sequencing-based repeat DNA analysis methodologies for the identification of molecular diagnostic targets has the ability to improve assay species-specificity and limits of detection.,By exploiting such high copy-number repeat sequences, the assays described here will facilitate soil transmitted helminth diagnostic efforts.,We recommend similar analyses when designing PCR-based diagnostic tests for the detection of other eukaryotic pathogens.

Soil-transmitted helminths (STH) infections, anaemia and malnutrition are major public health problems in school-age children in developing countries.,This study was conducted on 289 Orang Asli (aboriginal) schoolchildren in order to assess the current prevalence and predictors of anaemia and malnutrition, as well as the nutritional impacts of STH infections among these children.,A cross-sectional study was combined with a longitudinal follow-up three months after treatment with anthelminthic drugs.,Blood samples were collected from the children to measure haemoglobin (Hb) level.,Anthropometric and socioeconomic data were also collected and the children were screened for STH.,The baseline findings revealed that the prevalence of anaemia, significant stunting, underweight and wasting among the children were 41.0%, 28.0%, 29.2% and 12.5%, respectively.,Overall, the prevalence of trichuriasis, ascariasis and hookworm infections were 84.6%, 47.6% and 3.9%, respectively.,Haemoglobin level was significantly lower among the moderate-to-heavy infected children compared to the negative-to-light infected children.,Age <10years and moderate-to-heavy ascariasis were the predictors of anaemia.,Stunting was associated with gender, age, moderate-to-heavy ascariasis and trichuriasis.,Three months post-treatment assessment showed that the moderate-to-heavy infected children gained significant increment in their mean Hb level compared to the negative-to-light infected children (0.44 g/dL compared to 0.08 g/dL).,However, no difference was found in the mean increments in growth indices between the groups.,STH infections, anaemia and malnutrition are still prevalent and a matter of public health concern in Orang Asli communities in Malaysia.,Sustainable deworming programme at school and community levels among these populations will help to improve their health and nutritional status.

This systematic review elaborates the concepts and impacts of border malaria, particularly on the emergence and spread of Plasmodium falciparum and Plasmodium vivax multidrug resistance (MDR) malaria on Thailand-Myanmar and Thailand-Cambodia borders.,Border malaria encompasses any complex epidemiological settings of forest-related and forest fringe-related malaria, both regularly occurring in certain transmission areas and manifesting a trend of increased incidence in transmission prone areas along these borders, as the result of interconnections of human settlements and movement activities, cross-border population migrations, ecological changes, vector population dynamics, and multidrug resistance.,For regional and global perspectives, this review analyzes and synthesizes the rationales pertaining to transmission dynamics and the vulnerabilities of border malaria that constrain surveillance and control of the world's most MDR falciparum and vivax malaria on these chaotic borders.

Anti-malarial drugs can make a significant contribution to the control of malaria in endemic areas when used for prevention as well as for treatment.,Chemoprophylaxis is effective in preventing deaths and morbidity from malaria, but it is difficult to sustain for prolonged periods, may interfere with the development of naturally acquired immunity and will facilitate the emergence and spread of drug resistant strains if applied to a whole community.,However, chemoprophylaxis targeted to groups at high risk, such as pregnant women, or to periods of the year when the risk from malaria is greatest, can be an effective and cost effective malaria control tool and has fewer drawbacks.,Intermittent preventive treatment, which involves administration of anti-malarials at fixed time points, usually when a subject is already in contact with the health services, for example attendance at an antenatal or vaccination clinic, is less demanding of resources than chemoprophylaxis and is now recommended for the prevention of malaria in pregnant women and infants resident in areas with medium or high levels of malaria transmission.,Intermittent preventive treatment in older children, probably equivalent to targeted chemoprophylaxis, is also highly effective but requires the establishment of a specific delivery system.,Recent studies have shown that community volunteers can effectively fill this role.,Mass drug administration probably has little role to play in control of mortality and morbidity from malaria but may have an important role in the final stages of an elimination campaign.

Majority of individuals with history of visceral leishmaniasis (VL) exhibit strong immunity to re-infection, however, the mechanism of resistance is poorly understood.,It is unclear whether CD8+ T cells contribute to protection against Leishmania donovani infection through cytotoxic activity.,The present study aims to evaluate immunological mechanism associated with resistance to the disease in healed VL (HVL) individuals and further, the contribution of CD8+ T cells in the protective immunity.,Peripheral blood mononuclear cells (PBMCs) from VL, HVL and naive groups were exposed in vitro to total soluble Leishmania antigen (TSLA) from L. donovani.,The proliferation index was determined by ELISA based lymphoproliferative assay.,Cytokines and granzyme B levels were measured by CBA.,Activated T-cell populations were estimated using flow cytometry.,We observed significantly higher lymphoproliferation, cytokines and granzyme B levels in HVL group compared to naive or VL group.,More strikingly, we found a strong association (rs = 0.895, P < 0.0001) between proliferation index (PI) and granzyme B level, with a significant proportion of activated CD8+ T cells in HVL group.,Leishmania immune group (HVL) exhibited durable and strong cellular immune response to TSLA in terms of lymphoproliferation as well as production of Th1 cytokines and granzyme B.,Additionally, the elevated level of activated CD8+ T cells and stimulation of cytotoxic activity through granzyme B production, indicated a possible role of CD8+ T cells in resistance to L. donovani infection in the HVL group.,The online version of this article (doi:10.1186/s12879-014-0653-6) contains supplementary material, which is available to authorized users.

Visceral leishmaniasis is a chronic parasitic disease associated with severe immune dysfunction.,Treatment options are limited to relatively toxic drugs, and there is no vaccine for humans available.,Hence, there is an urgent need to better understand immune responses following infection with Leishmania species by studying animal models of disease and clinical samples from patients.,Here, we review recent discoveries in these areas and highlight shortcomings in our knowledge that need to be addressed if better treatment options are to be developed and effective vaccines designed.

Reactive case detection (RACD) is a widely practiced malaria elimination intervention whereby close contacts of index cases receive malaria testing to inform treatment and other interventions.,However, the optimal diagnostic and operational approaches for this resource-intensive strategy are not clear.,We conducted a 3-year prospective national evaluation of RACD in Eswatini, a malaria elimination setting.,Loop-mediated isothermal amplification (LAMP) was compared to traditional rapid diagnostic testing (RDT) for the improved detection of infections and for hotspots (RACD events yielding ≥1 additional infection).,The potential for index case-, RACD-, and individual-level factors to improve efficiencies was also evaluated.,Among 377 RACD events, 10 890 participants residing within 500 m of index cases were tested.,Compared to RDT, LAMP provided a 3-fold and 2.3-fold higher yield to detect infections (1.7% vs 0.6%) and hotspots (29.7% vs 12.7%), respectively.,Hotspot detection improved with ≥80% target population coverage and response times within 7 days.,Proximity to the index case was associated with a dose-dependent increased infection risk (up to 4-fold).,Individual-, index case-, and other RACD-level factors were considered but the simple approach of restricting RACD to a 200-m radius maximized yield and efficiency.,We present the first large-scale national evaluation of optimal RACD approaches from a malaria elimination setting.,To inform delivery of antimalarial drugs or other interventions, RACD, when conducted, should utilize more sensitive diagnostics and clear context-specific operational parameters.,Future studies of RACD’s impact on transmission may still be needed.,Optimal approaches to find malaria infections and hotspots in reactive case detection are not clear.,Here, molecular testing compared to standard rapid diagnostic testing and operational factors (≥80% coverage, response ≤7 days, and 200-m screening radius) maximized efficiency and yield.

The test positivity rate (TPR), defined as the number of laboratory-confirmed malaria tests per 100 suspected cases examined, is widely used by malaria surveillance programs as one of several key indicators of temporal trends in malaria incidence.,However, there have been few studies using empiric data to examine the quantitative nature of this relationship.,To characterize the relationship between the test positivity rate and the incidence of malaria, we fit regression models using the confirmed malaria case rate as the outcome of interest and TPR as the predictor of interest.,We varied the relationship between the two by alternating linear and polynomial terms for TPR, and compared the goodness of fit of each model.,A total of 7,668 encounters for malaria diagnostic testing were recorded over the study period within a catchment area of 25,617 persons.,The semi-annual TPR ranged from 4.5% to 59% and the case rates ranged from 0.5 to 560 per 1,000 persons.,The best fitting model was an exponential growth model (R2 = 0.80, AIC = 637).,At low transmission levels (TPR<10%), the correlation between TPR and CMCR was poor, with large reductions in the TPR, for example from 10% to 1%, was associated with a minimal change in the CMCR (3.9 to 1.7 cases per 1,000 persons).,At higher transmission levels, the exponential relationship made relatively small changes in TPR suggestive of sizeable change in estimated malaria incidence, suggesting that TPR remains a valuable surveillance indicator in such settings.,The TPR and the confirmed malaria case rate have a non-linear relationship, which is likely to have important implications for malaria surveillance programs, especially at the extremes of transmission.

Low-density asymptomatic infections of Plasmodium spp. are common in low endemicity areas worldwide, but outside Africa, their contribution to malaria transmission is poorly understood.,Community-based studies with highly sensitive molecular diagnostics are needed to quantify the asymptomatic reservoir of Plasmodium falciparum and P. vivax infections in Thai communities.,A cross-sectional survey of 4309 participants was conducted in three endemic areas in Kanchanaburi and Ratchaburi provinces of Thailand in 2012.,The presence of P. falciparum and P. vivax parasites was determined using 18S rRNA qPCR.,Gametocytes were also detected by pfs25 / pvs25 qRT-PCRs.,A total of 133 individuals were found infected with P. vivax (3.09%), 37 with P. falciparum (0.86%), and 11 with mixed P. vivax/ P. falciparum (0.26%).,The clear majority of both P. vivax (91.7%) and P. falciparum (89.8%) infections were not accompanied by any febrile symptoms.,Infections with either species were most common in adolescent and adult males.,Recent travel to Myanmar was highly associated with P. falciparum (OR = 9.0, P = 0.001) but not P. vivax infections (P = 0.13).,A large number of P. vivax (71.5%) and P. falciparum (72.0%) infections were gametocyte positive by pvs25/pfs25 qRT-PCR.,Detection of gametocyte-specific pvs25 and pfs25 transcripts was strongly dependent on parasite density. pvs25 transcript numbers, a measure of gametocyte density, were also highly correlated with parasite density (r 2 = 0.82, P < 0.001).,Asymptomatic infections with Plasmodium spp. were common in western Thai communities in 2012.,The high prevalence of gametocytes indicates that these infections may contribute substantially to the maintenance of local malaria transmission.,The online version of this article (10.1186/s13071-017-2407-y) contains supplementary material, which is available to authorized users.

Plasmodium vivax has the potential to infect 2.85 billion individuals worldwide.,Nevertheless, the limited number of studies investigating the immune status of individuals living in malaria-endemic areas, as well as the lack of reports investigating serological markers associated with clinical protection, has hampered development of vaccines for P. vivax.,It was previously demonstrated that naturally total IgG against the N-terminus of P. vivax merozoite surface protein 1 (Pv-MSP1) was associated with reduced risk of malarial infection.,Immune response against Pv-MSP1 (N-terminus) of 313 residents of the Rio Pardo rural settlement (Amazonas State, Brazil) was evaluated in a cross-sectional and longitudinal follow up over two months (on site) wherein gold standard diagnosis by thick blood smear and rRNA gene-based nested real-time PCR were used to discriminate symptomless Plasmodium vivax-infected individuals who did not develop clinical symptoms during a 2-months from those uninfected ones or who have had acute malaria.,The acquisition of antibodies against Pv-MSP1 was also evaluated as survival analysis by prospective study over a year collecting information of new malaria infections in surveillance database.,The majority of P. vivax-infected individuals (52-67%) showed immune recognition of the N-terminus of Pv-MSP1.,Interesting data on infected individuals who have not developed symptoms, total IgG levels against the N-terminus Pv-MSP1 were age-dependent and the IgG3 levels were significantly higher than levels of subjects had acute malaria or those uninfected ones.,The total IgG anti ICB2-5 was detected to be an important factor of protection against new malaria vivax attacks in survival analysis in a prospective survey (p = 0.029).,The study findings illustrate the importance of IgG3 associated to 2-months of symptomless in P. vivax infected individuals and open perspectives for the rationale of malaria vaccine designs capable to sustain high levels of IgG3 against polymorphic malaria antigens.

Weekly iron supplementation, given to young nulliparous women living in a malaria-endemic area, neither improved iron status nor increased malaria risk, suggesting that current iron recommendations may need revisiting for these women.,The safety of iron supplementation for young women is uncertain in malaria-endemic settings.,This was a double-blind, randomized controlled noninferiority trial in rural Burkina Faso.,A total of 1959 nulliparae were assigned to weekly supplementation (60 mg iron and 2.8 mg folic acid) (n = 980) or 2.8 mg folic acid (n = 979) until first antenatal visit (ANC1), or 18 months if remaining nonpregnant.,Three hundred fifteen women attended ANC1, and 916 remained nonpregnant.,There was no difference at ANC1 in parasitemia prevalence (iron, 53.4% [95% confidence interval {CI}, 45.7%-61.0%]; control, 55.3% [95% CI, 47.3%-62.9%]; prevalence ratio, 0.97 [95% CI, .79-1.18]; P = .82), anemia (adjusted effect, 0.96 [95% CI, .83-1.10]; P = .52), iron deficiency (adjusted risk ratio [aRR], 0.84 [95% CI, .46-1.54]; P = .58), or plasma iron biomarkers.,Outcomes in nonpregnant women were parasitemia (iron, 42.9% [95% CI, 38.3%-47.5%]; control, 39.2% [95% CI, 34.9%-43.7%]; prevalence ratio, 1.09 [95% CI, .93-1.28]; P = .282); anemia (aRR, 0.90 [95% CI, .78-1.05]; P = .17), and iron deficiency (aRR, 0.99 [95% CI, .77-1.28]; P = .96), with no iron biomarker differences.,Weekly iron supplementation did not increase malaria risk, improve iron status, or reduce anemia in young, mostly adolescent menstruating women, nor in early pregnancy.,World Health Organization Guidelines for universal supplementation for young nulliparous women may need reassessment.,NCT01210040.

Malaria is a significant public health problem in more than 100 countries and causes an estimated 200 million new infections every year.,Despite the significant effort to eradicate this dangerous disease, lack of complete knowledge of its physiopathology compromises the success in this enterprise.,In this paper we review oxidative stress mechanisms involved in the disease and discuss the potential benefits of antioxidant supplementation as an adjuvant antimalarial strategy.

The Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) was established in 2008 to answer strategic questions about schistosomiasis control.,For programme managers, a high-priority question is: what are the most cost-effective strategies for delivering preventive chemotherapy (PCT) with praziquantel (PZQ)?,This paper describes the process SCORE used to transform this question into a harmonized research protocol, the study design for answering this question, the village eligibility assessments and data resulting from the first year of the study.,Beginning in 2009, SCORE held a series of meetings to specify empirical questions and design studies related to different schedules of PCT for schistosomiasis control in communities with high (gaining control studies) and moderate (sustaining control studies) prevalence of Schistosoma infection among school-aged children.,Seven studies are currently being implemented in five African countries.,During the first year, villages were screened for eligibility, and data were collected on prevalence and intensity of infection prior to randomisation and the implementation of different schemes of PZQ intervention strategies.,These studies of different treatment schedules with PZQ will provide the most comprehensive data thus far on the optimal frequency and continuity of PCT for schistosomiasis infection and morbidity control.,We expect that the study outcomes will provide data for decision-making for country programme managers and a rich resource of information to the schistosomiasis research community.,The trials are registered at International Standard Randomised Controlled Trial registry (identifiers: ISRCTN99401114, ISRCTN14849830, ISRCTN16755535, ISRCTN14117624, ISRCTN95819193 and ISRCTN32045736).

Chronic soil-transmitted helminth (STH) infections have been associated with reduced physical fitness, but available evidence is limited.,The aim of this cross-sectional survey was to assess the feasibility of measuring children's physical fitness and to relate it to STH infections.,Our study was carried out among school-aged children of the Bulang ethnic group in rural southwest People's Republic of China (P.R.,China).,Standardized, quality-controlled methods were employed to determine STH infections (Kato-Katz technique), haemoglobin levels, anthropometry (body weight and height) and physical fitness (20-m shuttle run test).,A compliance of 87% suggested good acceptance of the methods used.,Among 69 children with complete data records, infection prevalence of Trichuris trichiura, Ascaris lumbricoides and hookworm were 81%, 44% and 6%, respectively.,The maximum volume of oxygen that can be utilized within 1 min during exhaustive exercise (VO2 max estimate) of T. trichiura-infected children was 1.94 ml kg-1 min-1 lower than that of their non-infected counterparts (P = 0.005).,Until exhaustion, T. trichiura-infected children had completed 6.14 20-m laps less (P = 0.004).,Additionally, the mean VO2 max estimate of stunted children was lowered by 1.63 ml kg-1 min-1 (P = 0.002) and they completed 5.32 20-m laps less (P = 0.001) compared to children of normal stature.,No significant association between stunting and infection with any STH species could be established.,Implementation of physical fitness tests in rural, resource-constraint settings is feasible.,The physical fitness of children who are stunted or infected with STHs, particularly T. trichiura, is significantly impaired.,We have launched a larger study and will determine the dynamics of school-aged children's physical fitness over a 7-month period after administration of anthelminthic drugs.

The protozoan Leishmania mexicana parasite causes chronic non-healing cutaneous lesions in humans and mice with poor parasite control.,The mechanisms preventing the development of a protective immune response against this parasite are unclear.,Here we provide data demonstrating that parasite sequestration by neutrophils is responsible for disease progression in mice.,Within hours of infection L. mexicana induced the local recruitment of neutrophils, which ingested parasites and formed extracellular traps without markedly impairing parasite survival.,We further showed that the L. mexicana-induced recruitment of neutrophils impaired the early recruitment of dendritic cells at the site of infection as observed by intravital 2-photon microscopy and flow cytometry analysis.,Indeed, infection of neutropenic Genista mice and of mice depleted of neutrophils at the onset of infection demonstrated a prominent role for neutrophils in this process.,Furthermore, an increase in monocyte-derived dendritic cells was also observed in draining lymph nodes of neutropenic mice, correlating with subsequent increased frequency of IFNγ-secreting T helper cells, and better parasite control leading ultimately to complete healing of the lesion.,Altogether, these findings show that L. mexicana exploits neutrophils to block the induction of a protective immune response and impairs the control of lesion development.,Our data thus demonstrate an unanticipated negative role for these innate immune cells in host defense, suggesting that in certain forms of cutaneous leishmaniasis, regulating neutrophil recruitment could be a strategy to promote lesion healing.

Neutrophils are the first cells recruited to the dermal site of Leishmania infection following injection by needle or sand fly bite.,The role of neutrophils in either promoting or suppressing host immunity remains controversial.,We discuss the events driving neutrophil recruitment, their interaction with the parasite and apoptotic fate, and the nature of their encounters with other innate cells.,We suggest that the influence of the neutrophil response on infection outcome critically depends on the timing of their recruitment and the tissue environment in which it occurs.

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

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

Rapid diagnostic tests (RDTs) for histidine rich protein 2 (HRP2) are often used to determine whether persons with fever should be treated with anti-malarials.,However, Plasmodium falciparum parasites with a deletion of the hrp2 gene yield false-negative RDTs and there are concerns the sensitivity of HRP2-based RDTs may fall when the intensity of transmission decreases.,This observational study enrolled 9226 patients at three health centres in Rwanda from April 2014 to April 2015.,It then compared the sensitivity of RDTs based on HRP2 and the Plasmodium lactate dehydrogenase (pLDH) to microscopy (thick smears) for the diagnosis of malaria.,PCR was used to determine whether deletions of the histidine-rich central repeat region of the hrp2 gene (exon 2) were associated with false-negative HRP2-based RDTs.,In comparison to microscopy, the sensitivity and specificity of HRP2- and pLDH-based RDTs were 89.5 and 86.2% and 80.2 and 94.3%, respectively.,When the results for both RDTs were combined, sensitivity rose to 91.8% and specificity was 85.7%.,Additionally, when smear positivity fell from 46 to 3%, the sensitivity of the HRP2-based RDT fell from 88 to 67%.,Of 370 samples with false-negative HRP2 RDT results for which PCR was performed, 140 (38%) were identified as P. falciparum by PCR.,Of the isolates identified as P. falciparum by PCR, 32 (23%) were negative for the hrp2 gene based on PCR.,Of the 32 P. falciparum isolates negative for hrp2 by PCR, 17 (53%) were positive based on the pLDH RDT.,This prospective study of RDT performance coincided with a decline in the intensity of malaria transmission in Kibirizi (fall in slide positivity from 46 to 3%).,This decline was associated with a decrease in HRP2 RDT sensitivity (from 88 to 67%).,While P. falciparum isolates without the hrp2 gene were an important cause of false-negative HRP2-based RDTs, most were identified by the pLDH-based RDT.,Although WHO does not recommend the use of combined HRP2/pLDH testing in sub-Saharan Africa, these results suggest that combination HRP2/pLDH-based RDTs could reduce the impact of false-negative HRP2-based RDTs for detection of symptomatic P. falciparum malaria.,The online version of this article (doi:10.1186/s12936-017-1768-1) contains supplementary material, which is available to authorized users.

Massive implementation of malaria diagnostics in low-resource countries is regarded as a pivotal strategy in control and elimination efforts.,Although malaria rapid diagnostic tests (RDTs) are considered a viable alternative, there are still obstacles to the widespread implementation of this strategy, such as reporting constraints and lack of proper quality assurance of RDT-based programmes at point-of-care (POC).,A prospective cohort of patients, seeking routine care for febrile episodes at health centres in malaria-endemic areas of Colombia, was used to assess the diagnostic performance of a device based on smartphone technology (Deki ReaderTM, former codename “GenZero”), that assists users at POC to process RDTs.,After informed consent, patients were enrolled into the study and blood samples were collected for thick blood smear (TBS) and RDT.,The RDT results were interpreted by both visual inspection and Deki Reader device and concordance between visual and device interpretation was measured.,Microscopy corrected by real-time polymerase chain reaction (PCR) and microscopy were “gold standard” tests to assess the diagnostic performance.,In total, 1,807 patients were enrolled at seven health centres in malaria-endemic areas of Colombia.,Thirty-three Plasmodium falciparum and 100 Plasmodium vivax cases were positive by corrected microscopy.,Both sensitivity and specificity were 93.9% (95% CI 69.7-95.2) and 98.7% (95% CI 98.5-99.4) for P. falciparum, and 98.0% (95% CI 90.3-98.9) and 97.9% (95% CI 97.1-98.5) for P. vivax.,Percentage concordance between visual and device interpretation of RDT was 98.5% and 99.0% for P. vivax and P. falciparum, respectively.The RDT, when compared to TBS, showed high sensitivity and specificity for P. falciparum in both visual and device interpretation, and good overall diagnostic performance for P. vivax.,Comparison between PCR as gold standard and visual and device interpretation showed acceptable overall performance for both species.,The diagnostic performance of the Deki Reader was comparable to visual interpretation of RDTs (without significant differences) for both malaria species.,Providing standardized automated interpretation of RDTs at POC in remote areas, in addition to almost real-time reporting of cases and enabling quality control would greatly benefit large-scale implementation of RDT-based malaria diagnostic programmes.

Sub-optimal responses to ivermectin (IVM) have emerged.,Targeting the Onchocerca volvulus Wolbachia endosymbionts with doxycycline is effective in clearing microfilariae in onchocerciasis patients with persistent microfilaridermia and in enhanced killing of adult worms after repeated standard IVM treatment.,Background.,Ivermectin (IVM) has been the drug of choice for the treatment of onchocerciasis.,However, there have been reports of persistent microfilaridermia in individuals from an endemic area in Ghana after many rounds of IVM, raising concerns of suboptimal response or even the emergence of drug resistance.,Because it is considered risky to continue relying only on IVM to combat this phenomenon, we assessed the effect of targeting the Onchocerca volvulus Wolbachia endosymbionts with doxycycline for these individuals with suboptimal response.,Methods.,One hundred sixty-seven patients, most of them with multiple rounds of IVM, were recruited in areas with IVM suboptimal response and treated with 100 mg/day doxycycline for 6 weeks.,Three and 12 months after doxycycline treatment, patients took part in standard IVM treatment.,Results.,At 20 months after treatment, 80% of living female worms from the placebo group were Wolbachia positive, whereas only 5.1% in the doxycycline-treated group contained bacteria.,Consistent with interruption of embryogenesis, none of the nodules removed from doxycycline-treated patients contained microfilariae, and 97% of those patients were without microfilaridermia, in contrast to placebo patients who remained at pretreatment levels (P < .001).,Moreover, a significantly enhanced number of dead worms were observed after doxycycline.,Conclusions.,Targeting the Wolbachia in O. volvulus is effective in clearing microfilariae in the skin of onchocerciasis patients with persistent microfilaridermia and in enhanced killing of adult worms after repeated standard IVM treatment.,Strategies can now be developed that include doxycycline to control onchocerciasis in areas where infections persist despite the frequent use of IVM.,Clinical Trials Registration.,ISRCTN 66649839.

microRNAs (miRNAs), a class of short, non-coding RNA can be found in a highly stable, cell-free form in mammalian body fluids.,Specific miRNAs are secreted by parasitic nematodes in exosomes and have been detected in the serum of murine and dog hosts infected with the filarial nematodes Litomosoides sigmodontis and Dirofilaria immitis, respectively.,Here we identify extracellular, parasite-derived small RNAs associated with Onchocerca species infecting cattle and humans.,Small RNA libraries were prepared from total RNA extracted from the nodule fluid of cattle infected with Onchocerca ochengi as well as serum and plasma from humans infected with Onchocerca volvulus in Cameroon and Ghana.,Parasite-derived miRNAs were identified based on the criteria that sequences unambiguously map to hairpin structures in Onchocerca genomes, do not align to the human genome and are not present in European control serum.,A total of 62 mature miRNAs from 52 distinct pre-miRNA candidates were identified in nodule fluid from cattle infected with O. ochengi of which 59 are identical in the genome of the human parasite O. volvulus.,Six of the extracellular miRNAs were also identified in sequencing analyses of serum and plasma from humans infected with O. volvulus.,Based on sequencing analysis the abundance levels of the parasite miRNAs in serum or plasma range from 5 to 127 reads/per million total host miRNA reads identified, comparable to our previous analyses of Schistosoma mansoni and L. sigmodontis miRNAs in serum.,All six of the O. volvulus miRNAs identified have orthologs in other filarial nematodes and four were identified in the serum of mice infected with L. sigmodontis.,We have identified parasite-derived miRNAs associated with onchocerciasis in cattle and humans.,Our results confirm the conserved nature of RNA secretion by diverse nematodes.,Additional species-specific small RNAs from O. volvulus may be present in serum based on the novel miRNA sequences identified in the nodule fluid.,In our analyses comparison to European control serum illuminates the scope for false-positives, warranting caution in criteria that should be applied to identification of biomarkers of infection.,The online version of this article (doi:10.1186/s13071-015-0656-1) contains supplementary material, which is available to authorized users.

Many microparasites infect new hosts with specialized life stages, requiring a subset of the parasite population to forgo proliferation and develop into transmission forms.,Transmission stage production influences infectivity, host exploitation, and the impact of medical interventions like drug treatment.,Predicting how parasites will respond to public health efforts on both epidemiological and evolutionary timescales requires understanding transmission strategies.,These strategies can rarely be observed directly and must typically be inferred from infection dynamics.,Using malaria as a case study, we test previously described methods for inferring transmission stage investment against simulated data generated with a model of within-host infection dynamics, where the true transmission investment is known.,We show that existing methods are inadequate and potentially very misleading.,The key difficulty lies in separating transmission stages produced by different generations of parasites.,We develop a new approach that performs much better on simulated data.,Applying this approach to real data from mice infected with a single Plasmodium chabaudi strain, we estimate that transmission investment varies from zero to 20%, with evidence for variable investment over time in some hosts, but not others.,These patterns suggest that, even in experimental infections where host genetics and other environmental factors are controlled, parasites may exhibit remarkably different patterns of transmission investment.

Protection against malaria in humans can be achieved by repeated exposure to infected mosquito bites during prophylactic chloroquine treatment (chemoprophylaxis and sporozoites (CPS)).,We established a new mouse model of CPS immunization to investigate the stage and strain-specificity of malaria immunity.,Immunization with Plasmodium chabaudi by mosquito bite under chloroquine cover does not generate pre-erythrocytic immunity, which is acquired only after immunization with high sporozoite doses.,Instead, CPS immunization by bite elicits long-lived protection against blood-stage parasites.,Blood-stage immunity is effective against a virulent, genetically distinct strain of P. chabaudi.,Importantly, if exposure to blood-stage parasitemia is extended, blood-stage parasites induce cross-stage immunity targeting pre-erythrocytic stages.,We therefore show that CPS immunization can induce robust, long-lived heterologous blood-stage immunity, in addition to protection against pre-erythrocytic parasites following high dose sporozoite immunization.,Cross-stage immunity elicited by blood-stage parasites may further enhance efficacy of this immunization regimen.,DOI:http://dx.doi.org/10.7554/eLife.05165.001,Malaria is a life-threatening infectious disease in humans that is caused by a single-celled parasite called Plasmodium.,The parasite is carried between people by mosquitos; when an infected mosquito bites a human, the parasite is injected into the bloodstream with the mosquito's saliva.,Plasmodium first infects liver cells but then re-enters the bloodstream, where it infects red blood cells leading to symptoms of disease.,If another mosquito bites the infected individual at this so-called ‘blood-stage’, the parasite can be passed to this mosquito and the cycle of transmission continues.,Currently there are no vaccines available that can effectively protect against malaria.,Although an experimental vaccine containing a weakened form of the parasite can protect against the liver-stage parasites, it fails to prevent the parasite from multiplying in the red blood cells.,Therefore, the individuals remain susceptible to severe malaria.,Recently, researchers have developed a new strategy for immunization that provides exposure to both liver-stage and blood-stage parasites.,Human volunteers taking an anti-malarial drug were deliberately exposed to mosquitos carrying the parasite on three separate occasions.,Although the volunteers were infected with the parasite, the anti-malarial drug killed the parasites inside the red blood cells.,After the end of the drug treatment, the volunteers were exposed to mosquitos carrying the parasite and they were still protected from infection.,These results are promising, but it is not clear if the volunteers have acquired immunity to liver-stage or blood-stage parasites, or even both.,To answer this important question, Nahrendorf et al. developed a similar immunization strategy in mice.,Just like the human volunteers, the mice were treated with an anti-malarial drug and exposed to mosquitos carrying Plasmodium on three separate occasions.,Although the immunizations did not protect the mice against early infection in the liver, they did provide long-term protection against parasites multiplying in the red-blood cells.,The immunity generated by this immunization strategy also protected the mice against another strain of Plasmodium, different to the one used in the immunizations.,The experiments also show that prolonged exposure to the blood-stage parasites can even lead to immunity against the liver-stage parasites.,Nahrendorf et al.'s findings show that this immunization strategy can protect individuals against both the liver-stage and blood-stage parasites.,The next challenges are to find out how the immunity generated by one stage of infection can protect against the other stages, and to discover which molecules on the parasite the immune system targets.,DOI:http://dx.doi.org/10.7554/eLife.05165.002

Malaria infection starts with injection of Plasmodium sporozoites by an Anopheles mosquito into the skin of the mammalian host.,How sporozoites locate and enter a blood vessel is a critical, but poorly understood process.,In this study, we examine sporozoite motility and their interaction with dermal blood vessels, using intravital microscopy in mice.,Our data suggest that sporozoites exhibit two types of motility: in regions far from blood vessels, they exhibit ‘avascular motility’, defined by high speed and less confinement, while in the vicinity of blood vessels their motility is more constrained.,We find that curvature of sporozoite tracks engaging with vasculature optimizes contact with dermal capillaries.,Imaging of sporozoites with mutations in key adhesive proteins highlight the importance of the sporozoite's gliding speed and its ability to modulate adhesive properties for successful exit from the inoculation site.,DOI:http://dx.doi.org/10.7554/eLife.07789.001,Malaria remains a devastating disease in many parts of the world.,Malaria parasites enter the host via the skin, where they are deposited by infected mosquitoes as they look for blood.,The parasites must exit the skin to reach the liver, where they multiply and ultimately infect red blood cells, where they cause the symptoms of the disease.,In the skin, the parasites must move to find blood vessels that they enter to travel via the blood circulation to the liver.,Only about 10-20% of parasites make it out of the skin, making this a bottleneck for the parasite.,Scientists have been working to develop vaccines that would protect people against malaria.,One way these could work would be to stop malaria parasites from leaving the skin and entering the blood vessels.,But to do that, more needs to be learnt about how the parasites move in the skin and enter the blood vessels.,Hopp et al., using a mouse model of malaria, created malaria parasites that produce a fluorescent protein that allows the parasites to be tracked after they have been injected into the skin of a mouse's ear.,This revealed that the parasites have two ways of moving.,After first being injected, the parasites move quickly and freely.,The parasites slow down when they come close to a blood vessel and move on or around the vessel for some time before entering it.,During this stage of movement, the parasites tend to move in paths that follow the curvature of the blood vessels, which may improve how well they make contact with the blood vessel surface and may enable them to find the areas of the vessels best suited for entry.,Next, Hopp et al. investigated how two parasite mutants move through mouse skin.,Both mutants had previously been found to be less likely than wild-type parasites to exit the inoculation site.,Hopp et al. found that one of the mutants moves slowly after being injected and so explores a smaller tissue volume than normal and encounters fewer blood vessels.,The second mutant parasite spends more time than normal moving on the surface of the blood vessels, but finds it difficult to enter them.,Continuing this work will allow us to learn more about the interactions between the parasite and the blood vessels, which in turn could reveal key events that could be targeted by a vaccine.,Furthermore, the significant amount of time that the parasites spend moving and looking for blood vessels in the skin could be a good time to target them with antibodies and prevent malaria infection.,DOI:http://dx.doi.org/10.7554/eLife.07789.002

Induction of antigen-specific CD8+ T cells offers the prospect of immunization against many infectious diseases, but no subunit vaccine has induced CD8+ T cells that correlate with efficacy in humans.,Here we demonstrate that a replication-deficient chimpanzee adenovirus vector followed by a modified vaccinia virus Ankara booster induces exceptionally high frequency T-cell responses (median >2400 SFC/106 peripheral blood mononuclear cells) to the liver-stage Plasmodium falciparum malaria antigen ME-TRAP.,It induces sterile protective efficacy against heterologous strain sporozoites in three vaccinees (3/14, 21%), and delays time to patency through substantial reduction of liver-stage parasite burden in five more (5/14, 36%), P=0.008 compared with controls.,The frequency of monofunctional interferon-γ-producing CD8+ T cells, but not antibodies, correlates with sterile protection and delay in time to patency (Pcorrected=0.005).,Vaccine-induced CD8+ T cells provide protection against human malaria, suggesting that a major limitation of previous vaccination approaches has been the insufficient magnitude of induced T cells.,Induction of protective immunity mediated by CD8+ T cells has been a long sought goal in vaccinology.,Here, Ewer et al. report induction of protective efficacy against Plasmodium falciparum malaria in a phase IIa prime-boost vaccine trial where efficacy correlates strongly with induced CD8 T-cell responses.

Supplemental Digital Content is available in the text,Malaria and human immunodeficiency virus (HIV) infections are globally important public health concerns.,The objectives of this study were (i) to determine the prevalence of malaria and HIV co-infections in people living in endemic countries, and (ii) to assess the effect of co-infection on anemia.,Studies were searched on electronic databases including PubMed, Embase, Medline, Google Scholar, and African Journals Online.,Observational studies, assessing the prevalence of co-infection and reporting its association with anemia, were included.,The methodological quality of included studies was assessed using a tool called the risk of bias assessment for non-randomized studies.,Heterogeneity among studies was investigated with the I-square test.,Pooled prevalence of the co-infection and its 95% confidence interval (CI) were estimated using the random-effect model, reflected on heterogeneity among studies.,Summary odds ratio (OR), summary standardized mean difference (SMD), and their corresponding 95% CIs were estimated, as appropriate.,Subgroup analysis and meta-regression were performed for robustness of results.,Publication bias was assessed by visualization of a funnel plot.,Twenty-three studies were included in the present study.,Overall, the pooled prevalence of co-infection was 19% (95% CI: 15-23%, I2: 98.1%), showing 26% (95% CI: 20-32%, I2: 98.7%) in adults, 12% (95% CI: 7-17%, I2: 95.0) in pregnant women, and 9% (95% CI: 6-11%, I2: 68.6%) in children.,Anemia was comparable between the monoinfected and co-infected adults (summary OR: 1.49, 95% CI: 0.93-2.37) and increased by 49% in co-infected pregnant women (summary OR: 1.49, 95% CI: 1.14-1.94).,The mean hemoglobin concentration was significantly lower in the co-infected group than the monoinfected group (summary SMD: −0.47, 95% CI: −0.61 to −0.33).,The results of meta-regression on the prevalence of co-infection using the publication year and total population as covariates showed the I2 value remained high implying a de facto random distribution of heterogeneity.,An asymmetrical funnel plot indicated the presence of publication bias.,Due to heterogeneity of the studies in this review, the results have to be interpreted with caution.,The findings of this study suggest that the prevalence of malaria and HIV co-infection, particularly in pregnant women, requires special attention from healthcare personnel.,Better understanding of the co-infection is crucial for designing treatment strategies.,Future well-powered, prospective designs assessing the interaction between malaria and HIV are recommended.

Mozambique presents a very high prevalence of both malaria and HIV infection, but the impact of co-cancel infection on morbidity in this population has been rarely investigated.,The aim of this study was to describe the prevalence and clinical characteristics of malaria in hospitalized adult HIV-positive patients, treated and untreated with combination anti-retroviral therapy (ART) and cotrimoxazole (CTX)-based chemoprophylaxis, compared to HIV negatives.,From November to December 2010, all adult patients consecutively admitted to the Department of Internal Medicine of Beira Central Hospital, Sofala Province, Mozambique, were submitted to HIV testing, malaria blood smear (MBS) and, in a subgroup of patients, also to the rapid malaria test (RDT).,Socio-demographical and clinical data were collected for all patients.,The association of both a positive MBS and/or RDT and diagnosis of clinical malaria with concomitant HIV infection (and use of CTX and/or ART) was assessed statistically.,Frequency of symptoms and hematological alterations in HIV patients with clinical malaria compared to HIV negatives was also analysed.,Sensitivity and specificity for RDT versus MBS were calculated for both HIV-positive and negative patients.,A total of 330 patients with available HIV test and MBS were included in the analysis, 220 of whom (66.7%) were HIV-positive.,In 93 patients, malaria infection was documented by MBS and/or RDT.,RDT sensitivity and specificity were 94% and 96%, respectively.,According to laboratory results, the initial malaria suspicion was discarded in about 10% of cases, with no differences between HIV-positive and negative patients.,A lower malaria risk was significantly associated with CTX prophylaxis (p=0.02), but not with ART based on non nucleoside reverse-transcriptase inhibitors (NNRTIs).,Overall, severe malaria seemed to be more common in HIV-positive patients (61.7%) compared to HIV-negatives (47.2%), while a significantly lower haemoglobin level was observed in the group of HIV-positive patients (9.9±2.8mg/dl) compared to those HIV-negative (12.1±2.8mg/dl) (p=0.003).,Malaria infection was rare in HIV-positive individuals treated with CTX for opportunistic infections, while no independent anti-malarial effect for NNRTIs was noted.,When HIV and malaria co-infection occurred, a high risk of complications, particularly anaemia, should be expected.

Nairobi is considered a low-risk area for malaria transmission, but travel can influence transmission of malaria.,We investigated the demographic characteristics and travel history of patients with documented fever and malaria in a study clinic in a population-based surveillance system over a 5-year period, January 1, 2007 to December 31, 2011.,During the study period, 11,480 (68%) febrile patients had a microscopy test performed for malaria, of which 2,553 (22%) were positive.,Malaria was detected year-round with peaks in January, May, and September.,Children aged 5-14 years had the highest proportion (28%) of positive results followed by children aged 1-4 years (23%).,Almost two-thirds of patients with malaria reported traveling outside Nairobi; 79% of these traveled to three counties in western Kenya.,History of recent travel (i.e., in past month) was associated with malaria parasitemia (odds ratio: 10.0, 95% confidence interval: 9.0-11.0).,Malaria parasitemia was frequently observed among febrile patients at a health facility in the urban slum of Kibera, Nairobi.,The majority of patients had traveled to western Kenya.,However, 34% reported no travel history, which raises the possibility of local malaria transmission in this densely populated, urban setting.,These findings have important implications for malaria control in large Nairobi settlements.

Temperature is a key determinant of environmental suitability for transmission of human malaria, modulating endemicity in some regions and preventing transmission in others.,The spatial modelling of malaria endemicity has become increasingly sophisticated and is now central to the global scale planning, implementation, and monitoring of disease control and regional efforts towards elimination, but existing efforts to model the constraints of temperature on the malaria landscape at these scales have been simplistic.,Here, we define an analytical framework to model these constraints appropriately at fine spatial and temporal resolutions, providing a detailed dynamic description that can enhance large scale malaria cartography as a decision-support tool in public health.,We defined a dynamic biological model that incorporated the principal mechanisms of temperature dependency in the malaria transmission cycle and used it with fine spatial and temporal resolution temperature data to evaluate time-series of temperature suitability for transmission of Plasmodium falciparum and P. vivax throughout an average year, quantified using an index proportional to the basic reproductive number.,Time-series were calculated for all 1 km resolution land pixels globally and were summarised to create high-resolution maps for each species delineating those regions where temperature precludes transmission throughout the year.,Within suitable zones we mapped for each pixel the number of days in which transmission is possible and an integrated measure of the intensity of suitability across the year.,The detailed evaluation of temporal suitability dynamics provided by the model is visualised in a series of accompanying animations.,These modelled products, made available freely in the public domain, can support the refined delineation of populations at risk; enhance endemicity mapping by offering a detailed, dynamic, and biologically driven alternative to the ubiquitous empirical incorporation of raw temperature data in geospatial models; and provide a rich spatial and temporal platform for future biological modelling studies.

Leishmania infantum infections in dogs play a crucial role in the transmission of pathogens causing visceral leishmaniasis to humans in the Gansu province, northwest China.,To be able to control zoonotic transmission of the parasite to humans, a non-invasive loop-mediated isothermal amplification (LAMP) assay to specifically detect L. infantum infections in dogs was developed.,The primers used in the LAMP assay were designed to target kinetoplast DNA minicircle sequences of the L. infantum isolate MCAN/CN/90/SC and tested using DNA isolated from promastigotes of different Leishmania species.,The LAMP assay was evaluated with conjunctional swab samples obtained from 111 and 33 dogs living in an endemic and a non-endemic region of zoonotic visceral leishmaniasis in the Gansu province, respectively.,The LAMP assay was also compared with conventional PCR, ELISA and microscopy using conjunctional swab, serum and bone marrow samples from the dogs, respectively.,The LAMP assay detected 1 fg of L. infantum DNA purified from cultured promastigotes which was 10-fold more sensitive than a conventional PCR test using Leishmania genus-specific primers.,No cross reaction was observed with DNA isolated from promastigotes of L. donovani, L. major, L. tropica, and L. braziliensis, and the L. infantum reference strain MHOM/TN/80/IPT1.,The L. infantum-positive rates obtained for field-collected samples were 61.3 %, 58.6 %, 40.5 % and 10.8 % by LAMP, PCR, ELISA and microscopy, respectively.,As only one out of the 33 samples from control dogs from the non-endemic region of zoonotic visceral leishmaniasis was positive by the LAMP assay and the PCR test, the observed true negative rate (specificity) was 97 % for both methods.,This study has shown that the non-invasive, conjunctional swab-based LAMP assay developed was more sensitive in the detection of leishmaniasis in dogs than PCR, ELISA and microscopy.,The findings indicate that the LAMP assay is a sensitive and specific method for the field surveillance of domestic dogs, particularly of asymptomatic canines, in ZVL-endemic areas in western China.

The diagnosis of visceral leishmaniasis (VL) in patients with fever and a large spleen relies on showing Leishmania parasites in tissue samples and on serological tests.,Parasitological techniques are invasive, require sophisticated laboratories, consume time, or lack accuracy.,Recently, rapid diagnostic tests that are easy to perform have become available.,To determine the diagnostic accuracy of rapid tests for diagnosing VL in patients with suspected disease presenting at health services in endemic areas.,We searched MEDLINE, EMBASE, LILACS, CIDG SR, CENTRAL, SCI‐expanded, Medion, Arif, CCT, and the WHO trials register on 3 December 2013, without applying language or date limits.,This review includes original, phase III, diagnostic accuracy studies of rapid tests in patients clinically suspected to have VL.,As reference standards, we accepted: (1) direct smear or culture of spleen aspirate; (2) composite reference standard based on one or more of the following: parasitology, serology, or response to treatment; and (3) latent class analysis.,Two review authors independently extracted data and assessed quality of included studies using the QUADAS‐2 tool.,Discrepancies were resolved by a third author.,We carried out a meta‐analysis to estimate sensitivity and specificity of rapid tests, using a bivariate normal model with a complementary log‐log link function.,We analysed each index test separately.,As possible sources of heterogeneity, we explored: geographical area, commercial brand of index test, type of reference standard, disease prevalence, study size, and risk of bias (QUADAS‐2).,We also undertook a sensitivity analysis to assess the influence of imperfect reference standards.,Twenty‐four studies containing information about five index tests (rK39 immunochromatographic test (ICT), KAtex latex agglutination test in urine, FAST agglutination test, rK26 ICT, and rKE16 ICT) recruiting 4271 participants (2605 with VL) were included.,We carried out a meta‐analysis for the rK39 ICT (including 18 studies; 3622 participants) and the latex agglutination test (six studies; 1374 participants).,The results showed considerable heterogeneity.,For the rK39 ICT, the overall sensitivity was 91.9% (95% confidence interval (95% CI) 84.8 to 96.5) and the specificity 92.4% (95% CI 85.6 to 96.8).,The sensitivity was lower in East Africa (85.3%; 95% CI 74.5 to 93.2) than in the Indian subcontinent (97.0%; 95% CI 90.0 to 99.5).,For the latex agglutination test, overall sensitivity was 63.6% (95% CI 40.9 to 85.6) and specificity 92.9% (95% CI 76.7 to 99.2).,The rK39 ICT shows high sensitivity and specificity for the diagnosis of visceral leishmaniasis in patients with febrile splenomegaly and no previous history of the disease, but the sensitivity is notably lower in east Africa than in the Indian subcontinent.,Other rapid tests lack accuracy, validation, or both.,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.,Rapid diagnostic tests for visceral leishmaniasis,Visceral leishmaniasis (or kala‐azar) is caused by a parasite, results in fever, a large spleen and other health problems, occuring in India, Bangladesh and Nepal, east Africa, the Mediterranean region and Brazil.,Without treatment people die, and proper treatment can result in cure, so diagnosis is important.,Many of the tests that are used to determine if a person has visceral leishmaniasis are complicated, costly, painful and sometimes dangerous for the patients.,Now rapid diagnostic tests that are safe and easy to perform are available.,This Cochrane review describes how accurate these rapid diagnostic tests are for diagnosing visceral leishmaniasis.,We summarize those studies that evaluated the rapid tests in people who, according to their physicians, could have the disease.,We only included studies in which the researchers had used established methods to distinguish the people with visceral leishmaniasis from those who did not have the disease.,We found 24 studies, which contained information about five different rapid tests.,A total of 4271 people participated in these studies.,One of the rapid tests (called the rK39 immunochromatographic test) gave correct, positive results in 92% of the people with visceral leishmaniasis and it gave correct, negative results in 92% of the people who did not have the disease.,This test worked better in India and Nepal than in east Africa.,In India and Nepal, it gave correct, positive results in 97% of the people with the disease.,In east Africa, it gave correct, positive results in only 85% of the people with the disease.,A second rapid test (called latex agglutination test) gave correct, positive results in 64% of the people with the disease and it gave correct, negative results in 93% of the people without the disease.,For the other rapid tests evaluated, there are too few studies to know how accurate they are.

The field standard for the detection of Schistosoma mansoni infection is Kato-Katz (KK), although it misses many active infections, especially light infections.,In 2014, a reassessment of S. mansoni prevalence was conducted in Rwanda using the more sensitive point-of-care circulating cathodic antigen (POC-CCA) rapid assay.,A total of 19,371 children from 399 schools were selected for testing for single urine CCA.,Of these, 8,697 children from 175 schools were also tested with single stool double-slide KK.,Samples from eight of these 175 schools were tested again with CCA and additionally with the highly specific and sensitive up-converting phosphor-lateral flow circulating anodic antigen (UCP-LF CAA) assay.,Latent class analysis was applied to all four test results to assess sensitivity and specificity of POC-CCA and estimate the proportion of trace results from Rwanda likely to be true infections.,The overall prevalence of S. mansoni infection in Rwanda when CCA trace results were considered negative was 7.4% (school interquartile range [IQR] 0-8%) and 36.1% (school IQR 20-47%) when trace was considered positive.,Prevalence by KK was 2.0% with a mean intensity of infection of 1.66 eggs per gram.,The proportion of active infections among children diagnosed with CCA trace was estimated by statistical analysis at 61% (Bayesian credibility interval: 50-72%).,These results indicate that S. mansoni infection is still widespread in Rwanda and prevalence is much underestimated by KK testing.,Circulating cathodic antigen is an affordable alternative to KK and more suitable for measuring S. mansoni prevalence in low-intensity regions.

Kato-Katz examination of stool smears is the field-standard method for detecting Schistosoma mansoni infection.,However, Kato-Katz misses many active infections, especially of light intensity.,Point-of-care circulating cathodic antigen (CCA) is an alternative field diagnostic that is more sensitive than Kato-Katz when intensity is low, but interpretation of CCA-trace results is unclear.,To evaluate trace results, we tested urine and stool specimens from 398 pupils from eight schools in Burundi using four approaches: two in Burundi and two in a laboratory in Leiden, the Netherlands.,In Burundi, we used Kato-Katz and point-of-care CCA (CCAB).,In Leiden, we repeated the CCA (CCAL) and also used Up-Converting Phosphor Circulating Anodic Antigen (CAA).,We applied Bayesian latent class analyses (LCA), first considering CCA traces as negative and then as positive.,We used the LCA output to estimate validity of the prevalence estimates of each test in comparison to the population-level infection prevalence and estimated the proportion of trace results that were likely true positives.,Kato-Katz yielded the lowest prevalence (6.8%), and CCAB with trace considered positive yielded the highest (53.5%).,There were many more trace results recorded by CCA in Burundi (32.4%) than in Leiden (2.3%).,Estimated prevalence with CAA was 46.5%.,LCA indicated that Kato-Katz had the lowest sensitivity: 15.9% [Bayesian Credible Interval (BCI): 9.2-23.5%] with CCA-trace considered negative and 15.0% with trace as positive (BCI: 9.6-21.4%), implying that Kato-Katz missed approximately 85% of infections.,CCAB underestimated disease prevalence when trace was considered negative and overestimated disease prevalence when trace was considered positive, by approximately 12 percentage points each way, and CAA overestimated prevalence in both models.,Our results suggest that approximately 52.2% (BCI: 37.8-5.8%) of the CCAB trace readings were true infections.,Whether measured in the laboratory or the field, CCA outperformed Kato-Katz at the low infection intensities in Burundi.,CCA with trace as negative likely missed many infections, whereas CCA with trace as positive overestimated prevalence.,In the absence of a field-friendly gold standard diagnostic, the use of a variety of diagnostics with differing properties will become increasingly important as programs move towards elimination of schistosomiasis.,It is clear that CCA is a valuable tool for the detection and mapping of S. mansoni infection in the field and CAA may be a valuable field tool in the future.,The online version of this article (10.1186/s13071-018-2700-4) contains supplementary material, which is available to authorized users.

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.

The final article in a series of three publications examining the global distribution of 41 dominant vector species (DVS) of malaria is presented here.,The first publication examined the DVS from the Americas, with the second covering those species present in Africa, Europe and the Middle East.,Here we discuss the 19 DVS of the Asian-Pacific region.,This region experiences a high diversity of vector species, many occurring sympatrically, which, combined with the occurrence of a high number of species complexes and suspected species complexes, and behavioural plasticity of many of these major vectors, adds a level of entomological complexity not comparable elsewhere globally.,To try and untangle the intricacy of the vectors of this region and to increase the effectiveness of vector control interventions, an understanding of the contemporary distribution of each species, combined with a synthesis of the current knowledge of their behaviour and ecology is needed.,Expert opinion (EO) range maps, created with the most up-to-date expert knowledge of each DVS distribution, were combined with a contemporary database of occurrence data and a suite of open access, environmental and climatic variables.,Using the Boosted Regression Tree (BRT) modelling method, distribution maps of each DVS were produced.,The occurrence data were abstracted from the formal, published literature, plus other relevant sources, resulting in the collation of DVS occurrence at 10116 locations across 31 countries, of which 8853 were successfully geo-referenced and 7430 were resolved to spatial areas that could be included in the BRT model.,A detailed summary of the information on the bionomics of each species and species complex is also presented.,This article concludes a project aimed to establish the contemporary global distribution of the DVS of malaria.,The three articles produced are intended as a detailed reference for scientists continuing research into the aspects of taxonomy, biology and ecology relevant to species-specific vector control.,This research is particularly relevant to help unravel the complicated taxonomic status, ecology and epidemiology of the vectors of the Asia-Pacific region.,All the occurrence data, predictive maps and EO-shape files generated during the production of these publications will be made available in the public domain.,We hope that this will encourage data sharing to improve future iterations of the distribution maps.

A drug for causal (ie, pre-erythrocytic) prophylaxis of Plasmodium falciparum malaria with prolonged activity would substantially advance malaria control.,DSM265 is an experimental antimalarial that selectively inhibits the parasite dihydroorotate dehydrogenase.,DSM265 shows in vitro activity against liver and blood stages of P falciparum.,We assessed the prophylactic activity of DSM265 against controlled human malaria infection (CHMI).,At the Institute of Tropical Medicine, Eberhard Karls University (Tübingen, Germany), healthy, malaria-naive adults were allocated to receive 400 mg DSM265 or placebo either 1 day (cohort 1A) or 7 days (cohort 2) before CHMI by direct venous inoculation (DVI) of 3200 aseptic, purified, cryopreserved P falciparum sporozoites (PfSPZ Challenge; Sanaria Inc, Rockville, MD, USA).,An additional group received daily atovaquone-proguanil (250-100 mg) for 9 days, starting 1 day before CHMI (cohort 1B).,Allocation to DSM265, atovaquone-proguanil, or placebo was randomised by an interactive web response system.,Allocation to cohort 1A and 1B was open-label, within cohorts 1A and 2, allocation to DSM265 and placebo was double-blinded.,All treatments were given orally.,Volunteers were treated with an antimalarial on day 28, or when parasitaemic, as detected by thick blood smear (TBS) microscopy.,The primary efficacy endpoint was time-to-parasitaemia, assessed by TBS.,All participants receiving at least one dose of chemoprophylaxis or placebo were considered for safety, those receiving PfSPZ Challenge for efficacy analyses.,Log-rank test was used to compare time-to-parasitemia between interventions.,The trial was registered with ClinicalTrials.gov, number NCT02450578.,22 participants were enrolled between Oct 23, 2015, and Jan 18, 2016.,Five participants received 400 mg DSM265 and two participants received placebo 1 day before CHMI (cohort 1A), six participants received daily atovaquone-proguanil 1 day before CHMI (cohort 1B), and six participants received 400 mg DSM265 and two participants received placebo 7 days before CHMI (cohort 2).,Five of five participants receiving DSM265 1 day before CHMI and six of six in the atovaquone-proguanil cohort were protected, whereas placebo recipients (two of two) developed malaria on days 11 and 14.,When given 7 days before CHMI, three of six volunteers receiving DSM265 became TBS positive on days 11, 13, and 24.,The remaining three DSM265-treated, TBS-negative participants of cohort 2 developed transient submicroscopic parasitaemia.,Both participants receiving placebo 7 days before CHMI became TBS positive on day 11.,The only possible DSM265-related adverse event was a moderate transient elevation in serum bilirubin in one participant.,A single dose of 400 mg DSM265 was well tolerated and had causal prophylactic activity when given 1 day before CHMI.,Future trials are needed to investigate further the use of DSM265 for the prophylaxis of malaria.,Global Health Innovative Technology Fund, Wellcome Trust, Bill & Melinda Gates Foundation through Medicines for Malaria Venture, and the German Center for Infection Research.

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.

A reduction in the global burden of malaria over the past two decades has encouraged efforts for regional malaria elimination.,Despite the need to target all Plasmodium species, current focus is mainly directed towards Plasmodium falciparum, and to a lesser extent P. vivax.,There is a substantial lack of data on both global and local transmission patterns of the neglected malaria parasites P. malariae and P. ovale spp.,We used a species-specific real-time PCR assay targeting the Plasmodium 18s rRNA gene to evaluate temporal trends in the prevalence of all human malaria parasites over a 22-year period in a rural village in Tanzania.We tested 2897 blood samples collected in five cross-sectional surveys conducted between 1994 and 2016.,Infections with P. falciparum, P. malariae, and P. ovale spp. were detected throughout the study period, while P. vivax was not detected.,Between 1994 and 2010, we found a more than 90% reduction in the odds of infection with all detected species.,The odds of P. falciparum infection was further reduced in 2016, while the odds of P. malariae and P. ovale spp. infection increased 2- and 6-fold, respectively, compared to 2010.,In 2016, non-falciparum species occurred more often as mono-infections.,The results demonstrate the persistent transmission of P. ovale spp., and to a lesser extent P. malariae despite a continued decline in P. falciparum transmission.,This illustrates that the transmission patterns of the non-falciparum species do not necessarily follow those of P. falciparum, stressing the need for attention towards non-falciparum malaria in Africa.,Malaria elimination will require a better understanding of the epidemiology of P. malariae and P. ovale spp. and improved tools for monitoring the transmission of all Plasmodium species, with a particular focus towards identifying asymptomatic carriers of infection and designing appropriate interventions to enhance malaria control.

Plasmodium falciparum infections presenting either as symptomatic or asymptomatic may contain sexual stage parasites (gametocytes) that are crucial to malaria transmission.,In this study, the prevalence of microscopic and submicroscopic asexual and gametocyte parasite stages were assessed in asymptomatic children from two communities in southern Ghana.,Eighty children aged twelve years and below, none of whom exhibited signs of clinical malaria living in Obom and Cape Coast were sampled twice, one during the rainy (July 2015) and subsequently during the dry (January 2016) season.,Venous blood was used to prepare thick and thin blood smears, spot a rapid malaria diagnostic test (PfHRP2 RDT) as well as prepare filter paper blood spots.,Blood cell pellets were preserved in Trizol for RNA extraction.,Polymerase chain reaction (PCR) and semi-quantitative real time reverse transcriptase PCR (qRT-PCR) were used to determine submicroscopic parasite prevalence.,In both sites 87% (95% CI: 78-96) of the asymptomatic individuals surveyed were parasites positive during the 6 month study period.,The prevalence of asexual and gametocyte stage parasites in the rainy season were both significantly higher in Obom than in Cape Coast (P < 0.001).,Submicroscopic gametocyte prevalence was highest in the rainy season in Obom but in the dry season in Cape Coast.,Parasite prevalence determined by PCR was similar to that determined by qRT-PCR in Obom but significantly lower than that determined by qRT-PCR in Cape Coast.,Communities with varying parasite prevalence exhibit seasonal variations in the prevalence of gametocyte carriers.,Submicroscopic asymptomatic parasite and gametocyte carriage is very high in southern Ghana, even during the dry season in communities with low microscopic parasite prevalence and likely to be missed during national surveillance exercises.

CD4+ effector lymphocytes (Teff) are traditionally classified by the cytokines they produce.,To determine the states that Teff actually adopt in frontline tissues in vivo, we applied single-cell transcriptome and chromatin analysis on colonic Teff cells, in germ-free or conventional mice, or after challenge with a range of phenotypically biasing microbes.,Subsets were marked by expression of interferon-signature or myeloid-specific transcripts, but transcriptome or chromatin structure could not resolve discrete clusters fitting classic TH subsets.,At baseline or at different times of infection, transcripts encoding cytokines or proteins commonly used as TH markers distributed in a polarized continuum, which was also functionally validated.,Clones derived from single progenitors gave rise to both IFN-γ and IL17-producing cells.,Most transcriptional variance was tied to the infecting agent, independent of the cytokines produced, and chromatin variance primarily reflected activity of AP1 and IRF transcription factor families, not the canonical subset master regulators T-bet, GATA3, RORγ.

Using a unique resource of samples from a controlled human malaria infection (CHMI) study, we identified a novel population of CD4+ T cells whose frequency in the peripheral blood was inversely correlated with parasite burden following P. falciparum infection.,These CD4+ T cells expressed the multifunctional ectoenzyme CD38 and had unique features that distinguished them from other CD4+ T cells.,Specifically, their phenotype was associated with proliferation, activation and cytotoxic potential as well as significantly impaired production of IFN-γ and other cytokines and reduced basal levels of activated STAT1.,A CD38+ CD4+ T cell population with similar features was identified in healthy uninfected individuals, at lower frequency.,CD38+ CD4+ T cells could be generated in vitro from CD38- CD4+ T cells after antigenic or mitogenic stimulation.,This is the first report of a population of CD38+ CD4+ T cells with a cytotoxic phenotype and markedly impaired IFN-γ capacity in humans.,The expansion of this CD38+ CD4+ T population following infection and its significant association with reduced blood-stage parasite burden is consistent with an important functional role for these cells in protective immunity to malaria in humans.,Their ubiquitous presence in humans suggests that they may have a broad role in host-pathogen defense.,ClinicalTrials.gov clinical trial numbers ACTRN12612000814875, ACTRN12613000565741 and ACTRN12613001040752

The success of the universal parasite-based malaria testing policy for fever patients attending primary health care (PHC) facilities in Tanzania will depend highly on health workers’ perceptions and practices.,The aim of this study was, therefore, to assess the present use of malaria diagnostics (rapid diagnostic tests (RDTs) and microscopy), prescription behaviour and factors affecting adherence to test results at PHC facilities in Kibaha District, Coast Region, Tanzania.,Exit interviews were conducted with fever patients at PHC facilities and information on diagnostic test performed and treatment prescribed were recorded.,Interviews with prescribers to assess their understanding, perceptions and practices related to RDTs were conducted, and health facility inventory performed to assess availability of staff, diagnostics and anti-malarial drugs.,The survey was undertaken at ten governmental PHC facilities, eight of which had functional diagnostics.,Twenty health workers were interviewed and 195 exit interviews were conducted with patients at the PHC facilities.,Of the 168 patients seen at facilities with available diagnostics, 105 (63%) were tested for malaria, 31 (30%) of whom tested positive.,Anti-malarial drugs were prescribed to all patients with positive test results, 14% of patients with negative results and 28% of patients not tested for malaria.,Antibiotics were more likely to be prescribed to patients with negative test results compared to patients with positive results (81 vs 39%, p < 0.01) and among non-tested compared to those tested for malaria (84 vs 69%, p = 0.01).,Stock-outs of RDTs and staff shortage accounted for the low testing rate, and health worker perceptions were the main reason for non-adherence to test results.,Anti-malarial prescription to patients with negative test results and those not tested is still practiced in Tanzania despite the universal malaria testing policy of fever patients.,The use of malaria diagnostics was also associated with higher prescription of antibiotics among patients with negative results.,Strategies to address health system factors and health worker perceptions associated with these practices are needed.

Health facility stock-outs of life saving malaria medicines are common across Africa.,Innovative ways of addressing this problem are urgently required.,We evaluated whether SMS based reporting of stocks of artemether-lumefantrine (AL) and rapid diagnostic tests (RDT) can result in reduction of stock-outs at peripheral facilities in Kenya.,All 87 public health facilities in five Kenyan districts were included in a 26 week project.,Weekly facility stock counts of four AL packs and RDTs were sent via structured incentivized SMS communication process from health workers’ personal mobile phones to a web-based system accessed by district managers.,The mean health facility response rate was 97% with a mean formatting error rate of 3%.,Accuracy of stock count reports was 79% while accuracy of stock-out reports was 93%.,District managers accessed the system 1,037 times at an average of eight times per week.,The system was accessed in 82% of the study weeks.,Comparing weeks 1 and 26, stock-out of one or more AL packs declined by 38 percentage-points.,Total AL stock-out declined by 5 percentage-points and was eliminated by the end of the project.,Stock-out declines of individual AL packs ranged from 14 to 32 percentage-points while decline in RDT stock-outs was 24 percentage-points.,District managers responded to 44% of AL and 73% of RDT stock-out signals by redistributing commodities between facilities.,In comparison with national trends, stock-out declines in study areas were greater, sharper and more sustained.,Use of simple SMS technology ensured high reporting rates of reasonably accurate, real-time facility stock data that were used by district managers to undertake corrective actions to reduce stock-outs.,Future work on stock monitoring via SMS should focus on assessing response rates without use of incentives and demonstrating effectiveness of such interventions on a larger scale.

Intestinal parasites are the most common infections in developing countries.,Prevalence and impacts of these parasites are high in pregnant women.,The aims of this study were to determine prevalence of helminthic infection and evaluate the determinant factors during pregnancy.,A cross-sectional study was conducted in Mecha district from November 2015 to January 2016.,The data were collected by interview technique and collecting the stool sample from each pregnant woman.,Descriptive statistics and binary logistic regression were used.,A total of 783 pregnant women were included.,The prevalence of intestinal parasite among pregnant women was 70.6% [95% CI 67 -74%].,Ascaris lumbricoides (32.7%) was the predominant intestinal parasite species.,Intestinal parasitic infection were 2.94 folds higher in the absence of latrine (AOR: 2.94 [95% CI: 1.5-5.8]).,Absence of regular hand washing habit increase the odds of infection by 3.33 folds higher (AOR: 3.33 [95% CI: 1.54-7.14]).,Not wearing shoe increased the odds of helminthic infection by 6.87 folds higher (AOR: 6.87 [95% CI: 3.67-12.9]).,Illiteracy increases the odds of intestinal parasitic infection by 2.32 folds higher (AOR: 2.32 [95% CI: 1.04-5.26]).,Ingestion of raw vegetables increases the odds of intestinal parasitic infection by 2.65 folds higher (AOR: 2.65 [95% CI: 3.23-9.9]).,The odds of intestinal parasitic infection were higher in rural areas (AOR: 2 [95% CI: 5-10]).,Intestinal parasitic infection was higher in women aged less than 21 years (AOR: 6.48 [95% CI: 2.91-14.4]).,The prevalence of helminthic infection is high in this study.,Latrine utilization, hand washing habit, eating raw vegetables and bare foot were the major determinant factors for the high prevalence.,Therefore, health education and improvements in sanitary infrastructure could achieve long-term and sustainable reductions in helminth prevalence.

Anemia is a significant public health problem in developing countries, particularly in pregnant women.,It may complicate pregnancy, sometimes resulting in tragic outcomes.,There is a lack of information on the magnitude of anemia among pregnant women in Southeast Ethiopia.,The aim of this study is, therefore, to determine the prevalence of anemia and assess associated factors among pregnant women attending antenatal care (ANC) at Bisidimo Hospital in Southeast Ethiopia.,A facility-based cross-sectional study, involving 258 pregnant women, was conducted from March to June 2013.,Socio-demographic, medical and obstetric data of the study participants were collected using structured questionnaire.,Hemoglobin was measured using a hematology analyzer and faecal specimens were examined to detect intestinal parasites.,Anemia in pregnancy was defined as hemoglobin <11 g/dl.,Overall, prevalence of anemia was 27.9%, of which 55% had mild anemia.,Rural residence (AOR =3.3, 95% CI: 1.5-7.4), intestinal parasitic infection (IPI) (AOR = 2.5, 95% CI: 1.3-4.8) and history of heavy cycle (AOR =2.7, 95% CI: 1.3-1.7) were predictors of anemia.,This study showed moderate prevalence of anemia among the pregnant women, with a sizable proportion having severe anemia.,Routine testing of pregnant women for IPIs and creating awareness on factors predisposing to anemia is recommended.

Schistosomiasis japonica remains a major public health concern in China.,There are many interventions implemented to control the transmission of the disease.,The purpose of the present study was to investigate the effects of an integrated control strategy for schistosomiasis control.,An integrated control strategy for schistosomiasis japonica with emphasis on removing cattle from snail-infested grasslands, providing farmers with mechanized farm equipment, improving sanitation by supplying tap water and building lavatories and latrines and providing boats with fecal-matter containers was implemented in 107 villages of the lower reaches of the Yangtze River, Jiangsu Province, China, during a 32-month period from May 2005 to 2008, and the effectiveness was investigated.,Following the effects of the comprehensive control, the snail habitat, infected snail habitat, snail infection rate, and S. japonicum prevalence in both humans and livestock all appeared a declining trend year by year, with reductions of 47.88%, 94.29%, 92.55%, 96.94%, and 100% compared with those before the comprehensive control.,In addition, all of the 17 counties achieved the infection control in 2007, and 7 reached the criteria of transmission control in 2008.,The confirmed snail habitats reduced from 107 to 20, and the acute infections have also been controlled for 2 successive years since 2007.,The integrated control strategy for schistosomiasis japonica is effective to control the transmission of S. japonicum.

Infection with the protozoan Toxoplasma gondii causes serious public health problems and is of great economic importance worldwide.,Protection from acute toxoplasmosis is known to be mediated by CD8+ T cells, but the T. gondii antigens and host genes required for eliciting protective immunity have been poorly defined.,The T. gondii dense granule protein 6 (GRA6), recently proved to be highly immunogenic and produces fully immune protection in T. gondii infected BALB/c mice with an H-2Ld gene.,The CD8+ T cell response of H-2Ld mice infected by the T. gondii strain seemed to target entirely to a single GRA6 peptide HF10-H-2Ld complex.,To determine whether a GRA6-based DNA vaccine can elicit protective immune responses to T. gondii in BALB/c mice, we constructed a eukaryotic expression vector pcDNA3.1-HisGRA6 and tested its immunogenicity in a mouse model.,BALB/c mice were vaccinated intramuscularly with three doses of GRA6 DNA and then challenged with a lethal dose of T. gondii RH strain tachyzoites.,All immunized mice developed high levels of serum anti-GRA6 IgG antibodies, and in vitro splenocyte proliferation was strongly enhanced in mice adjuvanted with levamisole (LMS).,Immunization with pcDNA3.1-HisGRA6 with LMS resulted in 53.3% survival of challenged BALB/c mice as compared to 40% survival of BALB/c without LMS.,Additionally, immunized Kunming mice without an allele of H-2Ld failed to survive.,Our result supports the concept that the acquired immune response is MHC restricted.,This study has a major implication for vaccine designs using a single antigen in a population with diverse MHC class I alleles.

Plasmodium ovale, considered the rarest of the malaria parasites of humans, consists of two morphologically identical but genetically distinct sympatric species, Plasmodium ovale curtisi and Plasmodium ovale wallikeri.,These parasites resemble morphologically to Plasmodium vivax with which they also share a tertian periodicity and the ability to cause relapses, making them easily misidentified as P. vivax.,Plasmodium ovale infections are rarely reported, but given the likelihood of misidentification, their prevalence might be underestimated.,Morphological and molecular analysis of confirmed malaria cases admitted in Singapore in 2012-2014 detected nine imported P. ovale cases that had been misidentified as P. vivax.,Since P. ovale had not been previously officially reported in Singapore, a retrospective analysis of available, frozen, archival blood samples was performed and returned two additional misidentified P. ovale cases in 2003 and 2006.,These eleven P. ovale samples were characterized with respect to seven molecular markers (ssrRNA, Potra, Porbp2, Pog3p, dhfr-ts, cytb, cox1) used in recent studies to distinguish between the two sympatric species, and to a further three genes (tufa, clpC and asl).,The morphological features of P. ovale and the differential diagnosis with P. vivax were reviewed and illustrated by microphotographs.,The genetic dimorphism between P. ovale curtisi and P. ovale wallikeri was assessed by ten molecular markers distributed across the three genomes of the parasite (Genbank KP050361-KP050470).,The data obtained for seven of these markers were compared with those published and confirmed that both P. ovale species were present.,This dimorphism was also confirmed for the first time on: (1) two genes from the apicoplast genome (tufA and clpC genes); and, (2) the asl gene that was used for phylogenetic analyses of other Plasmodium species, and that was found to harbour the highest number of dimorphic loci between the two P. ovale species.,Misidentified P. ovale infections are reported for the first time among imported malaria cases in Singapore.,Genetic dimorphism between P. ovale curtisi and P. ovale wallikeri was confirmed using markers from the parasites’ three genomes.,The apparent increase of imported P. ovale since 2012 (with yearly detection of cases) is puzzling.,Given decrease in the overall number of malaria cases recorded in Singapore since 2010 the ‘resurgence’ of this neglected species raises public health concerns.,The online version of this article (doi:10.1186/s12936-015-0985-8) contains supplementary material, which is available to authorized users.

Malaria Is A Life-Threatening Pathology In Africa.,Plasmodium Falciparum And Plasmodium Vivax Attract The Most Focus Because Of Their High Prevalence And Mortality.,Knowledge About The Prevalence Of The Cryptic Pathogens Plasmodium Ovale And Plasmodium Malariae Is Limited.,Thanks To Recombinant Tools, Their Seroprevalence Was Measured For The First Time, As Well As The Prevalence Of Mixed Infections In A Malaria-Asymptomatic Population In Benin, A Malaria-Endemic Country.,A Panel Of 1,235 Blood Donations Collected Over Ten Months In Benin Was Used For Validation Of The Recombinant Tools.,Recombinant P.,Falciparum, P.,Malariae, P.,Ovale MSP1, And P.,Falciparum AMA1 Were Engineered And Validated On A Biobank With Malaria-Infected Patients (N = 144) Using A Species-Speific ELISA Test (Recelisa).,Results Were Compared To An ELISA Using A Native P.,Falciparum Antigen (NatELISA).,Among Microscopically Negative African Blood Donors, 85% (1,050/1,235) Present Antibodies Directed To Native P.,Falciparum, 94.4% (1,166/1,235) To rPfMSP1 And rPfAMA1, 56.8% (702/1,235) To rPoMSP1, 67.5% (834/1235) To rPmMSP1 And 45.3% Of The Malaria Seropositive Population Had Antibodies Recognizing The Three Species.,A High Rate Of Antibodies Against P.,Ovale And P.,Malariae Was Found In Asymptomatic Blood Donors.,The Proportion Of Mixed Infections Involving Three Species Was Also Unexpected.,These Data Suggest That Determining Seroprevalence For These Cryptic Species Is An Appropriate Tool To Estimate Their Incidence, At The Eve Of Upcoming Anti-P.,Falciparum Vaccination Campaigns.

Concomitant infection with human immunodeficiency virus (HIV) and the Leishmania parasite is a growing public health problem, the result of the former spreading to areas where the latter is endemic.,Leishmania infection is usually asymptomatic in immunocompetent individuals, but the proportion of HIV+ individuals in contact with the parasite who remain asymptomatic is not known.,The aim of the present work was to examine the use of cytokine release assays in the detection of asymptomatic immune responders to Leishmania among HIV+ patients with no previous leishmaniasis or current symptomatology.,Eighty two HIV+ patients (all from Fuenlabrada, Madrid, Spain, where a leishmaniasis outbreak occurred in 2009) were examined for Leishmania infantum infection using molecular and humoral response-based methods.,None returned a positive molecular or serological result for the parasite.,Thirteen subjects showed a positive lymphoproliferative response to soluble Leishmania antigen (SLA), although the mean CD4+ T lymphocyte counts of these patients was below the normal range.,Stimulation of peripheral blood mononuclear cells (PBMC) or whole blood with SLA (the lymphoproliferative assay and whole blood assay respectively), led to the production of specific cytokines and chemokines.,Thus, despite being immunocompromised, HIV+ patients can maintain a Th1-type cellular response to Leishmania.,In addition, cytokine release assays would appear to be useful tools for detecting these individuals via the identification of IFN-γ in the supernatants of SLA-stimulated PBMC, and of IFN-γ, MIG and IL-2 in SLA-stimulated whole blood.,These biomarkers appear to be 100% reliable for detecting asymptomatic immune responders to Leishmania among HIV+ patients.

Spain has one of the world’s largest pools of organ donors and is a global leader in terms of the number of transplants it performs.,The current outbreak of leishmaniasis in Fuenlabrada (in the southwest of the region of Madrid, Spain) has involved 600 clinical cases since late 2009 (prevalence 0.2%).,It may therefore be wise to monitor the town’s transplanted population for Leishmania infantum; its members are immunosuppressed and at greater risk of infection and relapse following treatment.,The present work examines the use of cytokine release assays to determine the prevalence of Leishmania infection in this population, and to confirm recovery following treatment for visceral leishmaniasis (VL).,The humoral and cellular immune responses to L. infantum were characterized in 63 solid organ transplant (SOT) recipients from Fuenlabrada, 57 of whom reported no previous episode of VL (NVL subjects), and six of whom had been cured of VL (CVL subjects).,Seventeen subjects (12 NVL and 5 CVL) showed a patent lymphoproliferative response to soluble Leishmania antigen (SLA).,Stimulation of peripheral blood mononuclear cell cultures and of whole blood with SLA led to the production of different combinations of cytokines that might serve to confirm Leishmania infection or recovery from VL and help prevent cured patients from relapsing into this serious condition.

Schistosoma mansoni is a parasite of profound medical importance.,Current control focusses on mass praziquantel (PZQ) treatment of populations in endemic areas, termed Preventative Chemotherapy (PC).,Large-scale PC programmes exert prolonged selection pressures on parasites with the potential for, direct and/or indirect, emergence of drug resistance.,Molecular methods can help monitor genetic changes of schistosome populations over time and in response to drug treatment, as well as estimate adult worm burdens through parentage analysis.,Furthermore, methods such as in vitro drug sensitivity assays help phenotype in vivo parasite genotypic drug efficacy.,We conducted combined in vitro PZQ efficacy testing with population genetic analyses of S. mansoni collected from children from two schools in 2010, five years after the introduction of a National Control Programme.,Children at one school had received four annual PZQ treatments and the other school had received two mass treatments in total.,We compared genetic differentiation, indices of genetic diversity, and estimated adult worm burden from parasites collected in 2010 with samples collected in 2005 (before the control programme began) and in 2006 (six months after the first PZQ treatment).,Using 2010 larval samples, we also compared the genetic similarity of those with high and low in vitro sensitivity to PZQ.,We demonstrated that there were individual parasites with reduced PZQ susceptibility in the 2010 collections, as evidenced by our in vitro larval behavioural phenotypic assay.,There was no evidence, however, that miracidia showing phenotypically reduced susceptibility clustered together genetically.,Molecular analysis also demonstrated a significant reduction of adult worm load over time, despite little evidence of reduction in parasite infection intensity, as measured by egg output.,Genetic diversity of infections did not reduce over time, despite changes in the genetic composition of the parasite populations.,Genotypic and phenotypic monitoring did not indicate a selective sweep, as may be expected if PZQ treatment was selecting a small number of related “resistant” parasites, but there was evidence of genetic changes at the population level over time.,Genetic data were used to estimate adult worm burdens, which unlike parasite infection intensity, showed reductions over time, suggesting the relaxation of negative density-dependent constraints on parasite fecundity with PZQ treatment.,We thereby demonstrated that density-dependence in schistosome populations may complicate evaluation and monitoring of control programmes.,The online version of this article (10.1186/s13071-017-2533-6) contains supplementary material, which is available to authorized users.

For ethical and logistical reasons, population-genetic studies of parasites often rely on the non-invasive sampling of offspring shed from their definitive hosts.,However, if the sampled offspring are naturally derived from a small number of parents, then the strong family structure can result in biased population-level estimates of genetic parameters, particularly if reproductive output is skewed.,Here, we document and correct for the strong family structure present within schistosome offspring (miracidia) that were collected non-invasively from humans in western Kenya.,By genotyping 2,424 miracidia from 12 patients at 12 microsatellite loci and using a sibship clustering program, we found that the samples contained large numbers of siblings.,Furthermore, reproductive success of the breeding schistosomes was skewed, creating differential representation of each family in the offspring pool.,After removing the family structure with an iterative jacknifing procedure, we demonstrated that the presence of relatives led to inflated estimates of genetic differentiation and linkage disequilibrium, and downwardly-biased estimates of inbreeding coefficients (FIS).,For example, correcting for family structure yielded estimates of FST among patients that were 27 times lower than estimates from the uncorrected samples.,These biased estimates would cause one to draw false conclusions regarding these parameters in the adult population.,We also found from our analyses that estimates of the number of full sibling families and other genetic parameters of samples of miracidia were highly intercorrelated but are not correlated with estimates of worm burden obtained via egg counting (Kato-Katz).,Whether genetic methods or the traditional Kato-Katz estimator provide a better estimate of actual number of adult worms remains to be seen.,This study illustrates that family structure must be explicitly accounted for when using offspring samples to estimate the genetic parameters of adult parasite populations.

A century after its discovery, Chagas disease (CD) is still considered a public health problem.,Mortality caused by CD between 2000 and 2010 was described according to the specific underlying cause, year of occurrence, gender, age range, and region of Brazil.,The standardized mortality rate decreased 32.4%, from 3.4% in 2000 to 2.3% in 2010.,Most of the deaths (85.9%) occurred in male patients who were > 60 years of age caused by cardiac involvement.,The mortality rate caused by cardiac involvement decreased in all regions of Brazil, except in the North region, where it increased by 1.6%.,The Northeast had the smallest and the Central-West had the largest decrease.,The mortality rate caused by a compromised digestive tract increased in all regions.,Despite the control of transmission by vector and blood transfusions, CD should remain on the list of priority diseases for the public health service in Brazil, and surveillance actions cannot be interrupted.

A new epidemiological scenario involving the oral transmission of Chagas disease, mainly in the Amazon basin, requires innovative control measures.,Geospatial analyses of the Trypanosoma cruzi transmission cycle in the wild mammals have been scarce.,We applied interpolation and map algebra methods to evaluate mammalian fauna variables related to small wild mammals and the T. cruzi infection pattern in dogs to identify hotspot areas of transmission.,We also evaluated the use of dogs as sentinels of epidemiological risk of Chagas disease.,Dogs (n = 649) were examined by two parasitological and three distinct serological assays. kDNA amplification was performed in patent infections, although the infection was mainly sub-patent in dogs.,The distribution of T. cruzi infection in dogs was not homogeneous, ranging from 11-89% in different localities.,The interpolation method and map algebra were employed to test the associations between the lower richness in mammal species and the risk of exposure of dogs to T. cruzi infection.,Geospatial analysis indicated that the reduction of the mammal fauna (richness and abundance) was associated with higher parasitemia in small wild mammals and higher exposure of dogs to infection.,A Generalized Linear Model (GLM) demonstrated that species richness and positive hemocultures in wild mammals were associated with T. cruzi infection in dogs.,Domestic canine infection rates differed significantly between areas with and without Chagas disease outbreaks (Chi-squared test).,Geospatial analysis by interpolation and map algebra methods proved to be a powerful tool in the evaluation of areas of T. cruzi transmission.,Dog infection was shown to not only be an efficient indicator of reduction of wild mammalian fauna richness but to also act as a signal for the presence of small wild mammals with high parasitemia.,The lower richness of small mammal species is discussed as a risk factor for the re-emergence of Chagas disease.

Differentiation of canine hookworm species is crucial from both a veterinary and public health standpoint.,In Vietnam, three hookworm species, namely Ancylostoma caninum, Ancylostoma braziliense and Uncinaria stenocephala are reported to infect dogs.,In light of the emerging distribution of A. ceylanicum in Asia, this study aims to re-evaluate the status of Ancylostoma in dogs in Vietnam.,Faecal samples collected from 200 community dogs in Dak Lak province were subjected to faecal floatation for the detection of hookworm eggs.,Hookworm-positive samples were subjected to a PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) assay targeting the internal transcribed spacer (ITS) region of rDNA for hookworm species identification.,A subset of hookworm-positive samples was also subject to haplotype characterisation at the cytochrome oxidase-1 (COX-1) gene.,Detailed morphological criteria were utilised in addition to molecular markers, to identify adult hookworms recovered from necropsied dogs.,Of 200 canine faecal samples, 111 (55.5 %) were positive for hookworm eggs on faecal flotation.,Of these, 94/111 (84.7 %) were successfully amplified and assigned species status by PCR-RFLP targeting the ITS region.,In total, 54.3 % (51/94) dogs harboured single infections with A. ceylanicum, 33.0 % (31/94) with A. caninum, and 12.7 % (12/94) harboured mixed infections with both A. ceylanicum and A. caninum.,Adult worms recovered from necropsied dogs matched morphological description provided for A. ceylanicum, Looss (1911) for which the mediolateral and posteriolateral rays are parallel.,Characterisation of the COX-1 gene placed all Vietnamese canine isolates of A. ceylanicum within the ‘zoonotic’ haplotype.,Based on this information, it is apparent that the hookworms present in dogs in Vietnam are those of A. ceylanicum and not A. braziliense.,Owing to the endemic nature of this significant zoonosis in dogs, the study strongly advocates for specific identification of this hookworm in human hookworm surveys.

Hookworm infection is considered one of the most important poverty-promoting neglected tropical diseases, infecting 576 to 740 million people worldwide, especially in the tropics and subtropics.,These blood-feeding nematodes have a remarkable ability to downmodulate the host immune response, protecting themselves from elimination and minimizing severe host pathology.,While several mechanisms may be involved in the immunomodulation by parasitic infection, experimental evidences have pointed toward the possible involvement of regulatory T cells (Tregs) in downregulating effector T-cell responses upon chronic infection.,However, the role of Tregs cells in human hookworm infection is still poorly understood and has not been addressed yet.,In the current study we observed an augmentation of circulating CD4+CD25+FOXP3+ regulatory T cells in hookworm-infected individuals compared with healthy non-infected donors.,We have also demonstrated that infected individuals present higher levels of circulating Treg cells expressing CTLA-4, GITR, IL-10, TGF-β and IL-17.,Moreover, we showed that hookworm crude antigen stimulation reduces the number of CD4+CD25+FOXP3+ T regulatory cells co-expressing IL-17 in infected individuals.,Finally, PBMCs from infected individuals pulsed with excreted/secreted products or hookworm crude antigens presented an impaired cellular proliferation, which was partially augmented by the depletion of Treg cells.,Our results suggest that Treg cells may play an important role in hookworm-induced immunosuppression, contributing to the longevity of hookworm survival in infected people.

Land use and land cover changes, such as deforestation, agricultural expansion and urbanization, are one of the largest anthropogenic environmental changes globally.,Recent initiatives to evaluate the feasibility of malaria eradication have highlighted impacts of landscape changes on malaria transmission and the potential of these changes to undermine malaria control and elimination efforts.,Multisectoral approaches are needed to detect and minimize negative impacts of land use and land cover changes on malaria transmission while supporting development aiding malaria control, elimination and ultimately eradication.,Pathways through which land use and land cover changes disrupt social and ecological systems to increase or decrease malaria risks are outlined, identifying priorities and opportunities for a global malaria eradication campaign.,The impacts of land use and land cover changes on malaria transmission are complex and highly context-specific, with effects changing over time and space.,Landscape changes are only one element of a complex development process with wider economic and social dimensions affecting human health and wellbeing.,While deforestation and other landscape changes threaten to undermine malaria control efforts and have driven the emergence of zoonotic malaria, most of the malaria elimination successes have been underpinned by agricultural development and land management.,Malaria eradication is not feasible without addressing these changing risks while, conversely, consideration of malaria impacts in land management decisions has the potential to significantly accelerate progress towards eradication.,Multisectoral cooperation and approaches to linking malaria control and environmental science, such as conducting locally relevant ecological monitoring, integrating landscape data into malaria surveillance systems and designing environmental management strategies to reduce malaria burdens, are essential to achieve malaria eradication.

Hotspots constitute the major reservoir for residual malaria transmission, with higher malaria incidence than neighbouring areas, and therefore, have the potential to form the cornerstone for successful intervention strategies.,Detection of malaria hotspots is hampered by their heterogenous spatial distribution, and the laborious nature and low sensitivity of the current methods used to assess transmission intensity.,We adopt ecological theory underlying foraging in herbivorous insects to vector mosquito host seeking and modelling of fine-scale landscape features at the village level.,The overall effect of environmental variables on the density of indoor mosquitoes, sporozoite infected mosquitoes, and malaria incidence, was determined using generalized linear models.,Spatial analyses were used to identify hotspots for malaria incidence, as well as malaria vector density and associated sporozoite prevalence.,We identify household occupancy and location as the main predictors of vector density, entomological inoculation rate and malaria incidence.,We propose that the use of conventional vector control and malaria interventions, integrated with their intensified application targeting predicted hotspots, can be used to reduce malaria incidence in endemic and residual malaria settings.

Certain species of macaques are natural hosts of Plasmodium knowlesi and Plasmodium cynomolgi, which can both cause malaria in humans, and Plasmodium inui, which can be experimentally transmitted to humans.,A significant number of zoonotic malaria cases have been reported in humans throughout Southeast Asia, including Thailand.,There have been only two studies undertaken in Thailand to identify malaria parasites in non-human primates in 6 provinces.,The objective of this study was to determine the prevalence of P. knowlesi, P. cynomolgi, P. inui, Plasmodium coatneyi and Plasmodium fieldi in non-human primates from 4 new locations in Thailand.,A total of 93 blood samples from Macaca fascicularis, Macaca leonina and Macaca arctoides were collected from four locations in Thailand: 32 were captive M. fascicularis from Chachoengsao Province (CHA), 4 were wild M. fascicularis from Ranong Province (RAN), 32 were wild M. arctoides from Prachuap Kiri Khan Province (PRA), and 25 were wild M. leonina from Nakornratchasima Province (NAK).,DNA was extracted from these samples and analysed by nested PCR assays to detect Plasmodium, and subsequently to detect P. knowlesi, P. coatneyi, P. cynomolgi, P. inui and P. fieldi.,Twenty-seven of the 93 (29%) samples were Plasmodium-positive by nested PCR assays.,Among wild macaques, all 4 M. fascicularis at RAN were infected with malaria parasites followed by 50% of 32 M. arctoides at PRA and 20% of 25 M. leonina at NAK.,Only 2 (6.3%) of the 32 captive M. fascicularis at CHA were malaria-positive.,All 5 species of Plasmodium were detected and 16 (59.3%) of the 27 macaques had single infections, 9 had double and 2 had triple infections.,The composition of Plasmodium species in macaques at each sampling site was different.,Macaca arctoides from PRA were infected with P. knowlesi, P. coatneyi, P. cynomolgi, P. inui and P. fieldi.,The prevalence and species of Plasmodium varied among the wild and captive macaques, and between macaques at 4 sampling sites in Thailand.,Macaca arctoides is a new natural host for P. knowlesi, P. inui, P. coatneyi and P. fieldi.

Plasmodium knowlesi is now established as the fifth Plasmodium species to cause malaria in humans.,We describe a case of P. knowlesi infection acquired in Indonesian Borneo that was imported into Australia.,Clinicians need to consider this diagnosis in a patient who has acquired malaria in forest areas of Southeast Asia.

Visceral leishmaniasis (VL), is a parasitic disease that causes serious medical consequences if treatment is delayed.,Despite a decline in the number of VL cases in the Indian subcontinent, the commencement of the disease in newer areas continues to be a major concern.,Although serological diagnosis mainly by immunochromatographic tests has been found to be effective, a test of cure in different phases of treatment is still desired.,Even though a good prophylactic response has been obtained in murine models by a number of vaccine candidates, few have been proposed for human use.,In this study, nine antigenic components (31, 34, 36, 45, 51, 63, 72, 91 and 97 kDa) of Leishmania promastigote membrane antigens (LAg), were electroeluted and evaluated through ELISA to diagnose and distinguish active VL from one month cured and six months post-treatment patients.,Further, to investigate the immunogenicity of electroeluted proteins, human PBMCs of cured VL patients were stimulated with 31, 34, 51, 63, 72 and 91 kDa proteins.,We found that 34 and 51 kDa proteins show 100% sensitivity and specificity with healthy controls and other diseases.,After six months post-treatment, antibodies to 72 and 91 kDa antigens show a significant decline to almost normal levels.,This suggests that 34 and 51 kDa proteins are efficient in diagnosis, whereas 72 and 91 kDa proteins may be used to monitor treatment outcome.,In another assay, 51 and 63 kDa proteins demonstrated maximum ability to upregulate IFN-γ and IL-12 with minimum induction of IL-10 and TGF-β.,The results indicating that 51 and 63 kDa proteins could be strong candidates for human immunization against VL.,In contrast, 34 and 91 kDa proteins demonstrated a reverse profile and may not be a good vaccine candidate.,The preliminary data obtained in this study proposes the potential of some of the antigens in Leishmania diagnosis and for test of cure.,Additionally, some antigens demonstrated good immunoprophylactic cytokine production through T cell-mediated immune response, suggesting future vaccine candidates for VL.,However, further studies are necessary to explore these antigens in diagnosis and to access the long-term immune response.

Proliferation of Leishmania (L.) parasites depends on polyamine availability, which can be generated by the L-arginine catabolism and the enzymatic activity of arginase (ARG) of the parasites and of the mammalian hosts.,In the present study, we characterized and compared the arginase (arg) genes from pathogenic L. major and L. tropica and from non-pathogenic L. tarentolae.,We quantified the level of the ARG activity in promastigotes and macrophages infected with pathogenic L. major and L. tropica and non-pathogenic L. tarentolae amastigotes.,The ARG's amino acid sequences of the pathogenic and non-pathogenic Leishmania demonstrated virtually 98.6% and 88% identities with the reference L. major Friedlin ARG.,Higher ARG activity was observed in all pathogenic promastigotes as compared to non-pathogenic L. tarentolae.,In vitro infection of human macrophage cell line (THP1) with pathogenic and non-pathogenic Leishmania spp. resulted in increased ARG activities in the infected macrophages.,The ARG activities present in vivo were assessed in susceptible BALB/c and resistant C57BL/6 mice infected with L. major, L. tropica and L. tarentolae.,We demonstrated that during the development of the infection, ARG is induced in both strains of mice infected with pathogenic Leishmania.,However, in L. major infected BALB/c mice, the induction of ARG and parasite load increased simultaneously according to the time course of infection, whereas in C57BL/6 mice, the enzyme is upregulated solely during the period of footpad swelling.,In L. tropica infected mice, the footpads' swellings were slow to develop and demonstrated minimal cutaneous pathology and ARG activity.,In contrast, ARG activity was undetectable in mice inoculated with the non-pathogenic L. tarentolae.,Our data suggest that infection by Leishmania parasites can increase ARG activity of the host and provides essential polyamines for parasite salvage and its replication.,Moreover, the ARG of Leishmania is vital for parasite proliferation and required for infection in mice.,ARG activity can be used as one of the main marker of the disease severity.

Intensive malaria transmission along international borders is a significant impediment to malaria elimination in the Greater Mekong Subregion (GMS) of Southeast Asia.,Passive case detection (PCD) was used to study the dynamics and trends of malaria transmission at the China-Myanmar border to provide epidemiologic information for improved malaria control.,PCD was conducted in one hospital and 12 clinics near the Laiza town in northeast Myanmar from 2011 to 2016.,Clinical malaria was diagnosed by microscopy and demographic information was captured using a structured questionnaire at the time of the patient’s presentation for care.,Over the study period, 6175 (19.7%) malaria cases were confirmed by microscopy from 31,326 suspected cases.,The four human malaria parasite species were all identified, with Plasmodium vivax and Plasmodium falciparum accounting for 5607 (90.8%) and 481 (7.8%) of the confirmed cases, respectively.,In contrast to the steady decline of malaria in the general GMS, the study site had an upward trend of malaria incidence with vivax malaria outbreaks in 2013 and 2016.,Adult males, children under the age of 15, and those with occupations such as farming, being a soldier or student, had significantly higher risks of clinical malaria compared to having fevers from other aetiologies.,A self-reported history of clinical malaria was also associated with a higher risk of confirmed malaria.,The China-Myanmar border area has experienced an overall upward trend of malaria incidence in recent years with P. vivax becoming the predominant species.,Evidence-based control strategies need to focus on high-risk populations.

One of the major challenges for control and elimination of malaria is ongoing spread and emergence of drug resistance.,While epidemiology and surveillance of the drug resistance in falciparum malaria is being explored globally, there are few studies on drug resistance vivax malaria.,To assess the spread of drug-resistant vivax malaria in Myanmar, a multisite, prospective, longitudinal study with retrospective analysis of previous therapeutic efficacy studies, was conducted.,A total of 906 from nine study sites were included in retrospective analysis and 208 from three study sites in prospective study.,Uncomplicated vivax mono-infected patients were recruited and monitored with longitudinal follow-up until day 28 after treatment with chloroquine.,Amplification and sequence analysis of molecular markers, such as mutations in pvcrt-O, pvmdr1, pvdhps and pvdhfr, were done in day-0 samples in prospective study.,Clinical failure cases were found only in Kawthaung, southern Myanmar and western Myanmar sites within 2009-2016.,Chloroquine resistance markers, pvcrt-O ‘AAG’ insertion and pvmdr1 mutation (Y976F) showed higher mutant rate in southern and central Myanmar than western site: 66.7, 72.7 vs 48.3% and 26.7, 17.0 vs 1.7%, respectively.,A similar pattern of significantly higher mutant rate of antifolate resistance markers, pvdhps (S382A, K512M, A553G) and pvdhfr (F57L/I, S58R, T61M, S117T/N) were noted.,Although clinical failure rate was low, widespread distribution of chloroquine and antifolate resistance molecular makers alert to the emergence and spread of drug resistance vivax malaria in Myanmar.,Proper strategy and action plan to eliminate and contain the resistant strain strengthened together with clinical and molecular surveillance on drug resistance vivax is recommended.,The online version of this article (doi:10.1186/s12936-017-1770-7) contains supplementary material, which is available to authorized users.

In the Indian subcontinent, about 200 million people are at risk of developing visceral leishmaniasis (VL).,In 2005, the governments of India, Nepal and Bangladesh started the first regional VL elimination program with the aim to reduce the annual incidence to less than 1 per 10,000 by 2015.,A mathematical model was developed to support this elimination program with basic quantifications of transmission, disease and intervention parameters.,This model was used to predict the effects of different intervention strategies.,Parameters on the natural history of Leishmania infection were estimated based on a literature review and expert opinion or drawn from a community intervention trial (the KALANET project).,The transmission dynamic of Leishmania donovani is rather slow, mainly due to its long incubation period and the potentially long persistence of parasites in infected humans.,Cellular immunity as measured by the Leishmanin skin test (LST) lasts on average for roughly one year, and re-infection occurs in intervals of about two years, with variation not specified.,The model suggests that transmission of L. donovani is predominantly maintained by asymptomatically infected hosts.,Only patients with symptomatic disease were eligible for treatment; thus, in contrast to vector control, the treatment of cases had almost no effect on the overall intensity of transmission.,Treatment of Kala-azar is necessary on the level of the individual patient but may have little effect on transmission of parasites.,In contrast, vector control or exposure prophylaxis has the potential to efficiently reduce transmission of parasites.,Based on these findings, control of VL should pay more attention to vector-related interventions.,Cases of PKDL may appear after years and may initiate a new outbreak of disease; interventions should therefore be long enough, combined with an active case detection and include effective treatment.

Visceral leishmaniasis is the world' second largest vector-borne parasitic killer and a neglected tropical disease, prevalent in poor communities.,Long-lasting insecticidal nets (LNs) are a low cost proven vector intervention method for malaria control; however, their effectiveness against visceral leishmaniasis (VL) is unknown.,This study quantified the effect of LNs on exposure to the sand fly vector of VL in India and Nepal during a two year community intervention trial.,As part of a paired-cluster randomized controlled clinical trial in VL-endemic regions of India and Nepal we tested the effect of LNs on sand fly biting by measuring the antibody response of subjects to the saliva of Leishmania donovani vector Phlebotomus argentipes and the sympatric (non-vector) Phlebotomus papatasi.,Fifteen to 20 individuals above 15 years of age from 26 VL endemic clusters were asked to provide a blood sample at baseline, 12 and 24 months post-intervention.,A total of 305 individuals were included in the study, 68 participants provided two blood samples and 237 gave three samples.,A random effect linear regression model showed that cluster-wide distribution of LNs reduced exposure to P. argentipes by 12% at 12 months (effect 0.88; 95% CI 0.83-0.94) and 9% at 24 months (effect 0.91; 95% CI 0.80-1.02) in the intervention group compared to control adjusting for baseline values and pair.,Similar results were obtained for P. papatasi.,This trial provides evidence that LNs have a limited effect on sand fly exposure in VL endemic communities in India and Nepal and supports the use of sand fly saliva antibodies as a marker to evaluate vector control interventions.

In the Adami Tulu District, indoor residual spraying (IRS) and insecticide-treated nets (ITNs) has been the main tool used to control malaria.,The purpose of this study was to assess the effect of IRS and ITNs control strategies in Aneno Shisho kebele (lowest administrative unit of Ethiopia) compared with Kamo Gerbi (supplied ITN only) and Jela Aluto (no IRS and ITNs), with regards to the prevalence of malaria and mosquito density.,Cross-sectional surveys were conducted after heavy rains (October/November, 2006) and during the sporadic rains (April, 2007) in the three kebeles of Adami Tulu District.,Malaria infection was measured by means of thick and thin film.,Monthly collection of adult mosquitoes from October-December 2006 and April-May 2007 and sporozoite enzyme-linked immunosorbent assay (ELISA) on the collected mosquitoes were detected.,Data related to the knowledge of mode of malaria transmission and its control measures were collected.,Data collected on parasitological and knowledge, attitude and practice (KAP) surveys were managed and analysed using a statistical computer program SPSS version 13.0.,A P-value <0.05 was considered to be statistically significant.,The overall prevalence of malaria was 8.6% in Jela Aluto, 4.4% in Kamo Gerbi and 1.3% in Aneno Shisho in the two season surveys.,The vector, Anopheles gambiae s.l., Anopheles pharoensis and Anopheles coustani were recorded.,However, sporozoite ELISA on mosquito collections detected no infection.,The difference in overall malaria prevalence and mosquito density between the three kebeles was significant (P<0.05).,The present study has provided some evidence for the success of ITNs/IRS combined malaria control measures in Aneno Shisho kebele in Adami Tulu District.,Therefore, the combined ITNs/IRS malaria control measures must be expanded to cover all kebeles in the District of Ethiopia.

Insecticide treated nets (ITN) and indoor residual spraying (IRS) are the two pillars of malaria vector control in Africa, but both interventions are beset by quality and coverage concerns.,Data from three control programs were used to investigate the impact of: 1) the physical deterioration of ITNs, and 2) inadequate IRS spray coverage, on their respective protective effectiveness.,Malaria indicator surveys were carried out in 2009 and 2010 in Bioko Island, mainland Equatorial Guinea and Malawi to monitor infection with P.falciparum in children, mosquito net use, net condition and spray status of houses.,Nets were classified by their condition.,The association between infection and quality and coverage of interventions was investigated.,There was reduced odds of infection with P.falciparum in children sleeping under ITNs that were intact (Odds ratio (OR): 0.65, 95% CI: 0.55-0.77 and OR: 0.81, 95% CI: 0.56-1.18 in Equatorial Guinea and in Malawi respectively), but the protective effect became less with increasingly worse condition of the net.,There was evidence for a linear trend in infection per category increase in deterioration of nets.,In Equatorial Guinea IRS offered protection to those in sprayed and unsprayed houses alike when neighbourhood spray coverage was high (≥80%) compared to those living in areas of low IRS coverage (<20%), regardless of whether the house they lived in was sprayed or not (adjusted OR = 0.54, 95% CI 0.33-0.89).,ITNs provided only personal protection, offering no protection to non users.,Although similar effects were seen in Malawi, the evidence was much weaker than in Equatorial Guinea.,Universal coverage strategies should consider policies for repair and replacement of holed nets and promote the care of nets by their owners.,IRS programs should ensure high spray coverage since inadequate coverage gives little or no protection at all.

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

Household ownership of insecticide-treated mosquito nets (ITNs) is increasing, and coverage targets have been revised to address universal coverage with ITNs.,However, many households do not have enough nets to cover everyone, and the nets available vary in physical condition and insecticide treatment status.,Since 2004, the Government of Tanzania has been implementing the Tanzania National Voucher Scheme (TNVS), which distributes vouchers for ITNs through antenatal clinics to target pregnant women and their infants.,This analysis aimed to determine the following: (1) coverage patterns of bed nets within households according to physical condition and treatment status; (2) who might be at risk if mosquitoes were diverted from occupants of untreated nets to those not using nets?,(3) the degree to which those at highest risk of malaria use the most protective nets.,Data from the 2006 TNVS household survey were analysed to assess within-household distribution of net use.,The associations between net characteristics and net user were also evaluated.,Multivariate analysis was applied to the relationship between the number of holes per net and user characteristics while adjusting for confounders.,In households with a net:person ratio better than 1:4 (one net for every four household members), more than 80% of the people in such households reported using a net the previous night.,ITNs were most likely to be used by infants, young children (1-4 y), and women of childbearing age; they were least likely to be used by older women (≥50 y), older children (5-14 y), and adult men.,The nets used by infants and women of childbearing age were in better-than-average physical condition; the nets used by older women and older children were in worse-than-average condition; while young children and adult men used nets in intermediate (average) condition.,When adjusted for confounders, the nets used by young and older children had more holes than nets used by infants.,Infants and other vulnerable groups were most likely to sleep under the most protective nets.,Nevertheless, more communication efforts are needed to increase use of intact ITNs within households for children.,Further research is necessary to fully understand motivations influencing within-household net distribution.

Accurate quantitative assessment of infection with soil transmitted helminths and protozoa is key to the interpretation of epidemiologic studies of these parasites, as well as for monitoring large scale treatment efficacy and effectiveness studies.,As morbidity and transmission of helminth infections are directly related to both the prevalence and intensity of infection, there is particular need for improved techniques for assessment of infection intensity for both purposes.,The current study aimed to evaluate two multiplex PCR assays to determine prevalence and intensity of intestinal parasite infections, and compare them to standard microscopy.,Faecal samples were collected from a total of 680 people, originating from rural communities in Timor-Leste (467 samples) and Cambodia (213 samples).,DNA was extracted from stool samples and subject to two multiplex real-time PCR reactions the first targeting: Necator americanus, Ancylostoma spp., Ascaris spp., and Trichuris trichiura; and the second Entamoeba histolytica, Cryptosporidium spp., Giardia. duodenalis, and Strongyloides stercoralis.,Samples were also subject to sodium nitrate flotation for identification and quantification of STH eggs, and zinc sulphate centrifugal flotation for detection of protozoan parasites.,Higher parasite prevalence was detected by multiplex PCR (hookworms 2.9 times higher, Ascaris 1.2, Giardia 1.6, along with superior polyparasitism detection with this effect magnified as the number of parasites present increased (one: 40.2% vs.,38.1%, two: 30.9% vs.,12.9%, three: 7.6% vs.,0.4%, four: 0.4% vs.,0%).,Although, all STH positive samples were low intensity infections by microscopy as defined by WHO guidelines the DNA-load detected by multiplex PCR suggested higher intensity infections.,Multiplex PCR, in addition to superior sensitivity, enabled more accurate determination of infection intensity for Ascaris, hookworms and Giardia compared to microscopy, especially in samples exhibiting polyparasitism.,The superior performance of multiplex PCR to detect polyparasitism and more accurately determine infection intensity suggests that it is a more appropriate technique for use in epidemiologic studies and for monitoring large-scale intervention trials.

With one quarter of the world population infected, the intestinal nematode Ascaris lumbricoides is one of the most common infectious agents, especially in the tropics and sub-tropics.,Infection is caused by oral intake of eggs and can cause respiratory and gastrointestinal problems.,To identify high risk areas for intervention, it is necessary to understand the effects of climatic, environmental and socio-demographic conditions on A. lumbricoides infection.,Cross-sectional survey data of 6,366 study participants in the Mbeya region of South-Western Tanzania were used to analyze associations between remotely sensed environmental data and A. lumbricoides infection.,Non-linear associations were accounted for by using fractional polynomial regression, and socio-demographic and sanitary data were included as potential confounders.,The overall prevalence of A. lumbricoides infection was 6.8%.,Our final multivariable model revealed a significant non-linear association between rainfall and A. lumbricoides infection with peak prevalences at 1740 mm of mean annual rainfall.,Mean annual land surface temperature during the day was linearly modeled and negatively associated with A. lumbricoides infection (odds ratio (OR) = 0.87, 95% confidence interval (CI) = 0.78-0.97).,Furthermore, age, which also showed a significant non-linear association (infection maximum at 7.7 years), socio-economic status (OR = 0.82, CI = 0.68-0.97), and latrine coverage around the house (OR = 0.80, CI = 0.67-0.96) remained in the final model.,A. lumbricoides infection was associated with environmental, socio-demographic and sanitary factors both in uni- and multivariable analysis.,Non-linear analysis with fractional polynomials can improve model fit, resulting in a better understanding of the relationship between environmental conditions and helminth infection, and more precise predictions of high prevalence areas.,However, socio-demographic determinants and sanitary conditions should also be considered, especially when planning public health interventions on a smaller scale, such as the community level.

The Government of Tanzania is the main source of long-lasting insecticidal nets (LLINs) for its population.,Mosquito nets (treated and untreated) are also available in the commercial market.,To sustain investments and health gains in the fight against malaria, it is important for the National Malaria Control Programme to monitor LLIN coverage especially in the years between mass distributions and to understand what households do if their free nets are deemed unusable.,The aim of this paper was to assess standard LLIN indicators by wealth status in Tanzania in 2013, 2 years after the last mass campaign in 2011, and extend the analysis to untreated nets (UTNs) to investigate how households adapt when nets are not continuously distributed.,Between October-December 2013, a household survey was conducted in 3398 households in eight districts in Tanzania.,Using the Roll Back Malaria indicators, the study analysed: (1) household net ownership; (2) access to nets; (3) population net use and (4) net use:access ratio.,Outcomes were calculated for LLINs and UTNs.,Results were analysed by socio-economic quintiles and by district.,Only three of the eight districts had household LLIN ownership of more than 80%.,In 2013, less than a quarter of the households had one LLIN for every two people and only half of the population had access to an LLIN.,Only the wealthier quintiles increased their net ownership and access to levels above 80% through the addition of UTNs.,Overall net use of the population was low (LLINs: 32.8%; UTNs: 9.5%) and net use:access ratio was below target level (LLINs: 0.66; UTN: 0.50).,Both measures varied significantly by district.,Two years after the last mass campaign, the percentage of households or population with access to LLINs was low.,These findings indicate the average rate at which households in Tanzania lose their nets is higher than the rate at which they acquire new nets.,The wealthiest households topped up their household net ownership with UTNs.,Efforts to make LLINs available through commercial markets should be promoted, so those who can afford to buy nets purchase LLINs rather than UTNs.,Net use was low around 40% and mostly explained by lack of access to nets.,However, the use:access ratio was poor in Mbozi and Kahama districts warranting further investigations to understand other barriers to net use.,The online version of this article (10.1186/s12936-018-2247-z) contains supplementary material, which is available to authorized users.

Since 2004, the Global Fund-supported National Malaria Control Programme of Papua New Guinea (PNG) has been implementing country-wide free long-lasting insecticidal net (LLIN) distribution campaigns.,In 2009, after the first distribution, only 32.5% of the population used a LLIN, mainly due to an insufficient number of nets available.,This study investigated changes in mosquito net ownership and use following the continued free distribution of LLINs across PNG.,Five villages from each province and 30 households from each village were randomly sampled in a country-wide household survey in 2010/11.,A structured questionnaire administered to household heads recorded information on mosquito net ownership and use alongside household characteristics.,Revised ownership and access indicators were applied in the analysis to reveal coverage gaps.,The survey covered 1,996 households in 77 villages.,Ownership of at least one LLIN was reported by 81.8% of households, compared to 64.6% in 2009 (P = 0.002).,Sufficient LLINs to cover all household members (one net per two people) were found in 41.3% of the households (21.4% in 2009, P < 0.001).,Of all household members, 61.4% had access to a LLIN within their household (44.3% in 2009 P = 0.002), and 48.3% slept under a LLIN (32.5% in 2009, P = 0.001).,LLIN use in children under five years amounted to 58.2%, compared to 39.5% in 2009 (P < 0.001).,Significant regional differences in coverage and changes over time were observed.,A recent LLIN distribution was a key determinant of LLIN ownership (adj.,OR = 3.46) while families in high quality houses would frequently not own a LLIN (adj.,OR = 0.09).,Residents were more likely to use LLINs than household guests (OR = 2.04).,Repeated LLIN distribution has led to significant increases in mosquito net ownership and use with few regional exceptions.,Additional nets are required in areas where access is low, while major efforts are required to encourage the use of existing nets in region where access is high but use remains low.,Complementary vector control approaches should also be considered in such settings.

Quinine was first recognized as a potent antimalarial agent hundreds of years ago.,Since then, the beneficial effects of quinine and its more advanced synthetic forms, chloroquine and hydroxychloroquine, have been increasingly recognized in a myriad of other diseases in addition to malaria.,In recent years, antimalarials were shown to have various immunomodulatory effects, and currently have an established role in the management of rheumatic diseases, such as systemic lupus erythematosus and rheumatoid arthritis, skin diseases, and in the treatment of chronic Q fever.,Lately, additional metabolic, cardiovascular, antithrombotic, and antineoplastic effects of antimalarials were shown.,In this review, we discuss the known various immunomodulatory mechanisms of antimalarials and the current evidence for their beneficial effects in various diseases and in potential novel applications.

Improvement of quality of life and survival of cancer patients will be greatly enhanced by the development of highly effective drugs to selectively kill malignant cells.,Artemisinin and its analogs are naturally occurring antimalarials which have shown potent anticancer activity.,In primary cancer cultures and cell lines, their antitumor actions were by inhibiting cancer proliferation, metastasis, and angiogenesis.,In xenograft models, exposure to artemisinins substantially reduces tumor volume and progression.,However, the rationale for the use of artemisinins in anticancer therapy must be addressed by a greater understanding of the underlying mechanisms involved in their cytotoxic effects.,The primary targets for artemisinin and the chemical base for its preferential effects on heterologous tumor cells need yet to be elucidated.,The aim of this paper is to provide an overview of the recent advances and new development of this class of drugs as potential anticancer agents.

Insecticide spraying campaigns designed to suppress the principal vectors of the Chagas disease usually lack an active surveillance system that copes with house reinvasion.,Following an insecticide campaign with no subsequent surveillance over a 12-year period, we implemented a longitudinal intervention programme including periodic surveys for Triatoma infestans, full-coverage house spraying with insecticides, and selective control in a well-defined rural area of the Argentinean Chaco inhabited by Creoles and one indigenous group (Qom).,Here, we conducted a cross-sectional study and report the age-specific seroprevalence of human T. cruzi infection by group, and examine the association between human infection, the onset of the intervention, the relative density of infected domestic bugs, and the household number of infected people, dogs, or cats.,The seroprevalence of infection among 691 residents examined was 39.8% and increased steadily with age, reaching 53-70% in those older than 20 years.,The mean annual force of infection was 2.5 per 100 person-years (95% CI: 1.8-3.3%).,Infection in children younger than 16 years born before the intervention programme was two to four times higher in houses with infected T. infestans than in houses without them and was six times higher when there were both infected dogs or cats and bugs than when they were absent.,The model-averaged estimate of the intervention effect suggests that the odds of seropositivity were about nine times smaller for those born after the onset of the intervention than for those born before it, regardless of ethnic background, age, gender, household wealth, and cohabitation with T. cruzi-infected vectors or human hosts.,Human infection was also closely associated with the baseline abundance of infected domestic triatomines and the number of infected cohabitants.,Two of 43 children born after interventions were T. cruzi-seropositive; since their mothers were seropositive and both resided in apparently uninfested houses they were attributed to vertical transmission.,Alternatively, these cases could be due to non-local vector-borne transmission.,Our study reveals high levels of human infection with T. cruzi in the Argentinean Chaco, and the immediate impact of sustained vector surveillance and selective control actions on transmission.,The online version of this article (10.1186/s13071-018-3069-0) contains supplementary material, which is available to authorized users.

A new epidemiological scenario involving the oral transmission of Chagas disease, mainly in the Amazon basin, requires innovative control measures.,Geospatial analyses of the Trypanosoma cruzi transmission cycle in the wild mammals have been scarce.,We applied interpolation and map algebra methods to evaluate mammalian fauna variables related to small wild mammals and the T. cruzi infection pattern in dogs to identify hotspot areas of transmission.,We also evaluated the use of dogs as sentinels of epidemiological risk of Chagas disease.,Dogs (n = 649) were examined by two parasitological and three distinct serological assays. kDNA amplification was performed in patent infections, although the infection was mainly sub-patent in dogs.,The distribution of T. cruzi infection in dogs was not homogeneous, ranging from 11-89% in different localities.,The interpolation method and map algebra were employed to test the associations between the lower richness in mammal species and the risk of exposure of dogs to T. cruzi infection.,Geospatial analysis indicated that the reduction of the mammal fauna (richness and abundance) was associated with higher parasitemia in small wild mammals and higher exposure of dogs to infection.,A Generalized Linear Model (GLM) demonstrated that species richness and positive hemocultures in wild mammals were associated with T. cruzi infection in dogs.,Domestic canine infection rates differed significantly between areas with and without Chagas disease outbreaks (Chi-squared test).,Geospatial analysis by interpolation and map algebra methods proved to be a powerful tool in the evaluation of areas of T. cruzi transmission.,Dog infection was shown to not only be an efficient indicator of reduction of wild mammalian fauna richness but to also act as a signal for the presence of small wild mammals with high parasitemia.,The lower richness of small mammal species is discussed as a risk factor for the re-emergence of Chagas disease.

Schistosomiasis is one of the most neglected tropical parasitic disease which is common in Ethiopia.,It is disease of rural areas for decades but now days there are reports of schistosomiasis from urban settings.,Therefore, this study aimed to determine epidemiology of Schistosoma mansoni (S. mansoni) infection and associated determinant factors among school children attending primary schools nearby rivers in Jimma town, an urban setting, southwest Ethiopia.,A cross sectional study was conducted among 328 school children aged between 7-17 years in selected primary schools nearby rivers in Jimma town from March to April 2017.,For the diagnosis of S. mansoni, a single stool sample was obtained from each child and processed using double Kato Katz thick smear for quantification of S. mansoni ova examined using light microscope.,A questionnaire was used to collect socio demographic data and associated determinant factors for S. mansoni infection.,Data were analyzed using SPSS version 20.0.,Variables with P-value < 0.05 were significantly associated with S. mansoni infection.,The overall prevalence of S. mansoni infection was found to be 28.7%.,Majority of infection intensities were categorized as light with maximum egg per gram of stool (epg) was 1728.,The geometric mean of infection intensity was 102.3epg.,Schools distance from river (p = 0.001), swimming habit in rivers (p = 0.001) and crossing river on bare foot (p = 0.001) were independent risk factors for S. mansoni infection.,The study revealed S. mansoni infection is prevalent in Jimma town.,The school children were at moderate risk of morbidity caused by S. mansoni (prevalence ≥ 10% and < 50% according to WHO threshold), hence a biannual mass drug administration with praziquantel is required once every two years in the study area and promote health information on prevention, control, transmission and risk factors for S. mansoni infection.

Epidemiological information on the prevalence of intestinal parasitic infections in different regions is a prerequisite to develop appropriate control strategies.,Therefore, this present study was conducted to assess the magnitude and pattern of intestinal parasitism in highland and lowland dwellers in Gamo area, South Ethiopia.,Community-based cross-sectional study was conducted between September 2010 and July 2011 at Lante, Kolla Shelle, Dorze and Geressie kebeles of Gamo Gofa Zone, South Ethiopia.,The study sites and study participants were selected using multistage sampling method.,Data were gathered through house-to-house survey.,A total of 858 stool specimens were collected and processed using direct wet mount and formol-ether concentration techniques for the presence of parasite.,Out of the total examined subjects, 342(39.9%) were found positive for at least one intestinal parasite.,The prevalence of Entamoeba histolytica/dispar was the highest 98(11.4%), followed by Giardia lamblia 91(10.6%), Ascaris lumbricoides 67(7.8%), Strongyloides stercoralis 51(5.9%), hookworm 42(4.9%), Trichuris trichiura 24(2.8%), Taenia species 18(2.1%), Hymenolepis nana 7(0.6%) and Schistosoma mansoni 1(0.12%).,No statistically significant difference was observed in the prevalence of intestinal parasitic infections among lowland (37.9%) and highland dwellers (42.3%) (P = 0.185).,The prevalence of intestinal parasitic infection was not significantly different among the study sites but it was relatively higher in Geressie (42.8%) than other kebeles.,Sex was not associated with parasitic infections (P = 0.481).,No statistically significant difference of infection was observed among the age groups (P = 0.228) but it was higher in reproductive age group.,The high prevalence of intestinal parasitic infections among the lowland and highland dwellers in Gamo area indicated that parasitic infections are important public health problems.,Thus, infection control measures and the development of awareness strategies to improve sanitation and health education should be considered.

Since innate lymphoid cells (ILCs) have been found to play a role in the immune response to helminth parasites in rodents, we sought to determine their role in human helminth infection.,By developing multicolor flow cytometry-based methods to identify and enumerate circulating ILCs and their subsets, we were able to identify a subset of cKit+ ILCs defined as Lineage (Lin)−/CD45+/cKit+/CD127+ that were significantly expanded in the filarial-infected individuals (p = 0.0473) as were those cKit+ ILCs that produced IL-13.,Additionally, the frequency of these cKit+ ILCs correlated with the frequency of IL-17 producing CD4+ T cells (Th17 cells; p = 0.025).,To investigate the function of cKit+ ILCs, sorted, highly purified human ILCs were subjected to transcriptional profiling by RNAseq and compared to appropriate control cells.,These cKit+ ILCs expressed TLRs, a broad range of cytokines/cytokine receptors and MHC Class II molecules suggesting that these ILCs sense pathogens independent of other cell types.,Functional analysis revealed expanded cKit+ ILC-specific transcription and ILC-specific microRNA precursors.

In order to guarantee the fulfillment of their complex lifecycle, adult filarial nematodes release millions of microfilariae (MF), which are taken up by mosquito vectors.,The current strategy to eliminate lymphatic filariasis as a public health problem focuses upon interrupting this transmission through annual mass drug administration (MDA).,It remains unclear however, how many rounds of MDA are required to achieve low enough levels of MF to cease transmission.,Interestingly, with the development of further diagnostic tools a relatively neglected cohort of asymptomatic (non-lymphedema) amicrofilaremic (latent) individuals has become apparent.,Indeed, epidemiological studies have suggested that there are equal numbers of patent (MF+) and latent individuals.,Since the latter represent a roadblock for transmission, we studied differences in immune responses of infected asymptomatic male individuals (n = 159) presenting either patent (n = 92 MF+) or latent (n = 67 MF−) manifestations of Wuchereria bancrofti.,These individuals were selected on the basis of MF, circulating filarial antigen in plasma and detectable worm nests.,Immunological profiles of either Th1/Th17, Th2, regulatory or innate responses were determined after stimulation of freshly isolated PBMCs with either filarial-specific extract or bystander stimuli.,In addition, levels of total and filarial-specific antibodies, both IgG subclasses and IgE, were ascertained from plasma.,Results from these individuals were compared with those from 22 healthy volunteers from the same endemic area.,Interestingly, we observed that in contrast to MF+ patients, latent infected individuals had lower numbers of worm nests and increased adaptive immune responses including antigen-specific IL-5.,These data highlight the immunosuppressive status of MF+ individuals, regardless of age or clinical hydrocele and reveal immunological profiles associated with latency and immune-mediated suppression of parasite transmission.

Placental Plasmodium falciparum malaria can trigger intervillositis, a local inflammatory response more strongly associated with low birthweight than placental malaria infection alone.,Fetal growth (and therefore birthweight) is dependent on placental amino acid transport, which is impaired in placental malaria-associated intervillositis.,Here, we tested the hypothesis that mechanistic target of rapamycin (mTOR) signaling, a pathway known to regulate amino acid transport, is inhibited in placental malaria-associated intervillositis, contributing to lower birthweight.,We determined the link between intervillositis, mTOR signaling activity, and amino acid uptake in tissue biopsies from both uninfected placentas and malaria-infected placentas with and without intervillositis, and in an in vitro model using primary human trophoblast (PHT) cells.,We demonstrated that (1) placental mTOR activity is lower in cases of placental malaria with intervillositis, (2) placental mTOR activity is negatively correlated with the degree of inflammation, and (3) inhibition of placental mTOR activity is associated with reduced placental amino acid uptake and lower birthweight.,In PHT cells, we showed that (1) inhibition of mTOR signaling is a mechanistic link between placental malaria-associated intervillositis and decreased amino acid uptake and (2) constitutive mTOR activation partially restores amino acid uptake.,Our data support the concept that inhibition of placental mTOR signaling constitutes a mechanistic link between placental malaria-associated intervillositis and decreased amino acid uptake, which may contribute to lower birthweight.,Restoring placental mTOR signaling in placental malaria may increase birthweight and improve neonatal survival, representing a new potential therapeutic approach.,The online version of this article (doi:10.1186/s12916-016-0759-3) contains supplementary material, which is available to authorized users.

Pregnancy is a challenge to the maternal immune system as it must defend the body against pathogens while at the same time develop immune tolerance against the fetus growing inside the uterus.,Despite ex vivo techniques being used to understand these processes, in vivo techniques are missing.,To directly study these phenomena, we have developed a new microscope stage and surgical procedures for use in two-photon microscopy, for in vivo observation of the mouse placenta.,These tools and surgical procedures demonstrate fetal and maternal blood flow inside the labyrinth zone of the placenta, as well as its three dimensional structure.,It was also useful to identify Plasmodium chabaudi-infected red blood cells inside this labyrinth zone.,We believe this technique will represent an important contribution for expanding the available knowledge concerning cell dynamics and interactions at the fetal-maternal interface.

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.

National malaria control programmes and their partners must document progress associated with investments in malaria control.,While documentation has been achieved through population-based surveys for most interventions, measuring changes in malaria case management has been challenging because the increasing use of diagnostic tests reduces the denominator of febrile children who should receive anti-malarial treatment.,Thus the widely used indicator, “proportion of children under five with fever in the last two weeks who received anti-malarial treatment according to national policy within 24 hours from onset of fever” is no longer relevant.,An alternative sequence of indicators using a systems effectiveness approach was examined using data from nationally representative surveys in Zambia: the 2012 population-based Malaria Indictor Survey (MIS) and the 2011 Health Facility Survey (HFS).,The MIS measured fever treatment-seeking behaviour among 972 children under five years (CU5) and 1,848 people age five years and above.,The HFS assessed management of 435 CU5 and 429 people age five and above with fever/history of fever seeking care at 149 health facilities.,Consultation observation and exit interviews measured use of diagnostic tests, artemisinin combination therapy (ACT) prescription, and patient comprehension of prescribed regimens.,Systems effectiveness for malaria case management among CU5 was estimated as follows: [100% ACT efficacy] x [55% fever treatment-seeking from an appropriate provider (MIS)] x [71% malaria blood testing (HFS)] x [86% ACT prescription for positive cases (HFS)] x [73% patient comprehension of prescribed ACT drug regimens (HFS)] = 25%.,Systems effectiveness for malaria case management among people age five and above was estimated at 15%.,Tracking progress in malaria case management coverage can no longer rely solely on population-based surveys; the way forward likely entails household surveys to track trends in fever treatment-seeking behaviour, and facility/provider data to track appropriate management of febrile patients.,Applying health facility and population-based data to the systems effectiveness framework provides a cogent and feasible approach to documenting malaria case management coverage and identifying gaps to direct program action.,In Zambia, this approach identified treatment-seeking behaviour as the largest contributor to reduction in systems effectiveness for malaria case management.

Evaluating the effectiveness of malaria control interventions on the basis of their impact on transmission as well as impact on morbidity and mortality is becoming increasingly important as countries consider pre-elimination and elimination as well as disease control.,Data on prevalence and transmission are traditionally obtained through resource-intensive epidemiological and entomological surveys that become difficult as transmission decreases.,This work employs mathematical modeling to examine the relationships between malaria indicators allowing more easily measured data, such as routine health systems data on case incidence, to be translated into measures of transmission and other malaria indicators.,Simulations of scenarios with different levels of malaria transmission, patterns of seasonality and access to treatment were run with an ensemble of models of malaria epidemiology and within-host dynamics, as part of the OpenMalaria modeling platform.,For a given seasonality profile, regression analysis mapped simulation results of malaria indicators, such as annual average entomological inoculation rate, prevalence, incidence of uncomplicated and severe episodes, and mortality, to an expected range of values of any of the other indicators.,Results were validated by comparing simulated relationships between indicators with previously published data on these same indicators as observed in malaria endemic areas.,These results allow for direct comparisons of malaria transmission intensity estimates made using data collected with different methods on different indicators.,They also address key concerns with traditional methods of quantifying transmission in areas of differing transmission intensity and sparse data.,Although seasonality of transmission is often ignored in data compilations, the models suggest it can be critically important in determining the relationship between transmission and disease.,Application of these models could help public health officials detect changes of disease dynamics in a population and plan and assess the impact of malaria control interventions.

Larval control is of paramount importance in the reduction of malaria vector abundance and subsequent disease transmission reduction.,Understanding larval habitat succession and its ecology in different land use managements and cropping systems can give an insight for effective larval source management practices.,This study investigated larval habitat succession and ecological parameters which influence larval abundance in malaria epidemic prone areas of western Kenya.,A total of 51 aquatic habitats positive for anopheline larvae were surveyed and visited once a week for a period of 85 weeks in succession.,Habitats were selected and identified.,Mosquito larval species, physico-chemical parameters, habitat size, grass cover, crop cycle and distance to nearest house were recorded.,Polymerase chain reaction revealed that An. gambiae s.l was the most dominant vector species comprised of An.gambiae s.s (77.60%) and An.arabiensis (18.34%), the remaining 4.06% had no amplification by polymerase chain reaction.,Physico-chemical parameters and habitat size significantly influenced abundance of An. gambiae s.s (P = 0.024) and An. arabiensis (P = 0.002) larvae.,Further, larval species abundance was influenced by crop cycle (P≤0.001), grass cover (P≤0.001), while distance to nearest houses significantly influenced the abundance of mosquito species larvae (r = 0.920;P≤0.001).,The number of predator species influenced mosquito larval abundance in different habitat types.,Crop weeding significantly influenced with the abundance of An.gambiae s.l (P≤0.001) when preceded with fertilizer application.,Significantly higher anopheline larval abundance was recorded in habitats in pasture compared to farmland (P = 0.002).,When habitat stability and habitat types were considered, hoof print were the most productive followed by disused goldmines.,These findings suggest that implementation of effective larval control programme should be targeted with larval habitats succession information when larval habitats are fewer and manageable.,Crop cycles and distance from habitats to household should be considered as effective information in planning larval control.

Plasmodium vivax infects hepatocytes to form schizonts that cause blood infection, or dormant hypnozoites that can persist for months in the liver before leading to relapsing blood infections.,The molecular processes that drive P. vivax schizont and hypnozoite survival remain largely unknown, but they likely involve a rich network of host-pathogen interactions, including those occurring at the host-parasite interface, the parasitophorous vacuole membrane (PVM).,Using a recently developed P. vivax liver-stage model system we demonstrate that host aquaporin-3 (AQP3) localizes to the PVM of schizonts and hypnozoites within 5 days after invasion.,This recruitment is also observed in P. vivax-infected reticulocytes.,Chemical treatment with the AQP3 inhibitor auphen reduces P. vivax liver hypnozoite and schizont burden, and inhibits P. vivax asexual blood-stage growth.,These findings reveal a role for AQP3 in P. vivax liver and blood stages and suggest that the protein may be targeted for therapeutic treatment.,•Host aquaporin-3 (AQP3) is recruited to P. vivax hypnozoites and schizonts•The AQP3 inhibitor auphen inhibits P. vivax hypnozoites and schizonts•Host AQP3 is recruited to P. vivax-infected erythrocytes derived from patient samples•Auphen inhibits blood stages of clinical P. vivax isolates,Host aquaporin-3 (AQP3) is recruited to P. vivax hypnozoites and schizonts,The AQP3 inhibitor auphen inhibits P. vivax hypnozoites and schizonts,Host AQP3 is recruited to P. vivax-infected erythrocytes derived from patient samples,Auphen inhibits blood stages of clinical P. vivax isolates,Using a recently developed Plasmodium vivax liver-stage model, Posfai et al. describe the recruitment of human aquaporin-3 to the host-parasite interface during the liver and blood stages.,Furthermore, they demonstrate that an aquaporin-3 inhibitor, auphen, is effective against multiple parasite stages, including hypnozoites.

The causative agent of malaria, Plasmodium, replicates inside a membrane-bound parasitophorous vacuole (PV) that shields this intracellular parasite from the cytosol of the host cell1.,One common threat for intracellular pathogens is the homeostatic process of autophagy through which cells capture unwanted intracellular material for lysosomal degradation2.,During the liver stage of a malaria infection, Plasmodium parasites are targeted by the autophagy machinery of the host cell and the PV membrane (PVM) becomes decorated with several autophagy markers, including LC3 (microtubule-associated protein 1 light chain 3)3,4.,Here we show that Plasmodium berghei parasites infecting hepatic cells rely on the PVM transmembrane protein UIS3 to avoid elimination by host cell-mediated autophagy.,We found that UIS3 binds host LC3 through a non-canonical interaction with a specialised surface on LC3 where host proteins with essential functions during autophagy also bind.,UIS3 acts as a bona fide autophagy inhibitor by competing with host LC3-interacting proteins for LC3 binding.,Our work identifies UIS3, one of the most promising candidates for a genetically-attenuated vaccine against malaria5, as a unique and potent mediator of autophagy evasion in Plasmodium.,We propose that the protein-protein interaction between UIS3 and host LC3 represents a target for antimalarial drug development.

Malaria transmission is highly heterogeneous in most settings, resulting in the formation of recognizable malaria hotspots.,Targeting these hotspots might represent a highly efficacious way of controlling or eliminating malaria if the hotspots fuel malaria transmission to the wider community.,Hotspots of malaria will be determined based on spatial patterns in age-adjusted prevalence and density of antibodies against malaria antigens apical membrane antigen-1 and merozoite surface protein-1.,The community effect of interventions targeted at these hotspots will be determined.,The intervention will comprise larviciding, focal screening and treatment of the human population, distribution of long-lasting insecticide-treated nets and indoor residual spraying.,The impact of the intervention will be determined inside and up to 500 m outside the targeted hotspots by PCR-based parasite prevalence in cross-sectional surveys, malaria morbidity by passive case detection in selected facilities and entomological monitoring of larval and adult Anopheles populations.,This study aims to provide direct evidence for a community effect of hotspot-targeted interventions.,The trial is powered to detect large effects on malaria transmission in the context of ongoing malaria interventions.,Follow-up studies will be needed to determine the effect of individual components of the interventions and the cost-effectiveness of a hotspot-targeted approach, where savings made by reducing the number of compounds that need to receive interventions should outweigh the costs of hotspot-detection.,NCT01575613.,The protocol was registered online on 20 March 2012; the first community was randomized on 26 March 2012.

Philip Bejon and colleagues document the clustering of malaria episodes and malarial parasite infection.,These patterns may enable future prediction of hotspots of malaria infection and targeting of treatment or preventive interventions.,Infectious diseases often demonstrate heterogeneity of transmission among host populations.,This heterogeneity reduces the efficacy of control strategies, but also implies that focusing control strategies on “hotspots” of transmission could be highly effective.,In order to identify hotspots of malaria transmission, we analysed longitudinal data on febrile malaria episodes, asymptomatic parasitaemia, and antibody titres over 12 y from 256 homesteads in three study areas in Kilifi District on the Kenyan coast.,We examined heterogeneity by homestead, and identified groups of homesteads that formed hotspots using a spatial scan statistic.,Two types of statistically significant hotspots were detected; stable hotspots of asymptomatic parasitaemia and unstable hotspots of febrile malaria.,The stable hotspots were associated with higher average AMA-1 antibody titres than the unstable clusters (optical density [OD] = 1.24, 95% confidence interval [CI] 1.02-1.47 versus OD = 1.1, 95% CI 0.88-1.33) and lower mean ages of febrile malaria episodes (5.8 y, 95% CI 5.6-6.0 versus 5.91 y, 95% CI 5.7-6.1).,A falling gradient of febrile malaria incidence was identified in the penumbrae of both hotspots.,Hotspots were associated with AMA-1 titres, but not seroconversion rates.,In order to target control measures, homesteads at risk of febrile malaria could be predicted by identifying the 20% of homesteads that experienced an episode of febrile malaria during one month in the dry season.,That 20% subsequently experienced 65% of all febrile malaria episodes during the following year.,A definition based on remote sensing data was 81% sensitive and 63% specific for the stable hotspots of asymptomatic malaria.,Hotspots of asymptomatic parasitaemia are stable over time, but hotspots of febrile malaria are unstable.,This finding may be because immunity offsets the high rate of febrile malaria that might otherwise result in stable hotspots, whereas unstable hotspots necessarily affect a population with less prior exposure to malaria.,Please see later in the article for the Editors' Summary,Malaria, a mosquito-borne parasitic disease, is a major global public-health problem.,About half the world's population is at risk of malaria and about one million people (mainly children living in sub-Saharan Africa) die each year from the disease.,Malaria is transmitted to people through the bite of an infected mosquito.,Initially, the parasite replicates inside human liver cells but, about a week after infection, these cells release “merozoites” (one of the life-stages of the parasite), which invade red blood cells.,Here, the merozoites replicate rapidly before bursting out after 2-3 days and infecting more red blood cells.,The cyclical and massive increase in parasitemia (parasites in the bloodstream) that results from this pattern of replication is responsible for malaria's recurring fevers and can cause life-threatening organ damage and anemia (a lack of red blood cells).,Malaria can be prevented by controlling the mosquitoes that spread the parasite and by avoiding mosquito bites.,Effective treatment with antimalarial drugs can also reduce malaria transmission.,Like many other infectious diseases, the transmission of malaria is heterogeneous.,That is, even in places where malaria is always present, there are “hotspots” of transmission, areas where the risk of catching malaria is particularly high.,The existence of these hotspots, which are caused by a combination of genetic factors (for example, host susceptibility to infection) and environmental factors (for example, distance from mosquito breeding sites), reduces the efficacy of control strategies.,However, mathematical models suggest that focusing control strategies on transmission hotspots might be an effective way to reduce overall malaria transmission.,Efforts have been made to identify such hotspots using environmental data collected by satellites but with limited success.,In this study, therefore, the researchers investigate the heterogeneity of malaria transmission in the Kilifi District of Kenya over time by analyzing data collected over up to 12 years (“longitudinal” data) on malaria episodes and parasitemia in three groups (cohorts) of children living in 256 homesteads.,The researchers identified febrile malaria episodes in the homesteads by taking blood from children with fever (febrile children) to analyze for parasitemia.,They took blood once a year from all the study participants just before the rainy season (when malaria peaks) to look for symptom-free parasitemia and they also looked for antibodies (proteins made by the immune system that fight disease) against malaria parasites in the blood of the participants.,They then used a “spatial scan statistic” to look for heterogeneity of transmission and to identify transmission hotspots (groups of homesteads where the observed incidence of malaria or parasitemia was higher than would be expected if cases were evenly distributed).,The researchers identified two types of hotspots-stable hotspots of symptom-free parasitemia that were still hotspots several years later and unstable hotspots of febrile malaria that rarely stayed in the same place for more than a year or two.,Children living in the stable hotspots had slightly higher average amounts of antimalaria antibodies and developed malaria at a slightly lower average age than children living in the unstable hotspots.,These findings show that in Kilifi District, Kenya, hotspots of symptom-free parasitemia are stable over time but hotspots of febrile malaria are unstable.,The researchers suggest that rapid acquisition of immunity in the stable hotspots reduces the occurrence of febrile malaria whereas in the unstable hotspots there is a high incidence of febrile malaria because lack of previous exposure to the parasite means there is a low level of immunity.,Targeted strategies for malaria control should target both types of hotspots, suggest the researchers.,Stable hotspots of symptom-free parasitemia (which can be identified by parasite or antibody surveys or by remote environmental sensing) should be targeted because mosquito dispersion probably increases malaria transmission rates near these hotspots.,Unstable hotspots of febrile disease should be targeted to reduce both the burden of disease and transmission in the wider community.,Unstable hotspots of febrile malaria, the researchers suggest, could be efficiently identified in Kilifi District (and maybe elsewhere) by determining which homesteads had malaria outbreaks during September (part of the dry season) one year and then focusing control interventions on these homesteads the next year.,Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000304.,Information is available from the World Health Organization on malaria (in several languages),The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish),MedlinePlus provides links to additional information on malaria (in English and Spanish),Information is available from the Roll Back Malaria Partnership on the global control of malaria (in English and French) and on malaria in Kenya

Gambian human African trypanosomiasis (gHAT) is a neglected tropical disease caused by Trypanosoma brucei gambiense transmitted by tsetse flies (Glossina).,In Côte d’Ivoire, Bonon is the most important focus of gHAT, with 325 cases diagnosed from 2000 to 2015 and efforts against gHAT have relied largely on mass screening and treatment of human cases.,We assessed whether the addition of tsetse control by deploying Tiny Targets offers benefit to sole reliance on the screen-and-treat strategy.,In 2015, we performed a census of the human population of the Bonon focus, followed by an exhaustive entomological survey at 278 sites.,After a public sensitization campaign, ~2000 Tiny Targets were deployed across an area of 130 km2 in February of 2016, deployment was repeated annually in the same month of 2017 and 2018.,The intervention’s impact on tsetse was evaluated using a network of 30 traps which were operated for 48 hours at three-month intervals from March 2016 to December 2018.,A second comprehensive entomological survey was performed in December 2018 with traps deployed at 274 of the sites used in 2015.,Sub-samples of tsetse were dissected and examined microscopically for presence of trypanosomes.,The census recorded 26,697 inhabitants residing in 331 settlements.,Prior to the deployment of targets, the mean catch of tsetse from the 30 monitoring traps was 12.75 tsetse/trap (5.047-32.203, 95%CI), i.e.,6.4 tsetse/trap/day.,Following the deployment of Tiny Targets, mean catches ranged between 0.06 (0.016-0.260, 95%CI) and 0.55 (0.166-1.794, 95%CI) tsetse/trap, i.e.,0.03-0.28 tsetse/trap/day.,During the final extensive survey performed in December 2018, 52 tsetse were caught compared to 1,909 in 2015, with 11.6% (5/43) and 23.1% (101/437) infected with Trypanosoma respectively.,The annual deployment of Tiny Targets in the gHAT focus of Bonon reduced the density of Glossina palpalis palpalis by >95%.,Tiny Targets offer a powerful addition to current strategies towards eliminating gHAT from Côte d’Ivoire.

Important control efforts have led to a significant reduction of the prevalence of human African trypanosomiasis (HAT) in Côte d’Ivoire, but the disease is still present in several foci.,The existence of an animal reservoir of Trypanosoma brucei gambiense may explain disease persistence in these foci where animal breeding is an important source of income but where the prevalence of animal African trypanosomiasis (AAT) is unknown.,The aim of this study was to identify the trypanosome species circulating in domestic animals in both Bonon and Sinfra HAT endemic foci.,552 domestic animals (goats, pigs, cattle and sheep) were included.,Blood samples were tested for trypanosomes by microscopic observation, species-specific PCR for T. brucei sl, T. congolense, T. vivax and subspecies-specific PCR for T. b. gambiense and T. b. gambiense immune trypanolysis (TL).,Infection rates varied significantly between animal species and were by far the highest in pigs (30%).,T. brucei s.l was the most prevalent trypanosome species (13.7%) followed by T. congolense.,No T. b. gambiense was identified by PCR while high TL positivity rates were observed using T. b. gambiense specific variants (up to 27.6% for pigs in the Bonon focus).,This study shows that domestic animals are highly infected by trypanosomes in the studied foci.,This was particularly true for pigs, possibly due to a higher exposure of these animals to tsetse flies.,Whereas T. brucei s.l. was the most prevalent species, discordant results were obtained between PCR and TL regarding T. b. gambiense identification.,It is therefore crucial to develop better tools to study the epidemiological role of potential animal reservoir for T. b. gambiense.,Our study illustrates the importance of “one health” approaches to reach HAT elimination and contribute to AAT control in the studied foci.

Malaria intervention in Ethiopia has been strengthened significantly in the past decade.,The Ethiopian government recently stratified the country based upon annual parasite incidence into malaria free, low, moderate and high transmission strata.,Districts with low transmission were targeted for indigenous transmission elimination.,Surveillance on malaria disease incidence is needed for planning control and elimination efforts.,Clinical malaria was monitored prospectively in health facilities in Jimma town, Oromia Region, southwestern Ethiopia from July 2014 to June 2015.,Seasonal cross-sectional parasite prevalence surveys in local communities were conducted in 2014 and 2015 in eight kebeles.,Case report forms were administered to obtain sociodemographic and epidemiological information from patients.,A total of 1434 suspected malaria cases were examined from the health facilities and 428 confirmed malaria cases were found.,Among them, 327 (76.4 %) cases were Plasmodium vivax, 97 (22.7 %) were Plasmodium falciparum, and 4 (0.9 %) were mixed infection of P. vivax and P. falciparum.,The annual malaria incidence rate was 1.7 cases per 1000 people at risk.,Parasite prevalence in the community was less than 3 %.,Household ownership of insecticide-treated nets (ITNs) was 47.3 % (1173/2479) and ITN usage was 37.9 %.,All ITNs were long-lasting insecticidal nets, and repellent use was not found in the study area.,Being male and traveling were the significant risk factors for P. falciparum malaria.,For P. vivax malaria, risk factors included occupation and history of malaria illness during the preceding 30 days.,Epidemiological evidence suggested low clinical malaria incidence and prevalence in Jimma town.,More aggressive measures may be needed to further suppress vivax transmission.,Strategies should be planned targeting sustained control and elimination.,The online version of this article (doi:10.1186/s12936-016-1298-2) contains supplementary material, which is available to authorized users.

Despite targeted indoor residual spraying (IRS) over a six-year period and free mass distribution of long-lasting insecticide-treated nets (ITNs), malaria rates in northern Ghana remain high.,Outdoor sleeping and other night-time social, cultural and economic activities that increase exposure to infective mosquito bites are possible contributors.,This study was designed to document these phenomena through direct observation, and to explore the context in which they occur.,During the late dry season months of February and March 2014, study team members carried out continuous household observations from dusk to dawn in one village in Ghana’s Northern Region and one in Upper West Region.,In-depth interviews with health workers and community residents helped supplement observational findings.,Study team members completed observations of 182 individuals across 24 households, 12 households per site.,Between the two sites, they interviewed 14 health workers, six community health volunteers and 28 community residents.,In early evening, nearly all study participants were observed to be outdoors and active.,From 18.00-23.00 hours, socializing, night school, household chores, and small-scale economic activities were common.,All-night funerals, held outdoors and attended by large numbers of community members, were commonly reported and observed.,Outdoor sleeping was frequently documented at both study sites, with 42% of the study population sleeping outdoors at some time during the night.,While interviewees mentioned bed net use as important to malaria prevention, observed use was low for both indoor and outdoor sleeping.,Net access within households was 65%, but only 17% of those with access used a net at any time during the night.,Participants cited heat as the primary barrier and reported higher net use during the rainy season.,Outdoor sleeping and other night-time activities were extensive, and could significantly increase malaria risk.,These findings suggest that indoor-oriented control measures such as ITNs and IRS are insufficient to eliminate malaria in this setting, especially given the low net use observed.,Development and evaluation of complementary outdoor control strategies should be prioritized.,A research agenda is proposed to quantify the relative risk of outdoor night-time activities and test potential vector control interventions that might reduce that risk.

In order to sustain the gains achieved by current malaria control strategies, robust surveillance systems that monitor dynamics of vectors and their roles in malaria transmission over time are essential.,This longitudinal study demonstrates the trends in malaria vector dynamics and their relative contribution to malaria transmission in hyperendemic transmission settings in Tanzania.,The study was conducted in two villages within the Kilombero Valley, in rural Tanzania for five consecutive years (2008-2012).,Seventy-two houses were selected per village and each house was sampled for mosquitoes monthly using a CDC light trap.,Collected mosquitoes were assessed for species identity and sporozoite infection status using PCR and ELISA, respectively.,Anopheles funestus and Anopheles arabiensis susceptibility to insecticides was assessed using WHO guidelines.,A total of 100,810 malaria vectors were collected, of which 76% were Anopheles gambiae s. l. and 24% were An. funestus.,Of all An. funestus samples that amplified with PCR (n = 2,737), 97% were An. funestus s.s., 2% were Anopheles rivorulum and 1% Anopheles leesoni.,Whereas for An. gambiae s.l. (n = 8,117), 93% were An. arabiensis and 7% were Anopheles gambiae s.s.,The proportion of An. gambiae s.s. identified by PCR (2,924) declined from 0.2% in the year 2008 to undetectable levels in 2012.,Malaria transmission intensity significantly decreased from an EIR of 78.14 infectious bites/person/year in 2008 to 35 ib/p/yr in 2011 but rebounded to 226 ib/p/yr in 2012 coinciding with an increased role of An. funestus in malaria transmission.,Insecticide susceptibility tests indicated high levels of resistance in An. funestus against deltamethrin (87%), permethrin (65%), lambda cyhalothrin (74%), bendiocarb (65%), and DDT (66%).,Similarly, An. arabiensis showed insecticide resistance to deltamethrin (64%), permethrin (77%) and lambda cyhalothrin (42%) in 2014.,The results indicate the continuing role of An. arabiensis and the increasing importance of An. funestus in malaria transmission, and pyrethroid resistance development in both species.,Complementary vector control and surveillance tools are needed that target the ecology, behaviour and insecticide resistance management of these vector species, in order to preserve the efficacy of LLINs.

Eliminating malaria from highly endemic settings will require unprecedented levels of vector control.,To suppress mosquito populations, vector control products targeting their blood hosts must attain high biological coverage of all available sources, rather than merely high demographic coverage of a targeted resource subset, such as humans while asleep indoors.,Beyond defining biological coverage in a measurable way, the proportion of blood meals obtained from humans and the proportion of bites upon unprotected humans occurring indoors also suggest optimal target product profiles for delivering insecticides to humans or livestock.,For vectors that feed only occasionally upon humans, preferred animal hosts may be optimal targets for mosquito-toxic insecticides, and vapour-phase insecticides optimized to maximize repellency, rather than toxicity, may be ideal for directly protecting people against indoor and outdoor exposure.,However, for vectors that primarily feed upon people, repellent vapour-phase insecticides may be inferior to toxic ones and may undermine the impact of contact insecticides applied to human sleeping spaces, houses or clothing if combined in the same time and place.,These concepts are also applicable to other mosquito-borne anthroponoses so that diverse target species could be simultaneously controlled with integrated vector management programmes.,Measurements of these two crucial mosquito behavioural parameters should now be integrated into programmatically funded, longitudinal, national-scale entomological monitoring systems to inform selection of available technologies and investment in developing new ones.

Haemoproteus parasites are widespread, and several species cause diseases both in birds and blood-sucking insects.,These pathogens are transmitted by dipterans belonging to the Ceratopogonidae and Hippoboscidae, however certain vector species remain unknown for the majority of Haemoproteus spp.,Owls are often infected by Haemoproteus parasites, but experimental studies on vectors of these infections are lacking.,The aim of this study was to investigate sporogonic development of two widespread Haemoproteus parasites of owls, H. noctuae and H. syrnii in experimentally infected biting midges Culicoides impunctatus and Culicoides nubeculosus.,We also followed in vitro sporogonic development of these infections and determined their phylogenetic relationships with Haemoproteus spp., for which vectors have been identified.,Wild-caught C. impunctatus and laboratory reared C. nubeculosus were infected experimentally by allowing them to take blood meals on one individual long-eared owl (Asio otus) and one tawny owl (Strix aluco) harbouring mature gametocytes of H. noctuae (lineage hCIRCUM01) and H. syrnii (hCULCIB01), respectively.,The engorged insects were maintained in the laboratory at 16-18 °C, and dissected at intervals in order to follow the development of ookinetes, oocysts and sporozoites.,We also observed in vitro development of sexual stages of both parasites by exposure of infected blood to air.,The parasite lineages were determined by polymerase chain reaction-based methods.,Bayesian phylogeny was constructed in order to determine the relationships of owl parasites with other avian Haemoproteus spp., for which vectors have been identified.,Both H. noctuae and H. syrnii completed sporogony in C. nubeculosus, and H. noctuae completed sporogony in C. impunctatus.,Ookinetes, oocysts and sporozoites of these parasites were reported and described.,Gametes and ookinetes of both species readily developed in vitro.,In accordance with sporogony data, the phylogenetic analysis placed both parasite lineages in a clade of Culicoides spp.-transmitted avian Haemoproteus (Parahaemoproteus) spp.,Culicoides nubeculosus and C. impunctatus are vectors of H. noctuae and H. syrnii.,Phylogenies based on cytochrome b gene indicate parasite-vector relationships, and we recommend using them in predicting possible parasite-vector relationships and planning research on avian Haemoproteus spp. vectors in wildlife.

Blood-sucking flying insects play a key role in the transmission of pathogens of vector-borne diseases.,However, at least for the case of avian malaria parasites, the vast majority of studies focus on the interaction between parasites and vertebrate hosts, but there is a lack of information regarding the interaction between the parasites and the insect vectors.,Here, we identified the presence of malaria and malaria-like parasite lineages harbored by the potential vector Culicoides circumscriptus (Kieffer).,Also, we identified some nodes of the transmission network connecting parasite lineages, potential insect vectors and avian hosts by comparing Haemoproteus and Plasmodium lineages isolated from insects with those infecting wild birds in this and previous studies.,Using a molecular approach, we analysed the presence of blood parasites in a total of 97 biting midges trapped in the Doñana National Park (SW Spain) and surrounding areas.,Also, 123 blood samples from 11 bird species were analyzed for the presence of blood parasite infections.,Blood parasites Haemoproteus and Plasmodium were identified by amplification of a 478 bp fragment of the mitochondrial cytochrome b gen.,Thirteen biting midges harboured blood parasites including six Haemoproteus and two Plasmodium lineages, supporting the potential role of these insects on parasite transmission.,Moreover, ten (8.1%) birds carried blood parasites.,Seven Plasmodium and one Haemoproteus lineages were isolated from birds.,Overall, six new Haemoproteus lineages were described in this study.,Also, we identified the transmission networks of some blood parasites.,Two Haemoproteus lineages, hCIRCUM03 and GAGLA03, were identical to those isolated from Corvus monedula in southern Spain and Garrulus glandarius in Bulgaria, respectively.,Furthermore, the new Haemoproteus lineage hCIRCUM05 showed a 99% similarity with a lineage found infecting captive penguins in Japan.,The comparison of the parasite lineages isolated in this study with those previously found infecting birds allowed us to identify some potential nodes in the transmission network of avian blood parasite lineages.,These results highlight the complexity of the transmission networks of blood parasites in the wild that may involve a high diversity of susceptible birds and insect vectors.

Although malaria disease in urban and peri-urban areas of sub-Saharan Africa is a growing concern, the epidemiologic patterns and drivers of transmission in these settings remain poorly understood.,Factors associated with variation in malaria risk in urban and peri-urban areas were evaluated in this study.,A health facility-based, age and location-matched, case-control study of children 6-59 months of age was conducted in four urban and two peri-urban health facilities (HF) of Blantyre city, Malawi.,Children with fever who sought care from the same HF were tested for malaria parasites by microscopy and PCR.,Those testing positive or negative on both were defined as malaria cases or controls, respectively.,A total of 187 cases and 286 controls were studied.,In univariate analyses, higher level of education, possession of TV, and electricity in the house were negatively associated with malaria illness; these associations were similar in urban and peri-urban zones.,Having travelled in the month before testing was strongly associated with clinical malaria, but only for participants living in the urban zones (OR = 5.1; 95% CI = 1.62, 15.8).,Use of long-lasting insecticide nets (LLINs) the previous night was not associated with protection from malaria disease in any setting.,In multivariate analyses, electricity in the house, travel within the previous month, and a higher level of education were all associated with decreased odds of malaria disease.,Only a limited number of Anopheles mosquitoes were found by aspiration inside the households in the peri-urban areas, and none was collected from the urban households.,Travel was the main factor influencing the incidence of malaria illness among residents of urban Blantyre compared with peri-urban areas.,Identification and understanding of key mobile demographic groups, their behaviours, and the pattern of parasite dispersal is critical to the design of more targeted interventions for the urban setting.,The online version of this article (doi:10.1186/s12936-016-1623-9) contains supplementary material, which is available to authorized users.

School-age children have attracted relatively little attention as a group in need of special measures to protect them against malaria.,However, increasing success in lowering the level of malaria transmission in many previously highly endemic areas will result in children acquiring immunity to malaria later in life than has been the case in the past.,Thus, it can be anticipated that in the coming years there will be an increase in the incidence of both uncomplicated and severe malaria in school-age children in many previously highly endemic areas.,In this review, which focuses primarily on Africa, recent data on the prevalence of malaria parasitaemia and on the incidence of clinical malaria in African school-age children are presented and evidence that malaria adversely effects school performance is reviewed.,Long-lasting insecticide treated bednets (LLIN) are an effective method of malaria control but several studies have shown that school-age children use LLINs less frequently than other population groups.,Antimalarial drugs are being used in different ways to control malaria in school-age children including screening and treatment and intermittent preventive treatment.,Some studies of chemoprevention in school-age children have shown reductions in anaemia and improved school performance but this has not been the case in all trials and more research is needed to identify the situations in which chemoprevention is likely to be most effective and, in these situations, which type of intervention should be used.,In the longer term, malaria vaccines may have an important role in protecting this important section of the community from malaria.,Regardless of the control approach selected, it is important this is incorporated into the overall programme of measures being undertaken to enhance the health of African school-age children.

Prophylaxis with macrocyclic lactone (ML) endectocides is the primary strategy for heartworm control.,Recent evidence has confirmed that ML-resistant Dirofilaria immitis isolates have evolved.,Comparison of genomes of ML-resistant isolates show they are genetically distinct from wild-type populations.,Previously, we identified single nucleotide polymorphisms (SNPs) that are correlated with phenotypic ML resistance.,Since reliable in vitro assays are not available to detect ML resistance in L3 or microfilarial stages, the failure to reduce microfilaraemia in infected dogs treated with an ML has been proposed as a surrogate clinical assay for this purpose.,The goal of our study was to validate the genotype-phenotype correlation between SNPs associated with ML resistance and failure to reduce microfilaraemia following ML treatment and to identify a minimal number of SNPs that could be used to confirm ML resistance.,In this study, 29 participating veterinary clinics received a total of 148 kits containing supplies for blood collection, dosing and prepaid shipping.,Patients recruited after a diagnosis of heartworm infection were treated with a single standard dose of Advantage Multi® and a blood sample taken pre- and approximately 2-4 weeks post-treatment.,Each sample was processed by performing a modified Knott's Test followed by isolation of microfilariae, genomic DNA extraction and MiSeq sequencing of regions encompassing 10 SNP sites highly correlated with ML resistance.,We observed significant correlation of SNP loci frequencies with the ML microfilaricidal response phenotype.,Although all predictive SNP combination models performed well, a 2-SNP model was superior to other models tested.,The predictive ability of these markers for ML-resistant heartworms should be further evaluated in clinical and epidemiological contexts.,Image 1,•Recent evidence has confirmed that heartworm isolates have evolved the ability to survive ML prophylaxis.,•SNPs are highly correlated with phenotypic ML resistance, but none identifies a specific “resistance” gene.,•SNPs associated with ML resistance correlate with failure to reduce MF following ML treatment.,•A 2-SNP model could be employed to diagnose clinical cases of ML resistance.,Recent evidence has confirmed that heartworm isolates have evolved the ability to survive ML prophylaxis.,SNPs are highly correlated with phenotypic ML resistance, but none identifies a specific “resistance” gene.,SNPs associated with ML resistance correlate with failure to reduce MF following ML treatment.,A 2-SNP model could be employed to diagnose clinical cases of ML resistance.

Monthly topical and sustained-release injectable formulations of moxidectin are currently marketed; however, an oral formulation, while approved at a dose of 3 μg/kg, is not currently marketed in the United States.,Although resistance of heartworms to all macrocyclic lactone (ML) heartworm preventives (ivermectin, milbemycin, selamectin and moxidectin) has been demonstrated, to date no data have been reported on the effectiveness of oral moxidectin against recent isolates of Dirofilaria immitis.,A total of nine studies were conducted to determine the efficacy of moxidectin against a range of older and recently sourced heartworm isolates.,Dogs (groups of three to eight) were inoculated with 50 D. immitis infective larvae (L3) from nine different isolates (MP3, Michigan, JYD-34, ZoeMO-2012, ZoeKy-2013, ZoeLA-2013, GCFL-2014, AMAL-2014 and ZoeAL-2015) and treated 28-30 days later with single oral doses of 3 μg/kg of moxidectin.,Additionally, one group of dogs that was inoculated with JYD-34 was treated monthly for 3 consecutive months beginning 30 days post inoculation.,Dogs were held for approximately 4 months after the initial (or only) treatment and then necropsied for recovery of adult heartworms.,A single dose of 3 μg/kg of moxidectin was 100% effective in preventing the development of five of nine heartworm isolates (MP3, Michigan, ZoeKy, GCFL and ZoeAL isolates), confirming their susceptibility to oral moxidectin at this dose.,MP3 and Michigan are isolates sourced from the field more than 9 years ago, while ZoeKy, ZoeAL and GCFL were isolated from the field within the past 2 to 3 years.,Against JYD-34, ZoeMO, ZoeLA and AMAL isolates, a single dose of 3 μg/kg of moxidectin was not completely effective, with efficacies of 19%, 82%, 54% and 62%, respectively, demonstrating resistance of these heartworm isolates to oral moxidectin at this dosage.,Three consecutive monthly doses of 3 μg/kg of moxidectin were also incompletely effective against the JYD-34 isolate, with an efficacy of 44%.,JYD-34 was originally isolated in 2010, while ZoeMO, ZoeLA and AMAL were isolated within the past 2 to 3 years.,A single oral dose (3 μg/mg) of moxidectin was 100% effective in preventing the development of ML-susceptible heartworm isolates while being incompletely effective against ML-resistant isolates.

Here we discuss proteomic analyses of whole cell preparations of the mosquito stages of malaria parasite development (i.e. gametocytes, microgamete, ookinete, oocyst and sporozoite) of Plasmodium berghei.,We also include critiques of the proteomes of two cell fractions from the purified ookinete, namely the micronemes and cell surface.,Whereas we summarise key biological interpretations of the data, we also try to identify key methodological constraints we have met, only some of which we were able to resolve.,Recognising the need to translate the potential of current genome sequencing into functional understanding, we report our efforts to develop more powerful combinations of methods for the in silico prediction of protein function and location.,We have applied this analysis to the proteome of the male gamete, a cell whose very simple structural organisation facilitated interpretation of data.,Some of the in silico predictions made have now been supported by ongoing protein tagging and genetic knockout studies.,We hope this discussion may assist future studies.

Plasmodium vivax is a major cause of febrile illness in endemic areas of Asia, Central and South America, and the horn of Africa.,Plasmodium vivax infections are characterized by relapses of malaria arising from persistent liver stages of the parasite (hypnozoites) which can be prevented only by 8-aminoquinoline anti-malarials.,Tropical P. vivax relapses at three week intervals if rapidly eliminated anti-malarials are given for treatment, whereas in temperate regions and parts of the sub-tropics P. vivax infections are characterized either by a long incubation or a long-latency period between illness and relapse - in both cases approximating 8-10 months.,The epidemiology of the different relapse phenotypes has not been defined adequately despite obvious relevance to malaria control and elimination.,The number of sporozoites inoculated by the anopheline mosquito is an important determinant of both the timing and the number of relapses.,The intervals between relapses display a remarkable periodicity which has not been explained.,Evidence is presented that the proportion of patients who have successive relapses is relatively constant and that the factor which activates hypnozoites and leads to regular interval relapse in vivax malaria is the systemic febrile illness itself.,It is proposed that in endemic areas a large proportion of the population harbours latent hypnozoites which can be activated by a systemic illness such as vivax or falciparum malaria.,This explains the high rates of vivax following falciparum malaria, the high proportion of heterologous genotypes in relapses, the higher rates of relapse in people living in endemic areas compared with artificial infection studies, and, by facilitating recombination between different genotypes, contributes to P. vivax genetic diversity particularly in low transmission settings.,Long-latency P. vivax phenotypes may be more widespread and more prevalent than currently thought.,These observations have important implications for the assessment of radical treatment efficacy and for malaria control and elimination.

Malaria causes a reduction in haemoglobin that is compounded by primaquine, particularly in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.,The aim of this study was to determine the relative contributions to red cell loss of malaria and primaquine in patients with uncomplicated Plasmodium vivax.,A systematic review identified P. vivax efficacy studies of chloroquine with or without primaquine published between January 2000 and March 2017.,Individual patient data were pooled using standardised methodology, and the haematological response versus time was quantified using a multivariable linear mixed effects model with non-linear terms for time.,Mean differences in haemoglobin between treatment groups at day of nadir and day 42 were estimated from this model.,In total, 3421 patients from 29 studies were included: 1692 (49.5%) with normal G6PD status, 1701 (49.7%) with unknown status and 28 (0.8%) deficient or borderline individuals.,Of 1975 patients treated with chloroquine alone, the mean haemoglobin fell from 12.22 g/dL [95% CI 11.93, 12.50] on day 0 to a nadir of 11.64 g/dL [11.36, 11.93] on day 2, before rising to 12.88 g/dL [12.60, 13.17] on day 42.,In comparison to chloroquine alone, the mean haemoglobin in 1446 patients treated with chloroquine plus primaquine was − 0.13 g/dL [− 0.27, 0.01] lower at day of nadir (p = 0.072), but 0.49 g/dL [0.28, 0.69] higher by day 42 (p < 0.001).,On day 42, patients with recurrent parasitaemia had a mean haemoglobin concentration − 0.72 g/dL [− 0.90, − 0.54] lower than patients without recurrence (p < 0.001).,Seven days after starting primaquine, G6PD normal patients had a 0.3% (1/389) risk of clinically significant haemolysis (fall in haemoglobin > 25% to < 7 g/dL) and a 1% (4/389) risk of a fall in haemoglobin > 5 g/dL.,Primaquine has the potential to reduce malaria-related anaemia at day 42 and beyond by preventing recurrent parasitaemia.,Its widespread implementation will require accurate diagnosis of G6PD deficiency to reduce the risk of drug-induced haemolysis in vulnerable individuals.,This trial was registered with PROSPERO: CRD42016053312.,The date of the first registration was 23 December 2016.,The online version of this article (10.1186/s12916-019-1386-6) contains supplementary material, which is available to authorized users.

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.

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

Intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine in vulnerable populations reduces malaria morbidity in Africa, but resistance mutations in the parasite dhps gene (combined with dhfr mutations) threaten its efficacy.,We update a systematic review to map the prevalence of K540E and A581G mutations in 294 surveys of infected humans across Africa from 2004-present.,Interpreting these data is complicated by multiclonal infections in humans, especially in high transmission areas.,We extend statistical methods to estimate the frequency, i.e. the proportion of resistant clones in the parasite population at each location, and so standardise for varying transmission levels.,Both K540E and A581G mutations increased in prevalence and frequency in 60% of areas after 2008, highlighting the need for ongoing surveillance.,Resistance measures within countries were similar within 300 km, suggesting an appropriate spatial scale for surveillance.,Spread of the mutations tended to accelerate once their prevalence exceeded 10% (prior to fixation).,Frequencies of resistance in parasite populations are the same or lower than prevalence in humans, so more areas would be classified as likely to benefit from IPT if similar frequency thresholds were applied.,We propose that the use of resistance frequencies as well as prevalence measures for policy decisions should be evaluated.

The single celled eukaryote Trypanosoma cruzi, a parasite transmitted by numerous species of triatomine bug in the Americas, causes Chagas disease in humans.,T. cruzi generally reproduces asexually and appears to have a clonal population structure.,However, two of the six major circulating genetic lineages, TcV and TcVI, are TcII-TcIII inter-lineage hybrids that are frequently isolated from humans in regions where chronic Chagas disease is particularly severe.,Nevertheless, a prevalent view is that hybridisation events in T. cruzi were evolutionarily ancient and that active recombination is of little epidemiological importance.,We analysed genotypes of hybrid and non-hybrid T. cruzi strains for markers representing three distinct evolutionary rates: nuclear GPI sequences (n = 88), mitochondrial COII-ND1 sequences (n = 107) and 28 polymorphic microsatellite loci (n = 35).,Using Maximum Likelihood and Bayesian phylogenetic approaches we dated key evolutionary events in the T. cruzi clade including the emergence of hybrid lineages TcV and TcVI, which we estimated to have occurred within the last 60,000 years.,We also found evidence for recent genetic exchange between TcIII and TcIV and between TcI and TcIV.,These findings show that evolution of novel recombinants remains a potential epidemiological risk.,The clearly distinguishable microsatellite genotypes of TcV and TcVI were highly heterozygous and displayed minimal intra-lineage diversity indicative of even earlier origins than sequence-based estimates.,Natural hybrid genotypes resembled typical meiotic F1 progeny, however, evidence for mitochondrial introgression, absence of haploid forms and previous experimental crosses indicate that sexual reproduction in T. cruzi may involve alternatives to canonical meiosis.,Overall, the data support two independent hybridisation events between TcII and TcIII and a recent, rapid spread of the hybrid progeny in domestic transmission cycles concomitant with, or as a result of, disruption of natural transmission cycles by human activities.

The causative agent of Chagas disease, Trypanosoma cruzi, is divided into 6 Discrete Typing Units (DTU): Tc I, IIa, IIb, IIc, IId and IIe.,In order to assess the relative pathogenicities of different DTUs, blood samples from three different clinical groups of chronic Chagas disease patients (indeterminate, cardiac, megacolon) from Bolivia were analyzed for their circulating parasites lineages using minicircle kinetoplast DNA polymorphism.,Between 2000 and 2007, patients sent to the Centro Nacional de Enfermedades Tropicales for diagnosis of Chagas from clinics and hospitals in Santa Cruz, Bolivia, were assessed by serology, cardiology and gastro-intestinal examinations.,Additionally, patients who underwent colonectomies due to Chagasic magacolon at the Hospital Universitario Japonés were also included.,A total of 306 chronic Chagas patients were defined by their clinical types (81 with cardiopathy, 150 without cardiopathy, 100 with megacolon, 144 without megacolon, 164 with cardiopathy or megacolon, 73 indeterminate and 17 cases with both cardiopathy and megacolon).,DNA was extracted from 10 ml of peripheral venous blood for PCR analysis.,The kinetoplast minicircle DNA (kDNA) was amplified from 196 out of 306 samples (64.1%), of which 104 (53.3%) were Tc IId, 4 (2.0%) Tc I, 7 (3.6%) Tc IIb, 1 (0.5%) Tc IIe, 26 (13.3%) Tc I/IId, 1 (0.5%) Tc I/IIb/IId, 2 (1.0%) Tc IIb/d and 51 (25.9%) were unidentified.,Of the 133 Tc IId samples, three different kDNA hypervariable region patterns were detected; Mn (49.6%), TPK like (48.9%) and Bug-like (1.5%).,There was no significant association between Tc types and clinical manifestations of disease.,None of the identified lineages or sublineages was significantly associated with any particular clinical manifestations in the chronic Chagas patients in Bolivia.

Rapid diagnostic tests (RDTs) for malaria enable proper diagnosis and have been shown to reduce overuse of artemisinin combination therapy.,Few studies have evaluated the feasibility and use of RDTs in the private sector in Myanmar.,The objectives of the study were to: 1) understand the acceptability of using RDTs in the informal sector in Myanmar; 2) examine motivations for use among informal providers; and, 3) highlight decision-making and knowledge of providers for diagnostic testing and treatment.,Qualitative interviews were conducted with 30 informal providers.,Purposeful sampling was used to enrol study participants in the Mon and Shan State in Myanmar.,All interviews were conducted in Burmese, translated into English, and two researchers coded all interviews using Atlas ti.,Major themes identified included: 1) informal provider and outlet characteristics, including demographic and background characteristics; 2) the benefits and challenges of using RDTs according to providers; 3) provider experiences with using RDTs, including motivations for using the RDT; 4) adherence to test results, either positive or negative; and, 5) recommendations from informal providers to promote increased use of RDTs in their communities.,This study found that introducing RDTs to informal providers in Myanmar was feasible, resulting in improved provider empowerment and patient-provider relationships.,Specific challenges included facility infrastructure to use and dispose RDTs and provider knowledge.,This varied across the type of informal provider, with itinerant drug vendors more comfortable and knowledgeable about RDTs compared to general retail sellers and medical drug representatives.,This study found informal providers in Myanmar found the introduction of RDTs to be highly acceptable.,Providers discussed improvement in service quality including provider empowerment and patient-provider relationships.,The study also highlighted a number of challenges that informal providers face which may be used for future development of interventions.

The present study assessed malaria RDT kits for adequate and correct packaging, design and labelling of boxes and components.,Information inserts were studied for readability and accuracy of information.,Criteria for packaging, design, labelling and information were compiled from Directive 98/79 of the European Community (EC), relevant World Health Organization (WHO) documents and studies on end-users' performance of RDTs.,Typography and readability level (Flesch-Kincaid grade level) were assessed.,Forty-two RDT kits from 22 manufacturers were assessed, 35 of which had evidence of good manufacturing practice according to available information (i.e.,CE-label affixed or inclusion in the WHO list of ISO13485:2003 certified manufacturers).,Shortcomings in devices were (i) insufficient place for writing sample identification (n = 40) and (ii) ambiguous labelling of the reading window (n = 6).,Buffer vial labels were lacking essential information (n = 24) or were of poor quality (n = 16).,Information inserts had elevated readability levels (median Flesch Kincaid grade 8.9, range 7.1 - 12.9) and user-unfriendly typography (median font size 8, range 5 - 10).,Inadequacies included (i) no referral to biosafety (n = 18), (ii) critical differences between depicted and real devices (n = 8), (iii) figures with unrealistic colours (n = 4), (iv) incomplete information about RDT line interpretations (n = 31) and no data on test characteristics (n = 8).,Other problems included (i) kit names that referred to Plasmodium vivax although targeting a pan-species Plasmodium antigen (n = 4), (ii) not stating the identity of the pan-species antigen (n = 2) and (iii) slight but numerous differences in names displayed on boxes, device packages and information inserts.,Three CE labelled RDT kits produced outside the EC had no authorized representative affixed and the shape and relative dimensions of the CE symbol affixed did not comply with the Directive 98/79/EC.,Overall, RDTs with evidence of GMP scored better compared to those without but inadequacies were observed in both groups.,Overall, malaria RDTs showed shortcomings in quality of construction, design and labelling of boxes, device packages, devices and buffers.,Information inserts were difficult to read and lacked relevant information.

Delay in receiving treatment for uncomplicated malaria (UM) is often reported to increase the risk of developing severe malaria (SM), but access to treatment remains low in most high-burden areas.,Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as ‘test-and-treat’ policies administered by community health workers (CHWs).,We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with SM.,A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe Plasmodium falciparum malaria that included information on treatment delay, such as fever duration (inception to 22nd September 2017).,Studies identified included 5 case-control and 8 other observational clinical studies of SM and UM cases.,Risk of bias was assessed using the Newcastle-Ottawa scale, and all studies were ranked as ‘Good’, scoring ≥7/10.,Individual-patient data (IPD) were pooled from 13 studies of 3,989 (94.1% aged <15 years) SM patients and 5,780 (79.6% aged <15 years) UM cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen, and Zambia.,Definitions of SM were standardised across studies to compare treatment delay in patients with UM and different SM phenotypes using age-adjusted mixed-effects regression.,The odds of any SM phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (odds ratio [OR] = 1.33, 95% CI: 1.07-1.64 for a delay of >24 hours versus ≤24 hours; p = 0.009).,Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children, with an OR of 2.79 (95% CI:1.92-4.06; p < 0.001) for a delay of 2-3 days and 5.46 (95% CI: 3.49-8.53; p < 0.001) for a delay of >7 days, compared with receiving treatment within 24 hours from symptom onset.,We estimate that 42.8% of childhood SMA cases and 48.5% of adult SMA cases in the study areas would have been averted if all individuals were able to access treatment within the first day of symptom onset, if the association is fully causal.,In studies specifically recording onset of nonsevere symptoms, long treatment delay was moderately associated with other SM phenotypes (OR [95% CI] >3 to ≤4 days versus ≤24 hours: cerebral malaria [CM] = 2.42 [1.24-4.72], p = 0.01; respiratory distress syndrome [RDS] = 4.09 [1.70-9.82], p = 0.002).,In addition to unmeasured confounding, which is commonly present in observational studies, a key limitation is that many severe cases and deaths occur outside healthcare facilities in endemic countries, where the effect of delayed or no treatment is difficult to quantify.,Our results quantify the relationship between rapid access to treatment and reduced risk of severe disease, which was particularly strong for SMA.,There was some evidence to suggest that progression to other severe phenotypes may also be prevented by prompt treatment, though the association was not as strong, which may be explained by potential selection bias, sample size issues, or a difference in underlying pathology.,These findings may help assess the impact of interventions that improve access to treatment.,In a systematic review and meta-analysis, Andria Mousa and colleagues investigate associations between treatment delays and outcomes in severe malaria.

A detailed understanding of the human infectious reservoir is essential for improving malaria transmission-reducing interventions.,Here we report a multi-regional assessment of population-wide malaria transmission potential based on 1209 mosquito feeding assays in endemic areas of Burkina Faso and Kenya.,Across both sites, we identified 39 infectious individuals.,In high endemicity settings, infectious individuals were identifiable by research-grade microscopy (92.6%; 25/27), whilst one of three infectious individuals in the lowest endemicity setting was detected by molecular techniques alone.,The percentages of infected mosquitoes in the different surveys ranged from 0.05 (4/7716) to 1.6% (121/7749), and correlate positively with transmission intensity.,We also estimated exposure to malaria vectors through genetic matching of blood from 1094 wild-caught bloodfed mosquitoes with that of humans resident in the same houses.,Although adults transmitted fewer parasites to mosquitoes than children, they received more mosquito bites, thus balancing their contribution to the infectious reservoir.,Heterogeneity in the transmission potential of individual hosts is an important feature of malaria.,Here, the authors perform a multi-regional study of the human infectious reservoir in malaria-endemic regions of Burkina Faso and Kenya.

Trichomonas vaginalis is the most common, curable non-viral sexually transmitted infection (STI) worldwide.,Despite this burden of disease, it is not currently a reportable disease in the United States.,Recent advances in the epidemiology, diagnosis, and management of T. vaginalis infection are described in this article.,This includes updated global and U.S. prevalence data in women and men as well as recent epidemiological data in HIV-infected individuals and pregnant women.,Advances in molecular diagnostics are also reviewed, as are data from recent clinical trials regarding the treatment of trichomonas in women.

There is little data on Trichomonas vaginalis infection in Ghana.,This study evaluated the prevalence of trichomoniasis using different diagnostic methods and determined the risk factors for infection in patients.,A structured questionnaire was administered.,Vaginal swabs, urethral swabs and urine specimens were obtained from consenting patients; and the samples processed following standard protocols.,The presence of T. vaginalis was determined using wet mount microscopy and polymerase chain reaction (PCR) as gold standard.,We also assessed the diagnostic performance the JD’s Trichomonas V® rapid antigen test to inform clinical practice.,The PCR assay detected T. vaginalis positivity in 64 of 150 patients (42.6, 95%CI:35.0, 50.6) including all positive samples of wet mount microscopy and JD’s Trichomonas V® test.,Wet mount microscopy showed low sensitivity (31.6%), high specificity (100%), moderate positive predictive value (75.0%), moderate positive likelihood ratio (3.0), and weak agreement (Cohen’s kappa, 0.283) with PCR assay.,The JD’s Trichomonas V® test displayed lower sensitivity (25.0%), specificity (83.3%), and weaker measure of agreement (Cohen’s kappa, 0.233) with PCR.,In multivariate analysis, the strongest independent predictor for T. vaginalis was female gender [adjusted odds ratio (AOR), 24.89; 95% confidence interval (CI): 10.58, 51.21; P-value< 0.001].,Knowledge of STI showed a protective effect against infection with the parasite (AOR, 0.13; 95%CI: 0.07, 0.29; P-value< 0.017).,The sensitivity of wet mount microscopy was low for T. vaginalis screening in our region.,The JD’s Trichomonas V® test should not be considered as an alternative test.,We recommend mandatory PCR assay for confirmation of negative wet mount results.

There is a continuing need for novel approaches to tick control in dogs.,One such approach lies in the ability of lotilaner (Credelio™), an isoxazoline with a rapid onset of action, to provide sustained efficacy against ticks.,Two studies were undertaken to confirm lotilaner’s efficacy, at the minimum dose rate of 20 mg/kg, against the three most common tick species in Europe.,In each of two studies, 16 Beagle dogs, at least 6 months old, were ranked and blocked by tick counts from infestations placed approximately 1 week before treatment.,Within blocks, dogs were randomized to receive either lotilaner flavoured chewable tablets at as close as possible to, but not less than the minimum dose rate of 20 mg/kg, or to be sham-treated controls.,Study 1 assessed lotilaner efficacy against concurrent infestations with 50 (± 6) Rhipicephalus sanguineus and 70 (± 6) Ixodes ricinus; Study 2 infestations were with 50 (± 2) Dermacentor reticulatus.,Infestations were performed on Day -2 with counts on Day 2, 48 (± 2) hours post-treatment.,Post-treatment infestations were performed on Days 7, 14, 21, 28 and 35, and ticks were counted 48 (±2) hours post-infestations.,Efficacy was determined by the percent reduction in mean live tick counts.,Control group infestations for each tick species were adequate for assessing lotilaner efficacy at all assessment times.,On Day 2 no live ticks were found on any lotilaner-treated dog.,For subsequent counts, in Study 1 lotilaner was 100% effective in eliminating live I. ricinus and R. sanguineus on all but two occasions for each tick; on each of those occasions efficacy was sustained at greater than 98.0%.,In Study 2, except for a single unattached live tick found on Day 16, efficacy against D. reticulatus was 100% at every post-treatment assessment.,The high and sustained efficacy against the three common species of ticks in Europe, R. sanguineus, I. ricinus and D. reticulatus, demonstrates that lotilaner can be a valuable tool in the treatment of canine tick infestations.,Lotilaner flavoured chewable tablets were well tolerated and effectiveness was sustained through at least 35 days.,The online version of this article (doi: 10.1186/s13071-017-2477-x) contains supplementary material, which is available to authorized users.,See Additional file 1 for the French translation of the Abstract.

The preventive effect of fluralaner chewable tablets (Bravecto™) against transmission of Babesia canis by Dermacentor reticulatus ticks was evaluated.,Sixteen dogs, tested negative for B. canis by PCR and IFAT, were allocated to two study groups.,On day 0, dogs in one group (n = 8) were treated once orally with a fluralaner chewable tablet according to label recommendations and dogs in the control group (n = 8) remained untreated.,On days 2, 28, 56, 70 and 84, dogs were infested with 50 (±4) B. canis infected D. reticulatus ticks with tick in situ thumb counts 48 ± 4 h post-infestation.,Prior to each infestation, the D. reticulatus ticks were confirmed to harbour B. canis by PCR analysis.,On day 90, ticks were counted and removed from all dogs.,Efficacy against ticks was calculated for each assessment time point.,After treatment, all dogs were physically examined in conjunction with blood collection for PCR every 7 days, blood samples for IFAT were collected every 14 days and the dog’s rectal body temperature was measured thrice weekly.,From dogs displaying symptoms of babesiosis or were PCR positive, a blood smear was taken, and, if positive, dogs were rescue treated and replaced with a replacement dog.,The preventive effect was evaluated by comparing infected dogs in the treated group with infected dogs in the untreated control group.,All control dogs became infected with B. canis, as confirmed by PCR and IFAT.,None of the 8 treated dogs became infected with B. canis, as IFAT and PCR were negative throughout the study until day 112.,Fluralaner chewable tablet was 100 % effective against ticks on days 4, 30, 58, and 90 and an efficacy of 99.6 % and 99.2 % was achieved on day 72 and day 86 after treatment, respectively.,Over the 12-week study duration, a 100 % preventive effect against B. canis transmission was demonstrated.,A single oral administration of fluralaner chewable tablets effectively prevented the transmission of B. canis by infected D. reticulatus ticks over a 12-week period.

IgE specific to worm antigen (SWA) and pre-treatment eosinophil number, are associated with human immunity to re-infection with schistosomes after chemotherapeutic treatment.,Treatment significantly elevates circulating IL-5 24-hr post-treatment of Schistosoma mansoni.,Here we investigate if praziquantel treatment of human schistosomiasis haematobium also boosts circulating IL-5, the immunological and parasitological factors that predispose to this, and the relationship between these and subsequent immunity to post-treatment re-infection.,The relationship between pre-treatment SWA-IgE, eosinophil number and infection intensity and the 24-hr post-treatment IL-5 boost was investigated in a Malian cohort (aged 5-40 yrs), exposed to S. haematobium.,Eotaxin levels were measured at 24-hr post-treatment as a proxy of eosinophil migration.,The relationship between the 24-hr post-treatment IL-5 boost and later eosinophil numbers and SWA-IgE levels (9-wk post-treatment) was examined, then investigated in the context of subsequent levels of re-infection (2-yr post-treatment).,Circulating IL-5 levels increased 24-hr post-treatment and were associated with pre-treatment infection intensity, SWA-IgE levels, eosinophil number, as well as 24-hr post-treatment eotaxin levels. 24-hr IL-5 levels were, in turn, significantly associated with eosinophil number and elevated SWA-IgE 9-wk later.,These SWA-IgE levels were significantly associated with immunity to re-infection.,Early IL-5 production after treatment-induced exposure to S. haematobium worm antigen is positively associated with antigen dose (infection intensity), IgE availability for arming of effector cells at time of treatment and subsequent eosinophil migration response (as indicated by eotaxin levels).,The IL-5 produced is positively associated with increased downstream eosinophil number and increases in specific IgE levels, implicating this cytokine boost and its down-stream consequences in the production and maintenance of IgE, and subsequent re-infection immunity.

Schistosomes are blood-dwelling parasitic helminths which produce eggs in order to facilitate transmission.,Intestinal schistosomes lay eggs in the mesenteries, however, it is unclear how their eggs escape the vasculature to exit the host.,Using a murine model of infection, we reveal that Schistosoma mansoni exploits Peyer's Patches (PP) gut lymphoid tissue as a preferential route of egress for their eggs.,Egg deposition is favoured within PP as a result of their more abundant vasculature.,Moreover, the presence of eggs causes significant vascular remodeling leading to an expanded venule network.,Egg deposition results in a decrease in stromal integrity and lymphoid cellularity, including secretory IgA producing lymphocytes, and the focal recruitment of macrophages.,In mice lacking PP, egg excretion is significantly impaired, leading to greater numbers of ova being entrapped in tissues and consequently, exacerbated morbidity.,Thus, we demonstrate how schistosomes directly facilitate transmission from the host by targeting lymphoid tissue.,For the host, PP-dependency of egg egress represents a trade-off, as limiting potentially life-threatening morbidity is balanced by loss of PP structure and perturbed PP IgA production.

Many subsistence farmers in rural southeastern Tanzania regularly relocate to distant farms in river valleys to tend to crops for several weeks or months each year.,While there, they live in makeshift semi-open structures, usually far from organized health systems and where insecticide-treated nets (ITNs) do not provide adequate protection.,This study evaluated the potential of a recently developed technology, eave ribbons treated with the spatial repellent transfluthrin, for protecting migratory rice farmers in rural southeastern Tanzania against indoor-biting and outdoor-biting mosquitoes.,In the first test, eave ribbons (0.1 m × 24 m each) treated with 1.5% transfluthrin solution were compared to untreated ribbons in 24 randomly selected huts in three migratory communities over 48 nights.,Host-seeking mosquitoes indoors and outdoors were monitored nightly (18.00-07.00 h) using CDC light traps and CO2-baited BG malaria traps, respectively.,The second test compared efficacies of eave ribbons treated with 1.5% or 2.5% transfluthrin in 12 huts over 21 nights.,Finally, 286 farmers were interviewed to assess perceptions about eave ribbons, and their willingness to pay for them.,In the two experiments, when treated eave ribbons were applied, the reduction in indoor densities ranged from 56 to 77% for Anopheles arabiensis, 36 to 60% for Anopheles funestus, 72 to 84% for Culex, and 80 to 98% for Mansonia compared to untreated ribbons.,Reduction in outdoor densities was 38 to 77% against An. arabiensis, 36 to 64% against An. funestus, 63 to 88% against Culex, and 47 to 98% against Mansonia.,There was no difference in protection between the two transfluthrin doses.,In the survey, 58% of participants perceived the ribbons to be effective in reducing mosquito bites.,Ninety per cent were willing to pay for the ribbons, the majority of whom were willing to pay but less than US$2.17 (5000 TZS), one-third of the current prototype cost.,Transfluthrin-treated eave ribbons can protect migratory rice farmers, living in semi-open makeshift houses in remote farms, against indoor-biting and outdoor-biting mosquitoes.,The technology is acceptable to users and could potentially complement ITNs.,Further studies should investigate durability and epidemiological impact of eave ribbons, and the opportunities for improving affordability to users.

Previous studies demonstrated that fewer mosquitoes enter houses which are screened or have closed eaves.,There is little evidence about the effect on malaria infection in humans that changes in house construction may have.,This study examines the impact of protective housing improvements on malaria infection on Bioko Island.,Data from the annual malaria indicator surveys between 2009 and 2012 were used to assess trends in housing characteristics and their effect on RDT confirmed malaria infection in household members.,Odds ratios were adjusted for socio-economic status of the household.22726 children between the ages of 2 and 14 years were tested for P. falciparum.,Prevalence of infection in those living in houses with open eaves was 23.0% compared to 18.8% for those living in houses with closed eaves (OR = 0.81, 95% CI 0.67 - 0.98).,The prevalence of infection for children in screened houses was 9.1% versus 20.1% for those living in unscreened houses (OR = 0.44, 95% CI 0.27 - 0.71).,The proportion of houses with closed eaves increased from 66.0% in 2009 to 74.3% in 2012 (test for trend p = 0.01).,The proportion of screened houses remained unchanged over time at 1.3%.,As a malaria control intervention, house modification has the advantages that it is not affected by the growing threat of insecticide resistance; it protects all household members equally and at all times while indoors; and it offers protection against a number of vector borne diseases.,The study provides evidence in support of efforts to regulate or encourage housing improvements which impede vector access into residences as part of an integrated vector control approach to complement existing measures which have been only partially successful in reducing malaria transmission in some parts of Bioko.

Zambia national survey, administrative, health facility, and special study data were used to assess progress and impact in national malaria control between 2000 and 2008.,Zambia malaria financial support expanded from US$9 million in 2003 to US$ ~40 million in 2008.,High malaria prevention coverage was achieved and extended to poor and rural areas.,Increasing coverage was consistent in time and location with reductions in child (age 6-59 months) parasitemia and severe anemia (53% and 68% reductions, respectively, from 2006 to 2008) and with lower post-neonatal infant and 1-4 years of age child mortality (38% and 36% reductions between 2001/2 and 2007 survey estimates).,Zambia has dramatically reduced malaria transmission, disease, and child mortality burden through rapid national scale-up of effective interventions.,Sustained progress toward malaria elimination will require maintaining high prevention coverage and further reducing transmission by actively searching for and treating infected people who harbor malaria parasites.

Over the past decade malaria intervention coverage has been scaled up across Africa.,However, it remains unclear what overall reduction in transmission is achievable using currently available tools.,We developed an individual-based simulation model for Plasmodium falciparum transmission in an African context incorporating the three major vector species (Anopheles gambiae s.s., An. arabiensis, and An. funestus) with parameters obtained by fitting to parasite prevalence data from 34 transmission settings across Africa.,We incorporated the effect of the switch to artemisinin-combination therapy (ACT) and increasing coverage of long-lasting insecticide treated nets (LLINs) from the year 2000 onwards.,We then explored the impact on transmission of continued roll-out of LLINs, additional rounds of indoor residual spraying (IRS), mass screening and treatment (MSAT), and a future RTS,S/AS01 vaccine in six representative settings with varying transmission intensity (as summarized by the annual entomological inoculation rate, EIR: 1 setting with low, 3 with moderate, and 2 with high EIRs), vector-species combinations, and patterns of seasonality.,In all settings we considered a realistic target of 80% coverage of interventions.,In the low-transmission setting (EIR∼3 ibppy [infectious bites per person per year]), LLINs have the potential to reduce malaria transmission to low levels (<1% parasite prevalence in all age-groups) provided usage levels are high and sustained.,In two of the moderate-transmission settings (EIR∼43 and 81 ibppy), additional rounds of IRS with DDT coupled with MSAT could drive parasite prevalence below a 1% threshold.,However, in the third (EIR = 46) with An. arabiensis prevailing, these interventions are insufficient to reach this threshold.,In both high-transmission settings (EIR∼586 and 675 ibppy), either unrealistically high coverage levels (>90%) or novel tools and/or substantial social improvements will be required, although considerable reductions in prevalence can be achieved with existing tools and realistic coverage levels.,Interventions using current tools can result in major reductions in P. falciparum malaria transmission and the associated disease burden in Africa.,Reduction to the 1% parasite prevalence threshold is possible in low- to moderate-transmission settings when vectors are primarily endophilic (indoor-resting), provided a comprehensive and sustained intervention program is achieved through roll-out of interventions.,In high-transmission settings and those in which vectors are mainly exophilic (outdoor-resting), additional new tools that target exophagic (outdoor-biting), exophilic, and partly zoophagic mosquitoes will be required.,Please see later in the article for the Editors' Summary,Half the world's population is at risk of malaria, and every year nearly one million people-mainly children living in sub-Saharan Africa-die from this mosquito-borne parasitic disease.,Most malarial deaths are caused by Plasmodium falciparum, which is transmitted to people by mainly night-biting Anopheles mosquitoes.,When infected mosquitoes feed on people, they inject sporozoites, a parasitic form that replicates inside human liver cells.,After a few days, the liver cells release “merozoites,” which invade red blood cells where they replicate rapidly before bursting out and infecting more red blood cells.,This increase in the parasitic burden causes malaria's characteristic fever.,Infected red blood cells also release “gametocytes,” which infect mosquitoes when they take a blood meal.,In the mosquito, the gametocytes multiply and develop into sporozoites, thus completing the parasite's life cycle.,Malaria can be prevented by spraying the insides of houses (where most Anopheles species feed and rest) with insecticides (indoor residual spraying, IRS) and by sleeping under bed nets that have been treated with long-lasting insecticides (long-lasting insecticide nets, LLINs).,Mass screening and treatment (MSAT) with effective antimalarial drugs can also reduce malaria transmission.,Early attempts to eradicate malaria (reduce its global incidence to zero) in the 1950s reduced the incidence of malaria to zero in some countries (malaria elimination) and greatly reduced malarial illnesses and deaths in others (malaria control).,However, this eradication program was aborted in the 1970s in part because of emerging drug and insecticide resistance.,Recently, the advent of artemisinin-based combination therapies and new insecticides and the prospect of a malaria vaccine have renewed interest in controlling, eliminating, and ultimately eradicating malaria.,Consequently, in September 2008, the Roll Back Malaria Partnership launched the Global Malaria Action Plan, which aims to reduce malaria deaths to near zero by 2015.,But are the currently available tools for reducing malaria transmission sufficient to control and eliminate malaria in Africa, the continent where most malaria deaths occur?,In this study, the researchers use a new mathematical model of P. falciparum transmission to investigate this question.,The researchers' P. falciparum transmission model consists of “compartments” through which individuals pass as they become infected with parasites, develop immunity, become infectious to mosquitoes, and so on.,The researchers used published data about parasite prevalence (the proportion of the population infected with parasites) and about relevant aspects of mosquito, parasite, and human biology, to estimate the chances of an individual moving between compartments.,Finally, they used the model to explore the impact over 25 years of increased coverage of LLINs, IRS, and MSAT, and of a future vaccine on malaria transmission in six representative African settings.,In a low-transmission setting, 80% coverage with LLINs reduced the parasite prevalence to below 1% in all age groups.,In two moderate-transmission settings, LLIN scale-up alone failed to reach this target but the addition of IRS and MSAT drove the parasite prevalence below 1%.,However, this combination of interventions did not control malaria in a moderate-transmission setting in which a mosquito species that bites and rests outside houses contributes to malaria transmission.,Finally, in two high-transmission settings, parasite prevalence could be driven below 1% only by setting unrealistic coverage targets for existing interventions.,This new mathematical model greatly simplifies the complex dynamics of malaria transmission and includes several assumptions about which there is considerable uncertainty.,The findings of this study are not, therefore, firm predictions of the future of malaria control in specific settings.,Nevertheless, they suggest that it should be possible to make large reductions in malaria transmission and the associated disease burden in Africa over the next 25 years using currently available tools.,Specifically, in regions where transmission is low or moderate and mosquitoes mainly feed indoors, it should be possible to reduce parasite prevalence to less than 1% provided a sustained intervention program is achieved.,Importantly, however, these findings suggest that in regions where malaria transmission is high or where mosquitoes rest and bite outside houses, new approaches will be needed to control and eliminate malaria.,Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000324.,Information is available from the World Health Organization on malaria (in several languages); the 2009 World Malaria Report provides details of the current global malaria situation,The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish),Information is available from the Roll Back Malaria Partnership on its approach to the global control of malaria, including the Global Malaria Action Plan and a fact sheet on malaria in Africa,MedlinePlus provides links to additional information on malaria (in English and Spanish)

Unicellular eukaryotes of the genus Leishmania are collectively responsible for a heterogeneous group of diseases known as leishmaniasis.,The visceral form of leishmaniasis, caused by L. donovani or L. infantum, is a devastating condition, claiming 20,000 to 40,000 lives annually, with particular incidence in some of the poorest regions of the world.,Immunity to Leishmania depends on the development of protective type I immune responses capable of activating infected phagocytes to kill intracellular amastigotes.,However, despite the induction of protective responses, disease progresses due to a multitude of factors that impede an optimal response.,These include the action of suppressive cytokines, exhaustion of specific T cells, loss of lymphoid tissue architecture and a defective humoral response.,We will review how these responses are orchestrated during the course of infection, including both early and chronic stages, focusing on the spleen and the liver, which are the main target organs of visceral Leishmania in the host.,A comprehensive understanding of the immune events that occur during visceral Leishmania infection is crucial for the implementation of immunotherapeutic approaches that complement the current anti-Leishmania chemotherapy and the development of effective vaccines to prevent disease.

Visceral leishmaniasis is associated with atrophy and histological disorganization of splenic compartments.,In this paper, we compared organized and disorganized splenic lymphoid tissue from dogs naturally infected with Leishmania infantum assessing the size of the white pulp compartments, the distribution of T, B and S100+ dendritic cells, using immunohistochemistry and morphometry and the expression of CCR7 and the cytokines, CXCL13, lymphotoxin (LT)-α, LT-β, CCL19, CCL21, TNF-α, IL-10, IFN-γ and TGF-β, using by real time RT-PCR.,The lymphoid follicles and marginal zones were smaller (3.2 and 1.9 times, respectively; Mann-Whitney, P<0.02) in animals with disorganized splenic tissue in comparison to those with organized splenic lymphoid tissue.,In spleens with disorganized lymphoid tissue, the numbers of T cells and S100+ dendritic cells were decreased in the follicles, and the numbers of B cells were reduced in both the follicles and marginal zones.,CXCL13 mRNA expression was lower in animals with disorganized lymphoid tissue (0.5±0.4) compared to those with organized lymphoid tissue (2.7±2.9, both relative to 18S expression, P = 0.01).,These changes in the spleen were associated with higher frequency of severe disease (7/12) in the animals with disorganized than in animals with organized (2/13, Chi-square, P = 0.01) splenic lymphoid tissue.,The data presented herein suggest that natural infection with Leishmania infantum is associated with the impairment of follicular dendritic cells, CXCL13 expression, B cell migration and germinal center formation and associates these changes with severe clinical forms of visceral leishmaniasis.,Furthermore the fact that this work uses dogs naturally infected with Leishmania infantum emphasizes the relevance of the data presented herein for the knowledge on the canine and human visceral leishmaniasis.

Cerebral malaria (CM) is a life-threatening neurological syndrome caused by Plasmodium falciparum infection afflicting mainly children in Africa.,Current pathogenesis models implicate parasite and host-derived factors in impairing brain vascular endothelium (BVE) integrity.,Sequestration of Plasmodium-infected red blood cells (iRBCs) in brain microvessels is a hallmark of CM pathology.,However, the precise mechanisms driving loss of blood-brain barrier (BBB) function with consequent brain injury are still unsettled and it is plausible that distinct pathophysiology trajectories are involved.,Studies in humans and in the mouse model of CM indicate that inflammatory reactions intertwined with microcirculatory and coagulation disturbances induce alterations in vascular permeability and impair BBB integrity.,Yet, the role of BVE as initiator of immune responses against parasite molecules and iRBCs is largely unexplored.,Brain endothelial cells express pattern recognition receptors (PRR) and are privileged sensors of blood-borne infections.,Here, we focus on the hypothesis that innate responses initiated by BVE and subsequent interactions with immune cells are critical to trigger local effector immune functions and induce BBB damage.,Uncovering mechanisms of BVE involvement in sensing Plasmodium infection, recruiting of immune cells and directing immune effector functions could reveal pharmacological targets to promote BBB protection with potential applications in CM clinical management.

The immune responses against helminths have been investigated individually, and it is well-established that infected hosts develop an immunological memory to resist reinfection by the same pathogen.,In contrast, it is poorly understood how the host immune system responds to subsequent infection by unrelated parasites after elimination of the first infection.,We previously reported that infection of mice with Strongyloides venezuelensis induces the accumulation of group 2 innate lymphoid cells (ILC2s) in the lung.,Here, we demonstrated that S. venezuelensis-experienced (Sv-exp) mice became significantly resistant against infection by Nippostrongylus brasiliensis.,N. brasiliensis infection induced enhanced accumulation of ILC2s and eosinophils with increased expressions of mRNA for Th2 cytokines in the lungs of Sv-exp mice.,The resistance was dependent on ILC2s, and eosinophils but not on CD4+ T cells.,Furthermore, pulmonary ILC2s in Sv-exp mice acquired a highly responsive “trained” phenotype; in response to N. brasiliensis infection, they rapidly increased and produced IL-5 and IL-13, which in turn induced the early accumulation of eosinophils in the lungs.,IL-33 was required for the accumulation of ILC2s and the resistance of mice against N. brasiliensis infection but insufficient for the induction of trained ILC2s.,In conclusion, animals infected with one type of lung-migratory nematodes acquire a specific-antigen-independent resistance to another type of lung-migrating nematodes, providing animals with the capacity to protect against sequential infections with various lung-migratory nematodes.

Malaria and intestinal helminths co-infection are major public health problems particularly among school age children in Nigeria.,However the magnitude and possible interactions of these infections remain poorly understood.,This study determined the prevalence, impact and possible interaction of Plasmodium falciparum and intestinal helminths co-infection among school children in rural communities of Kwara State, Nigeria.,Blood, urine and stool samples were collected from 1017 primary school pupils of ages 4-15 years.,Stool samples were processed using both Kato-Katz and formol-ether concentration techniques and microscopically examined for intestinal helminths infection.,Urine samples were analyzed using sedimentation method for Schistosoma haematobium.,Plasmodium falciparum was confirmed by microscopy using thick and thin blood films methods and packed cell volume (PCV) was determined using hematocrit reader.,Univariate analysis and chi-square statistical tests were used to analyze the data.,Overall, 61.2% of all school children had at least an infection of either P. falciparum, S. haematobium, or intestinal helminth.,S. haematobium accounted for the largest proportion (44.4%) of a single infection followed by P. falciparum (20.6%).,The prevalence of malaria and helminth co-infection in the study was 14.4%.,Four species of intestinal helminths were recovered from the stool samples and these were hookworm (22.5%), Hymenolepis species (9.8%), Schistosoma mansoni (2.9%) and Enterobius vermicularis (0.6%).,The mean densities of P. falciparum in children co-infected with S. haematobium and hookworm were higher compared to those infected with P. falciparum only though not statistically significant (p = 0.062).,The age distribution of both S. haematobium (p = 0.049) and hookworm (p = 0.034) infected children were statistically significant with the older age group (10-15 years) recording the highest prevalence of 47.2% and 25% respectively.,Children who were infected with S. haematobium (RR = 1.3) and hookworm (RR = 1.4) have equal chances of being infected with P. falciparum as children with no worm infection.,On the other hand children infected with Hymenolepis spp. (p<0.0001) are more likely to be infected with P. falciparum than Hymenolepis spp. uninfected children (RR = 2.0),These findings suggest that multiple parasitic infections are common in school age children in rural communities of Kwara State Nigeria.,The Hymenolepis spp. induced increase susceptibility to P. falciparum could have important consequences on how concurrent infections affect the expression or pathogenesis of these infections.

Malaria and lymphatic filariasis (LF) continue to cause a considerable public health burden globally and are co-endemic in many regions of sub-Saharan Africa.,These infections are transmitted by the same mosquito species which raises important questions about optimal vector control strategies in co-endemic regions, as well as the effect of the presence of each infection on endemicity of the other; there is currently little consensus on the latter.,The need for comprehensive modelling studies to address such questions is therefore significant, yet very few have been undertaken to date despite the recognised explanatory power of reliable dynamic mathematical models.,Here, we develop a malaria-LF co-infection modelling framework that accounts for two key interactions between these infections, namely the increase in vector mortality as LF mosquito prevalence increases and the antagonistic Th1/Th2 immune response that occurs in co-infected hosts.,We consider the crucial interplay between these interactions on the resulting endemic prevalence when introducing each infection in regions where the other is already endemic (e.g. due to regional environmental change), and the associated timescale for such changes, as well as effects on the basic reproduction number R0 of each disease.,We also highlight potential perverse effects of vector controls on human infection prevalence in co-endemic regions, noting that understanding such effects is critical in designing optimal integrated control programmes.,Hence, as well as highlighting where better data are required to more reliably address such questions, we provide an important framework that will form the basis of future scenario analysis tools used to plan and inform policy decisions on intervention measures in different transmission settings.

The gambiense form of sleeping sickness is a neglected tropical disease, which is presumed to be anthroponotic.,However, the parasite persists in human populations at levels of considerable rarity and as such the existence of animal reservoirs has been posited.,Clarifying the impact of animal host reservoirs on the feasibility of interrupting sleeping sickness transmission through interventions is a matter of urgency.,We developed a mathematical model allowing for heterogeneous exposure of humans to tsetse, with animal populations that differed in their ability to transmit infections, to investigate the effectiveness of two established techniques, screening and treatment of at-risk populations, and vector control.,Importantly, under both assumptions, an integrated approach of human screening and vector control was supported in high transmission areas.,However, increasing the intensity of vector control was more likely to eliminate transmission, while increasing the intensity of human screening reduced the time to elimination.,Non-human animal hosts played important, but different roles in HAT transmission, depending on whether or not they contributed as reservoirs.,If they did not serve as reservoirs, sensitivity analyses suggested their attractiveness may instead function as a sink for tsetse bites.,These outcomes highlight the importance of understanding the ecological and environmental context of sleeping sickness in optimizing integrated interventions, particularly for moderate and low transmission intensity settings.

Maintaining adequate supplies of anti-malarial medicines at the health facility level in rural sub-Saharan Africa is a major barrier to effective management of the disease.,Lack of visibility of anti-malarial stock levels at the health facility level is an important contributor to this problem.,A 21-week pilot study, 'SMS for Life', was undertaken during 2009-2010 in three districts of rural Tanzania, involving 129 health facilities.,Undertaken through a collaborative partnership of public and private institutions, SMS for Life used mobile telephones, SMS messages and electronic mapping technology to facilitate provision of comprehensive and accurate stock counts from all health facilities to each district management team on a weekly basis.,The system covered stocks of the four different dosage packs of artemether-lumefantrine (AL) and quinine injectable.,Stock count data was provided in 95% of cases, on average.,A high response rate (≥ 93%) was maintained throughout the pilot.,The error rate for composition of SMS responses averaged 7.5% throughout the study; almost all errors were corrected and messages re-sent.,Data accuracy, based on surveillance visits to health facilities, was 94%.,District stock reports were accessed on average once a day.,The proportion of health facilities with no stock of one or more anti-malarial medicine (i.e. any of the four dosages of AL or quinine injectable) fell from 78% at week 1 to 26% at week 21.,In Lindi Rural district, stock-outs were eliminated by week 8 with virtually no stock-outs thereafter.,During the study, AL stocks increased by 64% and quinine stock increased 36% across the three districts.,The SMS for Life pilot provided visibility of anti-malarial stock levels to support more efficient stock management using simple and widely available SMS technology, via a public-private partnership model that worked highly effectively.,The SMS for Life system has the potential to alleviate restricted availability of anti-malarial drugs or other medicines in rural or under-resourced areas.

During a longitudinal study investigating the dynamics of malaria in Ugandan lakeshore communities, a consistently high malaria prevalence was observed in young children despite regular treatment.,To explore the short-term performance of artemether-lumefantrine (AL), a pilot investigation into parasite carriage after treatment(s) was conducted in Bukoba village.,A total of 163 children (aged 2-7 years) with a positive blood film and rapid antigen test were treated with AL; only 8·7% of these had elevated axillary temperatures.,On day 7 and then on day 17, 40 children (26·3%) and 33 (22·3%) were positive by microscopy, respectively.,Real-time PCR analysis demonstrated that multi-species Plasmodium infections were common at baseline, with 41·1% of children positive for Plasmodium falciparum/Plasmodium malariae, 9·2% for P. falciparum/ Plasmodium ovale spp. and 8·0% for all three species.,Moreover, on day 17, 39·9% of children infected with falciparum malaria at baseline were again positive for the same species, and 9·2% of those infected with P. malariae at baseline were positive for P. malariae.,Here, chronic multi-species malaria infections persisted in children after AL treatment(s).,Better point-of-care diagnostics for non-falciparum infections are needed, as well as further investigation of AL performance in asymptomatic individuals.

Asymptomatic parasitemia is common among schoolchildren living in areas of high malaria transmission, yet little is known about its effect on cognitive function in these settings.,To investigate associations between asymptomatic parasitemia, anemia, and cognition among primary schoolchildren living in a high malaria transmission setting, we studied 740 children enrolled in a clinical trial in Tororo, Uganda.,Parasitemia, measured by thick blood smears, was present in 30% of the children.,Infected children had lower test scores for abstract reasoning (adjusted mean difference [AMD] −0.6, 95% confidence interval [CI] −1.01 to −0.21) and sustained attention (AMD −1.6 95% CI −2.40 to −0.81) compared with uninfected children.,There was also evidence for a dose-response relationship between parasite density and scores for sustained attention.,No associations were observed between anemia and either test of cognition.,Schoolchildren in high transmission settings may experience cognitive benefits, from interventions aimed at reducing the prevalence of asymptomatic parasitemia.

It is the aim of the World Health Organisation to eliminate soil-transmitted helminths (STH) as a health problem in children.,To this end, the goal is to increase anthelmintic treatment coverage for soil transmitted helminths to reach 75 % in pre-school aged and school aged children by 2020 in endemic countries.,In this paper, we use mathematical models to investigate the impact of achieving this goal on the burdens of Ascaris lumbricoides, Trichuris trichuria and hookworm.,We employ a deterministic fully age-structured model of STH transmission and mass drug administration to examine the changes in worm burden in response to the known and projected coverage trends in children up to 2020 and beyond.,Parameters are estimated from worm expulsion data and age intensity profiles before treatment using maximum likelihood methods.,Model validation is performed using reinfection studies for Ascaris and analyses are conducted to assess the sensitivity of the predicted outcomes to variation in parameter estimates including transmission intensity (R0), children’s contributions to the pool of infective stages and drug coverage levels.,The impact of the required increase in coverage trends are quite different across the three species.,Ascaris burdens are reduced dramatically by 2020 with elimination predicted within studied the setting a further 10 years.,For Trichuris and hookworm, however, impact is more limited, due to issues of drug efficacy (Trichuris) and distribution of worms in the population (hookworm).,Sensitivity analysis indicates that results are largely robust.,However, validation against Ascaris data indicates that assumptions concerning re-infection among children may have to be revised.,The 2020 coverage target is predicted to have a major impact on Ascaris levels by 2020.,However, there is evidence from model validation that Ascaris in children is more resilient to treatment than currently assumed in the model.,Broader coverage across all age classes is required to break transmission for hookworm and alternative dual drug treatment approaches are needed for Trichuris.,The online version of this article (doi:10.1186/s13071-015-1135-4) contains supplementary material, which is available to authorized users.

There are remarkably few contemporary, population-based studies of intestinal nematode infection for sub-Saharan Africa.,This paper presents a comprehensive epidemiological analysis of hookworm infection intensity in a rural Ugandan community.,Demographic, kinship, socioeconomic and environmental data were collected for 1,803 individuals aged six months to 85 years in 341 households in a cross-sectional community survey.,Hookworm infection was assessed by faecal egg count.,Spatial variation in the intensity of infection was assessed using a Bayesian negative binomial spatial regression model and the proportion of variation explained by host additive genetics (heritability) and common domestic environment was estimated using genetic variance component analysis.,Overall, the prevalence of hookworm was 39.3%, with the majority of infections (87.7%) of light intensity (≤1000 eggs per gram faeces).,Intensity was higher among older individuals and was associated with treatment history with anthelmintics, walking barefoot outside the home, living in a household with a mud floor and education level of the household head.,Infection intensity also exhibited significant household and spatial clustering: the range of spatial correlation was estimated to be 82 m and was reduced by a half over a distance of 19 m.,Heritability of hookworm egg count was 11.2%, whilst the percentage of variance explained by unidentified domestic effects was 17.8%.,In conclusion, we suggest that host genetic relatedness is not a major determinant of infection intensity in this community, with exposure-related factors playing a greater role.

Visceral leishmaniasis, caused by Leishmania infantum, is a neglected tropical disease, to which efforts in the innovation of effective and affordable treatments remain limited, despite the rising incidence in several regions of the world.,In this work, the antileishmanial effects of sugiol were investigated in vitro.,This compound was isolated from the bark of Cupressus lusitanica and showed promising activity against L. infantum.,In spite of the positive results, it is known that the compound is a poorly water-soluble diterpene molecule, which hinders further investigation, especially in preclinical animal studies.,Thus, in an alternative delivery method, sugiol was entrapped in glucan-rich particles obtained from Saccharomyces cerevisiae yeast cell walls (YCWPs).,To evaluate the activity of sugiol, the experiments were divided into two parts: (i) the in vitro investigation of antileishmanial activity of free sugiol against L. infantum promastigotes after 24, 48, and 72 h of treatment and (ii) the evaluation of antileishmanial activity of sugiol entrapped in glucan-rich particles against intracellular L. infantum amastigotes.,Free sugiol induced the cell-death process in promastigotes, which was triggered by enhancing cytosolic calcium level and promoting the autophagy up to the first 24 h.,Over time, the presence of autophagic vacuoles became rarer, especially after treatment with lower concentrations of sugiol, but other cellular events intensified, like ROS production, cell shrinkage, and phosphatidylserine exposure.,Hyperpolarization of mitochondrial membrane potential was found at 72 h, induced by the mitochondria calcium uptake, causing an increase in ROS production and lipid peroxidation as a consequence.,These events resulted in the cell death of promastigotes by secondary necrosis.,Sugiol entrapped in glucan-rich particles was specifically recognized by dectin-1 receptor on the plasma membrane of macrophages, the main host cell of Leishmania spp.,Electron micrographs revealed particles containing sugiol within the infected macrophages and these particles were active against the intracellular L. infantum amastigotes without affecting the host cell.,Therefore, the YCWPs act like a Trojan horse to successfully deliver sugiol into the macrophage, presenting an interesting strategy to deliver water-insoluble drugs to parasitized cells.

Especially in tropical and developing countries, the clinically relevant protozoa Trypanosoma cruzi (Chagas disease), Trypanosoma brucei (sleeping sickness) and Leishmania species (leishmaniasis) stand out and infect millions of people worldwide leading to critical social-economic implications.,Low-income populations are mainly affected by these three illnesses that are neglected by the pharmaceutical industry.,Current anti-trypanosomatid drugs present variable efficacy with remarkable side effects that almost lead to treatment discontinuation, justifying a continuous search for alternative compounds that interfere with essential and specific parasite pathways.,In this scenario, the triggering of trypanosomatid cell death machinery emerges as a promising approach, although the exact mechanisms involved in unicellular eukaryotes are still unclear as well as the controversial biological importance of programmed cell death (PCD).,In this review, the mechanisms of autophagy, apoptosis-like cell death and necrosis found in pathogenic trypanosomatids are discussed, as well as their roles in successful infection.,Based on the published genomic and proteomic maps, the panel of trypanosomatid cell death molecules was constructed under different experimental conditions.,The lack of PCD molecular regulators and executioners in these parasites up to now has led to cell death being classified as an unregulated process or incidental necrosis, despite all morphological evidence published.,In this context, the participation of metacaspases in PCD was also not described, and these proteases play a crucial role in proliferation and differentiation processes.,On the other hand, autophagic phenotype has been described in trypanosomatids under a great variety of stress conditions (drugs, starvation, among others) suggesting that this process is involved in the turnover of damaged structures in the protozoa and is not a cell death pathway.,Death mechanisms of pathogenic trypanosomatids may be involved in pathogenesis, and the identification of parasite-specific regulators could represent a rational and attractive alternative target for drug development for these neglected diseases.

Control of schistosomiasis presently relies largely on preventive chemotherapy with praziquantel through mass drug administration (MDA) programs.,The Schistosomiasis Consortium for Operational Research and Evaluation has concluded five studies in four countries (Côte d’Ivoire, Kenya, Mozambique, and Tanzania) to evaluate alternative approaches to MDA.,Studies involved four intervention years, with final evaluation in the fifth year.,Mass drug administration given annually or twice over 4 years reduced average prevalence and intensity of schistosome infections, but not all villages that were treated in the same way responded similarly.,There are multiple ways by which responsiveness to MDA, or the lack thereof, could be measured.,In the analyses presented here, we defined persistent hotspots (PHS) as villages that achieved less than 35% reduction in prevalence and/or less than 50% reduction in infection intensity after 4 years of either school-based or community-wide MDA, either annually or twice in 4 years.,By this definition, at least 30% of villages in each of the five studies were PHSs.,We found no consistent relationship between PHSs and the type or frequency of intervention, adequacy of reported MDA coverage, and prevalence or intensity of infection at baseline.,New research is warranted to identify PHSs after just one or a few rounds of MDA, and new adaptive strategies need to be advanced and validated for turning PHSs into responder villages.

Programs for schistosomiasis control are advancing worldwide, with many benefits noted in terms of disease reduction.,Yet risk of reinfection and recurrent disease remain, even in areas with high treatment coverage.,In the search for means to better prevent new Schistosoma infections, attention has returned to an older strategy for transmission control, i.e., chemical mollusciciding, to suppress intermediate host snail species responsible for S. mansoni and S. haematobium transmission.,The objective of this systematic review and meta-analysis was to summarize prior experience in molluscicide-based control of Bulinus and Biomphalaria spp. snails, and estimate its impact on local human Schistosoma infection.,The review was registered at inception with PROSPERO (CRD42013006869).,Studies were identified by online database searches and hand searches of private archives.,Eligible studies included published or unpublished mollusciciding field trials performed before January 2014 involving host snails for S. mansoni or S. haematobium, with a primary focus on the use of niclosamide.,Among 63 included papers, there was large variability in terms of molluscicide dosing, and treatment intervals varied from 3-52 weeks depending on location, water source, and type of application.,Among 35 studies reporting on prevalence, random effects meta-analysis indicated that, on average, odds of infection were reduced 77% (OR 0.23, CI95% 0.17, 0.31) during the course of mollusciciding, with increased impact if combined with drug therapy, and progressively greater impact over time.,In 17 studies reporting local incidence, risk of new infection was reduced 64% (RR 0.36 CI95% 0.25, 0.5), but additional drug treatment did not appear to influence incidence effects.,While there are hurdles to implementing molluscicide control, its impact on local transmission is typically strong, albeit incomplete.,Based on past experience, regular focal mollusciciding is likely to contribute significantly to the move toward elimination of schistosomiasis in high risk areas.