Datasets:

GleghornLab

/

abstract_domain_parasitic

like 0

The World Health Organization targeted Trypanosoma brucei gambiense human African trypanosomiasis (gHAT) for elimination as a public health problem and for elimination of transmission.,To measure gHAT elimination success with prevalences close to zero, highly specific diagnostics are necessary.,Such a test exists in the form of an antibody-mediated complement lysis test, the trypanolysis test, but biosafety issues and technological requirements prevent its large-scale use.,We developed an inhibition ELISA with high specificity and sensitivity that is applicable in regional laboratories in gHAT endemic countries.,The T. b. gambiense inhibition ELISA (g-iELISA) is based on the principle that binding of monoclonal antibodies to specific epitopes of T. b. gambiense surface glycoproteins can be inhibited by circulating antibodies of gHAT patients directed against the same epitopes.,Using trypanolysis as reference test, the diagnostic accuracy of the g-iELISA was evaluated on plasma samples from 739 gHAT patients and 619 endemic controls and on dried blood spots prepared with plasma of 95 gHAT and 37 endemic controls.,Overall sensitivity and specificity on plasma were, respectively, 98.0% (95% CI 96.7-98.9) and 99.5% (95% CI 98.6-99.9).,With dried blood spots, sensitivity was 92.6% (95% CI 85.4-97.0), and specificity was 100% (95% CI 90.5-100.0).,The g-iELISA is stable for at least 8 months when stored at 2-8°C.,The g-iELISA might largely replace trypanolysis for monitoring gHAT elimination and for postelimination surveillance.,The g-iELISA kit is available for evaluation in reference laboratories in endemic countries.,The novel Trypanosoma brucei gambiense inhibition ELISA (g-iELISA) is a high-throughput diagnostic applicable in regional laboratories for monitoring gambiense-HAT elimination.,On plasma samples, sensitivity was 98.0% and specificity 99.5%, while on dried blood spots sensitivity was 92.6% and specificity 100%.

Following World Health Assembly resolutions 50.36 in 1997 and 56.7 in 2003, the World Health Organization (WHO) committed itself to supporting human African trypanosomiasis (HAT)-endemic countries in their efforts to remove the disease as a public health problem.,Mapping the distribution of HAT in time and space has a pivotal role to play if this objective is to be met.,For this reason WHO launched the HAT Atlas initiative, jointly implemented with the Food and Agriculture Organization of the United Nations, in the framework of the Programme Against African Trypanosomosis.,The distribution of HAT is presented for 23 out of 25 sub-Saharan countries having reported on the status of sleeping sickness in the period 2000 - 2009.,For the two remaining countries, i.e.,Angola and the Democratic Republic of the Congo, data processing is ongoing.,Reports by National Sleeping Sickness Control Programmes (NSSCPs), Non-Governmental Organizations (NGOs) and Research Institutes were collated and the relevant epidemiological data were entered in a database, thus incorporating (i) the results of active screening of over 2.2 million people, and (ii) cases detected in health care facilities engaged in passive surveillance.,A total of over 42 000 cases of HAT and 6 000 different localities were included in the database.,Various sources of geographic coordinates were used to locate the villages of epidemiological interest.,The resulting average mapping accuracy is estimated at 900 m.,Full involvement of NSSCPs, NGOs and Research Institutes in building the Atlas of HAT contributes to the efficiency of the mapping process and it assures both the quality of the collated information and the accuracy of the outputs.,Although efforts are still needed to reduce the number of undetected and unreported cases, the comprehensive, village-level mapping of HAT control activities over a ten-year period ensures a detailed and reliable representation of the known geographic distribution of the disease.,Not only does the Atlas serve research and advocacy, but, more importantly, it provides crucial evidence and a valuable tool for making informed decisions to plan and monitor the control of sleeping sickness.

Microtubules are cytoskeletal filaments essential for many cellular processes, including establishment and maintenance of polarity, intracellular transport, division and migration.,In most metazoan cells, the number and length of microtubules are highly variable, while they can be precisely defined in some protozoan organisms.,However, in either case the significance of these two key parameters for cells is not known.,Here, we quantitatively studied the impact of modulating microtubule number and length in Plasmodium, the protozoan parasite causing malaria.,Using a gene deletion and replacement strategy targeting one out of two α‐tubulin genes, we show that chromosome segregation proceeds in the oocysts even in the absence of microtubules.,However, fewer and shorter microtubules severely impaired the formation, motility and infectivity of Plasmodium sporozoites, the forms transmitted by the mosquito, which usually contain 16 microtubules.,We found that α‐tubulin expression levels directly determined the number of microtubules, suggesting a high nucleation barrier as supported by a mathematical model.,Infectious sporozoites were only formed in parasite lines featuring at least 10 microtubules, while parasites with 9 or fewer microtubules failed to transmit.

Asexual stage Plasmodium falciparum replicates and undergoes a tightly regulated developmental process in human erythrocytes.,One mechanism involved in the regulation of this process is posttranslational modification (PTM) of parasite proteins.,Palmitoylation is a PTM in which cysteine residues undergo a reversible lipid modification, which can regulate target proteins in diverse ways.,Using complementary palmitoyl protein purification approaches and quantitative mass spectrometry, we examined protein palmitoylation in asexual-stage P. falciparum parasites and identified over 400 palmitoylated proteins, including those involved in cytoadherence, drug resistance, signaling, development, and invasion.,Consistent with the prevalence of palmitoylated proteins, palmitoylation is essential for P. falciparum asexual development and influences erythrocyte invasion by directly regulating the stability of components of the actin-myosin invasion motor.,Furthermore, P. falciparum uses palmitoylation in diverse ways, stably modifying some proteins while dynamically palmitoylating others.,Palmitoylation therefore plays a central role in regulating P. falciparum blood stage development.,► A global approach identified >400 palmitoylated proteins in Plasmodium falciparum ► Palmitoyl proteins are central to invasion and other virulence-associated processes ► Palmitoylation is required for completion of the P. falciparum asexual life cycle ► P. falciparum uses palmitoylation dynamically for diverse regulatory purposes

Insecticide-treated nets (ITNs) are the primary tool for malaria vector control in sub-Saharan Africa, and have been responsible for an estimated two-thirds of the reduction in the global burden of malaria in recent years.,While the ultimate goal is high levels of ITN use to confer protection against infected mosquitoes, it is widely accepted that ITN use must be understood in the context of ITN availability.,However, despite nearly a decade of universal coverage campaigns, no country has achieved a measured level of 80% of households owning 1 ITN for 2 people in a national survey.,Eighty-six public datasets from 33 countries in sub-Saharan Africa (2005-2017) were used to explore the causes of failure to achieve universal coverage at the household level, understand the relationships between the various ITN indicators, and further define their respective programmatic utility.,The proportion of households owning 1 ITN for 2 people did not exceed 60% at the national level in any survey, except in Uganda’s 2014 Malaria Indicator Survey (MIS).,At 80% population ITN access, the expected proportion of households with 1 ITN for 2 people is only 60% (p = 0.003 R2 = 0.92), because individuals in households with some but not enough ITNs are captured as having access, but the household does not qualify as having 1 ITN for 2 people.,Among households with 7-9 people, mean population ITN access was 41.0% (95% CI 36.5-45.6), whereas only 6.2% (95% CI 4.0-8.3) of these same households owned at least 1 ITN for 2 people.,On average, 60% of the individual protection measured by the population access indicator is obscured when focus is put on the household “universal coverage” indicator.,The practice of limiting households to a maximum number of ITNs in mass campaigns severely restricts the ability of large households to obtain enough ITNs for their entire family.,The two household-level indicators-one representing minimal coverage, the other only ‘universal’ coverage-provide an incomplete and potentially misleading picture of personal protection and the success of an ITN distribution programme.,Under current ITN distribution strategies, the global malaria community cannot expect countries to reach 80% of households owning 1 ITN for 2 people at a national level.,When programmes assess the success of ITN distribution activities, population access to ITNs should be considered as the better indicator of “universal coverage,” because it is based on people as the unit of analysis.,The online version of this article (10.1186/s12936-018-2505-0) contains supplementary material, which is available to authorized users.

Mass drug administration (MDA) using dihydroartemisinin plus piperaquine (DHAp) represents a potential strategy to clear Plasmodium falciparum infections and reduce the human parasite reservoir.,A cluster-randomized controlled trial in Southern Province, Zambia, was used to assess the short-term impact of 2 rounds of community-wide MDA and household-level (focal) MDA with DHAp compared with no mass treatment.,Study end points included parasite prevalence in children, infection incidence, and confirmed malaria case incidence.,All end points significantly decreased after intervention, irrespective of treatment group.,Parasite prevalence from 7.71% at baseline to 0.54% after MDA in lower-transmission areas, resulting in an 87% reduction compared with control (adjusted odds ratio, 0.13; 95% confidence interval, .02-.92;P = .04).,No difference between treatment groups was observed in areas of high transmission.,The 5-month cumulative infection incidence was 70% lower (crude incidence rate ratio, 0.30; 95% confidence interval, .06-1.49; P = .14) and 58% lower (0.42; .18-.98;P = .046) after MDA compared with control in lower- and higher-transmission areas, respectively.,No significant impact of focal MDA was observed for any end point.,Two rounds of MDA with DHAp rapidly reduced infection prevalence, infection incidence, and confirmed case incidence rates, especially in low-transmission areas.,NCT02329301.

Leishmania infantum causes potentially life-threatening disease in humans.,To determine the extent of the animal reservoir for this pathogen in Bosnia and Herzegovina, we tested dogs and cats.,We found that a large proportion of dogs were exposed to or infected with L. infantum, indicating endemicity in dogs and zoonotic risk for humans.

As part of a World Health Organization-led effort to update the empirical evidence base for the leishmaniases, national experts provided leishmaniasis case data for the last 5 years and information regarding treatment and control in their respective countries and a comprehensive literature review was conducted covering publications on leishmaniasis in 98 countries and three territories (see ‘Leishmaniasis Country Profiles Text S1, S2, S3, S4, S5, S6, S7, S8, S9, S10, S11, S12, S13, S14, S15, S16, S17, S18, S19, S20, S21, S22, S23, S24, S25, S26, S27, S28, S29, S30, S31, S32, S33, S34, S35, S36, S37, S38, S39, S40, S41, S42, S43, S44, S45, S46, S47, S48, S49, S50, S51, S52, S53, S54, S55, S56, S57, S58, S59, S60, S61, S62, S63, S64, S65, S66, S67, S68, S69, S70, S71, S72, S73, S74, S75, S76, S77, S78, S79, S80, S81, S82, S83, S84, S85, S86, S87, S88, S89, S90, S91, S92, S93, S94, S95, S96, S97, S98, S99, S100, S101’).,Additional information was collated during meetings conducted at WHO regional level between 2007 and 2011.,Two questionnaires regarding epidemiology and drug access were completed by experts and national program managers.,Visceral and cutaneous leishmaniasis incidence ranges were estimated by country and epidemiological region based on reported incidence, underreporting rates if available, and the judgment of national and international experts.,Based on these estimates, approximately 0.2 to 0.4 cases and 0.7 to 1.2 million VL and CL cases, respectively, occur each year.,More than 90% of global VL cases occur in six countries: India, Bangladesh, Sudan, South Sudan, Ethiopia and Brazil.,Cutaneous leishmaniasis is more widely distributed, with about one-third of cases occurring in each of three epidemiological regions, the Americas, the Mediterranean basin, and western Asia from the Middle East to Central Asia.,The ten countries with the highest estimated case counts, Afghanistan, Algeria, Colombia, Brazil, Iran, Syria, Ethiopia, North Sudan, Costa Rica and Peru, together account for 70 to 75% of global estimated CL incidence.,Mortality data were extremely sparse and generally represent hospital-based deaths only.,Using an overall case-fatality rate of 10%, we reach a tentative estimate of 20,000 to 40,000 leishmaniasis deaths per year.,Although the information is very poor in a number of countries, this is the first in-depth exercise to better estimate the real impact of leishmaniasis.,These data should help to define control strategies and reinforce leishmaniasis advocacy.

White blood cells count (WBCc) is a bedrock in the estimation of malaria parasite density in malaria field trials, interventions and patient management.,White blood cells are indirectly and relatively used in microscopy to estimate the density of malaria parasite infections.,Due to frequent lack of facilities in some malaria-endemic countries, in order to quantify WBCc of patients, an assumed WBCc of 8.0 X 10(9)/L has been set by the World Health Organization to help in estimating malaria parasite densities.,This comparative analysis study, in Central Ghana, compiled laboratory data of 5,902 Plasmodium falciparum malaria parasite positive samples.,Samples were obtained from consented participants of age groups less than five years.,Full blood counts (FBC) of participants’ samples were analysed using the ABX Micros 60 Haematology Analyzer.,Blood slides were read by two competent microscopists to produce concordant results.,All internal and external quality control measures were carried out appropriately.,Parasite densities were calculated using participants’ absolute WBCc and assumed WBCc of 5,000 to 10,000 per microlitre of blood.,From the 5,902 Pf malaria positive samples, the mean (SD) WBCc and geometric mean parasite density were 10.4 (4.6) × 10(9)/L and 7,557/μL (95 % CI 7,144/μL to 7,994/μL) respectively.,The difference in the geometric mean parasite densities calculated using absolute WBCs and compared to densities with assumed WBCs counts were significantly lower for 5.0 × 10(9)/L; 3,937/μL, 6.0 × 10(9)/L; 4,725/μL and 8.0 × 10(9)/L; 6,300/μL.,However, the difference in geometric mean parasite density, 7,874/μL (95 % CI, 7,445/μL to 8,328/μL), with assumed WBCc of 10.0 × 10(9)/L was not significant.,Using the assumed WBCc of 8.0 X 10(9)/L or lower to estimate malaria parasite densities in Pf infected children less than five years old could result in significant underestimation of parasite burden.,Assumed WBCc of 10.0 × 10(9)/L at 95 % CI of geometric mean of parasite density statistically agreed with the parasite densities produce by the absolute WBCc of participants.,The study suggests where resources are limited, use of assumed WBCc of 10.0 × 10(9)/L of blood to estimate malaria parasite density in central Ghana.,Preferably, absolute WBCc should be used in drug efficacy and vaccine trials.

Prevalence of placental malaria has been widely used as a standard indicator to characterize malaria infection in epidemiologic surveys.,Placental malaria poses a greater diagnostic challenge, accurate and sensitive diagnostic tool for malaria infections in pregnancy is needed.,A cross sectional study was conducted at Medani Hospital, which serves catchment area which is characterized by unstable malaria transmission.,One hundred and seven placentae were investigated for malaria infection using polymerase chain reaction (PCR) and histology.,out of 107 investigated placentae, 33 (30.8%) and 34 (31.8%) were positive for malaria by histology (two (2%) and 31(29.0%) were acute and past infections, respectively) and PCR, respectively.,Out of 33 positive by histology, 15 were positive by the PCR while 18 were negative.,The sensitivity of the PCR was 45.5% (95% CI: 29.2%- 62.5%).,Out of 74 which were negative by histology, 19 were positive by the PCR.,This is translated in specificity of 74.3% (95% CI: 63.5%- 83.3%).,Of those tested positive by the PCR, 15 were positive by the histology, while 19 were negative.,This is translated into a positive predictive value of 44.1% (95% CI: 28.3%- 61.0%).,Of those 73 tested negative by the PCR, 55 were negative according to histology while 23 were positive.,This is translated into a negative predictive value of 75.3% (95% CI: 64.5%-84.2%).,PCR had low sensitivity and specificity in comparison to placental histology, perhaps because the vast majority of the placental infections were past infections.,Further research is needed.

Intestinal parasitic infections are posing significant morbidity worldwide.,In Ethiopia, due to poor socio-economic status, intestinal parasitic infections are highly prevalent.,The main aim of this study was to determine the prevalence of intestinal parasites and its associated risk factors among Yadot primary school children which is found in South-Eastern part of Ethiopia, in the district called Delo-Mena.,Institution based cross-sectional study was employed from March to April 2013.,In this study, a total of 340 students were selected using simple random sampling, and data on socio-demographic characteristics and factors associated with the prevalence of intestinal parasites as well as stool samples were collected and processed accordingly.,Statistical analysis was done using SPSS version 16, and binary and multivariate logistic regression analysis were conducted to measure the strength of association between dependent and independent variables.,The overall prevalence of intestinal parasites was 26.2%.,Poly-parasitism was detected in 6.2% of the students.,Consistently, students who were infected with single, double, triple and quadruple parasites were 20%, 4.7%, 1.2% and 0.3% respectively.,In line with this, the most prevalent parasites were Schistosoma mansoni 12.6%, followed by Entamoeba histolytica/dispar 5%, Ascaris lumbricoides 4.7%, and Hymenolepis nana 4.4%.,Regarding the risk factors for the infections, not knowing why they wash their hands before meal [(AOR = 0.20, 95% CI = 0.10-0.40), p < 0.001], water contact activities [(AOR = 2.28, 95% CI = 1.19-4.34), p = 0.012], not wearing protective shoe [(AOR = 0.27, 95% CI = 0.15-0.51), p < 0.001] were factors significantly associated with intestinal parasitic infections.,Intestinal parasitic infections were found to be highly prevalent among Yadot primary school children.,Hence, health education, improving sanitation, provision of safe drinking water, increasing latrine use, snail control and deworming to the students are crucial.

Intestinal schistosomiasis is widely distributed around Lake Victoria in Kenya where about 16 million people in 56 districts are at risk of the infection with over 9.1 million infected.,Its existence in rural settings has been extensively studied compared to urban settings where there is limited information about the disease coupled with low level of awareness.,This study therefore assessed community awareness on existence, signs and symptoms, causes, transmission, control and risk factors for contracting schistosomiasis as well as attitudes, health seeking behaviour and environmental antecedents that affect its control so as to identify knowledge gaps that need to be addressed in order to strengthen schistosomiasis control interventions in informal urban settings.,The study was carried out in an informal urban settlement where the prevalence of intestinal schistosomiasis was previously reported to be the highest (36%) among the eight informal settlements of Kisumu city.,The study adopted cross-sectional design and purposive sampling technique.,Eight focus group discussions were conducted with adult community members and eight key informant interviews with opinion leaders.,Data was audio recorded transcribed, coded and thematically analyzed using ATLAS.ti version 6 software.,Most respondents stated having heard about schistosomiasis but very few had the correct knowledge of signs and symptoms, causes, transmission and control of schistosomiasis.,However, there was moderate knowledge of risk factors and at high risk groups.,Their attitudes towards schistosomiasis and its control were generally indifferent with a general belief that they had no control over their environmental circumstances to reduce transmission.,Although schistosomiasis was prevalent in the study area, majority of the people in the community had low awareness.,This study, therefore, stresses the need for health education to raise community's awareness on schistosomiasis in such settings in order to augment prevention, control and elimination efforts.

Long-lasting insecticidal nets (LLINs) and indoor residual spraying of insecticide (IRS) are the primary vector control interventions used to prevent malaria in Africa.,Although both interventions are effective in some settings, high-quality evidence is rarely available to evaluate their effectiveness following deployment by a national malaria control program.,In Uganda, we measured changes in key malaria indicators following universal LLIN distribution in three sites, with the addition of IRS at one of these sites.,Comprehensive malaria surveillance was conducted from October 1, 2011, to March 31, 2016, in three sub-counties with relatively low (Walukuba), moderate (Kihihi), and high transmission (Nagongera).,Between 2013 and 2014, universal LLIN distribution campaigns were conducted in all sites, and in December 2014, IRS with the carbamate bendiocarb was initiated in Nagongera.,High-quality surveillance evaluated malaria metrics and mosquito exposure before and after interventions through (a) enhanced health-facility-based surveillance to estimate malaria test positivity rate (TPR), expressed as the number testing positive for malaria/number tested for malaria (number of children tested for malaria: Walukuba = 42,833, Kihihi = 28,790, and Nagongera = 38,690); (b) cohort studies to estimate the incidence of malaria, expressed as the number of episodes per person-year [PPY] at risk (number of children observed: Walukuba = 340, Kihihi = 380, and Nagongera = 361); and (c) entomology surveys to estimate household-level human biting rate (HBR), expressed as the number of female Anopheles mosquitoes collected per house-night of collection (number of households observed: Walukuba = 117, Kihihi = 107, and Nagongera = 107).,The LLIN distribution campaign substantially increased LLIN coverage levels at the three sites to between 65.0% and 95.5% of households with at least one LLIN.,In Walukuba, over the 28-mo post-intervention period, universal LLIN distribution was associated with no change in the incidence of malaria (0.39 episodes PPY pre-intervention versus 0.20 post-intervention; adjusted rate ratio [aRR] = 1.02, 95% CI 0.36-2.91, p = 0.97) and non-significant reductions in the TPR (26.5% pre-intervention versus 26.2% post-intervention; aRR = 0.70, 95% CI 0.46-1.06, p = 0.09) and HBR (1.07 mosquitoes per house-night pre-intervention versus 0.71 post-intervention; aRR = 0.41, 95% CI 0.14-1.18, p = 0.10).,In Kihihi, over the 21-mo post-intervention period, universal LLIN distribution was associated with a reduction in the incidence of malaria (1.77 pre-intervention versus 1.89 post-intervention; aRR = 0.65, 95% CI 0.43-0.98, p = 0.04) but no significant change in the TPR (49.3% pre-intervention versus 45.9% post-intervention; aRR = 0.83, 95% 0.58-1.18, p = 0.30) or HBR (4.06 pre-intervention versus 2.44 post-intervention; aRR = 0.71, 95% CI 0.30-1.64, p = 0.40).,In Nagongera, over the 12-mo post-intervention period, universal LLIN distribution was associated with a reduction in the TPR (45.3% pre-intervention versus 36.5% post-intervention; aRR = 0.82, 95% CI 0.76-0.88, p < 0.001) but no significant change in the incidence of malaria (2.82 pre-intervention versus 3.28 post-intervention; aRR = 1.10, 95% 0.76-1.59, p = 0.60) or HBR (41.04 pre-intervention versus 20.15 post-intervention; aRR = 0.87, 95% CI 0.31-2.47, p = 0.80).,The addition of three rounds of IRS at ~6-mo intervals in Nagongera was followed by clear decreases in all outcomes: incidence of malaria (3.25 pre-intervention versus 0.63 post-intervention; aRR = 0.13, 95% CI 0.07-0.27, p < 0.001), TPR (37.8% pre-intervention versus 15.0% post-intervention; aRR = 0.54, 95% CI 0.49-0.60, p < 0.001), and HBR (18.71 pre-intervention versus 3.23 post-intervention; aRR = 0.29, 95% CI 0.17-0.50, p < 0.001).,High levels of pyrethroid resistance were documented at all three study sites.,Limitations of the study included the observational study design, the lack of contemporaneous control groups, and that the interventions were implemented under programmatic conditions.,Universal distribution of LLINs at three sites with varying transmission intensity was associated with modest declines in the burden of malaria for some indicators, but the addition of IRS at the highest transmission site was associated with a marked decline in the burden of malaria for all indicators.,In highly endemic areas of Africa with widespread pyrethroid resistance, IRS using alternative insecticide formulations may be needed to achieve substantial gains in malaria control.,In this prospective observational study, Grant Dorsey and colleagues measure changes in malaria burden after long-lasting insecticidal net distribution and indoor residual spraying at three sites of in Uganda.

Malaria control programmes across Africa and beyond are facing increasing insecticide resistance in the major anopheline vectors.,In order to preserve or prolong the effectiveness of the main malaria vector interventions, up-to-date and easily accessible insecticide resistance data that are interpretable at operationally-relevant scales are critical.,Herein we introduce and demonstrate the usefulness of an online mapping tool, IR Mapper.,A systematic search of published, peer-reviewed literature was performed and Anopheles insecticide susceptibility and resistance mechanisms data were extracted and added to a database after a two-level verification process.,IR Mapper ( http://www.irmapper.com) was developed using the ArcGIS for JavaScript Application Programming Interface and ArcGIS Online platform for exploration and projection of these data.,Literature searches yielded a total of 4,084 susceptibility data points for 1,505 populations, and 2,097 resistance mechanisms data points for 1,000 populations of Anopheles spp. tested via recommended WHO methods from 54 countries between 1954 and 2012.,For the Afrotropical region, data were most abundant for populations of An. gambiae, and pyrethroids and DDT were more often used in susceptibility assays (51.1 and 26.8% of all reports, respectively) than carbamates and organophosphates.,Between 2001 and 2012, there was a clear increase in prevalence and distribution of confirmed resistance of An. gambiae s.l. to pyrethroids (from 41 to 87% of the mosquito populations tested) and DDT (from 64 to 91%) throughout the Afrotropical region.,Metabolic resistance mechanisms were detected in western and eastern African populations and the two kdr mutations (L1014S and L1014F) were widespread.,For An. funestus s.l., relatively few populations were tested, although in 2010-2012 resistance was reported in 50% of 10 populations tested.,Maps are provided to illustrate the use of IR Mapper and the distribution of insecticide resistance in malaria vectors in Africa.,The increasing pyrethroid and DDT resistance in Anopheles in the Afrotropical region is alarming.,Urgent attention should be afforded to testing An. funestus populations especially for metabolic resistance mechanisms.,IR Mapper is a useful tool for investigating temporal and spatial trends in Anopheles resistance to support the pragmatic use of insecticidal interventions.

Residual malaria transmission has been reported in many areas even with adequate indoor vector control coverage, such as long-lasting insecticidal nets (LLINs).,The increased insecticide resistance in Anopheles mosquitoes has resulted in reduced efficacy of the widely used indoor tools and has been linked with an increase in outdoor malaria transmission.,There are considerations of incorporating outdoor interventions into integrated vector management (IVM) to achieve malaria elimination; however, more information on the combination of tools for effective control is needed to determine their utilization.,A spatial individual-based model was modified to simulate the environment and malaria transmission activities in a hypothetical, isolated African village setting.,LLINs and outdoor attractive toxic sugar bait (ATSB) stations were used as examples of indoor and outdoor interventions, respectively.,Different interventions and lengths of efficacy periods were tested.,Simulations continued for 420 days, and each simulation scenario was repeated 50 times.,Mosquito populations, entomologic inoculation rates (EIRs), probabilities of local mosquito extinction, and proportion of time when the annual EIR was reduced below one were compared between different intervention types and efficacy periods.,In the village setting with clustered houses, the combinational intervention of 50% LLINs plus outdoor ATSBs significantly reduced mosquito population and EIR in short term, increased the probability of local mosquito extinction, and increased the time when annual EIR is less than one per person compared to 50% LLINs alone; outdoor ATSBs alone significantly reduced mosquito population in short term, increased the probability of mosquito extinction, and increased the time when annual EIR is less than one compared to 50% LLINs alone, but there was no significant difference in EIR in short term between 50% LLINs and outdoor ATSBs.,In the village setting with dispersed houses, the combinational intervention of 50% LLINs plus outdoor ATSBs significantly reduced mosquito population in short term, increased the probability of mosquito extinction, and increased the time when annual EIR is less than one per person compared to 50% LLINs alone; outdoor ATSBs alone significantly reduced mosquito population in short term, but there were no significant difference in the probability of mosquito extinction and the time when annual EIR is less than one between 50% LLIN and outdoor ATSBs; and there was no significant difference in EIR between all three interventions.,A minimum of 2 months of efficacy period is needed to bring out the best possible effect of the vector control tools, and to achieve long-term mosquito reduction, a minimum of 3 months of efficacy period is needed.,The results highlight the value of incorporating outdoor vector control into IVM as a supplement to traditional indoor practices for malaria elimination in Africa, especially in village settings of clustered houses where LLINs alone is far from sufficient.

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

Malaria remains a problem for many countries classified as malaria free through cases imported from endemic regions.,Imported cases to non-endemic countries often result in delays in diagnosis, are expensive to treat, and can sometimes cause secondary local transmission.,The movement of malaria in endemic countries has also contributed to the spread of drug resistance and threatens long-term eradication goals.,Here we focused on quantifying the international movements of malaria to improve our understanding of these phenomena and facilitate the design of mitigation strategies.,In this meta-analysis, we studied the database of publicly available nationally reported statistics on imported malaria in the past 10 years, covering more than 50 000 individual cases.,We obtained data from 40 non-endemic countries and recorded the geographical variations.,Infection movements were strongly skewed towards a small number of high-traffic routes between 2005 and 2015, with the west Africa region accounting for 56% (13 947/24 941) of all imported cases to non-endemic countries with a reported travel destination, and France and the UK receiving the highest number of cases, with more than 4000 reported cases per year on average.,Countries strongly linked by movements of imported cases are grouped by historical, language, and travel ties.,There is strong spatial clustering of plasmodium species types.,The architecture of the air network, historical ties, demographics of travellers, and malaria endemicity contribute to highly heterogeneous patterns of numbers, routes, and species compositions of parasites transported.,With global malaria eradication on the international agenda, malaria control altering local transmission, and the threat of drug resistance, understanding these patterns and their drivers is increasing in importance.,Bill & Melinda Gates Foundation, National Institutes of Health, UK Medical Research Council, UK Department for International Development, Wellcome Trust.

There is a critical need for developing new malaria diagnostic tools that are sensitive, cost effective and capable of performing large scale diagnosis.,The real-time PCR methods are particularly robust for large scale screening and they can be used in malaria control and elimination programs.,We have designed novel self-quenching photo-induced electron transfer (PET) fluorogenic primers for the detection of P. falciparum and the Plasmodium genus by real-time PCR.,A total of 119 samples consisting of different malaria species and mixed infections were used to test the utility of the novel PET-PCR primers in the diagnosis of clinical samples.,The sensitivity and specificity were calculated using a nested PCR as the gold standard and the novel primer sets demonstrated 100% sensitivity and specificity.,The limits of detection for P. falciparum was shown to be 3.2 parasites/µl using both Plasmodium genus and P. falciparum-specific primers and 5.8 parasites/µl for P. ovale, 3.5 parasites/µl for P. malariae and 5 parasites/µl for P. vivax using the genus specific primer set.,Moreover, the reaction can be duplexed to detect both Plasmodium spp. and P. falciparum in a single reaction.,The PET-PCR assay does not require internal probes or intercalating dyes which makes it convenient to use and less expensive than other real-time PCR diagnostic formats.,Further validation of this technique in the field will help to assess its utility for large scale screening in malaria control and elimination programs.

This is the first case of Plasmodium knowlesi infection in a Japanese traveller returning from Malaysia.,In September 2012, a previously healthy 35-year-old Japanese man presented to National Center for Global Health and Medicine in Tokyo with a two-day history of daily fever, mild headaches and mild arthralgia.,Malaria parasites were found in the Giemsa-stained thin blood smear, which showed band forms similar to Plasmodium malariae.,Although a nested PCR showed the amplification of the primer of Plasmodium vivax and Plasmodium knowlesi, he was finally diagnosed with P. knowlesi mono-infection by DNA sequencing.,He was treated with mefloquine, and recovered without any complications.,DNA sequencing of the PCR products is indispensable to confirm P. knowlesi infection, however there is limited access to DNA sequencing procedures in endemic areas.,The extent of P. knowlesi transmission in Asia has not been clearly defined.,There is limited availability of diagnostic tests and routine surveillance system for reporting an accurate diagnosis in the Asian endemic regions.,Thus, reporting accurately diagnosed cases of P. knowlesi infection in travellers would be important for assessing the true nature of this emerging human infection.

Plasmodium knowlesi, a simian malaria parasite, has been reported in humans in many Southeast Asian countries.,In Thailand, most of the limited numbers of cases reported so far were from areas near neighbouring countries, including Myanmar.,Blood samples collected from 171 Thai and 248 Myanmese patients attending a malaria clinic in Ranong province, Thailand, located near the Myanmar border were investigated for P. knowlesi using nested PCR assays.,Positive samples were also investigated by PCR for Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovale, and were confirmed by sequencing the gene encoding the circumsporozoite protein (csp).,Two samples, one obtained from a Thai and the other a Myanmese, were positive for P. knowlesi only.,Nucleotide sequences of the csp gene derived from these two patients were identical and phylogenetically indistinguishable from other P. knowlesi sequences derived from monkeys and humans.,Both patients worked in Koh Song, located in the Kawthoung district of Myanmar, which borders Thailand.,This study indicates that transmission of P. knowlesi is occurring in the Ranong province of Thailand or the Kawthoung district of Myanmar.,Further studies are required to assess the incidence of knowlesi malaria and whether macaques in these areas are the source of the infections.

The widespread distribution and relapsing nature of Plasmodium vivax infection present major challenges for malaria elimination.,To characterise the genetic diversity of this parasite within individual infections and across the population, we performed deep genome sequencing of >200 clinical samples collected across the Asia-Pacific region, and analysed data on >300,000 SNPs and 9 regions of the genome with large copy number variations.,Individual infections showed complex patterns of genetic structure, with variation not only in the number of dominant clones but also in their level of relatedness and inbreeding.,At the population level, we observed strong signals of recent evolutionary selection both in known drug resistance genes and at novel loci, and these varied markedly between geographical locations.,These findings reveal a dynamic landscape of local evolutionary adaptation in P. vivax populations, and provide a foundation for genomic surveillance to guide effective strategies for control and elimination.

Selection by host immunity and antimalarial drugs has driven extensive adaptive evolution in Plasmodium falciparum and continues to produce ever-changing landscapes of genetic variation.,We performed whole-genome sequencing of 69 P. falciparum isolates from Malawi and used population genetics approaches to investigate genetic diversity and population structure and identify loci under selection.,High genetic diversity (π = 2.4 × 10−4), moderately high multiplicity of infection (2.7), and low linkage disequilibrium (500-bp) were observed in Chikhwawa District, Malawi, an area of high malaria transmission.,Allele frequency-based tests provided evidence of recent population growth in Malawi and detected potential targets of host immunity and candidate vaccine antigens.,Comparison of the sequence variation between isolates from Malawi and those from 5 geographically dispersed countries (Kenya, Burkina Faso, Mali, Cambodia, and Thailand) detected population genetic differences between Africa and Asia, within Southeast Asia, and within Africa.,Haplotype-based tests of selection to sequence data from all 6 populations identified signals of directional selection at known drug-resistance loci, including pfcrt, pfdhps, pfmdr1, and pfgch1.,The sequence variations observed at drug-resistance loci reflect differences in each country's historical use of antimalarial drugs and may be useful in formulating local malaria treatment guidelines.

Among six dominant mosquito vector species involved in malaria transmission in India, Anopheles minimus is a major species in northeast India and held responsible for focal disease outbreaks characterized by high-rise of Plasmodium falciparum infections and attributable death cases.,It has been now genetically characterized that among the three-member species of the Minimus Complex spread in Asia, An. minimus (former species A) is prevalent in India including northeastern states and east-central state of Odisha.,It is recorded in all seasons and accounts for perennial transmission evidenced by records of sporozoite infections.,This species is highly anthropophilic, and largely endophilic and endophagic, recorded breeding throughout the year in slow flowing seepage water streams.,The populations of An. minimus in India are reported to be highly diverse indicating population expansion with obvious implications for judicious application of vector control interventions.,Given the rapid ecological changes due to deforestation, population migration and expansion and developmental activities, there is scope for further research on the existence of potential additional sibling species within the An. minimus complex and bionomics studies on a large geographical scale for species sanitation.,For control of vector populations, DDT continues to be applied on account of retaining susceptibility status even after decades of residual spraying.,Anopheles minimus is a highly adaptive species and requires continuous and sustained efforts for its effective control to check transmission and spread of drug-resistant malaria.,Anopheles minimus populations are reportedly diminishing in northeastern India whereas it has staged comeback in east-central State of Odisha after decades of disappearance with its eco-biological characteristics intact.,It is the high time to siege the opportunity for strengthening interventions against this species for its population diminution to sub-optimal levels for reducing transmission in achieving malaria elimination by target date of 2030.

After successfully reducing the malaria burden to pre-elimination levels over the past two decades, the national malaria programme in Vietnam has recently switched from control to elimination.,However, in forested areas of Central Vietnam malaria elimination is likely to be jeopardized by the high occurrence of asymptomatic and submicroscopic infections as shown by previous reports.,This paper presents the results of a malaria survey carried out in a remote forested area of Central Vietnam where we evaluated malaria prevalence and risk factors for infection.,After a full census (four study villages = 1,810 inhabitants), the study population was screened for malaria infections by standard microscopy and, if needed, treated according to national guidelines.,An additional blood sample on filter paper was also taken in a random sample of the population for later polymerase chain reaction (PCR) and more accurate estimation of the actual burden of malaria infections.,The risk factor analysis for malaria infections was done using survey multivariate logistic regression as well as the classification and regression tree method (CART).,A total of 1,450 individuals were screened.,Malaria prevalence by microscopy was 7.8% (ranging from 3.9 to 10.9% across villages) mostly Plasmodium falciparum (81.4%) or Plasmodium vivax (17.7%) mono-infections; a large majority (69.9%) was asymptomatic.,By PCR, the prevalence was estimated at 22.6% (ranging from 16.4 to 42.5%) with a higher proportion of P. vivax mono-infections (43.2%).,The proportion of sub-patent infections increased with increasing age and with decreasing prevalence across villages.,The main risk factors were young age, village, house structure, and absence of bed net.,This study confirmed that in Central Vietnam a substantial part of the human malaria reservoir is hidden.,Additional studies are urgently needed to assess the contribution of this hidden reservoir to the maintenance of malaria transmission.,Such evidence will be crucial for guiding elimination strategies.

Children carry most of the schistosomiasis burden.,While school-aged children are the principal target group of preventive chemotherapy with praziquantel, limited information on efficacy and safety exists for preschool-aged children.,Here, we conducted a meta-analysis of clinical trials of praziquantel for treating children with any form of schistosomiasis.,Efficacy was reported as cure rate (CR) and egg reduction rates (ERR); statistical corrections were applied based on methodological disparities across trials to derive the predicted geometrical mean ERR (pERRgm).,Safety was reported as frequencies of adverse events.,Forty-seven comparative and non-comparative studies were identified, enrolling 15,549 children of whom 14,340 (92%) were assessed between 3 and 8 weeks post-treatment with praziquantel 40 mg/kg (the WHO-recommended treatment, n = 8,380, 56%) or comparators (n = 5,960, 44%).,The median age was 10 years (range 1-19), 11% (n = 1,694) were preschool-aged.,The CR and pERRgm with praziquantel 40 mg/kg were respectively: S. haematobium, 73.6% (95% CI: 63.5-81.40, 25 study arms) and 94.7% (95% CI: 92.7-96.4); S. mansoni, 76.4% (95% CI: 71.5-81.0, 34 arms) and 95.3% (95% CI: 94.2-96.2); S. mansoni/S. haematobium, 67.6% (95% CI: 54.1-80.7, 5 arms) and 93.4% (95% CI: 89.9-96.2); S. japonicum, 94.7% (95% CI: 92.2-98.0) and 98.7% (95% CI: 98.3-99.2).,Mixed-effect multivariate analysis found no significant difference between preschool- and school-aged children for CR or pERRgm in S. haematobium (P = 0.309 and P = 0.490, respectively) or S. mansoni (P = 0.982 and P = 0.895) after controlling for time of assessment, formulation, intensity of infection and detection method.,Praziquantel was reportedly safe at all ages, with only mild reported adverse events which cleared rapidly after treatment.,Praziquantel 40 mg/kg was effective at reducing infection intensity in all Schistosoma species without differences between preschool- and school-aged children.,However, conclusions should be tempered because of the limited number of preschool-aged children enrolled, disparities in study procedures and limited information made available in publications, as well as the current imperfect test-of-cure.,Also, although reportedly well-tolerated, safety was inconsistently assessed.,Studies in target groups, individual-data meta-analysis and standardised methodologies are needed for more robust evidence-base.,The online version of this article (doi:10.1186/s13071-016-1958-7) contains supplementary material, which is available to authorized users.

As plans to expand mass drug treatment campaigns to fight schistosomiasis form, worries about reliance on praziquantel as the sole available treatment motivate the investigation for novel antischistosomal compounds.,Drug repurposing might be an inexpensive and effective source of novel antischistosomal leads.,1600 FDA approved compounds were first assayed against Schistosoma mansoni schistosomula at a concentration of 10 µM.,Active compounds identified from this screen were advanced to the adult worm screen at 33.33 µM, followed by hit characterization.,Leads with complementary pharmacokinetic and toxicity profiles were then selected for in vivo studies.,The in vitro screen identified 121 and 36 compounds active against the schistosomula and adult stage, respectively.,Further, in vitro characterization and comparison with already available pharmacokinetic and toxicity data identified 11 in vivo candidates.,Doramectin (10 mg/kg) and clofazimine (400 mg/kg) were found to be active in vivo with worm burden reductions of 60.1% and 82.7%, respectively.,The work presented here expands the knowledge of antischistosomal properties of already approved compounds and underscores variations observed between target-based and phenotypic approaches and among laboratories.,The two in vivo-active drugs identified in this study, doramectin and clofazimine are widely available and present as novel drug classes as starting points for further investigation.

The global distribution map of schistosomiasis shows a large overlap of Schistosoma haematobium- and S. mansoni-endemic areas in Africa.,Yet, little is known about the consequences of mixed Schistosoma infections for the human host.,A recent study in two neighboring co-endemic communities in Senegal indicated that infection intensities of both species were higher in mixed than in single infections.,Here, we investigated the relationship between mixed Schistosoma infections and morbidity in the same population.,So far, this has only been studied in children.,Schistosoma infection was assessed by microscopy.,Schistosoma-specific morbidity was assessed by ultrasound according to WHO guidelines.,Multivariable logistic regression models were used to identify independent risk factors for morbidity.,Complete parasitological and morbidity data were obtained from 403 individuals.,Schistosoma haematobium-specific bladder morbidity was observed in 83% and S. mansoni-specific hepatic fibrosis in 27% of the participants.,Bladder morbidity was positively associated with S. haematobium infection intensity (OR = 1.9 (95% CI 1.3-2.9) for a 10-fold increase in intensity).,Moreover, people with mixed infections tended to have less bladder morbidity than those with single S. haematobium infections (OR = 0.3 (95% CI 0.1-1.1)).,This effect appeared to be related to ectopic S. mansoni egg elimination in urine.,Hepatic fibrosis on the other hand was not related to S. mansoni infection intensity (OR = 0.9 (95% CI 0.6-1.3)), nor to mixed infections (OR = 1.0 (95% CI 0.7-1.7)).,This is the first population-wide study on the relationship between mixed Schistosoma infections and morbidity.,Mixed infections did not increase the risk of S. mansoni-associated morbidity.,They even tended to reduce the risk of S. haematobium-associated morbidity, suggesting a protective effect of S. mansoni infection on bladder morbidity.,These unexpected results may have important consequences for schistosomiasis control in co-endemic areas and warrant further investigation.

Given that helminth infections are thought to have strong immunomodulatory activity, the question whether helminth infections might affect responses to malaria antigens needs to be addressed.,Different cross-sectional studies using diverse methodologies have reported that helminth infections might either exacerbate or reduce the severity of malaria attacks.,The same discrepancies have been reported for parasitemia.,To determine the effect of geohelminth infections and their treatment on malaria infection and disease outcome, as well as on immunological parameters, the area of Nangapanda on Flores Island, Indonesia, where malaria and helminth parasites are co-endemic was selected for a longitudinal study.,Here a Double-blind randomized trial will be performed, incorporating repeated treatment with albendazole (400 mg) or placebo at three monthly intervals.,Household characteristic data, anthropometry, the presence of intestinal helminth and Plasmodium spp infections, and the incidence of malaria episodes are recorded.,In vitro cultures of whole blood, stimulated with a number of antigens, mitogens and toll like receptor ligands provide relevant immunological parameters at baseline and following 1 and 2 years of treatment rounds.,The primary outcome of the study is the prevalence of Plasmodium falciparum and P. vivax infection.,The secondary outcome will be incidence and severity of malaria episodes detected via both passive and active follow-up.,The tertiary outcome is the inflammatory cytokine profile in response to parasite antigens.,The project also facilitates the transfer of state of the art methodologies and technologies, molecular diagnosis of parasitic diseases, immunology and epidemiology from Europe to Indonesia.,The study will provide data on the effect of helminth infections on malaria.,It will also give information on anthelminthic treatment efficacy and effectiveness and could help develop evidence-based policymaking.,This study was approved by The Ethical Committee of Faculty of Medicine, University of Indonesia, ref:194/PT02.,FK/Etik/2006 and has been filed by ethics committee of the Leiden University Medical Center.,Clinical trial number:ISRCTN83830814.,The study is reported in accordance with the CONSORT guidelines for cluster-randomized studies.

The World Health Organization identified Uganda as one of the 10 highly endemic countries for schistosomiasis.,Annual mass drug administration (MDA) with praziquantel has led to a decline in intensity of Schistosoma mansoni infections in several areas.,However, as hotspots with high (re)infection rates remain, additional research on risk factors and implementing interventions to complement MDA are required to further reduce disease burden in these settings.,Through a mixed-methods study we aimed to gain deeper understanding of how gender may impact risk and reinfection in order to inform disease control programmes and ascertain if gender-specific interventions may be beneficial.,In Bugoto, Mayuge District, Eastern Uganda we conducted ethnographic observations (n = 16) and examined epidemiology (n = 55) and parasite population genetics (n = 16) in school-aged children (SAC), alongside a community-wide household survey (n = 130).,Water contact was frequent at home, school and in the community and was of domestic, personal care, recreational, religious or commercial nature.,Qualitative analysis of type of activity, duration, frequency, level of submersion and water contact sites in children showed only few behavioural differences in water contact between genders.,However, survey data revealed that adult women carried out the vast majority of household tasks involving water contact.,Reinfection rates (96% overall) and genetic diversity were high in boys (pre-He = 0.66; post-He = 0.67) and girls (pre-He = 0.65; post-He = 0.67), but no differences in reinfection rates (p = 0.62) or genetic diversity by gender before (p = 0.54) or after (p = 0.97) treatment were found.,This mixed methods approach showed complementary findings.,Frequent water exposure with few differences between boys and girls was mirrored by high reinfection rates and genetic diversity in both genders.,Disease control programmes should consider the high reinfection rates among SAC in remaining hotspots of schistosomiasis and the various purposes and settings in which children and adults are exposed to water.

In an effort to complement the current chemotherapy based schistosomiasis control interventions in Shinyanga district, community knowledge, perceptions and water contact practices were qualitatively assessed using focus group discussions and semi structured interviews involving 271 participants in one S. haematobium prevalent community of Ikingwamanoti village, Shinyanga district, Northwestern, Tanzania.,In October, 2016 we conducted 29 parent semi structured interviews and 16 focus group discussions with a total of 168 parent informants.,Adult participants were conveniently selected from three sub-villages of Butini, Miyu, and Bomani of Ikingwamanoti village, Shinyanga district.,In March, 2017, a total of 103 children informants participated in 10 focus group discussions and 20 semi structured interviews, administered to children from standard four, five, six and seven attending Ikingwamanoti Primary School.,Note taking and digital recorders were used to collect narrative data for thematic analysis of emergent themes.,Among participants, 75% parents and 50% children considered urinary schistosomiasis as a low priority health problem.,Of the informants, 70% children and 48.3% parents had misconceptions about the cause, modes of transmission and control of schistosomiasis demonstrating gaps in their biomedical knowledge of the disease.,Assessment of treatment seeking behavior for urinary schistosomiasis revealed a combination of traditional and modern health care sectors.,However, modern medicines were considered effective in the treatment of urinary schistosomiasis.,Lack of alternative sources of water for domestic and recreational activities and unhygienic water use habits exposed community members to high risk of acquiring urinary schistosomiasis.,Use of Schistosoma haematobium contaminated water sources for daily domestic and recreational use facilitated contraction of urinary schistosomiasis among community members in Shinyanga district.,People’s perceptions of urinary schistosomiasis as a less priority health problem promoted persistence of the disease.,Future efforts to control urinary schistosomiasis should take into account integrated approaches combining water, sanitation and hygiene, health education, alternative sources of clean and safe water to facilitate behavior change.,The online version of this article (10.1186/s12889-019-7041-5) contains supplementary material, which is available to authorized users.

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

The duration of infection is fundamental to the epidemiological behaviour of any infectious disease, but remains one of the most poorly understood aspects of malaria.,In endemic areas, the malaria parasite Plasmodium falciparum can cause both acute, severe infections and asymptomatic, chronic infections through its interaction with the host immune system.,Frequent superinfection and massive parasite genetic diversity make it extremely difficult to accurately measure the distribution of infection lengths, complicating the estimation of basic epidemiological parameters and the prediction of the impact of interventions.,Mathematical models have qualitatively reproduced parasite dynamics early during infection, but reproducing long-lived chronic infections remains much more challenging.,Here, we construct a model of infection dynamics to examine the consequences of common biological assumptions for the generation of chronicity and the impact of co-infection.,We find that although a combination of host and parasite heterogeneities are capable of generating chronic infections, they do so only under restricted parameter choices.,Furthermore, under biologically plausible assumptions, co-infection of parasite genotypes can alter the course of infection of both the resident and co-infecting strain in complex non-intuitive ways.,We outline the most important puzzles for within-host models of malaria arising from our analysis, and their implications for malaria epidemiology and control.

Reducing the human reservoir of malaria parasites is critical for elimination.,We conducted a community randomized controlled trial in Southern Province, Zambia to assess the impact of three rounds of a mass test and treatment (MTAT) intervention on malaria prevalence and health facility outpatient case incidence using random effects logistic regression and negative binomial regression, respectively.,Following the intervention, children in the intervention group had lower odds of a malaria infection than individuals in the control group (adjusted odds ratio = 0.47, 95% confidence interval [CI] = 0.24-0.90).,Malaria outpatient case incidence decreased 17% in the intervention group relative to the control group (incidence rate ratio = 0.83, 95% CI = 0.68-1.01).,Although a single year of MTAT reduced malaria prevalence and incidence, the impact of the intervention was insufficient to reduce transmission to a level approaching elimination where a strategy of aggressive case investigations could be used.,Mass drug administration, more sensitive diagnostics, and gametocidal drugs may potentially improve interventions targeting the human reservoir of malaria parasites.

Measurement of malaria burden is fraught with complexity, due to the natural history of the disease, delays in seeking treatment or failure of case management.,Attempts to establish an appropriate case definition for a malaria episode has often resulted in ambiguities and challenges because of poor information about treatment seeking, patterns of infection, recurrence of fever and asymptomatic infection.,While the primary reason for treating malaria is to reduce disease burden, the effects of treatment are generally ignored in estimates of the burden of malaria morbidity, which are usually presented in terms of numbers of clinical cases or episodes, with the main data sources being reports from health facilities and parasite prevalence surveys.,The use of burden estimates that do not consider effects of treatment, leads to under-estimation of the impact of improvements in case management.,Official estimates of burden very likely massively underestimate the impact of the roll-out of ACT as first-line therapy across Africa.,This paper proposes a novel approach for estimating burden of disease based on the point prevalence of malaria attributable disease, or equivalently, the days with malaria fever in unit time.,The technique makes use of data available from standard community surveys, analyses of fever patterns in malaria therapy patients, and data on recall bias.,Application of this approach to data from Zambia for 2009-2010 gave an estimate of 2.6 (95% credible interval: 1.5-3.7) malaria attributable fever days per child-year.,The estimates of recall bias, and of the numbers of days with illness contributing to single illness recalls, could be applied more generally.,To obtain valid estimates of the overall malaria burden using these methods, there remains a need for surveys to include the whole range of ages of hosts in the population and for data on seasonality patterns in confirmed case series.

The life-threatening diseases alveolar and cystic echinococcoses are caused by larvae of the tapeworms Echinococcus multilocularis and E. granulosus, respectively.,In both cases, intermediate hosts, such as humans, are infected by oral uptake of oncosphere larvae, followed by asexual multiplication and almost unrestricted growth of the metacestode within host organs.,Besides surgery, echinococcosis treatment relies on benzimidazole-based chemotherapy, directed against parasite beta-tubulin.,However, since beta-tubulins are highly similar between cestodes and humans, benzimidazoles can only be applied at parasitostatic doses and are associated with adverse side effects.,Mostly aiming at identifying alternative drug targets, the nuclear genome sequences of E. multilocularis and E. granulosus have recently been characterized, revealing a large number of druggable targets that are expressed by the metacestode.,Furthermore, recent cell biological investigations have demonstrated that E. multilocularis employs pluripotent stem cells, called germinative cells, which are the only parasite cells capable of proliferation and which give rise to all differentiated cells.,Hence, the germinative cells are the crucial cell type mediating proliferation of E. multilocularis, and most likely also E. granulosus, within host organs and should also be responsible for parasite recurrence upon discontinuation of chemotherapy.,Interestingly, recent investigations have also indicated that germinative cells might be less sensitive to chemotherapy because they express a beta-tubulin isoform with limited affinity to benzimidazoles.,In this article, we briefly review the recent findings concerning Echinococcus genomics and stem cell research and propose that future research into anti-echinococcosis drugs should also focus on the parasite’s stem cell population.

We have previously evaluated the vaccine efficacies of seven tetraspanins of Echinococcus multilocularis (Em-TSP1-7) against alveolar echinococcosis (AE) by subcutaneous (s.c.) administration with Freund's adjuvant.,Over 85% of liver cyst lesion number reductions (CLNR) were achieved by recombinant Em-TSP1 (rEm-TSP1) and -TSP3 (rEm-TSP3).,However, to develop an efficient and safe human vaccine, the efficacy of TSP mucosal vaccines must be thoroughly evaluated.,rEm-TSP1 and -TSP3 along with nontoxic CpG ODN (CpG oligodeoxynucleotides) adjuvant were intranasally (i.n.) immunized to BALB/c mice and their vaccine efficacies were evaluated by counting liver CLNR (experiment I).,37.1% (p<0.05) and 62.1% (p<0.001) of CLNR were achieved by these two proteins, respectively.,To study the protection-associated immune responses induced by rEm-TSP3 via different immunization routes (i.n. administration with CpG or s.c. immunization with Freund's adjuvant), the systemic and mucosal antibody responses were detected by ELISA (experiment II).,S.c. and i.n. administration of rEm-TSP3 achieved 81.9% (p<0.001) and 62.8% (p<0.01) CLNR in the liver, respectively.,Both the immunization routes evoked strong serum IgG, IgG1 and IgG2α responses; i.n. immunization induced significantly higher IgA responses in nasal cavity and intestine compared with s.c. immunization (p<0.001).,Both immunization routes induced extremely strong liver IgA antibody responses (p<0.001).,The Th1 and Th2 cell responses were assessed by examining the IgG1/IgG2α ratio at two and three weeks post-immunization.,S.c. immunization resulted in a reduction in the IgG1/IgG2α ratio (Th1 tendency), whereas i.n. immunization caused a shift from Th1 to Th2.,Moreover, immunohistochemistry showed that Em-TSP1 and -TSP3 were extensively located on the surface of E. multilocularis cysts, protoscoleces and adult worms with additional expression of Em-TSP3 in the inner part of protoscoleces and oncospheres.,Our study indicated that i.n. administration of rEm-TSP3 with CpG is able to induce both systemic and local immune responses and thus provides significant protection against AE.

Artemisinin combination therapies (ACTs) are used worldwide as first-line treatment against confirmed or suspected Plasmodium falciparum malaria.,Despite the success of ACTs at reducing the global burden of malaria, emerging resistance to artemisinin threatens these gains.,Countering onset of resistance might need deliberate tactics aimed at slowing the reduction in ACT effectiveness.,We assessed optimum use of ACTs at the population level, specifically focusing on a strategy of multiple first-line therapies (MFT), and comparing it with strategies of cycling or sequential use of single first-line ACTs.,With an individual-based microsimulation of regional malaria transmission, we looked at how to apply a therapy as widely as possible without accelerating reduction of efficacy by drug resistance.,We compared simultaneous distribution of artemether-lumefantrine, artesunate-amodiaquine, and dihydroartemisinin-piperaquine (ie, MFT) against strategies in which these ACTs would be cycled or used sequentially, either on a fixed schedule or when population-level efficacy reaches the WHO threshold of 10% treatment failure.,The main assessment criterion was total number of treatment failures per 100 people per year.,Additionally, we analysed the benefits of including a single non-ACT therapy in an MFT strategy, and did sensitivity analyses in which we varied transmission setting, treatment coverage, partner-drug half-life, fitness cost of drug resistance, and the relation between drug concentration and resistance evolution.,Use of MFT was predicted to reduce the long-term number of treatment failures compared with strategies in which a single first-line ACT is recommended.,This result was robust to various epidemiological, pharmacological, and evolutionary features of malaria transmission.,Inclusion of a single non-ACT therapy in an MFT strategy would have substantial benefits in reduction of pressure on artemisinin resistance evolution, delaying its emergence and slowing its spread.,Adjusting national antimalarial treatment guidelines to encourage simultaneous use of MFT is likely to extend the useful therapeutic life of available antimalarial drugs, resulting in long-term beneficial outcomes for patients.,Wellcome Trust, UK Medical Research Council, Li Ka Shing Foundation.

Ric Price and colleagues use hospital-based surveillance data to estimate the risk of severe anemia and mortality associated with endemic Plasmodium species in southern Papua, Indonesia.,Please see later in the article for the Editors' Summary,The burden of anemia attributable to non-falciparum malarias in regions with Plasmodium co-endemicity is poorly documented.,We compared the hematological profile of patients with and without malaria in southern Papua, Indonesia.,Clinical and laboratory data were linked for all patients presenting to a referral hospital between April 2004 and December 2012.,Data were available on patient demographics, malaria diagnosis, hemoglobin concentration, and clinical outcome, but other potential causes of anemia could not be identified reliably.,Of 922,120 patient episodes (837,989 as outpatients and 84,131 as inpatients), a total of 219,845 (23.8%) were associated with a hemoglobin measurement, of whom 67,696 (30.8%) had malaria.,Patients with P. malariae infection had the lowest hemoglobin concentration (n = 1,608, mean = 8.93 [95% CI 8.81-9.06]), followed by those with mixed species infections (n = 8,645, mean = 9.22 [95% CI 9.16-9.28]), P. falciparum (n = 37,554, mean = 9.47 [95% CI 9.44-9.50]), and P. vivax (n = 19,858, mean = 9.53 [95% CI 9.49-9.57]); p-value for all comparisons <0.001.,Severe anemia (hemoglobin <5 g/dl) was present in 8,151 (3.7%) patients.,Compared to patients without malaria, those with mixed Plasmodium infection were at greatest risk of severe anemia (adjusted odds ratio [AOR] 3.25 [95% CI 2.99-3.54]); AORs for severe anaemia associated with P. falciparum, P. vivax, and P. malariae were 2.11 (95% CI 2.00-2.23), 1.87 (95% CI 1.74-2.01), and 2.18 (95% CI 1.76-2.67), respectively, p<0.001.,Overall, 12.2% (95% CI 11.2%-13.3%) of severe anemia was attributable to non-falciparum infections compared with 15.1% (95% CI 13.9%-16.3%) for P. falciparum monoinfections.,Patients with severe anemia had an increased risk of death (AOR = 5.80 [95% CI 5.17-6.50]; p<0.001).,Not all patients had a hemoglobin measurement, thus limitations of the study include the potential for selection bias, and possible residual confounding in multivariable analyses.,In Papua P. vivax is the dominant cause of severe anemia in early infancy, mixed P. vivax/P. falciparum infections are associated with a greater hematological impairment than either species alone, and in adulthood P. malariae, although rare, is associated with the lowest hemoglobin concentration.,These findings highlight the public health importance of integrated genus-wide malaria control strategies in areas of Plasmodium co-endemicity.,Please see later in the article for the Editors' Summary,Malaria-a mosquito-borne parasitic disease-is a global public health problem.,Five parasites cause malaria-Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi.,Of these, P. vivax is the commonest and most widely distributed, whereas P. falciparum causes the most deaths-about a million every year.,All these parasites enter their human host when an infected mosquito takes a blood meal.,The parasites migrate to the liver where they replicate and mature into a parasitic form known as merozoites.,After 8-9 days, the merozoites are released from the liver cells and invade red blood cells where they replicate rapidly before bursting out and infecting more red blood cells.,Malaria's recurring flu-like symptoms are caused by this cyclical increase in parasites in the blood.,Malaria needs to be treated promptly with antimalarial drugs to prevent the development of potentially fatal complications.,Infections with P. falciparum in particular can cause anemia (a reduction in red blood cell numbers) and can damage the brain and other vital organs by blocking the capillaries that supply these organs with blood.,It is unclear what proportion of anemia is attributable to non-falciparum malarias in regions of the world where several species of malaria parasite are always present (Plasmodium co-endemicity).,Public health officials in such regions need to know whether non-falciparum malarias are a major cause of anemia when designing malaria control strategies.,If P. vivax, for example, is a major cause of anemia in an area where P. vivax and P. falciparum co-exist, then any malaria control strategies that are implemented need to take into account the biological differences between the parasites.,In this hospital-based cohort study, the researchers investigate the burden of severe anemia from the endemic Plasmodium species in southern Papua, Indonesia.,The researchers used hospital record numbers to link clinical and laboratory data for patients presenting to a referral hospital in southern Papua over an 8-year period.,The hemoglobin level (an indicator of anemia) was measured in about a quarter of hospital presentations (some patients attended the hospital several times).,A third of the presentations who had their hemoglobin level determined (67,696 presentations) had clinical malaria.,Patients with P. malariae infection had the lowest average hemoglobin concentration.,Patients with mixed species, P. falciparum, and P. vivax infections had slightly higher average hemoglobin levels but all these levels were below the normal range for people living in Papua.,Among the patients who had their hemoglobin status assessed, 3.7% had severe anemia.,After allowing for other factors that alter the risk of anemia (“confounding” factors such as age), patients with mixed Plasmodium infection were more than three times as likely to have severe anemia as patients without malaria.,Patients with P. falciparum, P. vivax, or P. malariae infections were about twice as likely to have severe anemia as patients without malaria.,About 12.2% of severe anemia was attributable to non-falciparum infections, 15.1% was attributable to P. falciparum monoinfections, and P. vivax was the dominant cause of severe anemia in infancy.,Finally, compared to patients without anemia, patients with severe anemia had nearly a 6-fold higher risk of death.,These findings provide a comparative assessment of the pattern of anemia associated with non-falciparum malarias in Papua and an estimate of the public health importance of these malarias.,Although the accuracy of these findings may be affected by residual confounding (for example, the researchers did not consider nutritional status when calculating how much malaria infection increases the risk of anemia) and other limitations of the study design, non-falciparum malarias clearly make a major contribution to the burden of anemia in southern Papua.,In particular, these findings reveal the large contribution that P. vivax makes to severe anemia in infancy, show that the hematological (blood-related) impact of P. malariae is most apparent in adulthood, and suggest, in contrast to some previous reports, that mixed P. vivax/P. falciparum infection is associated with a higher risk of severe anemia than monoinfection with either species.,These findings, which need to be confirmed in other settings, highlight the public health importance of implementing integrated malaria control strategies that aim to control all Plasmodium species rather than a single species in regions of Plasmodium co-endemicity.,Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001575.,This study is further discussed in a PLOS Medicine Perspective by Gosling and Hsiang,Information is available from the World Health Organization on malaria (in several languages); the 2012 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), including information on different Plasmodium species and a selection of personal stories about malaria,The Malaria Vaccine Initiative has fact sheets on Plasmodium falciparum malaria and on Plasmodium vivax malaria,MedlinePlus provides links to additional information on malaria and on anemia (in English and Spanish),Information is available from the WorldWide Antimalarial Resistance Network on antimalarial drug resistance for P. falciparum and P. vivax

Background.,Current malaria diagnostic tests, including microscopy and antigen-detecting rapid tests, cannot reliably detect low-density infections.,Molecular methods such as polymerase chain reaction (PCR) are highly sensitive but remain too complex for field deployment.,A new commercial molecular assay based on loop-mediated isothermal amplification (LAMP) was assessed for field use.,Methods.,Malaria LAMP (Eiken Chemical, Japan) was evaluated for samples from 272 outpatients at a rural Ugandan clinic and compared with expert microscopy, nested PCR, and quantitative PCR (qPCR).,Two technicians performed the assay after 3 days of training, using 2 alternative blood sample-preparation methods and visual interpretation of results by fluorescence assay.,Results.,Compared with 3-well nested PCR, the sensitivity of both LAMP and single-well nested PCR was 90%; the microscopy sensitivity was 51%.,For samples with a Plasmodium falciparum qPCR titer of ≥2 parasites/µL, LAMP sensitivity was 97.8% (95% confidence interval, 93.7%-99.5%).,Most false-negative LAMP results involved samples with parasitemia levels detectable by 3-well nested PCR but very low or undetectable by qPCR.,Conclusions.,Malaria LAMP in a remote Ugandan clinic achieved sensitivity similar to that of single-well nested PCR in a United Kingdom reference laboratory.,LAMP dramatically lowers the detection threshold achievable in malaria-endemic settings, providing a new tool for diagnosis, surveillance, and screening in elimination strategies.

Malaria rapid diagnostic tests (RDTs) offer significant potential to improve the diagnosis of malaria, and are playing an increasing role in malaria case management, control and elimination.,Peru, along with other South American countries, is moving to introduce malaria RDTs as components of malaria control programmes supported by the Global Fund for AIDS, TB and malaria.,The selection of the most suitable malaria RDTs is critical to the success of the programmes.,Eight of nine microscopy positive P. falciparum samples collected in Iquitos, Peru tested negative or weak positive using HRP2-detecting RDTs.,These samples were tested for the presence of pfhrp2 and pfhrp3 and their flanking genes by PCR, as well as the presence of HRP proteins by ELISA.,To investigate for geographic extent of HRP-deleted parasites and their temporal occurrence a retrospective study was undertaken on 148 microscopy positive P. falciparum samples collected in different areas of the Amazon region of Peru.,Eight of the nine isolates lacked the pfhrp2 and/or pfhrp3 genes and one or both flanking genes, and the absence of HRP was confirmed by ELISA.,The retrospective study showed that 61 (41%) and 103 (70%) of the 148 samples lacked the pfhrp2 or pfhrp3 genes respectively, with 32 (21.6%) samples lacking both hrp genes.,This is the first documentation of P. falciparum field isolates lacking pfhrp2 and/or pfhrp3.,The high frequency and wide distribution of different parasites lacking pfhrp2 and/or pfhrp3 in widely dispersed areas in the Peruvian Amazon implies that malaria RDTs targeting HRP2 will fail to detect a high proportion of P. falciparum in malaria-endemic areas of Peru and should not be used.,RDTs detecting parasite LDH or aldolase and quality microscopy should be use for malaria diagnosis in this region.,There is an urgent need for investigation of the abundance and geographic distribution of these parasites in Peru and neighbouring countries.

Controlled human malaria infection (CHMI) by direct venous inoculation (DVI) with 3,200 cryopreserved Plasmodium falciparum sporozoites (PfSPZ) consistently leads to parasitemia and malaria symptoms in malaria-naive adults.,We used CHMI by DVI to investigate infection rates, parasite kinetics, and malaria symptoms in lifelong malaria-exposed (semi-immune) Gabonese adults with and without sickle cell trait.,Eleven semi-immune Gabonese with normal hemoglobin (IA), nine with sickle cell trait (IS), and five nonimmune European controls with normal hemoglobin (NI) received 3,200 PfSPZ by DVI and were followed 28 days for parasitemia by thick blood smear (TBS) and quantitative polymerase chain reaction (qPCR) and for malaria symptoms.,End points were time to parasitemia and parasitemia plus symptoms.,PfSPZ Challenge was well tolerated and safe.,Five of the five (100%) NI, 7/11 (64%) IA, and 5/9 (56%) IS volunteers developed parasitemia by TBS, and 5/5 (100%) NI, 9/11 (82%) IA, and 7/9 (78%) IS by qPCR, respectively.,The time to parasitemia by TBS was longer in IA (geometric mean 16.9 days) and IS (19.1 days) than in NA (12.6 days) volunteers (P = 0.016, 0.021, respectively).,Five of the five, 6/9, and 1/7 volunteers with parasitemia developed symptoms (P = 0.003, NI versus IS).,Naturally adaptive immunity (NAI) to malaria significantly prolonged the time to parasitemia.,Sickle cell trait seemed to prolong it further.,NAI plus sickle cell trait, but not NAI alone, significantly reduced symptom rate.,Twenty percent (4/20) semi-immunes demonstrated sterile protective immunity.,Standardized CHMI with PfSPZ Challenge is a powerful tool for dissecting the impact of innate and naturally acquired adaptive immunity on malaria.

Effective progression of candidate antimalarials is dependent on optimal dosing in clinical studies, which is determined by a sound understanding of pharmacokinetics and pharmacodynamics (PK/PD).,Recently, two important translational models for antimalarials have been developed: the NOD/SCID/IL2Rγ−/− (NSG) model, whereby mice are engrafted with noninfected and Plasmodium falciparum-infected human erythrocytes, and the induced blood-stage malaria (IBSM) model in human volunteers.,The antimalarial mefloquine was used to directly measure the PK/PD in both models, which were compared to previously published trial data for malaria patients.,The clinical part was a single-center, controlled study using a blood-stage Plasmodium falciparum challenge inoculum in volunteers to characterize the effectiveness of mefloquine against early malaria.,The study was conducted in three cohorts (n = 8 each) using different doses of mefloquine.,The characteristic delay in onset of action of about 24 h was seen in both NSG and IBSM systems.,In vivo 50% inhibitory concentrations (IC50s) were estimated at 2.0 μg/ml and 1.8 μg/ml in the NSG and IBSM models, respectively, aligning with 1.8 μg/ml reported previously for patients.,In the IBSM model, the parasite reduction ratios were 157 and 195 for the 10- and 15-mg/kg doses, within the range of previously reported clinical data for patients but significantly lower than observed in the mouse model.,Linking mouse and human challenge models to clinical trial data can accelerate the accrual of critical data on antimalarial drug activity.,Such data can guide large clinical trials required for development of urgently needed novel antimalarial combinations.,(This trial was registered at the Australian New Zealand Clinical Trials Registry [http://anzctr.org.au] under registration number ACTRN12612000323820.)

The RTS,S/AS01 malaria vaccine candidate recently completed Phase III trials in 11 African sites.,Recommendations for its deployment will partly depend on predictions of public health impact in endemic countries.,Previous predictions of these used only limited information on underlying vaccine properties and have not considered country-specific contextual data.,Each Phase III trial cohort was simulated explicitly using an ensemble of individual-based stochastic models, and many hypothetical vaccine profiles.,The true profile was estimated by Bayesian fitting of these models to the site- and time-specific incidence of clinical malaria in both trial arms over 18 months of follow-up.,Health impacts of implementation via two vaccine schedules in 43 endemic sub-Saharan African countries, using country-specific prevalence, access to care, immunisation coverage and demography data, were predicted via weighted averaging over many simulations.,The efficacy against infection of three doses of vaccine was initially approximately 65 % (when immunising 6-12 week old infants) and 80 % (children 5-17 months old), with a 1 year half-life (exponential decay).,Either schedule will avert substantial disease, but predicted impact strongly depends on the decay rate of vaccine effects and average transmission intensity.,For the first time Phase III site- and time-specific data were available to estimate both the underlying profile of RTS,S/AS01 and likely country-specific health impacts.,Initial efficacy will probably be high, but decay rapidly.,Adding RTS,S to existing control programs, assuming continuation of current levels of malaria exposure and of health system performance, will potentially avert 100-580 malaria deaths and 45,000 to 80,000 clinical episodes per 100,000 fully vaccinated children over an initial 10-year phase.,The online version of this article (doi:10.1186/s12916-015-0408-2) contains supplementary material, which is available to authorized users.

Despite years of effort, a licensed malaria vaccine is not yet available.,One of the obstacles facing the development of a malaria vaccine is the extensive heterogeneity of many of the current malaria vaccine antigens.,To counteract this antigenic diversity, an effective malaria vaccine may need to elicit an immune response against multiple malaria antigens, thereby limiting the negative impact of variability in any one antigen.,Since most of the malaria vaccine antigens that have been evaluated in people have not elicited a protective immune response, there is a need to identify additional protective antigens.,In this study, the efficacy of three pre-erythrocytic stage malaria antigens was evaluated in a Plasmodium yoelii/mouse protection model.,Mice were immunized with plasmid DNA and vaccinia virus vectors that expressed one, two or all three P. yoelii vaccine antigens.,The immunized mice were challenged with 300 P. yoelii sporozoites and evaluated for subsequent infection.,Vaccines that expressed any one of the three antigens did not protect a high percentage of mice against a P. yoelii challenge.,However, vaccines that expressed all three antigens protected a higher percentage of mice than a vaccine that expressed PyCSP, the most efficacious malaria vaccine antigen.,Dissection of the multi-antigen vaccine indicated that protection was primarily associated with two of the three P. yoelii antigens.,The protection elicited by a vaccine expressing these two antigens exceeded the sum of the protection elicited by the single antigen vaccines, suggesting a potential synergistic interaction.,This work identifies two promising malaria vaccine antigen candidates and suggests that a multi-antigen vaccine may be more efficacious than a single antigen vaccine.

Background: Antimalarial antibody measurements are useful because they reflect historical and recent exposure to malaria.,As such, they may provide additional information to assess ongoing transmission in low endemic or pre-elimination settings where cases are rare.,In addition, the absence of antibody responses in certain individuals can indicate the cessation of transmission.,Commercial malaria enzyme-linked immunosorbent assays (ELISA) detect antimalarial antibodies and are commonly used to screen blood donations for possible malaria infection.,However, there is no standardized test to detect antimalarial antibodies for epidemiological use.,Here we compared five commercially available ELISA kits (Trinity Biotech, newbio, DiaPro, Cellabs, and NovaTec) in search of a standardized tool for supporting claims of absence of malaria transmission.,For comparison, a research-based (RB) ELISA protocol was performed alongside the commercial kits.,Results: The commercial kits were first compared using serum samples from known malaria-unexposed individuals (n = 223) and Toxoplasma-infected individuals (n = 191) to assess specificity and cross-reactivity against non-malaria infections.,In addition, 134 samples from ≥10-year-olds collected in a hyperendemic region in the Gambia in the early 1990s were used to assess sensitivity.,Three out of five kits showed high sensitivity (90-92%), high specificity (98-99%), low cross-reactivity (0-3%) and were considered user-friendly (Trinity Biotech, newbio and NovaTec).,Two of these kits (Trinity Biotech and NovaTec) were taken forward for epidemiological evaluation and results were compared to those using the RB-ELISA.,Samples from two pre-elimination settings (Praia, Cape Verde; n = 1,396, and Bataan, the Philippines; n = 1,824) were tested.,Serological results from both the Trinity Biotech kit and the RB-ELISA concurred with recent passively detected case counts in both settings.,Results from the Trinity Biotech kit reflected a significant decrease in the number of reported cases in Bataan in the 1990s better than the RB-ELISA.,Results from the NovaTec kit did not reflect transmission patterns in either setting.,Conclusion: The Trinity Biotech commercial ELISA kit was considered reliable for epidemiological use and accurately described transmission patterns in two (previously) malaria endemic settings.,The use of this simple and standardized serological tool may aid national control and elimination programs by confirming that regions are free from malaria.

Analyses of a case-control study among Afghan refugees in Pakistan find that a G6PD (glucose-6-phosphate dehydrogenase) “Mediterranean” type deficiency confers substantial protection against Plasmodium vivax malaria.,The most common form of malaria outside Africa, Plasmodium vivax, is more difficult to control than P. falciparum because of the latent liver hypnozoite stage, which causes multiple relapses and provides an infectious reservoir.,The African (A−) G6PD (glucose-6-phosphate dehydrogenase) deficiency confers partial protection against severe P. falciparum.,Recent evidence suggests that the deficiency also confers protection against P. vivax, which could explain its wide geographical distribution in human populations.,The deficiency has a potentially serious interaction with antirelapse therapies (8-aminoquinolines such as primaquine).,If the level of protection was sufficient, antirelapse therapy could become more widely available.,We therefore tested the hypothesis that G6PD deficiency is protective against vivax malaria infection.,A case-control study design was used amongst Afghan refugees in Pakistan.,The frequency of phenotypic and genotypic G6PD deficiency in individuals with vivax malaria was compared against controls who had not had malaria in the previous two years.,Phenotypic G6PD deficiency was less common amongst cases than controls (cases: 4/372 [1.1%] versus controls 42/743 [5.7%]; adjusted odds ratio [AOR] 0.18 [95% confidence interval (CI) 0.06-0.52], p = 0.001).,Genetic analysis demonstrated that the G6PD deficiency allele identified (Mediterranean type) was associated with protection in hemizygous deficient males (AOR = 0.12 [95% CI 0.02-0.92], p = 0.041).,The deficiency was also protective in females carrying the deficiency gene as heterozygotes or homozygotes (pooled AOR = 0.37 [95% CI 0.15-0.94], p = 0.037).,G6PD deficiency (Mediterranean type) conferred significant protection against vivax malaria infection in this population whether measured by phenotype or genotype, indicating a possible evolutionary role for vivax malaria in the selective retention of the G6PD deficiency trait in human populations.,Further work is required on the genotypic protection associated with other types of G6PD deficiency and on developing simple point-of-care technologies to detect it before administering antirelapse therapy.,Please see later in the article for the Editors' Summary,Malaria is a parasitic infection transmitted to people through the bite of an infected mosquito.,Although Plasmodium falciparum is responsible for most malaria deaths, P. vivax is the commonest, most widespread cause of malaria outside sub-Saharan Africa.,Like other malaria parasites, P. vivax has a complex life cycle.,Infected mosquitoes inject a parasitic form known as sporozoites into people where they replicate inside liver cells without causing symptoms.,About 8-9 days later, merozoites (another parasitic form) are released from the liver cells and invade red blood cells.,Here, they replicate rapidly before bursting out and infecting more red blood cells.,This increase in the parasitic burden causes malaria's characteristic symptoms (debilitating and recurring chills and fevers).,P. vivax infections are usually treated with chloroquine (although resistance to this drug is now emerging) but patients must also take primaquine, a drug that kills hypnozoites, a form of P. vivax that hibernates in the liver.,Hypnozoites can cause a relapse months after the initial bout of malaria and make P. vivax malaria harder to control than P. faciparum malaria.,Some mutations (DNA changes) protect their human carriers against specific disease-causing organisms.,These mutations occur at high frequencies in populations where these organisms are common.,For example, the widespread distribution of mutations that cause a deficiency in an enzyme called glucose-6-phosphate dehydrogenase (G6PD) mirrors the distribution of malaria and the African (A−) form of G6PD deficiency, a type of G6PD deficiency that is common in people of African origin, is known to provide partial protection against severe P. falciparum malaria-P. falciparum does not thrive in G6PD-deficient red blood cells.,In areas where P. vivax malaria is common, Mediterranean and Asian variants of G6PD deficiency are more widespread than A− G6PD, so the question is, do these variants protect against P. vivax malaria?,In this case-control study (a study in which the characteristics of people with and without a specific condition are compared), the researchers investigate whether G6PD deficiency protects against P. vivax infection in a population of Afghan refugees living in Pakistan.,The researchers enrolled 372 Afghan refugees who had had P. vivax malaria during the previous two years and 743 refugees who had not had malaria over the same period.,They measured G6PD activity in the participants' blood to detect “phenotypic” G6PD deficiency (reduced enzyme activity) and looked for the Mediterranean variant of the G6PD gene in the participants (“genotypic” G6PD deficiency).,5.7% of the controls but only 1.1% of the cases had phenotypic G6PD deficiency.,Statistical analyses indicated that participants with reduced G6PD levels were about one-fifth as likely to develop P. vivax malaria as those with normal G6PD levels after allowing for other factors that might affect their susceptibility to malaria, an adjusted odds ratio (AOR) of 0.18.,The genetic analysis indicated that the Mediterranean G6PD gene variant provided protection against P. vivax infection in men (AOR 0.12) and in women carrying either one or two defective copies of the G6PD gene (AOR 0.37); because the G6PD gene is on the X chromosome, men have only one copy of the gene but women have two copies.,These findings indicate that Mediterranean-type G6PD deficiency protects against P. vivax malaria infection in this population of Afghan refugees.,Although further studies are needed to determine whether other G6PD variants protect against P. vivax malaria, these findings suggest that P. vivax malaria might be responsible for the retention of the G6PD deficiency trait in some human populations.,In addition, these findings may have implications for the treatment of P. vivax malaria.,Currently, in most places where P. vivax malaria is common, primaquine is not given routinely because primaquine can trigger red blood cell death (hemolytic anemia) in G6PD-deficient people and tests for G6PD deficiency are rarely available.,These findings suggest that the risk of exposure to primaquine among people infected with P. vivax might be lower than previously assumed, because G6PD deficiency is less common among P. vivax-infected patients than among the general population.,Nevertheless, these findings are unlikely to increase the use of primaquine immediately.,Such an increase, the researchers suggest, will only occur if a simple test for G6PD deficiency is developed.,Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000283.,Information is available from the World Health Organization on malaria (in several languages),The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish),Information is available from the Wellcome Trust on all aspects of malaria, including a news item about G6PD deficiency protecting against severe P. falciparum malaria,MedlinePlus provides links to additional information on malaria (in English and Spanish),The Malaria Vaccine Initiative has a fact sheet on Plasmodium vivax malaria,Vivaxmalaria provides information about P. vivax,More about G6PD deficiency can be found on KidsHealth from the Nemours Children's Health System

An accurate diagnosis of soil-transmitted helminthiasis is important for individual patient management, for drug efficacy evaluation and for monitoring control programmes.,The Kato-Katz technique is the most widely used method detecting soil-transmitted helminth eggs in faecal samples.,However, detailed analyses of quality control, including false-positive and faecal egg count (FEC) estimates, have received little attention.,Over a 3-year period, within the frame of a series of randomised controlled trials conducted in Pemba, United Republic of Tanzania, 10% of randomly selected Kato-Katz thick smears were re-read for Trichuris trichiura and Ascaris lumbricoides eggs.,In case of discordant result (i.e. positive versus negative) the slides were re-examined a third time.,A result was assumed to be false-positive or false-negative if the result from the initial reading did not agree with the quality control as well as the third reading.,We also evaluated the general agreement in FECs between the first and second reading, according to internal and World Health Organization (WHO) guidelines.,From the 1,445 Kato-Katz thick smears subjected to quality control, 1,181 (81.7%) were positive for T. trichiura and 290 (20.1%) were positive for A. lumbricoides.,During quality control, very low rates of false-positive results were observed; 0.35% (n = 5) for T. trichiura and 0.28% (n = 4) for A. lumbricoides.,False-negative readings of Kato-Katz thick smears were obtained in 28 (1.94%) and 6 (0.42%) instances for T. trichiura and A. lumbricoides, respectively.,A high frequency of discordant results in FECs was observed (i.e.,10.0-23.9% for T. trichiura, and 9.0-11.4% for A. lumbricoides).,Our analyses show that the rate of false-positive diagnoses of soil-transmitted helminths is low.,As the probability of false-positive results increases after examination of multiple stool samples from a single individual, the potential influence of false-positive results on epidemiological studies and anthelminthic drug efficacy studies should be determined.,Existing WHO guidelines for quality control might be overambitious and might have to be revised, specifically with regard to handling disagreements in FECs.

The first-ever round of school-based mass drug administration (MDA) with praziquantel together with mebendazole targeting school-aged children in endemic districts was conducted in 2009 by the National Neglected Tropical Diseases Control Program.,To evaluate the impact of the treatment regimen, a cross-sectional sentinel site survey was conducted 6 months post-MDA.,Fifteen sentinel schools from six highly endemic districts (according to data from national and pre-MDA surveys) with Schistosoma mansoni affecting over 50% of the population, and moderate to high prevalence of hookworms (> 20%).,Approximately 30 children aged 9-14 years were selected from each school and stool samples (one per student) were examined by the Kato-Katz method.,The overall prevalence (and intensity) in these sentinel sites pre-MDA of S. mansoni was 69.0% (170.8 epg), hookworm: 41.7% (71.7 epg), Ascaris lumbricoides: 1.8% and Trichuris trichiura: 3.8%.,Six months post MDA, the findings were S. mansoni: 38.2% (47.3 epg) and hookworm: 14.5% (8.7 epg), representing a reduction from pre-MDA levels of 44.6% (65.2%) and 72.3% (87.9%) respectively.,The proportion of children who were moderately or heavily infected with S. mansoni fell from 35.6% pre MDA to 9.9% post MDA.,Significant reduction in S. mansoni and hookworm infection was achieved by this first round MDA in school-going children in Sierra Leone.,This reduction in infection burden can potentially contribute to a reduction of morbidity, such as anaemia, in these children.

China has made great progress in malaria control over the last century and now aims to eliminate malaria by 2020.,In 2012, the country launched its 1-3-7 surveillance and response strategy for malaria elimination.,The strategy involves to case reporting within 1 day, case investigation within 3 days, and focus investigation and public health actions within 7 days.,The aim of this study was to evaluate the challenges in and lessons learned during the implementation of the 1-3-7 strategy in China so far.,This qualitative study was conducted in two provinces in China: Gansu province (northwestern China) and Jiangsu province (southeastern China) in 2014.,Key informant interviews (n = 6) and in-depth interviews (n = 36) about the implementation aspects of the 1-3-7 strategy were conducted with malaria experts, health staff, laboratory practitioners, and village doctors at the provincial, city, county, township, and village levels.,Broad themes related to the challenges in and lessons learned during the implementation of the 1-3-7 strategy were identified according to: case reporting within 1 day, case investigation within 3 days, focus investigation within 7 days, and the overall strategy.,The major challenges outlined were related to respecting the timeline of surveillance procedures, the absence of or difficulties in following guidelines on conducting focus investigations, diagnostics, and the increasing number of returning migrant workers from malaria-endemic countries.,Important lessons learned revolve around the importance of continuous capacity building, supervision and motivation, quality control, information technology support, applied research, governmental commitment, and intersectoral collaboration.,Surveillance is a key intervention in malaria elimination programs.,The Chinese 1-3-7 strategy has already proven to be successful but still needs to be improved.,In particular, dealing appropriately with imported malaria cases through the screening of migrant workers from malaria-endemic countries is essential for achieving and sustaining malaria elimination in China.,China has perfect preconditions for successful malaria elimination provided political commitment and financial investment are guaranteed.,The 1-3-7 strategy may also be considered as a model for other countries.,The online version of this article (doi:10.1186/s40249-016-0188-8) contains supplementary material, which is available to authorized users.

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

Strongyloides stercoralis is a soil-transmitted nematode that can replicate within its host, leading to long-lasting and potentially fatal infections.,It is ubiquitous and highly prevalent in Cambodia.,The extent of morbidity associated with S. stercoralis infection is difficult to assess due to the broad spectrum of symptoms and, thus, remains uncertain.,Clinical signs were compared among S. stercoralis infected vs. non-infected participants in a cross-sectional survey conducted in 2012 in eight villages of Northern Cambodia, and before and after treatment with a single oral dose of ivermectin (200μg/kg BW) among participants harboring S. stercoralis.,Growth retardation among schoolchildren and adolescents was assessed using height-for-age and thinness using body mass index-for-age.,S. stercoralis prevalence was 31.1% among 2,744 participants.,Urticaria (55% vs.,47%, OR: 1.4, 95% CI: 1.1-1.6) and itching (52% vs.,48%, OR: 1.2, 95% CI: 1.0-1.4) were more frequently reported by infected participants.,Gastrointestinal, dermatological, and respiratory symptoms were less prevalent in 103 mono-infected participants after treatment.,Urticaria (66% vs.,11%, OR: 0.03, 95% CI: 0.01-0.1) and abdominal pain (81 vs.,27%, OR: 0.07, 95% CI: 0.02-0.2) mostly resolved by treatment.,S. stercoralis infection was associated with stunting, with 2.5-fold higher odds in case of heavy infection.,The morbidity associated with S. stercoralis confirmed the importance of gastrointestinal and dermatological symptoms unrelated to parasite load, and long-term chronic effects when associated with malnutrition.,The combination of high prevalence and morbidity calls for the integration of S. stercoralis into ongoing STH control measures in Cambodia.

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

We carried out a study to compare the performance, in terms of sensitivity and specificity, of the new SD BIOLINE® HAT rapid diagnostic test (RDT) with the card agglutination test for trypanosomiasis (CATT) for diagnosis of human African trypanosomiasis (HAT) in the Democratic Republic of the Congo (DRC).,Participants were enrolled actively by four mobile teams, and passively at four health facilities in three provinces.,Consenting participants were tested concurrently with the RDT and CATT on whole blood.,Those found positive by either test were tested with CATT on serial dilutions of plasma, and with a parasitological composite reference standard (CRS).,Cases were only the individuals found positive by the CRS, while controls were negative by both CATT and RDT, as well as those that were positive by CATT or RDT, but were negative by the CRS, and had no history of HAT.,Over five months, 131 cases and 13,527 controls were enrolled.,The sensitivity of the RDT was 92.0% (95% confidence interval (CI) = 86.1-95.5), which was significantly higher than CATT (sensitivity 69.1%; 95% CI = 60.7-76.4).,The sensitivity of CATT on plasma at a dilution of 1:8 was 59.0% (95% CI = 50.2-67.2).,The specificity of the RDT was 97.1% (95% CIs = 96.8-97.4) while that of CATT was 98.0% (95% CIs = 97.8, 98.2) and specificities of algorithms involving CATT at 1:8 dilution were 99.6% (95% CI = 99.5-99.7).,Reproducibility of results was excellent.,We concluded that an algorithm in which the SD BIOLINE® HAT RDT is used for screening is optimal for case detection in both passive and active screening settings.,However, the lower specificity of the RDT compared to that of CATT would result in a larger number of false positive individuals undergoing confirmatory testing.

Gambian sleeping sickness (human African trypanosomiasis, HAT) outbreaks are brought under control by case detection and treatment although it is recognised that this typically only reaches about 75% of the population.,Vector control is capable of completely interrupting HAT transmission but is not used because it is considered too expensive and difficult to organise in resource-poor settings.,We conducted a full scale field trial of a refined vector control technology to determine its utility in control of Gambian HAT.,The major vector of Gambian HAT is the tsetse fly Glossina fuscipes which lives in the humid zone immediately adjacent to water bodies.,From a series of preliminary trials we determined the number of tiny targets required to reduce G. fuscipes populations by more than 90%.,Using these data for model calibration we predicted we needed a target density of 20 per linear km of river in riverine savannah to achieve >90% tsetse control.,We then carried out a full scale, 500 km2 field trial covering two HAT foci in Northern Uganda to determine the efficacy of tiny targets (overall target density 5.7/km2).,In 12 months, tsetse populations declined by more than 90%.,As a guide we used a published HAT transmission model and calculated that a 72% reduction in tsetse population is required to stop transmission in those settings.,The Ugandan census suggests population density in the HAT foci is approximately 500 per km2.,The estimated cost for a single round of active case detection (excluding treatment), covering 80% of the population, is US$433,333 (WHO figures).,One year of vector control organised within the country, which can completely stop HAT transmission, would cost US$42,700.,The case for adding this method of vector control to case detection and treatment is strong.,We outline how such a component could be organised.

RNA-sequencing was used to detect transcriptional changes in six tissues of cats, seven days after T. gondii infection.,A total of 737 genes were differentially expressed (DEGs), of which 410 were up-regulated and 327 were down-regulated.,The liver exhibited 151 DEGs, lung (149 DEGs), small intestine (130 DEGs), heart (123 DEGs), brain (104 DEGs), and spleen (80 DEGs)-suggesting tissue-specific transcriptional patterns.,Gene ontology and KEGG analyses identified DEGs enriched in immune pathways, such as cytokine-cytokine receptor interaction, Jak-STAT signaling pathway, NOD-like receptor signaling pathway, NF-kappa B signaling pathway, MAPK signaling pathway, T cell receptor signaling pathway, and the cytosolic DNA sensing pathway.,C-X-C motif chemokine 10 (CXCL10) was involved in most of the immune-related pathways.,PI3K/Akt expression was down-regulated in all tissues, except the spleen.,The genes for phosphatase, indoleamine 2,3-dioxygenase, Hes Family BHLH Transcription Factor 1, and guanylate-binding protein 5, playing various roles in immune defense, were co-expressed across various feline tissues.,Multivariate K-means clustering analysis produced seven gene clusters featuring similar gene expression patterns specific to individual tissues, with lung tissue cluster having the largest number of DEGs.,These findings suggest the presence of a broad immune defense mechanism across various tissues in cats against acute T. gondii infection.

Toxoplasma gondii is an important zoonotic pathogen infecting one-third of the world’s population and numerous animals, causing significant healthcare burden and socioeconomic problems.,Vaccination is an efficient way to reduce global sero-prevalence, however, ideal vaccines are not yet available.,We recently discovered that the Toxoplasma mutant lacking both lactate dehydrogenases LDH1 and LDH2 (Δldh) grew well in vitro but was unable to propagate in mice, making it a good live vaccine candidate.,Here, we tested the protection efficacy of ME49 Δldh using a mouse model.,Vaccinated mice were efficiently protected from the lethal challenge of a variety of wild-type strains, including type 1 strain RH, type 2 strain ME49, type 3 strain VEG, and a field isolate of Chinese 1.,The protection efficacies of a single vaccination were nearly 100% for most cases and it worked well against the challenges of both tachyzoites and tissue cysts.,Re-challenging parasites were unable to propagate in vaccinated mice, nor did they make tissue cysts.,High levels of Toxoplasma-specific IgG were produced 30 days after immunization and stayed high during the whole tests (at least 125 days).,However, passive immunization of naïve mice with sera from vaccinated mice did reduce parasite propagation, but the overall protection against parasite infections was rather limited.,On the other hand, Δldh immunization evoked elevated levels of Th1 cytokines like INF-γ and IL-12, at early time points.,In addition, splenocytes extracted from immunized mice were able to induce quick and robust INF-γ and other pro-inflammatory cytokine production upon T. gondii antigen stimulation.,Together these results suggest that cellular immune responses are the main contributors to the protective immunity elicited by Δldh vaccination, and humoral immunity also contributes partially.,We also generated uracil auxotrophic mutants in ME49 and compared their immune protection efficiencies to the Δldh mutants.,The results showed that these two types of mutants have similar properties as live vaccine candidates.,Taken together, these results suggest that mutants lacking LDH were severely attenuated in virulence but were able to induce strong anti-toxoplasma immune responses, therefore are good candidates for live vaccines.

Since the demonstration of sterile protection afforded by injection of irradiated sporozoites, CD8+ T cells have been shown to play a significant role in protection from liver-stage malaria.,This is, however, dependent on the presence of an extremely high number of circulating effector cells, thought to be necessary to scan, locate, and kill infected hepatocytes in the short time that parasites are present in the liver.,We used an adoptive transfer model to elucidate the kinetics of the effector CD8+ T cell response in the liver following Plasmodium berghei sporozoite challenge.,Although effector CD8+ T cells require <24 h to find, locate, and kill infected hepatocytes, active migration of Ag-specific CD8+ T cells into the liver was not observed during the 2-d liver stage of infection, as divided cells were only detected from day 3 postchallenge.,However, the percentage of donor cells recruited into division was shown to indicate the level of Ag presentation from infected hepatocytes.,By titrating the number of transferred Ag-specific effector CD8+ T cells and sporozoites, we demonstrate that achieving protection toward liver-stage malaria is reliant on CD8+ T cells being able to locate infected hepatocytes, resulting in a protection threshold dependent on a fine balance between the number of infected hepatocytes and CD8+ T cells present in the liver.,With such a fine balance determining protection, achieving a high number of CD8+ T cells will be critical to the success of a cell-mediated vaccine against liver-stage malaria.

Background.,Immunization of healthy volunteers by bites from Plasmodium falciparum-infected mosquitoes during chloroquine chemoprophylaxis (hereafter, chemoprophylaxis and sporozoites [CPS] immunization) induces sterile protection against malaria.,CPS-induced protection is mediated by immunity against pre-erythrocytic stages, presumably at least partially by cytotoxic cellular responses.,We therefore aimed to investigate the association of CPS-induced cytotoxic T-cell markers with protection.,Methods.,In a double-blind randomized controlled trial, we performed dose titration of CPS immunization followed by homologous challenge infection in 29 subjects.,Immune responses were assessed by in vitro restimulation of peripheral blood mononuclear cells and flow cytometry.,Results.,Dose-dependent complete protection was obtained in 4 of 5 volunteers after immunization with bites from 45 P. falciparum-infected mosquitoes, in 8 of 9 volunteers with bites from 30, and in 5 of 10 volunteers with bites from 15 (odds ratio [OR], 5.0; 95% confidence interval [CI], 1.5-17).,Completely protected subjects had significantly higher proportions of CD4 T cells expressing the degranulation marker CD107a (OR, 8.4; 95% CI, 1.5-123; P = .011) and CD8 cells producing granzyme B (OR, 11; 95% CI, 1.9-212; P = .004) after P. falciparum restimulation.,Conclusions.,These data underline the efficiency of CPS immunization to induce sterile protection and support a possible role for cytotoxic CD4 and CD8 T-cell responses in pre-erythrocytic immunity.,Clinical Trials Registration.,NCT01218893.

Malaria is an increasing concern in Indonesia.,Socio-demographic factors were found to strongly influence malaria prevalence.,This research aimed to explore the associations between socio-demographic factors and malaria prevalence in Indonesia.,The study used a cross-sectional design and analysed relationships among the explanatory variables of malaria prevalence in five endemic provinces using multivariable logistic regression.,The analysis of baseline socio-demographic data revealed the following independent risk variables related to malaria prevalence: gender, age, occupation, knowledge of the availability of healthcare services, measures taken to protect from mosquito bites, and housing condition of study participants.,Multivariable analysis showed that participants who were unaware of the availability of health facilities were 4.2 times more likely to have malaria than those who were aware of the health facilities (adjusted odds ratio = 4.18; 95% CI 1.52-11.45; P = 0.005).,Factors that can be managed and would favour malaria elimination include a range of prevention behaviours at the individual level and using the networks at the community level of primary healthcare centres.,This study suggests that improving the availability of a variety of health facilities in endemic areas, information about their services, and access to these is essential.,The online version of this article (10.1186/s12936-019-2760-8) contains supplementary material, which is available to authorized users.

Extensive employment of long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) has substantially reduced malaria morbidity and mortality in sub-Saharan Africa.,These tools target indoor resting and biting vectors, and may select for vectors that bite and rest outdoors.,Thus, to significantly impact this residual malaria transmission outdoors, tools targeting outdoor transmission are required.,Repellents, used for personal protection, offer one solution.,However, the effectiveness of this method hinges upon its community acceptability.,This study assessed the feasibility of using repellents as a malaria prevention tool in Mbingu village, Ulanga, Southern Tanzania.,Change in knowledge, attitude and practice (KAP) in relation to repellent use was assessed before and after the implementation of a cluster randomized clinical trial on topical repellents in rural Tanzania where repellent and placebo lotion were provided free of charge to 940 households for a period of 14 months between July 2009 and August 2010.,Compliance, defined as the number of evenings that participants applied the recommended dose of repellent every month during the study period, was assessed using questionnaires, administered monthly during follow up of participants in the clinical trial.,Focus group discussions (FGDs) were conducted in the same community three years later to assess the community’s KAP in relation to repellents and preference to different repellent formats.,At baseline, only 0.32% (n = 2) households in the intervention arm and no households in the control arm had ever used topical repellents.,During follow-up surveys, significantly more households, 100% (n = 457) in intervention arm relative to the control, 84.03% (n = 379), (p = <0.001) perceived the repellent to be effective.,Post-study, 99.78% (n = 462) and 99.78% (n = 463), (p = 0.999) in the intervention and control arms respectively, were willing to continue repellent use.,Mosquito nuisance motivated repellent use.,From the FGDs, it emerged that most respondents preferred bed nets to repellents because of their longevity and cost effectiveness.,High repellent acceptability indicates their feasibility for malaria control in this community.,However, to improve the community’s uptake of repellents for use complimentary to LLINs for early evening and outdoor protection from mosquito bites, longer lasting and cheap formats are required.,The online version of this article (doi:10.1186/1475-2875-13-347) contains supplementary material, which is available to authorized users.

Chagas disease is caused by the parasite Trypanosoma cruzi, and it begins with a short acute phase characterized by high parasitemia followed by a life-long chronic phase with scarce parasitism.,Cardiac involvement is the most prominent manifestation, as 30% of infected subjects will develop abnormal ventricular repolarization with myocarditis, fibrosis and cardiomyocyte hypertrophy by undefined mechanisms.,Nevertheless, follow-up studies in chagasic patients, as well as studies with murine models, suggest that the intensity of clinical symptoms and pathophysiological events that occur during the acute phase of disease are associated with the severity of cardiac disease observed during the chronic phase.,In the present study we investigated the role of microRNAs (miRNAs) in the disease progression in response to T. cruzi infection, as alterations in miRNA levels are known to be associated with many cardiovascular disorders.,We screened 641 rodent miRNAs in heart samples of mice during an acute infection with the Colombiana T.cruzi strain and identified multiple miRNAs significantly altered upon infection.,Seventeen miRNAs were found significantly deregulated in all three analyzed time points post infection.,Among these, six miRNAs had their expression correlated with clinical parameters relevant to the disease, such as parasitemia and maximal heart rate-corrected QT (QTc) interval.,Computational analyses identified that the gene targets for these six miRNAs were involved in networks and signaling pathways related to increased ventricular depolarization and repolarization times, important factors for QTc interval prolongation.,The data presented here will guide further studies about the contribution of microRNAs to Chagas heart disease pathogenesis.

In Chagas disease, CD8+ T-cells are critical for the control of Trypanosoma cruzi during acute infection.,Conversely, CD8+ T-cell accumulation in the myocardium during chronic infection may cause tissue injury leading to chronic chagasic cardiomyopathy (CCC).,Here we explored the role of CD8+ T-cells in T. cruzi-elicited heart injury in C57BL/6 mice infected with the Colombian strain.,Cardiomyocyte lesion evaluated by creatine kinase-MB isoenzyme activity levels in the serum and electrical abnormalities revealed by electrocardiogram were not associated with the intensity of heart parasitism and myocarditis in the chronic infection.,Further, there was no association between heart injury and systemic anti-T. cruzi CD8+ T-cell capacity to produce interferon-gamma (IFNγ) and to perform specific cytotoxicity.,Heart injury, however, paralleled accumulation of anti-T. cruzi cells in the cardiac tissue.,In T. cruzi infection, most of the CD8+ T-cells segregated into IFNγ+ perforin (Pfn)neg or IFNγnegPfn+ cell populations.,Colonization of the cardiac tissue by anti-T. cruzi CD8+Pfn+ cells paralleled the worsening of CCC.,The adoptive cell transfer to T. cruzi-infected cd8 −/− recipients showed that the CD8+ cells from infected ifnγ−/− pfn +/+ donors migrate towards the cardiac tissue to a greater extent and caused a more severe cardiomyocyte lesion than CD8+ cells from ifnγ +/+ pfn −/− donors.,Moreover, the reconstitution of naïve cd8 −/− mice with CD8+ cells from naïve ifnγ +/+ pfn −/− donors ameliorated T. cruzi-elicited heart injury paralleled IFNγ+ cells accumulation, whereas reconstitution with CD8+ cells from naïve ifnγ −/− pfn +/+ donors led to an aggravation of the cardiomyocyte lesion, which was associated with the accumulation of Pfn+ cells in the cardiac tissue.,Our data support a possible antagonist effect of CD8+Pfn+ and CD8+IFNγ+ cells during CCC.,CD8+IFNγ+ cells may exert a beneficial role, whereas CD8+Pfn+ may play a detrimental role in T. cruzi-elicited heart injury.

Drug shops are a major source of care for children in low income countries but they provide sub-standard care.,We assessed the feasibility and effect on quality of care of introducing diagnostics and pre-packaged paediatric-dosage drugs for malaria, pneumonia and diarrhoea at drug shops in Uganda.,We adopted and implemented the integrated community case management (iCCM) intervention within registered drug shops.,Attendants were trained to perform malaria rapid diagnostic tests (RDTs) in each fever case and count respiratory rate in each case of cough with fast/difficult breathing, before dispensing recommended treatment.,Using a quasi-experimental design in one intervention and one non-intervention district, we conducted before and after exit interviews for drug seller practices and household surveys for treatment-seeking practices in May-June 2011 and May-June 2012.,Survey adjusted generalized linear models and difference-in-difference analysis was used.,3759 (1604 before/2155 after) household interviews and 943 (163 before/780 after) exit interviews were conducted with caretakers of children under-5.,At baseline, no child at a drug shop received any diagnostic testing before treatment in both districts.,After the intervention, while no child in the non-intervention district received a diagnostic test, 87.7% (95% CI 79.0-96.4) of children with fever at the intervention district drug shops had a parasitological diagnosis of malaria, prior to treatment.,The prevalence ratios of the effect of the intervention on treatment of cough and fast breathing with amoxicillin and diarrhoea with ORS/zinc at the drug shop were 2.8 (2.0-3.9), and 12.8 (4.2-38.6) respectively.,From the household survey, the prevalence ratio of the intervention effect on use of RDTs was 3.2 (1.9-5.4); Artemisinin Combination Therapy for malaria was 0.74 (0.65-0.84), and ORS/zinc for diarrhoea was 2.3 (1.2-4.7).,iCCM can be utilized to improve access and appropriateness of care for children at drug shops.

Presumptive treatment of all febrile patients with anti-malarials leads to massive over-treatment.,The aim was to assess the effect of implementing malaria rapid diagnostic tests (mRDTs) on prescription of anti-malarials in urban Tanzania.,The design was a prospective collection of routine statistics from ledger books and cross-sectional surveys before and after intervention in randomly selected health facilities (HF) in Dar es Salaam, Tanzania.,The participants were all clinicians and their patients in the above health facilities.,The intervention consisted of training and introduction of mRDTs in all three hospitals and in six HF.,Three HF without mRDTs were selected as matched controls.,The use of routine mRDT and treatment upon result was advised for all patients complaining of fever, including children under five years of age.,The main outcome measures were: (1) anti-malarial consumption recorded from routine statistics in ledger books of all HF before and after intervention; (2) anti-malarial prescription recorded during observed consultations in cross-sectional surveys conducted in all HF before and 18 months after mRDT implementation.,Based on routine statistics, the amount of artemether-lumefantrine blisters used post-intervention was reduced by 68% (95%CI 57-80) in intervention and 32% (9-54) in control HF.,For quinine vials, the reduction was 63% (54-72) in intervention and an increase of 2.49 times (1.62-3.35) in control HF.,Before-and-after cross-sectional surveys showed a similar decrease from 75% to 20% in the proportion of patients receiving anti-malarial treatment (Risk ratio 0.23, 95%CI 0.20-0.26).,The cluster randomized analysis showed a considerable difference of anti-malarial prescription between intervention HF (22%) and control HF (60%) (Risk ratio 0.30, 95%CI 0.14-0.70).,Adherence to test result was excellent since only 7% of negative patients received an anti-malarial.,However, antibiotic prescription increased from 49% before to 72% after intervention (Risk ratio 1.47, 95%CI 1.37-1.59).,Programmatic implementation of mRDTs in a moderately endemic area reduced drastically over-treatment with anti-malarials.,Properly trained clinicians with adequate support complied with the recommendation of not treating patients with negative results.,Implementation of mRDT should be integrated hand-in-hand with training on the management of other causes of fever to prevent irrational use of antibiotics.

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

Little is known about the impact of indoor residual spraying (IRS) in areas with intense malaria transmission such as sub-Saharan Africa.,In Malawi, IRS with lambda-cyhalothrin has been applied annually in an area of intense year-long transmission since 2007.,We evaluated the impact of IRS on parasitemia and anemia prevalence in children less than five years of age by using a cross-sectional household survey conducted in 2009, six months after the second IRS spray round.,We measured malaria parasitemia and anemia (hemoglobin level < 11 g/dL) in 899 children less than five years of age and used binomial regression to assess the impact of IRS by comparing children living in a household sprayed with IRS (direct IRS) with those in a household not sprayed with IRS, but in an IRS area (indirect IRS) and those living in a household not sprayed with IRS and not in an IRS area (no IRS).,In the IRS area, 77% of households reported receiving IRS.,Adjusting for bed net use, house construction, and socioeconomic status, we found that receiving direct IRS and indirect IRS were significantly associated with a 33% (95% confidence interval [CI] = 1-54%) and 46% (95% CI = 20-64%) reduction in parasitemia and a 21% (95% CI = 4-34%) and 30% (95% CI = 12-45%) reduction in anemia prevalence, respectively.

In the current context of high fatality rates associated with American visceral leishmaniasis (VL), the appropriate use of prognostic factors to identify patients at higher risk of unfavorable outcomes represents a potential tool for clinical practice.,This systematic review brings together information reported in studies conducted in Latin America, on the potential predictors of adverse prognosis (continued evolution of the initial clinical conditions of the patient despite the implementation of treatment, independent of the occurrence of death) and death from VL.,The limitations of the existing knowledge, the advances achieved and the approaches to be used in future research are presented.,The full texts of 14 studies conforming to the inclusion criteria were analyzed and their methodological quality examined by means of a tool developed in the light of current research tools.,Information regarding prognostic variables was synthesized using meta-analysis.,Variables were grouped according to the strength of evidence considering summary measures, patterns and heterogeneity of effect-sizes, and the results of multivariate analyses.,The strongest predictors identified in this review were jaundice, thrombocytopenia, hemorrhage, HIV coinfection, diarrhea, age <5 and age >40-50 years, severe neutropenia, dyspnoea and bacterial infections.,Edema and low hemoglobin concentration were also associated with unfavorable outcomes.,The main limitation identified was the absence of validation procedures for the few prognostic models developed so far.,Integration of the results from different investigations conducted over the last 10 years enabled the identification of consistent prognostic variables that could be useful in recognizing and handling VL patients at higher risk of unfavorable outcomes.,The development of externally validated prognostic models must be prioritized in future investigations.

As part of a World Health Organization-led effort to update the empirical evidence base for the leishmaniases, national experts provided leishmaniasis case data for the last 5 years and information regarding treatment and control in their respective countries and a comprehensive literature review was conducted covering publications on leishmaniasis in 98 countries and three territories (see ‘Leishmaniasis Country Profiles Text S1, S2, S3, S4, S5, S6, S7, S8, S9, S10, S11, S12, S13, S14, S15, S16, S17, S18, S19, S20, S21, S22, S23, S24, S25, S26, S27, S28, S29, S30, S31, S32, S33, S34, S35, S36, S37, S38, S39, S40, S41, S42, S43, S44, S45, S46, S47, S48, S49, S50, S51, S52, S53, S54, S55, S56, S57, S58, S59, S60, S61, S62, S63, S64, S65, S66, S67, S68, S69, S70, S71, S72, S73, S74, S75, S76, S77, S78, S79, S80, S81, S82, S83, S84, S85, S86, S87, S88, S89, S90, S91, S92, S93, S94, S95, S96, S97, S98, S99, S100, S101’).,Additional information was collated during meetings conducted at WHO regional level between 2007 and 2011.,Two questionnaires regarding epidemiology and drug access were completed by experts and national program managers.,Visceral and cutaneous leishmaniasis incidence ranges were estimated by country and epidemiological region based on reported incidence, underreporting rates if available, and the judgment of national and international experts.,Based on these estimates, approximately 0.2 to 0.4 cases and 0.7 to 1.2 million VL and CL cases, respectively, occur each year.,More than 90% of global VL cases occur in six countries: India, Bangladesh, Sudan, South Sudan, Ethiopia and Brazil.,Cutaneous leishmaniasis is more widely distributed, with about one-third of cases occurring in each of three epidemiological regions, the Americas, the Mediterranean basin, and western Asia from the Middle East to Central Asia.,The ten countries with the highest estimated case counts, Afghanistan, Algeria, Colombia, Brazil, Iran, Syria, Ethiopia, North Sudan, Costa Rica and Peru, together account for 70 to 75% of global estimated CL incidence.,Mortality data were extremely sparse and generally represent hospital-based deaths only.,Using an overall case-fatality rate of 10%, we reach a tentative estimate of 20,000 to 40,000 leishmaniasis deaths per year.,Although the information is very poor in a number of countries, this is the first in-depth exercise to better estimate the real impact of leishmaniasis.,These data should help to define control strategies and reinforce leishmaniasis advocacy.

Schistosomiasis is the most important human helminth infection due to its impact on public health.,The clinical manifestations are chronic and significantly decrease an individual’s quality of life.,Infected individuals suffer from long-term organ pathologies including fibrosis which eventually leads to organ failure.,The development of a vaccine against this parasitic disease would contribute to a long-lasting decrease in disease spectrum and transmission.,Our group has chosen Schistosoma mansoni (Sm) cathepsin B, a peptidase involved in parasite feeding, as a prospective vaccine candidate.,Our experimental formulation consisted of recombinant Sm-cathepsin B formulated in Montanide ISA 720 VG, a squalene based adjuvant containing a mannide mono-oleate emulsifier.,Parasitological burden was assessed by determining adult worm, hepatic egg, and intestinal egg numbers in each mouse.,Serum was used in ELISAs to evaluate production of antigen-specific antibodies, and isolated splenocytes were stimulated with the antigen for the analysis of cytokine secretion levels.,The Sm-cathepsin B and Montanide formulation conferred protection against a challenge infection by significantly reducing all forms of parasitological burdens.,Worm burden, hepatic egg burden and intestinal egg burden were decreased by 60 %, 62 %, and 56 %, respectively in immunized animals compared to controls (P = 0.0002, P < 0.0001, P = 0.0009, respectively).,Immunizations with the vaccine elicited robust production of Sm-cathepsin B specific antibodies (endpoint titers = 122,880).,Both antigen-specific IgG1 and IgG2c titers were observed, with the former having more elevated titers.,Furthermore, splenocytes isolated from the immunized animals, compared to control animals, secreted higher levels of key Th1 cytokines, IFN-γ, IL-12, and TNF-α, as well as the Th2 cytokines IL-5 and IL-4 when stimulated with recombinant Sm-cathepsin B.,The Th17 cytokine IL-17, the chemokine CCL5, and the growth factor GM-CSF were also significantly increased in the immunized animals compared to the controls.,The formulation tested in this study was able to significantly reduce all forms of parasite burden, stimulate robust production of antigen-specific antibodies, and induce a mixed Th1/Th2 response.,These results highlight the potential of Sm-cathepsin B/Montanide ISA 720 VG as a vaccine candidate against schistosomiasis.,The online version of this article (doi:10.1186/s12879-016-1444-z) contains supplementary material, which is available to authorized users.

Extensive use of praziquantel for treatment and control of schistosomiasis requires a comprehensive understanding of efficacy and safety of various doses for different Schistosoma species.,A systematic review and meta-analysis of comparative and non-comparative trials of praziquantel at any dose for any Schistosoma species assessed within two months post-treatment.,Of 273 studies identified, 55 were eligible (19,499 subjects treated with praziquantel, control treatment or placebo).,Most studied were in school-aged children (64%), S. mansoni (58%), and the 40 mg/kg dose (56%); 68% of subjects were in Africa.,Efficacy was assessed as cure rate (CR, n = 17,017) and egg reduction rate (ERR, n = 13,007); safety as adverse events (AE) incidence.,The WHO-recommended dose of praziquantel 40 mg/kg achieved CRs of 94.7% (95%CI 92.2-98.0) for S. japonicum, 77.1% (68.4-85.1) for S. haematobium, 76.7% (95%CI 71.9-81.2) for S. mansoni, and 63.5% (95%CI 48.2-77.0) for mixed S. haematobium/S. mansoni infections.,Using a random-effect meta-analysis regression model, a dose-effect for CR was found up to 40 mg/kg for S. mansoni and 30 mg/kg for S. haematobium.,The mean ERR was 95% for S. japonicum, 94.1% for S. haematobium, and 86.3% for S. mansoni.,No significant relationship between dose and ERR was detected.,Tolerability was assessed in 40 studies (12,435 subjects).,On average, 56.9% (95%CI 47.4-67.9) of the subjects receiving praziquantel 40 mg/kg experienced an AE.,The incidence of AEs ranged from 2.3% for urticaria to 31.1% for abdominal pain.,The large number of subjects allows generalizable conclusions despite the inherent limitations of aggregated-data meta-analyses.,The choice of praziquantel dose of 40 mg/kg is justified as a reasonable compromise for all species and ages, although in a proportion of sites efficacy may be lower than expected and age effects could not be fully explored.

Atovaquone/proguanil, registered as Malarone®, is a fixed-dose combination recommended for first-line treatment of uncomplicated Plasmodium falciparum malaria in non-endemic countries and its prevention in travellers.,Mutations in the cytochrome bc1 complex are causally associated with atovaquone resistance.,This systematic review assesses the clinical efficacy of atovaquone/proguanil treatment of uncomplicated malaria and examines the extent to which codon 268 mutation in cytochrome b influences treatment failure and recrudescence based on published information.,Data suggest that atovaquone/proguanil treatment efficacy is 89%-98% for P. falciparum malaria (from 27 studies including between 18 and 253 patients in each case) and 20%-26% for Plasmodium vivax malaria (from 1 study including 25 patients).,The in vitro P. falciparum phenotype of atovaquone resistance is an IC50 value >28 nM.,Case report analyses predict that recrudescence in a patient presenting with parasites carrying cytochrome b codon 268 mutation will occur on average at day 29 (95% CI: 22, 35), 19 (95% CI: 7, 30) days longer than if the mutation is absent.,Evidence suggests atovaquone/proguanil treatment for P. falciparum malaria is effective.,Late treatment failure is likely to be associated with a codon 268 mutation in cytochrome b, though recent evidence from animal models suggests these mutations may not spread within the population.,However, early treatment failure is likely to arise through alternative mechanisms, requiring further investigation.

Plasmodium parasites undergo a clinically silent and obligatory developmental phase in the host’s liver cells before they are able to infect erythrocytes and cause malaria symptoms.,To overcome the scarcity of compounds targeting the liver stage of malaria, we screened a library of 1037 existing drugs for their ability to inhibit Plasmodium hepatic development.,Decoquinate emerged as the strongest inhibitor of Plasmodium liver stages, both in vitro and in vivo.,Furthermore, decoquinate kills the parasite’s replicative blood stages and is active against developing gametocytes, the forms responsible for transmission.,The drug acts by selectively and specifically inhibiting the parasite’s mitochondrial bc1 complex, with little cross-resistance with the antimalarial drug atovaquone.,Oral administration of a single dose of decoquinate effectively prevents the appearance of disease, warranting its exploitation as a potent antimalarial compound.

The Zanzibar Elimination of Schistosomiasis Transmission (ZEST) project aimed to eliminate urogenital schistosomiasis as a public health problem from Pemba and to interrupt Schistosoma haematobium transmission from Unguja in 5 years.,A repeated cross-sectional cluster-randomized trial was implemented from 2011/12 till 2017.,On each island, 45 shehias were randomly assigned to receive one of three interventions: biannual mass drug administration (MDA) with praziquantel alone, or in combination with snail control or behavior change measures.,In cross-sectional surveys, a single urine sample was collected from ~9,000 students aged 9- to 12-years and from ~4,500 adults aged 20- to 55-years annually, and from ~9,000 1st year students at baseline and the final survey.,Each sample was examined for S. haematobium eggs by a single urine filtration.,Prevalence and infection intensity were determined.,Odds of infection were compared between the intervention arms.,Prevalence was reduced from 6.1% (95% confidence interval (CI): 4.5%-7.6%) to 1.7% (95% CI: 1.2%-2.2%) in 9- to 12-year old students, from 3.9% (95% CI: 2.8%-5.0%) to 1.5% (95% CI: 1.0%-2.0%) in adults, and from 8.8% (95% CI: 6.5%-11.2%) to 2.6% (95% CI: 1.7%-3.5%) in 1st year students from 2011/12 to 2017.,In 2017, heavy infection intensities occurred in 0.4% of 9- to 12-year old students, 0.1% of adults, and 0.8% of 1st year students.,Considering 1st year students in 2017, 13/45 schools in Pemba and 4/45 schools in Unguja had heavy infection intensities >1%.,There was no significant difference in prevalence between the intervention arms in any study group and year.,Urogenital schistosomiasis was eliminated as public health problem from most sites in Pemba and Unguja.,Prevalence was significantly reduced, but transmission was not interrupted.,Continued interventions that are adaptive and tailored to the micro-epidemiology of S. haematobium in Zanzibar are needed to sustain and advance the gains made by ZEST.

Control of human schistosomiasis remains a longstanding issue on the agenda of the Egyptian Ministry of Health and Population (MOHP).,Substantial impact on morbidity and prevalence of S. mansoni was widely reported after the National Schistosomiasis Control Program (NSCP) extended selective treatment with praziquantel (PZQ) to the Nile Delta in 1992 and upgrading this approach to mass drug administration (MDA) in 1997.,Disease elimination, however, eludes NSCP as the micro-level includes many high-risk foci that sustain transmission, which has not been subjected to investigation.,The study included five high-risk Nile Delta villages situated in the Kafr El-Sheikh Governorate.,The total sample size amounted to 2382 individuals of both sexes and all ages.,Diagnosis was based on four Kato-Katz slides from two consecutive stool samples.,Data were investigated using SPSS, comparing proportions with the Chi square test and means with the Student t test, while strength of the associations were subjected to Odds Ratio (OR) analysis.,The overall prevalence of schistosomiasis in the study area was found to be 29 %, while the mean geometric mean egg count (GMEC) was low (66.78 ± 4.4) indicating low intensity of infection.,The mean village prevalence rates ranged from 16.5 % to 49.5 % and the GMECs from 35.2 to 86.2 eggs per gram (EPG) of stool.,The difference of prevalence between villages was statistically significant at P < 0.05, and the prevalence was significantly higher among males than among females, P < 0.05, OR =1.4 and 95 % CI (1.16-1.60).,Infection peaked in the next youngest age group (5- ≤ 10 years of age) at an average prevalence of 50.8 % with the GMEC reaching 209 EPG of stool in the village with the highest prevalence.,The average prevalence and GMEC among children <5 years were 20.6 % and 92.7 EPG, respectively.,Transmission of S mansoni in high-risk areas in the Nile Delta remains uninterrupted calling for improved, more comprehensive control strategies.,Further investigations are needed to find out whether these results are due to inefficacy of PZQ, surviving immature worms or drug resistance.

A distinctive feature of Plasmodium vivax infections is the overall low parasite density in peripheral blood.,Thus, identifying asymptomatic infected individuals in endemic communities requires diagnostic tests with high sensitivity.,The detection limits of molecular diagnostic tests are primarily defined by the volume of blood analysed and by the copy number of the amplified molecular marker serving as the template for amplification.,By using mitochondrial DNA as the multi-copy template, the detection limit can be improved more than tenfold, compared to standard 18S rRNA targets, thereby allowing detection of lower parasite densities.,In a very low transmission area in Brazil, application of a mitochondrial DNA-based assay increased prevalence from 4.9 to 6.5%.,The usefulness of molecular tests in malaria epidemiological studies is widely recognized, especially when precise prevalence rates are desired.,Of concern, however, is the challenge of demonstrating test accuracy and quality control for samples with very low parasite densities.,In this case, chance effects in template distribution around the detection limit constrain reproducibility.,Rigorous assessment of false positive and false negative test results is, therefore, required to prevent over- or under-estimation of parasite prevalence in epidemiological studies or when monitoring interventions.,The online version of this article (10.1186/s12936-018-2201-0) contains supplementary material, which is available to authorized users.

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

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.

Intestinal schistosomiasis continues to be a significant cause of morbidity among communities located around Lake Victoria and on its islands.,Although epidemiological surveys have been conducted in other areas bordering the lake in western Kenya, Mbita district and its adjacent islands have never been surveyed, largely due to logistical challenges in accessing these areas.,Consequently, there is a paucity of data on prevalence of schistosomiasis and soil-transmitted helminth (STH) infections that are endemic in this region.,This cross-sectional study determined the prevalence, intensity of infection and geographical distribution of schistosome and STH infections among 4,065 children aged 5-19 years in 84 primary schools in Mbita and nearby islands of Lake Victoria (Mfangano, Ringiti, Rusinga and Takawiri), in western Kenya.,Single stool samples were collected and examined for eggs of Schistosoma mansoni and STHs (Hookworms, Ascaris lumbricoides and Trichuris trichiura) using the Kato-Katz technique.,Primary schools were mapped using geographical information system data on PDAs and prevalence maps generated using ArcView GIS software.,Overall, 65.6% (95% CI = 64.2-67.1%) of children were infected with one or more helminth species; 12.4% (95% CI = 11.4-13.4%) of children were infected with one or more STH species.,Mean school prevalence of S. mansoni infection was 60.5% (95% CI = 59.0-62.0%), hookworms 8.4% (95% CI = 7.6-9.3%), A. lumbricoides 3.3% (95% CI = 2.7-3.8%), and T. trichiura 1.6% (95% CI = 1.2-2.0%).,Interestingly, the mean S. mansoni prevalence was 2-fold higher on the islands (82%) compared to the mainland (41%) (z = 5.8755, P < 0.0001).,Similarly, intensity of infection was 54% higher on the islands (217.2 ± 99.3) compared to the mainland (141.3 ± 123.7) (z = 3.9374, P < 0.0001).,Schools in closest proximity to Lake Victoria had the highest S. mansoni prevalence while prevalence of STHs was more homogenously distributed.,The very high prevalence of schistosomiasis in Mbita and the 4 islands is quite alarming, and indicates an urgent and critical need for control interventions.,Findings from this survey indicate the need to implement treatment in remote areas not previously covered by mass drug administration programs.

Blastocystis is one of the most common intestinal parasites in humans and various animals worldwide.,Few studies are available regarding the genetic characterization of Blastocystis infections in humans in China.,In the present study, 609 fecal samples were collected from two- to six-year-old kindergarten children in southern Xinjiang and were examined by polymerase chain reaction (PCR).,The infection rate of Blastocystis was 14.3% (87/609); no significant difference was observed among counties and between sexes.,Blastocystis subtypes ST1 (n = 38), ST2 (n = 8), and ST3 (n = 41) were identified by sequence analysis of the small subunit ribosomal RNA gene.,Genetic polymorphisms were observed at the intra-subtype level, including seven variations for ST1 (ST1A to ST1G), four for ST2 (ST2A to ST2D), and two for ST3 (ST3A and ST3B); with ST1F and ST2B being new variations.,ST1 and ST3 are the two common Blastocystis subtypes in the study area.,More extensive studies in both humans and animals in different regions are needed to better characterize the transmission of Blastocystis.

Blastocystis is a genetically diverse and a common intestinal parasite of humans with a controversial pathogenic potential.,This study was carried out to identify the Blastocystis subtypes and their association with demographic and socioeconomic factors among outpatients living in Sebha city, Libya.,Blastocystis in stool samples were cultured followed by isolation, PCR amplification of a partial SSU rDNA gene, cloning, and sequencing.,The DNA sequences of isolated clones showed 98.3% to 100% identity with the reference Blastocystis isolates from the Genbank.,Multiple sequence alignment showed polymorphism from one to seven base substitution and/or insertion/deletion in several groups of non-identical nucleotides clones.,Phylogenetic analysis revealed three assemblage subtypes (ST) with ST1 as the most prevalent (51.1%) followed by ST2 (24.4%), ST3 (17.8%) and mixed infections of two concurrent subtypes (6.7%).,ST1 infection was significantly associated with female (P = 0.009) and low educational level (P = 0.034).,ST2 was also significantly associated with low educational level (P= 0.008) and ST3 with diarrhoea (P = 0.008).,Phylogenetic analysis of Libyan Blastocystis isolates identified three different subtypes; with ST1 being the predominant subtype and its infection was significantly associated with female gender and low educational level.,More extensive studies are needed in order to relate each Blastocystis subtype with clinical symptoms and potential transmission sources in this community.

We conducted standard insecticide susceptibility testing across western Kenya and found that the Anopheles gambiae mosquito has acquired high resistance to pyrethroids and DDT, patchy resistance to carbamates, but no resistance to organophosphates.,Use of non-pyrethroid-based vector control tools may be preferable for malaria prevention in this region.

Malaria kills millions around the world.,Until recently it was believed to be a disease of rural areas, since the Anopheles mosquito, which transmits Plasmodium species breeds in rural areas.,Urban malaria is emerging as a potential, but "avertable" crisis, in Africa.,In view of the rapidly growing number of small and medium-sized towns in Ethiopia there is a pressing need to improve the understanding of the epidemiology of malaria.,Therefore, the aim of this study was to determine malaria prevalence and associated risk factors in Jimma town.,A cross-sectional study was carried out in Jimma town from April 1 to May 28, 2010. 804 study participants were included from 291 households for microscopic examination of malaria parasites.,Socio-demography data and risk factors were collected using structured questionnaires.,Logistic regression analysis was done using SPSS 15.0 statistical software.,From a total of 804 study participants in current survey only 42 (5.2%) were positive for malaria parasites.,Plasmodium vivax, Plasmodium falciparum and mixed infection accounted 71.4%, 26.2% and 2.4%, respectively.,Higher malaria prevalence rate was observed among under-five children (11%).,Those who do not use insecticide-treated bed nets (ITN) were more likely to be infected with malaria (OR = 13.6; 95% CI 4.9-37.2, p < 0.001) compared with those who use the ITN.,Living in areas where stagnant water existed (OR = 2.1; 95% CI 1.00-4.2, p = 0.047) and its distance of existence <1 km from the house(OR = 2.1; 95% CI 2.0-15.8, p = 0.001) were more likely to be infected with malaria parasite compared with those who live away from stagnant at a distance greater than 1 km.,Malaria is a major health problem with P. vivax becoming a predominant species in the town.,The prevalence was strongly associated with proximity of residence to potential mosquito breeding sites.,Malaria is affecting significant proportions of the urban settlers and human activities nevertheless play an important role in bringing the mosquito breeding sites closer to residences.

Malaria is a public health problem in the Brazilian Amazon region.,In integrated vector management for malaria (anopheline) control, indoor residual spraying (IRS) represents one of the main tools in the basic strategy applied in the Amazonian states.,It is essential to understand the residual efficacy of insecticides on different surfaces to determine spray cycles, ensure their rational use, and prevent wastage.,This study aimed to evaluate the residual efficacy of six insecticide formulations used in the National Malaria Control Programme on four different types of walls in a field simulation at a “test house”.,The tests were performed as a field-simulating evaluation at a “test house” built in the municipality of Macapá.,Six insecticide formulations comprising four pyrethroids, a carbamate, and an organophosphate were used, and evaluated when applied on different wall surfaces: painted wood, unpainted wood, plastered cement, and unplastered cement.,The insecticides were applied to the interior walls of the “test house” by a trained technician.,In the bioassays performed with pyrethroids, deltamethrin water-dispersible granules (WG) performed particularly well, presenting residual bioefficacy of 8 months on both wood surfaces after the IRS, whereas alpha-cypermethrin suspension concentrate (SC) and etofenprox wettable powder (WP) demonstrated residual bioefficacy of 4 months on at least one of the wood surfaces; however, the pyrethroid lambda-cyhalothrin WP showed a low residual bioefficacy (< 3 months) on all tested surfaces, demonstrating its inefficiency for areas with a long transmission cycle of malaria.,For the carbamate-bendiocarb WP, residual bioefficacy for 3 months was achieved only on wood surfaces.,In general, the organophosphate pirimifos-methyl capsule suspension (CS) demonstrated the best result, with a mortality rate < 80% over a period of 6 months on all surfaces tested.,Insecticide efficiency varies among different types of surface; therefore, a “test house” is a valuable evaluation tool.,This work highlights the usefulness of associating the residual efficacy of insecticides on the surfaces commonly found in houses in endemic areas, together with knowledge about the transmission cycle duration of the transmission cycle and the insecticide susceptibility of the vector.,This association helps in the decision-making for the malaria control intervention regarding.

The majority of the mosquito and parasite life-history traits that combine to determine malaria transmission intensity are temperature sensitive.,In most cases, the process-based models used to estimate malaria risk and inform control and prevention strategies utilize measures of mean outdoor temperature.,Evidence suggests, however, that certain malaria vectors can spend large parts of their adult life resting indoors.,If significant proportions of mosquitoes are resting indoors and indoor conditions differ markedly from ambient conditions, simple use of outdoor temperatures will not provide reliable estimates of malaria transmission intensity.,To date, few studies have quantified the differential effects of indoor vs outdoor temperatures explicitly, reflecting a lack of proper understanding of mosquito resting behaviour and associated microclimate.,Published records from 8 village sites in East Africa revealed temperatures to be warmer indoors than outdoors and to generally show less daily variation.,Exploring the effects of these temperatures on malaria parasite development rate suggested indoor-resting mosquitoes could transmit malaria between 0.3 and 22.5 days earlier than outdoor-resting mosquitoes.,These differences translate to increases in transmission risk ranging from 5 to approaching 3,000%, relative to predictions based on outdoor temperatures.,The pattern appears robust for low- and highland areas, with differences increasing with altitude.,Differences in indoor vs outdoor environments lead to large differences in the limits and the intensity of malaria transmission.,This finding highlights a need to better understand mosquito resting behaviour and the associated microclimate, and to broaden assessments of transmission ecology and risk to consider the potentially important role of endophily.

A community-based cross-sectional study was done to assess Plasmodium falciparum exposure in areas with different malaria endemicity in north-eastern Tanzania using serological markers; PfAMA-1 and PfMSP-119.,Bondo had a higher seroprevalence 36.6% (188) for PfAMA-1 as compared to Hai 13.8% (33), χ2 = 34.66, p < 0.01.,Likewise, Bondo had a higher seroprevalence 201(36.6%) for PfMSP-1 as compared to Hai 41 (17.2%), χ2 = 29.62, p < 0.01.,Anti-PfAMA-1 titters were higher in malaria positive individuals (n = 47) than in malaria negative individuals (n = 741) (p = 0.07).,Anti-PfMSP-1 antibody concentrations were significantly higher in malaria-positive individuals (n = 47) than in malaria-negative individuals (n = 741) (p = 0.003).,Antibody response against PfAMA-1 was significantly different between the three age groups; < 5 years, 5 to 15 years and > 15 years in both sites of Bondo and Hai.,Likewise, antibody response against PfMSP-119 was significantly different between the three age groups in the two sites (p < 0.001).,We also found significant differences in the anti-PfAMA-1and anti-PfMSP-119 antibody concentrations among the three age groups in the two sites (p = 0.004 and 0.005) respectively.,Immunological indicators of P. falciparum exposure have proven to be useful in explaining long-term changes in the transmission dynamics, especially in low transmission settings.,The online version contains supplementary material available at 10.1186/s13104-021-05818-y.

Improved methods for malaria diagnosis are urgently needed.,Here, we evaluate a novel method named rotating-crystal magneto-optical detection (RMOD) in 956 suspected malaria patients in Papua New Guinea.,RMOD tests can be conducted within minutes and at low cost.,We systematically evaluate the capability of RMOD to detect infections by directly comparing it with expert light microscopy, rapid diagnostic tests and polymerase chain reaction on capillary blood samples.,We show that compared to light microscopy, RMOD exhibits 82% sensitivity and 84% specificity to detect any malaria infection and 87% sensitivity and 88% specificity to detect Plasmodium vivax.,This indicates that RMOD could be useful in P. vivax dominated elimination settings.,Parasite density correlates well with the quantitative magneto-optical signal.,Importantly, residual hemozoin present in malaria-negative patients is also detectable by RMOD, indicating its ability to detect previous infections.,This could be exploited to reveal transmission hotspots in low-transmission settings.,Here Arndt et al. establish rotating-crystal magneto-optical detection (RMOD) as a near-point-of-care diagnostic tool for malaria detection and report a sensitivity and specificity of 82% and 84%, respectively, as validated by analyzing a clinical population in a high transmission setting in Papua New Guinea.

The widespread presence of low-density asymptomatic infections with concurrent gametocytes may be a stumbling block for malaria elimination.,This study investigated the asymptomatic reservoir of Plasmodium falciparum and Plasmodium vivax infections in schoolchildren from five settings in northwest Ethiopia.,Two cross-sectional surveys were conducted in June and November 2015, enrolling 551 students from five schools and 294 students from three schools, respectively.,Finger prick whole blood and plasma samples were collected.,The prevalence and density of P. falciparum and P. vivax parasitaemia and gametocytaemia were determined by 18S rRNA quantitative PCR (qPCR) and pfs25 and pvs25 reverse transcriptase qPCR.,Antibodies against blood stage antigens apical membrane antigen-1 (AMA-1) and merozoite surface protein-1 (MSP-119) were measured for both species.,Whilst only 6 infections were detected by microscopy in 881 slides (0.7%), 107 of 845 blood samples (12.7%) were parasite positive by (DNA-based) qPCR. qPCR parasite prevalence between sites and surveys ranged from 3.8 to 19.0% for P. falciparum and 0.0 to 9.0% for P. vivax.,The median density of P. falciparum infections (n = 85) was 24.4 parasites/µL (IQR 18.0-34.0) and the median density of P. vivax infections (n = 28) was 16.4 parasites/µL (IQR 8.8-55.1).,Gametocyte densities by (mRNA-based) qRT-PCR were strongly associated with total parasite densities for both P. falciparum (correlation coefficient = 0.83, p = 0.010) and P. vivax (correlation coefficient = 0.58, p = 0.010).,Antibody titers against P. falciparum AMA-1 and MSP-119 were higher in individuals who were P. falciparum parasite positive in both surveys (p < 0.001 for both comparisons).,This study adds to the available evidence on the wide-scale presence of submicroscopic parasitaemia by quantifying submicroscopic parasite densities and concurrent gametocyte densities.,There was considerable heterogeneity in the occurrence of P. falciparum and P. vivax infections and serological markers of parasite exposure between the examined low endemic settings in Ethiopia.

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

Control of onchocerciasis as a public health problem in Africa relies on annual mass ivermectin distribution.,New tools are needed to achieve elimination of infection.,This study determined in a small number of Onchocerca volvulus infected individuals whether moxidectin, a veterinary anthelminthic, is safe enough to administer it in a future large study to further characterize moxidectin's safety and efficacy.,Effects on the parasite were also assessed.,Men and women from a forest area in South-eastern Ghana without ivermectin mass distribution received a single oral dose of 2 mg (N = 44), 4 mg (N = 45) or 8 mg (N = 38) moxidectin or 150 µg/kg ivermectin (N = 45) with 18 months follow up.,All ivermectin and 97%-100% of moxidectin treated participants had Mazzotti reactions.,Statistically significantly higher percentages of participants treated with 8 mg moxidectin than participants treated with ivermectin experienced pruritus (87% vs. 56%), rash (63% vs. 42%), increased pulse rate (61% vs. 36%) and decreased mean arterial pressure upon 2 minutes standing still after ≥5 minutes supine relative to pre-treatment (61% vs.,27%).,These reactions resolved without treatment.,In the 8 mg moxidectin and ivermectin arms, the mean±SD number of microfilariae/mg skin were 22.9±21.1 and 21.2±16.4 pre-treatment and 0.0±0.0 and 1.1±4.2 at nadir reached 1 and 3 months after treatment, respectively.,At 6 months, values were 0.0±0.0 and 1.6±4.5, at 12 months 0.4±0.9 and 3.4±4.4 and at 18 months 1.8±3.3 and 4.0±4.8, respectively, in the 8 mg moxidectin and ivermectin arm.,The reduction from pre-treatment values was significantly higher after 8 mg moxidectin than after ivermectin treatment throughout follow up (p<0.01).,The 8 mg dose of moxidectin was safe enough to initiate the large study.,Provided its results confirm those from this study, availability of moxidectin to control programmes could help them achieve onchocerciasis elimination objectives.,ClinicalTrails.gov NCT00300768

Anti-Wolbachia therapy delivers safe macrofilaricidal activity with superior therapeutic outcomes compared to all standard anti-filarial treatments, with the added benefit of substantial improvements in clinical pathology.,These outcomes can be achieved, in principle, with existing registered drugs, e.g. doxycycline, that are affordable, available to endemic communities and have well known, albeit population-limiting, safety profiles.,The key barriers to using doxycycline as an mass drug administration (MDA) strategy for widespread community-based control are the logistics of a relatively lengthy course of treatment (4-6 weeks) and contraindications in children under eight years and pregnancy.,Therefore, the primary goal of the anti-Wolbachia (A·WOL) consortium is to find drugs and regimens that reduce the period of treatment from weeks to days (7 days or less), and to find drugs which would be safe in excluded target populations (pregnancy and children).,A secondary goal is to refine regimens of existing antibiotics suitable for a more restricted use, prior to the availability of a regimen that is compatible with MDA usage.,For example, for use in the event of the emergence of drug-resistance, in individuals with high loiasis co-infection and at risk of severe adverse events (SAE) to ivermectin, or in post-MDA ‘endgame scenarios’, where test and treat strategies become more cost effective and deliverable.

Intermittent preventive treatment of malaria in pregnancy is a highly cost-effective intervention which significantly improves maternal and birth outcomes among mothers and their newborns who live in areas of moderate to high malaria transmission.,However, coverage in sub-Saharan Africa remains unacceptably low, calling for urgent action to increase uptake dramatically and maximize its public health impact.,The ‘Global Call to Action’ outlines priority actions that will pave the way to success in achieving national and international coverage targets.,Immediate action is needed from national health institutions in malaria-endemic countries, the donor community, the research community, members of the pharmaceutical industry and private sector, along with technical partners at the global and local levels, to protect pregnant women and their babies from the preventable, adverse effects of malaria in pregnancy.

Planning and evaluating malaria control strategies relies on accurate definition of parasite prevalence in the population.,A large proportion of asymptomatic parasite infections can only be identified by surveillance with molecular methods, yet these infections also contribute to onward transmission to mosquitoes.,The sensitivity of molecular detection by PCR is limited by the abundance of the target sequence in a DNA sample; thus, detection becomes imperfect at low densities.,We aimed to increase PCR diagnostic sensitivity by targeting multi-copy genomic sequences for reliable detection of low-density infections, and investigated the impact of these PCR assays on community prevalence data.,Two quantitative PCR (qPCR) assays were developed for ultra-sensitive detection of Plasmodium falciparum, targeting the high-copy telomere-associated repetitive element 2 (TARE-2, ∼250 copies/genome) and the var gene acidic terminal sequence (varATS, 59 copies/genome).,Our assays reached a limit of detection of 0.03 to 0.15 parasites/μl blood and were 10× more sensitive than standard 18S rRNA qPCR.,In a population cross-sectional study in Tanzania, 295/498 samples tested positive using ultra-sensitive assays.,Light microscopy missed 169 infections (57%).,18S rRNA qPCR failed to identify 48 infections (16%), of which 40% carried gametocytes detected by pfs25 quantitative reverse-transcription PCR.,To judge the suitability of the TARE-2 and varATS assays for high-throughput screens, their performance was tested on sample pools.,Both ultra-sensitive assays correctly detected all pools containing one low-density P. falciparum-positive sample, which went undetected by 18S rRNA qPCR, among nine negatives.,TARE-2 and varATS qPCRs improve estimates of prevalence rates, yet other infections might still remain undetected when absent in the limited blood volume sampled.,Measured malaria prevalence in communities is largely determined by the sensitivity of the diagnostic tool used.,Even when applying standard molecular diagnostics, prevalence in our study population was underestimated by 8% compared to the new assays.,Our findings highlight the need for highly sensitive tools such as TARE-2 and varATS qPCR in community surveillance and for monitoring interventions to better describe malaria epidemiology and inform malaria elimination efforts.,Ingrid Felger and colleagues developed an assay that targets multi-copy genomic sequences and can detect low-density infections with falciparum malaria parasites.,Nearly half the world's population is at risk of malaria, and more than 600,000 people die from this mosquito-borne parasitic infection every year.,Most of these deaths are caused by Plasmodium falciparum, which is transmitted to people by night-flying Anopheles mosquitoes.,These insects inject “sporozoites” into people, 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 parasitic burden causes malaria's characteristic fever, which needs to be treated promptly to prevent anemia and organ damage.,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 controlling the mosquitoes that spread the parasite and by avoiding mosquito bites.,Effective treatment with antimalarial drugs also helps to reduce malaria transmission and is a key component of global efforts to control and eliminate malaria.,Planning and evaluating malaria control and elimination efforts relies on having accurate and sensitive methods to measure parasite prevalence-the proportion of a population infected with parasites.,It is particularly important to know how many people are carrying low-density infections because although these individuals have no symptoms, they contribute to malaria transmission.,In the past, malaria was usually diagnosed by looking for parasites in blood using light microscopy, but molecular tests based on “quantitative polymerase chain reactions” (qPCRs) are now available that detect much lower parasite densities in blood (submicroscopic infections). qPCRs detect parasite-specific DNA sequences in patient blood samples, but reliable detection of low-density infections remains imperfect because the abundance of target sequences in patient samples limits the sensitivity of current qPCR methods.,Here, the researchers investigate whether the sensitivity of P. falciparum detection using qPCR can be improved by targeting multi-copy genomic sequences-DNA sequences that are repeated many times in the parasite's genetic blueprint.,The researchers developed two new qPCRs for P. falciparum by using the telomere-associated repetitive element 2 (TARE-2; 250 copies/genome) and the var gene acidic terminal sequence (varATS; 59 copies/genome) as target sequences.,Direct comparison of these qPCRs with the standard 18S rRNA qPCR for P. falciparum, which targets a gene present at 5-8 copies/genome, indicated that the new assays were ten times more sensitive than the standard assay and could detect as few as 0.03-0.15 parasites/μl blood.,Next, the researchers used light microscopy, 18S rRNA qPCR, and the two new qPCRs to look for P. falciparum parasites in 498 samples randomly selected from a malaria survey undertaken in Tanzania.,Parasite prevalences were 25% by light microscopy, 50% by 18S rRNA qPCR, and 58% by TARE-2 or varATS qPCR.,Compared to TARE-2 or varATS qPCR, 18S rRNA qPCR failed to identify 48 infections (16% of infections).,Moreover, 40% of the positive samples missed by 18S rRNA qPCR contained gametocytes (detected by a different PCR-based assay) and therefore came from individuals capable of transmitting malaria parasites to mosquitoes.,Finally, to test the suitability of the new ultra-sensitive assays for use in high-throughput screens, the researchers tested performance of the assays on sample pools.,Both tests correctly identified all pools containing one low-density P. falciparum-positive sample among nine negative samples, whereas 18S rRNA qPCR identified none of these pools.,These findings provide evidence of low-density malaria infections in individuals previously thought to be parasite-free, even after testing with a molecular diagnostic.,Notably, in the population considered in this study, the standard 18S rRNA qPCR underestimated parasite prevalence by nearly 10%.,The assays developed in this study have some important limitations, however.,First, they detect only P. falciparum, and malaria control programs ideally need assays that detect all the Plasmodium species that cause malaria.,Second, because the TARE-2 and varATS qPCRs require advanced laboratory infrastructure, they cannot be used in remote field settings.,Nevertheless, because low-density infections are likely to become increasingly common as countries improve malaria control, these findings highlight the need for ultra-sensitive tools such as the TARE-2 and varATS qPCRs for community surveillance and for monitoring the progress of malaria control and elimination programs.,Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001788.,Information is available from the World Health Organization on malaria (in several languages), including information on malaria diagnosis; the World Malaria Report 2014 provides details of the current global malaria situation,The US Centers for Disease Control and Prevention also provides information on all aspects of malaria; its website provides a selection of personal stories about malaria,Information is available from the Roll Back Malaria Partnership on the global control of malaria and on the Global Malaria Action Plan (in English and French),MedlinePlus provides links to additional information on malaria (in English and Spanish)

Control of mosquito-borne diseases is greatly compromised by spread of insecticide resistance, high implementation costs and sub-optimal compliance among users.,Improved housing has potential to reduce malaria transmission nearly as much as long-lasting insecticide-treated nets (LLINs), while also preventing other arthropod-borne diseases and improving overall well-being.,Yet, it is hardly promoted as mainstream intervention, partly because of high costs, minimal communal benefits to people in non-improved houses, and low scalability.,By exploiting biological observations of mosquito behaviours around dwellings, scientists have developed a new approach that integrates effective vector control into housing developments.,The technique involves blocking eave spaces in local houses, leaving a few cylindrical holes into which plastic tubes with insecticide-laden electrostatic nettings are inserted.,Where houses already have blocked eaves, these cylindrical holes are drilled and the tubes inserted.,The eave tube technology, as it is called, is an innovative new approach for implementing housing improvements, by creating a new scalable product that can be integrated in houses during or after construction.,It takes away insecticides from proximity of users, and instead puts them where mosquitoes are most likely to enter houses, thereby reducing insecticidal exposure among household occupants, while maximizing exposure of mosquitoes.,This way, lower quantities of insecticides are used, better house ventilation achieved, intervention costs reduced, and mass communal benefits achieved even were vectors are resistant to similar insecticides when delivered conventionally.,There are however still some critical pieces missing, notably epidemiological, social and economic evidence that the above assertions are true and sustainable.,Besides, there also some technical limitations to be considered, namely: (1) need for extensive house modifications before eave tubes are inserted, (2) ineligibility of poorest and highest-risk households living in housing structures not amenable to eave tubes, and (3) poor synergies when eave tubes are combined with LLINs or IRS in same households.,Overall, this paradigm significantly improves delivery of insecticides against disease-transmitting mosquitoes, and provides opportunities for scaling-up the long-neglected concept of house improvement as a malaria intervention.

In Cambodia, despite an impressive decline in prevalence over the last 10 years, malaria is still a public health problem in some parts of the country.,This is partly due to vectors that bite early and outdoors reducing the effectiveness of measures such as Long-Lasting Insecticidal Nets.,Repellents have been suggested as an additional control measure in such settings.,As part of a cluster-randomized trial on the effectiveness of topical repellents in controlling malaria infections at community level, a mixed-methods study assessed user rates and determinants of use.,Repellents were made widely available and Picaridin repellent reduced 97% of mosquito bites.,However, despite high acceptability, daily use was observed to be low (8%) and did not correspond to the reported use in surveys (around 70%).,The levels of use aimed for by the trial were never reached as the population used it variably across place (forest, farms and villages) and time (seasons), or in alternative applications (spraying on insects, on bed nets, etc.).,These findings show the key role of human behavior in the effectiveness of malaria preventive measures, questioning whether malaria in low endemic settings can be reduced substantially by introducing measures without researching and optimizing community involvement strategies.

Malaria caused by Plasmodium vivax is a highly prevalent infection world-wide, that was previously considered mild, but complications such as anemia have been highly reported in the past years.,In mice models of malaria, anti-phosphatidylserine (anti-PS) autoantibodies, produced by atypical B-cells, bind to uninfected erythrocytes and contribute to anemia.,In human patients with P. falciparum malaria, the levels of anti-PS, atypical B-cells and anemia are strongly correlated to each other.,In this study, we focused on assessing the relationship between autoantibodies, different B-cell populations and hemoglobin levels in two different cohorts of P. vivax patients from Colombia, South America.,In a first longitudinal cohort, our results show a strong inverse correlation between different IgG autoantibodies tested (anti-PS, anti-DNA and anti-erythrocyte) and atypical memory B-cells (atMBCs) with hemoglobin in both P. vivax and P. falciparum patients over time.,In a second cross-sectional cohort, we observed a stronger relation between hemoglobin levels, atMBCs and autoantibodies in complicated P. vivax patients compared to uncomplicated ones.,Altogether, these data constitute the first evidence of autoimmunity associating with anemia and complicated P. vivax infections, suggesting a role for its etiology through the expansion of autoantibody-secreting atMBCs.

Malaria control activities can have a disproportionately greater impact on Plasmodium falciparum than on P. vivax in areas where both species are coendemic.,We investigated temporal trends in malaria-related morbidity and mortality in Papua, Indonesia, before and after introduction of a universal, artemisinin-based antimalarial treatment strategy for all Plasmodium species.,A prospective, district-wide malariometric surveillance system was established in April 2004 to record all cases of malaria at community clinics and the regional hospital and maintained until December 2013.,In March 2006, antimalarial treatment policy was changed to artemisinin combination therapy for uncomplicated malaria and intravenous artesunate for severe malaria due to any Plasmodium species.,Over the study period, a total of 418,238 patients presented to the surveillance facilities with malaria.,The proportion of patients with malaria requiring admission to hospital fell from 26.9% (7,745/28,789) in the pre-policy change period (April 2004 to March 2006) to 14.0% (4,786/34,117) in the late transition period (April 2008 to December 2009), a difference of −12.9% (95% confidence interval [CI] −13.5% to −12.2%).,There was a significant fall in the mortality of patients presenting to the hospital with P. falciparum malaria (0.53% [100/18,965] versus 0.32% [57/17,691]; difference = −0.21% [95% CI −0.34 to −0.07]) but not in patients with P. vivax malaria (0.28% [21/7,545] versus 0.23% [28/12,397]; difference = −0.05% [95% CI −0.20 to 0.09]).,Between the same periods, the overall proportion of malaria due to P. vivax rose from 44.1% (30,444/69,098) to 53.3% (29,934/56,125) in the community clinics and from 32.4% (9,325/28,789) to 44.1% (15,035/34,117) at the hospital.,After controlling for population growth and changes in treatment-seeking behaviour, the incidence of P. falciparum malaria fell from 511 to 249 per 1,000 person-years (py) (incidence rate ratio [IRR] = 0.49 [95% CI 0.48-0.49]), whereas the incidence of P. vivax malaria fell from 331 to 239 per 1,000 py (IRR = 0.72 [95% CI 0.71-0.73]).,The main limitations of our study were possible confounding from changes in healthcare provision, a growing population, and significant shifts in treatment-seeking behaviour following implementation of a new antimalarial policy.,In this area with high levels of antimalarial drug resistance, adoption of a universal policy of efficacious artemisinin-based therapy for malaria infections due to any Plasmodium species was associated with a significant reduction in total malaria-attributable morbidity and mortality.,The burden of P. falciparum malaria was reduced to a greater extent than that of P. vivax malaria.,In coendemic regions, the timely elimination of malaria will require that safe and effective radical cure of both the blood and liver stages of the parasite is widely available for all patients at risk of malaria.,Ric Price and colleagues report on changes in Plasmodium falciparum and vivax malaria following a universal malaria treatment programme in Papua, Indonesia.

Antimalarial drug resistance has threatened global malaria control since chloroquine (CQ)-resistant Plasmodium falciparum emerged in Asia in the 1950s.,Understanding the impacts of changing antimalarial drug policy on resistance is critical for resistance management.,Plasmodium falciparum isolates were collected from 2003 to 2015 in western Kenya and analyzed for genetic markers associated with resistance to CQ (Pfcrt), sulfadoxine-pyrimethamine (SP) (Pfdhfr/Pfdhps), and artemether-lumefantrine (AL) (PfKelch13/Pfmdr1) antimalarials.,In addition, household antimalarial drug use surveys were administered.,Pfcrt 76T prevalence decreased from 76% to 6% from 2003 to 2015.,Pfdhfr/Pfdhps quintuple mutants decreased from 70% in 2003 to 14% in 2008, but increased to near fixation by 2015.,SP “super resistant” alleles Pfdhps 581G and 613S/T were not detected in the 2015 samples that were assessed.,The Pfmdr1 N86-184F-D1246 haplotype associated with decreased lumefantrine susceptibility increased significantly from 4% in 2005 to 51% in 2015.,No PfKelch13 mutations that have been previously associated with artemisinin resistance were detected in the study populations.,The increase in Pfdhfr/Pfdhps quintuple mutants that associates with SP resistance may have resulted from the increased usage of SP for intermittent preventative therapy in pregnancy (IPTp) and for malaria treatment in the community.,Prevalent Pfdhfr/Pfdhps mutations call for careful monitoring of SP resistance and effectiveness of the current IPTp program in Kenya.,In addition, the commonly occurring Pfmdr1 N86-184F-D1246 haplotype associated with increased lumefantrine tolerance calls for surveillance of AL efficacy in Kenya, as well as consideration for a rotating artemisinin-combination therapy regimen.

Antimalarial drug resistance is a major global challenge in malaria control and elimination.,Mutations in six different genes of Plasmodium falciparum (crt, mdr1, dhfr, dhps, ATPase6 and K-13 propeller) that confer resistance to chloroquine, sulphadoxine-pyrimethamine and artemisinin-based combination therapy were analyzed in samples from Chhattisgarh.,Seventy-eight percent of the samples were found to have a pfcrt mutation (53% double, 24% triple and 1% single mutant), and 59% of pfmdr1 genes were found to have an N86Y mutation.,Double mutations were recorded in pfdhfr gene among 76% of the samples while only 6% of the samples harbored mutant genotypes in pfdhps.,No mutation was found in the K-13 propeller gene, while only one sample showed a mutant genotype for the PfATPase6 gene.,The Tajima test confirmed that there is no role of evolutionary natural selection in drug resistance, and gene pairwise linkage of disequilibrium showed significant intragenic association.,The high level of pfcrt mutations suggests that parasite resistance to chloroquine is almost at a fixed level, whereas resistance to SP is evolving in the population and parasites remain sensitive to artemisinin derivatives.,These findings provide potential information and understanding of the evolution and spread of different drug resistance alleles in Chhattisgarh.

Gametocyte density and sex ratio can predict the proportion of mosquitoes that will become infected after feeding on blood of patients receiving nongametocytocidal drugs.,Because primaquine and methylene blue sterilize gametocytes before affecting their density and sex ratio, mosquito feeding experiments are required to demonstrate their early transmission-blocking effects.

Plasmodium falciparum gametocytes, the sexual stages responsible for malaria parasite transmission, develop in the human bone marrow parenchyma in proximity to the erythroblastic islands.,Yet, mechanisms underlying gametocytes interactions with these islands are unknown.,Here, we have investigated whether gametocyte-infected erythrocytes (GIE) adhere to erythroid precursors, and whether a putative adhesion may be mediated by a mechanism similar to the adhesion of erythrocytes infected with P. falciparum asexual stages to uninfected erythrocytes.,Cell-cell adhesion assays with human primary erythroblasts or erythroid cell lines revealed that immature GIE do not specifically adhere to erythroid precursors.,To determine whether adhesion may be dependent on binding of STEVOR proteins to Glycophorin C on the surface of erythroid cells, we used clonal lines and transgenic parasites that overexpress specific STEVOR proteins known to bind to Glycophorin C in asexual stages.,Our results indicate that GIE overexpressing STEVOR do not specifically adhere to erythroblasts, in agreement with our observation that the STEVOR adhesive domain is not exposed at the surface of GIE.

Helminths immunomodulate their hosts and induce a regulatory, anti-inflammatory milieu that prevents allergies and autoimmune diseases.,Helminth immunomodulation may benefit sepsis outcome by preventing exacerbated inflammation and severe pathology, but the influence on bacterial clearance remains unclear.,To address this, mice were chronically infected with the filarial nematode Litomosoides sigmodontis (L.s.) and the outcome of acute systemic inflammation caused by i.p.,Escherichia coli injection was determined.,L.s. infection significantly improved E. coli-induced hypothermia, bacterial clearance and sepsis survival and correlated with reduced concentrations of associated pro-inflammatory cytokines/chemokines and a less pronounced pro-inflammatory macrophage gene expression profile.,Improved sepsis outcome in L.s.-infected animals was mediated by macrophages, but independent of the alternatively activated macrophage subset.,Endosymbiotic Wolbachia bacteria that are present in most human pathogenic filariae, as well as L.s., signal via TLR2 and modulate macrophage function.,Here, gene expression profiles of peritoneal macrophages from L.s.-infected mice revealed a downregulation of genes involved in TLR signaling, and pulsing of macrophages in vitro with L.s. extract reduced LPS-triggered activation.,Subsequent transfer improved sepsis outcome in naïve mice in a Wolbachia- and TLR2-dependent manner.,In vivo, phagocytosis was increased in macrophages from L.s.-infected wild type, but not TLR2-deficient animals.,In association, L.s. infection neither improved bacterial clearance in TLR2-deficient animals nor ameliorated E. coli-induced hypothermia and sepsis survival.,These results indicate that chronic L.s. infection has a dual beneficial effect on bacterial sepsis, reducing pro-inflammatory immune responses and improving bacterial control.,Thus, helminths and their antigens may not only improve the outcome of autoimmune and allergic diseases, but may also present new therapeutic approaches for acute inflammatory diseases that do not impair bacterial control.

Mass drug administration (MDA) programmes against Onchocerca volvulus use ivermectin (IVM) which targets microfilariae (MF), the worm's offspring.,Most infected individuals are hyporesponsive and present regulated immune responses despite high parasite burden.,Recently, with MDA programmes, the existence of amicrofilaridermic (a-MF) individuals has become apparent but little is known about their immune responses.,Within this immunoepidemiological study, we compared parasitology, pathology and immune profiles in infection-free volunteers and infected individuals that were MF+ or a-MF.,The latter stemmed from villages in either Central or Ashanti regions of Ghana which, at the time of the study, had received up to eight or only one round of MDA respectively.,Interestingly, a-MF patients had fewer nodules and decreased IL-10 responses to all tested stimuli.,On the other hand, this patient group displayed contrary IL-5 profiles following in vitro stimulation or in plasma and the dampened response in the latter correlated to reduced eosinophils and associated factors but elevated neutrophils.,Furthermore, multivariable regression analysis with covariates MF, IVM or the region (Central vs.,Ashanti) revealed that immune responses were associated with different covariates: whereas O. volvulus-specific IL-5 responses were primarily associated with MF, IL-10 secretion had a negative correlation with times of individual IVM therapy (IIT).,All plasma parameters (eosinophil cationic protein, IL-5, eosinophils and neutrophils) were highly associated with MF.,With regards to IL-17 secretion, although no differences were observed between the groups to filarial-specific or bystander stimuli, these responses were highly associated with the region.,These data indicate that immune responses are affected by both, IIT and the rounds of IVM MDA within the community.,Consequently, it appears that a lowered infection pressure due to IVM MDA may affect the immune profile of community members even if they have not regularly participated in the programmes.

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

Plasmodium vivax has a dormant hepatic stage, called the hypnozoite, which can cause relapse months after the initial attack.,For 50 years, primaquine has been used as a hypnozoitocide to radically cure P. vivax infection, but major concerns remain regarding the side-effects of the drug and adherence to the 14-day regimen.,This study examined the effectiveness of using the directly-observed therapy (DOT) method for the radical treatment of P. vivax malaria infection, to prevent reappearance of the parasite within the 90-day follow-up period.,Other potential risk factors for the reappearance of P. vivax were also explored.,A randomized trial was conducted from May 2007 to January 2009 in a low malaria transmission area along the Thai-Myanmar border.,Patients aged ≥ 3 years diagnosed with P. vivax by microscopy, were recruited.,All patients were treated with the national standard regimen of chloroquine for three days followed by primaquine for 14 days.,Patients were randomized to receive DOT or self-administered therapy (SAT).,All patients were followed for three months to check for any reappearance of P. vivax.,Of the 216 patients enrolled, 109 were randomized to DOT and 107 to SAT.,All patients recovered without serious adverse effects.,The vivax reappearance rate was significantly lower in the DOT group than the SAT group (3.4/10,000 person-days vs.,13.5/10,000 person-days, p = 0.021).,Factors related to the reappearance of vivax malaria included inadequate total primaquine dosage received (< 2.75 mg/kg), duration of fever ≤ 2 days before initiation of treatment, parasite count on admission ≥ 10,000/µl, multiple P. vivax-genotype infection, and presence of P. falciparum infection during the follow-up period.,Adherence to the 14-day primaquine regimen is important for the radical cure of P. vivax malaria infection.,Implementation of DOT reduces the reappearance rate of the parasite, and may subsequently decrease P. vivax transmission in the area.

Pyronaridine-artesunate is a novel artemisinin-based combination therapy.,The efficacy and safety of pyronaridine-artesunate were compared with artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in children.,This phase III open-label randomized controlled non-inferiority trial was conducted in Western Kenya.,Children aged 6 months to ≤ 12 years with a bodyweight > 5 kg and microscopically confirmed P. falciparum malaria were randomly assigned in a 1:1 ratio to orally receive pyronaridine-artesunate or artemether-lumefantrine, dosed according to bodyweight, for 3 days.,Of 197 participants, 101 received pyronaridine-artesunate and 96 received artemether-lumefantrine.,The day-28 adequate clinical and parasitological response in the per-protocol population, PCR-corrected for reinfections, was 98.9% (93/94, 95% CI 94.2-99.8) for pyronaridine-artesunate and 96.4% (81/84, 95% CI 90.0-98.8) for artemether-lumefantrine.,Pyronaridine-artesunate was found to be non-inferior to artemether-lumefantrine: the treatment difference was 2.5% (95% CI − 2.8 to 9.0).,Adverse events occurred in 41.6% (42/101) and 34.4% (33/96) of patients in the pyronaridine-artesunate group and the artemether-lumefantrine group, respectively.,No participants were found to have alanine or aspartate aminotransferase levels > 3 times the upper limit of normal.,Pyronaridine-artesunate was well tolerated, efficacious and non-inferior to artemether-lumefantrine for the treatment of uncomplicated P. falciparum malaria in Kenyan children.,Results are in line with previous reports and inclusion of pyronaridine-artesunate in paediatric malaria treatment programmes should be considered.,This study is registered at clinicaltrials.gov under NCT02411994.,Registration date: 8 April 2015. https://clinicaltrials.gov/ct2/show/NCT02411994?,term=pyronaridine-artesunate&cond=Malaria&cntry=KE&rank=1,The online version of this article (10.1186/s12936-018-2340-3) contains supplementary material, which is available to authorized users.

Artemisinin combination therapies are considered the mainstay of malaria treatment, but pediatric-friendly formulations for the treatment of infants are scarce.,We sought to evaluate the efficacy and safety of a new dispersible-tablet formulation of dihydroartemisinin/piperaquine phosphate (DHA/PQP) in comparison to the marketed tablet (Eurartesim) in the treatment of infants with uncomplicated Plasmodium falciparum malaria.,Reported here are the results of a large phase II, randomized, open-label, multicenter trial conducted in African infants (6 to 12 months of age) from Mozambique, Burkina Faso, The Gambia, the Democratic Republic of the Congo, and Tanzania.,Primary efficacy endpoint was the PCR-corrected adequate clinical and parasitological response (ACPR) at day 28.,Analysis was performed for the intention-to-treat (ITT) and per-protocol (PP) populations.,A total of 201 patients received the dispersible-tablet formulation, and 99 received the conventional one administered as crushed tablets.,At day 28, the PCR-corrected ACPRs were 86.9% (ITT) and 98.3% (PP) in the dispersible-tablet group and 84.9% (ITT) and 100% (PP) in the crushed-tablet group.,At day 42, these values were 85.9% (ITT) and 96.5% (PP) in the dispersible-tablet group and 82.8% (ITT) and 96.4% (PP) in the crushed-tablet group.,The comparison between survival curves for time to new infections showed no statistically significant differences (P = 0.409).,The safety and tolerability profile for the two groups was similar in terms of type and frequency of adverse events and was consistent with that expected in African infants with malaria.,A standard 3-day treatment with the new dispersible DHA/PQP formulation is as efficacious as the currently used tablet in African infants and has a comparable safety profile.,(This trial was registered at ClinicalTrials.gov under registration no.,NCT01992900.)

Human population movement across country borders presents a real challenge for malaria control and elimination efforts in Cambodia and its neighbouring countries.,To quantify Plasmodium infection among the border-crossing population, including asymptomatic and artemisinin resistant (AR) parasites, three official border crossing points, one from each of Cambodia's borders with Thailand, Laos and Vietnam, were selected for sampling.,A total of 3206 participants (of 4110 approached) were recruited as they crossed the border, tested for malaria and interviewed.,By real-time polymerase chain reaction (RT-PCR), 5.4% of all screened individuals were found to harbour Plasmodium parasites.,The proportion was highest at the Laos border (11.5%).,Overall there were 97 P. vivax (55.7%), 55 P. falciparum (31.6%), two P. malariae (1.1%) and 20 mixed infections (11.5%).,Of identified infections, only 20% were febrile at the time of screening.,Of the 24 P. falciparum samples where a further PCR was possible to assess AR, 15 (62.5%) had mutations in the K13 propeller domain gene, all from participants at the Laos border point.,Malaria rapid diagnostic test (RDT) pLDH/HRP-2 identified a positivity rate of 3.2% overall and sensitivity compared to RT-PCR was very low (43.1%).,Main individual risk factors for infection included sex, fever, being a forest-goer, poor knowledge of malaria prevention methods and previous malaria infection.,Occupation, day of the week and time of crossing (morning vs. afternoon) also appeared to play an important role in predicting positive cases.,This study offers a novel approach to identify asymptomatic infections and monitor AR parasite flow among mobile and migrant populations crossing the borders.,Similar screening activities are recommended to identify other hot borders and characterise potential hot spots of AR.,Targeted “customised” interventions and surveillance activities should be implemented in these sites to accelerate elimination efforts in the region.

Mass drug administration (MDA), defined as the empiric administration of a therapeutic antimalarial regimen to an entire population at the same time, has been a historic component of many malaria control and elimination programmes, but is not currently recommended.,With renewed interest in MDA and its role in malaria elimination, this review aims to summarize the findings from existing research studies and program experiences of MDA strategies for reducing malaria burden and transmission.,To assess the impact of antimalarial MDA on population asexual parasitaemia prevalence, parasitaemia incidence, gametocytaemia prevalence, anaemia prevalence, mortality and MDA‐associated adverse events.,We searched the Cochrane Infectious Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE+, EMBASE, to February 2013.,We also searched CABS Abstracts, LILACS, reference lists, and recent conference proceedings.,Cluster‐randomized trials and non‐randomized controlled studies comparing therapeutic MDA versus placebo or no MDA, and uncontrolled before‐and‐after studies comparing post‐MDA to baseline data were selected.,Studies administering intermittent preventive treatment (IPT) to sub‐populations (for example, pregnant women, children or infants) were excluded.,Two authors independently reviewed studies for inclusion, extracted data and assessed risk of bias.,Studies were stratified by study design and then subgrouped by endemicity, by co‐administration of 8‐aminoquinoline plus schizonticide drugs and by plasmodium species.,The quality of evidence was assessed using the GRADE approach.,Two cluster‐randomized trials, eight non‐randomized controlled studies and 22 uncontrolled before‐and‐after studies are included in this review.,Twenty‐two studies (29 comparisons) compared MDA to placebo or no intervention of which two comparisons were conducted in areas of low endemicity (≤5%), 12 in areas of moderate endemicity (6‐39%) and 15 in areas of high endemicity (≥ 40%).,Ten studies evaluated MDA plus other vector control measures.,The studies used a wide variety of MDA regimens incorporating different drugs, dosages, timings and numbers of MDA rounds.,Many of the studies are now more than 30 years old.,Areas of low endemicity (≤5%),Within the first month post‐MDA, a single uncontrolled before‐and‐after study conducted in 1955 on a small Taiwanese island reported a much lower prevalence of parasitaemia following a single course of chloroquine compared to baseline (1 study, very low quality evidence).,This lower parasite prevalence was still present after more than 12 months (one study, very low quality evidence).,In addition, one cluster‐randomized trial evaluating MDA in a low endemic setting reported zero episodes of parasitaemia at baseline, and throughout five months of follow‐up in both the control and intervention arms (one study, very low quality evidence).,Areas of moderate endemicity (6‐39%),Within the first month post‐MDA, the prevalence of parasitaemia was much lower in three non‐randomized controlled studies from Kenya and India in the 1950s (RR 0.03, 95% CI 0.01 to 0.08, three studies, moderate quality evidence), and in three uncontrolled before‐and‐after studies conducted between 1954 and 1961 (RR 0.29, 95% CI 0.17 to 0.48, three studies,low quality evidence).,The longest follow‐up in these settings was four to six months.,At this time point, the prevalence of parasitaemia remained substantially lower than controls in the two non‐randomized controlled studies (RR 0.18, 95% CI 0.10 to 0.33, two studies, low quality evidence).,In contrast, the two uncontrolled before‐and‐after studies found mixed results: one found no difference and one found a substantially higher prevalence compared to baseline (not pooled, two studies, very low quality evidence).,Areas of high endemicity (≥40%),Within the first month post‐MDA, the single cluster‐randomized trial from the Gambia in 1999 found no significant difference in parasite prevalence (one study, low quality evidence).,However, prevalence was much lower during the MDA programmes in three non‐randomized controlled studies conducted in the 1960s and 1970s (RR 0.17, 95% CI 0.11 to 0.27, three studies, moderate quality evidence), and within one month of MDA in four uncontrolled before‐and‐after studies (RR 0.37, 95% CI 0.28 to 0.49, four studies,low quality evidence).,Four trials reported changes in prevalence beyond three months.,In the Gambia, the single cluster‐randomized trial found no difference at five months (one trial, moderate quality evidence).,The three uncontrolled before‐and‐after studies had mixed findings with large studies from Palestine and Cambodia showing sustained reductions at four months and 12 months, respectively, and a small study from Malaysia showing no difference after four to six months of follow‐up (three studies,low quality evidence).,8‐aminoquinolines,We found no studies directly comparing MDA regimens that included 8‐aminoquinolines with regimens that did not.,In a crude subgroup analysis with a limited number of studies, we were unable to detect any evidence of additional benefit of primaquine in moderate‐ and high‐transmission settings.,Plasmodium species,In studies that reported species‐specific outcomes, the same interventions resulted in a larger impact on Plasmodium falciparum compared to P. vivax.,MDA appears to reduce substantially the initial risk of malaria parasitaemia.,However, few studies showed sustained impact beyond six months post‐MDA, and those that did were conducted on small islands or in highland settings.,To assess whether there is an impact of MDA on malaria transmission in the longer term requires more quasi experimental studies with the intention of elimination, especially in low‐ and moderate‐transmission settings.,These studies need to address any long‐term outcomes, any potential barriers for community uptake, and contribution to the development of drug resistance.,22 March 2019,Update pending,Authors currently updating,The update is due to be published in 2019.,Administration of antimalarial drugs to whole populations,Malaria is the most important mosquito‐borne disease caused by a parasite, accounting for an estimated 660,000 deaths annually.,Fortunately, malaria is both preventable and treatable.,Several malaria control tools currently exist, and new and innovative approaches are continually under development.,The administration of drugs against malaria to whole populations, termed mass drug administration (MDA), was a component of many malaria elimination programmes in the 1950s, and is once again attracting interest as a malaria elimination tool.,As a consequence, it is important to review the currently available literature in order to assess the potential for this strategy to reduce malaria burden and transmission, and to identify gaps in our understanding.,This review assessed the impact of MDA on several malaria‐specific outcome measures.,Thirty‐two studies were included in this review, from sites in Asia, Africa, Europe and the Americas.,The review found that although MDA can reduce the initial risk of malaria‐specific outcomes, these reductions are often not sustained.,However, a few studies conducted on small islands or in highland areas did show sustained impact more than six months after MDA.,Adverse events were inadequately addressed in most studies.,Notable severe drug reactions, including haemolysis, haemoglobinuria, severe anaemia and death, were reported with 8‐aminoquinoline plus schizonticide drug co‐administration, while severe skin reactions were reported with sulphadoxine‐pyrimethamine plus artesunate plus primaquine.,Assessing the true impact of MDA programmes can be a challenge due to the heterogeneity of the study methods employed.,Nonetheless, this review can help guide future antimalarial MDA interventions and their evaluation.

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

This work summarizes the available data on the performance of rapid diagnostic tests (RDTs) for the detection of monoinfections due to Plasmodium species P. knowlesi, P. malariae, and P. ovale and indicates low performance of RDTs to detect these infections.,Despite the increased use and worldwide distribution of malaria rapid diagnostic tests (RDTs) that distinguish between Plasmodium falciparum and non-falciparum species, little is known about their performance detecting Plasmodium knowlesi (Pk), Plasmodium malariae (Pm), and Plasmodium ovale (Po).,This review seeks to analyze the results of published studies evaluating the diagnostic accuracy of malaria RDTs in detecting Pk, Pm, and Po monoinfections.,MEDLINE, EMBASE, Web of Science, and CENTRAL databases were systematically searched to identify studies that reported the performance of RDTs in detecting Pk, Pm, and Po monoinfections.,Among 40 studies included in the review, 3 reported on Pk, 8 on Pm, 5 on Po, 1 on Pk and Pm, and 23 on Pm and Po infections.,In the meta-analysis, estimates of sensitivities of RDTs in detecting Pk infections ranged 2%-48%.,Test performances for Pm and Po infections were less accurate and highly heterogeneous, mainly because of the small number of samples tested.,Limited data available suggest that malaria RDTs show suboptimal performance for detecting Pk, Pm, and Po infections.,New improved RDTs and appropriately designed cross-sectional studies to demonstrate the usefulness of RDTs in the detection of neglected Plasmodium species are urgently needed.

Since 1960, a total of seven species of monkey malaria have been reported as transmissible to man by mosquito bite: Plasmodium cynomolgi, Plasmodium brasilianum, Plasmodium eylesi, Plasmodium knowlesi, Plasmodium inui, Plasmodium schwetzi and Plasmodium simium.,With the exception of P. knowlesi, none of the other species has been found to infect humans in nature.,In this report, it is described the first known case of a naturally acquired P. cynomolgi malaria in humans.,The patient was a 39-year-old woman from a malaria-free area with no previous history of malaria or travel to endemic areas.,Initially, malaria was diagnosed and identified as Plasmodium malariae/P. knowlesi by microscopy in the Terengganu State Health Department.,Thick and thin blood films stained with 10% Giemsa were performed for microscopy examination.,Molecular species identification was performed at the Institute for Medical Research (IMR, Malaysia) and in the Malaria & Emerging Parasitic Diseases Laboratory (MAPELAB, Spain) using different nested PCR methods.,Microscopic re-examination in the IMR showed characteristics of Plasmodium vivax and was confirmed by a nested PCR assay developed by Snounou et al.,Instead, a different PCR assay plus sequencing performed at the MAPELAB confirmed that the patient was infected with P. cynomolgi and not with P. vivax.,This is the first report of human P. cynomolgi infection acquired in a natural way, but there might be more undiagnosed or misdiagnosed cases, since P. cynomolgi is morphologically indistinguishable from P. vivax, and one of the most used PCR methods for malaria infection detection may identify a P. cynomolgi infection as P. vivax.,Simian Plasmodium species may routinely infect humans in Southeast Asia.,New diagnostic methods are necessary to distinguish between the human and monkey malaria species.,Further epidemiological studies, incriminating also the mosquito vector(s), must be performed to know the relevance of cynomolgi malaria and its implication on human public health and in the control of human malaria.,The zoonotic malaria cannot be ignored in view of increasing interactions between man and wild animals in the process of urbanization.

Jane Carlton, Kazuyuki Tanabe and colleagues report the draft genome sequences of three Plasmodium cynomolgi strains isolated from infected monkeys.,Their comparative genomic analysis with P. vivax and P. knowlesi offers insights into these simian malaria parasites.,The online version of this article (doi:10.1038/ng.2375) contains supplementary material, which is available to authorized users.,P. cynomolgi, a malaria-causing parasite of Asian Old World monkeys, is the sister taxon of P. vivax, the most prevalent malaria-causing species in humans outside of Africa.,Because P. cynomolgi shares many phenotypic, biological and genetic characteristics with P. vivax, we generated draft genome sequences for three P. cynomolgi strains and performed genomic analysis comparing them with the P. vivax genome, as well as with the genome of a third previously sequenced simian parasite, Plasmodium knowlesi.,Here, we show that genomes of the monkey malaria clade can be characterized by copy-number variants (CNVs) in multigene families involved in evasion of the human immune system and invasion of host erythrocytes.,We identify genome-wide SNPs, microsatellites and CNVs in the P. cynomolgi genome, providing a map of genetic variation that can be used to map parasite traits and study parasite populations.,The sequencing of the P. cynomolgi genome is a critical step in developing a model system for P. vivax research and in counteracting the neglect of P. vivax.,The online version of this article (doi:10.1038/ng.2375) contains supplementary material, which is available to authorized users.

Intermittent preventive treatment (IPT) is a proven malaria control strategy in infants and pregnancy.,School-aged children represent 26 % of the African population, and an increasing percentage of them are scholarized.,Malaria is causing 50 % of deaths in this age group and malaria control efforts may shift the malaria burden to older age groups.,Schools have been suggested as a platform for health interventions delivery (deworming, iron-folic acid, nutrients supplementation, (boost-)immunization) and as a possible delivery system for IPT in schoolchildren (IPTsc).,However, the current evidence on the efficacy and safety of IPTsc is limited and the optimal therapeutic regimen remains controversial.,A systematic search for studies reporting efficacy and safety of IPT in schoolchildren was conducted using PubMed, Web of Science, Clinicaltrials and WHO/ICTRP database, and abstracts from congresses with the following key words: intermittent, preventive treatment AND malaria OR Plasmodium falciparum AND schoolchildren NOT infant NOT pregnancy.,Five studies were identified.,Most IPTsc regimes demonstrated substantial protection against malaria parasitaemia, with dihydroartemisinin-piperaquine (DP) given monthly having the highest protective effect (PE) (94 %; 95 % CI 93-96).,Contrarily, SP did not provide any PE against parasitaemia.,However, no IPT regimen provided a PE above 50 % in regard to anaemia, and highest protection was provided by SP+ amodiaquine (AQ) given four-monthly (50 %; 95 % CI 41-53).,The best protection against clinical malaria was observed in children monthly treated with DP (97 %; 95 % CI 87-98).,However, there was no protection when the drug was given three-monthly.,No severe adverse events were associated with the drugs used for IPTsc.,IPTsc may reduce the malaria-related burden in schoolchildren.,However, more studies assessing efficacy of IPT in particular against malaria-related anaemia and clinical malaria in schoolchildren must be conducted.

More than 75% of the total area of Ethiopia is malarious, making malaria the leading public health problem in Ethiopia.,The aim of this study was to investigate the prevalence rate and the associated socio-economic, geographic and demographic factors of malaria based on the rapid diagnosis test (RDT) survey results.,From December 2006 to January 2007, a baseline malaria indicator survey in Amhara, Oromiya and Southern Nation Nationalities and People (SNNP) regions of Ethiopia was conducted by The Carter Center.,This study uses this data.,The method of generalized linear model was used to analyse the data and the response variable was the presence or absence of malaria using the rapid diagnosis test (RDT).,The analyses show that the RDT result was significantly associated with age and gender.,Other significant covariates confounding variables are source of water, trip to obtain water, toilet facility, total number of rooms, material used for walls, and material used for roofing.,The prevalence of malaria for households with clean water found to be less.,Malaria rapid diagnosis found to be higher for thatch and stick/mud roof and earth/local dung plaster floor.,Moreover, spraying anti-malaria to the house was found to be one means of reducing the risk of malaria.,Furthermore, the housing condition, source of water and its distance, gender, and ages in the households were identified in order to have two-way interaction effects.,Individuals with poor socio-economic conditions are positively associated with malaria infection.,Improving the housing condition of the household is one of the means of reducing the risk of malaria.,Children and female household members are the most vulnerable to the risk of malaria.,Such information is essential to design improved strategic intervention for the reduction of malaria epidemic in Ethiopia.

The Sand cat (Felis margarita) is a small-sized felid found in sand and stone deserts ranging from the north of Africa to Asia, with the Arabian Peninsula as its centre of distribution.,The Sand cat captive breeding program at the Breeding Centre for Endangered Arabian Wildlife (BCEAW), Sharjah, UAE, has experienced high newborn mortality rates, and congenital toxoplasmosis was recently recognized as one of the causes of this mortality.,In the present study, one 18-month-old Sand cat (FM019) died of acute toxoplasmosis-associated hepatitis and pneumonitis acquired after birth; Toxoplasma gondii was demonstrated in histological sections which reacted with T. gondii polyclonal antibodies by immunohistochemistry (IHC).,T. gondii DNA was found by PCR of extracted DNA from liver and lung tissues of this cat.,Antibodies to T. gondii were found in serum examined in 1:1600 dilution in the modified agglutination test (MAT); its 2-year-old cage mate seroconverted (MAT titer 1:3200) at the same time.,Another Sand cat (FM017) was euthanized because of ill health when 3 years old; its MAT titer was >1:3200, and T. gondii tissue cysts were found in brain, heart, ocular muscles and skeletal muscle, confirmed by IHC.,Viable T. gondii was isolated by bioassays in mice inoculated with tissues of another chronically infected Sand cat (FM002); T. gondii was not found in histological sections of this cat.,T. gondii antibodies were found in several species of animals tested, notably in 49 of 57 wild felids at BCEAW.,A 7-year-old Sand cat (3657) from Al Wabra Wildlife Preservation (AWWP), Doha, State of Qatar died of acute visceral toxoplasmosis with demonstrable T. gondii tachyzoites by IHC, and T. gondii DNA by PCR, and a MAT titer of >3200.,T. gondii antibodies were found in 21 of 27 of wild felids at AWWP.,PCR-RFLP genotyping at 10 genetic loci revealed that these T. gondii isolates from Sand cat (FM002 and FM019) at BCEAW have an atypical genotype, which was previously reported in T. gondii isolates of dogs from Sri Lanka.,The genotype from the cat from AWWP (3657) is a genetic Type II strain with a Type I allele at locus Apico.,This is the first report of genetic characterization of T. gondii isolates from Middle East.

Recent population structure studies of T. gondii revealed that a few major clonal lineages predominated in different geographical regions.,T. gondii in South America is genetically and biologically divergent, whereas this parasite is remarkably clonal in North America and Europe with a few major lineages including Types I, II and III.,Information on genotypes and mouse virulence of T. gondii isolates from China is scarce and insufficient to investigate its population structure, evolution, and transmission.,Genotyping of 23 T. gondii isolates from different hosts using 10 markers for PCR-restriction fragment length polymorphism analyses (SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1 and Apico) revealed five genotypes; among them three genotypes were atypical and two were archetypal.,Fifteen strains belong to the Chinese 1 lineage, which has been previously reported as a widespread lineage from swine, cats, and humans in China.,Two human isolates fall into the type I and II lineages and the remaining isolates belong to two new atypical genotypes (ToxoDB#204 and #205) which has never been reported in China.,Our results show that these genotypes of T. gondii isolates are intermediately or highly virulent in mice except for the strain TgCtwh6, which maintained parasitemia in mice for 35 days post infection although it possesses the uniform genotype of Chinese 1.,Additionally, phylogenetic network analyses of all isolates of genotype Chinese 1 are identical, and there is no variation based on the sequence data generated for four introns (EF1, HP2, UPRT1 and UPRT7) and two dense granule proteins (GRA6 and GRA7).,A limited genetic diversity was found and genotype Chinese 1 (ToxoDB#9) is dominantly circulating in mainland China.,The results will provide a useful profile for deep insight to the population structure, epidemiology and biological characteristics of T. gondii in China.

Adoption of prevention and therapeutic innovations to ensure that National Malaria Control Programmes meet their incidence reduction targets is highly dependent on the conduct of rigorous clinical trials.,In Liberia, malaria control virtually halted during the recent Ebola epidemic, and could enormously benefit from innovations to protect its most vulnerable populations, including pregnant women, against malaria.,Health policy-planners could feel more inclined to adopt novel interventions with demonstrated safety and efficacy when trialled among their women population.,However, pregnant women are especially vulnerable when targeted as research participants.,Whilst some studies in the region attempted to understand the ethical issues around the conduct of clinical research, there is need of such information from Liberia to inform future malaria research.,This is a grounded theory study that aims to understand the barriers and opportunities for pregnant women to consent to participate in malaria research in Liberia.,The study was conducted between November 2016 and May 2017 at the St Joseph’s Catholic Hospital, Monrovia.,In-depth interviews and focus group discussions were held with hospital staff, traditional community representatives, and pregnant women.,According to the participants, useful strategies to motivate pregnant women to consent to participate in malaria research could be providing evidence-based education on malaria and research to the general population and encouraging engagement of traditional leaders in research design and community mobilization.,Fears and suspicions towards research and researchers, which were amplified during the conduct of Ebola vaccine and drug clinical trials, may influence women’s acceptance and willingness to engage in malaria research.,Population’s mistrust in the public healthcare system might hinder their acceptance of research, undermining the probability of their benefiting from any improved malaria control intervention.,Benchmarking for acceptable practices from previous public health interventions; building community discussion and dissemination platforms; and mapping communication and information errors from how previous research interventions were explained to the Liberian population, are strategies that might help ensure a safe and fully informed participation of pregnant women in malaria research.,Inequity issues impeding access and use of biomedical care for women must be tackled urgently.

Malaria is a major public health concern in the countries affected by the Ebola virus disease epidemic in West Africa.,We determined the feasibility of using molecular malaria diagnostics during an Ebola virus disease outbreak and report the incidence of Plasmodium spp. parasitemia in persons with suspected Ebola virus infection.

Maintaining the effectiveness of the currently recommended malaria vector control interventions while integrating new interventions will require monitoring key recommended indicators to identify threats to effectiveness including physiological and behavioural resistance to insecticides.,Country metadata on vector surveillance and control activities was collected using an online survey by National Malaria Control Programmes or partner organization officials.,Country and regional surveillance activities were analysed for alignment with indicators for priority vector surveillance objectives recommended by the World Health Organization.,Surveillance activities were also compared for countries in the E2020 (eliminating countries) and countries with more intense transmission.,Significant differences in monitoring priority vector indicators between Africa and Asia-Pacific country programmes were found as well as differences between countries approaching elimination and those controlling malaria.,Gaps were found between vector data collected and country management strategies (i.e., for insecticide resistance management and integrated vector control strategies) and for making programmatic decisions on surveillance and control using vector surveillance data.,Significant opportunities exist for increasing vector data collection on priority indicators and using these data for national programmatic decisions for both proactive insecticide resistance management and enhancing vector control.

Long-lasting insecticidal nets (LLINs) have been widely used as an effective alternative to conventional insecticide-treated nets (ITNs) for over a decade.,Due to the growing number of field trials and interventions reporting the effectiveness of LLINs in controlling malaria, there is a need to systematically review the literature on LLINs and ITNs to examine the relative effectiveness and characteristics of both insecticide nettings.,A systematic review of over 2000 scholarly articles published since the year 2000 was conducted.,The odds ratios (ORs) of insecticidal net effectiveness in reducing malaria were recorded.,The final dataset included 26 articles for meta-regression analysis, with a sample size of 154 subgroup observations.,While there is substantial heterogeneity in study characteristics and effect size, we found that the overall OR for reducing malaria by LLIN use was 0.44 (95% CI = 0.41-0.48, p < 0.01) indicating a risk reduction of 56%, while ITNs were slightly less effective with an OR of 0.59 (95% CI = 0.57-0.61, p <0.01).,A meta-regression model confirms that LLINs are significantly more effective than ITNs in the prevention of malaria, when controlling for other covariates.,For both types of nets, protective efficacy was greater in high transmission areas when nets were used for an extended period.,However, cross-sectional studies may overestimate the effect of the nets.,The results surprisingly suggest that nets are less effective in protecting children under the age of five, which may be due to differences in child behavior or inadequate coverage.,Compared to a previous meta-analysis, insecticide-treated nets appear to have improved their efficacy despite the risks of insecticide resistance.,These findings have practical implications for policymakers seeking effective malaria control strategies.

Natural killer (NK) cells provide the first line of defense against malaria parasite infection.,However, the molecular mechanisms through which NK cells are activated by parasites are largely unknown, so is the molecular basis underlying the variation in NK cell responses to malaria infection in the human population.,Here, we compared transcriptional profiles of responding and non-responding NK cells following exposure to Plasmodium-infected red blood cells (iRBCs) and identified MDA5, a RIG-I-like receptor involved in sensing cytosolic RNAs, to be differentially expressed.,Knockout of MDA5 in responding human NK cells by CRISPR/cas9 abolished NK cell activation, IFN-γ secretion, lysis of iRBCs.,Similarly, inhibition of TBK1/IKKε, an effector molecule downstream of MDA5, also inhibited activation of responding NK cells.,Conversely, activation of MDA5 by liposome-packaged poly I:C restored non-responding NK cells to lyse iRBCs.,We further show that microvesicles containing large parasite RNAs from iRBCs activated NK cells by fusing with NK cells.,These findings suggest that NK cells are activated through the MDA5 pathway by parasite RNAs that are delivered to the cytoplasm of NK cells by microvesicles from iRBCs.,The difference in MDA5 expression between responding and non-responding NK cells following exposure to iRBCs likely contributes to the variation in NK cell responses to malaria infection in the human population.

A highly efficacious vaccine is needed for malaria control and eradication.,Immunization with Plasmodium falciparum NF54 parasites under chemoprophylaxis (chemoprophylaxis and sporozoite (CPS)-immunization) induces the most efficient long-lasting protection against a homologous parasite.,However, parasite genetic diversity is a major hurdle for protection against heterologous strains.,We conducted a double-blind, randomized controlled trial in 39 healthy participants of NF54-CPS immunization by bites of 45 NF54-infected (n = 24 volunteers) or uninfected mosquitoes (placebo; n = 15 volunteers) against a controlled human malaria infection with the homologous NF54 or the genetically distinct NF135.,C10 and NF166.,C8 clones.,Cellular and humoral immune assays were performed as well as genetic characterization of the parasite clones.,NF54-CPS immunization induced complete protection in 5/5 volunteers against NF54 challenge infection at 14 weeks post-immunization, but sterilely protected only 2/10 and 1/9 volunteers against NF135.,C10 and NF166.,C8 challenge infection, respectively.,Post-immunization plasma showed a significantly lower capacity to block heterologous parasite development in primary human hepatocytes compared to NF54.,Whole genome sequencing showed that NF135.,C10 and NF166.,C8 have amino acid changes in multiple antigens targeted by CPS-induced antibodies.,Volunteers protected against heterologous challenge were among the stronger immune responders to in vitro parasite stimulation.,Although highly protective against homologous parasites, NF54-CPS-induced immunity is less effective against heterologous parasite clones both in vivo and in vitro.,Our data indicate that whole sporozoite-based vaccine approaches require more potent immune responses for heterologous protection.,This trial is registered in clinicaltrials.gov, under identifier NCT02098590.,The online version of this article (doi:10.1186/s12916-017-0923-4) contains supplementary material, which is available to authorized users.

The parasitic disease onchocerciasis is the second leading cause of preventable blindness, afflicting more than 18 million people worldwide.,Despite an available treatment, ivermectin, and control efforts by the World Health Organization, onchocerciasis remains a burden in many regions.,With an estimated 120 million people living in areas at risk of infection, efforts are now shifting from prevention to surveillance and elimination.,The lack of a robust, point-of-care diagnostic for an active Onchocerca infection has been a limiting factor in these efforts.,Previously, we reported the discovery of the biomarker N-acetyl-tyramine-O-glucuronide (NATOG) in human urine samples and its ability to track treatment progression between medicated patients relative to placebo; we also established its capability to monitor disease burden in a jird model.,NATOG is a human-produced metabolite of tyramine, which itself is produced as a nematode neurotransmitter.,The ability of NATOG to distinguish between active and past infection overcomes the limitations of antibody biomarkers and PCR methodologies.,Lateral flow immunoassay (LFIA) diagnostics offer the versatility and simplicity to be employed in the field and are inexpensive enough to be utilized in large-scale screening efforts.,Herein, we report the development and assessment of a NATOG-based urine LFIA for onchocerciasis, which accurately identified 85% of analyzed patient samples (N = 27).

The original aim of the African Programme for Onchocerciasis Control (APOC) was to control onchocerciasis as a public health problem in 20 African countries.,In order to identify all high risk areas where ivermectin treatment was needed to achieve control, APOC used Rapid Epidemiological Mapping of Onchocerciasis (REMO).,REMO involved spatial sampling of villages to be surveyed, and examination of 30 to 50 adults per village for palpable onchocercal nodules.,REMO has now been virtually completed and we report the results in two articles.,A companion article reports the delineation of high risk areas based on expert analysis.,The present article reports the results of a geostatistical analysis of the REMO data to map endemicity levels and estimate the number infected.,A model-based geostatistical analysis of the REMO data was undertaken to generate high-resolution maps of the predicted prevalence of nodules and of the probability that the true nodule prevalence exceeds the high risk threshold of 20%.,The number infected was estimated by converting nodule prevalence to microfilaria prevalence, and multiplying the predicted prevalence for each location with local data on population density.,The geostatistical analysis included the nodule palpation data for 14,473 surveyed villages.,The generated map of onchocerciasis endemicity levels, as reflected in the prevalence of nodules, is a significant advance with many new endemic areas identified.,The prevalence of nodules was > 20% over an area of 2.5 million km2 with an estimated population of 62 million people.,The results were consistent with the delineation of high risk areas of the expert analysis except for borderline areas where the prevalence fluctuated around 20%.,It is estimated that 36 million people would have been infected in the APOC countries by 2011 if there had been no ivermectin treatment.,The map of onchocerciasis endemicity levels has proven very valuable for onchocerciasis control in the APOC countries.,Following the recent shift to onchocerciasis elimination, the map continues to play an important role in planning treatment, evaluating impact and predicting treatment end dates in relation to local endemicity levels.

After infection with T. brucei AnTat 1.1, C57BL/6 mice lost splenic B2 B cells and lymphoid follicles, developed poor parasite-specific antibody responses, lost weight, became anemic and died with fulminating parasitemia within 35 days.,In contrast, infected C57BL/6 mice lacking the cytotoxic granule pore-forming protein perforin (Prf1 -/-) retained splenic B2 B cells and lymphoid follicles, developed high-titer antibody responses against many trypanosome polypeptides, rapidly suppressed parasitemia and did not develop anemia or lose weight for at least 60 days.,Several lines of evidence show that T. brucei infection-induced splenic B cell depletion results from natural killer (NK) cell-mediated cytotoxicity: i) B2 B cells were depleted from the spleens of infected intact, T cell deficient (TCR -/-) and FcγRIIIa deficient (CD16-/-) C57BL/6 mice excluding a requirement for T cells, NKT cell, or antibody-dependent cell-mediated cytotoxicity; ii) administration of NK1.1 specific IgG2a (mAb PK136) but not irrelevant IgG2a (myeloma M9144) prevented infection-induced B cell depletion consistent with a requirement for NK cells; iii) splenic NK cells but not T cells or NKT cells degranulated in infected C57BL/6 mice co-incident with B cell depletion evidenced by increased surface expression of CD107a; iv) purified NK cells from naïve C57BL/6 mice killed purified splenic B cells from T. brucei infected but not uninfected mice in vitro indicating acquisition of an NK cell activating phenotype by the post-infection B cells; v) adoptively transferred C57BL/6 NK cells prevented infection-induced B cell population growth in infected Prf1-/- mice consistent with in vivo B cell killing; vi) degranulated NK cells in infected mice had altered gene and differentiation antigen expression and lost cytotoxic activity consistent with functional exhaustion, but increased in number as infection progressed indicating continued generation.,We conclude that NK cells in T. brucei infected mice kill B cells, suppress humoral immunity and expedite early mortality.

BALB/c mice are highly susceptible while C57BL/6 are relatively resistant to experimental Trypanosoma congolense infection.,Although regulatory T cells (Tregs) have been shown to regulate the pathogenesis of experimental T. congolense infection, their exact role remains controversial.,We wished to determine whether Tregs contribute to distinct phenotypic outcomes in BALB/c and C57BL/6 mice and if so how they operate with respect to control of parasitemia and production of disease-exacerbating proinflammatory cytokines.,BALB/c and C57BL/6 mice were infected intraperitoneally (i.p) with 103 T. congolense clone TC13 and both the kinetics of Tregs expansion and intracellular cytokine profiles in the spleens and livers were monitored directly ex vivo by flow cytometry.,In some experiments, mice were injected with anti-CD25 mAb prior or post T. congolense infection or adoptively (by intravenous route) given highly enriched naïve CD25+ T lymphocytes prior to T. congolense infection and the inflammatory cytokine/chemokine levels and survival were monitored.,In contrast to a transient and non significant increase in the percentages and absolute numbers of CD4+CD25+Foxp3+ T cells (Tregs) in C57BL/6 mouse spleens and livers, a significant increase in the percentage and absolute numbers of Tregs was observed in spleens of infected BALB/c mice.,Ablation or increasing the number of CD25+ cells in the relatively resistant C57BL/6 mice by anti-CD25 mAb treatment or by adoptive transfer of CD25+ T cells, respectively, ameliorates or exacerbates parasitemia and production of proinflammatory cytokines.,Collectively, our results show that regulatory T cells contribute to susceptibility in experimental murine trypanosomiasis in both the highly susceptible BALB/c and relatively resistant C57BL/6 mice.

The widespread distribution and relapsing nature of Plasmodium vivax infection present major challenges for malaria elimination.,To characterise the genetic diversity of this parasite within individual infections and across the population, we performed deep genome sequencing of >200 clinical samples collected across the Asia-Pacific region, and analysed data on >300,000 SNPs and 9 regions of the genome with large copy number variations.,Individual infections showed complex patterns of genetic structure, with variation not only in the number of dominant clones but also in their level of relatedness and inbreeding.,At the population level, we observed strong signals of recent evolutionary selection both in known drug resistance genes and at novel loci, and these varied markedly between geographical locations.,These findings reveal a dynamic landscape of local evolutionary adaptation in P. vivax populations, and provide a foundation for genomic surveillance to guide effective strategies for control and elimination.

Plasmodium vivax is very rarely seen in West Africa, although specific detection methods are not widely applied in the region, and it is now considered to be absent from North Africa.,However, this parasite species has recently been reported to account for most malaria cases in Nouakchott, the capital of Mauritania, which is a large country at the interface of sub-Saharan West Africa and the Maghreb region in northwest Africa.,To determine the distribution of malaria parasite species throughout Mauritania, malaria cases were sampled in 2012 and 2013 from health facilities in 12 different areas.,These sampling sites were located in eight major administrative regions of the country, within different parts of the Sahara and Sahel zones.,Blood spots from finger-prick samples of malaria cases were processed to identify parasite DNA by species-specific PCR.,Out of 472 malaria cases examined, 163 (34.5 %) had P. vivax alone, 296 (62.7 %) Plasmodium falciparum alone, and 13 (2.8 %) had mixed P. falciparum and P. vivax infection.,All cases were negative for Plasmodium malariae and Plasmodium ovale.,The parasite species distribution showed a broad spectrum, P. vivax being detected at six of the different sites, in five of the country’s major administrative regions (Tiris Zemmour, Tagant, Brakna, Assaba, and the capital Nouakchott).,Most cases in Nouakchott were due to P. vivax, although proportions vary significantly among different health facilities in the city.,In the northern town of Zouérat, all cases were due to P. vivax, whereas almost all cases in the south of the country were due to P. falciparum.,All P. vivax cases tested were Duffy blood group positive.,It is important that P. vivax is recognized to be a widespread cause of malaria in Mauritania, occurring in diverse regions.,This should be noted by the World Health Organization, as it has significant implications for diagnosis, treatment and control of malaria in the northwestern part of Africa.

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.

Sri Lanka has a long history of malaria control, and over the past decade has had dramatic declines in cases amid a national conflict.,A case study of Sri Lanka's malaria programme was conducted to characterize the programme and explain recent progress.,The case study employed qualitative and quantitative methods.,Data were collected from published and grey literature, district-level and national records, and thirty-three key informant interviews.,Expenditures in two districts for two years - 2004 and 2009 - were compiled.,Malaria incidence in Sri Lanka has declined by 99.9% since 1999.,During this time, there were increases in the proportion of malaria infections due to Plasmodium vivax, and the proportion of infections occurring in adult males.,Indoor residual spraying and distribution of long-lasting insecticide-treated nets have likely contributed to the low transmission.,Entomological surveillance was maintained.,A strong passive case detection system captures infections and active case detection was introduced.,When comparing conflict and non-conflict districts, vector control and surveillance measures were maintained in conflict areas, often with higher coverage reported in conflict districts.,One of two districts in the study reported a 48% decline in malaria programme expenditure per person at risk from 2004 to 2009.,The other district had stable malaria spending.,Malaria is now at low levels in Sri Lanka - 124 indigenous cases were found in 2011.,The majority of infections occur in adult males and are due to P. vivax.,Evidence-driven policy and an ability to adapt to new circumstances contributed to this decline.,Malaria interventions were maintained in the conflict districts despite an ongoing war.,Sri Lanka has set a goal of eliminating malaria by the end of 2014.,Early identification and treatment of infections, especially imported ones, together with effective surveillance and response, will be critical to achieving this goal.

Hyperbilirubinaemia (bilirubin >51.3 μmol/L) alone is not indicative of severe malaria, and the immune response underlying hyperbilirubinaemia remains largely unexplored.,Liver damage associated with hyperbilirubinaemia may alter the expression of hepcidin, which regulates systemic iron by degrading ferroportin.,For this study, the association between hepcidin and the levels of cytokines and chemokines in the serum of individuals with mild and severe vivax malaria and subjects with malaria with isolated hyperbilirubinaemia was evaluated.,Cytokines/chemokines and hepcidin were measured in individuals with mild (n = 72) and severe (n = 17) vivax malaria, as well as in the serum of subjects with vivax malaria with isolated hyperbilirubinaemia (n = 14) from the Brazilian Amazon between 2009 and 2013 by multiplex assay and ELISA, respectively.,The polymorphism 744 G > T in the ferroportin gene was identified by restriction fragment-length polymorphism analysis and the restriction enzyme PvuII.,The polymorphism at position 744 G > T in the ferroportin gene was typed and no differences in the distributions of genotypes or alleles were observed between the study groups.,Subjects with severe malaria had higher levels of interleukin (IL)-2 and IL-13 than subjects with hyperbilirubinaemia.,No differences in the expression of immune markers were observed between subjects with mild malaria and those with hyperbilirubinaemia.,However, hepcidin levels were higher in individuals with severe malaria and hyperbilirubinaemia than those with mild malaria (p = 0.0002 and p = 0.0004, respectively) and cut-off values of hepcidin differentiated these groups from subjects with mild malaria.,Hepcidin was positively associated with IL-6 and IL-10 levels and with parasitaemia in subjects with mild malaria and with IFN-γ in subjects with severe malaria.,Malaria in the presence of hyperbilirubinaemia produces a less robust inflammatory response compared to severe cases of malaria.,Hepcidin levels are positively associated with immune markers in vivax malaria outcomes.,The online version of this article (doi:10.1186/s12936-015-0930-x) contains supplementary material, which is available to authorized users.

Plasmodium falciparum elicits host inflammatory responses that cause the symptoms and severe manifestations of malaria.,One proposed mechanism involves formation of immunostimulatory uric acid (UA) precipitates, which are released from sequestered schizonts into microvessels.,Another involves hypoxanthine and xanthine, which accumulate in parasitized red blood cells (RBCs) and may be converted by plasma xanthine oxidase to UA at schizont rupture.,These two forms of ‘parasite-derived’ UA stimulate immune cells to produce inflammatory cytokines in vitro.,We measured plasma levels of soluble UA and inflammatory cytokines and chemokines (IL-6, IL-10, sTNFRII, MCP-1, IL-8, TNFα, IP-10, IFNγ, GM-CSF, IL-1β) in 470 Malian children presenting with uncomplicated malaria (UM), non-cerebral severe malaria (NCSM) or cerebral malaria (CM).,UA levels were elevated in children with NCSM (median 5.74 mg/dl, 1.21-fold increase, 95% CI 1.09-1.35, n = 23, p = 0.0007) and CM (median 5.69 mg/dl, 1.19-fold increase, 95% CI 0.97-1.41, n = 9, p = 0.0890) compared to those with UM (median 4.60 mg/dl, n = 438).,In children with UM, parasite density and plasma creatinine levels correlated with UA levels.,These UA levels correlated with the levels of seven cytokines [IL-6 (r = 0.259, p<0.00001), IL-10 (r = 0.242, p<0.00001), sTNFRII (r = 0.221, p<0.00001), MCP-1 (r = 0.220, p<0.00001), IL-8 (r = 0.147, p = 0.002), TNFα (r = 0.132, p = 0.006) and IP-10 (r = 0.120, p = 0.012)].,In 39 children, UA levels were 1.49-fold (95% CI 1.34-1.65; p<0.0001) higher during their malaria episode [geometric mean titer (GMT) 4.67 mg/dl] than when they were previously healthy and aparasitemic (GMT 3.14 mg/dl).,Elevated UA levels may contribute to the pathogenesis of P. falciparum malaria by activating immune cells to produce inflammatory cytokines.,While this study cannot identify the cause of elevated UA levels, their association with parasite density and creatinine levels suggest that parasite-derived UA and renal function may be involved.,Defining pathogenic roles for parasite-derived UA precipitates, which we have not directly studied here, requires further investigation.,ClinicalTrials.gov NCT00669084

We investigated the efficacy, safety and cost of lime wash of household walls plus treatment of sand fly breeding places with bleach (i.e. environmental management or EM), insecticide impregnated durable wall lining (DWL), and bed net impregnation with slow release insecticide (ITN) for sand fly control in the Indian sub-continent.,This multi-country cluster randomized controlled trial had 24 clusters in each three sites with eight clusters per high, medium or low sand fly density stratum.,Every cluster included 45-50 households.,Five households from each cluster were randomly selected for entomological measurements including sand fly density and mortality at one, three, nine and twelve months post intervention.,Household interviews were conducted for socioeconomic information and intervention acceptability assessment.,Cost for each intervention was calculated.,There was a control group without intervention.,Sand fly mortality [mean and 95%CI] ranged from 84% (81%-87%) at one month to 74% (71%-78%) at 12 months for DWL, 75% (71%-79%) at one month to 49% (43%-55%) at twelve months for ITN, and 44% (34%-53%) at one month to 22% (14%-29%) at twelve months for EM.,Adjusted intervention effect on sand fly density measured by incidence rate ratio ranged from 0.28 (0.23-0.34) at one month to 0.62 (0.51-0.75) at 12 months for DWL; 0.72 (0.62-0.85) at one month to 1.02 (0.86-1.22) at 12 months for ITN; and 0.89 (0.76-1.03) at one months to 1.49 (1.26-1.74) at 12 months for EM.,Household acceptance of EM was 74% compared to 94% for both DWL and ITN.,Operational cost per household in USD was about 5, 8, and 2 for EM, DWL and ITN, respectively.,Minimal adverse reactions were reported for EM and ITN while 36% of households with DWL reported transient itching.,DWL is the most effective, durable and acceptable control method followed by ITN.,The Visceral Leishmaniasis (VL) Elimination Program in the Indian sub-continent should consider DWL and ITN for sand fly control in addition to IRS.

While significant focus has been given to net distribution, little is known about what is done with nets that leave a household, either to be used by others or when they are discarded.,To better understand the magnitude of sharing LLIN between households and patterns of discarding LLIN, the present study pools data from 14 post-campaign surveys to draw larger conclusions about the fate of nets that leave households.,Data from 14 sub-national post-campaign surveys conducted in Ghana, Senegal, Nigeria (10 states), and Uganda between 2009 and 2012 were pooled.,Survey design and data collection methods were similar across surveys.,The timing of surveys ranged from 2-16 months following their respective mass LLIN distributions.,Among the 14 surveys a total of 14,196 households reported owning 25,447 nets of any kind, of which 23,955 (94%) were LLINs.,In addition, a total of 4,102 nets were reported to have left the households in the sample: 63% were discarded, and 34% were given away.,Only 255 of the discarded nets were reported used for other purposes, representing less than 1% of the total sample of nets.,The majority (62.5%) of nets given away were given to or taken by relatives, while 31.1% were given to non-relatives.,Campaign nets were almost six times (OR 5.95, 4.25-8.32, p < 0.0001) more likely to be given away than non-campaign nets lost during the same period.,Nets were primarily given away within the first few months after distribution.,The overall rate of net redistribution was 5% of all nets.,Intra-household re-allocation of nets does occur, but was sensitive to current household net ownership and the time elapsed since mass distribution.,These factors can be addressed programmatically to further facilitate reallocation within a given community.,Secondly, the overwhelming majority of nets were used for malaria prevention.,Of the repurposed nets (<1% overall), the majority were already considered too torn, indicating they had already served out their useful life for malaria prevention.,National programmes and donor agencies should remain confident that overall, their investments in LLIN are being appropriately used.

Asymptomatic carriers of Plasmodium falciparum serve as a reservoir of parasites for malaria transmission.,Identification and treatment of asymptomatic carriers within a region may reduce the parasite reservoir and influence malaria transmission in that area.,Using computer simulation, this analysis explored the impact of community screening campaigns (CSC) followed by systematic treatment of P. falciparum asymptomatic carriers (AC) with artemether-lumefantrine (AL) on disease transmission.,The model created by Okell et al (originally designed to explore the impact of the introduction of treatment with artemisinin-based combination therapy on malaria endemicity) was modified to represent CSC and treatment of AC with AL, with the addition of malaria vector seasonality.,The age grouping, relative distribution of age in a region, and degree of heterogeneity in disease transmission were maintained.,The number and frequency of CSC and their relative timing were explored in terms of their effect on malaria incidence.,A sensitivity analysis was conducted to determine the factors with the greatest impact on the model predictions.,The simulation showed that the intervention that had the largest effect was performed in an area with high endemicity (entomological inoculation rate, EIR > 200); however, the rate of infection returned to its normal level in the subsequent year, unless the intervention was repeated.,In areas with low disease burden (EIR < 10), the reduction was sustained for over three years after a single intervention.,Three CSC scheduled in close succession (monthly intervals) at the start of the dry season had the greatest impact on the success of the intervention.,Community screening and treatment of asymptomatic carriers with AL may reduce malaria transmission significantly.,The initial level of disease intensity has the greatest impact on the potential magnitude and duration of malaria reduction.,When combined with other interventions (e.g. long-lasting insecticide-treated nets, rapid diagnostic tests, prompt diagnosis and treatment, and, where appropriate, indoor residual spraying) the effect of this intervention can be sustained for many years, and it could become a tool to accelerate the reduction in transmission intensity to pre-elimination levels.,Repeated interventions at least every other year may help to prolong the effect.,The use of an effective diagnostic tool and a highly effective ACT, such as AL, is also vital.,The modelling supports the evaluation of this approach in a prospective clinical trial to reduce the pool of infective vectors for malaria transmission in an area with marked seasonality.

Malaria inflicts significant costs on households and on the economy of malaria endemic countries.,There is also evidence that the economic burden is higher among the poorest in a population, and that cost burdens differ significantly between wet and dry seasons.,What is not clear is whether, and how, the economic burden of malaria differs by disease endemicity.,The need to account for geographical and epidemiological differences in the estimation of the social and economic burden of malaria is well recognized, but there is limited data, if any, to support this argument.,This study sought to contribute towards filling this gap by comparing malaria cost burdens in four Kenyan districts of different endemicity.,A cross-sectional household survey was conducted during the peak malaria transmission season in the poorest areas in four Kenyan districts with differing malaria transmission patterns (n = 179 households in Bondo; 205 Gucha; 184 Kwale; 141 Makueni).,There were significant differences in duration of fever, perception of fever severity and cost burdens.,Fever episodes among adults and children over five years in Gucha and Makueni districts (highland endemic and low acute transmission districts respectively) lasted significantly longer than episodes reported in Bondo and Kwale districts (high perennial transmission and seasonal, intense transmission, respectively).,Perceptions of illness severity also differed between districts: fevers reported among older children and adults in Gucha and Makueni districts were reported as severe compared to those reported in the other districts.,Indirect and total costs differed significantly between districts but differences in direct costs were not significant.,Total household costs were highest in Makueni (US$ 19.6 per month) and lowest in Bondo (US$ 9.2 per month).,Cost burdens are the product of complex relationships between social, economic and epidemiological factors.,The cost data presented in this study reflect transmission patterns in the four districts, suggesting that a relationship between costs burdens and the nature of transmission might exist, and that the same warrants more attention from researchers and policy makers.

In Nigeria, access to malaria diagnostics may be expanded if drug retailers were allowed to administer malaria rapid diagnostic tests (RDTs).,A 2012 pilot intervention showed that short message service (SMS) reminder messages could boost treatment adherence to RDT results by 10-14% points.,This study aimed to replicate the SMS intervention in a different population, and additionally test the effect of an expanded message about anticipated RDT access policy change on customers’ acceptability for drug retailers’ administration of RDTs.,One day after being tested with an RDT, participants who purchased malaria treatment from drug shops were randomized to receive (1) a basic SMS reminder repeating the RDT result and appropriate treatment actions, (2) an expanded SMS reminder additionally saying that the ‘government might allow pharmacists/chemists to do RDTs’ or (3) no SMS reminders (i.e. control).,Using regression analysis, we estimate intent-to-treat (ITT) and treatment effects on the treated for 686 study participants.,Results corroborate previous findings that a basic SMS reminder increased treatment adherence [odds ratio (OR) = 1.53, 95% CI 0.96-2.44] and decreased use of unnecessary anti-malarials for RDT-negative adults [OR = 0.63, 95% CI 0.39-1.00].,The expanded SMS also increased adherence for adults [OR = 1.42, 95% CI 0.97-2.07], but the effects for sick children differed-the basic SMS did not have any measurable impact on treatment adherence [OR = 0.87, 95% CI 0.24-3.09] or use of unnecessary anti-malarials [OR = 1.27, 95% CI 0.32-1.93], and the expanded SMS actually led to poorer treatment adherence [OR = 0.26, 95% CI 0.10-0.66] and increased use of unnecessary anti-malarials [OR = 4.67, 95% CI 1.76-12.43].,Further, the targeted but neutral message in the expanded SMS lowered acceptance for drug retailers' administration of RDTs [OR = 0.55, 95% CI 0.10-2.93], counter to what we hypothesized.,Future SMS interventions should show consistent positive results across populations and be attuned to message length and content before initiating a larger messaging campaign.

Plasmodium vivax threatens nearly half the world’s population and is a significant impediment to achievement of the millennium development goals.,It is an important, but incompletely understood, cause of anaemia.,This review synthesizes current evidence on the epidemiology, pathogenesis, treatment and consequences of vivax-associated anaemia.,Young children are at high risk of clinically significant and potentially severe vivax-associated anaemia, particularly in countries where transmission is intense and relapses are frequent.,Despite reaching lower densities than Plasmodium falciparum, Plasmodium vivax causes similar absolute reduction in red blood cell mass because it results in proportionately greater removal of uninfected red blood cells.,Severe vivax anaemia is associated with substantial indirect mortality and morbidity through impaired resilience to co-morbidities, obstetric complications and requirement for blood transfusion.,Anaemia can be averted by early and effective anti-malarial treatment.

Ingestion of the obligate intracellular protozoan parasite Toxoplasma gondii causes an acute infection that leads to chronic infection of the host.,To facilitate the acute phase of the infection, T. gondii manipulates the host response by secreting rhoptry organelle proteins (ROPs) into host cells during its invasion.,A few key ROP proteins with signatures of kinases or pseudokinases (ROPKs) act as virulence factors that enhance parasite survival against host gamma interferon-stimulated innate immunity.,However, the roles of these and other ROPK proteins in establishing chronic infection have not been tested.,Here, we deleted 26 ROPK gene loci encoding 31 unique ROPK proteins of type II T. gondii and show that numerous ROPK proteins influence the development of chronic infection.,Cyst burdens were increased in the Δrop16 knockout strain or moderately reduced in 11 ROPK knockout strains.,In contrast, deletion of ROP5, ROP17, ROP18, ROP35, or ROP38/29/19 (ROP38, ROP29, and ROP19) severely reduced cyst burdens.,Δrop5 and Δrop18 knockout strains were less resistant to host immunity-related GTPases (IRGs) and exhibited >100-fold-reduced virulence.,ROP18 kinase activity and association with the parasitophorous vacuole membrane were necessary for resistance to host IRGs.,The Δrop17 strain exhibited a >12-fold defect in virulence; however, virulence was not affected in the Δrop35 or Δrop38/29/19 strain.,Resistance to host IRGs was not affected in the Δrop17, Δrop35, or Δrop38/29/19 strain.,Collectively, these findings provide the first definitive evidence that the type II T. gondii ROPK proteome functions as virulence factors and facilitates additional mechanisms of host manipulation that are essential for chronic infection and transmission of T. gondii.,Reactivation of chronic Toxoplasma gondii infection in individuals with weakened immune systems causes severe toxoplasmosis.,Existing treatments for toxoplasmosis are complicated by adverse reactions to chemotherapy.,Understanding key parasite molecules required for chronic infection provides new insights into potential mechanisms that can interrupt parasite survival or persistence in the host.,This study reveals that key secreted rhoptry molecules are used by the parasite to establish chronic infection of the host.,Certain rhoptry proteins were found to be critical virulence factors that resist innate immunity, while other rhoptry proteins were found to influence chronic infection without affecting virulence.,This study reveals that rhoptry proteins utilize multiple mechanisms of host manipulation to establish chronic infection of the host.,Targeted disruption of parasite rhoptry proteins involved in these biological processes opens new avenues to interfere with chronic infection with the goal to either eliminate chronic infection or to prevent recrudescent infections.

Toxoplasma gondii has evolved a number of strategies to evade immune responses in its many hosts.,Previous genetic mapping of crosses between clonal type 1, 2, and 3 strains of T. gondii, which are prevalent in Europe and North America, identified two rhoptry proteins, ROP5 and ROP18, that function together to block innate immune mechanisms activated by interferon gamma (IFNg) in murine hosts.,However, the contribution of these and other virulence factors in more genetically divergent South American strains is unknown.,Here we utilized a cross between the intermediately virulent North American type 2 ME49 strain and the highly virulent South American type 10 VAND strain to map the genetic basis for differences in virulence in the mouse.,Quantitative trait locus (QTL) analysis of this new cross identified one peak that spanned the ROP5 locus on chromosome XII.,CRISPR-Cas9 mediated deletion of all copies of ROP5 in the VAND strain rendered it avirulent and complementation confirmed that ROP5 is the major virulence factor accounting for differences between type 2 and type 10 strains.,To extend these observations to other virulent South American strains representing distinct genetic populations, we knocked out ROP5 in type 8 TgCtBr5 and type 4 TgCtBr18 strains, resulting in complete loss of virulence in both backgrounds.,Consistent with this, polymorphisms that show strong signatures of positive selection in ROP5 were shown to correspond to regions known to interface with host immunity factors.,Because ROP5 and ROP18 function together to resist innate immune mechanisms, and a significant interaction between them was identified in a two-locus scan, we also assessed the role of ROP18 in the virulence of South American strains.,Deletion of ROP18 in South American type 4, 8, and 10 strains resulted in complete attenuation in contrast to a partial loss of virulence seen for ROP18 knockouts in previously described type 1 parasites.,These data show that ROP5 and ROP18 are conserved virulence factors in genetically diverse strains from North and South America, suggesting they evolved to resist innate immune defenses in ancestral T. gondii strains, and they have subsequently diversified under positive selection.

The development of immunoregulatory networks is important to prevent disease.,However, these same networks allow pathogens to persist and reduce vaccine efficacy.,Here, we identify type I interferons (IFNs) as important regulators in developing anti-parasitic immunity in healthy volunteers infected for the first time with Plasmodium falciparum.,Type I IFNs suppressed innate immune cell function and parasitic-specific CD4+ T cell IFNγ production, and they promoted the development of parasitic-specific IL-10-producing Th1 (Tr1) cells.,Type I IFN-dependent, parasite-specific IL-10 production was also observed in P. falciparum malaria patients in the field following chemoprophylaxis.,Parasite-induced IL-10 suppressed inflammatory cytokine production, and IL-10 levels after drug treatment were positively associated with parasite burdens before anti-parasitic drug administration.,These findings have important implications for understanding the development of host immune responses following blood-stage P. falciparum infection, and they identify type I IFNs and related signaling pathways as potential targets for therapies or vaccine efficacy improvement.

CD4+ T cells that produce IFN-γ are the source of host-protective IL-10 during primary infection with a number of different pathogens, including Plasmodium spp.,The fate of these CD4+IFN-γ+IL-10+ T cells following clearance of primary infection and their subsequent influence on the course of repeated infections is, however, presently unknown.,In this study, utilizing IFN-γ-yellow fluorescent protein (YFP) and IL-10-GFP dual reporter mice, we show that primary malaria infection-induced CD4+YFP+GFP+ T cells have limited memory potential, do not stably express IL-10, and are disproportionately lost from the Ag-experienced CD4+ T cell memory population during the maintenance phase postinfection.,CD4+YFP+GFP+ T cells generally exhibited a short-lived effector rather than effector memory T cell phenotype postinfection and expressed high levels of PD-1, Lag-3, and TIGIT, indicative of cellular exhaustion.,Consistently, the surviving CD4+YFP+GFP+ T cell-derived cells were unresponsive and failed to proliferate during the early phase of secondary infection.,In contrast, CD4+YFP+GFP− T cell-derived cells expanded rapidly and upregulated IL-10 expression during secondary infection.,Correspondingly, CD4+ T cells were the major producers within an accelerated and amplified IL-10 response during the early stage of secondary malaria infection.,Notably, IL-10 exerted quantitatively stronger regulatory effects on innate and CD4+ T cell responses during primary and secondary infections, respectively.,The results in this study significantly improve our understanding of the durability of IL-10-producing CD4+ T cells postinfection and provide information on how IL-10 may contribute to optimized parasite control and prevention of immune-mediated pathology during repeated malaria infections.

The search for new macrofilaricidal drugs against onchocerciasis that can be administered in shorter regimens than required for doxycycline (DOX, 200mg/d given for 4-6 weeks), identified minocycline (MIN) with superior efficacy to DOX.,Further reduction in the treatment regimen may be achieved with co-administration with standard anti-filarial drugs.,Therefore a randomized, open-label, pilot trial was carried out in an area in Ghana endemic for onchocerciasis, comprising 5 different regimens: the standard regimen DOX 200mg/d for 4 weeks (DOX 4w, N = 33), the experimental regimens MIN 200mg/d for 3 weeks (MIN 3w; N = 30), DOX 200mg/d for 3 weeks plus albendazole (ALB) 800mg/d for 3 days (DOX 3w + ALB 3d, N = 32), DOX 200mg/d for 3 weeks (DOX 3w, N = 31) and ALB 800mg for 3 days (ALB 3d, N = 30).,Out of 158 randomized participants, 116 (74.4%) were present for the follow-up at 6 months of whom 99 participants (63.5%) followed the treatment per protocol and underwent surgery.,Histological analysis of the adult worms in the extirpated nodules revealed absence of Wolbachia in 98.8% (DOX 4w), 81.4% (DOX 3w + ALB 3d), 72.7% (MIN 3w), 64.1% (DOX 3w) and 35.2% (ALB 3d) of the female worms.,All 4 treatment regimens showed superiority to ALB 3d (p < 0.001, p < 0.001, p = 0.002, p = 0.008, respectively), which was confirmed by real-time PCR.,Additionally, DOX 4w showed superiority to all other treatment arms.,Furthermore DOX 4w and DOX 3w + ALB 3d showed a higher amount of female worms with degenerated embryogenesis compared to ALB 3d (p = 0.028, p = 0.042, respectively).,These results confirm earlier studies that DOX 4w is sufficient for Wolbachia depletion and the desired parasitological effects.,The data further suggest that there is an additive effect of ALB (3 days) on top of that of DOX alone, and that MIN shows a trend for stronger potency than DOX.,These latter two results are preliminary and need confirmation in a fully randomized controlled phase 2 trial.,Trial Registration: ClinicalTrials.gov #06010453

The three major soil-transmitted helminths (STH) Ascaris lumbricoides, Trichuris trichiura and Necator americanus/Ancylostoma duodenale are among the most widespread parasites worldwide.,Despite the global expansion of preventive anthelmintic treatment, standard operating procedures to monitor anthelmintic drug efficacy are lacking.,The objective of this study, therefore, was to define the efficacy of a single 400 milligram dose of albendazole (ALB) against these three STH using a standardized protocol.,Seven trials were undertaken among school children in Brazil, Cameroon, Cambodia, Ethiopia, India, Tanzania and Vietnam.,Efficacy was assessed by the Cure Rate (CR) and the Fecal Egg Count Reduction (FECR) using the McMaster egg counting technique to determine fecal egg counts (FEC).,Overall, the highest CRs were observed for A. lumbricoides (98.2%) followed by hookworms (87.8%) and T. trichiura (46.6%).,There was considerable variation in the CR for the three parasites across trials (country), by age or the pre-intervention FEC (pre-treatment).,The latter is probably the most important as it had a considerable effect on the CR of all three STH.,Therapeutic efficacies, as reflected by the FECRs, were very high for A. lumbricoides (99.5%) and hookworms (94.8%) but significantly lower for T. trichiura (50.8%), and were affected to different extents among the 3 species by the pre-intervention FEC counts and trial (country), but not by sex or age.,Our findings suggest that a FECR (based on arithmetic means) of >95% for A. lumbricoides and >90% for hookworms should be the expected minimum in all future surveys, and that therapeutic efficacy below this level following a single dose of ALB should be viewed with concern in light of potential drug resistance.,A standard threshold for efficacy against T. trichiura has yet to be established, as a single-dose of ALB is unlikely to be satisfactory for this parasite.,ClinicalTrials.gov NCT01087099

Trypanosoma cruzi interacts with host cells, including cardiomyocytes, and induces the production of cytokines, chemokines, metalloproteinases, and glycan-binding proteins.,Among the glycan-binding proteins is Galectin-3 (Gal-3), which is upregulated after T. cruzi infection.,Gal-3 is a member of the lectin family with affinity for β-galactose containing molecules; it can be found in both the nucleus and the cytoplasm and can be either membrane-associated or secreted.,This lectin is involved in several immunoregulatory and parasite infection process.,Here, we explored the consequences of Gal-3 deficiency during acute and chronic T. cruzi experimental infection.,Our results demonstrated that lack of Gal-3 enhanced in vitro replication of intracellular parasites, increased in vivo systemic parasitaemia, and reduced leukocyte recruitment.,Moreover, we observed decreased secretion of pro-inflammatory cytokines in spleen and heart of infected Gal-3 knockout mice.,Lack of Gal-3 also led to elevated mast cell recruitment and fibrosis of heart tissue.,In conclusion, galectin-3 expression plays a pivotal role in controlling T. cruzi infection, preventing heart damage and fibrosis.

Human African trypanosomiasis is a lethal disease caused by the extracellular parasite Trypanosoma brucei.,The proteins secreted by T. brucei inhibit the maturation of dendritic cells and their ability to induce lymphocytic allogenic responses.,To better understand the pathogenic process, we combined different approaches to characterize these secreted proteins.,Overall, 444 proteins were identified using mass spectrometry, the largest parasite secretome described to date.,Functional analysis of these proteins revealed a strong bias toward folding and degradation processes and to a lesser extent toward nucleotide metabolism.,These features were shared by different strains of T. brucei, but distinguished the secretome from published T. brucei whole proteome or glycosome.,In addition, several proteins had not been previously described in Trypanosoma and some constitute novel potential therapeutic targets or diagnostic markers.,Interestingly, a high proportion of these secreted proteins are known to have alternative roles once secreted.,Furthermore, bioinformatic analysis showed that a significant proportion of proteins in the secretome lack transit peptide and are probably not secreted through the classical sorting pathway.,Membrane vesicles from secretion buffer and infested rat serum were purified on sucrose gradient and electron microscopy pictures have shown 50- to 100-nm vesicles budding from the coated plasma membrane.,Mass spectrometry confirmed the presence of Trypanosoma proteins in these microvesicles, showing that an active exocytosis might occur beyond the flagellar pocket.,This study brings out several unexpected features of the secreted proteins and opens novel perspectives concerning the survival strategy of Trypanosoma as well as possible ways to control the disease.,In addition, concordant lines of evidence support the original hypothesis of the involvement of microvesicle-like bodies in the survival strategy allowing Trypanosoma to exchange proteins at least between parasites and/or to manipulate the host immune system.

Plasmodium sporozoites are the infective forms of malaria parasite to vertebrate host and undergo dramatic changes in their transcriptional repertoire during maturation in mosquito salivary glands.,We report here the role of a novel and conserved Plasmodium berghei protein encoded by PBANKA_091090 in maturation of Exo-erythrocytic Forms (EEFs) and designate it as Sporozoite surface Protein Essential for Liver stage Development (PbSPELD).,PBANKA_091090 was previously annotated as PB402615.00.0 and its transcript was recovered at maximal frequency in the Serial Analysis of the Gene Expression (SAGE) of Plasmodium berghei salivary gland sporozoites.,An orthologue of this transcript was independently identified in Plasmodium vivax sporozoite microarrays and was designated as Sporozoite Conserved Orthologous Transcript-2 (scot-2).,Functional characterization through reverse genetics revealed that PbSPELD is essential for Plasmodium liver stage maturation. mCherry transgenic of PbSPELD localized the protein to plasma membrane of sporozoites and early EEFs.,Global microarray analysis of pbspeld ko revealed EEF attenuation being associated with down regulation of genes central to general transcription, cell cycle, proteosome and cadherin signaling. pbspeld mutant EEFs induced pre-erythrocytic immunity with 50% protective efficacy.,Our studies have implications for attenuating the human Plasmodium liver stages by targeting SPELD locus.

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.

The social determinants of health (SDHs) condition disease distribution and the ways they are handled.,Socio-economic inequalities are closely linked to the occurrence of neglected tropical diseases, but empirical support is limited in the case of Chagas disease, caused by the protozoan Trypanosoma cruzi.,Herein we assessed the relationship between key structural SDHs and the risk of T. cruzi vector-borne transmission in rural communities of the Argentine Chaco occupied by creoles and an indigenous group (Qom).,We used multiple correspondence analysis to quantify the household-level socio-economic position (social vulnerability and assets indices), access to health and sanitation services, and domestic host availability.,We identified the most vulnerable population subgroups by comparing their demographic profiles, mobility patterns and distribution of these summary indices, then assessed their spatial correlation and household-level effects on vector domiciliary indices as transmission risk surrogates.,Qom households had higher social vulnerability and fewer assets than creoles, as did local movers and migrant households compared with non-movers.,We found significantly positive effects of social vulnerability and domestic host availability on infected Triatoma infestans abundance, after adjusting for ethnicity.,Access to health and sanitation services had no effect on transmission risk.,Only social vulnerability displayed significant global spatial autocorrelation up to 1 km.,A hotspot of infected vectors overlapped with an aggregation of most vulnerable households.,This synthetic approach to assess socio-economic related inequalities in transmission risk provides key information to guide targeted vector control actions, case detection and treatment of Chagas disease, towards sustainability of interventions and greater reduction of health inequalities.,The online version of this article (10.1186/s13071-019-3444-5) contains supplementary material, which is available to authorized users.

Plasmodium falciparum PfRH5 protein binds Ripr, CyRPA and Pf113 to form a complex that is essential for merozoite invasion of erythrocytes.,The inter-genomic conservation of the PfRH5 complex proteins makes them attractive blood stage vaccine candidates.,However, little is known about how antibodies to PfRH5, CyRPA and Pf113 are acquired and maintained in naturally exposed populations, and the role of PfRH5 complex proteins in naturally acquired immunity.,To provide such data, we studied 206 Ghanaian children between the ages of 1-12 years, who were symptomatic, asymptomatic or aparasitemic and healthy.,Plasma levels of antigen-specific IgG and IgG subclasses were measured by ELISA at several time points during acute disease and convalescence.,On the day of admission with acute P. falciparum malaria, the prevalence of antibodies to PfRH5-complex proteins was low compared to other merozoite antigens (EBA175, GLURP-R0 and GLURP-R2).,At convalescence, the levels of RH5-complex-specific IgG were reduced, with the decay of PfRH5-specific IgG being slower than the decay of IgG specific for CyRPA and Pf113.,No correlation between IgG levels and protection against P. falciparum malaria was observed for any of the PfRH5 complex proteins.,From this we conclude that specific IgG was induced against proteins from the PfRH5-complex during acute P. falciparum malaria, but the prevalence was low and the IgG levels decayed rapidly after treatment.,These data indicate that the levels of IgG specific for PfRH5-complex proteins in natural infections in Ghanaian children were markers of recent exposure only.