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Reliable measures of disease burden over time are necessary to evaluate the impact of interventions and assess sub-national trends in the distribution of infection.,Three Malaria Indicator Surveys (MISs) have been conducted in Madagascar since 2011.,They provide a valuable resource to assess changes in burden that is complementary to the country’s routine case reporting system.,A Bayesian geostatistical spatio-temporal model was developed in an integrated nested Laplace approximation framework to map the prevalence of Plasmodium falciparum malaria infection among children from 6 to 59 months in age across Madagascar for 2011, 2013 and 2016 based on the MIS datasets.,The model was informed by a suite of environmental and socio-demographic covariates known to influence infection prevalence.,Spatio-temporal trends were quantified across the country.,Despite a relatively small decrease between 2013 and 2016, the prevalence of malaria infection has increased substantially in all areas of Madagascar since 2011.,In 2011, almost half (42.3%) of the country’s population lived in areas of very low malaria risk (<1% parasite prevalence), but by 2016, this had dropped to only 26.7% of the population.,Meanwhile, the population in high transmission areas (prevalence >20%) increased from only 2.2% in 2011 to 9.2% in 2016.,A comparison of the model-based estimates with the raw MIS results indicates there was an underestimation of the situation in 2016, since the raw figures likely associated with survey timings were delayed until after the peak transmission season.,Malaria remains an important health problem in Madagascar.,The monthly and annual prevalence maps developed here provide a way to evaluate the magnitude of change over time, taking into account variability in survey input data.,These methods can contribute to monitoring sub-national trends of malaria prevalence in Madagascar as the country aims for geographically progressive elimination.,The online version of this article (10.1186/s12916-018-1060-4) contains supplementary material, which is available to authorized users.

A blood test that captures cumulative exposure over time and assesses levels of naturally acquired immunity (NAI) would provide a critical tool to monitor the impact of interventions to reduce malaria transmission and broaden our understanding of how NAI develops around the world as a function of age and exposure.,This article describes a collaborative effort in multiple International Centers of Excellence in Malaria Research (ICEMRs) to develop such tests using malaria-specific antibody responses as biosignatures of transmission and immunity.,The focus is on the use of Plasmodium falciparum and Plasmodium vivax protein microarrays to identify a panel of the most informative antibody responses in diverse malaria-endemic settings representing an unparalleled spectrum of malaria transmission and malaria species mixes before and after interventions to reduce malaria transmission.

Carriage and density of gametocytes, the transmission stages of malaria parasites, are determined for predicting the infectiousness of humans to mosquitoes.,This measure is used for evaluating interventions that aim at reducing malaria transmission.,Gametocytes need to be detected by amplification of stage-specific transcripts, which requires RNA-preserving blood sampling.,For simultaneous, highly sensitive quantification of both, blood stages and gametocytes, we have compared and optimized different strategies for field and laboratory procedures in a cross sectional survey in 315 5-9 yr old children from Papua New Guinea. qRT-PCR was performed for gametocyte markers pfs25 and pvs25, Plasmodium species prevalence was determined by targeting both, 18S rRNA genes and transcripts.,RNA-based parasite detection resulted in a P. falciparum positivity of 24.1%; of these 40.8% carried gametocytes.,P. vivax positivity was 38.4%, with 38.0% of these carrying gametocytes.,Sensitivity of DNA-based parasite detection was substantially lower with 14.1% for P. falciparum and 19.6% for P. vivax.,Using the lower DNA-based prevalence of asexual stages as a denominator increased the percentage of gametocyte-positive infections to 59.1% for P. falciparum and 52.4% for P. vivax.,For studies requiring highly sensitive and simultaneous quantification of sexual and asexual parasite stages, 18S rRNA transcript-based detection saves efforts and costs.,RNA-based positivity is considerably higher than other methods.,On the other hand, DNA-based parasite quantification is robust and permits comparison with other globally generated molecular prevalence data.,Molecular monitoring of low density asexual and sexual parasitaemia will support the evaluation of effects of up-scaled antimalarial intervention programs and can also inform about small scale spatial variability in transmission intensity.

Natural immunity to Plasmodium falciparum has been widely studied, but its effects on parasite dynamics are poorly understood.,Acquisition and clearance rates of untreated infections are key elements of the dynamics of malaria, but estimating these parameters is challenging because of frequent super-infection and imperfect detectability of parasites.,Consequently, information on effects of host immune status or age on infection dynamics is fragmentary.,An age-stratified cohort of 347 individuals from Northern Ghana was sampled six times at 2 month intervals.,High-throughput capillary electrophoresis was used to genotype the msp-2 locus of all P. falciparum infections detected by PCR.,Force of infection (FOI) and duration were estimated for each age group using an immigration-death model that allows for imperfect detection of circulating parasites.,Allowing for imperfect detection substantially increased estimates of FOI and duration.,Effects of naturally acquired immunity on the FOI and duration would be reflected in age dependence in these indices, but in our cohort data FOI tended to increase with age in children.,Persistence of individual parasite clones was characteristic of all age-groups.,Duration peaked in 5-9 year old children (average duration 319 days, 95% confidence interval 318;320).,The main age-dependence is on parasite densities, with only small age-variations in the FOI and persistence of infections.,This supports the hypothesis that acquired immunity controls transmission mainly by limiting blood-stage parasite densities rather than changing rates of acquisition or clearance of infections.

The Plasmodium vivax Duffy binding protein (DBP) is a prime target of the protective immune response and a promising vaccine candidate for P. vivax malaria.,Naturally acquired immunity (NAI) protects against malaria in adults residing in infection-endemic regions, and the passive transfer of malarial immunity confers protection.,A vaccine that replicates NAI will effectively prevent disease.,Here, we report the structures of DBP region II in complex with human-derived, neutralizing monoclonal antibodies obtained from an individual in a malaria-endemic area with naturally acquired immunity.,We identified protective epitopes by X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, mutational mapping, and P. vivax invasion studies.,These approaches reveal that naturally-acquired human antibodies neutralize P. vivax by targeting the DARC-binding site and dimer interface of P. vivax DBP.,Antibody binding is unaffected by polymorphisms in the vicinity of epitopes, suggesting the antibodies have evolved to engage multiple polymorphic variants of DBP.,The human antibody epitopes are broadly conserved and are distinct from previously defined epitopes for broadly conserved murine mAbs.,A library of globally conserved epitopes of neutralizing human antibodies opens new horizons for rational design of strain-transcending DBP-based vaccines and therapeutics against P. vivax.

Plasmodium vivax malaria is a major public health challenge in Latin America, Asia and Oceania, with 130-435 million clinical cases per year worldwide.,Invasion of host blood cells by P. vivax mainly depends on a type I membrane protein called Duffy binding protein (PvDBP).,The erythrocyte-binding motif of PvDBP is a 170 amino-acid stretch located in its cysteine-rich region II (PvDBPII), which is the most variable segment of the protein.,To test whether diversifying natural selection has shaped the nucleotide diversity of PvDBPII in Brazilian populations, this region was sequenced in 122 isolates from six different geographic areas.,A Bayesian method was applied to test for the action of natural selection under a population genetic model that incorporates recombination.,The analysis was integrated with a structural model of PvDBPII, and T- and B-cell epitopes were localized on the 3-D structure.,The results suggest that: (i) recombination plays an important role in determining the haplotype structure of PvDBPII, and (ii) PvDBPII appears to contain neutrally evolving codons as well as codons evolving under natural selection.,Diversifying selection preferentially acts on sites identified as epitopes, particularly on amino acid residues 417, 419, and 424, which show strong linkage disequilibrium.,This study shows that some polymorphisms of PvDBPII are present near the erythrocyte-binding domain and might serve to elude antibodies that inhibit cell invasion.,Therefore, these polymorphisms should be taken into account when designing vaccines aimed at eliciting antibodies to inhibit erythrocyte invasion.

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.

Helminths induce potent Th2-type immune responses that can mediate worm expulsion but the importance of this response in controlling acute tissue damage caused by migrating multi-cellular parasites through vital tissues remains uncertain.,We used a helminth infection model where parasitic nematode larvae migrate transiently through the lung causing damage resulting in hemorrhage and inflammation.,Our findings showed initial elevations in IL-17 contributed to inflammation and lung damage while subsequent IL-4R signaling controlled IL-17 elevations, enhanced expression of insulin-like growth factor 1 and IL-10 and stimulated development of M2 cells, each of which contributed to rapid resolution of tissue damage.,These studies indicate an essential role for the Th2-type immune response in mediating acute wound healing during helminth infection.

Malaria is a widespread disease caused mainly by the Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) protozoan parasites.,Depending on the parasite responsible for the infection, high morbidity and mortality can be triggered.,To escape the host immune responses, Plasmodium parasites disturb the functionality of B cell subsets among other cell types.,However, some antibodies elicited during a malaria infection have the potential to block pathogen invasion and dissemination into the host.,Thus, the question remains, why is protection not developed and maintained after the primary parasite exposure?,In this review, we discuss different aspects of B cell responses against Plasmodium antigens during malaria infection.,Since most studies have focused on the quantification of serum antibody titers, those B cell responses have not been fully characterized.,However, to secrete antibodies, a complex cellular response is set up, including not only the activation and differentiation of B cells into antibody-secreting cells, but also the participation of other cell subsets in the germinal center reactions.,Therefore, a better understanding of how B cell subsets are stimulated during malaria infection will provide essential insights toward the design of potent interventions.

Leishmania infantum causes a chronic infectious disease named visceral leishmaniasis (VL).,We employed a non-human primate model to monitor immune parameters over time and gain new insights into the disease.,Rhesus macaques were infected with L. infantum and the T helper and B cell immunological profiles characterized during acute and chronic phases of infection.,Parasite detection in visceral compartments during the acute phase was associated with differentiation of effector memory CD4 T cells and increased levels of Th1 transcripts.,At the chronic phase, parasites colonized novel lymphoid niches concomitant with increased expression of IL10.,Despite the occurrence of hypergammaglobulinemia, the production of parasite-specific IgG was poor, being confined to the acute phase and positively correlated with the frequency of an activated memory splenic B cell population.,We noticed the expansion of a splenic CD4 T cell population expressing CXCR5 and Bcl-6 during acute infection that was associated with the differentiation of the activated memory B cell population.,Moreover, the number of splenic germinal centers peaked at one month after infection, hence paralleling the production of specific IgG.,However, at chronic infection these populations contracted impacting the production of parasite-specific IgG.,Our study provides new insights into the immune events taking place in a physiologically relevant host and a mechanistic basis for the inefficient humoral response during VL.

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

Plasmodium vivax and Plasmodium falciparum malaria remain highly endemic in the Pacific Islands including Lihir Island, Papua New Guinea.,Lihir Gold Limited is conducting mining activities and funded an integrated vector control intervention within the villages surrounding the mine.,The aim of this study was to assess the impact of such programme by comparing the epidemiological trends of malaria in different parts of the island.,Two cross-sectional surveys were conducted before and after the intervention (2006-2010) to determine malaria prevalence in mine-impact (MI) and non-MI areas.,Incidence of malaria was estimated for the Lihir Medical Centre catchment area using island population denominators and a health-centre passive case detection ongoing from 2006-2011.,A total of 2,264 and 1,653 children < 15 were surveyed in the cross-sectional studies.,The prevalence of any malaria parasitaemia initially was 31.5% in MI areas and, 34.9% in non-MI (POR 1.17; 95 CI 0.97 - 1.39).,After four years there was a significant reduction in prevalence in the MI areas (5.8%; POR 0.13, 95 CI 0.09-0.20), but reduction was less marked in non-MI areas (26.9%; POR 0.69, 95 CI 0.58-0.81).,28,747 patients were included in the evaluation of incidence trends and overall malaria in local Lihirian population in MI areas declined over time, while it remained at similar high levels among migrants.,The age-incidence analysis showed that for each higher age range the malaria incidence declines compared to that of the previous stratum.,There was a substantial reduction in prevalence and incidence rates of both P. vivax and P. falciparum in the mining area following implementation of a malaria control intervention, which was not seen in the area outside the mining activities.

Mass drug administration for elimination of Plasmodium falciparum malaria is recommended by WHO in some settings.,We used consensus modelling to understand how to optimise the effects of mass drug administration in areas with low malaria transmission.,We collaborated with researchers doing field trials to establish a standard intervention scenario and standard transmission setting, and we input these parameters into four previously published models.,We then varied the number of rounds of mass drug administration, coverage, duration, timing, importation of infection, and pre-administration transmission levels.,The outcome of interest was the percentage reduction in annual mean prevalence of P falciparum parasite rate as measured by PCR in the third year after the final round of mass drug administration.,The models predicted differing magnitude of the effects of mass drug administration, but consensus answers were reached for several factors.,Mass drug administration was predicted to reduce transmission over a longer timescale than accounted for by the prophylactic effect alone.,Percentage reduction in transmission was predicted to be higher and last longer at lower baseline transmission levels.,Reduction in transmission resulting from mass drug administration was predicted to be temporary, and in the absence of scale-up of other interventions, such as vector control, transmission would return to pre-administration levels.,The proportion of the population treated in a year was a key determinant of simulated effectiveness, irrespective of whether people are treated through high coverage in a single round or new individuals are reached by implementation of several rounds.,Mass drug administration was predicted to be more effective if continued over 2 years rather than 1 year, and if done at the time of year when transmission is lowest.,Mass drug administration has the potential to reduce transmission for a limited time, but is not an effective replacement for existing vector control.,Unless elimination is achieved, mass drug administration has to be repeated regularly for sustained effect.,Bill & Melinda Gates Foundation.

The RTS,S/AS01 malaria vaccine targets the circumsporozoite protein, inducing antibodies associated with the prevention of Plasmodium falciparum infection.,We assessed the association between anti-circumsporozoite antibody titres and the magnitude and duration of vaccine efficacy using data from a phase 3 trial done between 2009 and 2014.,Using data from 8922 African children aged 5-17 months and 6537 African infants aged 6-12 weeks at first vaccination, we analysed the determinants of immunogenicity after RTS,S/AS01 vaccination with or without a booster dose.,We assessed the association between the incidence of clinical malaria and anti-circumsporozoite antibody titres using a model of anti-circumsporozoite antibody dynamics and the natural acquisition of protective immunity over time.,RTS,S/AS01-induced anti-circumsporozoite antibody titres were greater in children aged 5-17 months than in those aged 6-12 weeks.,Pre-vaccination anti-circumsporozoite titres were associated with lower immunogenicity in children aged 6-12 weeks and higher immunogenicity in those aged 5-17 months.,The immunogenicity of the booster dose was strongly associated with immunogenicity after primary vaccination.,Anti-circumsporozoite titres wane according to a biphasic exponential distribution.,In participants aged 5-17 months, the half-life of the short-lived component of the antibody response was 45 days (95% credible interval 42-48) and that of the long-lived component was 591 days (557-632).,After primary vaccination 12% (11-13) of the response was estimated to be long-lived, rising to 30% (28-32%) after a booster dose.,An anti-circumsporozoite antibody titre of 121 EU/mL (98-153) was estimated to prevent 50% of infections.,Waning anti-circumsporozoite antibody titres predict the duration of efficacy against clinical malaria across different age categories and transmission intensities, and efficacy wanes more rapidly at higher transmission intensity.,Anti-circumsporozoite antibody titres are a surrogate of protection for the magnitude and duration of RTS,S/AS01 efficacy, with or without a booster dose, providing a valuable surrogate of effectiveness for new RTS,S formulations in the age groups considered.,UK Medical Research Council.

Scabies and impetigo are common, important and treatable skin conditions.,Reports from several Pacific island countries show extremely high prevalence of these two conditions, but for many countries, including the Solomon Islands, there is a paucity of epidemiological data.,Ten rural villages in the Western Province of the Solomon Islands were included in the study, chosen so that data collection could be integrated with an existing project investigating clinical and serological markers of yaws.,All residents were eligible to participate, and 1908 people were enrolled.,Participants were interviewed and examined by a paediatric registrar, who recorded relevant demographic information, and made a clinical diagnosis of scabies and/or impetigo, severity and distribution.,The total unweighted prevalence of scabies was 19.2% (95% confidence interval [CI] 17.5-21.0), and age and gender weighted prevalence 19.2% (95%CI 16.7-21.9).,The adult prevalence of scabies was 10.4% (95%CI 8.2-13.2), and the highest prevalence was found in infants < 1 year of age (34.1%, adjusted odds ratio [AOR] compared with adults: 3.6, 95%CI 2.2-6.0) and children aged 1-4 years (25.7%, AOR 2.6, 95%CI 1.7-3.9).,Scabies affected two or more body regions in 80.9% of participants, and 4.4% of scabies cases were classified as severe.,The total unweighted prevalence of active impetigo was 32.7% (95%CI 30.6-34.8), and age and gender weighted prevalence 26.7% (95%CI 24.2-29.5).,The highest prevalence was found in children aged 1-4 years (42.6%, AOR compared with adults: 4.1, 95%CI 2.9-5.8).,Scabies infestation was associated with active impetigo infection (AOR 2.0, 95%CI 1.6-2.6); with 41.1% of active impetigo cases also having scabies.,Scabies and impetigo are very common in the rural Western Province of the Solomon Islands.,Scabies infestation is strongly associated with impetigo.,Community control strategies for scabies may reduce the burden of both conditions and their downstream complications.

Scabies is a major public health problem in the Pacific and is associated with an increased risk of bacterial skin infections, glomerulonephritis and rheumatic fever.,Mass drug administration with ivermectin is a promising strategy for the control of scabies.,Mass treatment with ivermectin followed by active case finding was conducted in five communities in the Solomon Islands between 1997 and 2000 and resulted in a significant reduction in the prevalence of both scabies and bacterial skin infections.,We conducted a prospective follow-up study of the communities where the original scabies control programme had been undertaken.,All residents underwent a standardised examination for the detection of scabies and impetigo.,Three hundred and thirty eight residents were examined, representing 69% of the total population of the five communities.,Only 1 case of scabies was found, in an adult who had recently returned from the mainland.,The prevalence of active impetigo was 8.8% overall and 12.4% in children aged 12 years or less.,We found an extremely low prevalence of scabies 15 years after the cessation of a scabies control programme.,The prevalence of impetigo had also declined further since the end of the control programme.,Our results suggest that a combination of mass treatment with ivermectin and intensive active case finding may result in long term control of scabies.,Larger scale studies and integration with other neglected tropical disease control programmes should be priorities for scabies control efforts.

Modulation of the host immune response by nematode parasites has been widely reported.,Rhodaneses (thiosulfate: cyanide sulfurtransferases) are present in a wide range of organisms, such as archaea, bacteria, fungi, plants and animals.,Previously, it was reported that a rhodanese homologue could be bound by goat peripheral blood mononuclear cells (PBMCs) in vivo.,In the present study, we cloned and produced a recombinant rhodanese protein originating from Haemonchus contortus (rHCRD), a parasitic nematode of small ruminants. rHCRD was co-incubated with goat PBMCs to assess its immunomodulatory effects on proliferation, apoptosis and cytokine secretion.,We verified that the natural HCRD protein localized predominantly to the bowel wall and body surface of the parasite.,We further demonstrated that serum produced by goats artificially infected with H. contortus successfully recognized rHCRD, which bound to goat PBMCs. rHCRD suppressed proliferation of goat PBMCs stimulated by concanavalin A but did not induce apoptosis in goat PBMCs.,The production of TNF-α and IFN-γ decreased significantly, whereas secretion of IL-10 and TGF-β1 increased, in goat PBMCs after exposure to rHCRD. rHCRD also inhibited phagocytosis by goat monocytes.,Moreover, rHCRD downregulated the expression of major histocompatibility complex (MHC)-II on goat monocytes in a dose-dependent manner, but did not alter MHC-I expression.,These results propose a possible immunomodulatory target that may help illuminate the interactions between parasites and their hosts at the molecular level and reveal innovative protein species as candidate drug and vaccine targets.

Fasciola gigantica-induced immunomodulation is a major hurdle faced by the host for controlling infection.,Here, we elucidated the role of F. gigantica Ras-related protein Rab10 (FgRab10) in the modulation of key functions of peripheral blood mononuclear cells (PBMCs) of goats.,We cloned and expressed recombinant FgRab10 (rFgRab10) protein and examined its effects on several functions of goat PBMCs.,Protein interactors of rFgRab10 were predicted in silico by querying the databases Intact, String, BioPlex and BioGrid.,In addition, a total energy analysis of each of the identified interactions was also conducted.,Gene Ontology (GO) enrichment analysis was carried out using FuncAssociate 3.0.,The FgRab10 gene (618 bp), encodes 205-amino-acid residues with a molecular mass of ~23 kDa, had complete nucleotide sequence homology with F. hepatica Ras family protein gene (PIS87503.1).,The rFgRab10 protein specifically cross-reacted with anti-Fasciola antibodies as shown by Western blot and immunofluorescence analysis.,This protein exhibited multiple effects on goat PBMCs, including increased production of cytokines [interleukin-2 (IL-2), IL-4, IL-10, transforming growth factor beta (TGF-β) and interferon gamma (IFN-γ)] and total nitric oxide (NO), enhancing apoptosis and migration of PBMCs, and promoting the phagocytic ability of monocytes.,However, it significantly inhibited cell proliferation.,Homology modelling revealed 63% identity between rFgRab10 and human Rab10 protein (Uniprot ID: P61026).,Protein interaction network analysis revealed more stabilizing interactions between Rab proteins geranylgeranyltransferase component A 1 (CHM) and Rab proteins geranylgeranyltransferase component A 2 (CHML) and rFgRab10 protein.,Gene Ontology analysis identified RabGTPase mediated signaling as the most represented pathway.,rFgRab10 protein exerts profound influences on various functions of goat PBMCs.,This finding may help explain why F. gigantica is capable of provoking recognition by host immune cells, less capable of destroying this successful parasite.,The online version of this article (10.1186/s13071-018-3148-2) contains supplementary material, which is available to authorized users.

Hookworm infection is a major public health problem that threatens about 500 million people throughout tropical areas of the world.,Adult hookworms survive for many years in the host intestine, where they suck blood, causing iron deficiency anemia and malnutrition.,Numerous molecules, named excretory/secretory (ES) products, are secreted by hookworm adults and/or larvae to aid in parasite survival and pathobiology.,Although the molecular cloning and characterization of hookworm ES products began 25 years ago, the biological role and molecular nature of many of them are still unclear.,Hookworm ES products, with distinct structures and functions, have been linked to many essential events in the disease pathogenesis.,These events include host invasion and tissue migration, parasite nourishment and reproduction, and immune modulation.,Several of these products represent promising vaccine targets for controlling hookworm disease and therapeutic targets for many inflammatory diseases.,This review aims to summarize our present knowledge about hookworm ES products, including their role in parasite biology, host-parasite interactions, and as vaccine and pharmaceutical targets and to identify research gaps and future research directions in this field.

Necator americanus Glutathione-S-Transferase-1 (Na-GST-1) plays a role in the digestion of host hemoglobin by adult N. americanus hookworms.,Vaccination of laboratory animals with recombinant Na-GST-1 is associated with significant protection from challenge infection.,Recombinant Na-GST-1 was expressed in Pichia pastoris and adsorbed to aluminum hydroxide adjuvant (Alhydrogel) according to current Good Manufacturing Practice.,Two Phase 1 trials were conducted in 142 healthy adult volunteers in the United States and Brazil, first in hookworm-naïve individuals and then in residents of a N. americanus endemic area in Brazil.,Volunteers received one of three doses of recombinant Na-GST-1 (10, 30, or 100 μg) adjuvanted with Alhydrogel, adjuvanted with Alhydrogel and co-administered with an aqueous formulation of Glucopyranosyl Lipid A (GLA-AF), or the hepatitis B vaccine.,Vaccinations were administered via intramuscular injection on days 0, 56, and 112.,Na-GST-1/Alhydrogel was well tolerated in both hookworm-naïve and hookworm-exposed adults, with the most common adverse events being mild to moderate injection site pain and tenderness, and mild headache and nausea; no vaccine-related severe or serious adverse events were observed.,Antigen-specific IgG antibodies were induced in a dose-dependent fashion, with increasing levels observed after each vaccination in both trials.,The addition of GLA-AF to Na-GST-1/Alhydrogel did not result in significant increases in specific IgG responses.,In both the US and Brazil studies, the predominant IgG subclass induced against Na-GST-1 was IgG1, with lesser amounts of IgG3.,Vaccination of both hookworm-naïve and hookworm-exposed adults with recombinant Na-GST-1 was safe, well tolerated, and resulted in significant antigen-specific IgG responses.,Based on these results, this vaccine will be advanced into clinical trials in children and eventual efficacy studies.,ClinicalTrials.gov (NCT01261130 for the Brazil trial and NCT01385189 for the US trial)

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

In recent years, an unprecedented emphasis has been given to the control of neglected tropical diseases, including soil-transmitted helminths (STHs).,The mainstay of STH control is school-based deworming (SBD), but mathematical modelling has shown that in all but very low transmission settings, SBD is unlikely to interrupt transmission, and that new treatment strategies are required.,This study seeks to answer the question: is it possible to interrupt the transmission of STH, and, if so, what is the most cost-effective treatment strategy and delivery system to achieve this goal?,Two cluster randomised trials are being implemented in contrasting settings in Kenya.,The interventions are annual mass anthelmintic treatment delivered to preschool- and school-aged children, as part of a national SBD programme, or to entire communities, delivered by community health workers.,Allocation to study group is by cluster, using predefined units used in public health provision-termed community units (CUs).,CUs are randomised to one of three groups: receiving either (1) annual SBD; (2) annual community-based deworming (CBD); or (3) biannual CBD.,The primary outcome measure is the prevalence of hookworm infection, assessed by four cross-sectional surveys.,Secondary outcomes are prevalence of Ascaris lumbricoides and Trichuris trichiura, intensity of species infections and treatment coverage.,Costs and cost-effectiveness will be evaluated.,Among a random subsample of participants, worm burden and proportion of unfertilised eggs will be assessed longitudinally.,A nested process evaluation, using semistructured interviews, focus group discussions and a stakeholder analysis, will investigate the community acceptability, feasibility and scale-up of each delivery system.,Study protocols have been reviewed and approved by the ethics committees of the Kenya Medical Research Institute and National Ethics Review Committee, and London School of Hygiene and Tropical Medicine.,The study has a dedicated web site.,NCT02397772.

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

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

The merozoite surface protein 1 (msp1) is one of the most studied vaccine candidate genes in mammalian Plasmodium spp. to have been used for investigations of epidemiology, population structures, and immunity to infections.,However methodological difficulties have impeded the use of nuclear markers such as msp1 in Plasmodium parasites causing avian malaria.,Data from an infection transcriptome of the host generalist avian malaria parasite Plasmodium relictum was used to identify and characterize the msp1 gene from two different isolates (mtDNA lineages SGS1 and GRW4).,The aim was to investigate whether the msp1 gene in avian malaria species shares the properties of the msp1 gene in Plasmodium falciparum in terms of block variability, conserved anchor points and repeat motifs, and further to investigate the degree to which the gene might be informative in avian malaria parasites for population and epidemiological studies.,Reads from 454 sequencing of birds infected with avian malaria was used to develop Sanger sequencing protocols for the msp1 gene of P. relictum.,Genetic variability between variable and conserved blocks of the gene was compared within and between avian malaria parasite species, including P. falciparum.,Genetic variability of the msp1 gene in P. relictum was compared with six other nuclear genes and the mtDNA gene cytochrome b.,The msp1 gene of P. relictum shares the same general pattern of variable and conserved blocks as found in P. falciparum, although the variable blocks exhibited less variability than P. falciparum.,The variation across the gene blocks in P. falciparum spanned from being as conserved as within species variation in P. relictum to being as variable as between the two avian malaria species (P. relictum and Plasmodium gallinaceum) in the variable blocks.,In P. relictum the highly conserved p19 region of the peptide was identified, which included two epidermal growth factor-like domains and a fully conserved GPI anchor point.,This study provides protocols for evaluation of the msp1 gene in the avian malaria generalist parasite P. relictum.,The msp1 gene in avian Plasmodium shares the genetic properties seen in P. falciparum, indicating evolutionary conserved functions for the gene.,The data on the variable blocks of the gene show that the msp1 gene in P. relictum might serve as a good candidate gene for future population and epidemiological studies of the parasite.

Vector-borne diseases are particularly responsive to changing environmental conditions.,Diurnal temperature variation has been identified as a particularly important factor for the development of malaria parasites within vectors.,Here, we conducted a survey across France, screening populations of the house sparrow (Passer domesticus) for malaria (Plasmodium relictum).,We investigated whether variation in remotely-sensed environmental variables accounted for the spatial variation observed in prevalence and parasitemia.,While prevalence was highly correlated to diurnal temperature range and other measures of temperature variation, environmental conditions could not predict spatial variation in parasitemia.,Based on our empirical data, we mapped malaria distribution under climate change scenarios and predicted that Plasmodium occurrence will spread to regions in northern France, and that prevalence levels are likely to increase in locations where transmission already occurs.,Our findings, based on remote sensing tools coupled with empirical data suggest that climatic change will significantly alter transmission of malaria parasites.

The intestinal parasite, Cryptosporidium, is a major contributor to global child mortality and causes opportunistic infection in immune deficient individuals.,Innate resistance to Cryptosporidium, which specifically invades enterocytes, is dependent on the production of IFN-γ, yet whether enterocytes contribute to parasite control is poorly understood.,In this study, utilizing a mouse-adapted strain of C. parvum, we show that epithelial-derived IL-18 synergized with IL-12 to stimulate innate lymphoid cell (ILC) production of IFN-γ required for early parasite control.,The loss of IFN-γ-mediated STAT1 signaling in enterocytes, but not dendritic cells or macrophages, antagonized early parasite control.,Transcriptional profiling of enterocytes from infected mice identified an IFN-γ signature and enrichment of the anti-microbial effectors IDO, GBP and IRG.,Deletion experiments identified a role for Irgm1/m3 in parasite control.,Thus, enterocytes promote ILC production of IFN-γ that acts on enterocytes to restrict the growth of Cryptosporidium.

The apicomplexan parasite Cryptosporidium is a leading global cause of severe diarrhoeal disease and an important contributor to early childhood mortality.,Currently, there are no fully effective treatments or vaccines available.,Parasite transmission occurs through ingestion of oocysts, through either direct contact or consumption of contaminated water or food.,Oocysts are meiotic spores and the product of parasite sex.,Cryptosporidium has a single-host life cycle in which both asexual and sexual processes occur in the intestine of infected hosts.,Here, we genetically engineered strains of Cryptosporidium to make life cycle progression and parasite sex tractable.,We derive reporter strains to follow parasite development in culture and in infected mice and define the genes that orchestrate sex and oocyst formation through mRNA sequencing of sorted cells.,After 2 d, parasites in cell culture show pronounced sexualization, but productive fertilization does not occur and infection falters.,By contrast, in infected mice, male gametes successfully fertilize female parasites, which leads to meiotic division and sporulation.,To rigorously test for fertilization, we devised a two-component genetic-crossing assay using a reporter that is activated by Cre recombinase.,Our findings suggest obligate developmental progression towards sex in Cryptosporidium, which has important implications for the treatment and prevention of the infection.,Infection with Cryptosporidium parvum is a leading cause of severe diarrhoeal disease and childhood mortality worldwide.,Using tools they recently developed to genetically engineer Cryptosporidium, the authors define life cycle stage-specific markers and generate reporter parasites, making life cycle progression and parasite sex tractable.

Plasmodium spp., the causative agent of malaria, caused 212 million infections in 2016 with 445,000 deaths, mostly in children.,Adults acquire enough immunity to prevent clinical symptoms but never develop sterile immunity.,The only vaccine for malaria, RTS,S, shows promising protection of a limited duration against clinical malaria in infants but no significant protection against severe disease.,There is now abundant evidence that T cell functions are inhibited during malaria, which may explain why vaccine are not efficacious.,Studies have now clearly shown that T cell immunity against malaria is subdued by multiple the immune regulatory receptors, in particular, by programmed cell-death-1 (PD-1).,Given there is an urgent need for an efficacious malarial treatment, compounded with growing drug resistance, a better understanding of malarial immunity is essential.,This review will examine molecular signals that affect T cell-mediated immunity against malaria.

Immunity to malaria could be categorized broadly as antiparasite or antidisease immunity.,While most vaccine research efforts have focused on antiparasite immunity, the evidence from endemic populations suggest that antidisease immunity is an important component of natural immunity to malaria.,The processes that mediate antidisease immunity have, however, attracted little to no attention, and most interests have been directed towards the antibody responses.,This review evaluates the evidence for antidisease immunity in endemic areas and discusses the possible mechanisms responsible for it.,Given the key role that inflammation plays in the pathogenesis of malaria, regulation of the inflammatory response appears to be a major mechanism for antidisease immunity in naturally exposed individuals.

Malaria is a major cause of morbidity and mortality in many African countries and parts of Asia and South America.,Novel approaches to combating the disease have emerged in recent years and several drug candidates are now being tested clinically.,However, it is long before these novel drugs can hit the market, especially due to a scarcity of safety and efficacy data.,To reduce the malaria burden, the Medicines for Malaria Venture (MMV) was established in 1999 to develop novel medicines through industry and academic partners’ collaboration.,However, no reviews were focused following various preclinical and clinical studies published since the MMV initiation (2000) to till date.,We identify promising approaches in the global portfolio of antimalarial medicines, and highlight challenges and patient specific concerns of these novel molecules.,We discuss different clinical studies focusing on the evaluation of novel drugs against malaria in different human trials over the past five years.,The drugs KAE609 and DDD107498 are still being evaluated in Phase I trials and preclinical developmental studies.,Both the safety and efficacy of novel compounds such as KAF156 and DSM265 need to be assessed further, especially for use in pregnant women.,Synthetic non-artemisinin ozonides such as OZ277 raised concerns in terms of its insufficient efficacy against high parasitic loads.,Aminoquinoline-based scaffolds such as ferroquine are promising but should be combined with good partner drugs for enhanced efficacy.,AQ-13 induced electrocardiac events, which led to prolonged QTc intervals.,Tafenoquine, the only new anti-relapse scaffold for patients with a glucose-6-phosphate dehydrogenase deficiency, has raised significant concerns due to its hemolytic activity.,Other compounds, including methylene blue (potential transmission blocker) and fosmidomycin (DXP reductoisomerase inhibitor), are available but cannot be used in children.,At this stage, we are unable to identify a single magic bullet against malaria.,Future studies should focus on effective single-dose molecules that can act against all stages of malaria in order to prevent transmission.,Newer medicines have also raised concerns in terms of efficacy and safety.,Overall, more evidence is needed to effectively reduce the current malaria burden.,Treatment strategies that target the blood stage with transmission-blocking properties are needed to prevent future drug resistance.,The online version of this article (doi:10.1186/s40249-016-0196-8) contains supplementary material, which is available to authorized users.

Malaria is a disease that still affects a significant proportion of the global human population.,Whilst advances have been made in lowering the numbers of cases and deaths, it is clear that a strategy based solely on disease control year on year, without reducing transmission and ultimately eradicating the parasite, is unsustainable.,This article highlights the current mainstay treatments alongside a selection of emerging new clinical molecules from the portfolio of Medicines for Malaria Venture (MMV) and our partners.,In each case, the key highlights from each research phase are described to demonstrate how these new potential medicines were discovered.,Given the increased focus of the community on eradicating the disease, the strategy for next generation combination medicines that will provide such potential is explained.

A previous cohort study in Malawi showed that users of new insecticide-treated bed nets (ITNs) were significantly protected against malaria compared to non-users, despite moderate levels of pyrethroid resistance among the primary mosquito vectors.,The present study investigated whether ITNs that were 1-2 years old continued to protect users in the same area with moderate pyrethroid resistance.,One year following a baseline cross-sectional malaria parasitaemia prevalence survey and universal distribution of deltamethrin ITNs (May 2012), a fixed cohort of 1223 children aged 6-59 months was enrolled (April 2013).,Children were tested for parasitaemia at monthly scheduled visits and at unscheduled sick visits from May to December 2013 using rapid diagnostic tests.,ITN use the prior night and the condition of ITNs (based on presence of holes) was assessed by caregiver self-report.,The incidence rate ratio (RR) comparing malaria infection among users and non-users of ITNs was modelled using generalized estimating equations adjusting for potential confounders and accounting for repeated measures on each child.,The protective efficacy (PE) of ITN use was calculated as 1 − RR.,In this cohort, self-reported ITN use remained consistently high (> 95%) over the study period.,Although users of ITNs were slightly more protected compared to non-users of ITNs, the difference in incidence of infection was not statistically significant (RR 0.83, 95% confidence interval [CI] 0.54-1.27).,Among ITN users, malaria incidence was significantly lower in users of ITNs with no holes (of any size) compared to users of ITNs with ≥ 1 hole (RR 0.82, 95% CI 0.69-0.98).,There was no significant PE of using 1-2 year-old ITNs on the incidence of malaria in children in an area of moderate pyrethroid resistance, but among ITN users, the authors found increased protection by ITNs with no holes compared to ITNs with holes.,Given the moderate levels of pyrethroid resistance in the primary malaria vector and recent evidence of added benefits of ITNs with synergists or non-pyrethroid insecticides, next-generation ITNs may be a useful strategy to address pyrethroid resistance and should be further explored in Malawi.

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

Adherence of Plasmodium falciparum‐infected erythrocytes to host endothelium is conferred through the parasite‐derived virulence factor P. falciparum erythrocyte membrane protein 1 (PfEMP1), the major contributor to malaria severity.,PfEMP1 located at knob structures on the erythrocyte surface is anchored to the cytoskeleton, and the Plasmodium helical interspersed subtelomeric (PHIST) gene family plays a role in many host cell modifications including binding the intracellular domain of PfEMP1.,Here, we show that conditional reduction of the PHIST protein PFE1605w strongly reduces adhesion of infected erythrocytes to the endothelial receptor CD36.,Adhesion to other endothelial receptors was less affected or even unaltered by PFE1605w depletion, suggesting that PHIST proteins might be optimized for subsets of PfEMP1 variants.,PFE1605w does not play a role in PfEMP1 transport, but it directly interacts with both the intracellular segment of PfEMP1 and with cytoskeletal components.,This is the first report of a PHIST protein interacting with key molecules of the cytoadherence complex and the host cytoskeleton, and this functional role seems to play an essential role in the pathology of P. falciparum.

Export of proteins into the infected erythrocyte is critical for malaria parasite survival.,The majority of effector proteins are thought to export via a proteinaceous translocon, resident in the parasitophorous vacuole membrane surrounding the parasite.,Identification of the Plasmodium translocon of exported proteins and its biochemical association with exported proteins suggests it performs this role.,Direct evidence for this, however, is lacking.,Here using viable purified Plasmodium falciparum merozoites and three-dimensional structured illumination microscopy, we investigate remodelling events immediately following parasite invasion.,We show that multiple complexes of the Plasmodium translocon of exported proteins localize together in foci that dynamically change in clustering behaviour.,Furthermore, we provide conclusive evidence of spatial association between exported proteins and exported protein 2, a core component of the Plasmodium translocon of exported proteins, during native conditions and upon generation of translocation intermediates.,These data provide the most direct cellular evidence to date that protein export occurs at regions of the parasitophorous vacuole membrane housing the Plasmodium translocon of exported proteins complex.,During red blood cell infection, malaria parasites export hundreds of proteins that remodel the host cell surface.,Cowman and colleagues identify a putative protein translocator complex spatially associated with exported proteins, revealing the cellular domains involved in protein export.

To assess the ownership and use of mosquito nets in 2014, in Mozambique.,This observational and cross-sectional study assessed, in February and March 2015, 69 districts (nine of 11 provinces of Mozambique) that have benefited from the mass distribution of mosquito nets.,The Lot Quality Assurance Sampling methodology was used.,Each locality was denominated supervision area.,The Lot Quality Assurance Sampling opts for a minimum of 19 households (in this case, we decided for a minimum of 100 households per district) from each supervision area to assess an indicator (in this case, two indicators were assessed: ownership and use of mosquito nets).,Two questions guided the research: a) received a mosquito net; b) used a mosquito net the night before.,A total of 6,725 households were assessed.,Eighty three percent of them had received mosquito nets in the campaign.,Of the 6,232 respondents, 82.0% said they used mosquito nets the night before.,The districts of the provinces with low coverage of ownership and use were Tete (69.5% and 60.0%, respectively), Zambezia (79.0% and 60.0%, respectively), and Gaza (81.6% and 70.7%, respectively).,The largest coverage of ownership and use were observed in the districts of Nampula (96.7% and 93.8%, respectively) and Niassa (86.0% and 85.4% respectively).,In the districts assessed, the progression of ownership and use of mosquito nets is satisfactory.,Nampula and Niassa are the only provinces where ownership and use are at desired levels.

Insecticide treated nets (ITNs) and indoor residual spraying (IRS) are effective vector control tools that protect against malaria.,There is conflicting evidence regarding whether using ITNs and IRS in combination provides additional benefit over using either of these methods alone.,This study investigated factors that may modify the effect of the combined use of IRS and ITNs compared to using ITNs alone on malaria infection prevalence.,Secondary analysis was carried out on data from a cluster randomised trial in north-west Tanzania. 50 clusters received ITNs from a universal coverage campaign; of these 25 were randomly allocated to additionally receive two rounds of IRS in 2012.,In cross-sectional household surveys children 0.5-14 years old were tested for Plasmodium falciparum infections (PfPR) two, six and ten months after the first IRS round.,IRS protected those sleeping under nets (OR = 0.38, 95%CI 0.26-0.57) and those who did not (OR = 0.43, 95%CI 0.29-0.63).,The protective effect of IRS was not modified by community level ITN use (ITN use<50%, OR = 0.39, 95%CI 0.26-0.59; ITN use> = 50%, OR = 0.46, 95%CI 0.28-0.74).,The additional protection from IRS was similar in low (<10% PfPR, OR = 0.38, 95%CI 0.19-0.75) and high transmission areas (≥10% PfPR, OR = 0.34, 95%CI 0.18-0.67).,ITN use was protective at the individual-level regardless of whether the village had been sprayed (OR = 0.83, 95%CI 0.70-0.98).,Living in a sprayed village was protective regardless of whether the individual slept under an ITN last night (OR = 0.41, 95%CI 0.29-0.58).,Implementing IRS in addition to ITNs was beneficial for individuals from villages with a wide range of transmission intensities and net utilisation levels.,Net users received additional protection from IRS.,ITNs were providing some individual protection, even in this area with high levels of pyrethroid insecticide resistance.,These results demonstrate that there is a supplementary benefit of IRS even when ITNs are effective.,ClinicalTrials.gov NCT01697852

Mass drug administration (MDA) with artemisinin combination therapy is a potentially useful tool for malaria elimination programs, but its success depends partly on drug effectiveness and treatment coverage in the targeted population.,As part of a cluster-randomized controlled trial in Southern Province, Zambia evaluating the impact of MDA and household focal MDA (fMDA) with dihydroartemisinin-piperaquine (DHAp), sub-studies were conducted investigating population drug adherence rates and effectiveness of DHAp as administered in clearing Plasmodium falciparum infections following household mass administration.,Adherence information was reported for 181,534 of 336,821 DHAp (53.9%) treatments administered during four rounds of MDA/fMDA, of which 153,197 (84.4%) reported completing the full course of DHAp.,The proportion of participants fully adhering to the treatment regimen differed by MDA modality (MDA versus fMDA), RDT status, and whether the first dose was observed by those administering treatments.,Among a subset of participants receiving DHAp and selected for longitudinal follow-up, 58 were positive for asexual-stage P. falciparum infection by microscopy at baseline.,None of the 45 participants followed up at days 3 and/or 7 were slide positive for asexual-stage parasitemia.,For those with longer term follow-up, one participant was positive 47 days after treatment, and two additional participants were positive after 69 days, although these two were determined to be new infections by genotyping.,High completion of a 3-day course of DHAp and parasite clearance in the context of household MDA are promising as Zambia’s National Malaria Programme continues to weigh appropriate interventions for malaria elimination.

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

Disease manifestations in neurocysticercosis (NCC) are frequently due to inflammation of degenerating Taenia solium brain cysts.,Exacerbated inflammation post anthelmintic treatment is associated with leakage of the blood brain barrier (BBB) using Evans blue (EB) staining.,How well EB extravasation into the brain correlates with magnetic resonance imaging (MRI) using gadolinium (Gd) enhancement as a contrast agent and pericystic inflammation was analyzed in pigs harboring brain cysts of Taenia solium.,Three groups of 4 naturally infected pigs were assessed.,The first and second groups were treated with both praziquantel plus albendazole and sacrificed two and five days post treatment, respectively.,A third untreated group remained untreated.,Pigs were injected with EB two hours prior to evaluation by Gd-enhanced T1-MRI, and euthanized.,The EB staining for each cyst capsule was scored (EB grades were 0: 0%; 1: up to 50%; 2: over 50% but less than 100%; 3: 100%).,Similarly, the Gd enhancement around each cyst was qualitatively and quantitatively scored from the MRI.,The extent of pericystic inflammation on histology was scored in increasing severity as IS1, IS2, IS3 and IS4.,Grade 3 EB staining and enhancement was only seen in treated capsules.,Also, treated groups had higher Gd intensity than the untreated group.,Grades of enhancement correlated significantly with Gd enhancement intensity.,EB staining was correlated with Gd enhancement intensity and with IS4 in the treated groups.,These correlations were stronger in internally located cysts compared to superficial cysts in treated groups.,EB staining and Gd enhancement strongly correlate.,The intensity of enhancement determined by MRI is a good indication of the degree of inflammation.,Similarly, EB staining highly correlates with the degree of inflammation and may be applied to study inflammation in the pig model of NCC.

The ability of Taenia solium to modulate the immune system likely contributes to their longevity in the human host.,We tested the hypothesis that the nature of the immune response is related to the location of parasite and clinical manifestations of infection.,Peripheral blood mononuclear cells (PBMC) were obtained from untreated patients with neurocysticercosis (NCC), categorized as having parenchymal or subarachnoid infection by the presence of cysts exclusively within the parenchyma or in subarachnoid spaces of the brain, and from uninfected (control) individuals matched by age and gender to each patient.,Using multiplex detection technology, sera from NCC patients and controls and cytokine production by PBMC after T. solium antigen (TsAg) stimulation were assayed for levels of inflammatory and regulatory cytokines.,PBMC were phenotyped by flow cytometry ex vivo and following in vitro stimulation with TsAg.,Sera from patients with parenchymal NCC demonstrated significantly higher Th1 (IFN-γ/IL-12) and Th2 (IL-4/IL-13) cytokine responses and trends towards higher levels of IL-1β/IL-8/IL-5 than those obtained from patients with subarachnoid NCC.,Also higher in vitro antigen-driven TNF-β secretion was detected in PBMC supernatants from parenchymal than in subarachnoid NCC.,In contrast, there was a significantly higher IL-10 response to TsAg stimulation in patients with subarachnoid NCC compared to parenchymal NCC.,Although no differences in regulatory T cells (Tregs) frequencies were found ex vivo, there was a trend towards greater expansion of Tregs upon TsAg stimulation in subarachnoid than in parenchymal NCC when data were normalized for the corresponding controls.,T. solium infection of the subarachnoid space is associated with an enhanced regulatory immune response compared to infection in the parenchyma.,The resulting anti-inflammatory milieu may represent a parasite strategy to maintain a permissive environment in the host or diminish inflammatory damage from the host immune response in the central nervous system.

After years of implementing Roll Back Malaria (RBM) interventions, the changing landscape of malaria in terms of risk factors and spatial pattern has not been fully investigated.,This paper uses the 2010 malaria indicator survey data to investigate if known malaria risk factors remain relevant after many years of interventions.,We adopted a structured additive logistic regression model that allowed for spatial correlation, to more realistically estimate malaria risk factors.,Our model included child and household level covariates, as well as climatic and environmental factors.,Continuous variables were modelled by assuming second order random walk priors, while spatial correlation was specified as a Markov random field prior, with fixed effects assigned diffuse priors.,Inference was fully Bayesian resulting in an under five malaria risk map for Malawi.,Malaria risk increased with increasing age of the child.,With respect to socio-economic factors, the greater the household wealth, the lower the malaria prevalence.,A general decline in malaria risk was observed as altitude increased.,Minimum temperatures and average total rainfall in the three months preceding the survey did not show a strong association with disease risk.,The structured additive regression model offered a flexible extension to standard regression models by enabling simultaneous modelling of possible nonlinear effects of continuous covariates, spatial correlation and heterogeneity, while estimating usual fixed effects of categorical and continuous observed variables.,Our results confirmed that malaria epidemiology is a complex interaction of biotic and abiotic factors, both at the individual, household and community level and that risk factors are still relevant many years after extensive implementation of RBM activities.

Malaria control programs require a detailed understanding of the contemporary spatial distribution of infection risk to efficiently allocate resources.,We used model based geostatistics (MBG) techniques to generate a contemporary map of Plasmodium falciparum malaria risk in Indonesia in 2010.,Plasmodium falciparum Annual Parasite Incidence (PfAPI) data (2006-2008) were used to map limits of P. falciparum transmission.,A total of 2,581 community blood surveys of P. falciparum parasite rate (PfPR) were identified (1985-2009).,After quality control, 2,516 were included into a national database of age-standardized 2-10 year old PfPR data (PfPR2-10) for endemicity mapping.,A Bayesian MBG procedure was used to create a predicted surface of PfPR2-10 endemicity with uncertainty estimates.,Population at risk estimates were derived with reference to a 2010 human population count surface.,We estimate 132.8 million people in Indonesia, lived at risk of P. falciparum transmission in 2010.,Of these, 70.3% inhabited areas of unstable transmission and 29.7% in stable transmission.,Among those exposed to stable risk, the vast majority were at low risk (93.39%) with the reminder at intermediate (6.6%) and high risk (0.01%).,More people in western Indonesia lived in unstable rather than stable transmission zones.,In contrast, fewer people in eastern Indonesia lived in unstable versus stable transmission areas.,While further feasibility assessments will be required, the immediate prospects for sustained control are good across much of the archipelago and medium term plans to transition to the pre-elimination phase are not unrealistic for P. falciparum.,Endemicity in areas of Papua will clearly present the greatest challenge.,This P. falciparum endemicity map allows malaria control agencies and their partners to comprehensively assess the region-specific prospects for reaching pre-elimination, monitor and evaluate the effectiveness of future strategies against this 2010 baseline and ultimately improve their evidence-based malaria control strategies.

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.

Sandflies are vectors of Leishmania, the causative agent of leishmaniasis in mammalian hosts, including humans.,The protozoan parasite is transmitted by the sandfly bite during salivation that occurs at the moment of blood feeding.,The components of vector saliva include anticlotting and vasodilatory factors that facilitate blood flow and immunomodulatory factors that inhibit wound healing and quell the immune response.,Not surprisingly, these factors also play important roles in the establishment of Leishmania infection.,To date, the majority of knowledge that has been generated regarding the process of Leishmania infection, including L. infantum chagasi transmission has been gathered by using intradermal or subcutaneous inoculation of purified parasites.,This study presents the establishment of a transmission model of Leishmania infantum chagasi by the bite of Lutzomyia longipalpis, the vector of American visceral leishmaniasis.,The parasites were successfully transmitted by infected sandfly bites to mice and hamsters, indicating that both animals are good experimental models.,The L. infantum chagasi dose that was transmitted in each single bite ranged from 10 to 10, 000 parasites, but 75% of the sandflies transmitted less than 300 parasites.,The strategy for initiating infection by sandfly bite of experimental animals facilitates future investigations into the complex and dynamic mechanisms of visceral leishmaniasis.,It is important to elucidate the transmission mechanism of vector bites.,This model represents a useful tool to study L. infantum chagasi infection transmitted by the vector.

Saudi Arabia has implemented strategies for the eradication of malaria.,However, influx of people from countries endemic for malaria for either employment or Hajj makes the country highly susceptible to malaria importation.,The Makkah region is known to host millions of immigrants yearly and has a surveillance system to monitor the incidence of malaria.,The objective of this study was to examine malaria patients, nationality, and parasite type in Makkah region between 2008 and 2011.,A retrospective analysis of all reported malaria cases from 19 sentinel sites in Makkah region, Saudi Arabia, for the period between 2008 and 2011.,Analysis of surveillance data were analyzed using SPSS software, version 15.0 (SPSS Inc, Chicago).,A total of 318 malaria cases were reported in these 4 years, of which only 3.6% of cases were less than 10 years of age, including 2 cases below 5 years.,Non-Saudis were 95% and Pakistanis, Nigerians, and Indians accounted for 62.0%.,Plasmodium falciparum (67%).,Plasmodium vivax (32%) and Plasmodium ovale (1.6%) were the notable parasites.,The low frequency of malaria in Makkah suggests that Saudi Arabia is in the consolidation phase of malaria eradication.,The absence of local transmission of malaria is indicated by low frequency of malaria in children less than 5 years of age, and high frequency of malaria in non-Saudis is evidence of malaria importation.,Health workers attending to foreigners with febrile illness from Pakistan, Nigeria, and India should consider malaria as their first line of suspicion.

Robust and responsive surveillance systems are critical for malaria elimination.,The ideal information system that supports malaria elimination includes: rapid and complete case reporting, incorporation of related data, such as census or health survey information, central data storage and management, automated and expert data analysis, and customized outputs and feedback that lead to timely and targeted responses.,Spatial information enhances such a system, ensuring cases are tracked and mapped over time.,Data sharing and coordination across borders are vital and new technologies can improve data speed, accuracy, and quality.,Parts of this ideal information system exist and are in use, but have yet to be linked together coherently.,Malaria elimination programs should support the implementation and refinement of information systems to support surveillance and response and ensure political and financial commitment to maintain the systems and the human resources needed to run them.,National malaria programs should strive to improve the access and utility of these information systems and establish cross-border data sharing mechanisms through the use of standard indicators for malaria surveillance.,Ultimately, investment in the information technologies that support a timely and targeted surveillance and response system is essential for malaria elimination.

Coinfection with malaria and HIV is common in Sub-Saharan Africa.,In the advent of a decline in the global incidence of malaria, it is important to generate updated data on the burden of malaria in people living with HIV (PLWHIV).,This study was designed to determine the prevalence of malaria in PLWHIV in Yaounde, Cameroon, as well determine the association between CD4 + T cell count and malaria in the study population.,In a cross sectional study performed between April 2015 and June 2016, 355 PLWHIV were enrolled and blood samples were collected for analysis.,Complete blood count was performed using an automated haematology analyser (Mindray®, BC-2800) and CD4 + T cell count was performed using a flow cytometer (BD FASCount™).,Giemsa-stained blood films were examined to detect malaria parasite.,The Pearson’s chi-square, student’s T-test, ANOVA, and correlation analysis were all performed as part of the statistical analyses.,The prevalence of malaria observed in the study was 7.3 % (95 % CI: 4.8-10.6).,No significant association was observed between the prevalence of malaria and age or gender.,The prevalence of malaria was higher in participants who were not sleeping in insecticide treated bed nets, ITNs (p < 0.001); and in participants who were not on cotrimoxazole prophylaxis (p = 0.002).,The prevalence of malaria (p < 0.001) and malaria parasite density (p = 0.005) were observed to be progressively higher in participants with CD4 + T cell count below 200cells/μl.,Furthermore, the mean CD4 + T cell count was observed to be lower in participants coinfected with malaria compared to non-coinfected participants (323.5 vs 517.7) (p < 0.001).,In this study, a negative correlation was observed between malaria parasite density and CD4 + T cell count (p = 0.019).,A low prevalence of malaria was observed in the study population.,Some of the factors accounting for the low prevalence of malaria in this study population may include the health seeking habit of PLWHIV, the use of cotrimoxazole based chemoprophylaxis, and their cautious use of ITNs.

In South Africa, studies on the prevalence of intestinal helminth co-infection amongst HIV-infected patients as well as possible interactions between these two infections are limited.,To investigate the prevalence of intestinal helminth infestation amongst adults living with HIV or AIDS at Mthatha General Hospital.,Study participants were recruited at the outpatient department of Mthatha General Hospital, Mthatha, South Africa.,This cross-sectional study was conducted between October and December 2013 amongst consecutive consenting HIV-positive adult patients.,Socio-demographic and clinical information were obtained using data collection forms and structured interviews.,Stool samples were collected to investigate the presence of helminths whilst blood samples were obtained for the measurement of CD4+ T-cell count and viral load.,Data were obtained on 231 participants, with a mean age of 34.9 years, a mean CD4 count of 348 cells/µL and a mean viral load of 4.8 log10 copies/mL.,Intestinal helminth prevalence was 24.7%, with Ascaris Lumbricoides (42.1%) the most prevalent identified species.,Statistically significant association was found between CD4 count of less than 200 cells/µL and helminth infection (p = 0.05).,No statistically significant association was found between intestinal helminth infection and the mean CD4 count (p = 0.79) or the mean viral load (p = 0.98).,A high prevalence of intestinal helminth infections was observed amongst the study population.,Therefore, screening and treatment of helminths should be considered as part of the management of HIV and AIDS in primary health care.

The World Health Organization recommends parasitological confirmation of malaria prior to treatment.,Malaria rapid diagnostic tests (RDTs) represent one diagnostic method that is used in a variety of contexts to overcome limitations of other diagnostic techniques.,Malaria RDTs increase the availability and feasibility of accurate diagnosis and may result in improved quality of care.,Though RDTs are used in a variety of contexts, no studies have compared how well or effectively RDTs are used across these contexts.,This review assesses the diagnostic use of RDTs in four different contexts: health facilities, the community, drug shops and schools.,A comprehensive search of the Pubmed database was conducted to evaluate RDT execution, test accuracy, or adherence to test results in sub-Saharan Africa.,Original RDT and Plasmodium falciparum focused studies conducted in formal health care facilities, drug shops, schools, or by CHWs between the year 2000 and December 2016 were included.,Studies were excluded if they were conducted exclusively in a research laboratory setting, where staff from the study team conducted RDTs, or in settings outside of sub-Saharan Africa.,The literature search identified 757 reports.,A total of 52 studies were included in the analysis.,Overall, RDTs were performed safely and effectively by community health workers provided they receive proper training.,Analogous information was largely absent for formal health care workers.,Tests were generally accurate across contexts, except for in drug shops where lower specificities were observed.,Adherence to RDT results was higher among drug shop vendors and community health workers, while adherence was more variable among formal health care workers, most notably with negative test results.,Malaria RDTs are generally used well, though compliance with test results is variable - especially in the formal health care sector.,If low adherence rates are extrapolated, thousands of patients may be incorrectly diagnosed and receive inappropriate treatment resulting in a low quality of care and unnecessary drug use.,Multidisciplinary research should continue to explore determinants of good RDT use, and seek to better understand how to support and sustain the correct use of this diagnostic tool.,The online version of this article (doi:10.1186/s12889-017-4398-1) contains supplementary material, which is available to authorized users.

Artemisinin-based combination therapy (ACT) following a confirmed parasitological diagnosis is recommended by the World Health Organization (WHO) and the Congolese National Malaria Control Program (NMCP).,However, commitment and competence of all stakeholders (patients, medical professionals, governments and funders) is required to achieve effective case management and secure the “useful therapeutic life” of the recommended drugs.,The health seeking behaviour of patients and health care professionals’ practices for malaria management were assessed.,This was an observational study embedded in a two-stage cluster randomized survey conducted in one health centre (HC) in each of the 12 selected health zones in Kinshasa city.,All patients with clinical malaria diagnosis were eligible.,Their health seeking behaviour was recorded on a specific questionnaire, as well as the health care practitioners’ practices.,The last were not aware that their practices would be assessed.,Six hundred and twenty four patients were assessed, of whom 136 (21.8%) were under five years.,Three hundred and thirty five (55%) had taken medication prior to the current consultation (self -medication with any product or visiting another HC) of whom 47(14%) took an antimalarial drug, and 56 (9%) were treated presumptively.,Among those, 53.6% received monotherapy either with quinine, artesunate, phytomedicines, sulfadoxine-pyrimethamine or amodiaquine.,On the other side, when clinicians were informed about laboratory results, monotherapy was prescribed in 39.9% of the confirmed malaria cases.,Only 285 patients (45.7%) were managed in line with WHO and NMCP guidelines, of whom 120 (19.2%) were prescribed an ACT after positive blood smear and 165 (26.4%) received no antimalarial after a negative result.,This study shows the discrepancy between malaria policies and the reality on the field in Kinshasa, regarding patients’ health seeking behaviour and health professionals’ practices.,Consequently, the poor compliance to the policies may contribute to the genesis and spread of antimalarial drug resistance and also have a negative impact on the burden of the disease.

Diet composition may play a crucial role in shaping host immune responses and commensal gut microbiota populations.,Bioactive dietary components, such as inulin, have been extensively studied for their bioactive properties, particularly in modulating gut immune function and reducing inflammation.,It has been shown that colonization with gastrointestinal parasitic worms (helminths) may alleviate chronic inflammation through promotion of T-helper cell type (Th) 2 and T-regulatory immune responses and alterations in the gut microbiome.,In this study, we investigated if dietary inulin could modulate mucosal immune function in pigs during colonization with the porcine whipworm Trichuris suis.,T. suis infection induced a typical Th2-biased immune response characterized by transcriptional changes in Th2- and barrier function-related genes, accompanied by intestinal remodeling through increased epithelial goblet and tuft cell proliferation.,We observed that inulin also up-regulated Th2-related immune genes (IL13, IL5), and suppressed Th1-related pro-inflammatory genes (IFNG, IL1A, IL8) in the colon.,Notably, inulin augmented the T. suis-induced responses with increased transcription of key Th2 and mucosal barrier genes (e.g., IL13, TFF3), and synergistically suppressed pro-inflammatory genes, such as IFNG and CXCL9.,16S rRNA sequencing of proximal colon digesta samples revealed that inulin supplementation reduced the abundance of bacterial phyla linked to inflammation, such as Proteobacteria and Firmicutes, and simultaneously increased Actinobacteria and Bacteroidetes.,Interestingly, pigs treated with both inulin and T. suis displayed the highest Bacteroidetes: Firmicutes ratio and the lowest gut pH, suggesting an interaction of diet and helminth infection that stimulates the growth of beneficial bacterial species.,Overall, our data demonstrate that T. suis infection and inulin co-operatively enhance anti-inflammatory immune responses, which is potentially mediated by changes in microbiota composition.,Our results highlight the intricate interactions between diet, immune function and microbiota composition in a porcine helminth infection model.,This porcine model should facilitate further investigations into the use of bioactive diets as immunomodulatory mediators against inflammatory conditions, and how diet and parasites may influence gut health.

The mucin Muc5ac is essential for the expulsion of Trichuris muris and other gut-dwelling nematodes.,De novo expression of Muc5ac, a mucin not normally expressed in the intestinal tract, is induced in the cecum of mice resistant to Trichuris muris infection.,In this study, we investigated the role of Muc5ac, which is detected shortly before worm expulsion and is associated with the production of interleukin-13 (IL-13), in resistance to this nematode.,Muc5ac-deficient mice were incapable of expelling T. muris from the intestine and harbored long-term chronic infections, despite developing strong TH2 responses.,Muc5ac-deficient mice had elevated levels of IL-13 and, surprisingly, an increase in the TH1 cytokine IFN-γ.,Because TH1 inflammation is thought to favor chronic nematode infection, IFN-γ was neutralized in vivo, resulting in an even stronger TH2-type immune response.,Nevertheless, despite a more robust TH2 effector response, the Muc5ac-deficient mice remained highly susceptible to chronic T. muris infection.,Importantly, human MUC5AC had a direct detrimental effect on nematode vitality.,Moreover, the absence of Muc5ac caused a significant delay in the expulsion of two other gut-dwelling nematodes (Trichinella spiralis and Nippostrongylus brasiliensis).,Thus, for the first time, we identify a single mucin, Muc5ac, as a direct and critical mediator of resistance during intestinal nematode infection.

Malaria-associated acute respiratory distress syndrome (MA-ARDS) and acute lung injury (ALI) are complications that cause lung damage and often leads to death.,The MA-ARDS/ALI is associated with a Type 1 inflammatory response mediated by T lymphocytes and IFN-γ.,Here, we used the Plasmodium berghei NK65 (PbN)-induced MA-ALI/ARDS model that resembles human disease and confirmed that lung CD4+ and CD8+ T cells predominantly expressed Tbet and IFN-γ.,Surprisingly, we found that development of MA-ALI/ARDS was dependent on functional CCR4, known to mediate the recruitment of Th2 lymphocytes and regulatory T cells.,However, in this Type 1 inflammation-ARDS model, CCR4 was not involved in the recruitment of T lymphocytes, but was required for the emergence of TNF-α/iNOS producing dendritic cells (Tip-DCs) in the lungs.,In contrast, recruitment of Tip-DCs and development of MA-ALI/ARDS were not altered in CCR2−/− mice.,Importantly, we showed that NOS2−/− mice are resistant to PbN-induced lung damage, indicating that reactive nitrogen species produced by Tip-DCs play an essential role in inducing MA-ARDS/ALI.,Lastly, our experiments suggest that production of IFN-γ primarily by CD8+ T cells is required for inducing Tip-DCs differentiation in the lungs and the development of MA-ALI/ARDS model.

Microscopic examination of Giemsa-stained thin blood smears remains the gold standard method used to quantify and stage malaria parasites.,However, this technique is tedious, and requires trained microscopists.,We have developed a fast and simple flow cytometry method to quantify and stage, various malaria parasites in red blood cells in whole blood or in vitro cultured Plasmodium falciparum.,The parasites were stained with dihydroethidium and Hoechst 33342 or SYBR Green I and leukocytes were identified with an antibody against CD45.,Depending on the DNA stains used, samples were analyzed using different models of flow cytometers.,This protocol, which does not require any washing steps, allows infected red blood cells to be distinguished from leukocytes, as well as allowing non-infected reticulocytes and normocytes to be identified.,It also allows assessing the proportion of parasites at different developmental stages.,Lastly, we demonstrate how this technique can be applied to antimalarial drug testing.

South Africa is one of many countries committed to malaria elimination with a target of 2018 and all malaria-endemic provinces, including Mpumalanga, are increasing efforts towards this ambitious goal.,The reduction of imported infections is a vital element of an elimination strategy, particularly if a country is already experiencing high levels of imported infections.,Border control of malaria is one tool that may be considered.,A metapopulation, non-linear stochastic ordinary differential equation model is used to simulate malaria transmission in Mpumalanga and Maputo province, Mozambique (the source of the majority of imported infections) to predict the impact of a focal screen and treat campaign at the Mpumalanga-Maputo border.,This campaign is simulated by nesting an individual-based model for the focal screen and treat campaign within the metapopulation transmission model.,The model predicts that such a campaign, simulated for different levels of resources, coverage and take-up rates with a variety of screening tools, will not eliminate malaria on its own, but will reduce transmission substantially.,Making the campaign mandatory decreases transmission further though sub-patent infections are likely to remain undetected if the diagnostic tool is not adequately sensitive.,Replacing screening and treating with mass drug administration results in substantially larger decreases as all (including sub-patent) infections are treated before movement into Mpumalanga.,The reduction of imported cases will be vital to any future malaria control or elimination strategy.,This simulation predicts that FSAT at the Mpumalanga-Maputo border will be unable to eliminate local malaria on its own, but may still play a key role in detecting and treating imported infections before they enter the country.,Thus FSAT may form part of an integrated elimination strategy where a variety of interventions are employed together to achieve malaria elimination.,The online version of this article (doi:10.1186/s12936-015-0776-2) contains supplementary material, which is available to authorized users.

Given progress in malaria control in recent years, many control programmes in sub-Saharan Africa will soon be required to strengthen systems for surveillance in order to further drive transmission to zero.,Yet few practical experiences are available to guide control programmes in designing surveillance system components in low transmission, pre-elimination, and elimination phases.,A malaria case investigation programme was piloted for 12 weeks in 2012 in Richard Toll district of northern Senegal.,Malaria infections (N = 110) were identified through facility-based passive case detection and investigated within three days.,Rapid diagnostic tests (RDT) and a brief questionnaire were administered to 5,520 individuals living within the index case compound or within five neighbouring compounds.,In comparison with family and neighbours, index cases were more likely to be male, age 15-49, and to report travel within the past 15 days that entailed an overnight stay.,Twenty-three (0.4%) of family/neighbours were RDT-positive.,Potential risk factors for infection among family and neighbours were examined, including: sex, age, occupation, travel history, bed net usage, and residence (index vs neighbouring compound).,Adjusting for all factors, relative risk (RR) of infection was associated with residence in the index case household (RR = 3.18, p < 0.05) and recent travel, including travel to Dakar (RR = 19.93, p < 0.001), travel within the region (RR = 9.57, p < 0.01), and to other regions in Senegal (RR = 94.30, p < 0.001).,Recent fever among RDT-positive family/neighbours was uncommon (30%).,Modifications to testing criteria were examined to optimize the efficiency of secondary case investigations in this population.,Limiting blood testing to residents of the index case compound and neighbours with recent travel or fever would have identified 20/23 (87%) of the infections through testing 1,173 individuals.,Information on the remaining three infections suggests that additional screening for boarding school attendees may facilitate identification of all cases.,The primary risk factor for malaria infection in the low transmission district of Richard Toll is travel.,Additional intervention and monitoring strategies to target travellers at risk of malaria infection are needed in this region.,Optimizing case investigation with specific targeted testing and treatment of at-risk family and neighbours strengthens the systems needed for continued progress towards malaria elimination in northern Senegal.

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

Most Plasmodium falciparum-detecting rapid diagnostic tests (RDTs) target histidine-rich protein 2 (PfHRP2).,However, P. falciparum isolates with deletion of the pfhrp2 gene and its homolog gene, pfhrp3, have been detected.,We carried out an extensive investigation on 365 P. falciparum dried blood samples collected from seven P. falciparum endemic sites in Colombia between 2003 and 2012 to genetically characterise and geographically map pfhrp2- and/or pfhrp3-negative P. falciparum parasites in the country.,We found a high proportion of pfhrp2-negative parasites only in Amazonas (15/39; 38.5%), and these parasites were also pfhrp3-negative.,These parasites were collected between 2008 and 2009 in Amazonas, while pfhrp3-negative parasites (157/365, 43%) were found in all the sites and from each of the sample collection years evaluated (2003 to 2012).,We also found that all pfhrp2- and/or pfhrp3-negative parasites were also negative for one or both flanking genes.,Six sub-population clusters were established with 93.3% (14/15) of the pfhrp2-negative parasites grouped in the same cluster and sharing the same haplotype.,This haplotype corresponded with the genetic lineage BV1, a multidrug resistant strain that caused two outbreaks reported in Peru between 2010 and 2013.,We found this BV1 lineage in the Colombian Amazon as early as 2006.,Two new clonal lineages were identified in these parasites from Colombia: the genetic lineages EV1 and F.,PfHRP2 sequence analysis revealed high genetic diversity at the amino acid level, with 17 unique sequences identified among 53 PfHRP2 sequences analysed.,The use of PfHRP2-based RDTs is not recommended in Amazonas because of the high proportion of parasites with pfhrp2 deletion (38.5%), and implementation of new strategies for malaria diagnosis and control in Amazonas must be prioritised.,Moreover, studies to monitor and genetically characterise pfhrp2-negative P. falciparum parasites in the Americas are warranted, given the extensive human migration occurring in the region.

During a medical entomology course in Boa Vista, Roraima, colonies of Triatoma maculata closely associated with pigeon nests were observed in concrete air-conditioner box located on the external plastered and cemented walls of a modern brick-built apartment block.,In only one eight-hole ceramic brick, located inside one air-conditioner box, 127 specimens of T. maculata were collected.,T. maculata is a recognised vector of Trypanosoma cruzi in the surrounding area and its domiciliation increases the risk of Chagas disease transmission.

Recolonization from untreated households is a serious threat to long-term vector control.,Chagas disease vector control campaigns are being conducted in Latin America, but little is known about medium-term or long-term effectiveness of these efforts, especially in urban areas.,After analyzing entomologic data for 56,491 households during the treatment phase of a Triatoma infestans bug control campaign in Arequipa, Peru, during 2003-2011, we estimated that 97.1% of residual infestations are attributable to untreated households.,Multivariate models for the surveillance phase of the campaign obtained during 2009-2012 confirm that nonparticipation in the initial treatment phase is a major risk factor (odds ratio [OR] 21.5, 95% CI 3.35-138).,Infestation during surveillance also increased over time (OR 1.55, 95% CI 1.15-2.09 per year).,In addition, we observed a negative interaction between nonparticipation and time (OR 0.73, 95% CI 0.53-0.99), suggesting that recolonization by vectors progressively dilutes risk associated with nonparticipation.,Although the treatment phase was effective, recolonization in untreated households threatens the long-term success of vector control.

Plasmodium vivax infection is known to be rare in West/Central Africa, the most accepted explanation being the lack of expression of erythroid Duffy antigen in the local human populations.,Duffy negativity prevents the parasite to exploit the entry mechanism on the red blood cell surface.,However, there are a growing number of reported vivax infections in Duffy-negative individuals.,Data on P. vivax circulation in Cameroon are limited.,The aim of the study was to evaluate the P. vivax presence, and its association with the Duffy genotype in West Cameroon.,Overall, 484 blood samples were collected consecutively from febrile outpatients attending the Dschang’s Hospital (West Cameroon) during a 3-months period.,Plasmodium vivax infection was detected by PCR in 5.6% (n = 27/484) of the cases, representing 38.6% (n = 27/70) of all Plasmodium infections detected.,All P. vivax infected individuals showed a Duffy-negative genotype, and the frequency of Duffy-positive individuals in the whole tested population was 1.7%.,The results of this study confirm the circulation of P. vivax in Cameroon, as well as that the lack of expression of Duffy-antigen does not confer full protection against vivax malaria acquisition.

The malaria rapid diagnostic tests (RDTs) are now widely used in the world.,Compared to Plasmodium falciparum, a poor sensitivity of RDTs was reported against Plasmodium vivax based on the adopted antibody against pan-Plasmodium antigen lactate dehydrogenase (pLDH) or aldolase.,Levels of pLDH were measured from patient with P. vivax, and the correlations between the levels of pLDH and the sensitivities of RDTs were analysed among Republic of Korea (ROK) isolates.,Three RDTs, OptiMAL test, SD BIOLINE Malaria Ag P.f/Pan test, Humasis Malaria Pf/Pan antigen test, and the Genedia pLDH antigen ELISA were performed with blood samples from 152 febrile patients and 100 healthy controls.,Three malaria RDTs revealed sensitivities between 85.5 (131/152) and 86.8% (132/152) with highest sensitivity for the detection of P.vivax by pLDH antigen ELISA test (145/152, 95.4%) in comparison to traditional microscopy using Giemsa-stained slides.,None of the healthy control tested positive by three RDTs or ELISA, indicating 100% specificity in their respective test.,Levels of pLDH among Korean P. vivax isolates ranged between 0 ng/mL and 22,387.2 ng/mL (mean ± standard deviation 3,917.5 ± 6,120.9 ng/mL).,The lower detection limits of three RDTs were between 25 and 50 ng/mL with artificially diluted samples.,The moderate degree of correlation was observed between parasitaemia and concentrations of pLDH (r = 0.4, p < 0.05).,The pLDH levels of P. vivax are the main explanation for the variations in the performance of pLDH-based RDTs.,Therefore, comparing sensitivities of RDT may need to include targeted biomarker value of patients.

Historically, the diagnosis of soil-transmitted helminths (STHs) (e.g., Strongyloides stercoralis, Trichuris trichiura, Ancylostoma duodenale, Necator americanus, and Ascaris lumbricoides) has relied on often-insensitive microscopy techniques.,Over the past several years, there has been an effort to use molecular diagnostics, particularly quantitative polymerase chain reaction (qPCR), to detect intestinal pathogens.,While some platforms have been approved by regulatory bodies (e.g., Food and Drug Administration) to detect intestinal bacteria, viruses, and protozoa, there are no approved tests currently available for STH.,Although studies comparing qPCR to microscopy methods for STH are imperfect, due in large part to a lack of a sufficient gold standard, they do show a significant increase in sensitivity and specificity of qPCR compared with microscopic techniques.,These studies, as well as the advantages and disadvantages of using qPCR for STH diagnosis, are discussed.,Guidelines for those designing future studies utilizing qPCR are proposed for optimizing results, as is the proposition for using standardized molecular diagnostics routinely for STH in clinical laboratories and for field-based studies when possible.

•A Bayesian latent class meta-analysis of diagnostic tests for soil-transmitted helminths was performed.,•Overall sensitivity of evaluated diagnostic tests was low.,•Test performance was strongly influenced by intensity of infection.,•FLOTAC method sensitivity was highest overall and in both intensity groups.,•The performance of the Kato-Katz method in high intensity settings was acceptable.,A Bayesian latent class meta-analysis of diagnostic tests for soil-transmitted helminths was performed.,Overall sensitivity of evaluated diagnostic tests was low.,Test performance was strongly influenced by intensity of infection.,FLOTAC method sensitivity was highest overall and in both intensity groups.,The performance of the Kato-Katz method in high intensity settings was acceptable.,Reliable, sensitive and practical diagnostic tests are an essential tool in disease control programmes for mapping, impact evaluation and surveillance.,To provide a robust global assessment of the relative performance of available diagnostic tools for the detection of soil-transmitted helminths, we conducted a meta-analysis comparing the sensitivities and the quantitative performance of the most commonly used copro-microscopic diagnostic methods for soil-transmitted helminths, namely Kato-Katz, direct microscopy, formol-ether concentration, McMaster, FLOTAC and Mini-FLOTAC.,In the absence of a perfect reference standard, we employed a Bayesian latent class analysis to estimate the true, unobserved sensitivity of compared diagnostic tests for each of the soil-transmitted helminth species Ascaris lumbricoides, Trichuris trichiura and the hookworms.,To investigate the influence of varying transmission settings we subsequently stratified the analysis by intensity of infection.,Overall, sensitivity estimates varied between the different methods, ranging from 42.8% for direct microscopy to 92.7% for FLOTAC.,The widely used double slide Kato-Katz method had a sensitivity of 74-95% for the three soil-transmitted helminth species at high infection intensity, however sensitivity dropped to 53-80% in low intensity settings, being lowest for hookworm and A. lumbricoides.,The highest sensitivity, overall and in both intensity groups, was observed for the FLOTAC method, whereas the sensitivity of the Mini-FLOTAC method was comparable with the Kato-Katz method.,FLOTAC average egg count estimates were significantly lower compared with Kato-Katz, while the compared McMaster counts varied.,In conclusion, we demonstrate that the Kato-Katz and Mini-FLOTAC methods had comparable sensitivities.,We further show that test sensitivity of the Kato-Katz method is reduced in low transmission settings.

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

Areas that are endemic for malaria are also highly endemic for hepatitis B virus (HBV) infection.,Nevertheless, it is unknown whether HBV infection modifies the clinical presentation of malaria.,This study aimed to address this question.,An observational study of 636 individuals was performed in Rondônia, western Amazon, Brazil between 2006 and 2007.,Active and passive case detections identified Plasmodium infection by field microscopy and nested Polymerase Chain Reaction (PCR).,HBV infections were identified by serology and confirmed by real-time PCR.,Epidemiological information and plasma cytokine profiles were studied.,The data were analyzed using adjusted multinomial logistic regression.,Plasmodium-infected individuals with active HBV infection were more likely to be asymptomatic (OR: 120.13, P<0.0001), present with lower levels of parasitemia and demonstrate a decreased inflammatory cytokine profile.,Nevertheless, co-infected individuals presented higher HBV viremia.,Plasmodium parasitemia inversely correlated with plasma HBV DNA levels (r = −0.6; P = 0.0003).,HBV infection diminishes the intensity of malaria infection in individuals from this endemic area.,This effect seems related to cytokine balance and control of inflammatory responses.,These findings add important insights to the understanding of the factors affecting the clinical outcomes of malaria in endemic regions.

Current first-line treatments for uncomplicated falciparum malaria rapidly clear the asexual stages of the parasite, but do not fully prevent parasite transmission by mosquitoes.,The standard membrane feeding assay (SMFA) is the biological gold standard assessment of transmission reducing activity (TRA), but its throughput is limited by the need to determine mosquito infection status by dissection and microscopy.,Here we present a novel dissection-free luminescence based SMFA format using a transgenic Plasmodium falciparum reporter parasite without resistance to known antimalarials and therefore unrestricted in its utility in compound screening.,Analyses of sixty-five compounds from the Medicines for Malaria Venture validation and malaria boxes identified 37 compounds with high levels of TRA (>80%); different assay modes allowed discrimination between gametocytocidal and downstream modes of action.,Comparison of SMFA data to published assay formats for predicting parasite infectivity indicated that individual in vitro screens show substantial numbers of false negatives.,These results highlight the importance of the SMFA in the screening pipeline for transmission reducing compounds and present a rapid and objective method.,In addition we present sixteen diverse chemical scaffolds from the malaria box that may serve as a starting point for further discovery and development of malaria transmission blocking drugs.

Migrating cells are guided in complex environments mainly by chemotaxis or structural cues presented by the surrounding tissue.,During transmission of malaria, parasite motility in the skin is important for Plasmodium sporozoites to reach the blood circulation.,Here we show that sporozoite migration varies in different skin environments the parasite encounters at the arbitrary sites of the mosquito bite.,In order to systematically examine how sporozoite migration depends on the structure of the environment, we studied it in micro-fabricated obstacle arrays.,The trajectories observed in vivo and in vitro closely resemble each other suggesting that structural constraints can be sufficient to guide Plasmodium sporozoites in complex environments.,Sporozoite speed in different environments is optimized for migration and correlates with persistence length and dispersal.,However, this correlation breaks down in mutant sporozoites that show adhesion impairment due to the lack of TRAP-like protein (TLP) on their surfaces.,This may explain their delay in infecting the host.,The flexibility of sporozoite adaption to different environments and a favorable speed for optimal dispersal ensures efficient host switching during malaria transmission.

The efficacy of a novel oral combination product, Simparica Trio™, containing sarolaner, moxidectin and pyrantel was evaluated against five tick species that commonly infest dogs in the USA, Amblyomma americanum, Amblyomma maculatum, Dermacentor variabilis, Ixodes scapularis and Rhipicephalus sanguineus.,Laboratory studies were conducted against two different strains of each tick species.,In each study, 10 purpose-bred Beagle or mixed-breed dogs were randomly allocated to one of two treatment groups based on pre-treatment host-suitability tick counts.,Dogs were infested with approximately 50 (45-55) unfed adult ticks on Days -2, 5, 12, 19, 26 and 33.,On Day 0, dogs received either a single oral dose of Simparica Trio™ at the minimum label dose of 1.2 mg/kg sarolaner, 24 µg/kg moxidectin and 5 mg/kg pyrantel (as pamoate salt) or placebo.,Tick counts were conducted at 48 h post-treatment and after each subsequent weekly re-infestation for A. maculatum, D. variabilis, I. scapularis and R. sanguineus studies and at 48 hours or at 72 h post-treatment and after weekly re-infestation in the first and second A. americanum studies, respectively.,No treatment-related adverse reactions occurred in any study.,In all studies, placebo-treated dogs maintained infestations throughout the entire study duration, and dogs treated with Simparica Trio™ had significantly lower (P ≤ 0.0010) mean live tick counts than placebo-treated dogs at all time-points.,Against A. maculatum, D. variabilis, I. scapularis and R. sanguineus, a single oral dose of Simparica Trio™ evaluated at 48 h post-treatment provided ≥ 98.9% efficacy against existing infestations, and within 48 h of re-infestation efficacy was ≥ 90.4% through at least Day 28 (except for R. sanguineus on Day 14 in a single study with an efficacy of 89.7%).,Against A. americanum, Simparica Trio™ provided ≥ 99.4% efficacy at ≤ 72 h after treatment of existing infestations and maintained ≥ 98.4% efficacy at ≤ 72 h after re-infestation through at least Day 35.,A single dose of Simparica Trio™ administered orally at the minimum label dosage of 1.2 mg/kg sarolaner, 24 µg/kg moxidectin and 5 mg/kg pyrantel provided treatment and control of the common tick species infesting dogs in the USA for at least one month.

In the past decade, canine thelaziosis due to Thelazia callipaeda has been diagnosed in an increasing number of European countries, with endemic areas being identified.,A multi-center field trial was conducted in endemic areas in France and Spain to evaluate the efficacy of monthly administrations of the oral milbemycin oxime/afoxolaner combination (NexGard Spectra®) for the prevention of T. callipaeda infection in at-risk dogs.,A total of 79 dogs negative for T. callipaeda and with a clinical history of eyeworm infection in the past two years completed the study.,Dogs were randomly allocated either to a negative control group (42 dogs) or to the NexGard Spectra® treated group (37 dogs).,All dogs were followed up for a 6-month period and assessed monthly for the presence of nematodes on the eyes and for the signs of ocular thelaziosis (e.g., conjunctivitis, keratitis, and ocular discharge).,When the presence of nematodes was confirmed, the conjunctival fornix was flushed with a saline solution for parasite recovery and counting, and the dogs were treated appropriately.,Recovered parasites were stored in 70% alcohol for subsequent morphological identification.,During the course of the study, 57.1% (24/42) of the control dogs were diagnosed positive for Thelazia infection, which illustrates a high incidence rate of parasite infection.,Conversely, no eyeworm was recovered from any of the 37 dogs that received NexGard Spectra®.,All parasites sampled were confirmed to be T. callipaeda.,This clinical field study demonstrated that monthly administrations of NexGard Spectra® provided 100% preventive efficacy against canine thelaziosis.

We recently developed a superhydrophobic cone-based method for the collection of mosquito excreta/feces (E/F) for the molecular xenomonitoring of vector-borne parasites showing higher throughput compared to the traditional approach.,To test its field applicability, we used this platform to detect the presence of filarial and malaria parasites in two villages of Ghana and compared results to those for detection in mosquito carcasses and human blood.,We compared the molecular detection of three parasites (Wuchereria bancrofti, Plasmodium falciparum and Mansonella perstans) in mosquito E/F, mosquito carcasses and human blood collected from the same households in two villages in the Savannah Region of the country.,We successfully detected the parasite DNA in mosquito E/F from indoor resting mosquitoes, including W. bancrofti which had a very low community prevalence (2.5-3.8%).,Detection in the E/F samples was concordant with detection in insect whole carcasses and human blood, and a parasite not vectored by mosquitoes was detected as well.Our approach to collect and test mosquito E/F successfully detected a variety of parasites at varying prevalence in the human population under field conditions, including a pathogen (M. perstans) which is not transmitted by mosquitoes.,The method shows promise for further development and applicability for the early detection and surveillance of a variety of pathogens carried in human blood.

The Sri Lankan Anti-Filariasis campaign distributed five rounds of mass drug administration (MDA with diethylcarbamazine plus albendazole) to some 10 million people in eight districts between 2002 and 2006.,Sri Lanka was recognized by the WHO for having eliminated lymphatic filariasis (LF) as a public health problem in 2016.,However, recent studies by our group documented pockets with persistent LF in coastal Sri Lanka, especially in Galle district.,The present study was performed to reexamine an area previously identified as a potential hotspot for persistent LF (Balapitiya Public Health Inspector area, population 17,500).,A community survey documented high rates for circulating filarial antigenemia (3%, confidence interval [CI]: 1.8-4.9) and microfilaremia (1%, CI: 0.5-2.5%).,Circulating filarial antigenemia rates were 2.8-fold higher in males than females.,High prevalence was also observed for anti-filarial antibodies in young children (5.7%, CI: 3.7-8.4%) and for filarial DNA in vector mosquitoes (5.2%, CI: 4.2-6.3%).,Spatial data showed that persistent LF was dispersed across the entire study area.,Other studies showed that persistent LF was not limited to Balapitiya and not solved by additional rounds of MDA.,Molecular xenomonitoring studies conducted in 2016 in 22 of 168 Public Health Midwife areas in the coastal Galle evaluation unit (approximate population 600,000) found that 179 of 660 (27%) pools of Culex collected from all areas were positive for Wuchereria bancrofti DNA by quantitative polymerase chain reaction; the estimated infection rate in mosquitoes was 1.26%, CI: 1.0-1.5%.,Interventions other than routine MDA will be required to remove LF hotspots in Balapitiya and in other areas in coastal Sri Lanka.

Malaria and HIV are two important public health issues.,However, evidence on HIV-Plasmodium vivax co-infection (HIV/PvCo) is scarce, with most of the available information related to Plasmodium falciparum on the African continent.,It is unclear whether HIV can change the clinical course of vivax malaria and increase the risk of complications.,In this study, a systematic review of HIV/PvCo studies was performed, and recent cases from the Brazilian Amazon were included.,Medical records from a tertiary care centre in the Western Brazilian Amazon (2009-2018) were reviewed to identify HIV/PvCo hospitalized patients.,Demographic, clinical and laboratory characteristics and outcomes are reported.,Also, a systematic review of published studies on HIV/PvCo was conducted.,Metadata, number of HIV/PvCo cases, demographic, clinical, and outcome data were extracted.,A total of 1,048 vivax malaria patients were hospitalized in the 10-year period; 21 (2.0%) were HIV/PvCo cases, of which 9 (42.9%) had AIDS-defining illnesses.,This was the first malaria episode in 11 (52.4%) patients.,Seven (33.3%) patients were unaware of their HIV status and were diagnosed on hospitalization.,Severe malaria was diagnosed in 5 (23.8%) patients.,One patient died.,The systematic review search provided 17 articles (12 cross-sectional or longitudinal studies and 5 case report studies).,A higher prevalence of studies involved cases in African and Asian countries (35.3 and 29.4%, respectively), and the prevalence of reported co-infections ranged from 0.1 to 60%.,Reports of HIV/PvCo are scarce in the literature, with only a few studies describing clinical and laboratory outcomes.,Systematic screening for both co-infections is not routinely performed, and therefore the real prevalence of HIV/PvCo is unknown.,This study showed a low prevalence of HIV/PvCo despite the high prevalence of malaria and HIV locally.,Even though relatively small, this is the largest case series to describe HIV/PvCo.

Serology has become an increasingly important tool for the surveillance of a wide range of infectious diseases.,It has been particularly useful to monitor malaria transmission in elimination settings where existing metrics such as parasite prevalence and incidence of clinical cases are less sensitive.,Seroconversion rates, based on antibody prevalence to Plasmodium falciparum asexual blood-stage antigens, provide estimates of transmission intensity that correlate with entomological inoculation rates but lack precision in settings where seroprevalence is still high.,Here we present a new and widely applicable method, based on cross-sectional data on individual antibody levels.,We evaluate its use as a sero-surveillance tool in a Tanzanian setting with declining malaria prevalence.,We find that the newly developed mathematical models produce more precise estimates of transmission patterns, are robust in high transmission settings and when sample sizes are small, and provide a powerful tool for serological evaluation of malaria transmission intensity.

An effective malaria vaccine, deployed in conjunction with other malaria interventions, is likely to substantially reduce the malaria burden.,Efficacy against severe malaria will be a key driver for decisions on implementation.,An initial study of an RTS, S vaccine candidate showed promising efficacy against severe malaria in children in Mozambique.,Further evidence of its protective efficacy will be gained in a pivotal, multi-centre, phase III study.,This paper describes the case definitions of severe malaria used in this study and the programme for standardized assessment of severe malaria according to the case definition.,Case definitions of severe malaria were developed from a literature review and a consensus meeting of expert consultants and the RTS, S Clinical Trial Partnership Committee, in collaboration with the World Health Organization and the Malaria Clinical Trials Alliance.,The same groups, with input from an Independent Data Monitoring Committee, developed and implemented a programme for standardized data collection.,The case definitions developed reflect the typical presentations of severe malaria in African hospitals.,Markers of disease severity were chosen on the basis of their association with poor outcome, occurrence in a significant proportion of cases and on an ability to standardize their measurement across research centres.,For the primary case definition, one or more clinical and/or laboratory markers of disease severity have to be present, four major co-morbidities (pneumonia, meningitis, bacteraemia or gastroenteritis with severe dehydration) are excluded, and a Plasmodium falciparum parasite density threshold is introduced, in order to maximize the specificity of the case definition.,Secondary case definitions allow inclusion of co-morbidities and/or allow for the presence of parasitaemia at any density.,The programmatic implementation of standardized case assessment included a clinical algorithm for evaluating seriously sick children, improvements to care delivery and a robust training and evaluation programme for clinicians.,The case definition developed for the pivotal phase III RTS, S vaccine study is consistent with WHO recommendations, is locally applicable and appropriately balances sensitivity and specificity in the diagnosis of severe malaria.,Processes set up to standardize severe malaria data collection will allow robust assessment of the efficacy of the RTS, S vaccine against severe malaria, strengthen local capacity and benefit patient care for subjects in the trial.,Clinicaltrials.gov NCT00866619

The Malaria Eradication Research Agenda (malERA) Consultative Group on Diagnoses and Diagnostics outline a research and development agenda to provide the diagnosis and diagnostic tools required for malaria eradication.,Many of malaria's signs and symptoms are indistinguishable from those of other febrile diseases.,Detection of the presence of Plasmodium parasites is essential, therefore, to guide case management.,Improved diagnostic tools are required to enable targeted treatment of infected individuals.,In addition, field-ready diagnostic tools for mass screening and surveillance that can detect asymptomatic infections of very low parasite densities are needed to monitor transmission reduction and ensure elimination.,Antibody-based tests for infection and novel methods based on biomarkers need further development and validation, as do methods for the detection and treatment of Plasmodium vivax.,Current rapid diagnostic tests targeting P. vivax are generally less effective than those targeting Plasmodium falciparum.,Moreover, because current drugs for radical cure may cause serious side effects in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, more information is needed on the distribution of G6PD-deficiency variants as well as tests to identify at-risk individuals.,Finally, in an environment of very low or absent malaria transmission, sustaining interest in elimination and maintaining resources will become increasingly important.,Thus, research is required into the context in which malaria diagnostic tests are used, into diagnostics for other febrile diseases, and into the integration of these tests into health systems.

Severe malaria may influence inner ear function, although this possibility has not been examined prospectively.,In a retrospective analysis, hearing impairment was found in 9 of 23 patients with cerebral malaria.,An objective method to quickly evaluate the function of the inner ear are the otoacoustic emissions.,Negative transient otoacoustic emissions are associated with a threshold shift of 20 dB and above.,This prospective multicenter study analyses otoacoustic emissions in patients with severe malaria up to the age of 10 years.,In three study sites (Ghana, Gabon, Kenya) 144 patients with severe malaria and 108 control children were included.,All malaria patients were treated with parental artesunate.,In the control group, 92.6 % (n = 108, 95 % confidence interval 86.19-6.2 %) passed otoacoustic emission screening.,In malaria patients, 58.5 % (n = 94, malaria vs controls p < 0.001, 95 % confidence interval 48.4-67.9 %) passed otoacoustic emission screening at the baseline measurement.,The value increased to 65.2 % (n = 66, p < 0.001, 95 % confidence interval 53.1-75.5 %) at follow up 14-28 days after diagnosis of malaria.,The study population was divided into severe non-cerebral malaria and severe malaria with neurological symptoms (cerebral malaria).,Whereas otoacoustic emissions in severe malaria improved to a passing percentage of 72.9 % (n = 48, 95 % confidence interval 59-83.4 %) at follow-up, the patients with cerebral malaria showed a drop in the passing percentage to 33 % (n = 18) 3-7 days after diagnosis.,This shows a significant impairment in the cerebral malaria group (p = 0.012 at days 3-7, 95 % confidence interval 16.3-56.3 %; p = 0.031 at day 14-28, 95 % confidence interval 24.5-66.3 %).,The presented data show that 40 % of children have involvement of the inner ear early in severe malaria.,In children, audiological screening after severe malaria infection is not currently recommended, but is worth investigating in larger studies.

Proveblue®, a methylene blue dye that complies with European Pharmacopoeia and contains limited organic impurities and heavy metals of recognized toxicity, showed in vitro synergy against Plasmodium falciparum when combined with atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase.,The objective of this study was to evaluate the in vivo efficacy of Proveblue® when combined with atorvastatin in a murine model of experimental cerebral malaria.,Forty female C57Bl6/N mice were divided into four groups (control, atorvastatin 40 mg/kg for seven days, Proveblue® 10 mg/kg for five days and atorvastatin combined with Proveblue®), infected with Plasmodium berghei ANKA parasites by intraperitoneal inoculation and observed for 45 days.,Treatment with atorvastatin alone did not demonstrate an effect significantly different from no treatment (p = 0.0573).,All the mice treated by atorvastatin alone died.,Treatment with Proveblue® or a combination of Proveblue® and atorvastatin was significantly increased survival of cerebral malaria (p = 0.0011 and 0.0002, respectively).,Although there was only one death in the atorvastatin and Proveblue® combination treatment group (10%) versus two deaths (22%) with Proveblue® treatment, the effect on cerebral malaria was not significant (p = 0.283).,The present work demonstrated, for the first time, the high efficacy of Proveblue® in preventing cerebral malaria.,Atorvastatin alone or in combination appears to possess limited use for preventing cerebral malaria.,Combination of atorvastatin with lower doses of Proveblue® (<10 mg/kg/day) should be evaluated to show potential synergistic effects in cerebral malaria prevention.

Tafenoquine (TQ) and primaquine (PQ) are 8-aminoquinolines (8-AQ) with anti-hypnozoite activity against vivax malaria.,PQ is the only FDA-approved medicine for preventing relapsing Plasmodium vivax infection and TQ is currently in phase 3 clinical trials for the same indication.,Recent studies have provided evidence that cytochrome P450 (CYP) metabolism via CYP2D6 plays a role in PQ efficacy against P. vivax and have suggested that this effect may extend to other 8-AQs, including TQ.,Here, a retrospective pharmacogenetic (PGx) investigation was performed to assess the impact of CYP2D6 metabolism on TQ and PQ efficacy in the treatment of P. vivax in the DETECTIVE study (TAF112582), a recently completed, randomized, phase 2b dose-ranging clinical trial.,The impact of CYP2D6 on TQ pharmacokinetics (PK) was also investigated in TAF112582 TQ-treated subjects and in vitro CYP metabolism of TQ was explored.,A limitation of the current study is that TAF112582 was not designed to be well powered for PGx, thus our findings are based on TQ or PQ efficacy in CYP2D6 intermediate metabolizers (IM), as there were insufficient poor metabolizers (PM) to draw any conclusion on the impact of the PM phenotype on efficacy.,The impact of genetically-predicted CYP2D6 reduced metabolism on relapse-free efficacy six months post-dosing of TQ or PQ, both administered in conjunction with chloroquine (CQ), was assessed using exact statistical methods in 198 P. vivax-infected study participants comparing IM to extensive metabolizers (EM).,The influence of CYP2D6 metabolizer phenotypes on TQ PK was assessed comparing median TQ area under the curve (AUC).,In vitro metabolism of TQ was investigated using recombinant, over-expressed human CYP enzymes and human hepatocytes.,Metabolite identification experiments were performed using liquid chromatography-mass spectrometry.,Reduction of CYP2D6 activity was not associated with an increase in relapse-rate in TQ-treated subjects (p = 0.57).,In contrast, and in accordance with recent literature, CYP2D6 IMs were more common (p = 0.05) in PQ-treated subjects who relapsed (50 %) than in subjects who remained relapse-free (17 %).,Further, CYP2D6 metabolizer phenotypes had no significant effect on TQ AUC, and only minimal metabolism of TQ could be detected in hepatic in vitro systems.,Together, these data provide preliminary evidence that in CYP2D6 IMs, TQ efficacy in P. vivax-infected individuals is not diminished to the same extent as PQ.,As there were no PMs in either the TQ or PQ treatment arms of TAF112582, no conclusions could be drawn on potential differences in PMs.,These findings suggest that differential effects of CYP2D6 metabolism on TQ and PQ efficacy could be a differentiation factor between these 8-AQs, but results remain to be confirmed prospectively in the ongoing phase 3 studies.,The online version of this article (doi:10.1186/s12936-016-1145-5) contains supplementary material, which is available to authorized users.

Tafenoquine (TQ) is an 8-aminoquinoline (8AQ) that has been tested in several Phase II and Phase III clinical studies and is currently in late stage development as an anti-malarial prophylactic agent.,NPC-1161B is a promising 8AQ in late preclinical development.,It has recently been reported that the 8AQ drug primaquine requires metabolic activation by CYP 2D6 for efficacy in humans and in mice, highlighting the importance of pharmacogenomics in the target population when administering primaquine.,A logical follow-up study was to determine whether CYP 2D activation is required for other compounds in the 8AQ structural class.,In the present study, the anti-malarial activities of NPC-1161B and TQ were assessed against luciferase expressing Plasmodium berghei in CYP 2D knock-out mice in comparison with normal C57BL/6 mice (WT) and with humanized/CYP 2D6 knock-in mice by monitoring luminescence with an in vivo imaging system.,These experiments were designed to determine the direct effects of CYP 2D metabolic activation on the anti-malarial efficacy of NPC-1161B and TQ.,NPC-1161B and TQ exhibited no anti-malarial activity in CYP 2D knock-out mice when dosed at their ED100 values (1 mg/kg and 3 mg/kg, respectively) established in WT mice.,TQ anti-malarial activity was partially restored in humanized/CYP 2D6 knock-in mice when tested at two times its ED100.,The results reported here strongly suggest that metabolism of NPC-1161B and TQ by the CYP 2D enzyme class is essential for their anti-malarial activity.,Furthermore, these results may provide a possible explanation for therapeutic failures for patients who do not respond to 8AQ treatment for relapsing malaria.,Because CYP 2D6 is highly polymorphic, variable expression of this enzyme in humans represents a significant pharmacogenomic liability for 8AQs which require CYP 2D metabolic activation for efficacy, particularly for large-scale prophylaxis and eradication campaigns.

Malaria can be transmitted by blood transfusion from human to human and it is responsible for the majority of transfusion-transmitted infectious diseases worldwide.,In sub-Saharan Africa, it had been estimated that almost a quarter of blood donations contain malaria parasites.,Since rapid diagnostic tests and thick blood smear microscopy lack sensitivity for low density parasitaemia, particularly in asymptomatic adults, the most reliable method to assess the problem of transfusion-transmitted malaria are nucleic acid-based molecular approaches such as quantitative polymerase chain reaction.,The study was undertaken to determine the prevalence of sub-microscopic malaria parasite infection among blood donors in Malabo, Equatorial Guinea.,Between July and August 2017, a total of 200 individual blood samples from blood donors at the Malabo Blood Bank were collected and screened by rapid diagnostic tests and thick blood smear microscopy.,Retrospectively, the same samples were analysed for the presence of undetected, low-density malaria parasites using quantitative polymerase chain reaction.,In comparison to 6.5% (13/200) by rapid diagnostic test and 2.0% (4/200) by microscopy, the proportion of Plasmodium falciparum positive blood donations analysed by quantitative polymerase chain reaction was significantly higher (26%, 52/200).,Densities of P. falciparum positive blood donations were ranging from 0.06 to 3707.0 parasites/µL with 79.6% below 100 parasites/µL and therefore not detectable by non-molecular malaria diagnostic tests. qPCR based species identification revealed that P. falciparum was the dominating species responsible for 88.1% (52/59) of positive blood donations, followed by Plasmodium malariae (15.3%, 9/59) and Plasmodium ovale (3.4%, 2/59).,This study confirms that in malaria endemic settings, sub-patent malaria infections among blood donors are prevalent.,In blood collected from healthy donors living in Malabo, P. falciparum, P. malariae and P. ovale parasites were identified.,Currently widely used malaria diagnostic tools have missed more than 75% of P. falciparum containing blood donations, demonstrating the value of quantitative polymerase chain reaction to reliably detect low density P. falciparum infections.,Since the availability of molecular diagnostic methods in malaria endemic countries is still limited, the blood recipients living in malaria endemic countries should be treated following WHO recommendations.,The online version of this article (10.1186/s12936-019-2639-8) contains supplementary material, which is available to authorized users.

Sensitive field-deployable diagnostic tests can assist malaria programs in achieving elimination.,The performance of a new Alere™ Malaria Ag P.f Ultra Sensitive rapid diagnostic test (uRDT) was compared with the currently available SD Bioline Malaria Ag P.f RDT in blood specimens from asymptomatic individuals in Nagongera, Uganda, and in a Karen Village, Myanmar, representative of high- and low-transmission areas, respectively, as well as in pretreatment specimens from study participants from four Plasmodium falciparum-induced blood-stage malaria (IBSM) studies.,A quantitative reverse transcription PCR (qRT-PCR) and a highly sensitive enzyme-linked immunosorbent assay (ELISA) test for histidine-rich protein II (HRP2) were used as reference assays.,The uRDT showed a greater than 10-fold lower limit of detection for HRP2 compared with the RDT.,The sensitivity of the uRDT was 84% and 44% against qRT-PCR in Uganda and Myanmar, respectively, and that of the RDT was 62% and 0% for the same two sites.,The specificities of the uRDT were 92% and 99.8% against qRT-PCR for Uganda and Myanmar, respectively, and 99% and 99.8% against the HRP2 reference ELISA.,The RDT had specificities of 95% and 100% against qRT-PCR for Uganda and Myanmar, respectively, and 96% and 100% against the HRP2 reference ELISA.,The uRDT detected new infections in IBSM study participants 1.5 days sooner than the RDT.,The uRDT has the same workflow as currently available RDTs, but improved performance characteristics to identify asymptomatic malaria infections.,The uRDT may be a useful tool for malaria elimination strategies.

Malaria control was strengthened in Zambia over the past decade.,The two primary interventions for vector control are indoor residual spraying (IRS) and long-lasting insecticide-treated nets (LLINs).,Using passive malaria surveillance data collected from 2006 to 2011 through the Zambian District Health Information System, the associations between increased coverage with LLINs and IRS and the burden of malaria in Zambia were evaluated.,National passive malaria surveillance data from 2006 to 2011 were analysed.,A district-level, random-effects model with Poisson regression was used to explore the association between malaria cases and coverage with LLINs and IRS.,Malaria cases and LLINs and IRS coverage were mapped to visualize spatiotemporal variation in malaria for each year.,From 2006-2011, 24.6 million LLINs were distributed and 6.4 million houses were sprayed with insecticide.,Coverage with LLINs was not uniformly distributed over the study period and IRS was targeted to central and southern districts where malaria transmission was low.,LLIN coverage was associated with a reduction in malaria cases, although an increase in the number of malaria cases was reported in some districts over the study period.,A high burden of malaria persisted in north-eastern Zambia, whereas a reduction in the number of reported malaria cases was observed in western and southern Zambia.,Enhanced and targeted interventions in north-eastern Zambia where the burden of malaria remains high, as well as efforts to sustain low malaria transmission in the south-west, will be necessary for Zambia to achieve the national goal of being malaria free by 2030.

Indonesia has set 2030 as its deadline for elimination of malaria transmission in the archipelago, with regional deadlines established according to present levels of malaria endemicity and strength of health infrastructure.,The Municipality of Sabang which historically had one of the highest levels of malaria in Aceh province aims to achieve elimination by the end of 2013.,From 2008 to 2010, baseline surveys of malaria interventions, mapping of all confirmed malaria cases, categorization of residual foci of malaria transmission and vector surveys were conducted in Sabang, Aceh, a pilot district for malaria elimination in Indonesia.,To inform future elimination efforts, mass screening from the focal areas to measure prevalence of malaria with both microscopy and PCR was conducted.,G6PD deficiency prevalence was also measured.,Despite its small size, a diverse mixture of potential malaria vectors were documented in Sabang, including Anopheles sundaicus, Anopheles minimus, Anopheles aconitus and Anopheles dirus.,Over a two-year span, the number of sub-villages with ongoing malaria transmission reduced from 61 to 43.,Coverage of malaria diagnosis and treatment, IRS, and LLINs was over 80%.,Screening of 16,229 residents detected 19 positive people, for a point prevalence of 0.12%.,Of the 19 positive cases, three symptomatic infections and five asymptomatic infections were detected with microscopy and 11 asymptomatic infections were detected with PCR.,Of the 19 cases, seven were infected with Plasmodium falciparum, 11 were infected with Plasmodium vivax, and one subject was infected with both species.,Analysis of the 937 blood samples for G6PD deficiency revealed two subjects (0.2%) with deficient G6PD.,The interventions carried out by the government of Sabang have dramatically reduced the burden of malaria over the past seven years.,The first phase, carried out between 2005 and 2007, included improved malaria diagnosis, introduction of ACT for treatment, and scale-up of coverage of IRS and LLINs.,The second phase, from 2008 to 2010, initiated to eliminate the persistent residual transmission of malaria, consisted of development of a malaria database to ensure rapid case reporting and investigation, stratification of malaria foci to guide interventions, and active case detection to hunt symptomatic and asymptomatic malaria carriers.

Helminths use various immunomodulatory and anti-inflammatory strategies to evade immune attack by the host.,During pathological conditions, these strategies alter the course of disease by reducing immune-mediated pathology.,The study examines the therapeutic effect of the nematode L4 stage based on an in vivo model of multiple sclerosis, monophasic encephalomyelitis (EAE), induced by sensitization with MOG35-55 peptide in C57BL/6 female mice infected with the intestinal nematode Heligmosomoides polygyrus.,The EAE remission was correlated with altered leukocyte number identified in the central nervous system (CNS), and temporary permeability of the blood-brain barrier at the histotrophic phase of infection.,At 6 days post-infection, when the L4 stage had almost completely attenuated the clinical severity and pathological signs of EAE, CD25+ cell numbers expanded significantly, with parallel growth of CD8+ and CD4+, both CD25+Foxp3+ and CD25+Foxp3− subsets and alternatively activated macrophages.,The phenotypic changes in distinct subsets of cerebrospinal fluid cells were correlated with an inhibited proliferative response of encephalitogenic T cells and elevated levels of nerve growth factor and TGF-β.,These results enhance our understanding of mechanisms involved in the inhibition of immune responses in the CNS during nematode infection.

Immunity to many human and murine gastrointestinal helminth parasites requires interleukin-4 (IL-4)-directed type 2 helper (TH2) differentiation of CD4+ T cells to elicit type-2 immunity.,Despite a good understanding of the inflammatory cascade elicited following helminth infection, the initial source of IL-4 is unclear.,Previous studies using the rat helminth parasite Nippostronglyus brasiliensis, identified an important role for basophil-derived IL-4 for TH2 differentiation.,However, basophils are redundant for TH2 differentiation following infection with the natural helminth parasite of mice Heligmosomoides polygyrus, indicating that other sources of IL-4 are required.,In this study using H. polygyrus, which is controlled by IL-4-dependent immunity, we identified that group-2 innate lymphoid cells (ILC2s) produced significant amounts of IL-4 and IL-2 following H. polygyrus infection.,Leukotriene D4 was sufficient to stimulate IL-4 secretion by ILC2s, and the supernatant from activated ILC2s could potently drive TH2 differentiation in vitro in an IL-4-dependent manner.,Furthermore, specific deletion of IL-4 from ILC2s compromised TH2 differentiation in vivo.,Overall, this study highlights a previously unrecognized and important role for ILC2-derived IL-4 for TH2 differentiation in a natural TH2-dependent model of human helminthiasis.

Chagas disease (CD), a neglected tropical disease caused by the protozoan Trypanosoma cruzi, affects around six million individuals in Latin America.,Currently, CD occurs worldwide, becoming a significant public health concern due to its silent aspect and high morbimortality rate.,T. cruzi presents different escape strategies which allow its evasion from the host immune system, enabling its persistence and the establishment of chronic infection which leads to the development of chronic Chagas cardiomyopathy (CCC).,The potent immune stimuli generated by T. cruzi persistence may result in tissue damage and inflammatory response.,In addition, molecular mimicry between parasites molecules and host proteins may result in cross-reaction with self-molecules and consequently in autoimmune features including autoantibodies and autoreactive cells.,Although controversial, there is evidence demonstrating a role for autoimmunity in the clinical progression of CCC.,Nevertheless, the exact mechanism underlying the generation of an autoimmune response in human CD progression is unknown.,In this review, we summarize the recent findings and hypotheses related to the autoimmune mechanisms involved in the development and progression of CCC.

Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and affects ca. 10 million people worldwide.,About 30% of Chagas disease patients develop chronic Chagas disease cardiomyopathy (CCC), a particularly lethal inflammatory cardiomyopathy that occurs decades after the initial infection, while most patients remain asymptomatic.,Mortality rate is higher than that of noninflammatory cardiomyopathy.,CCC heart lesions present a Th1 T-cell-rich myocarditis, with cardiomyocyte hypertrophy and prominent fibrosis.,Data suggest that the myocarditis plays a major pathogenetic role in disease progression.,Major unmet goals include the thorough understanding of disease pathogenesis and therapeutic targets and identification of prognostic genetic factors.,Chagas disease thus remains a neglected disease, with no vaccines or antiparasitic drugs proven efficient in chronically infected adults, when most patients are diagnosed.,Both familial aggregation of CCC cases and the fact that only 30% of infected patients develop CCC suggest there might be a genetic component to disease susceptibility.,Moreover, previous case-control studies have identified some genes associated to human susceptibility to CCC.,In this paper, we will review the immunopathogenesis and genetics of Chagas disease, highlighting studies that shed light on the differential progression of Chagas disease patients to CCC.

Proinflammatory cytokines are involved in clearance of Plasmodium falciparum, and very high levels of these cytokines have been implicated in the pathogenesis of severe malaria.,In order to determine how cytokines vary with disease severity and syndrome, we enrolled Malawian children presenting with cerebral malaria (CM), severe malarial anemia (SMA), and uncomplicated malaria (UCM) and healthy controls.,We analyzed serum cytokine concentrations in acute infection and in convalescence.,With the exception of interleukin 5 (IL-5), cytokine concentrations were highest in acute CM, followed by SMA, and were only mildly elevated in UCM.,Cytokine concentrations had fallen to control levels when remeasured at 1 month of convalescence in all three clinical malaria groups.,Ratios of IL-10 to tumor necrosis factor alpha (TNF-α) and of IL-10 to IL-6 followed a similar pattern.,Children presenting with acute CM had significantly higher concentrations of TNF-α (P < 0.001), interferon gamma (IFN-γ) (P = 0.0019), IL-2 (P = 0.0004), IL-6 (P < 0.001), IL-8 (P < 0.001), and IL-10 (P < 0.001) in sera than healthy controls.,Patients with acute CM had significantly higher concentrations of IL-6 (P < 0.001) and IL-10 (P = 0.0003) than those presenting with acute SMA.,Our findings are consistent with the concept that high levels of proinflammatory cytokines, despite high levels of the anti-inflammatory cytokine IL-10, could contribute to the pathogenesis of CM.

Endothelial protein C receptor (EPCR) was recently identified as a key receptor for Plasmodium falciparum erythrocyte membrane protein 1 mediating sequestration of P. falciparum-infected erythrocytes in patients suffering from severe malaria.,Soluble EPCR (sEPCR) inhibits binding of P. falciparum to EPCR in vitro and increased levels of sEPCR have been associated with the H3 haplotype of the EPCR encoding PROCR gene.,It has been hypothesized that elevated sEPCR levels, possibly linked to the PROCR H3 genetic variant, may confer protection against severe forms of malaria.,This study determined the frequencies of PROCR haplotypes H1-4 and plasma levels of sEPCR in a Tanzanian study population to investigate a possible association with severe malaria.,Study participants were children under 5 years of age admitted at the Korogwe District Hospital (N = 143), and diagnosed as having severe malaria (N = 52; including cerebral malaria N = 17), uncomplicated malaria (N = 24), or an infection other than malaria (N = 67).,In addition, blood samples from 71 children living in nearby villages were included.,The SNPs defining the haplotypes of PROCR gene were determined by post-PCR ligation detection reaction-fluorescent microsphere assay.,Individuals carrying at least one H3 allele had significantly higher levels of sEPCR than individuals with no H3 alleles (P < 0.001).,No difference in the frequency of H3 was found between the non-malaria patients, malaria patients or the village population (P > 0.1).,Plasma levels of sEPCR differed between these three groups, with higher sEPCR levels in the village population compared to the hospitalized patients (P < 0.001) and higher levels in malaria patients compared to non-malaria patients (P = 0.001).,However, no differences were found in the distribution of H3 (P = 0.2) or levels of sEPCR (P = 0.8) between patients diagnosed with severe and uncomplicated malaria.,Frequencies of SNPs determining PROCR haplotypes were in concordance with other African studies.,The PROCR H3 allele was associated with higher levels of sEPCR, confirming earlier findings, however, in this Tanzanian population; neither PROCR haplotype nor level of sEPCR was associated with severe malaria, however, larger studies are needed to confirm these findings.

The increase in multidrug resistant Plasmodium falciparum infections threatens the malaria elimination goals in countries within the Greater Mekong Sub-region.,A multi-pronged approach assuring access to basic malaria control measures, including insecticide-treated bed nets and early diagnosis and treatment was followed by mass drug administrations (MDA) in southern Savannakhet Province, Laos.,The main objective of this study was to evaluate the effectiveness and safety of mass drug administrations as well as their effects on the dynamic of asymptomatic P. falciparum infections in 4 malaria endemic villages.,Two villages were randomized to early MDA consisting of 3 rounds of a 3-day course of dihydroartemisinin-piperaquine with a single low dose of primaquine.,In the other 2 villages MDA was deferred by 1 year.,A total of 1036 residents were enrolled in early MDA villages and 883 in control villages (deferred-MDA).,Tri-monthly parasitaemia surveys using uPCR were conducted for a year in the 4 villages.,Eighty-four percent (872/1036) of the residents participated in the MDAs, of whom 90% (781/872) completed 3 rounds of MDA (9 doses).,In intervention villages, the prevalence of asymptomatic P. falciparum infections decreased by 85% after MDA from 4.8% (95% CI 3.4-6.4) at baseline (month 0 or M0) to 0.7% (95% CI 0.3-1.6) at month 12.,In control villages there was a decrease of 33% in P. falciparum prevalence between M0: 17.5% (95% CI 15.9-20.3) and M12: 11.6% (95% CI 9.3-14.2).,In bivariate and multivariate analyses P. falciparum infections were significantly reduced with early MDA (adjusted incidence rate ratios (AIRR): 0.08, CI 0.01-0.091) and completion of 3 MDA rounds (AIRR: 0.06; CI 0.01-0.66).,A quarter of participants (226/872) reported adverse events of which 99% were mild.,The study found a significant reduction in P. falciparum prevalence and incidence following MDA.,MDA was safe, well tolerated, feasible, and achieved high population coverage and adherence.,MDAs must be integrated in multi-pronged approaches such as vector control and preventive measures with a focus on specific risk groups such as mobile, migrant population and forest goers for a sustained period to eliminate the remaining parasite reservoirs.,Trial registration ClinicalTrials.gov Identifier: NCT01872702

In Cambodian villages, 3-month mass drug administration with high coverage using dihydroartemisinin-piperaquine was safe and was followed by the absence of clinical Plasmodium falciparum cases for at least 1 year, despite the presence of multidrug-resistant parasites.,The increase in multidrug-resistant Plasmodium falciparum in Southeast Asia suggests a need for acceleration of malaria elimination.,We evaluated the effectiveness and safety of mass drug administration (MDA) to interrupt malaria transmission.,Four malaria-endemic villages in western Cambodia were randomized to 3 rounds of MDA (a 3-day course of dihydroartemisinin with piperaquine-phosphate), administered either early in or at the end of the study period.,Comprehensive malaria treatment records were collected during 2014-2017.,Subclinical parasite prevalence was estimated by ultrasensitive quantitative polymerase chain reaction quarterly over 12 months.,MDA coverage with at least 1 complete round was 88% (1999/2268), ≥2 rounds 73% (1645/2268), and all 3 rounds 58% (1310/2268).,Plasmodium falciparum incidence in intervention and control villages was similar over the 12 months prior to the study: 39 per 1000 person-years (PY) vs 45 per 1000 PY (P = .50).,The primary outcome, P. falciparum incidence in the 12 months after MDA, was lower in intervention villages (1.5/1000 PY vs 37.1/1000 PY; incidence rate ratio, 24.5 [95% confidence interval], 3.4-177; P = .002).,Following MDA in 2016, there were no clinical falciparum malaria cases over 12 months (0/2044 PY) in all 4 villages.,Plasmodium vivax prevalence decreased markedly in intervention villages following MDA but returned to approximately half the baseline prevalence by 12 months.,No severe adverse events were attributed to treatment.,Mass drug administrations achieved high coverage, were safe, and associated with the absence of clinical P. falciparum cases for at least 1 year.,NCT01872702.

Schistosomiasis is a human parasitic disease responsible for serious consequences for public health, as well as severe socioeconomic impacts in developing countries.,Here, we provide evidence that the adaptor molecule STING plays an important role in Schistosoma mansoni infection.,S. mansoni DNA is sensed by cGAS leading to STING activation in murine embryonic fibroblasts (MEFs).,Sting−/− and C57BL/6 (WT) mice were infected with schistosome cercariae in order to assess parasite burden and liver pathology.,Sting−/− mice showed worm burden reduction but no change in the number of eggs or granuloma numbers and area when compared to WT animals.,Immunologically, a significant increase in IFN-γ production by the spleen cells was observed in Sting−/− animals.,Surprisingly, Sting−/− mice presented an elevated percentage of neutrophils in lungs, bronchoalveolar lavage, and spleens.,Moreover, Sting−/− neutrophils exhibited increased survival rate, but similar ability to kill schistosomula in vitro when stimulated with IFN-γ when compared to WT cells.,Finally, microbiota composition was altered in Sting−/− mice, revealing a more inflammatory profile when compared to WT animals.,In conclusion, this study demonstrates that STING signaling pathway is important for S. mansoni DNA sensing and the lack of this adaptor molecule leads to enhanced resistance to infection.

Granulomatous and fibrosing inflammation in response to soluble egg antigen (SEA) from Schistosoma japonicum (S. japonicum) is the main pathological process of S. japonicum infection.,Inflammasome activation has recently been implicated in the pathogenesis of liver disease.,However, the role of inflammasome activation in schistosomiasis-associated liver fibrosis (SSLF) has not been extensively studied.,In this study, it is demonstrated that the NLRP3 inflammasome is markedly activated in mouse HSCs both in vivo and in vitro during S. japonicum infection.,Furthermore, it is demonstrated that inhibition of NLRP3 inflammasome significantly alleviates the liver inflammation and collagen deposition that are induced by infection with S. japonicum.,The mechanism of SEA-induced NLRP3 inflammasome activation is studied in isolated, cultured mouse HSCs and it is shown that SEA-induced NLRP3 inflammasome activation in HSCs is dependent upon the activities of spleen tyrosine kinase (Syk), an enzyme usually associated with a pathogen recognition receptor for fungal pathogens.,Moreover, it is demonstrated that Dectin-1 and JNK signaling are also involved in SEA-induced NLRP3 inflammasome activation in HSCs.,These data shed new light on the mechanisms of NLRP3 inflammasome activation during an infection with S. japonicum, and further characterize its role in schistosomiasis-associated liver fibrosis (SSLF).

Protozoan parasites of the genus Leishmania cause severe human and veterinary diseases worldwide, termed leishmaniases.,A hallmark of Leishmania biology is its capacity to adapt to a variety of unpredictable fluctuations inside its human host, notably pharmacological interventions, thus, causing drug resistance.,Here we investigated mechanisms of environmental adaptation using a comparative genomics approach by sequencing 10 new clinical isolates of the L. donovani, L. major, and L. tropica complexes that were sampled across eight distinct geographical regions.,Our data provide new evidence that parasites adapt to environmental change in the field and in culture through a combination of chromosome and gene amplification that likely causes phenotypic variation and drives parasite fitness gains in response to environmental constraints.,This novel form of gene expression regulation through genomic change compensates for the absence of classical transcriptional control in these early-branching eukaryotes and opens new venues for biomarker discovery.,Protozoan parasites of the genus Leishmania adapt to environmental change through chromosome and gene copy number variations.,Only little is known about external or intrinsic factors that govern Leishmania genomic adaptation.,Here, by conducting longitudinal genome analyses of 10 new Leishmania clinical isolates, we uncovered important differences in gene copy number among genetically highly related strains and revealed gain and loss of gene copies as potential drivers of long-term environmental adaptation in the field.,In contrast, chromosome rather than gene amplification was associated with short-term environmental adaptation to in vitro culture.,Karyotypic solutions were highly reproducible but unique for a given strain, suggesting that chromosome amplification is under positive selection and dependent on species- and strain-specific intrinsic factors.,We revealed a progressive increase in read depth towards the chromosome ends for various Leishmania isolates, which may represent a nonclassical mechanism of telomere maintenance that can preserve integrity of chromosome ends during selection for fast in vitro growth.,Together our data draw a complex picture of Leishmania genomic adaptation in the field and in culture, which is driven by a combination of intrinsic genetic factors that generate strain-specific phenotypic variations, which are under environmental selection and allow for fitness gain.

Leishmania infantum (syn.,L. chagasi) is the causative agent of visceral leishmaniasis (VL) in the New World (NW) with endemic regions extending from southern USA to northern Argentina.,The two hypotheses about the origin of VL in the NW suggest (1) recent importation of L. infantum from the Old World (OW), or (2) an indigenous origin and a distinct taxonomic rank for the NW parasite.,Multilocus microsatellite typing was applied in a survey of 98 L. infantum isolates from different NW foci.,The microsatellite profiles obtained were compared to those of 308 L. infantum and 20 L. donovani strains from OW countries previously assigned to well-defined populations.,Two main populations were identified for both NW and OW L. infantum.,Most of the NW strains belonged to population 1, which corresponded to the OW MON-1 population.,However, the NW population was much more homogeneous.,A second, more heterogeneous, population comprised most Caribbean strains and corresponded to the OW non-MON-1 population.,All Brazilian L. infantum strains belonged to population 1, although they represented 61% of the sample and originated from 9 states.,Population analysis including the OW L. infantum populations indicated that the NW strains were more similar to MON-1 and non-MON-1 sub-populations of L. infantum from southwest Europe, than to any other OW sub-population.,Moreover, similarity between NW and Southwest European L. infantum was higher than between OW L. infantum from distinct parts of the Mediterranean region, Middle East and Central Asia.,No correlation was found between NW L. infantum genotypes and clinical picture or host background.,This study represents the first continent-wide analysis of NW L. infantum population structure.,It confirmed that the agent of VL in the NW is L. infantum and that the parasite has been recently imported multiple times to the NW from southwest Europe.

The Three Gorges Dam, located in the largest endemic area of schistosomiasis in China, is one of the world’s largest hydroelectric projects to date.,Some large-scale hydro projects have resulted in schistosomiasis emergence or re-emergence.,Therefore, the dam’s potential impact on the transmission of Schistosoma japonicum has raised concerns from medical researchers worldwide.,A systematic literature review, coupled with an analysis of data on the water level and snail density in the Yangtze River was conducted to assess the impact of the dam on schistosomiasis transmission after more than 10 years of operation.,The dam has significantly altered the water levels in the Yangtze River according to different seasons.,These changes directly impact the ecology of the schistosome snail host.,Due to the dam, there has been a reduction in the density of Oncomelania snails and/or changes in the distribution of snails.,The prevalence of infection with S. japonicum has decreased in the downstream areas of the dam, including in the Dongting and Poyang Lakes.,The prevalence of infection with S. japonicum in humans has decreased from 6.80 % in 2002 (before the dam began operating) to 0.50 % in 2012, and the number of people infected with S. japonicum have decreased from 94 208 in 2002 to 59 200 in 2011 in the Poyang Lake region.,The presence of the dam does not seem to affect snail breeding or the prevalence of schistosomiasis in the Three Gorges Reservoir.,Overall, the Three Gorges Dam has significantly contributed to changes in hydrology after more than 10 years of the dam operating.,The changes caused by the dam, together with integrated control of schistosomiasis, might be accelerating the progress towards eliminating the transmission of S. japonicum in the middle and lower reaches of the Yangtze River.,Despite the positive effect the dam is having in controlling S. japonicum transmission, continued surveillance is required to monitor the future ecological impacts of the dam over the long term.,The online version of this article (doi:10.1186/s40249-016-0156-3) contains supplementary material, which is available to authorized users.

Over the past decades China has made a great stride in controlling schistosomiasis, eliminating transmission of Schistosoma japonicum in 5 provinces and remarkably reducing transmission intensities in the rest of the seven endemic provinces.,Recently, an integrated control strategy, which focuses on interventions on humans and bovines, has been implemented throughout endemic areas in China.,This strategy assumes that a reduction in transmission of S. japonicum from humans and bovines to the intermediate Oncomelania snail host would eventually block the transmission of this parasite, and has yielded effective results in some endemic areas.,Yet the transmission of S. japonicum is relatively complicated - in addition to humans and bovines, more than 40 species of mammalians can serve as potential zoonotic reservoirs.,Here, we caution that some factors - potential roles of other mammalian reservoirs and human movement in sustaining the transmission, low sensitivity/specificity of current diagnostic tools for infections, praziquantel treatment failures, changes in environmental and socio-economic factors such as flooding in key endemic areas - may pose great obstacles towards transmission interruption of the parasite.,Assessing potential roles of these factors in the transmission and implications for current control strategies aiming at transmission interruption is needed.

The RTS,S/AS01 vaccine against Plasmodium falciparum malaria infection completed phase III trials in 2014 and demonstrated efficacy against clinical malaria of approximately 36% over 4 years for a 4-dose schedule in children aged 5-17 months.,Pilot vaccine implementation has recently begun in 3 African countries.,If the pilots demonstrate both a positive health impact and resolve remaining safety concerns, wider roll-out could be recommended from 2021 onwards.,Vaccine demand may, however, outstrip initial supply.,We sought to identify where vaccine introduction should be prioritised to maximise public health impact under a range of supply constraints using mathematical modelling.,Using a mathematical model of P. falciparum malaria transmission and RTS,S vaccine impact, we estimated the clinical cases and deaths averted in children aged 0-5 years in sub-Saharan Africa under 2 scenarios for vaccine coverage (100% and realistic) and 2 scenarios for other interventions (current coverage and World Health Organization [WHO] Global Technical Strategy targets).,We used a prioritisation algorithm to identify potential allocative efficiency gains from prioritising vaccine allocation among countries or administrative units to maximise cases or deaths averted.,If malaria burden at introduction is similar to current levels-assuming realistic vaccine coverage and country-level prioritisation in areas with parasite prevalence >10%-we estimate that 4.3 million malaria cases (95% credible interval [CrI] 2.8-6.8 million) and 22,000 deaths (95% CrI 11,000-35,000) in children younger than 5 years could be averted annually at a dose constraint of 30 million.,This decreases to 3.0 million cases (95% CrI 2.0-4.7 million) and 14,000 deaths (95% CrI 7,000-23,000) at a dose constraint of 20 million, and increases to 6.6 million cases (95% CrI 4.2-10.8 million) and 38,000 deaths (95% CrI 18,000-61,000) at a dose constraint of 60 million.,At 100% vaccine coverage, these impact estimates increase to 5.2 million cases (95% CrI 3.5-8.2 million) and 27,000 deaths (95% CrI 14,000-43,000), 3.9 million cases (95% CrI 2.7-6.0 million) and 19,000 deaths (95% CrI 10,000-30,000), and 10.0 million cases (95% CrI 6.7-15.7 million) and 51,000 deaths (95% CrI 25,000-82,000), respectively.,Under realistic vaccine coverage, if the vaccine is prioritised sub-nationally, 5.3 million cases (95% CrI 3.5-8.2 million) and 24,000 deaths (95% CrI 12,000-38,000) could be averted at a dose constraint of 30 million.,Furthermore, sub-national prioritisation would allow introduction in almost double the number of countries compared to national prioritisation (21 versus 11).,If vaccine introduction is prioritised in the 3 pilot countries (Ghana, Kenya, and Malawi), health impact would be reduced, but this effect becomes less substantial (change of <5%) if 50 million or more doses are available.,We did not account for within-country variation in vaccine coverage, and the optimisation was based on a single outcome measure, therefore this study should be used to understand overall trends rather than guide country-specific allocation.,These results suggest that the impact of constraints in vaccine supply on the public health impact of the RTS,S malaria vaccine could be reduced by introducing the vaccine at the sub-national level and prioritising countries with the highest malaria incidence.,Alexandra Hogan and colleagues explore strategies to optimize vaccine allocation for maximum public health benefit in the face of potential supply constraints.

The COVID-19 pandemic has resulted in millions of infections, hundreds of thousands of deaths and major societal disruption due to lockdowns and other restrictions introduced to limit disease spread.,Relatively little attention has been paid to understanding how the pandemic has affected treatment, prevention and control of malaria, which is a major cause of death and disease and predominantly affects people in less well-resourced settings.,Recent successes in malaria control and elimination have reduced the global malaria burden, but these gains are fragile and progress has stalled in the past 5 years.,Withdrawing successful interventions often results in rapid malaria resurgence, primarily threatening vulnerable young children and pregnant women.,Malaria programmes are being affected in many ways by COVID-19.,For prevention of malaria, insecticide-treated nets need regular renewal, but distribution campaigns have been delayed or cancelled.,For detection and treatment of malaria, individuals may stop attending health facilities, out of fear of exposure to COVID-19, or because they cannot afford transport, and health care workers require additional resources to protect themselves from COVID-19.,Supplies of diagnostics and drugs are being interrupted, which is compounded by production of substandard and falsified medicines and diagnostics.,These disruptions are predicted to double the number of young African children dying of malaria in the coming year and may impact efforts to control the spread of drug resistance.,Using examples from successful malaria control and elimination campaigns, we propose strategies to re-establish malaria control activities and maintain elimination efforts in the context of the COVID-19 pandemic, which is likely to be a long-term challenge.,All sectors of society, including governments, donors, private sector and civil society organisations, have crucial roles to play to prevent malaria resurgence.,Sparse resources must be allocated efficiently to ensure integrated health care systems that can sustain control activities against COVID-19 as well as malaria and other priority infectious diseases.,As we deal with the COVID-19 pandemic, it is crucial that other major killers such as malaria are not ignored.,History tells us that if we do, the consequences will be dire, particularly in vulnerable populations.

In January and February 2019, a malacological survey was conducted in the area surrounding the residence of a 12-year-old child that had contracted cerebral angiostrongyliasis in the municipality of Macapá, capital of the Amapá State, northern Brazil.,The serological examination was positive for Angiostrongylus cantonensis infection, the principal etiological agent of this parasitosis.,A sample of 54 molluscs was artificially and individually digested for parasitological analysis, containing 38 specimens of Achatina fulica, nine specimens of Bulimulus tenuissimus and seven specimens of Sarasinula linguaeformis.,A. fulica was the most abundant mollusc, and the only species infected with A. cantonensis, as well as presenting co-infections with other nematodes.,This is the first report of cerebral angiostrongyliasis in the Amazon Region, and the first record of A. fulica infected with A. cantonensis in Amapá.,These findings highlight the potential risks of human angiostrongyliasis, and the need to implement public health measures to control the spread of the disease.

Angiostrongylus cantonensis has been the only parasite among Angiostrongylidae to cause human central nervous system infection characterized by eosinophilic meningitis or meningoencephalitis.,The mechanism of the extensive neurological impairments of hosts caused by A. cantonensis larvae remains unclear.,The aim of the present study was to investigate apoptosis, necroptosis and autophagy in the brains of mice infected with A. cantonensis, which will be valuable for better understanding the pathogenesis of angiostrongyliasis cantonensis.,Functional and histological neurological impairments of brain tissues from mice infected with A. cantonensis were measured by the Morris water maze test and haematoxylin and eosin (H&E) staining, respectively.,The transcriptional and translational levels of apoptosis-, necroptosis- and autophagy-related genes were quantified by quantitative real-time polymerase chain reaction (RT-PCR), and assessed by western blot and immunohistochemistry (IHC) analysis.,Apoptotic and necroptotic cells and their distributions in infected brain tissues were analysed by flow cytometry and transmission electron microscopy (TEM).,Inflammatory response in the central nervous system deteriorated as A. cantonensis infection evolved, as characterized by abundant inflammatory cell infiltration underneath the meninges, which peaked at 21 days post-infection (dpi).,The learning and memory capacities of the mice were significantly decreased at 14 dpi, indicating prominent impairment of their cognitive functions.,Compared with those of the control group, the mRNA levels of caspase-3, -4, -6, and RIP3 and the protein levels of caspase-4, cleaved caspase-3, cleaved caspase-6, RIP3, and pRIP3 were obviously elevated.,However, no changes in the mRNA or protein levels of FADD, Beclin-1 or LC3B were evident, indicating that apoptosis and necroptosis, but not autophagy, occurred in the brain tissues of mice infected with A. cantonensis.,The quantitative RT-PCR, western blot, IHC, flow cytometry and TEM results further revealed the apoptotic and necroptotic microglia, astrocytes and neurons in the parenchymal and hippocampal regions of infected mice.,To our knowledge, we showed for the first time that A. cantonensis infection causes the apoptosis and necroptosis of microglia and astrocytes in the parenchymal and hippocampal regions of host brain tissues, further demonstrating the pathogenesis of A. cantonensis infection and providing potential therapeutic targets for the management of angiostrongyliasis.

•Disinfection of calf pens with slaked lime delayed onset of diarrhea.,•Lime disinfection improved body condition in the calves.,•Lime disinfection did not affect diarrhea incidence or duration.,•Lime disinfection may help manage Cryptosporidium-associated diarrhea in problem herds.,Disinfection of calf pens with slaked lime delayed onset of diarrhea.,Lime disinfection improved body condition in the calves.,Lime disinfection did not affect diarrhea incidence or duration.,Lime disinfection may help manage Cryptosporidium-associated diarrhea in problem herds.,Diarrhea is common in young calves and is often caused by Cryptosporidium parvum infection.,The aim of this study was to investigate if disinfection of calf pens with hydrated lime would reduce contamination of C. parvum oocysts and improve calf health in herds with C. parvum associated diarrhea problems.,Four dairy herds with ongoing C. parvum associated calf diarrhea problems each participated in the study over six to seven months.,During the study period, all pens/huts for young calves were cleaned according to the usual farm routine before a new calf entered.,Hydrated lime was then used to disinfect half of the pens/huts.,Diarrhea incidence was recorded by the farmers and by veterinarians, who clinically examined the calves every second month.,In total, 402 calves participated in the study.,The farmers detected diarrhea in 214 (53%) calves, with similar proportions in calves kept in lime disinfected and control pens.,Age at diarrhea onset was significantly higher in lime disinfected pens than in control pens, 9.0 days and 7.6 days, respectively.,There was no difference between the groups regarding duration or severity index recorded by the farmers.,The body condition score in 6-8 week old calves was significantly higher in calves that had been kept in lime disinfected pens during their first weeks of life, indicating that calves in disinfected pens/huts were less affected by their infections.,Faecal samples from 5 to 21 day old calves, were collected on four occasions at each farm (n = 95).,Cryptosporidium positive samples were found at all samplings in all four herds.,Cryptosporidium spp. was detected in 79 (83%) samples with no difference between lime disinfected and control pens.,C. parvum was the dominant species.,Two different C. parvum subtypes were found; IIaA16G1R1b in three herds and IIaA16G1R1b_variant in one herd.,Only one subtype was found in each herd.,Disinfection of calf pens with slaked lime delayed onset of diarrhea and improved the body condition in the calves, but did not affect diarrhea incidence or duration.,Although lime disinfection alone will not be sufficient to control Cryptosporidium associated diarrhea in herds with extensive calf diarrhea problems, these results suggest that it can be a valuable complement to other measures.

Cryptosporidium is a leading cause of diarrheal disease and an important contributor to early childhood mortality, malnutrition, and growth faltering.,Older children in high endemicity regions appear resistant to infection, while previously unexposed adults remain susceptible.,Experimental studies in humans and animals support the development of disease resistance, but we do not understand the mechanisms that underlie protective immunity to Cryptosporidium.,Here, we derive an in vivo model of Cryptosporidium infection in immunocompetent C57BL/6 mice by isolating parasites from naturally infected wild mice.,Similar to human cryptosporidiosis, this infection causes intestinal pathology, and interferon-γ controls early infection while T cells are critical for clearance.,Importantly, mice that controlled a live infection were resistant to secondary challenge and vaccination with attenuated parasites provided protection equal to live infection.,Both parasite and host are genetically tractable and this in vivo model will facilitate mechanistic investigation and rational vaccine design.,•We isolated and sequenced Cryptosporidium tyzzeri, a natural mouse pathogen•C. tyzzeri can be genetically manipulated using CRISPR-driven homologous repair•C. tyzzeri models human cryptosporidiosis with T cell- and IFN-γ-dependent resolution•Mice develop protective immunity following both live infection and vaccination,We isolated and sequenced Cryptosporidium tyzzeri, a natural mouse pathogen,C. tyzzeri can be genetically manipulated using CRISPR-driven homologous repair,C. tyzzeri models human cryptosporidiosis with T cell- and IFN-γ-dependent resolution,Mice develop protective immunity following both live infection and vaccination,Cryptosporidiosis is an important diarrheal disease that lacks effective treatment and vaccination.,Sateriale et al. isolate Cryptosporidium tyzzeri from naturally infected wild mice and derive a model of infection in immunocompetent mice in which both parasite and host are genetically tractable.,The mechanisms of protective immunity are now open to analysis.

Human Plasmodium infection produces a robust adaptive immune response.,Time courses for 104 children followed for 42 days after initiation of Plasmodium falciparum chemotherapy were assayed for antibody levels to the five isotypes of human immunoglobulins (Ig) and 4 subclasses of IgG for 32 P. falciparum antigens encompassing all 4 parasite stages of human infection.,IgD and IgE against these antigens were undetectable at 1:100 serum concentration, but other Ig isotypes and IgG subclasses were consistently observed against all antigens.,Five quantitative parameters were developed to directly compare Ig response among isotypes and antigens: Cmax, maximum antibody level; ΔC, difference between Cmax and the antibody level at Day 0; tmax, time in days to reach Cmax; t1/2, Ig signal half-life in days; tneg, estimated number of days until complete loss of Ig signal.,Classical Ig patterns for a bloodborne pathogen were seen with IgM showing early tmax and IgG production highest among Ig isotypes.,However, some unexpected trends were observed such as IgA showing a biphasic pattern for many antigens.,Variability among these dynamics of Ig acquisition and loss was noted for different P. falciparum antigens and able to be compared both quantitatively and statistically.,This parametrization methodology allows direct comparison of Ig isotypes produced against various Plasmodium antigens following malaria infection, and the same methodology could be applied to other longitudinal serologic studies from P. falciparum or different pathogens.,Specifically for P. falciparum seroepidemiological studies, reliable and quantitative estimates regarding the IgG dynamics in human populations can better optimize modeling efforts for serological outputs.

Identifying highly immunogenic blood stage antigens which can work as target for naturally acquired antibodies in different eco-epidemiological settings is an important step for designing malaria vaccine.,Blood stage proteins of Plasmodium vivax, apical membrane antigen-1 (PvAMA-1) and 19 kDa fragment of merozoite surface protein (PvMSP-119) are such promising vaccine candidate antigens.,This study determined the naturally-acquired antibody response to PvAMA-1 and PvMSP-119 antigens in individuals living in three geographically diverse malaria endemic regions of India.,A total of 234 blood samples were collected from individuals living in three different eco-epidemiological settings, Chennai, Nadiad, and Rourkela of India.,Indirect ELISA was performed to measure human IgG antibodies against recombinant PvAMA-1 and PvMSP-119 antigens.,The difference in seroprevalence and factors associated with antibody responses at each site was statistically analysed.,The overall seroprevalence was 40.6% for PvAMA-1 and 62.4% for PvMSP-119.,Seroprevalence to PvAMA-1 was higher in Chennai (47%) followed by Nadiad (46.7%) and Rourkela (27.6%).,For PvMSP-119, seroprevalence was higher in Chennai (80.3%) as compared to Nadiad (53.3%) and Rourkela (57.9%).,Seroprevalence for both the antigens were found to be higher in Chennai where P. vivax is the dominant malaria species.,In addition, heterogeneous antibody response was observed for PvAMA-1 and PvMSP-119 antigens at each of the study sites.,Two factors, age and malaria positivity were significantly associated with seropositivity for both the antigens PvAMA-1 and PvMSP-119.,These data suggest that natural acquired antibody response is higher for PvMSP-119 antigen as compared to PvAMA-1 antigen in individuals living in three geographically diverse malaria endemic regions in India.,PvMSP-119 appears to be highly immunogenic in Indian population and has great potential as a malaria vaccine candidate.,The differences in immune response against vaccine candidate antigens in different endemic settings should be taken into account for development of asexual stage based P. vivax malaria vaccine, which in turn can enhance malaria control efforts.

The importance of the submicroscopic reservoir of Plasmodium infections for malaria elimination depends on its size, which is generally considered small in low transmission settings.,The precise estimation of this reservoir requires more sensitive parasite detection methods.,The prevalence of asymptomatic, sub-microscopic malaria was assessed by a sensitive, high blood volume quantitative real-time polymerase chain reaction method in three countries of the Greater Mekong Sub-region.,Cross-sectional surveys were conducted in three villages in western Cambodia, four villages along the Thailand-Myanmar border and four villages in southwest Vietnam.,Malaria parasitaemia was assessed by Plasmodium falciparum/pan malaria rapid diagnostic tests (RDTs), microscopy and a high volume ultra-sensitive real-time polymerase chain reaction (HVUSqPCR: limit of detection 22 parasites/mL).,All villagers older than 6 months were invited to participate.,A census before the surveys identified 7355 residents in the study villages.,Parasite prevalence was 224/5008 (4 %) by RDT, 229/5111 (5 %) by microscopy, and 988/4975 (20 %) when assessed by HVUSqPCR.,Of these 164 (3 %) were infected with P. falciparum, 357 (7 %) with Plasmodium vivax, 56 (1 %) with a mixed infection, and 411 (8 %) had parasite densities that were too low for species identification.,A history of fever, male sex, and age of 15 years or older were independently associated with parasitaemia in a multivariate regression model stratified by site.,Light microscopy and RDTs identified only a quarter of all parasitaemic participants.,The asymptomatic Plasmodium reservoir is considerable, even in low transmission settings.,Novel strategies are needed to eliminate this previously under recognized reservoir of malaria transmission.,The online version of this article (doi:10.1186/s12936-015-0906-x) contains supplementary material, which is available to authorized users.

To achieve the goal of malaria elimination in low transmission areas such as in Cambodia, new, inexpensive, high-throughput diagnostic tools for identifying very low parasite densities in asymptomatic carriers are required.,This will enable a switch from passive to active malaria case detection in the field.,DNA extraction and real-time PCR assays were implemented in an “in-house” designed mobile laboratory allowing implementation of a robust, sensitive and rapid malaria diagnostic strategy in the field.,This tool was employed in a survey organized in the context of the MalaResT project (NCT01663831).,The real-time PCR screening and species identification assays were performed in the mobile laboratory between October and November 2012, in Rattanakiri Province, to screen approximately 5,000 individuals in less than four weeks and treat parasite carriers within 24-48 hours after sample collection.,An average of 240 clinical samples (and 40 quality control samples) was tested every day, six/seven days per week.,Some 97.7% of the results were available <24 hours after the collection.,A total of 4.9% were positive for malaria.,Plasmodium vivax was present in 61.1% of the positive samples, Plasmodium falciparum in 45.9%, Plasmodium malariae in 7.0% and Plasmodium ovale in 2.0%.,The operational success of this diagnostic set-up proved that molecular testing and subsequent treatment is logistically achievable in field settings.,This will allow the detection of clusters of asymptomatic carriers and to provide useful epidemiological information.,Fast results will be of great help for staff in the field to track and treat asymptomatic parasitaemic cases.,The concept of the mobile laboratory could be extended to other countries for the molecular detection of malaria or other pathogens, or to culture vivax parasites, which does not support long-time delay between sample collection and culture.

A widely prevalent disease, toxoplasmosis poses serious health threats to both humans and animals; therefore, development of an ideal DNA vaccine against Toxoplasma gondii is needed eagerly.,The purpose of the present study is to assess the protective efficacy of a DNA vaccine encoding the T. gondii toxofilin gene (pEGFP-toxofilin).,In addition, toxofilin DNA vaccine combined with the individual adjuvants, alum or monophosphoryl lipid A (MPLA), or a mixture of alum-MPLA adjuvant were screened for their ability to enhance antibody responses.,Using bioinformatics, we analyzed the gene and amino acid sequences of the toxofilin protein, recognizing and identifying several potential linear B and T helper (Th)-1 cell epitopes.,BALB/c mice were immunized three times with either toxofilin DNA vaccine alone or in combination with the adjuvants such as alum, MPLA or an alum-MPLA mixture.,The systemic immune response was evaluated by cytokine, the percentage of CD4 (+) and CD8 (+) T cells and specific antibody measurement.,Two weeks after the last immunization, protective efficacy was evaluated by challenging intraperitoneally with 1 × 104 tachyzoites of T. gondii or intragastrically with 20 cysts of T. gondii PRU strain.,All experimentally immunized mice developed strong humoral and cellular immune responses compared with the control groups.,Moreover, by comparison with the non-adjuvant toxofilin DNA vaccine group, adding alum adjuvant to toxofilin DNA vaccine resulted in an increase in humoral response and a skewed Th2 response.,However, the MPLA adjuvant with toxofilin DNA vaccine induced significantly enhanced humoral and Th1-biased immune responses.,Importantly, the co-administration of alum-MPLA adjuvant in combination with the toxofilin DNA vaccine shifted the Th2 immune response to a Th1 response compared with the alum-toxofilin group, and elicited the strongest humoral and Th1 responses among all the groups.,At the same time, a longer survival time and less cyst amounts against T. gondii infection were also observed in the alum-MPLA-toxofilin group in comparison with single or no adjuvant groups.,Toxoplasma gondii toxofilin is a promising vaccine candidate that warrants further development.,Co-administration of the alum-MPLA adjuvant mixture with DNA vaccine could effectively enhance immunogenicity and strongly skew the cellular immune response towards a Th1 phenotype.

Toxoplasma gondii can infect all warm-blooded animals including humans.,Infection with T. gondii is probably the leading cause of posterior uveitis in humans and the most comment route of transmission is raw and undercooked meat from infected animals.,T. gondii calcium-dependent protein kinase 1 (TgCDPK1) plays a critical role in direct parasite motility, host-cell invasion, and egress.,We constructed a DNA vaccine expressing TgCDPK1 inserted into eukaryotic expression vector pVAX I and evaluated the immune protection induced by pVAX-CDPK1 in Kunming mice.,Mice immunized with pVAX-CDPK1 intramuscularly and/or with a plasmid encoding IL-15 and IL-21 (pVAX-IL-21-IL-15).,The immune responses were analyzed including lymphoproliferative assay, cytokine, antibody measurements, lymphocyte surface markers by flow cytometry and protective efficacy were measured as survival and cysts numbers after challenge 1 to 2 months post vaccination.,Immunization with pVAX-CDPK1 or pVAX-IL-21-IL-15 alone developed strong humoral responses and Th1 type cellular immune responses, and the significantly (P < 0.05) increase of both the percentages of CD4+ and CD8+ T cells compared with all the controls (blank control, PBS, and pVAX).,Co-injection of pVAX-IL-21-IL-15 significantly increased humoral and cellular immune responses compared to the group of pVAX-CDPK1 or pVAX-IL-21-IL-15.,Challenge experiments showed that co-administration of pVAX-IL-21-IL-15 and pVAX-CDPK1 significantly (P < 0.05) increased survival time (19.2 ± 5.1 days) compared with pVAX-CDPK1 (17.3 ± 4.3 days) or pVAX-IL-21-IL-15 (12.0 ± 2.0 days) alone, and pVAX-IL-21-IL-15 + pVAX-CDPK1 significantly reduced the number of brain cysts (72.7%) in contrast to pVAX-ROP13 (45.7%) or pVAX-IL-21-IL-15 alone (43.6%).,TgCDPK1 is identified to be a promising vaccine candidate for inducing a strong humoral and cellular response against T. gondii infection, and thus synergistic of mIL-21 and mIL-15 can induce non-specific immune responses, but also facilitate specific humoral as well as cellular immune responses elicited by DNA vaccine against acute and chronic T. gondii infection in mice.,The online version of this article (doi:10.1186/1471-2334-14-487) contains supplementary material, which is available to authorized users.

Since the year 2000, a concerted campaign against malaria has led to unprecedented levels of intervention coverage across sub-Saharan Africa.,Understanding the effect of this control effort is vital to inform future control planning.,However, the effect of malaria interventions across the varied epidemiological settings of Africa remains poorly understood owing to the absence of reliable surveillance data and the simplistic approaches underlying current disease estimates.,Here we link a large database of malaria field surveys with detailed reconstructions of changing intervention coverage to directly evaluate trends from 2000 to 2015 and quantify the attributable effect of malaria disease control efforts.,We found that Plasmodium falciparum infection prevalence in endemic Africa halved and the incidence of clinical disease fell by 40% between 2000 and 2015.,We estimate that interventions have averted 663 (542-753 credible interval) million clinical cases since 2000.,Insecticide-treated nets, the most widespread intervention, were by far the largest contributor (68% of cases averted).,Although still below target levels, current malaria interventions have substantially reduced malaria disease incidence across the continent.,Increasing access to these interventions, and maintaining their effectiveness in the face of insecticide and drug resistance, should form a cornerstone of post-2015 control strategies.

Anopheles gambiae, An. arabiensis, and An. funestus are widespread malaria vectors in Africa.,Anopheles rivulorum is the next most widespread species in the An. funestus group.,The role of An. rivulorum as a malaria vector has not been fully studied, although it has been found to be a minor or opportunistic transmitter of Plasmodium falciparum.,Mosquitoes were collected indoors over a 12-hour period using a light source attached to a rotating bottle collector in order to determine peak activity times and to provide DNA for meal source identification.,Gravid female mosquitoes were collected indoors via an aspirator to generate F1 progeny for testing insecticidal susceptibility.,Blood meal sources were identified using a multiplexed PCR assay for human and bovine cytochrome-B, and by matching sequences generated with primers targeting vertebrate and mammalian cytochrome-B segments to the Genbank database.,Anopheles rivulorum fed on human blood in the early evening between 18:00 and 20:00, when insecticide-treated bed nets are not in use, and the presence of Plasmodium falciparum sporozoites in 0.70% of the An. rivulorum individuals tested was demonstrated.,Susceptibility to permethrin, deltamethrin, and DDT is higher in An. rivulorum (84.8%, 91.4%, and 100%, respectively) than in An. funestus s.s.,(36.8%, 36.4%, and 70%, respectively), whereas mortality rates for propoxur and fenitrothion were 100% for both species.,Resistance to pyrethroids was very high in An. funestus s.s. and the potential of the development of high resistance was suspected in An. rivulorum.,Given the tendency for An. rivulorum to be active early in the evening, the presence of P. falciparum in the species, and the potential for the development of pyrethroid resistance, we strongly advocate reconsideration of the latent ability of this species as an epidemiologically important malaria vector.

Falciparum malaria is an important cause of acute symptomatic seizures in children admitted to hospitals in sub-Saharan Africa, and these seizures are associated with neurological disabilities and epilepsy.,However, it is difficult to determine the proportion of seizures attributable to malaria in endemic areas since a significant proportion of asymptomatic children have malaria parasitaemia.,We studied children aged 0-13 years who had been admitted with a history of seizures to a rural Kenyan hospital between 2002 and 2008.,We examined the changes in the incidence of seizures with the reduction of malaria.,Logistic regression was used to model malaria-attributable fractions for seizures (the proportion of seizures caused by malaria) to determine if the observed decrease in acute symptomatic seizures was a measure of seizures that are attributable to malaria.,The overall incidence of acute symptomatic seizures over the period was 651/100 000/year (95% confidence interval 632-670) and it was 400/100 000/year (95% confidence interval 385-415) for acute complex symptomatic seizures (convulsive status epilepticus, repetitive or focal) and 163/100 000/year (95% confidence interval 154-173) for febrile seizures.,From 2002 to 2008, the incidence of all acute symptomatic seizures decreased by 809/100 000/year (69.2%) with 93.1% of this decrease in malaria-associated seizures.,The decrease in the incidence of acute complex symptomatic seizures during the period was 111/100 000/year (57.2%) for convulsive status epilepticus, 440/100 000/year (73.7%) for repetitive seizures and 153/100 000/year (80.5%) for focal seizures.,The adjusted malaria-attributable fractions for seizures with parasitaemia were 92.9% (95% confidence interval 90.4-95.1%) for all acute symptomatic seizures, 92.9% (95% confidence interval 89.4-95.5%) for convulsive status epilepticus, 93.6% (95% confidence interval 90.9-95.9%) for repetitive seizures and 91.8% (95% confidence interval 85.6-95.5%) for focal seizures.,The adjusted malaria-attributable fractions for seizures in children above 6 months of age decreased with age.,The observed decrease in all acute symptomatic seizures (809/100 000/year) was similar to the predicted decline (794/100 000/year) estimated by malaria-attributable fractions at the beginning of the study.,In endemic areas, falciparum malaria is the most common cause of seizures and the risk for seizures in malaria decreases with age.,The reduction in malaria has decreased the burden of seizures that are attributable to malaria and this could lead to reduced neurological disabilities and epilepsy in the area.

Cerebral malaria, a disorder characterised by coma, parasitaemia, and no other evident cause of coma, is challenging to diagnose definitively in endemic regions that have high rates of asymptomatic parasitaemia and limited neurodiagnostic facilities.,A recently described malaria retinopathy improves diagnostic specificity.,We aimed to establish whether retinopathy-positive cerebral malaria is a risk factor for epilepsy or other neurodisabilities.,Between 2005 and 2007, we did a prospective cohort study of survivors of cerebral malaria with malaria retinopathy in Blantyre, Malawi.,Children with cerebral malaria were identified at the time of their index admission and age-matched to concurrently admitted children without coma or nervous system infection.,Initially matching of cases to controls was 1:1 but, in 2006, enrolment criteria for cerebral malaria survivors were revised to limit inclusion to children with cerebral malaria and retinopathy on the basis of indirect ophthalmoscopic examination; matching was then changed to 1:2 and the revised inclusion criteria were applied retrospectively for children enrolled previously.,Clinical assessments at discharge and standardised nurse-led follow-up every 3 months thereafter were done to identify children with new seizure disorders or other neurodisabilities.,A Kaplan-Meier survival analysis was done for incident epilepsy.,132 children with retinopathy-positive cerebral malaria and 264 age-matched, non-comatose controls were followed up for a median of 495 days (IQR 195-819). 12 of 132 cerebral malaria survivors developed epilepsy versus none of 264 controls (odds ratio [OR] undefined; p<0·0001). 28 of 121 cerebral malaria survivors developed new neurodisabilities, characterised by gross motor, sensory, or language deficits, compared with two of 253 controls (OR 37·8, 95% CI 8·8-161·8; p<0·0001).,The risk factors for epilepsy in children with cerebral malaria were a higher maximum temperature (39·4°C [SD 1·2] vs 38·5°C [1·1]; p=0·01) and acute seizures (11/12 vs 76/120; OR 6·37, 95% CI 1·02-141·2), and male sex was a risk factor for new neurodisabilities (20/28 vs 38/93; OR 3·62, 1·44-9·06).,Almost a third of retinopathy-positive cerebral malaria survivors developed epilepsy or other neurobehavioural sequelae.,Neuroprotective clinical trials aimed at managing hyperpyrexia and optimising seizure control are warranted.,US National Institutes of Health and Wellcome Trust.

Cutaneous leishmaniasis causes a high disease burden in Colombia, and available treatments present systemic toxicity, low patient compliance, contraindications, and high costs.,The purpose of this study was to estimate the cost-effectiveness of thermotherapy versus Glucantime in patients with cutaneous leishmaniasis in Colombia.,Cost-effectiveness study from an institutional perspective in 8133 incident cases.,Data on therapeutic efficacy and safety were included, calculating standard costs; the outcomes were disability adjusted life years (DALYs) and the number of patients cured.,The information sources were the Colombian Public Health Surveillance System, disease burden studies, and one meta-analysis of controlled clinical trials.,Incremental cost-effectiveness was determined, and uncertainty was evaluated with tornado diagrams and Monte Carlo simulations.,Thermotherapy would generate costs of US$ 501,621; the handling of adverse effects, US$ 29,224; and therapeutic failures, US$ 300,053.,For Glucantime, these costs would be US$ 2,731,276, US$ 58,254, and US$ 406,298, respectively.,With thermotherapy, the cost would be US$ 2062 per DALY averted and US$ 69 per patient cured; with Glucantime, the cost would be US$ 4241 per DALY averted and US$ 85 per patient cured.,In Monte Carlo simulations, thermotherapy was the dominant strategy for DALYs averted in 67.9% of cases and highly cost-effective for patients cured in 72%.,In Colombia, thermotherapy can be included as a cost-effective strategy for the management of cutaneous leishmaniasis.,Its incorporation into clinical practice guidelines could represent savings of approximately US$ 10,488 per DALY averted and costs of US$ 116 per additional patient cured, compared to the use of Glucantime.,These findings show the relevance of the incorporation of this treatment in our country and others with similar parasitological, clinical, and epidemiological patterns.

Historically, the target in the schistosomiasis control has shifted from infection to morbidity, then back to infection, but now as a public health problem, before moving on to transmission control.,Currently, all endemic countries are encouraged to increase control efforts and move towards elimination as required by the World Health Organization (WHO) roadmap for the global control of the neglected tropical diseases (NTDs) and the WHA65.21 resolution issued by the World Health Assembly.,However, schistosomiasis prevalence is still alarmingly high and the global number of disability-adjusted life years (DALYs) due to this infection has in fact increased due to inclusion of some ‘subtle’ clinical symptoms not previously counted.,There is a need to restart and improve efforts to reach the elimination goal.,To that end, the first conference of the Global Schistosomiasis Alliance (GSA) Research Working Group was held in mid-June 2016 in Shanghai, People’s Republic of China.,It reviewed current progress in schistosomiasis control and elimination, identified pressing operational research gaps that need to be addressed and discussed new tools and strategies required to make elimination a reality.,The articles emanating from the lectures and discussions during this meeting, together with some additional invited papers, have been collected as a special issue of the ‘Infectious Diseases of Poverty’ entitled ‘Schistosomiasis Research: Providing the Tools Needed for Elimination’, consisting of 26 papers in all.,This paper refers to these papers and discusses critical questions arising at the conference related to elimination of schistosomiasis.,The currently most burning questions are the following: Can schistosomiasis be eliminated?,Does it require better, more highly sensitive diagnostics?,What is the role of preventive chemotherapy at the elimination stage?,Is praziquantel sufficient or do we need new drugs?,Contemplating these questions, it is felt that the heterogeneity of the endemic areas in the world requires WHO policies to be upgraded instituting new, differentiated guidelines.,The online version of this article (doi: 10.1186/s40249-017-0370-7) contains supplementary material, which is available to authorized users.

Earth observation (EO) is the use of remote sensing and in situ observations to gather data on the environment.,It finds increasing application in the study of environmentally modulated neglected tropical diseases (NTDs).,Obtaining and assuring the quality of the relevant spatially and temporally indexed EO data remain challenges.,Our objective was to review the Earth observation products currently used in studies of NTD epidemiology and to discuss fundamental issues relating to spatial data quality (SDQ), which limit the utilization of EO and pose challenges for its more effective use.,We searched Web of Science and PubMed for studies related to EO and echinococossis, leptospirosis, schistosomiasis, and soil-transmitted helminth infections.,Relevant literature was also identified from the bibliographies of those papers.,We found that extensive use is made of EO products in the study of NTD epidemiology; however, the quality of these products is usually given little explicit attention.,We review key issues in SDQ concerning spatial and temporal scale, uncertainty, and the documentation and use of quality information.,We give examples of how these issues may interact with uncertainty in NTD data to affect the output of an epidemiological analysis.,We conclude that researchers should give careful attention to SDQ when designing NTD spatial-epidemiological studies.,This should be used to inform uncertainty analysis in the epidemiological study.,SDQ should be documented and made available to other researchers.

Until 2009, the Laverania subgenus counted only two representatives: Plasmodium falciparum and Plasmodium reichenowi.,The recent development of non-invasive methods allowed re-exploration of plasmodial diversity in African apes.,Although a large number of great ape populations have now been studied regarding Plasmodium infections in Africa, there are still vast areas of their distribution that remained unexplored.,Gabon constitutes an important part of the range of western central African great ape subspecies (Pan troglodytes troglodytes and Gorilla gorilla gorilla), but has not been studied so far.,In the present study, the diversity of Plasmodium species circulating in great apes in Gabon was analysed.,The analysis of 1,261 faecal samples from 791 chimpanzees and 470 gorillas collected from 24 sites all over Gabon was performed.,Plasmodium infections were characterized by amplification and sequencing of a portion of the Plasmodium cytochrome b gene.,The analysis of the 1,261 samples revealed that at least six Plasmodium species circulate in great apes in Gabon (Plasmodium praefalciparum, Plasmodium gorA (syn Plasmodium adleri), Plasmodium gorB (syn Plasmodium blacklocki) in gorillas and Plasmodium gaboni, P. reichenowi and Plasmodium billcollinsi in chimpanzees).,No new phylogenetic lineages were discovered.,The average infection rate was 21.3% for gorillas and 15.4% for chimpanzees.,A logistic regression showed that the probability of infection was significantly dependent on the freshness of the droppings but not of the host species or of the average pluviometry of the months of collection.

The interleukin 32 (IL-32) is a proinflammatory cytokine produced by immune and non-immune cells.,It can be induced during bacterial and viral infections, but its production was never investigated in protozoan infections.,American Tegumentary Leishmaniasis (ATL) is caused by Leishmania protozoan leading to cutaneous, nasal or oral lesions.,The aim of this study was to evaluate the expression of IL-32 in cutaneous and mucosal lesions as well as in peripheral blood mononuclear cells (PBMC) exposed to Leishmania (Viannia) braziliensis.,IL-32, tumour necrosis factor (TNF) and IL-10 protein expression was evaluated by immunohistochemistry in cutaneous, mucosal lesions and compared to healthy specimens.,The isoforms of IL-32α, β, δ, γ mRNA, TNF mRNA and IL-10 mRNA were assessed by qPCR in tissue biopsies of lesions and healthy skin and mucosa.,In addition, PBMC from healthy donors were cultured with amastigotes of L.,(V.) braziliensis.,In lesions, the parasite subgenus was identified by PCR-RFLP.,We showed that the mRNA expression of IL-32, in particular IL-32γ was similarly up-regulated in lesions of cutaneous (CL) or mucosal (ML) leishmaniasis patients.,IL-32 protein was produced by epithelial, endothelial, mononuclear cells and giant cells.,The IL-32 protein expression was associated with TNF in ML but not in CL.,IL-32 was not associated with IL-10 in both CL and ML.,Expression of TNF mRNA was higher in ML than in CL lesions, however levels of IL-10 mRNA were similar in both clinical forms.,In all lesions in which the parasite was detected, L.,(Viannia) subgenus was identified.,Interestingly, L.,(V.) braziliensis induced only IL-32γ mRNA expression in PBMC from healthy individuals.,These data suggest that IL-32 plays a major role in the inflammatory process caused by L.,(Viannia) sp or that IL-32 is crucial for controlling the L.,(Viannia) sp infection.

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.

Trichinellosis is a meat-borne zoonotic disease caused by parasites of the genus Trichinella.,To date, 12 taxa have been described.,The identification of Trichinella species is crucial in order to identify the possible source of infection, the geographical origin of the parasite and to assess risk of infection for domestic pigs and humans.,Specific identification of the etiological agent is not always feasible using direct methods since the source of infection can be untraceable.,The aim of this study was to develop a diagnostic tool to infer the causative Trichinella species using western blot patterns of sera derived from infected animal and human hosts.,Sera from mice experimentally infected with Trichinella spiralis, Trichinella britovi, Trichinella pseudospiralis and Trichinella papuae were tested by western blot using homologous and heterologous crude worm extracts (CWE) and a highly sensitive detection system based on chemiluminescence.,In addition, sera from pigs experimentally infected with T. spiralis, T. britovi and T. pseudospiralis and from patients with confirmed T. spiralis, T. britovi and T. pseudospiralis infections, were also included.,Sera from mice infected with one Trichinella species reacted with CWE proteins from all four investigated species.,Likewise, sera derived from pigs and humans infected with one Trichinella species reacted with CWE proteins from all the three investigated species.,Using T. spiralis CWE, sera from T. pseudospiralis-infected hosts yielded a characteristic pattern of reactivity using Wb, which differed to that produced by T. spiralis/T. britovi- or T. papuae-infected host sera.,The present study suggests that western blot using T. spiralis CWE may be a useful tool to distinguish Trichinella infections caused by T. pseudospiralis from those caused by T. spiralis or T. britovi.,This method may support epidemiological investigations, particularly when the source of infection is not traceable.,The online version of this article (10.1186/s13071-018-3244-3) contains supplementary material, which is available to authorized users.

Trichinellosis is one of the most serious foodborne parasitic zoonosis with worldwide distribution, and it is necessary to develop a vaccine to interrupt transmission from animals to humans.,Trichinella spiralis adult-specific DNase II-1 (TsDNase II) were identified by immunoproteomics in surface or excretory/secretory proteins of adult worms (AW) and intestinal infective larvae (IIL).,The aim of this study was to investigate the systemic, mucosal responses and immune protection elicited by oral vaccination with TsDNase II DNA vaccine delivered by attenuated Salmonella typhimurium strain⊿cyaSL1344.,Oral vaccination with TsDNase II DNA vaccine triggered an obvious mucosal sIgA response and a systemic IgG response in mice, and IgG1 was predominant.,Th1 (IFN-γ) and Th2 (IL-4, 10) cytokines were distinctly increased in the spleen and mesenteric lymph node (MLN) cells of vaccinated mice.,An indirect immunofluorescent test revealed that native TsDNase II is present at the cuticle of this nematode after the 2nd molting, further confirming that TsDNase II is adult-specific and expressed at AW and pre-adult stages.,Oral immunization of mice with TsDNase II exhibited a 53.85% reduction in AW and a 59.26% reduction in ML after larval challenge.,The in vitro NBL production of adult females from TsDNase II-vaccinated mice was also reduced in comparison with pcDNA3.1 or the PBS control group (P < 0.01).,Our results show that oral immunization of mice with TsDNase II produced an intestinal and systematic concurrent Th1/Th2 immune response, and a significant immune protection against challenge.,The online version of this article (10.1186/s13567-018-0614-y) contains supplementary material, which is available to authorized users.

The majority of Plasmodium falciparum malaria diagnoses in Africa are made using rapid diagnostic tests (RDTs) that detect histidine-rich protein 2.,Increasing reports of false-negative RDT results due to parasites with deletions of the pfhrp2 and/or pfhrp3 genes (pfhrp2/3) raise concern about existing malaria diagnostic strategies.,We previously identified pfhrp2-negative parasites among asymptomatic children in the Democratic Republic of the Congo (DRC), but their impact on diagnosis of symptomatic malaria is unknown.,We performed a cross-sectional study of false-negative RDTs in symptomatic subjects in 2017.,Parasites were characterized by microscopy; RDT; pfhrp2/3 genotyping and species-specific PCR assays; a bead-based immunoassay for Plasmodium antigens; and/or whole-genome sequencing.,Among 3627 symptomatic subjects, 427 (11.8%) had RDT-/microscopy + results.,Parasites from eight (0.2%) samples were initially classified as putative pfhrp2/3 deletions by PCR, but antigen testing and whole-genome sequencing confirmed the presence of intact genes.,56.8% of subjects had PCR-confirmed malaria.,Non-falciparum co-infection with P. falciparum was common (13.2%).,Agreement between PCR and HRP2-based RDTs was satisfactory (Cohen’s kappa = 0.66) and superior to microscopy (0.33).,Symptomatic malaria due to pfhrp2/3-deleted P. falciparum was not observed.,Ongoing HRP2-based RDT use is appropriate for the detection of falciparum malaria in the DRC.

An accurate diagnosis is essential for the rapid and appropriate treatment of malaria.,The accuracy of the histidine-rich protein 2 (PfHRP2)-based rapid diagnostic test (RDT) Palutop+4® was assessed here.,One possible factor contributing to the failure to detect malaria by this test is the diversity of the parasite PfHRP2 antigens.,PfHRP2 detection with the Palutop+4® RDT was carried out.,The pfhrp2 and pfhrp3 genes were amplified and sequenced from 136 isolates of Plasmodium falciparum that were collected in Dakar, Senegal from 2009 to 2011.,The DNA sequences were determined and statistical analyses of the variation observed between these two genes were conducted.,The potential impact of PfHRP2 and PfHRP3 sequence variation on malaria diagnosis was examined.,Seven P. falciparum isolates (5.9% of the total isolates, regardless of the parasitaemia; 10.7% of the isolates with parasitaemia ≤0.005% or ≤250 parasites/μl) were undetected by the PfHRP2 Palutop+4® RDT.,Low parasite density is not sufficient to explain the PfHRP2 detection failure.,Three of these seven samples showed pfhrp2 deletion (2.4%).,The pfhrp3 gene was deleted in 12.8%.,Of the 122 PfHRP2 sequences, 120 unique sequences were identified.,Of the 109 PfHRP3 sequences, 64 unique sequences were identified.,Using the Baker’s regression model, at least 7.4% of the P. falciparum isolates in Dakar were likely to be undetected by PfHRP2 at a parasite density of ≤250 parasites/μl (slightly lower than the evaluated prevalence of 10.7%).,This predictive prevalence increased significantly between 2009 and 2011 (P = 0.0046).,In the present work, 10.7% of the isolates with a parasitaemia ≤0.005% (≤250 parasites/μl) were undetected by the PfHRP2 Palutop+4® RDT (7.4% by the predictive Baker’model).,In addition, all of the parasites with pfhrp2 deletion (2.4% of the total samples) and 2.1% of the parasites with parasitaemia >0.005% and presence of pfhrp2 were not detected by PfHRP2 RDT.,PfHRP2 is highly polymorphic in Senegal.,Efforts should be made to more accurately determine the prevalence of non-sensitive parasites to pfHRP2.

The automated haematology analyzer XN-30 (Sysmex, Kobe, Japan) easily and rapidly detects malarial parasites in clinical blood samples using flow cytometry.,The XN-30 analyzer is able to distinguish each developmental stage by measuring DNA content and cell size.,Thus, it was expected to be capable of quantifying the developmental stages of cultured falciparum parasite.,To achieve this requirement, a modified algorithm was tested for its validity and reliability using in vitro cultured falciparum parasite.,The XN-30 analyzer automatically measured each developmental stage as well as total parasitaemia.,Comparison of the parasitaemia obtained using the XN-30 analyzer equipped with the modified algorithm with that obtained using microscopy examination of Giemsa-stained smears revealed the greater sensitivity and reproducibility of the former.,The XN-30 analyzer also detected free merozoites and purified gametocytes.,The XN-30 analyzer allows the precise recognition and enumeration of total and each developmental stages of cultured falciparum parasites, and permits the sensitive and reproducible calculation of parasitaemia.,The results indicate the potential of the XN-30 analyzer for basic research on malarial biology, anti-malarial drug discovery, and evaluation of drug efficacy.,The online version of this article (10.1186/s12936-018-2208-6) contains supplementary material, which is available to authorized users.

The transmission of malaria by blood transfusion was one of the first recorded incidents of transfusion-transmitted infections (TTIs).,Although the World Health Organization (WHO) recommends that blood for transfusion should be screened for TTIs, malaria screening is not performed in most malaria-endemic countries in sub-Saharan Africa (SSA).,The transfusion of infected red blood cells may lead to severe post-transfusion clinical manifestations of malaria, which could be rapidly fatal.,Ensuring that blood supply in endemic countries is free from malaria is highly problematical, as most of the donors may potentially harbour low levels of malaria parasites.,Pre-transfusion screening within endemic settings has been identified as a cost-effective option for prevention of transfusion-transmitted malaria (TTM).,But currently, there is no screening method that is practical, affordable and suitably sensitive for use by blood banks in SSA.,Even if this method was available, rejection of malaria-positive donors would considerably jeopardize the blood supply and increase morbidity and mortality, especially among pregnant women and children who top the scale of blood transfusion users in SSA.,In this context, the systematic prophylaxis of recipients with anti-malarials could constitute a good alternative, as it prevents any deferral of donor units as well as the occurrence of TTM.,With the on-going programme, namely the Affordable Medicine Facility - Malaria, there is an increase in the availability of low-priced artemisinin-based combination therapy that can be used for systematic prophylaxis.,It appears nonetheless an urgent need to conduct cost-benefit studies in order to evaluate each of the TTM preventive methods.,This approach could permit the design and implementation of an evidence-based measure of TTM prevention in SSA, advocating thereby its widespread use in the region.

Border malaria, a shared phenomenon in the Greater Mekong Sub-region of Southeast Asia, is a major obstacle for regional malaria elimination.,Along the China-Myanmar border, an additional problem arose as a result of the settlement of internally displaced people (IDP) in the border region.,Since asymptomatic malaria significantly impacts transmission dynamics, assessment of the prevalence, dynamics and risk factors of asymptomatic malaria infections is necessary.,Cross-sectional surveys were carried out in 3 seasons (March and April, July and November) and 2 sites (villages and IDP camps) in 2015.,A total of 1680 finger-prick blood samples were collected and used for parasite detection by microscopy and nested RT-PCR (nRT-PCR).,Logistic regression models were used to explore the risk factors associated with asymptomatic malaria at individual and household levels.,The prevalence of asymptomatic Plasmodium infections was 23.3% by nRT-PCR, significantly higher than that detected by microscopy (1.5%).,The proportions of Plasmodium vivax, Plasmodium falciparum and mixed-species infections were 89.6, 8.1 and 2.3%, respectively.,Asymptomatic infections showed obvious seasonality with higher prevalence in the rainy season.,Logistic regression analysis identified males and school children (≤ 15 years) as the high-risk populations.,Vector-based interventions, including bed net and indoor residual spray, were found to have significant impacts on asymptomatic Plasmodium infections, with non-users of these measures carrying much higher risks of infection.,In addition, individuals living in poorly constructed households or farther away from clinics were more prone to asymptomatic infections.,Sub-microscopic Plasmodium infections were highly prevalent in the border human populations from IDP camps and surrounding villages.,Both individual- and household-level risk factors were identified, which provides useful information for identifying the high-priority populations to implement targeted malaria control.

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

Natural immunity to Plasmodium falciparum has been widely studied, but its effects on parasite dynamics are poorly understood.,Acquisition and clearance rates of untreated infections are key elements of the dynamics of malaria, but estimating these parameters is challenging because of frequent super-infection and imperfect detectability of parasites.,Consequently, information on effects of host immune status or age on infection dynamics is fragmentary.,An age-stratified cohort of 347 individuals from Northern Ghana was sampled six times at 2 month intervals.,High-throughput capillary electrophoresis was used to genotype the msp-2 locus of all P. falciparum infections detected by PCR.,Force of infection (FOI) and duration were estimated for each age group using an immigration-death model that allows for imperfect detection of circulating parasites.,Allowing for imperfect detection substantially increased estimates of FOI and duration.,Effects of naturally acquired immunity on the FOI and duration would be reflected in age dependence in these indices, but in our cohort data FOI tended to increase with age in children.,Persistence of individual parasite clones was characteristic of all age-groups.,Duration peaked in 5-9 year old children (average duration 319 days, 95% confidence interval 318;320).,The main age-dependence is on parasite densities, with only small age-variations in the FOI and persistence of infections.,This supports the hypothesis that acquired immunity controls transmission mainly by limiting blood-stage parasite densities rather than changing rates of acquisition or clearance of infections.

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

It has been suggested recently, based on pharmacokinetic-pharmacodynamic modelling exercises, that twice daily dosing of artemisinins increases malaria parasite killing and so could “dramatically enhance and restore drug effectiveness” in artemisinin resistant P. falciparum malaria infections.,It was recommended that split dosing should be incorporated into all artemisinin combination regimen designs.,To explain why parasite clearance rates were not faster with split dose regimens it was concluded that splenic malaria parasite clearance capacity was readily exceeded, resulting in the accumulation of dead parasites in the circulation, that parasite clearance was therefore an unreliable measure of drug efficacy, and instead that human immunity is the primary determinant of clearance rates.,To test these various hypotheses we performed a logistic meta-regression analysis of cure rates from all falciparum malaria treatment trials (n = 40) with monotherapy arms containing artemisinin or a derivative (76 arms).,There was no evidence that split dosing enhanced cure rates.

Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug.,Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined.,Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network.,Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ.,Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001) were significant independent risk factors for recrudescence in patients treated with AL.,AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1.,Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.

Implementation of malaria control strategies may face major social and cultural challenges.,Hence, understanding local knowledge about malaria helps in designing sustainable community-based malaria control programmes.,We designed a pilot survey in communities in the Central African Republic to evaluate recognition of malaria symptoms, perceptions of the causes of malaria and knowledge of key preventive measures.,This cross-sectional study was conducted in four districts.,Households were selected by multi-stage cluster random sampling, with villages (in Lobaye, Ouham and Ouaka) and boroughs (in Bangui City) as first-stage units and households as second-stage units.,A total of 2920 householders were interviewed.,Most of the respondents attributed malaria to mosquito bites (65.5%), but less than 50% were familiar with the classical symptoms of malaria.,Hygiene and sanitation were the most frequently mentioned methods for preventing malaria (81.1%).,Despite the relatively high rate of ownership of insecticide-treated nets (72.1%), community perception of these nets as a preventive measure against mosquito bites was very low (6.5%).,The correct perceptions that mosquitoes cause malaria transmission and of environmental management for prevention are encouraging; however, awareness about the usefulness of insecticide treated-nets for malaria prevention must be raised.,This study provided the national malaria control programme with baseline data for planning appropriate health education in communities.

Ethiopia has a long history of controlling malaria using vector control tools.,Community knowledge and perceptions of malaria and use of malaria vector control interventions vary.,The aim of this study was to determine malaria-related knowledge and perceptions among women and to determine the use of malaria vector control interventions, mainly indoor residual spraying (IRS) and insecticide-treated nets (ITNs), among households in Kersa, Eastern Ethiopia.,A cross-sectional survey was conducted in Kersa Demographic Surveillance and Health Research Center (KDS-HRC) site from October to November 2010.,A total of 2,867 households were involved in the study.,The data was collected via face-to-face interviews with the women of the household using a pre-tested questionnaire.,The questionnaire contained closed, semiclosed, and open-ended questions to explore the reasons for non-use of the interventions.,Each knowledge, perception, and practice question was analyzed separately.,Of the total women, 2,463 (85.9%) had heard of malaria.,Of them, 1,413 (57.4%) mentioned malaria as a communicable disease.,But, only 793 (56.1%) of them associated mosquito bites with malaria transmission.,Seven hundred and ninety-eight of the respondents (27.8%) had IRS coverage, and of these, 59 (7.4%) had re-plastered their interior walls following the application of insecticides.,Of net-owning households, 33.5% had used at least one long-lasting insecticide-treated net (LLIN) the night before the survey.,Societal reasons such as holy days and dislike of the insecticide mainly due to fear of its effects on their livestock, were the main reasons for re-spondents replastering their walls.,A substantial number of women had heard about malaria, but there was a knowledge gap regarding the route of malaria transmission.,Less than one-third of the surveyed household houses were sprayed with insecticides, and a low proportion of net-owning households actually used their nets.,Efforts must be made to ensure the correct channeling of information about malaria, particularly regarding the importance of using malaria vector control interventions.,Furthermore, to maximize the benefit of the intervention in the district, IRC coverage and LLIN use need to be stronger.

Antimalarial chemotherapy, globally reliant on artemisinin-based combination therapies (ACTs), is threatened by the spread of drug resistance in Plasmodium falciparum parasites.,Here we use zinc-finger nucleases to genetically modify the multidrug resistance-1 transporter PfMDR1 at amino acids 86 and 184, and demonstrate that the widely prevalent N86Y mutation augments resistance to the ACT partner drug amodiaquine and the former first-line agent chloroquine.,In contrast, N86Y increases parasite susceptibility to the partner drugs lumefantrine and mefloquine, and the active artemisinin metabolite dihydroartemisinin.,The PfMDR1 N86 plus Y184F isoform moderately reduces piperaquine potency in strains expressing an Asian/African variant of the chloroquine resistance transporter PfCRT.,Mutations in both digestive vacuole-resident transporters are thought to differentially regulate ACT drug interactions with host haem, a product of parasite-mediated haemoglobin degradation.,Global mapping of these mutations illustrates where the different ACTs could be selectively deployed to optimize treatment based on regional differences in PfMDR1 haplotypes.,Antimalarial chemotherapy relies on combination therapies (ACTs) consisting of an artemisinin derivative and a partner drug.,Here, the authors study the effects of globally prevalent mutations in a multidrug resistance transporter (PfMDR1) on the parasite's susceptibility to ACT drugs.

The efficacy of artemisinin-based combination therapy (ACT) for Plasmodium falciparum malaria may be threatened by parasites with reduced responsiveness to artemisinins.,Among 298 ACT-treated children from Mbita, Kenya, submicroscopic persistence of P. falciparum on day 3 posttreatment was associated with subsequent microscopically detected parasitemia at days 28 or 42.,DNA sequences of resistance-associated parasite loci pfcrt, pfmdr1, pfubp1, and pfap2mu were determined in the Mbita cohort before treatment, on days 2 and 3 after initiation of treatment, and on the day of treatment failure.,Parasites surviving ACT on day 2 or day 3 posttreatment were significantly more likely than the baseline population to carry the wild-type haplotypes of pfcrt (CVMNK at codons 72-76; P < .001) and pfmdr1 (NFD at codons 86, 184, 1246; P < .001).,In contrast, variant alleles of the novel candidate resistance genes pfap2mu (S160N/T; P = .006) and pfubp-1 (E1528D; P < .001) were significantly more prevalent posttreatment.,No genetic similarities were found to artemisinin-tolerant parasites recently described in Cambodia.,Among treated children in western Kenya, certain P. falciparum genotypes defined at pfcrt, pfmdr1, pfap2mu, and pfubp1 more often survive ACT at the submicroscopic level, and contribute to onward transmission and subsequent patent recrudescence.

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.

Recognising the burden helminth infections impose on human populations, and particularly the poor, major intervention programmes have been launched to control onchocerciasis, lymphatic filariasis, soil-transmitted helminthiases, schistosomiasis, and cysticercosis.,The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps.,A summary of current helminth control initiatives is presented and available tools are described.,Most of these programmes are highly dependent on mass drug administration (MDA) of anthelmintic drugs (donated or available at low cost) and require annual or biannual treatment of large numbers of at-risk populations, over prolonged periods of time.,The continuation of prolonged MDA with a limited number of anthelmintics greatly increases the probability that drug resistance will develop, which would raise serious problems for continuation of control and the achievement of elimination.,Most initiatives have focussed on a single type of helminth infection, but recognition of co-endemicity and polyparasitism is leading to more integration of control.,An understanding of the implications of control integration for implementation, treatment coverage, combination of pharmaceuticals, and monitoring is needed.,To achieve the goals of morbidity reduction or elimination of infection, novel tools need to be developed, including more efficacious drugs, vaccines, and/or antivectorial agents, new diagnostics for infection and assessment of drug efficacy, and markers for possible anthelmintic resistance.,In addition, there is a need for the development of new formulations of some existing anthelmintics (e.g., paediatric formulations).,To achieve ultimate elimination of helminth parasites, treatments for the above mentioned helminthiases, and for taeniasis and food-borne trematodiases, will need to be integrated with monitoring, education, sanitation, access to health services, and where appropriate, vector control or reduction of the parasite reservoir in alternative hosts.,Based on an analysis of current knowledge gaps and identification of priorities, a research and development agenda for intervention tools considered necessary for control and elimination of human helminthiases is presented, and the challenges to be confronted are discussed.

Antimalarial resistance is rapidly spreading across parts of southeast Asia where dihydroartemisinin-piperaquine is used as first-line treatment for Plasmodium falciparum malaria.,The first published reports about resistance to antimalarial drugs came from western Cambodia in 2013.,Here, we analyse genetic changes in the P falciparum population of western Cambodia in the 6 years before those reports.,We analysed genome sequence data on 1492 P falciparum samples from 11 locations across southeast Asia, including 464 samples collected in western Cambodia between 2007 and 2013.,Different epidemiological origins of resistance were identified by haplotypic analysis of the kelch13 artemisinin resistance locus and the plasmepsin 2-3 piperaquine resistance locus.,We identified more than 30 independent origins of artemisinin resistance, of which the KEL1 lineage accounted for 140 (91%) of 154 parasites resistant to dihydroartemisinin-piperaquine.,In 2008, KEL1 combined with PLA1, the major lineage associated with piperaquine resistance.,By 2013, the KEL1/PLA1 co-lineage had reached a frequency of 63% (24/38) in western Cambodia and had spread to northern Cambodia.,The KEL1/PLA1 co-lineage emerged in the same year that dihydroartemisinin-piperaquine became the first-line antimalarial drug in western Cambodia and spread rapidly thereafter, displacing other artemisinin-resistant parasite lineages.,These findings have important implications for management of the global health risk associated with the current outbreak of multidrug-resistant malaria in southeast Asia.,Wellcome Trust, Bill & Melinda Gates Foundation, Medical Research Council, UK Department for International Development, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases.

Recent progress in malaria control has caused renewed interest in mass drug administration (MDA) as a potential elimination strategy but the evidence base is limited.,China has extensive experience with MDA, but it is not well documented.,An ecological study was conducted to describe the use of MDA for the control and elimination of Plasmodium vivax in Jiangsu Province and explore the association between MDA and malaria incidence.,Two periods were focused on: 1973 to 1983 when malaria burden was high and MDA administered to highly endemic counties province-wide, and 2000 to 2009, when malaria burden was low and a focal approach was used in two counties.,All available data about the strategies implemented, MDA coverage, co-interventions, incidence, and adverse events were collected and described.,Joinpoint analysis was used to describe trends in incidence and the relationship between MDA coverage and incidence was explored in negative binomial regression models.,From 1973 to 1983, MDA with pyrimethamine and primaquine was used on a large scale, with up to 30 million people in target counties covered in a peak year (50% of the total population).,Joinpoint analyses identified declines in annual incidence, -56.7% (95% CI -75.5 to -23.7%) from 1973-1976 and -12.4% (95% CI -24.7 to 2.0%) from 1976-1983.,Population average negative binomial models identified a relationship between higher total population MDA coverage and lower monthly incidence from 1973-1976, IRR 0.98 (95% CI 0.97 to 1.00), while co-interventions, rainfall and GDP were not associated.,From 2000-2009, incidence in two counties declined (annual change -43.7 to -14.0%) during a time when focal MDA using chloroquine and primaquine was targeted to villages and/or individuals residing near passively detected index cases (median 0.04% of total population).,Although safety data were not collected systematically, there were rare reports of serious but non-fatal events.,In Jiangsu Province, China, large-scale MDA was implemented and associated with declines in high P. vivax malaria transmission; a more recent focal approach may have contributed to interruption of transmission.,MDA should be considered a potential key strategy for malaria control and elimination.

Plasmodium knowlesi poses a health threat throughout Southeast Asian communities and currently causes most cases of malaria in Malaysia.,This zoonotic parasite species has been studied in Macaca mulatta (rhesus monkeys) as a model for severe malarial infections, chronicity, and antigenic variation.,The phenomenon of Plasmodium antigenic variation was first recognized during rhesus monkey infections.,Plasmodium-encoded variant proteins were first discovered in this species and found to be expressed at the surface of infected erythrocytes, and then named the Schizont-Infected Cell Agglutination (SICA) antigens.,SICA expression was shown to be spleen dependent, as SICA expression is lost after P. knowlesi is passaged in splenectomized rhesus.,Here we present data from longitudinal P. knowlesi infections in rhesus with the most comprehensive analysis to date of clinical parameters and infected red blood cell sequestration in the vasculature of tissues from 22 organs.,Based on the histopathological analysis of 22 tissue types from 11 rhesus monkeys, we show a comparative distribution of parasitized erythrocytes and the degree of margination of the infected erythrocytes with the endothelium.,Interestingly, there was a significantly higher burden of parasites in the gastrointestinal tissues, and extensive margination of the parasites along the endothelium, which may help explain gastrointestinal symptoms frequently reported by patients with P. knowlesi malarial infections.,Moreover, this margination was not observed in splenectomized rhesus that were infected with parasites not expressing the SICA proteins.,This work provides data that directly supports the view that a subpopulation of P. knowlesi parasites cytoadheres and sequesters, likely via SICA variant antigens acting as ligands.,This process is akin to the cytoadhesive function of the related variant antigen proteins, namely Erythrocyte Membrane Protein-1, expressed by Plasmodium falciparum.

Pedro Alonso and colleagues introduce the Malaria Eradication Research Agenda (malERA) initiative and the set of articles published in this PLoS Medicine Supplement that distill the research questions key to malaria eradication.,The interruption of malaria transmission worldwide is one of the greatest challenges for international health and development communities.,The current expert view suggests that, by aggressively scaling up control with currently available tools and strategies, much greater gains could be achieved against malaria, including elimination from a number of countries and regions; however, even with maximal effort we will fall short of global eradication.,The Malaria Eradication Research Agenda (malERA) complements the current research agenda-primarily directed towards reducing morbidity and mortality-with one that aims to identify key knowledge gaps and define the strategies and tools that will result in reducing the basic reproduction rate to less than 1, with the ultimate aim of eradication of the parasite from the human population.,Sustained commitment from local communities, civil society, policy leaders, and the scientific community, together with a massive effort to build a strong base of researchers from the endemic areas will be critical factors in the success of this new agenda.

Apart from its direct impact on public health and well-being, malaria had placed significant socioeconomic burden on both individuals and whole health systems.,This study was conducted to investigate the hospitalization cost of malaria and explore the inter-province variation during the National Malaria Elimination Programme in China.,Information on medical expenditure for malaria treatment was extracted from inpatient medical records in Henan, Hainan and Guangxi Province.,The costs were adjusted to the price in 2014 and converted to USD (United States Dollars).,Non-parametric and parametric methods were employed to estimate hospitalization costs and non-parametric bootstrap method was used for the comparison of hospitalization costs among sample provinces and to estimate the uncertainty of differences in inter-province hospitalization costs.,The hospitalization cost and daily cost of 426 malaria inpatients were 929.8 USD and 143.12 USD respectively.,The average length of stay was 11.95 days.,The highest cost of hospitalization services occurred in tertiary hospitals (956 USD per episode).,Whereas the lowest ones occurred in internal departments (424 USD).,Medications, laboratory tests and supportive resources for treatment were the most important components of hospitalization costs, respectively responsible for 45.31, 24.70, and 20.09% of the total hospitalization costs.,The hospitalization cost per episode in Henan Province was significantly higher than that in Hainan an in Guangxi Province, with incremental costs of 713 USD (95% confidence interval 419.70, 942.50) and of 735.58 USD (95% CI 606.50, 878.00), respectively.,The differences in the daily costs between Henan and Hainan along with Guangxi provinces were 75.33 USD (95% CI 40.33, 96.67) and 93.56 USD (95% CI 83.58, 105.28), respectively.,Although the prevalence of malaria cases has considerably declined, the direct hospitalization costs of malaria in the household remain high and the inter-province variations need to be seriously considered in the formulation the further interventions regarding hospitalization cost control.,This study suggests that economic risk protection mechanisms targeting at malaria inpatients should be redesigned.,The drug price addition policy in public hospitals should be gradually reformed or abolished coupling with increasing government subsidies along with the charges for treatment services to reduce the hospitalization cost.,The policy for cost control in the provincial hospitals should be implemented in comparison with the policy in other provinces, where the status of economic and geography are similar.

The current roll-out of rapid diagnostic tests (RDTs) in many endemic countries has resulted in the reporting of fewer cases of malaria-attributed illnesses.,However, lack of knowledge of the prevalence of other febrile illnesses and affordable diagnostic tests means that febrile patients are not managed optimally.,This study assessed the prevalence of commonly treatable or preventable febrile illnesses in children between 6 months and 15 years using rapid diagnostic tests at the point-of-care.,Febrile children were enrolled between February-April 2014 at a health facility after obtaining informed consent from parent.,Eligible participants were aged 6 months-15 years with a history of fever in the last 24 h or axillary temperature ≥38 °C at consultation.,All participants were tested using RDTs for malaria, typhoid, toxoplasmosis and rubella.,Malaria parasites were further identified by microscopy and PCR.,Clinical and household characteristics were recorded and association with pathogens determined.,Of the 315 children enrolled, the mean age was 5.8 ± 3.8 years.,Stomach pain (41.2 %) was the most reported symptom.,Prior to attending the health facility, 70.8 % had taken antipyretics, 27.9 % antimalarials, 11.4 % antibiotics and 13.3 % antifungal drugs.,Among 315 children with fever, based on RDTs, 56.8 % were infected with malaria, 4.4 % with typhoid, 3.2 % with acute toxoplasmosis, and 1.3 % with rubella (all positive for rubella were in the same family and not vaccinated).,All non-malarial infections were co-infections and approximately 30 % of the fever cases went un-diagnosed.,Malaria prevalence by microscopy and PCR was 43.4 and 70.2 % respectively.,The sensitivity and specificity of RDTs for the diagnosis of malaria were 75.98 and 100 % respectively, with 0.73 measurement agreement between RDTs and microscopy while that of RDT and PCR were 81 and 100 % respectively with a K value of 0.72.,The use of Insecticide Treated Bednets was 44 %.,There was a significant association between ITN non-usage and malaria (p = 0. 029) as well as drinking water and presence of typhoid (p = 0.047).,No association was observed between type of housing and malaria, or toxoplasmosis and raising cats.,Though malaria still remains the major cause of fever in children, using RDTs for other treatable febrile illnesses like typhoid and toxoplasmosis could facilitate the optimal management of febrile illnesses in children especially when these occur as co-infections with malaria,The online version of this article (doi:10.1186/s12879-016-1996-y) contains supplementary material, which is available to authorized users.

The immune response during falciparum malaria mediates both harmful and protective effects on the host; however the participating molecules have not been fully defined.,Interleukin (IL)-27 is a pleiotropic cytokine exerting both inflammatory and anti-inflammatory effects, but data on IL-27 in malaria patients are scarce.,Clinical data and blood samples were collected from adults in Mozambique with P. falciparum infection, with (n = 70) and without (n = 61) HIV-1 co-infection, from HIV-infected patients with similar symptoms without malaria (n = 58) and from healthy controls (n = 52).,In vitro studies were performed in endothelial cells and PBMC using hemozoin crystals.,Samples were analyzed using enzyme immunoassays and quantitative PCR.,(i) IL-27 was markedly up-regulated in malaria patients compared with controls and HIV-infected patients without malaria, showing no relation to HIV co-infection. (ii) IL-27 was correlated with P. falciparum parasitemia and von Willebrand factor as a marker of endothelial activation, but not with disease severity. (iii) In vitro, IL-27 modulated the hemozoin-mediated cytokine response in endothelial cells and PBMC with enhancing effects on IL-6 and attenuating effects on IL-8.,Our findings show that IL-27 is regulated during falciparum malaria, mediating both inflammatory and anti-inflammatory effects, potentially playing an immune-regulatory role during falciparum malaria.

Malaria causes hepatic inflammation and damage, which contribute to disease severity.,The pro-inflammatory cytokine interleukin (IL)-1α is released by non-hematopoietic or hematopoietic cells during liver injury.,This study established the role of IL-1α in the liver pathology caused by blood-stage P. chabaudi malaria.,During acute infection, hepatic inflammation and necrosis were accompanied by NLRP3 inflammasome-independent IL-1α production.,Systemically, IL-1α deficiency attenuated weight loss and hypothermia but had minor effects on parasitemia control.,In the liver, the absence of IL-1α reduced the number of TUNEL+ cells and necrotic lesions.,This finding was associated with a lower inflammatory response, including TNF-α production.,The main source of IL-1α in the liver of infected mice was inflammatory cells, particularly neutrophils.,The implication of IL-1α in liver inflammation and necrosis caused by P. chabaudi infection, as well as in weight loss and hypothermia, opens up new perspectives for improving malaria outcomes by inhibiting IL-1 signaling.

Visceral leishmaniasis (VL) causes significant mortality and morbidity in many parts of the world.,There is an urgent need for the development of new, effective treatments for this disease.,We describe the development of a novel anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold.,The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of VL, has suitable physicochemical, pharmacokinetic and toxicological properties for further development and has been declared a preclinical candidate.,Detailed mode of action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a novel, druggable, target for VL.

Chagas disease, leishmaniasis, and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually1.,The diseases are caused by infection with the kinetoplastid parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., respectively.,These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drug(s) modulating the activity of a conserved parasite target2.,However, no such molecular targets or broad spectrum drugs have been identified to date.,Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection.,GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice.,Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases.

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

Visceral Leishmaniasis (VL) is a vector-borne disease transmitted by Phlebotomus argentipes.,To understand the VL seasonality, annual and monthly variations of VL incidence and its relationship to meteorological variables, the numbers of VL cases reported in Muzaffarpur district, Bihar, India from 1990 to 2008 were studied.,Annual VL incidence per 10,000 and the total number of annual VL cases reported at block Community Health Centres (CHC), Public Hospitals or Non-Governmental Organisations (NGO) and the number of VL cases per month from 2000 to 2008 as well as the monthly average of cases for 2000-08, 2000-04 and 2005-08 periods along with the monthly averages of temperature, rainfall and relative humidity were plotted.,VL Standardised Incidence Ratios per block were computed for the periods of 1990-1993, 1994-1998, 1999-2004 and 2005-2008 and month wise from 2002 to 2008.,A negative binomial regression model was used to evaluate the association between meteorological variables and the number of VL cases per month from 2000 to 2008.,A total of 68,358 VL cases were reported in Muzaffarpur district from 1990 to 2008, ranging from 1,2481 in 1992 to 1,161 in 2001.,The blocks with the highest number of cases shifted from East (1990-98) to West (1999-2008).,Monthly averages of cases ranged from 149 to 309, highest peak in March-April and another one in July.,Monthly VL incidence was associated positively to rainfall and negatively to relative humidity and the numbers of VL cases in the previous month.,The number of cases reported to the public health sector allowed the describing of the spatial distribution and temporal variations in the Muzaffarpur from 1990 to 2008.,However, to assess the actual VL burden, as well as the efficacy of the control measures applied in the district, reporting from private practices and NGOs should be encouraged.

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

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

In China, the prevalence of malaria has reduced dramatically due to the elimination programme.,The continued success of the programme will depend upon the accurate diagnosis of the disease in the laboratory.,The basic requirements for this are a reliable malaria diagnosis laboratory network and quality management system to support case verification and source tracking.,The baseline information of provincial malaria laboratories in the China malaria diagnosis reference laboratory network was collected and analysed, and a quality-assurance activity was carried out to assess their accuracies in malaria diagnosis by microscopy using WHO standards and PCR.,By the end of 2013, nineteen of 24 provincial laboratories have been included in the network.,In the study, a total of 168 staff were registered and there was no bias in their age, gender, education level, and position.,Generally Plasmodium species were identified with great accuracy by microscopy and PCR.,However, Plasmodium ovale was likely to be misdiagnosed as Plasmodium vivax by microscopy.,China has established a laboratory network for primary malaria diagnosis which will cover a larger area.,Currently, Plasmodium species can be identified fairly accurately by microscopy and PCR.,However, laboratory staff need additional trainings on accurate identification of P. ovale microscopically and good performance of PCR operations.

Primaquine is the only drug available for preventing relapse following a primary attack by Plasmodium vivax malaria.,This drug imposes several important problems: daily dosing over two weeks; toxicity in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency; partner blood schizontocides possibly impacting primaquine safety and efficacy; cytochrome P-450 abnormalities impairing metabolism and therapeutic activity; and some strains of parasite may be tolerant or resistant to primaquine.,There are many possible causes of repeated relapses in a patient treated with primaquine.,A 56-year-old Caucasian woman from New Zealand traveled to New Ireland, Papua New Guinea for two months in 2012.,One month after returning home she stopped daily doxycycline prophylaxis against malaria, and one week later she became acutely ill and hospitalized with a diagnosis of Plasmodium vivax malaria.,Over the ensuing year she suffered four more attacks of vivax malaria at approximately two-months intervals despite consuming primaquine daily for 14 days after each of those attacks, except the last.,Genotype of the patient’s cytochrome P-450 2D6 alleles (*5/*41) corresponded with an intermediate metabolizer phenotype of predicted low activity.,Multiple relapses in patients taking primaquine as prescribed present a serious clinical problem, and understanding the basis of repeated therapeutic failure is a challenging technical problem.,This case highlights these issues in a single traveler, but these problems will also arise as endemic nations approach elimination of malaria transmission.

Globally, hookworms infect 440 million people in developing countries.,Especially children and women of childbearing age are at risk of developing anaemia as a result of infection.,To control hookworm infection and disease (i.e. reduce the prevalence of medium and heavy infection to <1 %), the World Health Organization has set the target to provide annual or semi-annual preventive chemotherapy (PC) with albendazole (ALB) or mebendazole (MEB) to at least 75 % of all children and women of childbearing age in endemic areas by 2020.,Here, we predict the feasibility of achieving <1 % prevalence of medium and heavy infection, based on simulations with an individual-based model.,We developed WORMSIM, a new generalized individual-based modelling framework for transmission and control of helminths, and quantified it for hookworm transmission based on published data.,We simulated the impact of standard and more intense PC strategies on trends in hookworm infection, and explored the potential additional impact of interventions that improve access to water, sanitation, and hygiene (WASH).,The individual-based framework allowed us to take account of inter-individual heterogeneities in exposure and contribution to transmission of infection, as well as in participation in successive PC rounds.,We predict that in low and medium endemic areas, current PC strategies (including targeting of WCBA) will achieve control of hookworm infection (i.e. the parasitological target) within 2 years.,In highly endemic areas, control can be achieved with semi-annual PC with ALB at 90 % coverage, combined with interventions that reduce host contributions to the environmental reservoir of infection by 50 %.,More intense PC strategies (high frequency and coverage) can help speed up control of hookworm infection, and may be necessary in some extremely highly endemic settings, but are not a panacea against systematic non-participation to PC.,Control of hookworm infection by 2020 is feasible with current PC strategies (including targeting of WCBA).,In highly endemic areas, PC should be combined with health education and/or WASH interventions.,The online version of this article (doi:10.1186/s13071-015-1151-4) contains supplementary material, which is available to authorized users.

Traditional methods using microscopy for the detection of helminth infections have limited sensitivity.,Polymerase chain reaction (PCR) assays enhance detection of helminths, particularly low burden infections.,However, differences in test performance may modify the ability to detect associations between helminth infection, risk factors, and sequelae.,We compared these associations using microscopy and PCR.,This cross-sectional study was nested within a randomized clinical trial conducted at 3 sites in Kenya.,We performed microscopy and real-time multiplex PCR for the stool detection and quantification of Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale, Strongyloides stercoralis, and Schistosoma species.,We utilized regression to evaluate associations between potential risk factors or outcomes and infection as detected by either method.,Of 153 HIV-positive adults surveyed, 55(36.0%) and 20(13.1%) were positive for one or more helminth species by PCR and microscopy, respectively (p<0.001).,PCR-detected infections were associated with farming (Prevalence Ratio 1.57, 95% CI: 1.02, 2.40), communal water source (PR 3.80, 95% CI: 1.01, 14.27), and no primary education (PR 1.54, 95% CI: 1.14, 2.33), whereas microscopy-detected infections were not associated with any risk factors under investigation.,Microscopy-detected infections were associated with significantly lower hematocrit and hemoglobin (means of -3.56% and -0.77 g/dl) and a 48% higher risk of anemia (PR 1.48, 95% CI: 1.17, 1.88) compared to uninfected.,Such associations were absent for PCR-detected infections unless infection intensity was considered, Infections diagnosed with either method were associated with increased risk of eosinophilia (PCR PR 2.42, 95% CI: 1.02, 5.76; microscopy PR 2.92, 95% CI: 1.29, 6.60).,Newer diagnostic methods, including PCR, improve the detection of helminth infections.,This heightened sensitivity may improve the identification of risk factors for infection while reducing ability to discriminate infections associated with adverse clinical outcomes.,Quantitative assays can be used to differentiate infection loads and discriminate infections associated with sequelae.

Malaria and cryptosporidiosis are major burdens to both global health and economic development in many countries.,Malaria caused >400,000 deaths in 2017, and cryptosporidiosis is estimated to cause >200,000 deaths a year.,The spread of drug resistance is a growing concern for malaria treatment, and there is no effective treatment for malnourished or immunocompromised children infected with Cryptosporidium.,New treatments with novel mechanisms of action are needed for both diseases.,We present a selective inhibitor of both Plasmodium and Cryptosporidium lysyl-tRNA synthetase capable of clearing parasites from mouse models of malaria and cryptosporidiosis infection.,This provides very strong validation of lysyl-tRNA synthetase as a drug target in these organisms and a lead for further drug discovery.,Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality.,New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets.,The natural product cladosporin is active against blood- and liver-stage Plasmodium falciparum and Cryptosporidium parvum in cell-culture studies.,Target deconvolution in P. falciparum has shown that cladosporin inhibits lysyl-tRNA synthetase (PfKRS1).,Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs.,Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both PfKRS1 and C. parvum KRS (CpKRS).,In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED90 = 1.5 mg/kg, once a day for 4 d).,Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between PfKRS1 and CpKRS.,This series of compounds inhibit CpKRS and C. parvum and Cryptosporidium hominis in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models.,X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for PfKRS1 and CpKRS vs. (human) HsKRS.,Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.

Such isolates should undergo drug susceptibility testing periodically to detect emerging resistance.,Nitroimidazoles (metronidazole and tinidazole) are the only recommended drugs for treating Trichomonas vaginalis infection, and previous samples that assessed resistance of such isolates have been limited in geographic scope.,We assessed the prevalence of in vitro aerobic metronidazole and tinidazole resistance among T. vaginalis isolates from multiple geographic sites in the United States.,Swab specimens were obtained from women who underwent routine pelvic examinations at sexually transmitted disease clinics in 6 US cities.,Cultured T. vaginalis isolates were tested for nitroimidazole resistance (aerobic minimum lethal concentration [MLC] >50 µg/mL).,Of 538 T. vaginalis isolates, 23 (4.3%) exhibited low-level in vitro metronidazole resistance (minimum lethal concentrations 50-100 µg/mL).,No isolates exhibited moderate- to high-level metronidazole resistance or tinidazole resistance.,Results highlight the possibility that reliance on a single class of antimicrobial drugs for treating T. vaginalis infections may heighten vulnerability to emergence of resistance.,Thus, novel treatment options are needed.

Mass drug administration of praziquantel is the World Health Organization’s endorsed control strategy for schistosomiasis.,A decade of annual treatments across sub-Saharan Africa has resulted in significant reductions of infection prevalence and intensity levels, although ‘hotspots’ remain.,Repeated drug treatments place strong selective pressures on parasites, which may affect life-history traits that impact transmission dynamics.,Understanding drug treatment responses and the evolution of such traits can help inform on how to minimise the risk of drug resistance developing, maximise sustainable control programme success, and improve diagnostic protocols.,We performed a four-generation Schistosoma mansoni praziquantel selection experiment in mice and snails.,We used three S. mansoni lines: a praziquantel-resistant isolate (R), a praziquantel-susceptible isolate (S), and a co-infected line (RS), under three treatment regimens: untreated, 25 mg/kg praziquantel, or 50 mg/kg praziquantel.,Life-history traits, including parasite adult-worm establishment, survival, reproduction (fecundity), and associated morbidity, were recorded in mice across all four generations.,Predictor variables were tested in a series of generalized linear mixed effects models to determine which factors had a significant influence on parasite life-history traits in definitive hosts under different selection regimes.,Praziquantel pressure significantly reduced adult-worm burdens across all generations and isolates, including within R-lines.,However, previous drug treatment resulted in an increase in adult-worm establishment with increasing generation from P1 to F3.,The highest worm numbers were in the co-infected RS line.,Praziquantel treatment decreased adult-worm burden, but had a larger negative impact on the mean daily number of miracidia, a proxy for fecundity, across all three parasite isolates.,Our predicted cost of resistance was not supported by the traits we measured within the murine host.,We did not find evidence for negative adult worm density-dependent effects on fecundity.,In contrast, of the adult worms that survived treatment, even low doses of praziquantel significantly reduced adult-worm fecundity.,Such reductions in worm fecundity post treatment suggest that egg - based measures of drug efficacy, such as Kato-Katz, may overestimate the short-term effect of praziquantel on adult - worm burdens.,These findings have important implications for S. mansoni transmission control, diagnostic protocols, and the potential for undetected selection toward drug resistance.,The online version of this article (doi:10.1186/s40249-017-0324-0) contains supplementary material, which is available to authorized users.

Recent evidence indicates that pre-school children (PSC) living in S. mansoni highly endemic areas are at similar risk of schistosomiasis infection and morbidity as their school aged siblings.,Recognizing this fact, the World Health Organization (WHO) is considering including this age group in highly endemic areas in control programmes using mass drug administration (MDA).,However, detailed epidemiological information on S. mansoni infection among PSC is lacking for many endemic areas, specifically in Tanzania.,This study was conducted to determine the prevalence of S. mansoni infection and its associated risk factors among PSC in Ukerewe Island, North-Western Tanzania.,This was a cross-sectional study, which studied 400 PSC aged 1-6 years.,The Kato-Katz (K-K) technique and the point of care circulating cathodic antigen (CCA) immunodiagnostic test were used to diagnose S. mansoni infection in stool and urine samples respectively.,A pre-tested questionnaire was used to collect demographic data and water contact behaviour of the children from their parents/guardians.,Based on the K-K technique, 44.4 % (95 % CI: 39.4-49.4) pre-school children were infected with S. mansoni and the overall geometric mean eggs per gram of faeces (GM-epg) was 110.6 epg with 38.2 and 14.7 % having moderate and heavy intensity infections respectively.,Based on the CCA, 80.1 %, (95 % CI: 76.0-84.0) were infected if a trace was considered positive, and 45.9 %, (95 % CI: 40.9-50.9), were infected if a trace was considered negative.,Reported history of lake visits (AOR = 2.31, 95 % CI: 1.06-5.01, P < 0.03) and the proximity to the lake shore (<500 m) (AOR = 2.09, 95 % CI: 1.05-4.14, P < 0.03) were significantly associated with S. mansoni infection.,Reported lake visit frequency (4-7 days/week) was associated with heavy intensities of S. mansoni infection (P < 0.00).,The prevalence of S. mansoni infection in the study population using K-K and CCA-trace-negative was moderate.,The frequency of lake visits and the proximity to the lake shore were associated with the infection of S. mansoni and its intensity.,These findings call for the need to include the PSC in MDA programmes, public health education and provision of safe water for bathing.

Malaria remains an important public health problem in Peru where incidence has been increasing since 2011.,Of over 55,000 cases reported in 2017, Plasmodium vivax was the predominant species (76%), with P. falciparum responsible for the remaining 24%.,Nyssorhynchus darlingi (previously Anopheles darlingi) is the main vector in Amazonian Peru, where hyperendemic Plasmodium transmission pockets have been found.,Mazán district has pronounced spatial heterogeneity of P. vivax malaria.,However, little is known about behavior, ecology or seasonal dynamics of Ny. darlingi in Mazán.,This study aimed to gather baseline information about bionomics of malaria vectors and transmission risk factors in a hyperendemic malaria area of Amazonian Peru.,To assess vector biology metrics, five surveys (two in the dry and three in the rainy season), including collection of sociodemographic information, were conducted in four communities in 2016-2017 on the Napo (Urco Miraño, URC; Salvador, SAL) and Mazán Rivers (Visto Bueno, VIB; Libertad, LIB).,Human-biting rate (HBR), entomological inoculation rate (EIR) and human blood index (HBI) were measured to test the hypothesis of differences in entomological indices of Ny. darlingi between watersheds.,A generalized linear mixed effect model (GLMM) was constructed to model the relationship between household risk factors and the EIR.,Nyssorhynchus darlingi comprised 95% of 7117 Anophelinae collected and its abundance was significantly higher along the Mazán River.,The highest EIRs (3.03-4.54) were detected in March and June in URC, LIB and VIB, and significantly more Ny. darlingi were infected outdoors than indoors.,Multivariate analysis indicated that the EIR was >12 times higher in URC compared with SAL.,The HBI ranged from 0.42-0.75; humans were the most common blood source, followed by Galliformes and cows.,There were dramatic differences in peak biting time and malaria incidence with similar bednet coverage in the villages.,Nyssorhynchus darlingi is the predominant contributor to malaria transmission in the Mazán District, Peru.,Malaria risk in these villages is higher in the peridomestic area, with pronounced heterogeneities between and within villages on the Mazán and the Napo Rivers.,Spatiotemporal identification and quantification of the prevailing malaria transmission would provide new evidence to orient specific control measures for vulnerable or at high risk populations.,The online version of this article (10.1186/s13071-019-3619-0) contains supplementary material, which is available to authorized users.

A substantial proportion of Plasmodium species infections are asymptomatic with densities too low to be detectable with standard diagnostic techniques.,The importance of such asymptomatic plasmodium infections in malaria transmission is probably related to their duration and density.,To explore the duration of asymptomatic plasmodium infections and changes in parasite densities over time, a cohort of participants who were infected with Plasmodium parasites was observed over a 2-year follow-up period.,In this open cohort study, inhabitants of four villages in Vietnam were invited to participate in baseline and subsequent 3-monthly surveys up to 24 months, which included the collection of venous blood samples.,Samples were batch-screened using ultra-sensitive (u)PCR (lower limit of detection of 22 parasites per mL).,Participants found to be infected by uPCR during any of these surveys were invited to join a prospective cohort and provide monthly blood samples.,We estimated the persistence of Plasmodium falciparum and Plasmodium vivax infections and changes in parasite densities over a study period of 24 months.,Between Dec 1, 2013, and Jan 8, 2016, 356 villagers participated in between one and 22 surveys.,These study participants underwent 4248 uPCR evaluations (11·9 tests per participant). 1874 (32%) of 4248 uPCR tests indicated a plasmodium infection; 679 (36%) of 1874 tests were P falciparum monoinfections, 507 (27%) were P vivax monoinfections, 463 (25%) were co-infections with P falciparum and P vivax, and 225 (12%) were indeterminate species of Plasmodium.,The median duration of P falciparum infection was 2 months (IQR 1-3); after accounting for censoring, participants had a 20% chance of having parasitaemia for 4 months or longer.,The median duration of P vivax infection was 6 months (3-9), and participants had a 59% chance of having parasitaemia for 4 months or longer.,The parasite densities of persistent infections oscillated; following ultralow-density infections, high-density infections developed frequently.,Persistent largely asymptomatic P vivax and P falciparum infections are common in this area of low seasonal malaria transmission.,Infections with low-density parasitaemias can develop into much higher density infections at a later time, which are likely to sustain malaria endemicity.,The Wellcome Trust, Bill & Melinda Gates Foundation.

Accurate detection of filarial parasites in humans is essential for the implementation and evaluation of mass drug administration programs to control onchocerciasis and lymphatic filariasis.,Determining the infection levels in vector populations is also important for assessing transmission, deciding when drug treatments may be terminated and for monitoring recrudescence.,Immunological methods to detect infection in humans are available, however, cross-reactivity issues have been reported.,Nucleic acid-based molecular assays offer high levels of specificity and sensitivity, and can be used to detect infection in both humans and vectors.,In this study we developed loop-mediated isothermal amplification (LAMP) tests to detect three different filarial DNAs in human and insect samples using pH sensitive dyes for enhanced visual detection of amplification.,Furthermore, reactions were performed in a portable, non-instrumented nucleic acid amplification (NINA) device that provides a stable heat source for LAMP.,The efficacy of several strand displacing DNA polymerases were evaluated in combination with neutral red or phenol red dyes.,Colorimetric NINA-LAMP assays targeting Brugia Hha I repeat, Onchocerca volvulus GST1a and Wuchereria bancrofti LDR each exhibit species-specificity and are also highly sensitive, detecting DNA equivalent to 1/10-1/5000th of one microfilaria.,Reaction times varied depending on whether a single copy gene (70 minutes, O. volvulus) or repetitive DNA (40 min, B. malayi and W. bancrofti) was employed as a biomarker.,The NINA heater can be used to detect multiple infections simultaneously.,The accuracy, simplicity and versatility of the technology suggests that colorimetric NINA-LAMP assays are ideally suited for monitoring the success of filariasis control programs.

Loa loa infections have emerged as a serious public health problem in patients co-infected with Onchocerca volvulus or Wuchereria bancrofti because of severe adverse neurological reactions after treatment with ivermectin.,Accurate diagnostic tests are needed for careful mapping in regions where mass drug administration is underway.,Loop-mediated isothermal amplification (LAMP) has become a widely adopted screening method because of its operational simplicity, rapidity and versatility of visual detection readout options.,Here, we present a multi-step bioinformatic pipeline to generate diagnostic candidates suitable for LAMP and experimentally validate this approach using one of the identified candidates to develop a species-specific LAMP assay for L. loa.,The pipeline identified ~140 new L. loa specific DNA repeat families as putative biomarkers of infection.,The consensus sequence of one family, repeat family 4 (RF4), was compiled from ~ 350 sequences dispersed throughout the L. loa genome and maps to a L. loa-specific region of the long terminal repeats found at the boundaries of Bel/Pao retrotransposons.,PCR and LAMP primer sets targeting RF4 specifically amplified L. loa but not W. bancrofti, O. volvulus, Brugia malayi, human or mosquito DNA.,RF4 LAMP detects the DNA equivalent of one microfilaria (100 pg) in 25-30 minutes and as little as 0.060 pg of L. loa DNA (~1/1600th of a microfilaria) purified from spiked blood samples in approximately 50 minutes.,In summary, we have successfully employed a bioinformatic approach to mine the L. loa genome for species-specific repeat families that can serve as new DNA biomarkers for LAMP.,The RF4 LAMP assay shows promise as a field tool for the implementation and management of mass drug administration programs and warrants further testing on clinical samples as the next stage in development towards this goal.

Malaria is the number one public health problem in Nigeria, responsible for about 30% of deaths in under-fives and 25% of deaths in infants and 11% maternal mortality.,This study estimated the economic burden of malaria in Nigeria using the cost of illness approach.,A cross-sectional study was undertaken in two malaria holo-endemic communities in Nigeria, involving both community and hospital based surveys.,A random sample of 500 households was interviewed using interviewer administered questionnaire.,In addition, 125 exit interviews for inpatient department stays (IPD) and outpatient department visits (OPD) were conducted and these were complemented with data abstraction from 125 patient records.,From the household survey, over half of the households (57.6%) had an episode of malaria within one month to the date of the interview.,The average household expenditure per case was 12.57US$ and 23.20US$ for OPD and IPD respectively.,Indirect consumer costs of treatment were higher than direct consumer medical costs.,From a health system perspective, the recurrent provider costs per case was 30.42 US$ and 48.02 US$ for OPD and IPD while non recurrent provider costs were 133.07US$ and 1857.15US$ for OPD and IPD.,The mode of payment was mainly through out-of-pocket spending (OOPS).,Private expenditure on treatment of malaria constitutes a high economic burden to households and to the health system.,Removal of user fees and interventions that will decrease the use of OOPS for treatment of malaria will significantly decrease the economic burden of malaria to both households and the health system.

Agricultural practices such as the use of irrigation during rice cultivation, the use of ponds for fish farming and the storage of water in tanks for livestock provide suitable breeding grounds for anthropophylic mosquitoes.,The most common anthropophylic mosquito in Nigeria which causes much of the morbidity and mortality associated with malaria is the anopheles mosquito.,Farmers are therefore at high risk of malaria - a disease which seriously impacts on agricultural productivity.,Unfortunately information relating to agricultural practices and farmers' behavioural antecedent factors that could assist malaria programmers plan and implement interventions to reduce risk of infections among farmers is scanty.,Farmers' knowledge about malaria and agricultural practices which favour the breeding of mosquitoes in Fashola and Soku, two rural farming communities in Oyo State were therefore assessed in two rural farming communities in Oyo State.,This descriptive cross-sectional study involved the collection of data through the use of eight Focus Group Discussions (FGDs) and the interview of 403 randomly selected farmers using semi-structured questionnaires.,These sets of information were supplemented with observations of agricultural practices made in 40 randomly selected farms.,The FGD data were recorded on audio-tapes, transcribed and subjected to content analysis while the quantitative data were analyzed using descriptive and inferential statistics.,Most respondents in the two communities had low level of knowledge of malaria causation as only 12.4% stated that mosquito bite could transmit the disease.,Less than half (46.7%) correctly mentioned the signs and symptoms of malaria as high body temperature, body pains, headache, body weakness and cold/fever.,The reported main methods for preventing mosquito bites in the farming communities included removal of heaps of cassava tuber peelings (62.3%), bush burning/clearing (54.6%) and clearing of ditches (33.7%).,The dumping of cassava tuber peelings which allows the collection of pools of water in the farms storage of peeled cassava tubers soaked in water in uncovered plastic containers, digging of trenches, irrigation of farms and the presence of fish ponds were the observed major agricultural practices that favoured mosquito breeding on the farms.,A significant association was observed between respondents' knowledge about malaria and agricultural practices which promote mosquito breeding.,Respondents' wealth quintile level was also seen to be associated with respondents' knowledge about malaria and agricultural practices which promote mosquito breeding.,Farmers' knowledge of malaria causation and signs and symptoms was low, while agricultural practices which favour mosquito breeding in the farming communities were common.,There is an urgent need to engage farmers in meaningful dialogue on malaria reduction initiatives including the modification of agricultural practices which favour mosquito breeding.,Multiple intervention strategies are needed to tackle the factors related to malaria prevalence and mosquito abundance in the communities.

Since the turn of the century, a remarkable expansion has been achieved in the range and effectiveness of products and strategies available to prevent, treat, and control malaria, including advances in diagnostics, drugs, vaccines, and vector control.,These advances have once again put malaria elimination on the agenda.,However, it is clear that even with the means available today, malaria control and elimination pose a formidable challenge in many settings.,Thus, currently available resources must be used more effectively, and new products and approaches likely to achieve these goals must be developed.,This paper considers tools (both those available and others that may be required) to achieve and maintain malaria elimination.,New diagnostics are needed to direct treatment and detect transmission potential; new drugs and vaccines to overcome existing resistance and protect against clinical and severe disease, as well as block transmission and prevent relapses; and new vector control measures to overcome insecticide resistance and more powerfully interrupt transmission.,It is also essential that strategies for combining new and existing approaches are developed for different settings to maximise their longevity and effectiveness in areas with continuing transmission and receptivity.,For areas where local elimination has been recently achieved, understanding which measures are needed to maintain elimination is necessary to prevent rebound and the reestablishment of transmission.,This becomes increasingly important as more countries move towards elimination.,David Kaslow and colleagues examine the progress in reasearch for diagnostics, drugs, vaccines, and vector control in malaria elimination and eradication and propose a research agenda.

In Senegal, considerable efforts have been made to reduce malaria morbidity and mortality during the last decade.,This resulted in a marked decrease of malaria cases.,With the decline of malaria cases, transmission has become sparse in most Senegalese health districts.,This study investigated malaria hotspots in Keur Soce sites by using geographically-weighted regression.,Because of the occurrence of hotspots, spatial modelling of malaria cases could have a considerable effect in disease surveillance.,This study explored and analysed the spatial relationships between malaria occurrence and socio-economic and environmental factors in small communities in Keur Soce, Senegal, using 6 months passive surveillance.,Geographically-weighted regression was used to explore the spatial variability of relationships between malaria incidence or persistence and the selected socio-economic, and human predictors.,A model comparison of between ordinary least square and geographically-weighted regression was also explored.,Vector dataset (spatial) of the study area by village levels and statistical data (non-spatial) on malaria confirmed cases, socio-economic status (bed net use), population data (size of the household) and environmental factors (temperature, rain fall) were used in this exploratory analysis.,ArcMap 10.2 and Stata 11 were used to perform malaria hotspots analysis.,From Jun to December, a total of 408 confirmed malaria cases were notified.,The explanatory variables-household size, housing materials, sleeping rooms, sheep and distance to breeding site returned significant t values of −0.25, 2.3, 4.39, 1.25 and 2.36, respectively.,The OLS global model revealed that it explained about 70 % (adjusted R2 = 0.70) of the variation in malaria occurrence with AIC = 756.23.,The geographically-weighted regression of malaria hotspots resulted in coefficient intercept ranging from 1.89 to 6.22 with a median of 3.5.,Large positive values are distributed mainly in the southeast of the district where hotspots are more accurate while low values are mainly found in the centre and in the north.,Geographically-weighted regression and OLS showed important risks factors of malaria hotspots in Keur Soce.,The outputs of such models can be a useful tool to understand occurrence of malaria hotspots in Senegal.,An understanding of geographical variation and determination of the core areas of the disease may provide an explanation regarding possible proximal and distal contributors to malaria elimination in Senegal.

Stage-specific transcription is a fundamental biological process in the life cycle of the Plasmodium parasite.,Proteins containing the AP2 DNA-binding domain are responsible for stage-specific transcriptional regulation and belong to the only known family of transcription factors in Plasmodium parasites.,Comprehensive identification of their target genes will advance our understanding of the molecular basis of stage-specific transcriptional regulation and stage-specific parasite development.,AP2-O is an AP2 family transcription factor that is expressed in the mosquito midgut-invading stage, called the ookinete, and is essential for normal morphogenesis of this stage.,In this study, we identified the genome-wide target genes of AP2-O by chromatin immunoprecipitation-sequencing and elucidate how this AP2 family transcription factor contributes to the formation of this motile stage.,The analysis revealed that AP2-O binds specifically to the upstream genomic regions of more than 500 genes, suggesting that approximately 10% of the parasite genome is directly regulated by AP2-O.,These genes are involved in distinct biological processes such as morphogenesis, locomotion, midgut penetration, protection against mosquito immunity and preparation for subsequent oocyst development.,This direct and global regulation by AP2-O provides a model for gene regulation in Plasmodium parasites and may explain how these parasites manage to control their complex life cycle using a small number of sequence-specific AP2 transcription factors.

Liver-stage malaria parasites are a promising target for drugs and vaccines against malaria infection.,However, little is currently known about gene regulation in this stage.,In this study, we used the rodent malaria parasite Plasmodium berghei and showed that an AP2-family transcription factor, designated AP2-L, plays a critical role in the liver-stage development of the parasite.,AP2-L-depleted parasites proliferated normally in blood and in mosquitoes.,However, the ability of these parasites to infect the liver was approximately 10,000 times lower than that of wild-type parasites.,In vitro assays showed that the sporozoites of these parasites invaded hepatocytes normally but that their development stopped in the middle of the liver schizont stage.,Expression profiling using transgenic P. berghei showed that fluorescent protein-tagged AP2-L increased rapidly during the liver schizont stage but suddenly disappeared with the formation of the mature liver schizont.,DNA microarray analysis showed that the expression of several genes, including those of parasitophorous vacuole membrane proteins, was significantly decreased in the early liver stage of AP2-L-depleted parasites.,Investigation of the targets of this transcription factor should greatly promote the exploration of liver-stage antigens and the elucidation of the mechanisms of hepatocyte infection by malaria parasites.

Burkina Faso belongs to a group of countries in which human African trypanosomiasis (HAT), caused by Trypanosoma brucei gambiense, is no longer considered to be a public health problem.,Although no native cases have been detected since 1993, there is still the risk of HAT re-emergence due to significant population movements between Burkina Faso and active HAT foci in Côte d’Ivoire.,Since 2014, Burkina Faso receives support from the WHO to implement a passive surveillance program.,This resulted in the detection in 2015 of the first putative native HAT case since two decades.,However, epidemiological entomological and molecular biology investigations have not been able to identify with certainty the origin of this infection or to confirm that it was due to T. b. gambiense.,This case emphasises the need to strengthen passive surveillance of the disease for sustained elimination of HAT as a public health problem in Burkina Faso.

Individual rapid tests for serodiagnosis (RDT) of human African trypanosomiasis (HAT) are particularly suited for passive screening and surveillance.,However, so far, no large scale evaluation of RDTs has been performed for diagnosis of Trypanosoma brucei gambiense HAT in West Africa.,The objective of this study was to assess the diagnostic accuracy of 2 commercial HAT-RDTs on stored plasma samples from West Africa.,SD Bioline HAT and HAT Sero-K-Set were performed on 722 plasma samples originating from Guinea and Côte d’Ivoire, including 231 parasitologically confirmed HAT patients, 257 healthy controls, and 234 unconfirmed individuals whose blood tested antibody positive in the card agglutination test but negative by parasitological tests.,Immune trypanolysis was performed as a reference test for trypanosome specific antibody presence.,Sensitivities in HAT patients were respectively 99.6% for SD Bioline HAT, and 99.1% for HAT Sero-K-Set, specificities in healthy controls were respectively 87.9% and 88.3%.,Considering combined positivity in both RDTs, increased the specificity significantly (p≤0.0003) to 93.4%, while 98.7% sensitivity was maintained.,Specificities in controls were 98.7-99.6% for the combination of one or two RDTs with trypanolysis, maintaining a sensitivity of at least 98.1%.,The observed specificity of the single RDTs was relatively low.,Serial application of SD Bioline HAT and HAT Sero-K-Set might offer superior specificity compared to a single RDT, maintaining high sensitivity.,The combination of one or two RDTs with trypanolysis seems promising for HAT surveillance.

Estimating the changing burden of malaria disease remains difficult owing to limitations in health reporting systems.,Here, we use a transmission model incorporating acquisition and loss of immunity to capture age-specific patterns of disease at different transmission intensities.,The model is fitted to age-stratified data from 23 sites in Africa, and we then produce maps and estimates of disease burden.,We estimate that in 2010 there were 252 (95% credible interval: 171-353) million cases of malaria in sub-Saharan Africa that active case finding would detect.,However, only 34% (12-86%) of these cases would be observed through passive case detection.,We estimate that the proportion of all cases of clinical malaria that are in under-fives varies from above 60% at high transmission to below 20% at low transmission.,The focus of some interventions towards young children may need to be reconsidered, and should be informed by the current local transmission intensity.,Reduction in malaria transmission has changed the age pattern of malaria incidence.,This study brings insights into the changes in age distributions of clinical malaria across Africa, with importance for improving within-population targeting of malaria control interventions.

Malaria is almost invariably ranked as the leading cause of morbidity and mortality in Africa.,There is growing evidence of a decline in malaria transmission, morbidity and mortality over the last decades, especially so in East Africa.,However, there is still doubt whether this decline is reflected in a reduction of the proportion of malaria among fevers.,The objective of this systematic review was to estimate the change in the Proportion of Fevers associated with Plasmodium falciparum parasitaemia (PFPf) over the past 20 years in sub-Saharan Africa.,Search strategy.,In December 2009, publications from the National Library of Medicine database were searched using the combination of 16 MeSH terms.,Selection criteria.,Inclusion criteria: studies 1) conducted in sub-Saharan Africa, 2) patients presenting with a syndrome of 'presumptive malaria', 3) numerators (number of parasitologically confirmed cases) and denominators (total number of presumptive malaria cases) available, 4) good quality microscopy.,Data collection and analysis.,The following variables were extracted: parasite presence/absence, total number of patients, age group, year, season, country and setting, clinical inclusion criteria.,To assess the dynamic of PFPf over time, the median PFPf was compared between studies published in the years ≤2000 and > 2000.,39 studies conducted between 1986 and 2007 in 16 different African countries were included in the final analysis.,When comparing data up to year 2000 (24 studies) with those afterwards (15 studies), there was a clear reduction in the median PFPf from 44% (IQR 31-58%; range 7-81%) to 22% (IQR 13-33%; range 2-77%).,This dramatic decline is likely to reflect a true change since stratified analyses including explanatory variables were performed and median PFPfs were always lower after 2000 compared to before.,There was a considerable reduction of the proportion of malaria among fevers over time in Africa.,This decline provides evidence for the policy change from presumptive anti-malarial treatment of all children with fever to laboratory diagnosis and treatment upon result.,This should insure appropriate care of non-malaria fevers and rationale use of anti-malarials.

This study reports an updated description on malaria vector diversity, behaviour, insecticide resistance and malaria transmission in the Diébougou and Dano peri-urban areas, Burkina Faso.,Mosquitoes were caught monthly using CDC light traps and pyrethrum spray catches.,Mosquitoes were identified using morphological taxonomic keys.,PCR techniques were used to identify the species of the Anopheles gambiae complex and insecticide resistance mechanisms in a subset of Anopheles vectors.,The Plasmodium sporozoite infection status and origins of blood meals of female mosquitoes were determined by ELISA methods.,Larvae were collected, breed in the insectary and tested for phenotypic resistance against four insecticides using WHO bioassays.,This study contributed to update the entomological data in two peri-urban areas of Southwest Burkina Faso.,Anopheles populations were mostly anthropophilic and endophilic in both areas and exhibit high susceptibility to an organophosphate insecticide.,This offers an alternative for the control of these pyrethroid-resistant populations.,These data might help the National Malaria Control Programme for decision-making about vector control planning and resistance management.,This study contributed to update the entomological data in two peri-urban areas of Southwest Burkina Faso.,Anopheles populations were mostly anthropophilic and endophilic in both areas and exhibit high susceptibility to an organophosphate insecticide.,This offers an alternative for the control of these pyrethroid-resistant populations.,These data might help the National Malaria Control Programme for decision-making about vector control planning and resistance management.

Screening of houses to prevent mosquito entry is increasingly being recommended as an effective and practical method against malaria transmission through reduced human-mosquito contact.,The objective of the study was to assess community knowledge and perceptions on malaria prevention and house screening in a malaria endemic area of Western Kenya.,A cross-sectional household survey was conducted in 2017 in Nyabondo area of western Kenya.,A total of 80 households were randomly selected to participate in the study within 16 villages.,Structured questionnaires, focus group discussions and key informant interviews were used to collect data.,A total of 80 respondents participated in the survey and more than half (53.8%) reported to have attained primary education.,About 91% of the respondents had previously seen or heard malaria messages and this was associated with the respondents level of education (χ2 = 10.163; df 4; P = 0.038, 95% CI).,However, other variables like gender, marital status, religion and occupation were not significantly associated with knowledge in malaria.,Insecticide treated mosquito nets was by far the most reported known (97.4%) and applied (97.6%) personal protective while only 15.6% respondents were aware of house screening.,The major reason given for screening doors, windows and eaves was to prevent entry of mosquito and other insects (> 85%).,Lack of awareness was the major reason given for not screening houses.,Grey colour was the most preferred choice for screen material (48%), and the main reason given was that grey matched the colour of the walls (21%) and did not ‘gather’ dust quickly.,House screening was not a common intervention for self-protection against malaria vectors in the study area.,There is need to advocate and promote house screening to increase community knowledge on this as an additional integrated vector management strategy for malaria control.,The online version of this article (10.1186/s12889-019-6723-3) contains supplementary material, which is available to authorized users.

The absence of the Duffy protein at the surface of erythrocytes was considered for decades to confer full protection against Plasmodium vivax as this blood group is the receptor for the key parasite ligand P. vivax Duffy binding protein (PvDBP).,However, it is now clear that the parasite is able to break through this protection and induce clinical malaria in Duffy-negative people, although the underlying mechanisms are still not understood.,Here, we briefly review the evidence of Duffy-negative infections by P. vivax and summarize the current hypothesis at the basis of this invasion process.,We discuss those in the perspective of malaria-elimination challenges, notably in African countries.

Blood group variants are characteristic of population groups, and can show conspicuous geographic patterns.,Interest in the global prevalence of the Duffy blood group variants is multidisciplinary, but of particular importance to malariologists due to the resistance generally conferred by the Duffy-negative phenotype against Plasmodium vivax infection.,Here we collate an extensive geo-database of surveys, forming the evidence-base for a multi-locus Bayesian geostatistical model to generate global frequency maps of the common Duffy alleles to refine the global cartography of the common Duffy variants.,We show that the most prevalent allele globally was FY*A, while across sub-Saharan Africa the predominant allele was the silent FY*BES variant, commonly reaching fixation across stretches of the continent.,The maps presented not only represent the first spatially and genetically comprehensive description of variation at this locus, but also constitute an advance towards understanding the transmission patterns of the neglected P. vivax malaria parasite.,The global prevalence of the Duffy blood group variants is important due to the resistance that the Duffy-negative phenotype generally confers upon Plasmodium vivax infection.,Hay et al. generate global frequency maps of the common Duffy alleles to show transmission patterns of the malaria parasite.

In areas where schistosomiasis control programs have been implemented, morbidity and prevalence have been greatly reduced.,However, to sustain these reductions and move towards interruption of transmission, new tools for disease surveillance are needed.,Genomic methods have the potential to help trace the sources of new infections, and allow us to monitor drug resistance.,Large-scale genotyping efforts for schistosome species have been hindered by cost, limited numbers of established target loci, and the small amount of DNA obtained from miracidia, the life stage most readily acquired from humans.,Here, we present a method using next generation sequencing to provide high-resolution genomic data from S. japonicum for population-based studies.,We applied whole genome amplification followed by double digest restriction site associated DNA sequencing (ddRADseq) to individual S. japonicum miracidia preserved on Whatman FTA cards.,We found that we could effectively and consistently survey hundreds of thousands of variants from 10,000 to 30,000 loci from archived miracidia as old as six years.,An analysis of variation from eight miracidia obtained from three hosts in two villages in Sichuan showed clear population structuring by village and host even within this limited sample.,This high-resolution sequencing approach yields three orders of magnitude more information than microsatellite genotyping methods that have been employed over the last decade, creating the potential to answer detailed questions about the sources of human infections and to monitor drug resistance.,Costs per sample range from $50-$200, depending on the amount of sequence information desired, and we expect these costs can be reduced further given continued reductions in sequencing costs, improvement of protocols, and parallelization.,This approach provides new promise for using modern genome-scale sampling to S. japonicum surveillance, and could be applied to other schistosome species and other parasitic helminthes.

Urbanization is increasing across the globe, and diseases once considered rural can now be found in urban areas due to the migration of populations from rural endemic areas, local transmission within the city, or a combination of factors.,We investigated the epidemiologic characteristics of urban immigrants and natives living in a neighborhood of Salvador, Brazil where there is a focus of transmission of Schistosoma mansoni.,In a cross-sectional study, all inhabitants from 3 sections of the community were interviewed and examined.,In order to determine the degree of parasite differentiation between immigrants and the native born, S. mansoni eggs from stools were genotyped for 15 microsatellite markers.,The area received migrants from all over the state, but most infected children had never been outside of the city, and infected snails were present at water contact sites.,Other epidemiologic features suggested immigration contributed little to the presence of infection.,The intensity and prevalence of infection were the same for immigrants and natives when adjusted for age, and length of immigrant residence in the community was positively associated with prevalence of infection.,The population structure of the parasites also supported that the contribution from immigration was small, since the host-to-host differentiation was no greater in the urban parasite population than a rural population with little distant immigration, and there had been little differentiation in the urban population over the past 7 years.,Public health efforts should focus on eliminating local transmission, and once eliminated, reintroduction from distant migration is unlikely.

Plasmodium vivax is considered to be absent from western Africa, where the prevalence of Duffy-negative red blood cell phenotype proves to be high.,Several studies have, however, detected P. vivax infection cases in this part of Africa, raising the question of what is the actual prevalence of P. vivax in local populations.,The presence of P. vivax was investigated in a large population of healthy blood donors in Benin using microscopy, serology and molecular detection.,The seroprevalence was measured with species-specific ELISA using two recombinant P. vivax proteins, namely rPvMSP1 and rPvCSP1.,Specific molecular diagnosis of P. vivax infection was carried out using nested-PCR.,The performances and cut-off values of both rPvCSP1 and rPvMSP1 ELISA were first assessed using sera from P. vivax-infected patients and from non-exposed subjects.,Among 1234 Beninese blood donors, no parasites were detected when using microscopy, whereas 28.7% (354/1234) of patients exhibited had antibodies against rPvMSP1, 21.6% (266/1234) against rPvCSP1, and 15.2% (187/1234) against both.,Eighty-four samples were selected for nested-PCR analyses, of which 13 were positive for P. vivax nested-PCR and all Duffy negative.,The results of the present study highlight an unexpectedly high exposure of Beninese subjects to P. vivax, resulting in sub-microscopic infections.,This suggests a probably underestimated and insidious parasite presence in western Africa.,While the vaccination campaigns and therapeutic efforts are all focused on Plasmodium falciparum, it is also essential to consider the epidemiological impact of P. vivax.,The online version of this article (doi:10.1186/s12936-016-1620-z) contains supplementary material, which is available to authorized users.

A research priority for Plasmodium vivax malaria is to improve our understanding of the spatial distribution of risk and its relationship with the burden of P. vivax disease in human populations.,The aim of the research outlined in this article is to provide a contemporary evidence-based map of the global spatial extent of P. vivax malaria, together with estimates of the human population at risk (PAR) of any level of transmission in 2009.,The most recent P. vivax case-reporting data that could be obtained for all malaria endemic countries were used to classify risk into three classes: malaria free, unstable (<0.1 case per 1,000 people per annum (p.a.)) and stable (≥0.1 case per 1,000 p.a.),P. vivax malaria transmission.,Risk areas were further constrained using temperature and aridity data based upon their relationship with parasite and vector bionomics.,Medical intelligence was used to refine the spatial extent of risk in specific areas where transmission was reported to be absent (e.g., large urban areas and malaria-free islands).,The PAR under each level of transmission was then derived by combining the categorical risk map with a high resolution population surface adjusted to 2009.,The exclusion of large Duffy negative populations in Africa from the PAR totals was achieved using independent modelling of the gene frequency of this genetic trait.,It was estimated that 2.85 billion people were exposed to some risk of P. vivax transmission in 2009, with 57.1% of them living in areas of unstable transmission.,The vast majority (2.59 billion, 91.0%) were located in Central and South East (CSE) Asia, whilst the remainder were located in America (0.16 billion, 5.5%) and in the Africa+ region (0.10 billion, 3.5%).,Despite evidence of ubiquitous risk of P. vivax infection in Africa, the very high prevalence of Duffy negativity throughout Central and West Africa reduced the PAR estimates substantially.,After more than a century of development and control, P. vivax remains more widely distributed than P. falciparum and is a potential cause of morbidity and mortality amongst the 2.85 billion people living at risk of infection, the majority of whom are in the tropical belt of CSE Asia.,The probability of infection is reduced massively across Africa by the frequency of the Duffy negative trait, but transmission does occur on the continent and is a concern for Duffy positive locals and travellers.,The final map provides the spatial limits on which the endemicity of P. vivax transmission can be mapped to support future cartographic-based burden estimations.

Malaria is a major public health issue in much of the world, and the mosquito vectors which drive transmission are key targets for interventions.,Mathematical models for planning malaria eradication benefit from detailed representations of local mosquito populations, their natural dynamics and their response to campaign pressures.,A new model is presented for mosquito population dynamics, effects of weather, and impacts of multiple simultaneous interventions.,This model is then embedded in a large-scale individual-based simulation and results for local elimination of malaria are discussed.,Mosquito population behaviours, such as anthropophily and indoor feeding, are included to study their effect upon the efficacy of vector control-based elimination campaigns.,Results for vector control tools, such as bed nets, indoor spraying, larval control and space spraying, both alone and in combination, are displayed for a single-location simulation with vector species and seasonality characteristic of central Tanzania, varying baseline transmission intensity and vector bionomics.,The sensitivities to habitat type, anthropophily, indoor feeding, and baseline transmission intensity are explored.,The ability to model a spectrum of local vector species with different ecologies and behaviours allows local customization of packages of interventions and exploration of the effect of proposed new tools.

Phase III trials of the malaria vaccine, RTS, S, are now underway across multiple sites of varying transmission intensity in Africa.,Heterogeneity in exposure, vaccine response and waning of efficacy may bias estimates of vaccine efficacy.,Theoretical arguments are used to identify the expected effects of a) heterogeneity in exposure to infectious bites; b) heterogeneity in individual's response to the vaccine; and c) waning efficacy on measures of vaccine efficacy from clinical trials for an infection-blocking vaccine.,Heterogeneity in exposure and vaccine response leads to a smaller proportion of trial participants becoming infected than one would expect in a homogeneous setting.,This causes estimates of vaccine efficacy from clinical trials to be underestimated if transmission heterogeneity is ignored, and overestimated if heterogeneity in vaccine response is ignored.,Waning of vaccine efficacy can bias estimates of vaccine efficacy in both directions.,Failure to account for heterogeneities in exposure and response, and waning of efficacy in clinical trials can lead to biased estimates of malaria vaccine efficacy.,Appropriate methods to reduce these biases need to be used to ensure accurate interpretation and comparability between trial sites of results from the upcoming Phase III clinical trials of RTS, S.

Assays which enable the detection of schistosome gut-associated circulating anodic (CAA) and cathodic (CCA) antigen in serum or urine are increasingly used as a diagnostic tool for schistosome infection.,However, little is known about the production and clearance of these circulating antigens in relation to the sex and reproductive maturity of the parasite.,Here we describe CAA and CCA excretion patterns by exploring a mouse model after exposure to 36 male-only, female-only and mixed (male/female) Schistosoma mansoni cercariae.,We found that serum and urine CAA levels, analysed at 3 weeks intervals, peaked at 6 weeks post-infection.,Worms recovered after perfusion at 14 weeks were cultured ex vivo.,Male parasites excreted more circulating antigens than females, in the mouse model as well as ex vivo.,In mixed infections (supporting egg production), serum CAA levels correlated to the number of recovered worms, whereas faecal egg counts or Schistosoma DNA in stool did not.,No viable eggs and no inflammation were seen in the livers from mice infected with female worms only.,Ex vivo, CAA levels were higher than CCA levels.,Our study confirms that CAA levels reflect worm burden and allows detection of low-level single-sex infections.

We developed a laboratorial platform to release a commercial platform used in the PCR-ELISA for the molecular diagnosis of schistosomiasis mansoni.,On following, PCR-ELISA platform laboratorial was evaluated in 206 feces samples collected of individual living in a Brazilian low endemicity area.,The PCR-ELISA laboratorial platform indicated a prevalence rate of 25.2%, which was higher than the Kato-Katz technique (18.4%) and lower than the commercial platform (30.1%).,Considering Kato-Katz technique as the reference, there were 97.4% and 91.1% of relative sensitivity and specificity rates, respectively.,The laboratorial platform presented good precision, performance diagnostic, and can be used in replacement to the commercial platform for diagnosis of schistosomiasis by PCR-ELISA.,The online version of this article (10.1186/s13104-018-3571-7) contains supplementary material, which is available to authorized users.

Glutathione-S-transferase (GST) is a widespread multigene family of detoxification enzymes.,The vaccination of mice with recombinant GST of 24 kDa from Trichinella spiralis elicited a low immune protection against challenge infection.,The objective of this study was to characterize the T. spiralis putative GST gene (TspGST) encoding a 30.8 kDa protein and to evaluate its potential as a candidate antigen for anti-Trichinella vaccine.,The full-length cDNA sequence of TspGST from T. spiralis muscle larvae (ML) was expressed in E. coli.,The enzymatic activity and antigenicity of the rTspGST were identified by spectrophotometry, Western blot, and ELISA.,The expression of TspGST at T. spiralis various stages was investigated by RT-PCR and indirect immunofluorescent test (IIFT).,Serum level of total IgG, IgG1, and IgG2a antibodies against rTspGST were measured by ELISA.,The immune protection produced by vaccination with rTspGST against T. spiralis was evaluated.,The sequencing results showed that the cDNA of TspGST was 840 bp, and encoded a protein of 279 amino acids, which had a molecular size of 30.8 kDa and a pI of 5.21.,Its amino acid sequence shares 37% similarity with TsGST.,The rTspGST protein had enzymatic activity of GST.,On Western blot and ELISA analysis, the native TspGST protein with 30.8 kDa in crude antigens derived from adult worms (AW), newborn larvae (NBL), infective intestinal larvae (IIL) and ML was recognized by anti-rTspGST sera, but the ML ES antigens could be not recognized by anti-rTspGST sera.,Expression of TspGST was found in all of T. spiralis various stages (AW, NBL, ML, and IIL).,An immunolocalization analysis identified TspGST in different stages (mainly in cuticles) of the nematode.,The mice vaccinated with the rTspGST elicited Th2-predominant immune responses, showed a 34.38% reduction of adult worms and a 43.70% reduction of muscle larvae.,Immunization with rTspGST produced a partial immune protection, and the rTspGST could be regarded as a potential candidate target for an anti-Trichinella vaccine.

Trichinella spiralis is an intracellular parasite that can cause a serious threat to human health by causing trichinellosis.,The aminopeptidase (AP) was found in the proteins produced by T. spiralis infective larvae after in vitro co-culture with intestinal epithelial cells, but its characteristics and function are unknown.,The purpose of this study was to identify the T. spiralis aminopeptidase (TsAP) and to investigate its potential as a vaccine candidate antigen against T. spiralis infection.,T. spiralis aminopeptidase (TsAP) gene encoding a 54.7 kDa protein was cloned and expressed in Escherichia coli, and purified recombinant TsAP protein was used to immunize BALB/c mice.,The antibodies obtained were used to determine where TsAP was localized in the parasite.,Transcription and expression of TsAP in different developmental stages of T. spiralis were observed by RT-PCR and Immunofluorescence test (IFT).,The immune protection of recombinant TsAP protein against T. spiralis infection in BALB/c mice was evaluated.,Anti-TsAP antibodies recognized the native protein migrating at 54.7 kDa by Western blotting of the crude antigens from muscle larvae.,Transcription and expression of TsAP gene was observed in different developmental stages (adult worms, newborn larvae, pre-encapsulated larvae and muscle larvae).,TsAP appears to be a cytoplasmic protein located primarily at the cuticle and internal organs of this parasite.,After a challenge infection with T. spiralis infective larvae, mice immunized with the recombinant TsAP protein displayed a 38.1% reduction in adult worm burden and 59.1% reduction in muscle larval burden.,In this study, T. spiralis aminopeptidase (TsAP) was first characterized and will help reveal its potential biological functions.,TsAP is a novel potential vaccine candidate antigen that merits further investigation.

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.

The evolution of drug resistance in malaria parasites highlights a need to identify and evaluate strategies that could extend the useful therapeutic life of anti-malarial drugs.,Such strategies are deployed to best effect before resistance has emerged, under conditions of great uncertainty.,Here, the emergence and spread of resistance was modelled using a hybrid framework to evaluate prospective strategies, estimate the time to drug failure, and weigh uncertainty.,The waiting time to appearance was estimated as the product of low mutation rates, drug pressure, and parasite population sizes during treatment.,Stochastic persistence and the waiting time to establishment were simulated as an evolving branching process.,The subsequent spread of resistance was simulated in simple epidemiological models.,Using this framework, the waiting time to the failure of artemisinin combination therapy (ACT) for malaria was estimated, and a policy of multiple first-line therapies (MFTs) was evaluated.,The models quantify the effects of reducing drug pressure in delaying appearance, reducing the chances of establishment, and slowing spread.,By using two first-line therapies in a population, it is possible to reduce drug pressure while still treating the full complement of cases.,At a global scale, because of uncertainty about the time to the emergence of ACT resistance, there was a strong case for MFTs to guard against early failure.,Our study recommends developing operationally feasible strategies for implementing MFTs, such as distributing different ACTs at the clinic and for home-based care, or formulating different ACTs for children and adults.

To validate assumptions about the length of the distribution-replacement cycle for long-lasting insecticidal nets (LLINs) in Rwanda, the Malaria and other Parasitic Diseases Division, Rwanda Ministry of Health, used World Health Organization methods to independently confirm the three-year LLIN serviceable life span recommendation of WHO.,Approximately 3,000 coded LLINs, distributed as part of a national campaign, were monitored in six sites, by means of six-monthly visits to selected houses.,Two indicators, survivorship/attrition, a measure of the number of nets remaining, and fabric integrity, the proportion of remaining nets in either ‘good’, ‘serviceable’ or ‘needs replacement’ condition, based on holes in the net material, were tracked.,To validate the assumption that the intervention would remain effective for three years, LLIN coverage, calculated using either survivorship, or integrity, by removing nets in the ‘needs replacement’ category from the survivorship total, was compared with the predicted proportion of nets remaining, derived from a net loss model, that assumes an LLIN serviceable life of three years.,After two years, there was close agreement between estimated LLIN survivorship at all sites, 75% (range 64-84%), and the predicted proportion of nets remaining, 75%.,However, when integrity was considered, observed survivorship at all sites, declined to 42% (range 10-54%).,More than half, 58%, of the LLINs fell into the ‘needs replacement’ category after two years.,While these nets were counted for survivorship, they were judged to be of little-to-no benefit to a user.,Therefore, when integrity was taken into account, survivorship was significantly lower than predicted, suggesting that net serviceable life was actually closer to two, rather than three years, and, by extension, that the impact of the intervention during year three of the LLIN distribution-replacement cycle could be well below that seen in years one and two.

Despite the extensive ownership and use of insecticide-treated nets (ITNs) over the last decade, the effective lifespan of these nets, especially their physical integrity, under true operational conditions is not well-understood.,Usefulness of nets declines primarily due to physical damage or loss of insecticidal activity.,A community based cross-sectional survey was used to determine the physical condition and to identify predictors of poor physical condition for bed nets owned by individuals from communities in Kwale County, coastal Kenya.,A proportionate hole index (pHI) was used as a standard measure, and the cut-offs for an ‘effective net’ (offer substantial protection against mosquito bites) and ‘ineffective nets’ (offer little or no protection against mosquito bites) were determined (pHI ≤88 (about ≤500 cm2 of holes surface area) and pHI of >88 (≥500 cm2 of holes surface area), respectively).,The vast majority (78%) of the surveyed nets had some holes.,The median pHI was 92 (range: 1-2,980).,Overall, half of the nets were categorized as ‘effective nets’ or ‘serviceable nets’.,Physical deterioration of nets was associated with higher use and washing frequency.,Young children and older children were found to use ineffective bed nets significantly more often than infants, while the physical integrity of nets owned by pregnant women was similar to those owned by infants.,Estuarine environment inhabitants owned nets with the worst physical condition, while nets owned by the coastal slope inhabitants were in fairly good physical condition.,The results suggest that bed nets are optimally utilized when they are new and physically intact.,Thereafter, bed net utilization decreases gradually with increasing physical deterioration, with most net owners withdrawing physically damaged nets from routine use.,This withdrawal commonly happens following 1.5 years of use, making bed net use the most important predictor of physical integrity.,On average, the nets were washed twice within six months prior to the survey.,Washing frequency was significantly influenced by the bed net colour and bed net age.,Lack of knowledge on reasons for net retreatment and the retreatment procedure was evident, while net repair was minimal and did not seem to improve the physical condition of the nets.,The “catch-up” bed net distribution strategies are sufficient for ensuring adequate ownership and utilization of ‘effective nets’ in the targeted groups, but bi-annual mass distribution is necessary to provide similar ownership and utilization for the other groups not targeted by “catch-up” strategies.,Monitoring and maintenance strategies that will deliver locally appropriate education messages on net washing and repair will enhance the effectiveness of malaria control programmes, and further research to assess ineffective nets need is needed.

The efficacy of thermotherapy for the treatment of cutaneous leishmaniasis presents diverse results with low statistical power.,To evaluate the efficacy of thermotherapy to treat cutaneous leishmaniasis.,A meta-analysis of controlled clinical trials in 12 databases based on the implementation of a research protocol with inclusion and exclusion criteria and an assessment of methodological quality.,The reproducibility and completeness were guaranteed in the information search and extraction.,Heterogeneity, sensitivity and publication bias were assessed by graphical methods (Galbraith, L'Abblé, funnel plot, Egger plot, and influence plot) and analytical methods (DerSimonian-Laird, Begg and Egger).,Random-effects forest plots were constructed, and a cumulative meta-analysis was performed.,Eight studies were included with 622 patients who underwent thermotherapy, with an efficacy of 73.2% (95% confidence interval (CI) = 69.6-76.7%), and with 667 patients who underwent systemic treatment, with an efficacy of 70.6% (95% CI=67.1-74.1%).,Heterogeneity between studies, good sensitivity for the combined measure, and no publication bias were observed.,The relative risk for comparison of the efficacy of treatment was 1.02 (95%CI=0.91, 1.15), showing that the effectiveness of thermotherapy is equal to that of pentavalent antimonial drugs.,Due to its efficacy, greater safety and lower cost, thermotherapy should be the first treatment option for cutaneous leishmaniasis in areas where the prevalence of the mucocutaneous form is low and in patients with contraindications to systemic treatment, such as kidney, liver and heart diseases, as well as in pregnant women, infants, and patients with human immunodeficiency virus infection/acquired immune deficiency syndrome.

A previously published proof of principle phase IIa trial with 113 patients from Kabul showed that bipolar high-frequency (HF) electro-cauterization (EC) of cutaneous leishmaniasis (CL) ulcers and subsequent moist wound treatment (MWT) closed 85% of all Leishmania (L.) tropica lesions within 60 days.,A three-armed phase IIb, randomized and controlled clinical trial was performed in Mazar-e-Sharif.,L. tropica- or L. major-infected CL patients received intradermal sodium stibogluconate (SSG) (Group I); HF-EC followed by MWT with 0.045% DAC N-055 (Group II); or MWT with 0.045% DAC N-055 in basic crème alone (Group III).,The primary outcome was complete epithelialisation before day 75 after treatment start.,87 patients enrolled in the trial were randomized into group I (n = 24), II (n = 32) and III (n = 31).,The per-protocol analysis of 69 (79%) patients revealed complete epithelialisation before day 75 in 15 (of 23; 65%) patients of Group I, in 23 (of 23; 100%) patients of Group II, and in 20 (of 23; 87%) patients of Group III (p = 0.004, Fisher’s Exact Test).,In the per-protocol analysis, wound closure times were significantly different between all regimens in a pair-wise comparison (p = 0.000039, Log-Rank (Mantel-Cox) test).,In the intention-to-treat analysis wound survival times in Group II were significantly different from those in Group I (p = 0.000040, Log-Rank (Mantel-Cox) test).,Re-ulcerations occurred in four (17%), three (13%) and seven (30%) patients of Group I, II or III, respectively (p = 0.312, Pearson Chi-Square Test).,Treatment of CL ulcers with bipolar HF-EC followed by MWT with 0.045% DAC N-055 or with DAC N-055 alone showed shorter wound closure times than with the standard SSG therapy.,The results merit further exploration in larger trials in the light of our current knowledge of in vitro and in vivo activities of chlorite.,Clinicaltrials.gov ID: NCT00996463.,Registered: 15th October 2009.,The online version of this article (doi:10.1186/s12879-014-0619-8) contains supplementary material, which is available to authorized users.

Leishmania mexicana (Lm) causes localized (LCL) and diffuse (DCL) cutaneous leishmaniasis.,DCL patients have a poor cellular immune response leading to chronicity.,It has been proposed that CD8 T lymphocytes (CD8) play a crucial role in infection clearance, although the role of CD8 cytotoxicity in disease control has not been elucidated.,Lesions of DCL patients have been shown to harbor low numbers of CD8, as compared to patients with LCL, and leishmanicidal treatment restores CD8 numbers.,The marked response of CD8 towards Leishmania parasites led us to analyze possible functional differences between CD8 from patients with LCL and DCL.,We compared IFNγ production, antigen-specific proliferation, and cytotoxicity of CD8 purified from PBMC against autologous macrophages (MO) infected with Leishmania mexicana (MOi).,Additionally, we analyzed tissue biopsies from both groups of patients for evidence of cytotoxicity associated with apoptotic cells in the lesions.,We found that CD8 cell of DCL patients exhibited low cytotoxicity, low antigen-specific proliferation and low IFNγ production when stimulated with MOi, as compared to LCL patients.,Additionally, DCL patients had significantly less TUNEL+ cells in their lesions.,These characteristics are similar to cellular “exhaustion” described in chronic infections.,We intended to restore the functional capacity of CD8 cells of DCL patients by preincubating them with TLR2 agonists: Lm lipophosphoglycan (LPG) or Pam3Cys.,Cytotoxicity against MOi, antigen-specific proliferation and IFNγ production were restored with both stimuli, whereas PD-1 (a molecule associated with cellular exhaustion) expression, was reduced.,Our work suggests that CD8 response is associated with control of Lm infection in LCL patients and that chronic infection in DCL patients leads to a state of CD8 functional exhaustion, which could facilitate disease spread.,This is the first report that shows the presence of functionally exhausted CD8 T lymphocytes in DCL patients and, additionally, that pre-stimulation with TLR2 ligands can restore the effector mechanisms of CD8 T lymphocytes from DCL patients against Leishmania mexicana-infected macrophages.

In human leishmaniasis Th1/Th2 dichotomy similar to murine model is not clearly defined and surrogate marker(s) of protection is not yet known.,In this study, Th1/Th2 cytokines (IL-5, IL-10, IL-13 and IFN-γ) profile induced by purified CD4+/CD8+ T cells in response to Leishmania antigens were assessed at transcript and protein levels in 14 volunteers with a history of self-healing cutaneous leishmaniasis (HCL) and compared with 18 healthy control volunteers.,CD4+/CD8+/CD14+ cells were purified from peripheral blood using magnetic beads; CD4+/CD8+ T cells were co-cultured with autologous CD14+ monocytes in the presence of soluble Leishmania antigens (SLA).,Stimulation of either CD4+ T cells or CD8+ T cells of HCL volunteers with SLA induced a significantly (P<0.05) higher IFN-γ production compared with the cells of controls.,Upregulation of IFN-γ gene expression in CD4+ cells (P<0.001) and CD8+ cells (P = 0.006) of HCL volunteers was significantly more than that of controls.,Significantly (P<0.05) higher fold-expression of IFN-γ gene was seen in CD4+ cells than in CD8+ cells.,In HCL volunteers a significantly (P = 0.014) higher number of CD4+ cells were positive for intracellular IFN-γ production than CD8+ cells.,Collectively, the volunteers have shown maintenance of specific long-term immune responses characterized by a strong reaction to leishmanin skin test and IFN-γ production.,The dominant IFN-γ response was the result of expansion of both CD4+ and CD8+ T cells.,The results suggested that immune response in protected individuals with a history of zoonotic cutaneous leishmaniasis (ZCL) due to L. major is mediated not only through the expansion of antigen-specific IFN-γ producing CD4+ Th1 cells, but also through IFN-γ producing CD8+ T cells.

Human alveolar echinococcosis (AE) is a severe zoonotic disease caused by the metacestode stage of Echinococcus multilocularis.,AE is commonly associated with a long incubation period that may last for more than ten years.,The objective of this systematic literature review was to identify and summarize the current knowledge on statistically relevant potential risk factors (PRFs) associated with AE in humans.,Six bibliographic databases were searched, generating a total of 1,009 publications.,Following the removal of duplicate records and the exclusion of papers that failed to meet the criteria of a previously agreed a priori protocol, 23 publications were retained; however, 6 of these did not contain data in a format that allowed their inclusion in the meta-analysis.,The remaining 17 publications (6 case-control and 11 cross-sectional studies) were meta-analysed to investigate associations between AE and PRFs.,Pooled odds ratios (OR) were used as a measure of effect and separately analysed for case-control and cross-sectional studies.,In the case-control studies, the following PRFs for human AE showed higher odds of outcome: “dog ownership”, “cat ownership”, “have a kitchen garden”, “occupation: farmer”, “haymaking in meadows not adjacent to water”, “went to forests for vocational reasons”, “chewed grass” and “hunting / handling foxes”.,In the cross-sectional studies, the following PRFs showed higher odds of outcome: “dog ownership”, “play with dogs”, “gender: female”, “age over 20 years”, “ethnic group: Tibetan”, “low income”, “source of drinking water other than well or tap”, “occupation: herding” and “low education”.,Our meta-analysis confirmed that the chance of AE transmission through ingestion of food and water contaminated with E. multilocularis eggs exists, but showed also that food- and water-borne PRFs do not significantly increase the risk of infection.,This systematic review analysed international peer-reviewed articles that have over the years contributed to our current understanding of the epidemiology of human AE.,The identification of potential risk factors may help researchers and decision makers improve surveillance and/or preventive measures that aim at decreasing human infection with E. multilocularis.,More primary studies are needed to confirm potential risk factors and their role in the epidemiology of human AE.

During 1982-2007, alveolar echinococcosis (AE) was diagnosed in 407 patients in France, a country previously known to register half of all European patients.,To better define high-risk groups in France, we conducted a national registry-based study to identify areas where persons were at risk and spatial clusters of cases.,We interviewed 180 AE patients about their way of life and compared responses to those of 517 controls.,We found that almost all AE patients lived in 22 départements in eastern and central France (relative risk 78.63, 95% CI 52.84-117.02).,Classification and regression tree analysis showed that the main risk factor was living in AE-endemic areas.,There, most at-risk populations lived in rural settings (odds ratio [OR] 66.67, 95% CI 6.21-464.51 for farmers and OR 6.98, 95% CI 2.88-18.25 for other persons) or gardened in nonrural settings (OR 4.30, 95% CI 1.82-10.91).,These findings can help sensitization campaigns focus on specific groups.