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Background: Liver diseases of infectious and non-infectious etiology cause considerable morbidity and mortality, particularly in low- and middle-income countries (LMICs). However, data on the prevalence of liver diseases and underlying risk factors in LMICs are scarce. The objective of this study was to elucidate the occurrence of infectious diseases among individuals with chronic liver damage in a rural setting of Côte d'Ivoire. Methodology: In 2021, we screened 696 individuals from four villages in the southern part of Côte d'Ivoire for hepatic fibrosis and steatosis, employing transient elastography (TE) and controlled attenuation parameter (CAP). We classified CAP ≥248 dB/m as steatosis, TE ≥7.2 kPa as fibrosis, and did subgroup analysis for participants with TE ranging from 7.2 kPa to 9.1 kPa. Clinical and microbiologic characteristics were compared to an age- and sex-matched control group (TE <6.0 kPa; n = 109). Stool samples were subjected to duplicate Kato-Katz thick smears for diagnosis of Schistosoma mansoni. Venous blood samples were examined for hepatitis B and hepatitis C virus. Additionally, an abdominal ultrasound examination was performed. Principal findings: Among 684 individuals with valid TE measurements, TE screening identified hepatic pathologies in 149 participants (17% with fibrosis and 6% with steatosis). 419 participants were included for further analyses, of which 261 had complete microbiological analyses available. The prevalence of S. mansoni, hepatitis B, and hepatitis C were 30%, 14%, and 7%, respectively. Logistic regression analysis revealed higher odds for having TE results between 7.2 kPa and 9.1 kPa in individuals with S. mansoni infection (odds ratio [OR] = 3.02, 95% confidence interval [CI] = 1.58–5.76, P = 0.001), while HCV infection (OR = 5.02, 95% CI = 1.72–14.69, P = 0.003) and steatosis (OR = 4.62, 95% CI = 1.60–13.35, P = 0.005) were found to be risk factors for TE ≥9.2 kPa. Conclusions/Significance: Besides viral hepatitis, S. mansoni also warrants consideration as a pathogen causing liver fibrosis in Côte d'Ivoire. In-depth diagnostic work-up among individuals with abnormal TE findings might be a cost-effective public health strategy. Author summary: At a global scale, chronic liver diseases such as liver fibrosis or cirrhosis are increasing. Causes and risk factors vary from one setting to another. In Europe, alcohol abuse, viral hepatitis, and fatty liver disease are the leading causes. Neglected tropical diseases, especially infections with parasites such as Schistosoma mansoni, are known to cause liver damage in low- and middle-income countries. Precise data on the relevance of infections with S. mansoni compared to other causes of liver fibrosis are scarce. In this study, we aimed to elucidate the infectious diseases etiology of chronic liver diseases in a schistosomiasis-endemic setting of Côte d'Ivoire. We screened residents from four villages in the southern part of Côte d'Ivoire with transient elastography, a non-invasive method that detects liver fibrosis or -cirrhosis by liver stiffness. Participants were tested for schistosomiasis and viral hepatitis, and a questionnaire was used to collect sociodemographic data. We found that liver fibrosis was common (17%), with S. mansoni being the most detected pathogen (30%). Liver diseases have a high morbidity and mortality, resulting in liver cancer or gastrointestinal haemorrhage. Schistosomiasis and hepatitis C, in particular, can be treated effectively today, so a screening program with transient elastography and subsequent treatment could prevent complications of liver disease. [ABSTRACT FROM AUTHOR]

Background/Aim: School-aged children in low- and middle-income countries carry the highest burden of intestinal helminth infections, such as soil-transmitted helminths (STH). STH infections have been associated with negative consequences for child physical and cognitive development and wellbeing. With the epidemiological transition and rise in cardiovascular disease (CVD), studies have shown that helminth infections may influence glucose metabolism by preventing obesity. Thus, the aim of this study was to determine the association of STH infections in schoolchildren from Gqeberha, focusing on physical activity, physical fitness, and clustered CVD risk score. Methods: This cross-sectional study involved 680 schoolchildren (356 girls and 324 boys; mean age 8.19 years, SD±1.4) from disadvantaged communities in Gqeberha (formerly, Port Elizabeth), South Africa. Stool samples were collected and examined for STH infections using the Kato-Katz method. Physical activity (accelerometer) and physical fitness (grip strength, 20 m shuttle run) were measured using standard procedures. Furthermore, anthropometry, blood pressure, as well as glycated haemoglobin and lipid profile from capillary blood samples were assessed. We employed one-way ANOVAs to identify the associations of STH infections in terms of species and infection intensity with physical activity, physical fitness, and clustered CVD risk score. Results: We found a low STH infection prevalence (7.2%) in our study, with participants infected with at least one intestinal helminth species. In comparison to their non-infected peers, children infected with STH had lower mean grip strength scores, but higher mean VO2max estimation and higher levels of MVPA (p <.001). When considering type and intensity of infection, a positive association of A. lumbricoides infection and MVPA was found. In contrast, light T. trichiura-infected children had significantly lower grip strength scores compared to non and heavily-infected children. VO2max and MVPA were positively associated with light T. trichiura infection. No significant association between the clustered CVD risk score and infection with any STH species was evident. Conclusions: STH-infected children had lower grip strength scores than their non-infected peers, yet, achieved higher VO2max and MVPA scores. Our study highlights that the type and intensity of STH infection is relevant in understanding the disease burden of STH infections on children's health. The findings of our study must be interpreted cautiously due to the low infection rate, and more research is needed in samples with higher prevalence rates or case-control designs. Author summary: South Africa is experiencing a change in lifestyle and traditional dietary habits, causing a growing burden of non-communicable diseases (diabetes, obesity and cardiovascular diseases). In addition to this growing burden of non-communicable diseases, communicable diseases (parasitic worm infections) still exist, especially in historically marginalised communities characterised by poverty, high unemployment, and lack of access to adequate sanitation and clean water. These communities foster the transmission and increase the risk of soil-transmitted helminth infections, especially in schoolchildren. A total of 680 schoolchildren aged 6–12 years were examined for soil-transmitted helminth infections, physical activity, physical fitness and cardiovascular disease risk. The analyses showed that being infected was associated with lower grip strength scores. Surprisingly, infected children had higher cardiorespiratory fitness and MVPA. We observed no association between being infected and the clustered cardiovascular disease risk score. We observed a positive association between A. lumbricoides infection and MVPA. While T. trichiura was negatively associated with grip strength and positively associated with cardiorespiratory fitness and MVPA. This study corroborated previous studies regarding low grip strength in infected children. Furthermore, our findings contributed new insights on the importance of the type and intensity of helminth infection in understanding the disease burden of helminth infections on children's health. [ABSTRACT FROM AUTHOR]

Background: Most studies assessing praziquantel (PZQ) efficacy have used relatively insensitive diagnostic methods, thereby overestimating cure rate (CR) and intensity reduction rate (IRR). To determine accurately PZQ efficacy, we employed more sensitive DNA and circulating antigen detection methods. Methodology: A sub-analysis was performed based on a previously published trial conducted in children from Côte d'Ivoire with a confirmed Schistosoma mansoni infection, who were randomly assigned to a standard (single dose of PZQ) or intense treatment group (4 repeated doses of PZQ at 2-week intervals). CR and IRR were estimated based on PCR detecting DNA in a single stool sample and the up-converting particle lateral flow (UCP-LF) test detecting circulating anodic antigen (CAA) in a single urine sample, and compared with traditional Kato-Katz (KK) and point-of-care circulating cathodic antigen (POC-CCA). Principal findings: Individuals positive by all diagnostic methods (i.e., KK, POC-CCA, PCR, and UCP-LF CAA) at baseline were included in the statistical analysis (n = 125). PCR showed a CR of 45% (95% confidence interval (CI) 32–59%) in the standard and 78% (95% CI 66–87%) in the intense treatment group, which is lower compared to the KK results (64%, 95% CI 52–75%) and 88%, 95% CI 78–93%). UCP-LF CAA showed a significantly lower CR in both groups, 16% (95% CI 11–24%) and 18% (95% CI 12–26%), even lower than observed by POC-CCA (31%, 95% CI 17–35% and 36%, 95% CI 26–47%). A substantial reduction in DNA and CAA-levels was observed after the first treatment, with no further decrease after additional treatment and no significant difference in IRR between treatment groups. Conclusion/Significance: The efficacy of (repeated) PZQ treatment was overestimated when using egg-based diagnostics. Quantitative worm-based diagnostics revealed that active Schistosoma infections are still present despite multiple treatments. These results stress the need for using accurate diagnostic tools to monitor different PZQ treatment strategies, in particular when moving toward elimination of schistosomiasis. Clinical trial registration: www.clinicaltrials.gov, NCT02868385. Author summary: Efficacy of praziquantel (PZQ) for the treatment of schistosomiasis is usually assessed by classical microscopic detection of parasite eggs in stool or urine. Due to low sensitivity, especially in case of low-intensity infections, the prevalence of infection is underestimated leading to an overestimated cure rate (CR) when using these methods. In a repeated treatment trial, the efficacy of one versus four repeated PZQ treatments, given at 2-week intervals, was investigated in school-age children from Côte d'Ivoire by applying a range of diagnostic methods, including traditional microscopy as well as more sensitive DNA and circulating antigen detection methods. Our results demonstrate that PZQ efficacy measurements vary based on the diagnostic method used: while egg-based diagnostics (stool microscopy and DNA detection methods) show an improved CR after repeated treatment, the CR determined by worm-based diagnostics (urine circulating antigen detection methods) remained poor over time. Although all four diagnostic methods showed a significant reduction in intensity of infection already after a single treatment, more accurate antigen diagnostics revealed that, in most cases, worms remain present even after multiple treatments. Hence, using accurate diagnostic tools is essential to determine the true infection status and to monitor and evaluate treatment programs. [ABSTRACT FROM AUTHOR]

The plant pathogen Pseudomonas syringae secretes multiple effectors that modulate plant defenses. Some effectors trigger defenses due to specific recognition by plant immune complexes, whereas others can suppress the resulting immune responses. The HopZ3 effector of P. syringae pv. syringae B728a (PsyB728a) is an acetyltransferase that modifies not only components of plant immune complexes, but also the Psy effectors that activate these complexes. In Arabidopsis, HopZ3 acetylates the host RPM1 complex and the Psy effectors AvrRpm1 and AvrB3. This study focuses on the role of HopZ3 during tomato infection. In Psy-resistant tomato, the main immune complex includes PRF and PTO, a RIPK-family kinase that recognizes the AvrPto effector. HopZ3 acts as a virulence factor on tomato by suppressing AvrPto1Psy-triggered immunity. HopZ3 acetylates AvrPto1Psy and the host proteins PTO, SlRIPK and SlRIN4s. Biochemical reconstruction and site-directed mutagenesis experiments suggest that acetylation acts in multiple ways to suppress immune signaling in tomato. First, acetylation disrupts the critical AvrPto1Psy-PTO interaction needed to initiate the immune response. Unmodified residues at the binding interface of both proteins and at other residues needed for binding are acetylated. Second, acetylation occurs at residues important for AvrPto1Psy function but not for binding to PTO. Finally, acetylation reduces specific phosphorylations needed for promoting the immune-inducing activity of HopZ3's targets such as AvrPto1Psy and PTO. In some cases, acetylation competes with phosphorylation. HopZ3-mediated acetylation suppresses the kinase activity of SlRIPK and the phosphorylation of its SlRIN4 substrate previously implicated in PTO-signaling. Thus, HopZ3 disrupts the functions of multiple immune components and the effectors that trigger them, leading to increased susceptibility to infection. Finally, mass spectrometry used to map specific acetylated residues confirmed HopZ3's unusual capacity to modify histidine in addition to serine, threonine and lysine residues. Author summary: By secreting virulence proteins (effectors) into their hosts, pathogenic bacteria hijack host cellular processes to promote bacterial colonization and disease development. For the plant pathogen Pseudomonas syringae, the coordinated action of effectors often mediates modifications of host defense proteins to inhibit their function. However, plants have evolved the ability to induce innate immunity upon recognition of effector-induced modifications of host proteins. How do pathogens circumvent the immune-inducing activity of certain effectors? They deploy more effectors to suppress these defenses. HopZ3, an acetyltransferase from P. syringae, is unique among plant pathogen effectors characterized so far in its ability to modify not only multiple components of the effector-triggered immune pathway, but also the triggering effector itself. Through the direct acetylation of residues involved in the interaction and activation of the bacterial effector AvrPto1Psy and tomato kinase PTO, HopZ3 modifications disrupt their binding and block phosphorylations necessary for immune induction. Additionally, HopZ3 acetylates other possible components in the PTO signaling pathway, including activation sites in SlRIPK kinase, leading to suppression of its activity and reduced phosphorylation of SlRIN4s. Our study emphasizes the importance of HopZ3-dependent acetylation of immune complexes and bacterial effectors across plant species in the suppression of effector-induced immunity. [ABSTRACT FROM AUTHOR]

Background: The prevalence of Schistosoma mansoni infection is usually assessed by the Kato-Katz diagnostic technique. However, Kato-Katz thick smears have low sensitivity, especially for light infections. Egg count models fitted on individual level data can adjust for the infection intensity-dependent sensitivity and estimate the 'true' prevalence in a population. However, application of these models is complex and there is need for adjustments that can be done without modelling expertise. This study provides estimates of the 'true' S. mansoni prevalence from population summary measures of observed prevalence and infection intensity using extensive simulations parametrized with data from different settings in sub-Saharan Africa. Methodology: An individual-level egg count model was applied to Kato-Katz data to determine the S. mansoni infection intensity-dependent sensitivity for various sampling schemes. Observations in populations with varying forces of transmission were simulated, using standard assumptions about the distribution of worms and their mating behavior. Summary measures such as the geometric mean infection, arithmetic mean infection, and the observed prevalence of the simulations were calculated, and parametric statistical models fitted to the summary measures for each sampling scheme. For validation, the simulation-based estimates are compared with an observational dataset not used to inform the simulation. Principal findings: Overall, the sensitivity of Kato-Katz in a population varies according to the mean infection intensity. Using a parametric model, which takes into account different sampling schemes varying from single Kato-Katy to triplicate slides over three days, both geometric and arithmetic mean infection intensities improve estimation of sensitivity. The relation between observed and 'true' prevalence is remarkably linear and triplicate slides per day on three consecutive days ensure close to perfect sensitivity. Conclusions/Significance: Estimation of 'true' S. mansoni prevalence is improved when taking into account geometric or arithmetic mean infection intensity in a population. We supply parametric functions and corresponding estimates of their parameters to calculate the 'true' prevalence for sampling schemes up to 3 days with triplicate Kato-Katz thick smears per day that allow estimation of the 'true' prevalence. Author summary: The World Health Organization (WHO) recommends the Kato-Katz diagnostic method, i.e., counting eggs in a thick-smear of stool using light microscopy, for estimation of Schistosoma mansoni infection prevalence. While the diagnostic specificity of Kato-Katz very high, the sensitivity varies strongly with infection intensity and the number of samples collected and thick smears per sample tested. Therefore, the performance of Kato-Katz in a population depends on the distribution of infections in the population and individual-level data is needed to determine the 'true' prevalence of infection. However, modelling capacity to determine 'true' prevalence from individual-level data is often not available to programme managers. In this study, we therefore provide simple equations to estimate the 'true' prevalence and associated uncertainty from observed prevalence and arithmetic or geometric mean infection intensity for a variety of common sampling schemes. We find that by including information about the mean infection intensity in a population the estimation of 'true' prevalence can be improved compared to assuming a constant value for the diagnostic sensitivity and supply parameters and functions to calculate the 'true' prevalence of infection. [ABSTRACT FROM AUTHOR]

Background: Oral ivermectin is a safe broad spectrum anthelminthic used for treating several neglected tropical diseases (NTDs). Currently, ivermectin use is contraindicated in children weighing less than 15 kg, restricting access to this drug for the treatment of NTDs. Here we provide an updated systematic review of the literature and we conducted an individual-level patient data (IPD) meta-analysis describing the safety of ivermectin in children weighing less than 15 kg. Methodology/Principal findings: A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for IPD guidelines by searching MEDLINE via PubMed, Web of Science, Ovid Embase, LILACS, Cochrane Database of Systematic Reviews, TOXLINE for all clinical trials, case series, case reports, and database entries for reports on the use of ivermectin in children weighing less than 15 kg that were published between 1 January 1980 to 25 October 2019. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42017056515. A total of 3,730 publications were identified, 97 were selected for potential inclusion, but only 17 sources describing 15 studies met the minimum criteria which consisted of known weights of children less than 15 kg linked to possible adverse events, and provided comprehensive IPD. A total of 1,088 children weighing less than 15 kg were administered oral ivermectin for one of the following indications: scabies, mass drug administration for scabies control, crusted scabies, cutaneous larva migrans, myiasis, pthiriasis, strongyloidiasis, trichuriasis, and parasitic disease of unknown origin. Overall a total of 1.4% (15/1,088) of children experienced 18 adverse events all of which were mild and self-limiting. No serious adverse events were reported. Conclusions/Significance: Existing limited data suggest that oral ivermectin in children weighing less than 15 kilograms is safe. Data from well-designed clinical trials are needed to provide further assurance. Author summary: Oral ivermectin is a safe and efficacious drug for the treatment of neglected tropical diseases. To date, ivermectin is not indicated in children weighing less than 15 kg because there have been insufficient safety data to support a change of recommendation. A PRISMA-level systematic review was conducted, and 97 potential sources were identified. All lead investigators were contacted to share individual patient data if they could provide the minimum criteria. These were the known weights of the children less than 15 kg in whom there were possible adverse events. A total of 17 investigators replied, sharing individual-level patient data (IPD) from 15 studies, which represent a database of 1,088 children weighing less than 15 kg treated with oral ivermectin. Overall 18 adverse events were reported in 1.4% (15/1,088) of children, all of which were mild and self-limiting. No serious adverse events were recorded. These data suggest that ivermectin is safe for use in children weighing less than 15 kilograms. Further data from well-designed clinical trials are needed to assess the safety of oral ivermectin at escalating doses in children weighing less than 15 kg. [ABSTRACT FROM AUTHOR]

Background: Preventive chemotherapy using praziquantel is the mainstay for schistosomiasis control. However, there is little evidence on what is supposed to be the most effective school-based treatment strategy to sustain morbidity control. The aim of this study was to compare differences in Schistosoma mansoni prevalence and infection intensity between three different schedules of school-based preventive chemotherapy in an area with moderate prevalence of S. mansoni in Côte d'Ivoire. Methodology: Seventy-five schools were randomly assigned to one of three intervention arms: (i) annual school-based preventive chemotherapy with praziquantel (40 mg/kg) over four years; (ii) praziquantel treatment only in the first two years, followed by two years whithout treatment; and (iii) praziquantel treatment in years 1 and 3 without treatment in-between. Cross-sectional parasitologic surveys were carried out prior to each round of preventive chemotherapy. The difference in S. mansoni prevalence and infection intensity was assessed by multiple Kato-Katz thick smears, among children aged 9–12 years at the time of each survey. First-grade children, aged 5–8 years who had never received praziquantel, were also tested at baseline and at the end of the study. Principal findings: Overall, 7,410 children aged 9–12 years were examined at baseline and 7,223 at the final survey. The baseline prevalence of S. mansoni was 17.4%, 20.2%, and 25.2% in arms 1, 2, and 3, respectively. In the final year, we observed the lowest prevalence of 10.4% in arm 1, compared to 18.2% in arm 2 and 17.5% in arm 3. The comparison between arms 1 and 2 estimated an odds ratio (OR) of 0.52 but the difference was not statistically significant (95% confidence interval (CI) = 0.23–1.16). Likewise the difference between arms 1 and 3 lacked statistical significance (OR = 0.55, 95% CI = 0.23–1.29). There was no noteworthy difference observed between arms 2 and 3 (OR = 1.06, 95% CI = 0.64–1.75). The lowest S. mansoni fecal egg counts in the final year survey were observed in arm 1 (7.9 eggs per gram of stool (EPG)). However, compared with 11.5 EPG in arm 2 and 15.4 EPG in arm 3, the difference lacked statistical significance. There were 4,812 first-grade children examined at baseline and 4,513 in the final survey. The overall prevalence of S. mansoni in these children slightly decreased in arms 1 (from 4.5% to 3.6%) and 2 (from 4.7% to 4.3%), but increased in arm 3 (from 6.8% to 7.9%). However, there was no significant difference in prevalence and infection intensity observed between study arms. Conclusions/significance: The three treatment schedules investigated led to a reduction in the prevalence and intensity of S. mansoni infection among children aged 9–12 years. Comparing intervention arms at the end of the study, no statistically significant differences were observed between annual treatement and the other two treatment schedules, neither in reduction of prevalence nor intensity of infection. It is important to combine our results with those of three sister trials conducted simultaneously in other African countries, before final recommendations can be drawn. Author summary: The World Health Organization (WHO) recommends preventive chemotherapy with praziquantel as the global strategy for morbidity control of schistosomiasis. The guidelines include target groups and treatment frequencies based on prevalence in school-age children. However, these recommendations are based on expert opinion. The Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) put forward a series of cluster-randomized trials in different African countries, including Côte d'Ivoire, to identify the most suitable approach to gain and sustain the control of schistosomiasis. Results from Côte d'Ivoire did not show statistically significant differences between three school-based treatment schedules (i.e., annual treatment over four years; treatment only in the first two years, followed by two years whithout treatment; and treatment every other year without treatment in-between) in reducing prevalence and intensity of Schistosoma mansoni infection among children aged 9–12 years. The results in first-grade children with an age of 5–8 years entering school who had never received deworming drugs showed no significant difference in the prevalence and intensity of S. mansoni infection between the different treatments at the study end, suggesting that the three strategies were not significantly different for reducing the disease transmission in affected communities. However, our data should be combined with other SCORE studies carried out elsewhere in Africa. A meta-analysis including the results of the sister trials could help to conclude and make more generic recommendations. [ABSTRACT FROM AUTHOR]

Background: Better knowledge of the efficacy and safety of single 40 mg/kg oral praziquantel in preschool-age children is required, should preventive chemotherapy programs for schistosomiasis be expanded to include this age group. Methodology: We analyzed individual participant-level data from 16 studies (13 single-arm or cohort studies and three randomized trials), amounting to 683 preschool-age children (aged <6 years) and 2,010 school-age children (aged 6–14 years). Children had a documented Schistosoma mansoni or S. haematobium infection, were treated with single 40 mg/kg oral praziquantel, and assessed between 21 and 60 days post-treatment. Efficacy was expressed as arithmetic mean and individual egg reduction rate (ERR) and meta-analyzed using general linear models and mixed models. Safety was summarized using reported adverse events (AEs). Principal findings: Preschool-age children had significantly lower baseline Schistosoma egg counts and more losses to follow-up compared to school-age children. No difference in efficacy was found between preschool- and school-age children using a general linear model of individual-participant ERR with baseline log-transformed egg count as covariate and study, age, and sex as fixed variables, and a mixed model with a random effect on the study. Safety was reported in only four studies (n = 1,128 individuals); few AEs were reported in preschool-age children 4 and 24 hours post-treatment as well as at follow-up. Three severe but not serious AEs were recorded in school-age children during follow-up. Conclusions/Significance: There is no indication that single 40 mg/kg oral praziquantel would be less efficacious and safe in preschool-age children compared to school-age children, with the caveat that only few randomized comparisons exist between the two age groups. Preventive chemotherapy might therefore be extended to preschool-age children, with proper monitoring of its efficacy and safety. Author summary: Schistosomiasis is a diseases caused by helminths (parasitic worms) which affects the intestinal and urinary systems. In areas where schistosomiasis is endemic, the disease is controlled by the large scale distributing of praziquantel, primarily targeting school-age children. Younger children (preschool-age) too might be affected by schistosomiasis, but are currently not receiving praziquantel within treatment campaigns. Instead, preschool-age children are treated on a case-by-case basis because the current praziquantel formulation is not adapted to young children. Questions have also been raised as to whether the standard dose of 40 mg/kg given once is effective in preschool-age children. To answer this question, we collected individual-participant data from a series of studies in which 40 mg/kg of praziquantel had been given to children with intestinal or urogenital schistosomiasis, and compared its efficacy and tolerability across age-groups. Since few direct comparisons had been made, we used statistical tools to make these comparisons. We found no evidence that treatment is less efficacious in preschool- than in school-age children and conclude that 40 mg/kg praziquantel may be given to preschool-age children in large-scale programs. When this happens, efficacy and tolerability will have to be closely monitored. [ABSTRACT FROM AUTHOR]

Background: Preventive chemotherapy with praziquantel (PZQ) is the cornerstone of schistosomiasis control. However, a single dose of PZQ (40 mg/kg) does not cure all infections. Repeated doses of PZQ at short intervals might increase efficacy in terms of cure rate (CR) and intensity reduction rate (IRR). Here, we determined the efficacy of a single versus four repeated treatments with PZQ on Schistosoma mansoni infection in school-aged children from Côte d'Ivoire, using two different diagnostic tests. Methods: An open-label, randomized controlled trial was conducted from October 2018 to January 2019. School-aged children with a confirmed S. mansoni infection based on Kato-Katz (KK) and point-of-care circulating cathodic antigen (POC-CCA) urine cassette test were randomly assigned to receive either a single or four repeated doses of PZQ, administered at two-week intervals. The primary outcome was the difference in CR between the two treatment arms, measured by triplicate KK thick smears 10 weeks after the first treatment. Secondary outcomes included CR estimated by POC-CCA, IRR by KK and POC-CCA, and safety of repeated PZQ administration. Principal findings: During baseline screening, 1,022 children were assessed for eligibility of whom 153 (15%) had a detectable S. mansoni infection, and hence, were randomized to the standard treatment group (N = 70) and the intense treatment group (N = 83). Based on KK, the CR was 42% (95% confidence interval (CI) 31–52%) in the standard treatment group and 86% (95% CI 75–92%) in the intense treatment group. Observed IRR was 72% (95% CI 55–83%) in the standard treatment group and 95% (95% CI 85–98%) in the intense treatment group. The CR estimated by POC-CCA was 18% (95% CI 11–27%) and 36% (95% CI 26–46%) in the standard and intense treatment group, respectively. Repeated PZQ treatment did not result in a higher number of adverse events. Conclusion/significance: The observed CR using KK was significantly higher after four repeated treatments compared to a single treatment, without an increase in adverse events. Using POC-CCA, the observed CR was significantly lower than measured by KK, indicating that PZQ may be considerably less efficacious as concluded by KK. Our findings highlight the need for reliable and more accurate diagnostic tools, which are essential for monitoring treatment efficacy, identifying changes in transmission, and accurately quantifying the intensity of infection in distinct populations. In addition, the higher CR in the intense treatment group suggests that more focused and intense PZQ treatment can help to advance schistosomiasis control. Trial registration: www.clinicaltrials.govNCT02868385. Author summary: The previously established efficacy of the widely used drug praziquantel (PZQ) against schistosomiasis might have been overestimated due to the use of inaccurate diagnostic methods. Repeated PZQ treatment at short intervals in areas with ongoing transmission could more effectively target non-susceptible schistosomula as they will have matured into drug susceptible worms within a few weeks. In the current study, we aimed to determine the cure rate (CR) of repeated PZQ, measured by the Kato-Katz (KK) technique and the point-of-care circulating cathodic antigen (POC-CCA) test, respectively. An open-label, randomized controlled trial was conducted assigning 153 school-aged children with a confirmed S. mansoni infection to two groups, one receiving a single PZQ treatment, while the second group received four repeated PZQ treatments, given at two-week intervals. Based on the KK test, the CR was significantly higher after four repeated treatments compared to a single treatment. When using POC-CCA, a diagnostic method that has not been utilized before in studies assessing the efficacy of four repeated PZQ treatments, the CR was much lower, even after four repeated PZQ treatments. Our results indicate that worms are still present after multiple PZQ treatments and that PZQ might be less efficacious than previously published. [ABSTRACT FROM AUTHOR]

Background: Carriers of the sickle cell trait (HbAS) usually remain asymptomatic. However, under conditions of low tissue oxygenation, red blood cell sickling and vascular obstruction may develop. Chronic kidney disease (CKD) can arise from conditions promoting low-oxygen in kidney tissue, which may be aggravated by the presence of the sickle cell trait. In addition, CKD can arise from other genetic traits. Aim: To compare the frequency of HbAS among hemodialysis patients and the general newborn population of Salvador (Bahia-Brazil), as well as to investigate the frequencies of apolipoprotein L1 risk variants in patients undergoing hemodialysis. Methods: A cross-sectional study included 306 patients with ESRD (End Stage Renal Disease) on hemodialysis for no more than three years. Hemoglobin profiles were characterized by high-performance liquid chromatography. To estimate the sickle cell trait frequency in the general population of Salvador, we analyzed data collected by a local neonatal screening program between 2011 and 2016. To exclude the potential contributing effect of the apolipoprotein L1 (APOL1) gene variants, we performed genotyping by PCR and DNA sequencing of 45 patients. Results: The frequency of HbAS was significantly higher in hemodialysis patients (9.8%) than in the general population (4.6%): Odds Ratio = 2.32 (95% CI = 1.59–3.38). No differences in demographic, clinical or laboratory data were found among patients with or without the sickle cell trait. The frequency of patients with none, one or two APOL1 risk haplotypes (G1 and G2) for CKD were 80%, 18% and 2%, respectively. Conclusions: The frequency of the sickle cell trait is higher in patients with ESRD on hemodialysis compared to the general population. APOL1 haplotypes do not seem to be the determinant of ESRD in these patients. [ABSTRACT FROM AUTHOR]

Background: Intervention guidelines against Schistosoma mansoni are based on the Kato-Katz technique. However, Kato-Katz thick smears show low sensitivity, especially for light-intensity infections. The point-of-care circulating cathodic antigen (POC-CCA) is a promising rapid diagnostic test detecting antigen output of living worms in urine and results are reported as trace, 1+, 2+, and 3+. The use of POC-CCA for schistosomiasis mapping, control, and surveillance requires translation of the Kato-Katz prevalence thresholds into POC-CCA relative treatment cut-offs. Furthermore, the infection status of egg-negative but antigen-positive individuals and the intensity-dependent sensitivity of POC-CCA should be estimated to determine its suitability for verification of disease elimination efforts. Methodology: We used data from settings in Africa and the Americas characterized by a wide range of S. mansoni endemicity. We estimated infection intensity-dependent sensitivity and specificity of each test at the unit of the individual, using a hierarchical Bayesian egg-count model that removes the need to define a ‘gold’ standard applied to data with multiple Kato-Katz thick smears and POC-CCA urine cassette tests. A simulation study was carried out based on the model estimates to assess the relation of the two diagnostic tests for different endemicity scenarios. Principal findings: POC-CCA showed high specificity (> 95%), and high sensitivity (> 95%) for moderate and heavy infection intensities, and moderate sensitivity (> 75%) for light infection intensities, and even for egg-negative but antigen-positive infections. A 10% duplicate slide Kato-Katz thick smear prevalence corresponded to a 15–40% prevalence of ≥ trace-positive POC-CCA, and 10–20% prevalence of ≥ 1+ POC-CCA. The prevalence of ≥ 2+ POC-CCA corresponded directly to single slide Kato-Katz prevalence for all prevalence levels. Conclusions/significance: The moderate sensitivity of POC-CCA, even for very light S. mansoni infections where the sensitivity of Kato-Katz is very low, and the identified relationship between Kato-Katz and POC-CCA prevalence thresholds render the latter diagnostic tool useful for surveillance and initial estimation of elimination of S. mansoni. For prevalence below 10% based on a duplicate slide Kato-Katz thick smear, we suggest using POC-CCA including trace results to evaluate treatment needs and propose new intervention thresholds that need to be validated in different settings. [ABSTRACT FROM AUTHOR]

The Kato-Katz technique is the most widely used diagnostic method in epidemiologic surveys and drug efficacy trials pertaining to intestinal schistosomiasis and soil-transmitted helminthiasis. However, the sensitivity of the technique is low, particularly for the detection of light-intensity helminth infections. Examination of multiple stool samples reduces the diagnostic error; yet, most studies rely on a single Kato-Katz thick smear, thus underestimating infection prevalence. We present a model which estimates the sensitivity of the Kato-Katz technique in Schistosoma mansoni and hookworm, as a function of infection intensity for repeated stool sampling and provide estimates of the age-dependent ‘true’ prevalence. We find that the sensitivity for S. mansoni diagnosis is dominated by missed light infections, which have a low probability to be diagnosed correctly even through repeated sampling. The overall sensitivity strongly depends on the mean infection intensity. In particular at an intensity of 100 eggs per gram of stool (EPG), we estimate a sensitivity of 50% and 80% for one and two samples, respectively. At an infection intensity of 300 EPG, we estimate a sensitivity of 62% for one sample and 90% for two samples. The sensitivity for hookworm diagnosis is dominated by day-to-day variation with typical values for one, two, three, and four samples equal to 50%, 75%, 85%, and 95%, respectively, while it is only weakly dependent on the mean infection intensity in the population. We recommend taking at least two samples and estimate the ‘true’ prevalence of S. mansoni considering the dependence of the sensitivity on the mean infection intensity and the ‘true’ hookworm prevalence by taking into account the sensitivity given in the current study. [ABSTRACT FROM AUTHOR]

The article describes the new approaches in health care, especially for neglected tropical diseases in urban settings with limited resources. It refers to the development and implementation of handheld and mobile-phone microscope technologies to deliver high-quality laboratory diagnostic capability to resource-constrained settings. It also discusses the strengths and limitations of using mobile microscopy in hand-held devices to communities in need.

Background: Schistosoma haematobium infections are responsible for significant urinary tract (UT) complications. Schistosomiasis control programs aim to reduce morbidity, yet the extent of morbidity in preschool-aged children and the impact of treatment on morbidity reduction are not well studied. Methodology: Our study was embedded in a randomized, placebo-controlled, single-blind trial in Côte d’Ivoire, which evaluated the efficacy and safety of three doses (20, 40 and 60 mg/kg) of praziquantel in school-aged (SAC) and preschool-aged (PSAC) children infected with S. haematobium. Enrolled children were invited to participate in an ultrasound examination prior and six months after treatment. At these time points 3 urine samples were collected for parasitological and clinical examinations. Principal findings: 162 PSAC and 141 SAC participated in the ultrasound examination at baseline, of which 128 PSAC and 122 SAC were present at follow-up. At baseline 43% (70/162) of PSAC had UT morbidity, mostly at bladder level and 7% had hydronephrosis. 67% (94/141) of SAC revealed mainly moderate UT pathology, 4% presented pseudopolyps on the bladder wall, and 6% had pyelectasis. At follow up, 45% of PSAC and 58% of SAC were S. haematobium positive, mostly harboring light infection intensities (41% and 51%, respectively). Microhematuria was present in 33% of PSAC and 42% of SAC and leukocyturia in 53% and 40% of PSAC and SAC, respectively. 50% (64/128) of PSAC and 58% (71/122) of SAC presented urinary tract morbidity, which was mainly mild. A significant correlation (p<0.05) was observed between praziquantel treatment and reversal of S. haematobium induced morbidity. Progression of UT pathology decreased with increasing praziquantel dosages. A worsening of morbidity was observed among children in the placebo group. Conclusion/Significance: Bladder morbidity is widespread among PSAC. Praziquantel treatment is significantly associated with the reversal of S. haematobium induced morbidity, which underscores the importance of preventive chemotherapy programs. These programs should be expanded to PSAC to prevent or decrease the prevalence of morbidity in young children. This trial is registered as an International Standard Randomized Controlled Trial, number ISRCTN15280205. [ABSTRACT FROM AUTHOR]

The article presents a study by the European Commission on persistent digestive disorders in low- and middle-income countries. It identifies the most important neglected tropical diseases and other infectious agents that lead to the clinical condition, examine the accuracy of current and available diagnostic methods, and determine clinical management options.

Background: Schistosomiasis affects millions of people, yet treatment options are limited. The antimalarial Synriam (piperaquine 150 mg/arterolane 750 mg) and the anthelminthic moxidectin revealed promising antischistosomal properties in preclinical or clinical studies. Methodology: We conducted two single-blind, randomized exploratory Phase 2 trials in Schistosoma mansoni and S. haematobium-infected adolescents in northern and central Côte d’Ivoire. Our primary endpoints were cure rates (CRs) and egg reduction rates (ERRs) based on geometric mean and safety. Each subject was asked to provide two stool samples (S. mansoni trial) for Kato-Katz analysis or three urine samples (S. haematobium trial) for urine filtration and one finger prick for malaria screening at baseline and follow-up. Participants were randomly assigned to either moxidectin, Synriam, Synriam plus praziquantel or praziquantel. Principal Findings: 128 adolescents (age: 12–17 years) were included in each study. Against S. haematobium moxidectin and Synriam revealed low efficacy. On the other hand, Synriam plus praziquantel and praziquantel yielded CRs of 60.0% and 38.5% and ERRs of 96.0% and 93.5%, respectively. CRs observed in the treatment of S. mansoni were 13.0%, 6.7%, 27.0%, and 27.6% for moxidectin, Synriam, Synriam plus praziquantel and praziquantel, respectively. ERRs ranged from 64.9% (Synriam) to 87.5% (praziquantel). Conclusion/Significance: Synriam and moxidectin show low efficacy against S. haematobium, hence an ancillary benefit is not expected when these drugs are used for treating onchocerciasis and malaria in co-endemic settings. Further studies are needed to corroborate our findings that moxidectin and Synriam show moderate ERRs against S. mansoni. [ABSTRACT FROM AUTHOR]

Background: A key epidemiologic feature of schistosomiasis is its focal distribution, which has important implications for the spatial targeting of preventive chemotherapy programs. We evaluated the diagnostic accuracy of a urine pooling strategy using a point-of-care circulating cathodic antigen (POC-CCA) cassette test for detection of Schistosoma mansoni, and employed simulation modeling to test the classification accuracy and efficiency of this strategy in determining where preventive chemotherapy is needed in low-endemicity settings. Methodology: We performed a cross-sectional study involving 114 children aged 6–15 years in six neighborhoods in Azaguié Ahoua, south Côte d’Ivoire to characterize the sensitivity and specificity of the POC-CCA cassette test with urine samples that were tested individually and in pools of 4, 8, and 12. We used a Bayesian latent class model to estimate test characteristics for individual POC-CCA and quadruplicate Kato-Katz thick smears on stool samples. We then developed a microsimulation model and used lot quality assurance sampling to test the performance, number of tests, and total cost per school for each pooled testing strategy to predict the binary need for school-based preventive chemotherapy using a 10% prevalence threshold for treatment. Principal Findings: The sensitivity of the urine pooling strategy for S. mansoni diagnosis using pool sizes of 4, 8, and 12 was 85.9%, 79.5%, and 65.4%, respectively, when POC-CCA trace results were considered positive, and 61.5%, 47.4%, and 30.8% when POC-CCA trace results were considered negative. The modeled specificity ranged from 94.0–97.7% for the urine pooling strategies (when POC-CCA trace results were considered negative). The urine pooling strategy, regardless of the pool size, gave comparable and often superior classification performance to stool microscopy for the same number of tests. The urine pooling strategy with a pool size of 4 reduced the number of tests and total cost compared to classical stool microscopy. Conclusions/Significance: This study introduces a method for rapid and efficient S. mansoni prevalence estimation through examining pooled urine samples with POC-CCA as an alternative to widely used stool microscopy. [ABSTRACT FROM AUTHOR]

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

Effective methods for delivering bioprobes into the cells of intact plants are essential for investigating diverse biological processes. Increasing research on trees, such as Populus spp., for bioenergy applications is driving the need for techniques that work well with tree species. This report introduces vertically aligned carbon nanofiber (VACNF) arrays as a new tool for microdelivery of labeled molecules to Populus leaf tissue and whole plants. We demonstrated that VACNFs penetrate the leaf surface to deliver sub-microliter quantities of solution containing fluorescent or radiolabeled molecules into Populus leaf cells. Importantly, VACNFs proved to be gentler than abrasion with carborundum, a common way to introduce material into leaves. Unlike carborundum, VACNFs did not disrupt cell or tissue integrity, nor did they induce production of hydrogen peroxide, a typical wound response. We show that femtomole to picomole quantities of labeled molecules (fluorescent dyes, small proteins and dextran), ranging from 0.5–500 kDa, can be introduced by VACNFs, and we demonstrate the use of the approach to track delivered probes from their site of introduction on the leaf to distal plant regions. VACNF arrays thus offer an attractive microdelivery method for the introduction of biomolecules and other probes into trees and potentially other types of plants. [ABSTRACT FROM AUTHOR]

Background: The Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) has launched several large-scale trials to determine the best strategies for gaining and sustaining control of schistosomiasis and transitioning toward elimination. In Côte d’Ivoire, a 5-year cluster-randomized trial is being implemented in 75 schools to sustain the control of schistosomiasis mansoni. We report Schistosoma mansoni infection levels in children one year after the initial school-based treatment (SBT) with praziquantel and compare with baseline results to determine the effect of the intervention. Methodology: The baseline cross-sectional survey was conducted in late 2011/early 2012 and the first follow-up in May 2013. Three consecutive stool samples were collected from 9- to 12-year-old children in 75 schools at baseline and 50 schools at follow-up. Stool samples were subjected to duplicate Kato-Katz thick smears. Directly observed treatment (DOT) coverage of the SBT was assessed and the prevalence and intensity of S. mansoni infection compared between baseline and follow-up. Principal Findings: The S. mansoni prevalence in the 75 schools surveyed at baseline was 22.1% (95% confidence interval (CI): 19.5–24.4%). The DOT coverage was 84.2%. In the 50 schools surveyed at baseline and one year after treatment, the overall prevalence of S. mansoni infection decreased significantly from 19.7% (95% CI: 18.5–20.8%) to 12.8% (95% CI: 11.9–13.8%), while the arithmetic mean S. mansoni eggs per gram of stool (EPG) among infected children slightly increased from 92.2 EPG (95% CI: 79.2–105.3 EPG) to 109.3 EPG (95% CI: 82.7–135.9 EPG). In two of the 50 schools, the prevalence increased significantly, despite a DOT coverage of >75%. Conclusions/Significance: One year after the initial SBT, the S. mansoni prevalence had decreased. Despite this positive trend, an increase was observed in some schools. Moreover, the infection intensity among S. mansoni-infected children was slightly higher at the 1-year follow-up compared to the baseline situation. Our results emphasize the heterogeneity of transmission dynamics and provide a benchmark for the future yearly follow-up surveys of this multi-year SCORE intervention study. [ABSTRACT FROM AUTHOR]

Background: The control of schistosomiasis emphasizes preventive chemotherapy with praziquantel, which aims at decreasing infection intensity and thus morbidity in individuals, as well as transmission in communities. Standardizing methods to assess treatment efficacy is important to compare trial outcomes across settings, and to monitor program effectiveness consistently. We compared customary methods and looked at possible complementary approaches in order to derive suggestions for standardizing outcome measures. Methodology/Principal Findings: We analyzed data from 24 studies conducted at African, Asian, and Latin American sites, enrolling overall 4,740 individuals infected with Schistosoma mansoni, S. haematobium, or S. japonicum, and treated with praziquantel at doses of 40–80 mg/kg. We found that group-based arithmetic and geometric means can be used interchangeably to express egg reduction rates (ERR) only if treatment efficacy is high (>95%). For lower levels of efficacy, ERR estimates are higher with geometric than arithmetic means. Using the distribution of individual responses in egg excretion, 6.3%, 1.7% and 4.3% of the subjects treated for S. haematobium, S. japonicum and S. mansoni infection, respectively, had no reduction in their egg counts (ERR = 0). The 5th, 10th, and 25th centiles of the subjects treated for S. haematobium had individual ERRs of 0%, 49.3%, and 96.5%; the corresponding values for S. japonicum were 75%, 99%, and 99%; and for S. mansoni 18.2%, 65.3%, and 99.8%. Using a single rather than quadruplicate Kato-Katz thick smear excluded 19% of S. mansoni-infected individuals. Whilst the effect on estimating ERR was negligible by individual studies, ERR estimates by arithmetic means were 8% lower with a single measurement. Conclusions/Significance: Arithmetic mean calculations of Schistosoma ERR are more sensitive and therefore more appropriate to monitor drug performance than geometric means. However, neither are satisfactory to identify poor responders. Group-based response estimated by arithmetic mean and the distribution of individual ERRs are correlated, but the latter appears to be more apt to detect the presence and to quantitate the magnitude of suboptimal responses to praziquantel. Author Summary: To identify whether a person is infected with parasitic worms, stool or urine samples are examined for worm eggs. The drug praziquantel is used against the parasitic disease schistosomiasis. However, there is no definitive agreement as to how the efficacy of praziquantel is best expressed. We put together a database from various studies of the efficacy of praziquantel against schistosomiasis. Efficacy was measured using customary methods: cure rate (CR: percentage of people with eggs in their stool/urine before treatment who became egg-negative after treatment); and egg reduction rate (ERR; percentage reduction in the number of eggs in the stool/urine after treatment, where the mean number of eggs from all people treated is calculated using either geometric or arithmetic means). We found that arithmetic and geometric means can be used interchangeably only if treatment efficacy is very high; arithmetic means are more sensitive to capture drops in efficacy expressed by ERR. A valid complement for drug efficacy monitoring is to study the distribution of individual responses in egg excretion that allows identifying in a single measure both those who had an adequate response to treatment and those who respond less well; e.g., the 5% of the patients with the lowest ERRs. [ABSTRACT FROM AUTHOR]

A central mechanism of virulence of extracellular bacterial pathogens is the injection into host cells of effector proteins that modify host cellular functions. HopW1 is an effector injected by the type III secretion system that increases the growth of the plant pathogen Pseudomonas syringae on the Columbia accession of Arabidopsis. When delivered by P. syringae into plant cells, HopW1 causes a reduction in the filamentous actin (F-actin) network and the inhibition of endocytosis, a known actin-dependent process. When directly produced in plants, HopW1 forms complexes with actin, disrupts the actin cytoskeleton and inhibits endocytosis as well as the trafficking of certain proteins to vacuoles. The C-terminal region of HopW1 can reduce the length of actin filaments and therefore solubilize F-actin in vitro. Thus, HopW1 acts by disrupting the actin cytoskeleton and the cell biological processes that depend on actin, which in turn are needed for restricting P. syringae growth in Arabidopsis. [ABSTRACT FROM AUTHOR]

Background: The Kato-Katz technique is widely used for the diagnosis of Schistosoma mansoni, but shows low sensitivity in light-intensity infections. We assessed the accuracy of a commercially available point-of-care circulating cathodic antigen (POC-CCA) cassette test for the diagnosis of S. mansoni in preschool-aged children before and after praziquantel administration. Methodology: A 3-week longitudinal survey with a treatment intervention was conducted in Azaguié, south Côte d'Ivoire. Overall, 242 preschoolers (age range: 2 months to 5.5 years) submitted two stool and two urine samples before praziquantel administration, and 86 individuals were followed-up posttreatment. Stool samples were examined with duplicate Kato-Katz thick smears for S. mansoni. Urine samples were subjected to POC-CCA cassette test for S. mansoni, and a filtration method for S. haematobium diagnosis. Principal Findings: Before treatment, the prevalence of S. mansoni, as determined by quadruplicate Kato-Katz, single CCA considering 'trace' as negative (t−), and single CCA with 'trace' as positive (t+), was 23.1%, 34.3% and 64.5%, respectively. Using the combined results (i.e., four Kato-Katz and duplicate CCA(t−)) as diagnostic 'gold' standard, the sensitivity of a single Kato-Katz, a single CCA(t−) or CCA(t+) was 28.3%, 69.7% and 89.1%, respectively. Three weeks posttreatment, the sensitivity of a single Kato-Katz, single CCA(t−) and CCA(t+) was 4.0%, 80.0% and 84.0%, respectively. The intensity of the POC-CCA test band reaction was correlated with S. mansoni egg burden (odds ratio = 1.2, p = 0.04). Conclusions/Significance: A single POC-CCA cassette test appears to be more sensitive than multiple Kato-Katz thick smears for the diagnosis of S. mansoni in preschool-aged children before and after praziquantel administration. The POC-CCA cassette test can be recommended for the rapid identification of S. mansoni infections before treatment. Additional studies are warranted to determine the usefulness of POC-CCA for assessing drug efficacy and monitoring the impact of control interventions. Author Summary: The strategy to control morbidity due to infection with the blood fluke Schistosoma mansoni is to regularly treat school-aged children with the drug praziquantel. Recent studies suggest that in highly endemic areas preschoolers might need to be included in such deworming campaigns. An accurate diagnosis is important to assess how many preschool-aged children need treatment, but the widely used Kato-Katz technique does not detect all infections. We assessed the accuracy of a point-of-care (POC) test that is based on the detection of the fluke's circulating cathodic antigen (CCA) in children's urine. We obtained two stool and two urine samples from 242 preschoolers in Côte d'Ivoire before and from 86 of these children after praziquantel treatment. Stool samples were examined with the Kato-Katz technique and urine samples with the POC-CCA test for S. mansoni. The sensitivity of one POC-CCA was much higher than a single Kato-Katz for S. mansoni diagnosis before (69.7% versus 28.3%) and after treatment (80.0% versus 4.0%). The POC-CCA therefore is useful for the rapid identification of S. mansoni-infected preschoolers who need treatment. The application of the POC-CCA test for monitoring of schistosomiasis control interventions needs further investigation. [ABSTRACT FROM AUTHOR]

Background: An accurate diagnosis of helminth infection is important to improve patient management. However, there is considerable intra- and inter-specimen variation of helminth egg counts in human feces. Homogenization of stool samples has been suggested to improve diagnostic accuracy, but there are no detailed investigations. Rapid disintegration of hookworm eggs constitutes another problem in epidemiological surveys. We studied the spatial distribution of Schistosoma mansoni and hookworm eggs in stool samples, the effect of homogenization, and determined egg counts over time in stool samples stored under different conditions. Methodology: Whole-stool samples were collected from 222 individuals in a rural part of south Côte d'Ivoire. Samples were cut into four pieces and helminth egg locations from the front to the back and from the center to the surface were analyzed. Some samples were homogenized and fecal egg counts (FECs) compared before and after homogenization. The effect of stool storing methods on FECs was investigated over time, comparing stool storage on ice, covering stool samples with a water-soaked tissue, or keeping stool samples in the shade. Principal Findings: We found no clear spatial pattern of S. mansoni and hookworm eggs in fecal samples. Homogenization decreased S. mansoni FECs (p = 0.026), while no effect was observed for hookworm and other soil-transmitted helminths. Hookworm FECs decreased over time. Storing stool samples on ice or covered with a moist tissue slowed down hookworm egg decay (p<0.005). Conclusions/Significance: Our findings have important implications for helminth diagnosis at the individual patient level and for epidemiological surveys, anthelmintic drug efficacy studies and monitoring of control programs. Specifically, homogenization of fecal samples is recommended for an accurate detection of S. mansoni eggs, while keeping collected stool samples cool and moist delayed the disintegration of hookworm eggs. Author Summary: An accurate diagnosis of parasitic worm (helminth) infections is important for adequate patient treatment and disease control programs. Helminth eggs in human stool samples are used as an indicator of infection intensity and morbidity. However, little is known about the exact distribution of helminth eggs in stool samples. Homogenization has been suggested to improve the diagnostic accuracy. Hookworm eggs disintegrate over time, which makes their detection challenging in epidemiological surveys. We determined the location of helminth eggs in entire stool samples from 222 individuals in Côte d'Ivoire. We also investigated whether homogenization has an effect on the detection of eggs, and determined egg counts over time in stool samples stored on ice, covered with a moist tissue, or kept in the shade. No clear pattern of helminth egg distribution was found in human stool samples. Homogenization resulted in more accurate egg counts of the blood fluke Schistosoma mansoni, while it did not affect other helminths. Keeping stool samples on ice or covered with a wet tissue slows down the disintegration of hookworm eggs. Our findings have important implications for individual patient management and the design and implementation of epidemiological surveys and helminth disease control programs. [ABSTRACT FROM AUTHOR]

Background: In sub-Saharan Africa the recommended strategy to control schistosomiasis is preventive chemotherapy. Emphasis is placed on school-aged children, but in high endemicity areas, preschool-aged children are also at risk, and hence might need treatment with praziquantel. Since a pediatric formulation (e.g., syrup) is not available outside of Egypt, crushed praziquantel tablets are used, but the efficacy and safety of this treatment regimen is insufficiently studied. Methodology: We assessed the efficacy and safety of crushed praziquantel tablets among preschool-aged children (<6 years) in the Azaguié district, south Côte d'Ivoire, where Schistosoma mansoni and S. haematobium coexist. Using a cross-sectional design, children provided two stool and two urine samples before and 3 weeks after treatment. Crushed praziquantel tablets, mixed with water, were administered at a dose of 40 mg/kg. Adverse events were assessed and graded 4 and 24 hours posttreatment by interviewing mothers/guardians. Principal Findings: Overall, 160 preschool-aged children had at least one stool and one urine sample examined with duplicate Kato-Katz thick smears and a point-of-care circulating cathodic antigen (POC-CCA) cassette for S. mansoni, and urine filtration for S. haematobium diagnosis before and 3 weeks after praziquantel administration. According to the Kato-Katz and urine filtration results, we found high efficacy against S. mansoni (cure rate (CR), 88.6%; egg reduction rate (ERR), 96.7%) and S. haematobium (CR, 88.9%; ERR, 98.0%). POC-CCA revealed considerably lower efficacy against S. mansoni (CR, 53.8%). Treatment was generally well tolerated, but moderately severe adverse events (i.e., body and face inflammation), were observed in four Schistosoma egg-negative children. Conclusions/Significance: Crushed praziquantel administered to preschool-aged children at a dose of 40 mg/kg is efficacious against S. mansoni and S. haematobium in a co-endemic setting of Côte d'Ivoire. Further research is required with highly sensitive diagnostic tools and safety must be investigated in more depth. Trial Registration: Controlled-Trials.com ISRCTN53172722 Author Summary: Schistosomiasis is a parasitic worm infection that plagues more than 200 million people in the developing world, particularly in sub-Saharan Africa. The current strategy to control schistosomiasis is to regularly administer the deworming drug praziquantel to school-aged children. Younger children before reaching school-age are not included in these deworming campaigns, because they are considered at low risk of schistosomiasis, and because the amount of available data to evaluate the safety of praziquantel in young children is insufficient. We conducted a study in two villages in southern Côte d'Ivoire and examined the stool and urine of more than 250 children (<6 years) for schistosome eggs and antigens. Children were treated with crushed praziquantel tablets (40 mg/kg) and the efficacy of this treatment was determined 3 weeks after treatment. The safety of the treatment was assessed by interviewing mothers of treated children for adverse events (e.g., abdominal pain, diarrhea, and headache). Complete data records were available for 160 children. Praziquantel cleared most of the infections. The treatment was generally well tolerated, but we observed four children who were not infected at the baseline survey who developed face and body inflammation that required close supervision by the study physician. [ABSTRACT FROM AUTHOR]

Background: An accurate diagnosis of helminth infection is important to improve patient management. However, there is considerable intra- and inter-specimen variation of helminth egg counts in human feces. Homogenization of stool samples has been suggested to improve diagnostic accuracy, but there are no detailed investigations. Rapid disintegration of hookworm eggs constitutes another problem in epidemiological surveys. We studied the spatial distribution of Schistosoma mansoni and hookworm eggs in stool samples, the effect of homogenization, and determined egg counts over time in stool samples stored under different conditions. Methodology: Whole-stool samples were collected from 222 individuals in a rural part of south Côte d'Ivoire. Samples were cut into four pieces and helminth egg locations from the front to the back and from the center to the surface were analyzed. Some samples were homogenized and fecal egg counts (FECs) compared before and after homogenization. The effect of stool storing methods on FECs was investigated over time, comparing stool storage on ice, covering stool samples with a water-soaked tissue, or keeping stool samples in the shade. Principal Findings: We found no clear spatial pattern of S. mansoni and hookworm eggs in fecal samples. Homogenization decreased S. mansoni FECs (p = 0.026), while no effect was observed for hookworm and other soil-transmitted helminths. Hookworm FECs decreased over time. Storing stool samples on ice or covered with a moist tissue slowed down hookworm egg decay (p<0.005). Conclusions/Significance: Our findings have important implications for helminth diagnosis at the individual patient level and for epidemiological surveys, anthelmintic drug efficacy studies and monitoring of control programs. Specifically, homogenization of fecal samples is recommended for an accurate detection of S. mansoni eggs, while keeping collected stool samples cool and moist delayed the disintegration of hookworm eggs. [ABSTRACT FROM AUTHOR]

Background: In sub-Saharan Africa the recommended strategy to control schistosomiasis is preventive chemotherapy. Emphasis is placed on school-aged children, but in high endemicity areas, preschool-aged children are also at risk, and hence might need treatment with praziquantel. Since a pediatric formulation (e.g., syrup) is not available outside of Egypt, crushed praziquantel tablets are used, but the efficacy and safety of this treatment regimen is insufficiently studied. Methodology: We assessed the efficacy and safety of crushed praziquantel tablets among preschool-aged children (<6 years) in the Azaguié district, south Côte d'Ivoire, where Schistosoma mansoni and S. haematobium coexist. Using a cross-sectional design, children provided two stool and two urine samples before and 3 weeks after treatment. Crushed praziquantel tablets, mixed with water, were administered at a dose of 40 mg/kg. Adverse events were assessed and graded 4 and 24 hours posttreatment by interviewing mothers/guardians. Principal Findings: Overall, 160 preschool-aged children had at least one stool and one urine sample examined with duplicate Kato-Katz thick smears and a point-of-care circulating cathodic antigen (POC-CCA) cassette for S. mansoni, and urine filtration for S. haematobium diagnosis before and 3 weeks after praziquantel administration. According to the Kato-Katz and urine filtration results, we found high efficacy against S. mansoni (cure rate (CR), 88.6%; egg reduction rate (ERR), 96.7%) and S. haematobium (CR, 88.9%; ERR, 98.0%). POC-CCA revealed considerably lower efficacy against S. mansoni (CR, 53.8%). Treatment was generally well tolerated, but moderately severe adverse events (i.e., body and face inflammation), were observed in four Schistosoma egg-negative children. Conclusions/Significance: Crushed praziquantel administered to preschool-aged children at a dose of 40 mg/kg is efficacious against S. mansoni and S. haematobium in a co-endemic setting of Côte d'Ivoire. Further research is required with highly sensitive diagnostic tools and safety must be investigated in more depth. Trial Registration: Controlled-Trials.com ISRCTN53172722 [ABSTRACT FROM AUTHOR]

Background: Promising results have been reported for a urine circulating cathodic antigen (CCA) test for the diagnosis of Schistosoma mansoni. We assessed the accuracy of a commercially available CCA cassette test (designated CCA-A) and an experimental formulation (CCA-B) for S. mansoni diagnosis. Methodology: We conducted a cross-sectional survey in three settings of Côte d'Ivoire: settings A and B are endemic for S. mansoni, whereas S. haematobium co-exists in setting C. Overall, 446 children, aged 8–12 years, submitted multiple stool and urine samples. For S. mansoni diagnosis, stool samples were examined with triplicate Kato-Katz, whereas urine samples were tested with CCA-A. The first stool and urine samples were additionally subjected to an ether-concentration technique and CCA-B, respectively. Urine samples were examined for S. haematobium using a filtration method, and for microhematuria using Hemastix dipsticks. Principal Findings: Considering nine Kato-Katz as diagnostic 'gold' standard, the prevalence of S. mansoni in setting A, B and C was 32.9%, 53.1% and 91.8%, respectively. The sensitivity of triplicate Kato-Katz from the first stool and a single CCA-A test was 47.9% and 56.3% (setting A), 73.9% and 69.6% (setting B), and 94.2% and 89.6% (setting C). The respective sensitivity of a single CCA-B was 10.4%, 29.9% and 75.0%. The ether-concentration technique showed a low sensitivity for S. mansoni diagnosis (8.3–41.0%). The specificity of CCA-A was moderate (76.9–84.2%); CCA-B was high (96.7–100%). The likelihood of a CCA-A color reaction increased with higher S. mansoni fecal egg counts (odds ratio: 1.07, p<0.001). A concurrent S. haematobium infection or the presence of microhematuria did not influence the CCA-A test results for S. mansoni diagnosis. Conclusion/Significance: CCA-A showed similar sensitivity than triplicate Kato-Katz for S. mansoni diagnosis with no cross-reactivity to S. haematobium and microhematuria. The low sensitivity of CCA-B in our study area precludes its use for S. mansoni diagnosis. Author Summary: We aimed to assess the accuracy of a commercially available rapid diagnostic test for the detection of an infection with the blood fluke Schistosoma mansoni in urine. In total, 446 school children from three different settings of south Côte d'Ivoire provided three stool and three urine samples. Stool samples were examined with the widely used Kato-Katz technique and analyzed with a microscope for S. mansoni eggs. Urine samples were examined with a filtration method for S. haematobium eggs and with a rapid diagnostic test for S. mansoni that is based on detecting circulating cathodic antigens (CCA). We used a commercially available test (designated CCA-A) and an experimental formulation (CCA-B). Examination of nine Kato-Katz thick smears per child revealed a prevalence of S. mansoni in the three settings of 32.9%, 53.1%, and 91.8%. The sensitivity of triplicate Kato-Katz from the first stool sample was comparable to a single CCA-A (47.9–94.2% vs. 56.3–89.6%), and significantly higher than the sensitivity of a single CCA-B test (10.4–75.0%). CCA-A showed a considerably lower specificity than CCA-B (76.9–84.2% vs. 96.7–100%). In the settings studied in south Côte d'Ivoire, the CCA-A test holds promise for the diagnosis of S. mansoni, whereas results with CCA-B were suboptimal. [ABSTRACT FROM AUTHOR]

Background: Schistosomiasis and soil-transmitted helminthiasis are important public health problems in sub-Saharan Africa causing malnutrition, anemia, and retardation of physical and cognitive development. However, the effect of these diseases on physical fitness remains to be determined. Methodology: We investigated the relationship between schistosomiasis, soil-transmitted helminthiasis and physical performance of children, controlling for potential confounding of Plasmodium spp. infections and environmental parameters (i.e., ambient air temperature and humidity). A cross-sectional survey was carried out among 156 school children aged 7–15 years from Côte d'Ivoire. Each child had two stool and two urine samples examined for helminth eggs by microscopy. Additionally, children underwent a clinical examination, were tested for Plasmodium spp. infection with a rapid diagnostic test, and performed a maximal multistage 20 m shuttle run test to assess their maximal oxygen uptake (VO2 max) as a proxy for physical fitness. Principal Findings: The prevalence of Schistosoma haematobium, Plasmodium spp., Schistosoma mansoni, hookworm and Ascaris lumbricoides infections was 85.3%, 71.2%, 53.8%, 13.5% and 1.3%, respectively. Children with single, dual, triple, quadruple and quintuple species infections showed VO2 max of 52.7, 53.1, 52.2, 52.6 and 55.6 ml kg−1 min−1, respectively. The VO2 max of children with no parasite infections was 53.5 ml kg−1 min−1. No statistically significant difference was detected between any groups. Multivariable analysis revealed that VO2 max was influenced by sex (reference: female, coef. = 4.02, p<0.001) and age (years, coef. = −1.23, p<0.001), but not by helminth infection and intensity, Plasmodium spp. infection, and environmental parameters. Conclusion/Significance: School-aged children in Côte d'Ivoire showed good physical fitness, irrespective of their helminth infection status. Future studies on children's physical fitness in settings where helminthiasis and malaria co-exist should include pre- and post-intervention evaluations and the measurement of hemoglobin and hematocrit levels and nutritional parameters as potential co-factors to determine whether interventions further improve upon fitness. Author Summary: The burden of parasitic worm infections is considerable, particularly in developing countries. It is acknowledged that parasitic worm infections negatively impact on children's school performance and physical development. A deeper understanding of these linkages is important for updating burden of disease measures. We investigated the relationship between worm infection status and physical fitness of 156 school children from Côte d'Ivoire and controlled for potential confounding of Plasmodium infection (the causative agent of malaria) and environmental parameters (temperature and humidity). Children were diagnosed for parasitic worm and Plasmodium infections, examined by a physician, and participated in a 20 m shuttle run test to assess their maximal oxygen uptake (VO2 max) as a proxy for physical fitness. Most of the children had parasitic worms and a Plasmodium infection. Nevertheless, their physical fitness was excellent (average VO2 max: 52.7 ml kg−1 min−1). The level of VO2 max was only influenced by sex and age, but not by parasitic worms and Plasmodium infections. In future studies, the dynamics of children's physical performance should be assessed before and after control interventions, including the assessment of blood hemoglobin, hematocrit, and nutritional indicators to determine whether physical fitness in worm- and Plasmodium-infected individuals can be further improved. [ABSTRACT FROM AUTHOR]

Background: Ceramide kinase (CERK) is a key regulator of cell survival in dicotyledonous plants and animals. Much less is known about the roles of CERK and ceramides in mediating cellular processes in monocot plants. Here, we report the characterization of a ceramide kinase, OsCERK, from rice (Oryza sativa spp. Japonica cv. Nipponbare) and investigate the effects of ceramides on rice cell viability. Principal Findings: OsCERK can complement the Arabidopsis CERK mutant acd5. Recombinant OsCERK has ceramide kinase activity with Michaelis-Menten kinetics and optimal activity at 7.0 pH and 40°C. Mg2+ activates OsCERK in a concentrationdependent manner. Importantly, a CXXXCXXC motif, conserved in all ceramide kinases and important for the activity of the human enzyme, is critical for OsCERK enzyme activity and in planta function. In a rice protoplast system, inhibition of CERK leads to cell death and the ratio of added ceramide and ceramide-1-phosphate, CERK's substrate and product, respectively, influences cell survival. Ceramide-induced rice cell death has apoptotic features and is an active process that requires both de novo protein synthesis and phosphorylation, respectively. Finally, mitochondria membrane potential loss previously associated with ceramide-induced cell death in Arabidopsis was also found in rice, but it occurred with different timing. Conclusions: OsCERK is a bona fide ceramide kinase with a functionally and evolutionarily conserved Cys-rich motif that plays an important role in modulating cell fate in plants. The vital function of the conserved motif in both human and rice CERKs suggests that the biochemical mechanism of CERKs is similar in animals and plants. Furthermore, ceramides induce cell death with similar features in monocot and dicot plants. [ABSTRACT FROM AUTHOR]