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Praziquantel (PZQ) is the drug of choice for schistosomiasis. The potential drug resistance necessitates the search for adjunct or alternative therapies to PZQ. Previous functional genomics has shown that RNAi inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) gene in Schistosoma adult worms significantly improved the effectiveness of PZQ. Here we tested the in vitro efficacy of 15 selective and non-selective CaMK inhibitors against Schistosoma mansoni and showed that PZQ efficacy was improved against refractory juvenile parasites when combined with these CaMK inhibitors. By measuring CaMK activity and the mobility of adult S. mansoni, we identified two non-selective CaMK inhibitors, Staurosporine (STSP) and 1Naphthyl PP1 (1NAPP1), as promising candidates for further study. The impact of STSP and 1NAPP1 was investigated in mice infected with S. mansoni in the presence or absence of a sub-lethal dose of PZQ against 2- and 7-day-old schistosomula and adults. Treatment with STSP/PZQ induced a significant (47–68%) liver egg burden reduction compared with mice treated with PZQ alone. The findings indicate that the combination of STSP and PZQ dosages significantly improved anti-schistosomal activity compared to PZQ alone, demonstrating the potential of selective and non-selective CaMK/kinase inhibitors as a combination therapy with PZQ in treating schistosomiasis.
Toxoplasma gondii rhoptry protein TgROP18 is a polymorphic virulence effector that targets immunity-related GTPases (IRGs) in rodents. Given that IRGs are uniquely diversified in rodents and not in other T. gondii intermediate hosts, the role of TgROP18 in manipulating non-rodent cells is unclear. Here we show that in human cells TgROP18I interacts with the interferon-gamma-inducible protein N-myc and STAT interactor (NMI) and that this is a property that is unique to the type I TgROP18 allele. Specifically, when expressed ectopically in mammalian cells only TgROP18I co-immunoprecipitates with NMI in IFN-γ-treated cells, while TgROP18II does not. In parasites expressing TgROP18I or TgROP18II, NMI only co-immunoprecipitates with TgROP18I and this is associated with allele-specific immunolocalization of NMI on the parasitophorous vacuolar membrane (PVM). We also found that TgROP18I reduces NMI association with IFN-γ-activated sequences (GAS) in the IRF1 gene promoter. Finally, we determined that polymorphisms in the C-terminal kinase domain of TgROP18I are required for allele-specific effects on NMI. Together, these data further define new host pathway targeted by TgROP18I and provide the first function driven by allelic differences in the highly polymorphic ROP18 locus.
The Clinical and Translational Science Award (CTSA) Consortium, about 60 NIH-supported CTSA hubs at academic health care institutions nationwide, is charged with improving the clinical and translational research enterprise. Together with the NIH National Center for Advancing Translational Sciences (NCATS), the Consortium implemented Common Metrics and a shared performance improvement framework.
Initial implementation across hubs was assessed using quantitative and qualitative methods over a 19-month period. The primary outcome was implementation of three Common Metrics and the performance improvement framework. Challenges and facilitators were elicited.
Among 59 hubs with data, all began implementing Common Metrics, but about one-third had completed all activities for three metrics within the study period. The vast majority of hubs computed metric results and undertook activities to understand performance. Differences in completion appeared in developing and carrying out performance improvement plans. Seven key factors affected progress: hub size and resources, hub prior experience with performance management, alignment of local context with needs of the Common Metrics implementation, hub authority in the local institutional structure, hub engagement (including CTSA Principal Investigator involvement), stakeholder engagement, and attending training and coaching.
Implementing Common Metrics and performance improvement in a large network of research-focused organizations proved feasible but required substantial time and resources. Considerable heterogeneity across hubs in data systems, existing processes and personnel, organizational structures, and local priorities of home institutions created disparate experiences across hubs. Future metric-based performance management initiatives across heterogeneous local contexts should anticipate and account for these types of differences.
OBJECTIVES/GOALS: Non-alcoholic steatohepatitis (NASH) is a leading cause of cirrhosis in the world for which no anti-fibrotic therapies exist. We hypothesized that BMS-22 and maraviroc (MVC), chemokine receptor 2 (CCR2) and 5 (CCR5) antagonists, respectively, would diminish the fibrogenic activity of "fat-exposed" murine pHSCs. METHODS/STUDY POPULATION: pHSCs were isolated from livers of 6 week old male mice following 4 weeks on a NASH-inducing choline-deficient high fat diet (CDAHFD, “fat-exposed”) or standard diet (SD) and passaged in vitro. Early passage (6-12) pHSCs were plate-adhered and TGF-b-treated (10ng/mL) to maximally activate their pro-fibrogenic genes, collagen 1α1 (Col1A1), tissue inhibitor of metalloproteinase 1 (TIMP1), or α-smooth muscle actin (ACTA2). CDAHFD and SD pHSCs were then treated for 48 hours with increasing doses of BMS-22 or MVC (range: 0.3-120ng/mL) to determine (1) the degree of attenuation of the pro-fibrogenic response as measured by qPCR of fibrogenic genes (Col1A1, TIMP1,ACTA2); (2) enhancement of a fibrolytic response as measured by qPCR of matrix metalloproteinases (MMP) 2, 9 and 13 genes; and (3) pHSC migration using the scratch assay. Cell viability and CCR2 and CCR5 gene expression in response to escalating doses of antagonists were also measured. RESULTS/ANTICIPATED RESULTS: Plate- and TGF-b activated CDAHFD pHSCs had a 2-fold greater, dose-dependent attenuation of their pro-fibrogenic activity in response to BMS-CCR2-22 and MVC, when compared with plate- and TGF-b activated SD pHSCs, as measured by reductions in collagen 1α1 (Col1A1) and α-smooth muscle actin (ACTA2) gene expression. TIMP1 gene expression was unaffected by drug treatment for 48 hours. Cell viability was not affected up to doses of 30ng/mL of each drug. pHSCs also demonstrated a dose-dependent increase in CCR2, CCR5 and MMP-9 gene expression in response to surface receptor antagonism. Migration assays comparing CDAHFD and SD pHSCs in response to escalating doses of MVC and BMS-22 are ongoing and expected to demonstrate a significantly decreased migratory capacity of CDAHFD pHSCs than SD pHSCs in response to therapy, reflecting the increased susceptibility of the “fat-exposed” pHSCs to anti-fibrotic therapy than normal pHSCs. DISCUSSION/SIGNIFICANCE OF IMPACT: Anti-fibrotic drugs that dampen pro-fibrogenic activities of “fat-exposed” pHSCs are urgently needed. CCR2 and CCR5 antagonists, BMS-22 and MVC, respectively, can selectively dampen the pro-fibrogenic response of fat-exposed pHSCs, and must be considered for future trials in human NASH. CONFLICT OF INTEREST DESCRIPTION: Dr. Jill Smith has a patent licensing agreement with Immune Therapeutics, Inc.
To assess the impact of a newly developed Central-Line Insertion Site Assessment (CLISA) score on the incidence of local inflammation or infection for CLABSI prevention.
A pre- and postintervention, quasi-experimental quality improvement study.
Setting and participants:
Adult inpatients with central venous catheters (CVCs) hospitalized in an intensive care unit or oncology ward at a large academic medical center.
We evaluated CLISA score impact on insertion site inflammation and infection (CLISA score of 2 or 3) incidence in the baseline period (June 2014–January 2015) and the intervention period (April 2015–October 2017) using interrupted times series and generalized linear mixed-effects multivariable analyses. These were run separately for days-to-line removal from identification of a CLISA score of 2 or 3. CLISA score interrater reliability and photo quiz results were evaluated.
Among 6,957 CVCs assessed 40,846 times, percentage of lines with CLISA score of 2 or 3 in the baseline and intervention periods decreased by 78.2% (from 22.0% to 4.7%), with a significant immediate decrease in the time-series analysis (P < .001). According to the multivariable regression, the intervention was associated with lower percentage of lines with a CLISA score of 2 or 3, after adjusting for age, gender, CVC body location, and hospital unit (odds ratio, 0.15; 95% confidence interval, 0.06–0.34; P < .001). According to the multivariate regression, days to removal of lines with CLISA score of 2 or 3 was 3.19 days faster after the intervention (P < .001). Also, line dwell time decreased 37.1% from a mean of 14 days (standard deviation [SD], 10.6) to 8.8 days (SD, 9.0) (P < .001). Device utilization ratios decreased 9% from 0.64 (SD, 0.08) to 0.58 (SD, 0.06) (P = .039).
The CLISA score creates a common language for assessing line infection risk and successfully promotes high compliance with best practices in timely line removal.
India has the second largest number of people with type 2 diabetes (T2D) globally. Epidemiological evidence indicates that consumption of white rice is positively associated with T2D risk, while intake of brown rice is inversely associated. Thus, we explored the effect of substituting brown rice for white rice on T2D risk factors among adults in urban South India. A total of 166 overweight (BMI ≥ 23 kg/m2) adults aged 25–65 years were enrolled in a randomised cross-over trial in Chennai, India. Interventions were a parboiled brown rice or white rice regimen providing two ad libitum meals/d, 6 d/week for 3 months with a 2-week washout period. Primary outcomes were blood glucose, insulin, glycosylated Hb (HbA1c), insulin resistance (homeostasis model assessment of insulin resistance) and lipids. High-sensitivity C-reactive protein (hs-CRP) was a secondary outcome. We did not observe significant between-group differences for primary outcomes among all participants. However, a significant reduction in HbA1c was observed in the brown rice group among participants with the metabolic syndrome (−0·18 (se 0·08) %) relative to those without the metabolic syndrome (0·05 (se 0·05) %) (P-for-heterogeneity = 0·02). Improvements in HbA1c, total and LDL-cholesterol were observed in the brown rice group among participants with a BMI ≥ 25 kg/m2 compared with those with a BMI < 25 kg/m2 (P-for-heterogeneity < 0·05). We observed a smaller increase in hs-CRP in the brown (0·03 (sd 2·12) mg/l) compared with white rice group (0·63 (sd 2·35) mg/l) (P = 0·04). In conclusion, substituting brown rice for white rice showed a potential benefit on HbA1c among participants with the metabolic syndrome and an elevated BMI. A small benefit on inflammation was also observed.
The authors demonstrate that gold-binding peptides displayed on the outer membrane of Escherichia coli enhance bioelectrochemical charge transfer by binding gold nanoparticles. Microbial fuel cells were run with different gold-binding peptides displayed and with different nanoparticle sizes, and the results were correlated with transmission electron microscopy (TEM) imaging of nanoparticle binding. When a gold-binding peptide is displayed and 5 nm gold nanoparticles are present, up to 4× power generation over E. coli not displaying a gold-binding peptide is observed. While an enhanced current is observed using the previously published M6G9, the largest enhancement is observed when a new longer peptide named M9G18 is used.
Re-planning mid-treatment, with the adjustment of target volumes, has been performed as part of the normal workflow at our institution. We sought to quantify the benefit of this approach and identify factors to optimise plan adaptive strategies.
Materials and methods:
Patients with locally advanced oropharyngeal cancer treated to 70 Gy with concurrent chemoradiation (CCRT) on TomoTherapy® who underwent re-planning during the treatment were eligible. Survival and prognostic factors were evaluated with Kaplan–Meier and Cox proportional hazards, two-side p-value <0·05 significant.
Forty-two patients were identified with Stage III (n = 5), IVA (n = 34) and IVB (n = 3) [AJCC 7th] disease. Median re-planning dose was 40 Gy (14–60 Gy). Median change in mean total parotid dose was reduction of 1 Gy (range –7·5 Gy to +13·9 Gy). The volume of PTV70 and PTV60 receiving 99% of the prescribed (V99) dose was increased by 2·2% (–3·3 to +16·6%) and 1·9% (–11·5 to +12·6%) by re-planning. As a continuous variable, increasing per cent nodal regression was associated with the improved disease control in a multivariate model including stage, pack years smoking and human papilloma viral (HPV) status (HR: 0·85, 0·71–0·99, p = 0·05).
Adaptive planning generates a superior plan for the majority of patients, but there is modest overall parotid gland sparing.
In 2013 a prediction was made that the South-East Asian subspecies of Bengal Florican Houbaropsis bengalensis blandini would be extinct within 10 years. In 2018 we conducted a survey in the Tonle Sap floodplain, Cambodia, of the last population of Bengal Florican in South-East Asia. We found that the rate of decline in displaying males was 55% over five years, a decline comparable to that recorded between 2005–2007 and 2012. The estimated number of displaying males in 2018 was 104 (95% CI: 89–117), down from 216 (156–275) in 2012. We also conducted surveys by flushing birds in the non-breeding season, which indicated that the sex ratio of males to females is 3:1. We therefore estimate that the total population of adult Bengal Floricans in Cambodia in 2018 was 138 (119–156), making H. b. blandini the most threatened bustard taxon. The number of sites that support displaying male Bengal Floricans was reduced from 10 to four between 2012 and 2018. Between 2012 and 2018 we monitored numbers of displaying males in most years at the sites that support 80% of the total population. The only site where numbers of birds are stable is Stoung-Chikraeng Bengal Florican Conservation Area, where there were 44 (25–63) displaying males in 2018. This is the only site that has an ongoing NGO-government conservation programme. Our data indicate that Bengal Floricans are lost from sites when the area of grassland falls below 25 km2. We found evidence that displaying male Bengal Floricans abandon display territories when grassland is lost, this also creates hope that they may disperse and could colonise newly created habitat. All remaining sites that support Bengal Floricans in Cambodia are imperilled and we outline what must be done to reduce the possibility that H. b. blandini will be extinct by 2023.
Nearby star-forming galaxies offer a unique environment to study the populations of young (<100 Myr) accreting binaries. These systems are tracers of past populations of massive stars that heavily affect their immediate environment and parent galaxies. Using a Chandra X-ray Visionary program, we investigate the young neutron-star binary population in the low metallicity of the Small Magellanic Cloud (SMC) by reaching quiescent X-ray luminosity levels (~few times 1032 erg/s). We present the first measurement of the formation efficiency of high-mass X-ray binaries (HMXBs) as a function of the age of their parent stellar populations by using 3 indicators: the number ratio of HMXBs to OB stars, to the SFR, and to the stellar mass produced during the specific star-formation burst they are associated with. In all cases, we find that the HMXB formation efficiency increases as a function of time up to ~40–60 Myr, and then gradually decreases.
Based on the data from the Next Generation Virgo cluster Survey (NGVS), we statistically study the photometric properties of globular clusters (GCs), ultra-compact dwarfs (UCDs) and dwarf nuclei in the Virgo core (M87) region. We found an obvious negative color (g - z) gradient in GC system associate with M87, i.e. GCs in the outer regions are bluer. However, such color gradient does not exist in UCD system, neither in dwarf nuclei system around M87. In addition, we found that many UCDs are surrounded by extended, low surface brightness envelopes. The dwarf nuclei and UCDs show different spatial distributions from GCs, with dwarf nuclei and UCDs (especially for the UCDs with visible envelopes) lying at larger distances to the Virgo center. These results support the view that UCDs (at least for a fraction of UCDs) are more tied to dwarf nuclei than to GCs.
To investigate the effects of soybean isoflavone (SI) on immunity in infectious bursal disease virus (IBDV)-infected broilers, chicks were fed the same basal diet supplemented with 0 (non-infected control), 0 (infected control), 10, 20 or 40 mg/kg SI for 44 days. At 21 days old, chickens were inoculated with bursal infectious dose causing 50% morbidity of the IBDV BC 6/85 strain by the eye-drop and nasal route (except for non-infected controls). Results showed that, over 1–23 days post-infection (dpi), there was a significant interaction between SI supplementation level and time: high-level SI supplementation increased peripheral T lymphocyte proliferation, percentages of CD3+, CD4+ and CD8+ T lymphocytes, CD4+ to CD8+ ratio, serum concentrations of IgA, IgM and IgG, and IBDV antibody titres. Except for serum IgA and IgM, these variables increased over time with far higher values at 23 dpi than earlier. Compared with non-infected controls, IBDV inoculation decreased peripheral T lymphocyte proliferation at 3 dpi, percentages of CD3+, CD4+ and CD8+ T lymphocytes, and serum IgG, IgM concentration at 23 dpi, and increased IBDV antibody titres at 7, 15 and 23 dpi. Supplemental SI quadratically increased peripheral T lymphocyte proliferation, CD4+ to CD8+ ratio and serum IgA concentration at 3 dpi, percentages of CD3+, CD4+ and CD8+ T lymphocytes at 3 and 23 dpi, and serum IgM concentration and IBDV antibody titres at 23 dpi. These results indicate that dietary SI improved cellular and humoral immunity of IBDV-infected birds and may enhance resistance of Yellow-feathered broilers to infectious diseases.
We have searched optical u′g′r′i′z′ imaging of 22 deg2 centred on the nearby giant elliptical galaxy NGC 5128 for new dwarf galaxies in the Centaurus A group. We report 45 promising new candidates, which are broadly consistent with the properties of nearby dwarf spheroidal galaxies and extend the size-luminosity relation toward fainter total luminosities and smaller sizes for known dwarf galaxies outside the Local Group (LG). Altogether, these new results show NGC 5128 to be the host of a large reservoir of low-mass dwarf galaxies that is at least as rich as that of the LG and is ripe for detailed follow-up observations.
Introduction: Approximately 50% of patients discharged from the Emergency Department (ED) after syncope have no cause found. Long-term outcomes among syncope patients are not well studied, to guide physicians regarding outpatient testing and follow-up. The objective of this study was to conduct a systematic review for long-term (one year) outcomes among ED patients with syncope. We aim to use the results of this review to guide us in prospective analysis of one year outcomes with our large database of syncope patients. Methods: We searched Cochrane Central Register of Controlled Trials, Medline and Medline in Process, PubMed, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) from the inception to June, 2017. We included studies that reported long-term outcomes among adult ED patients (16 years or older) with syncope. We excluded studies on pediatric patients, and studies that included syncope mimickers: pre-syncope, seizure, intoxication, loss of consciousness after head trauma. We also excluded case reports, letters to the editor and review articles. Outcomes included death, syncope recurrence requiring hospitalization, arrhythmias and procedural interventions for arrhythmias. We selected articles based on title and abstract review during phase-1 and conducted full article review during phase-2. Meta-analysis was performed by pooling the outcomes using random effects model (RevMan v.5.3; Cochrane Collaboration). Results: Initial literature search generated 2094 articles after duplicate removal. 50 articles remained after phase-1 (=0.85) and 16 articles were included in the systematic review after phase-2 (=0.86). The 16 included studies enrolled a total of 44,755 patients. Pooled analysis at 1-year follow-up showed the following outcomes: 7% mortality; 14% recurrence of syncope requiring hospitalization; one study reported that 0.6% of patients had a pacemaker inserted; and two studies reported 0.8 11.5% of patients suffered new arrhythmias. Conclusion: An important proportion of ED patients with syncope suffer outcomes at 1-year. Appropriate follow-up is needed to prevent long-term adverse outcomes. Further prospective research to identify patients at risk for long-term important cardiac outcomes and death is needed.
To determine whether self-reports of disaster-related psychological distress predict older adults’ health care utilization during the year after Hurricane Sandy, which hit New Jersey on October 29, 2012.
Respondents were from the ORANJ BOWL Study, a random-digit dialed sample from New Jersey recruited from 2006 to 2008. Medicare hospital, emergency department (ED) and outpatient claims data from 2012 and 2013 were matched to 1607 people age 65 and older in 2012 who responded to follow-up surveys conducted from July 2013 to July 2015 to determine their hurricane-related experiences.
In total, 7% (107) of respondents reported they experienced a lot versus 93% (1493) respondents reported they experienced little or no fear and distress from Hurricane Sandy. Those who experienced a lot versus little or no fear and distress had higher probability of all-cause hospital admissions and more ED visits through 3 months (hazard ratio [HR]: 2.19, 95% CI: 1.03-4.63; incidence ratio [IR]: 2.57, 95% CI: 1.21-5.35), and ED and outpatient visits (IR: 2.20, 95% CI: 1.44-3.37; IR: 1.37, 95% CI: 1.02-1.87) through the year after the hurricane.
A self-reported assessment of disaster-related psychological distress is a strong predictor of older adults’ health care needs the year after the disaster. The results indicate that disaster preparedness should extend beyond acute health care needs to address longer-term health consequences of disasters. (Disaster Med Public Health Preparedness. 2018;12:578–581)
Pre-Quaternary terrestrial climate variability is less well understood than that during the Quaternary. The continuous eolian Red Clay sequence underlying the well-known Quaternary loess-paleosol sequence on the Chinese Loess Plateau (CLP) provides an opportunity to study pre-Quaternary terrestrial climate variability in East Asia. Here, we present new mineral magnetic records for a recently found Red Clay succession from Shilou area on the eastern CLP, and demonstrate a marked East Asian climate shift across the Miocene-Pliocene boundary (MPB). Pedogenic fine-grained magnetite populations, ranging from superparamagnetic (SP)/single domain (SD) up to small pseudo-single domain (PSD) sizes (i.e., from <30 nm up to ~1000 nm), dominate the magnetic properties. Importantly, our mineral magnetic results indicate that both pedogenic formation of SP grains and transformation of SP grains to SD and small PSD grains accelerated across the MPB in the Shilou Red Clay, which are indicative of enhanced pedogenesis. We relate this enhanced pedogenesis to increased soil moisture availability on the CLP, associated with stronger Asian Summer Monsoon precipitation during an overall period of global cooling. Our study thus provides new insights into the Miocene-Pliocene climate transition in East Asia.
Lattice Boltzmann method (LBM) is adopted to compute two and three-dimensional lid driven cavity flows to examine the influence of memory management on the computational performance using Graphics Processing Unit (GPU). Both single and multi-relaxation time LBM are adopted. The computations are conducted on nVIDIA GeForce Titan, Tesla C2050 and GeForce GTX 560Ti. The performance using global memory deteriorates greatly when multi relaxation time (MRT) LBM is used, which is due to the scheme requesting more information from the global memory than its single relaxation time (SRT) LBM counterpart. On the other hand, adopting on chip memory the difference using MRT and SRT is not significant. Also, performance of LBM streaming procedure using offset reading surpasses offset writing ranging from 50% to 100% and this applies to both SRT and MRT LBM. Finally, comparisons using different GPU platforms indicate that Titan as expected outperforms other devices, and attains 227 and 193 speedup over its Intel Core i7-990 CPU counterpart and four times faster than GTX 560Ti and Tesla C2050 for three dimensional cavity flow simulations respectively with single and double precisions.
Integration of photonic devices on silicon (Si) substrates is a key method in enabling large scale manufacturing of Si-based photonic–electronic circuits for next generation systems with high performance, small form factor, low power consumption, and low cost. Germanium (Ge) is a promising material due to its pseudo-direct bandgap and its compatibility with Si-CMOS processing. In this article, we present our recent progress on achieving high quality germanium-on-silicon (Ge/Si) materials. Subsequently, the performance of various functional devices such as photodetectors, lasers, waveguides, and sensors that are fabricated on the Ge/Si platform are discussed. Some possible future works such as the incorporation of tin (Sn) into Ge will be proposed. Finally, some applications based on a fully monolithic integrated photonic–electronic chip on an Si platform will be highlighted at the end of this article.
Schistosomiasis in China has been substantially reduced due to an effective control programme employing various measures including bovine and human chemotherapy, and the removal of bovines from endemic areas. To fulfil elimination targets, it will be necessary to identify other possible reservoir hosts for Schistosoma japonicum and include them in future control efforts. This study determined the infection prevalence of S. japonicum in rodents (0–9·21%), dogs (0–18·37%) and goats (6·9–46·4%) from the Dongting Lake area of Hunan province, using a combination of traditional coproparasitological techniques (miracidial hatching technique and Kato-Katz thick smear technique) and molecular methods [quantitative real-time PCR (qPCR) and droplet digital PCR (ddPCR)]. We found a much higher prevalence in goats than previously recorded in this setting. Cattle and water buffalo were also examined using the same procedures and all were found to be infected, emphasising the occurrence of active transmission. qPCR and ddPCR were much more sensitive than the coproparasitological procedures with both KK and MHT considerably underestimating the true prevalence in all animals surveyed. The high level of S. japonicum prevalence in goats indicates that they are likely important reservoirs in schistosomiasis transmission, necessitating their inclusion as targets of control, if the goal of elimination is to be achieved in China.