Chinese patients with sporadic Hirschsprung's disease are predominantly represented by a single RET haplotype.

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A Clinical and Epidemiological Investigation of the First Reported Human Infection With the Zoonotic Parasite Trypanosoma evansi in Southeast Asia

Background. Trypanosoma is a genus of unicellular parasitic flagellate protozoa. Trypanosoma brucei species and Trypanosoma cruzi are the major agents of human trypanosomiasis; other Trypanosoma species can cause human disease, but are rare. In March 2015, a 38-year-old woman presented to a healthcare facility in southern Vietnam with fever, headache, and arthralgia. Microscopic examination of blood revealed infection with Trypanosoma. Methods. Microscopic observation, polymerase chain reaction (PCR) amplification of blood samples, and serological testing were performed to identify the infecting species. The patient's blood was screened for the trypanocidal protein apolipoprotein L1 (APOL1), and a field investigation was performed to identify the zoonotic source. Results. PCR amplification and serological testing identified the infecting species as Trypanosoma evansi. Despite relapsing 6 weeks after completing amphotericin B therapy, the patient made a complete recovery after 5 weeks of suramin. The patient was found to have 2 wild-type APOL1 alleles and a normal serum APOL1 concentration. After responsive animal sampling in the presumed location of exposure, cattle and/or buffalo were determined to be the most likely source of the infection, with 14 of 30 (47%) animal blood samples testing PCR positive for T. evansi. Conclusions. We report the first laboratory-confirmed case of T. evansi in a previously healthy individual without APOL1 deficiency, potentially contracted via a wound while butchering raw beef, and successfully treated with suramin. A linked epidemiological investigation revealed widespread and previously unidentified burden of T. evansi in local cattle, highlighting the need for surveillance of this infection in animals and the possibility of further human cases

Quality Assessment of Printable Strain Hardening Cementitious Composites Manufactured in Two Different Printing Facilities

Over the past few years, several studies have shown the potential of three-dimensional concrete printing (3DCP) for applications in building and civil engineering. However, only a few studies have compared the properties of the fresh printing material and the quality of the printed elements from different printing facilities. Variations in the manufacturing conditions caused by the mixing procedures, the pumping device and the nozzle shape and/or dimensions may influence the quality of the printed elements. This study investigates the differences in the fresh and hardened properties of a printing material tested in two different printing facilities. The pump pressure and temperature experienced by the printing material during the printing session are monitored real-time. Hardened properties are measured for the printed elements, such as the bending capacity, the apparent density, and the air void content. The research shows that two different printing facilities may result in printed elements with relative differences in flexural strength and volumetric density of 49% and 7%, respectively

HOXB5 Cooperates with NKX2-1 in the Transcription of Human RET

The enteric nervous system (ENS) regulates peristaltic movement of the gut, and abnormal ENS causes Hirschsprung's disease (HSCR) in newborns. HSCR is a congenital complex genetic disorder characterised by a lack of enteric ganglia along a variable length of the intestine. The receptor tyrosine kinase gene (RET) is the major HSCR gene and its expression is crucial for ENS development. We have previously reported that (i) HOXB5 transcription factor mediates RET expression, and (ii) mouse with defective HOXB5 activity develop HSCR phenotype. In this study, we (i) elucidate the underlying mechanisms that HOXB5 mediate RET expression, and (ii) examine the interactions between HOXB5 and other transcription factors implicated in RET expression. We show that human HOXB5 binds to the promoter region 5′ upstream of the binding site of NKX2-1 and regulates RET expression. HOXB5 and NKX2-1 form a protein complex and mediate RET expression in a synergistic manner. HSCR associated SNPs at the NKX2-1 binding site (-5G>A rs10900296; -1A>C rs10900297), which reduce NKX2-1 binding, abolish the synergistic trans-activation of RET by HOXB5 and NKX2-1. In contrast to the synergistic activation of RET with NKX2-1, HOXB5 cooperates in an additive manner with SOX10, PAX3 and PHOX2B in trans-activation of RET promoter. Taken together, our data suggests that HOXB5 in coordination with other transcription factors mediates RET expression. Therefore, defects in cis- or trans-regulation of RET by HOXB5 could lead to reduction of RET expression and contribute to the manifestation of the HSCR phenotype

Serum Alpha-fetoprotein Levels and Clinical Outcomes in the Phase III CELESTIAL Study of Cabozantinib versus Placebo in Patients with Advanced Hepatocellular Carcinoma

PURPOSE: The phase III CELESTIAL study demonstrated improved overall survival (OS) and progression-free survival (PFS) with cabozantinib versus placebo in patients with previously treated, advanced hepatocellular carcinoma (HCC). We analyzed outcomes by baseline alpha-fetoprotein (AFP) and on-treatment AFP changes. PATIENTS AND METHODS: Serum AFP was measured every 8 weeks by blinded, centralized testing. Outcomes were analyzed by baseline AFP bifurcated at 400 ng/mL and by on-treatment AFP response (≥20% decrease from baseline at Week 8). The optimal cutoff for change in AFP at Week 8 was evaluated using maximally selected rank statistics. RESULTS: Median OS for cabozantinib versus placebo was 13.9 versus 10.3 months [HR, 0.81; 95% confidence interval (CI), 0.62-1.04] for patients with baseline AFP <400 ng/mL, and 8.5 versus 5.2 months (HR, 0.71; 95% CI, 0.54-0.94) for patients with baseline AFP ≥400 ng/mL. Week 8 AFP response rate was 50% for cabozantinib versus 13% for placebo. In the cabozantinib arm, median OS for patients with and without AFP response was 16.1 versus 9.1 months (HR, 0.61; 95% CI, 0.45-0.84). AFP response was independently associated with longer OS. The optimal cutoff for association with OS in the cabozantinib arm was ≤0% change in AFP at Week 8 [AFP control; HR 0.50 (95% CI, 0.35-0.71)]. HRs for PFS were consistent with those for OS. CONCLUSIONS: Cabozantinib improved outcomes versus placebo across a range of baseline AFP levels. On-treatment AFP response and control rates were higher with cabozantinib than placebo, and were associated with longer OS and PFS with cabozantinib

Effectiveness, cost-effectiveness and cost-benefit of a single annual professional intervention for the prevention of childhood dental caries in a remote rural Indigenous community

Background The aim of the study is to reduce the high prevalence of tooth decay in children in a remote, rural Indigenous community in Australia, by application of a single annual dental preventive intervention. The study seeks to (1) assess the effectiveness of an annual oral health preventive intervention in slowing the incidence of dental caries in children in this community, (2) identify the mediating role of known risk factors for dental caries and (3) assess the cost-effectiveness and cost-benefit of the intervention. Methods/design The intervention is novel in that most dental preventive interventions require regular re-application, which is not possible in resource constrained communities. While tooth decay is preventable, self-care and healthy habits are lacking in these communities, placing more emphasis on health services to deliver an effective dental preventive intervention. Importantly, the study will assess cost-benefit and cost-effectiveness for broader implementation across similar communities in Australia and internationally. Discussion There is an urgent need to reduce the burden of dental decay in these communities, by implementing effective, cost-effective, feasible and sustainable dental prevention programs. Expected outcomes of this study include improved oral and general health of children within the community; an understanding of the costs associated with the intervention provided, and its comparison with the costs of allowing new lesions to develop, with associated treatment costs. Findings should be generalisable to similar communities around the world. The research is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), registration number ACTRN12615000693527; date of registration: 3rd July 2015

Identification of a wide spectrum of ciliary gene mutations in nonsyndromic biliary atresia patients implicates ciliary dysfunction as a novel disease mechanism

Background: Biliary atresia (BA) is the most common obstructive cholangiopathy in neonates, often progressing to end-stage cirrhosis. BA pathogenesis is believed to be multifactorial, but the genetic contribution, especially for nonsyndromic BA (common form: > 85%) remains poorly defined. Methods: We conducted whole exome sequencing on 89 nonsyndromic BA trios to identify rare variants contributing to BA etiology. Functional evaluation using patients’ liver biopsies, human cell and zebrafish models were performed. Clinical impact on respiratory system was assessed with clinical evaluation, nasal nitric oxide (nNO), high speed video analysis and transmission electron microscopy. Findings: We detected rare, deleterious de novo or biallelic variants in liver-expressed ciliary genes in 31.5% (28/89) of the BA patients. Burden test revealed 2.6-fold (odds ratio (OR) [95% confidence intervals (CI)]= 2.58 [1.15–6.07], adjusted p = 0.034) over-representation of rare, deleterious mutations in liver-expressed ciliary gene set in patients compared to controls. Functional analyses further demonstrated absence of cilia in the BA livers with KIF3B and TTC17 mutations, and knockdown of PCNT, KIF3B and TTC17 in human control fibroblasts and cholangiocytes resulted in reduced number of cilia. Additionally, CRISPR/Cas9-engineered zebrafish knockouts of KIF3B, PCNT and TTC17 displayed reduced biliary flow. Abnormally low level of nNO was detected in 80% (8/10) of BA patients carrying deleterious ciliary mutations, implicating the intrinsic ciliary defects. Interpretation: Our findings support strong genetic susceptibility for nonsyndromic BA. Ciliary gene mutations leading to cholangiocyte cilia malformation and dysfunction could be a key biological mechanism in BA pathogenesis. Funding: The study is supported by General Research Fund, HMRF Commissioned Paediatric Research at HKCH and Li Ka Shing Faculty of Medicine Enhanced New Staff Start-up Fund

Coxiella burnetii Phagocytosis Is Regulated by GTPases of the Rho Family and the RhoA Effectors mDia1 and ROCK

The GTPases belonging to the Rho family control the actin cytoskeleton rearrangements needed for particle internalization during phagocytosis. ROCK and mDia1 are downstream effectors of RhoA, a GTPase involved in that process. Coxiella burnetii, the etiologic agent of Q fever, is internalized by the host´s cells in an actin-dependent manner. Nevertheless, the molecular mechanism involved in this process has been poorly characterized. This work analyzes the role of different GTPases of the Rho family and some downstream effectors in the internalization of C. burnetii by phagocytic and non-phagocytic cells. The internalization of C. burnetii into HeLa and RAW cells was significantly inhibited when the cells were treated with Clostridium difficile Toxin B which irreversibly inactivates members of the Rho family. In addition, the internalization was reduced in HeLa cells that overexpressed the dominant negative mutants of RhoA, Rac1 or Cdc42 or that were knocked down for the Rho GTPases. The pharmacological inhibition or the knocking down of ROCK diminished bacterium internalization. Moreover, C. burnetii was less efficiently internalized in HeLa cells overexpressing mDia1-N1, a dominant negative mutant of mDia1, while the overexpression of the constitutively active mutant mDia1-ΔN3 increased bacteria uptake. Interestingly, when HeLa and RAW cells were infected, RhoA, Rac1 and mDia1 were recruited to membrane cell fractions. Our results suggest that the GTPases of the Rho family play an important role in C. burnetii phagocytosis in both HeLa and RAW cells. Additionally, we present evidence that ROCK and mDia1, which are downstream effectors of RhoA, are involved in that processFil: Salinas Ojeda, Romina Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Ortiz Flores, Rodolfo Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Distel, Jesús Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Aguilera, Milton Osmar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Colombo, Maria Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Beron, Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentin

Chronology of prescribing error during the hospital stay and prediction of pharmacist's alerts overriding: a prospective analysis

<p>Abstract</p> <p>Background</p> <p>Drug prescribing errors are frequent in the hospital setting and pharmacists play an important role in detection of these errors. The objectives of this study are (1) to describe the drug prescribing errors rate during the patient's stay, (2) to find which characteristics for a prescribing error are the most predictive of their reproduction the next day despite pharmacist's alert (<it>i.e</it>. override the alert).</p> <p>Methods</p> <p>We prospectively collected all medication order lines and prescribing errors during 18 days in 7 medical wards' using computerized physician order entry. We described and modelled the errors rate according to the chronology of hospital stay. We performed a classification and regression tree analysis to find which characteristics of alerts were predictive of their overriding (<it>i.e</it>. prescribing error repeated).</p> <p>Results</p> <p>12 533 order lines were reviewed, 117 errors (errors rate 0.9%) were observed and 51% of these errors occurred on the first day of the hospital stay. The risk of a prescribing error decreased over time. 52% of the alerts were overridden (<it>i.e </it>error uncorrected by prescribers on the following day. Drug omissions were the most frequently taken into account by prescribers. The classification and regression tree analysis showed that overriding pharmacist's alerts is first related to the ward of the prescriber and then to either Anatomical Therapeutic Chemical class of the drug or the type of error.</p> <p>Conclusions</p> <p>Since 51% of prescribing errors occurred on the first day of stay, pharmacist should concentrate his analysis of drug prescriptions on this day. The difference of overriding behavior between wards and according drug Anatomical Therapeutic Chemical class or type of error could also guide the validation tasks and programming of electronic alerts.</p