Diagnostic value of combined serum biomarkers for the evaluation of liver fibrosis in chronic hepatitis C infection: A multicenter, noninterventional, observational study

Background/Aims: The hepatitis C virus (HCV) infection is important cause of chronic hepatitis. Liver biopsy is considered the gold standard for assessment of fibrosis but this procedure is an invasive procedure. We aimed to evaluate the diagnostic efficiency of non-invasive serum biomarkers, separately and in combinations, on liver fibrosis in treatment-naive chronic hepatitis C (CHC) patients. Materials and Methods: Two hundred and sixteen treatment-naive CHC patients were enrolled from 32 locations across Turkey in this open-labelled, non-interventional prospective observational study. FibroTest®, aspartate aminotransferase-to-platelet ratio index(APRI), aspartate aminotransferase and alanine aminotransferase ratio (AAR), fibrosis index based on four factors (FIB-4), Age-platelet(AP) index and Forns index were measured and compared with Metavir scores got from liver biopsies. Results: Data from 182 patients with baseline liver biopsy were suitable for analysis. One hundred and twenty patients (65.9%) had F0-F1 fibrosis and 62 patients (34.1%) had F2-F4 fibrosis. APRI 0.732 area under the curve(AUC) indicated advanced fibrosis with 69% sensitivity and 77% specificity. FIB-4 0.732 AUC and FibroTest 0.715 AUC indicated advanced fibrosis with 69% and 78.4% sensitivity, and 75% and 71.4% specificity, respectively. The combined use of tests also led to an increase in AUC and specificity. Combinations of FibroTest with APRI and/or FIB-4, and FIB-4 with APRI were optimal for the evaluation of liver fibrosis. Conclusion: Fibrotest, FIB-4, APRI, AP index and Forns index exhibit good diagnostic performance for determining liver fibrosis in CHC patients, and the use of at least two tests together will increase their diagnostic value still further. © Copyright 2018 by The Turkish Society of Gastroenterology

Using schedulers to test probabilistic distributed systems

This is the author's accepted manuscript. The final publication is available at Springer via http://dx.doi.org/10.1007/s00165-012-0244-5. Copyright © 2012, British Computer Society.Formal methods are one of the most important approaches to increasing the confidence in the correctness of software systems. A formal specification can be used as an oracle in testing since one can determine whether an observed behaviour is allowed by the specification. This is an important feature of formal testing: behaviours of the system observed in testing are compared with the specification and ideally this comparison is automated. In this paper we study a formal testing framework to deal with systems that interact with their environment at physically distributed interfaces, called ports, and where choices between different possibilities are probabilistically quantified. Building on previous work, we introduce two families of schedulers to resolve nondeterministic choices among different actions of the system. The first type of schedulers, which we call global schedulers, resolves nondeterministic choices by representing the environment as a single global scheduler. The second type, which we call localised schedulers, models the environment as a set of schedulers with there being one scheduler for each port. We formally define the application of schedulers to systems and provide and study different implementation relations in this setting

A photometric and spectroscopic study of the new dwarf spheroidal galaxy in Hercules

Our aim is to provide as clean and as complete a sample as possible of red giant branch stars that are members of the Hercules dSph galaxy. With this sample we explore the velocity dispersion and the metallicity of the system. Stromgren photometry and multi-fibre spectroscopy are combined to provide information about the evolutionary state of the stars (via the Stromgren c_1 index) and their radial velocities. Based on this information we have selected a clean sample of red giant branch stars, and show that foreground contamination by Milky Way dwarf stars can greatly distort the results. Our final sample consists of 28 red giant branch stars in the Hercules dSph galaxy. Based on these stars we find a mean photometric metallicity of -2.35 dex which is consistent with previous studies. We find evidence for an abundance spread. Using those stars for which we have determined radial velocities we find a systemic velocity of 45.2 km/s with a dispersion of 3.72 km/s, this is lower than values found in the literature. Furthermore we identify the horizontal branch and estimate the mean magnitude of the horizontal branch of the Hercules dSph galaxy to be V_0=21.17, which corresponds to a distance of 147 kpc. We have shown that a proper cleaning of the sample results in a smaller value for the velocity dispersion of the system. This has implications for galaxy properties derived from such velocity dispersions.Comment: 24 pages, 28 figure

Canadian guidelines for rhinosinusitis: practical tools for the busy clinician

Acute bacterial rhinosinusitis (ABRS) and chronic rhinosinusitis (CRS) frequently present in clinical practice. Guidelines for management of these conditions have been published extensively in the past. However, a set of guidelines that addressed issues specific to the Canadian environment while offering clear guidance for first-line clinicians was needed, and resulted in the recent publication of Canadian clinical practice guidelines for ABRS and CRS. In addition to addressing issues specific to Canadian physicians, the presented guidelines are applicable internationally, and offer single algorithms for the diagnosis and management of ABRS and CRS, as well as expert opinion in areas that do not have an extensive evidence base. This commentary presents major points from the guidelines, as well as the intended impact of the guidelines on clinical practice

Bisphosphonates as antimyeloma drugs

In patients with symptomatic multiple myeloma (MM), bisphosphonate (BP) treatment has been widely used to prevent bone loss and preserve skeletal health because of its proven effects on inhibiting osteoclast-mediated bone resorption. In addition to their effects on osteoclasts, it is becoming increasingly evident that BPs may have additional effects on the bone microenvironment and cells other than osteoclasts that may potentially inhibit the development and progression of MM. This review focuses on the pathophysiology of MM with an emphasis on the events that drive MM progression within the bone and the mechanisms by which BPs may inhibit specific processes. The underlying molecular mechanisms that drive the modulation of cellular fate and function and consequent physiological outcomes are described. Direct effects on myeloma cell growth and survival and the interactions between myeloma cells and the bone microenvironment are discussed. Clinical evidence of the antimyeloma effects of BPs is emerging and is also reviewed

Prevalence and burden of HBV co-infection among people living with HIV:A global systematic review and meta-analysis

Globally, in 2017 35 million people were living with HIV (PLHIV) and 257 million had chronic HBV infection (HBsAg positive). The extent of HIV-HBsAg co-infection is unknown. We undertook a systematic review to estimate the global burden of HBsAg co-infection in PLHIV. We searched MEDLINE, Embase and other databases for published studies (2002-2018) measuring prevalence of HBsAg among PLHIV. The review was registered with PROSPERO (#CRD42019123388). Populations were categorized by HIV-exposure category. The global burden of co-infection was estimated by applying regional co-infection prevalence estimates to UNAIDS estimates of PLHIV. We conducted a meta-analysis to estimate the odds of HBsAg among PLHIV compared to HIV-negative individuals. We identified 506 estimates (475 studies) of HIV-HBsAg co-infection prevalence from 80/195 (41.0%) countries. Globally, the prevalence of HIV-HBsAg co-infection is 7.6% (IQR 5.6%-12.1%) in PLHIV, or 2.7 million HIV-HBsAg co-infections (IQR 2.0-4.2). The greatest burden (69% of cases; 1.9 million) is in sub-Saharan Africa. Globally, there was little difference in prevalence of HIV-HBsAg co-infection by population group (approximately 6%-7%), but it was slightly higher among people who inject drugs (11.8% IQR 6.0%-16.9%). Odds of HBsAg infection were 1.4 times higher among PLHIV compared to HIV-negative individuals. There is therefore, a high global burden of HIV-HBsAg co-infection, especially in sub-Saharan Africa. Key prevention strategies include infant HBV vaccination, including a timely birth-dose. Findings also highlight the importance of targeting PLHIV, especially high-risk groups for testing, catch-up HBV vaccination and other preventative interventions. The global scale-up of antiretroviral therapy (ART) for PLHIV using a tenofovir-based ART regimen provides an opportunity to simultaneously treat those with HBV co-infection, and in pregnant women to also reduce mother-to-child transmission of HBV alongside HIV

Genome Sequence of a Lancefield Group C Streptococcus zooepidemicus Strain Causing Epidemic Nephritis: New Information about an Old Disease

Outbreaks of disease attributable to human error or natural causes can provide unique opportunities to gain new information about host-pathogen interactions and new leads for pathogenesis research. Poststreptococcal glomerulonephritis (PSGN), a sequela of infection with pathogenic streptococci, is a common cause of preventable kidney disease worldwide. Although PSGN usually occurs after infection with group A streptococci, organisms of Lancefield group C and G also can be responsible. Despite decades of study, the molecular pathogenesis of PSGN is poorly understood. As a first step toward gaining new information about PSGN pathogenesis, we sequenced the genome of Streptococcus equi subsp. zooepidemicus strain MGCS10565, a group C organism that caused a very large and unusually severe epidemic of nephritis in Brazil. The genome is a circular chromosome of 2,024,171 bp. The genome shares extensive gene content, including many virulence factors, with genetically related group A streptococci, but unexpectedly lacks prophages. The genome contains many apparently foreign genes interspersed around the chromosome, consistent with the presence of a full array of genes required for natural competence. An inordinately large family of genes encodes secreted extracellular collagen-like proteins with multiple integrin-binding motifs. The absence of a gene related to speB rules out the long-held belief that streptococcal pyrogenic exotoxin B or antibodies reacting with it singularly cause PSGN. Many proteins previously implicated in GAS PSGN, such as streptokinase, are either highly divergent in strain MGCS10565 or are not more closely related between these species than to orthologs present in other streptococci that do not commonly cause PSGN. Our analysis provides a comparative genomics framework for renewed appraisal of molecular events underlying APSGN pathogenesis

Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

BACKGROUND Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTS In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. CONCLUSIONS Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239.