Rifaximin has the potential to prevent complications of cirrhosis

Background: Cirrhosis-related complications are associated with poor prognosis. With our analyses, we examined the potential benefit of rifaximin in reducing the risk of developing cirrhosis-related complications. Methods: Adults with cirrhosis and hepatic encephalopathy (HE) in remission were randomly assigned to receive rifaximin 550 mg twice daily or placebo for 6 months with concomitant lactulose permitted. Post hoc analyses examined time to cirrhosis-related complications (HE, spontaneous bacterial peritonitis (SBP), variceal bleeding, acute kidney injury/hepatorenal syndrome). Subgroup analyses evaluated efficacy for select baseline disease characteristics. Results: Of patients receiving rifaximin (n = 140) and placebo (n = 159), 53.6% and 49.1%, respectively, had baseline Model for End-Stage Liver Disease (MELD) score ⩾ 12 and international normalized ratio (INR) ⩾ 1.2. Baseline ascites was observed in 36.4% (rifaximin) and 34.6% (placebo) of patients. In patients with MELD score ⩾ 12 and INR ⩾ 1.2, rifaximin reduced the relative risk (RR) of any first complication experienced during trial by 59% [hazard ratio (HR) = 0.41, 95% confidence interval (CI): 0.25–0.67; p \u3c 0.001] versus placebo. For patients with baseline ascites, rifaximin reduced the RR of any first complication experienced during trial by 42% versus placebo (HR = 0.58, 95% CI: 0.34–1.0; p = 0.045). For some subgroups, there was a decrease in RR of complications of SBP, variceal bleeding, and acute kidney injury/hepatorenal syndrome with rifaximin versus placebo, although there were few events reported in the study. Conclusion: Rifaximin may reduce the incidence of cirrhosis-related complications and the recurrence of overt HE. [ClinicalTrials.gov identifier: NCT00298038.

ORIGINAL ARTICLE: Will An Additional Observer Enhance Adenoma Detection During Colonoscopy?

Background: Due to varied level of experience, the detection rate of adenoma on colonoscopy is different. In presence of both fellows and attending the incidence rates of adenoma are shown to increase in a small study reported by Rogart et al [4]. Based on similar hypothesis, a study was undertaken with much larger sample size to improve the power of the study. Aims and objective: To know if presence of additional observer will enhance adenoma detection during colonoscopy. Material and Methods: 2236 consecutive colonoscopies performed at Metro Health Medical Centre, Cleveland, Ohio were included in the study from July 2005 to August 2006. Cases with history of colorectal, surgical resection of colon, inflammatory bowel diseases and hereditary polyposis syndrome were excluded. Inpatient colonoscopies were also excluded. With all usual precautions for colonoscopy and after giving polyethylene glycol electrolyte (PEGEL) colonoscopies were performed by one of the nine experienced staff attending using an Olympus colonoscope and Evis Exera processors. All colonoscopies performed by fellows were supervised by an attending throughout the procedure. Advanced adenomas were defined as adenomas greater than 1 cm size. Statistical analysis was done using Tall hassee, FL software; Fisher’s exact test, unpaired t test and multiple logistic regression analysis were performed. p-value of <0.05 is considered as statistically significant. Results: Of the total 2236 colonoscopies included in the study, 1527 were performed by fellows under supervision of attending and 709 by the attending. There was no significant difference in patient demographics, caecal intubation or poor preparation colonoscopies. The mean age of the group was 55 years in both of the groups. There was no statistically significant different in the polyp detection rate (35% Vs 36.8%) as well as overall adenoma detection rate (28.4% Vs 27.7%) between these two groups of performers. However, increased rate of adenoma detection was seen for the adenomas of size 0.5 to 1.00 cm in the fellow and attending group (7.2%) as compared to attending alone group (4.0%). There was no difference in the number of colonoscopies aborted due to poor bowel preparations There was no statistically significant difference in the number of colonoscopies aborted due to poor bowel prep, 91(5.9%) Vs 32(4.5%). Conclusions: Our retrospective study has shown no improvement in the rate of adenoma detection when fellows performed colonoscopy with a supervising attending in comparison to procedures performed by attending alone. In fact, Adenoma Detection Rate (ADR) and caecal intubation rates are increasingly seen as important quality measure. We propose that ADR needs to be used as a tool to assess trainee competency and should be a marker to evaluate proper training. These could be evaluated in randomized prospective trials in future

Rifaximin Treatment in Hepatic Encephalopathy

Background Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established. Methods In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy. Results Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P Conclusions Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038.

A cost comparison study to review community versus acute hospital models of nursing care delivered to oncology patients

Purpose: Ireland's Sláintecare health plan is placing an increased focus on primary care. A community oncology nursing programme was developed to train community nurses to deliver care in the community. While the initial pilot was proven to be clinically safe, no cost evaluation was carried out. This study aims to compare the costs of providing cancer support services in a day-ward versus in the community. Methods: 183 interventions (40 in day-ward and 143 in community) were timed and costed using healthcare professional salaries and the Human Capital method. Results: From the healthcare provider perspective, the day-ward was a significantly cheaper option by an average of €17.13 (95% CI €13.72 - €20.54, p < 0.001). From the societal perspective, the community option was cheaper by an average of €2.77 (95% CI -€3.02 – €8.55), although this was a non-significant finding. Sensitivity analyses indicate that the community service may be significantly cheaper from the societal perspective. Conclusions: Given the demand for cost-viable options for primary care services, this programme may represent a national option for cancer care in Ireland when viewed from the societal perspective

Developing the principles of chair based exercise for older people: a modified Delphi study

Background Chair based exercise (CBE) is suggested to engage older people with compromised health and mobility in an accessible form of exercise. A systematic review looking at the benefits of CBE for older people identified a lack of clarity regarding a definition, delivery, purpose and benefits. This study aimed to utilise expert consensus to define CBE for older people and develop a core set of principles to guide practice and future research. Methods The framework for consensus was constructed through a team workshop identifying 42 statements within 7 domains. A four round electronic Delphi study with multi-disciplinary health care experts was undertaken. Statements were rated using a 5 point Likert scale of agreement and free text responses. A threshold of 70% agreement was used to determine consensus. Free text responses were analysed thematically. Between rounds a number of strategies (e.g., amended wording of statements, generation and removal of statements) were used to move towards consensus. Results 16 experts agreed on 46 statements over four rounds of consultation (Round 1: 22 accepted, 3 removed, 5 new and 17 modified; Round 2: 16 accepted, 0 removed, 4 new and 6 modified; Round 3: 4 accepted, 2 removed, 0 new and 4 modified; Round 4: 4 accepted, 0 removed, 0 new, 0 modified). Statements were accepted in all seven domains: the definition of CBE (5), intended users (3), potential benefits (8), structure (12), format (8), risk management (7) and evaluation (3). The agreed definition of CBE had five components: 1. CBE is primarily a seated exercise programme; 2. The purpose of using a chair is to promote stability in both sitting and standing; 3. CBE should be considered as part of a continuum of exercise for frail older people where progression is encouraged; 4. CBE should be used flexibly to respond to the changing needs of frail older people; and 5. Where possible CBE should be used as a starting point to progress to standing programmes. Conclusions Consensus has been reached on a definition and a set of principles governing CBE for older people; this provides clarity for implementation and future research about CBE

A systematic review and meta-analysis of the characteristics of multiple perpetrator sexual offences

This systematic review examined the demographic and offence variables in group sexual offending. Eight bibliographic databases and three thesis portals were searched. The reference lists of five papers and one textbook were hand searched. Nine experts were contacted for ongoing or unpublished studies. The total number of hits was 1853, of which 55 were duplicates, 1769 were irrelevant, 14 did not meet the inclusion criteria and one paper was unobtainable. The remaining 15 papers were quality assessed before the data were extracted and synthesized. There were 2,873 cases of Multiple Perpetrator Sexual (MPS) offences in total. The majority of MPS offending in the included studies involved perpetrators in their early twenties (90% of studies), of Black/African Caribbean ethnicity (30.1%), and operated as part of a „duo‟ (49.8%). Thirty-five percent of MPS offences were committed by perpetrators with a previous conviction, with 11% of the cases showing a previous conviction for sexual offending. Offenders were most likely to approach victims outdoors with the offence itself occurring indoors. The most frequent offence behaviors included vaginal rape, multiple penetration and fellatio. A model of MPS offending is suggested based on the findings of this review. Future research should aim to explore and refine theories of MPS offending in order to understand the etiology of this unique offending group

Immunogenicity of Self-Associated Aggregates and Chemically Cross-Linked Conjugates of the 42 kDa Plasmodium falciparum Merozoite Surface Protein-1

Self-associated protein aggregates or cross-linked protein conjugates are, in general, more immunogenic than oligomeric or monomeric forms. In particular, the immunogenicity in mice of a recombinant malaria transmission blocking vaccine candidate, the ookinete specific Plasmodium falciparum 25 kDa protein (Pfs25), was increased more than 1000-fold when evaluated as a chemical cross-linked protein-protein conjugate as compared to a formulated monomer. Whether alternative approaches using protein complexes improve the immunogenicity of other recombinant malaria vaccine candidates is worth assessing. In this work, the immunogenicity of the recombinant 42 kDa processed form of the P. falciparum merozoite surface protein 1 (MSP142) was evaluated as a self-associated, non-covalent aggregate and as a chemical cross-linked protein-protein conjugate to ExoProtein A, which is a recombinant detoxified form of Pseudomonas aeruginosa exotoxin A. MSP142 conjugates were prepared and characterized biochemically and biophysically to determine their molar mass in solution and stoichiometry, when relevant. The immunogenicity of the MSP142 self-associated aggregates, cross-linked chemical conjugates and monomers were compared in BALB/c mice after adsorption to aluminum hydroxide adjuvant, and in one instance in association with the TLR9 agonist CPG7909 with an aluminum hydroxide formulation. Antibody titers were assessed by ELISA. Unlike observations made for Pfs25, no significant enhancement in MSP142 specific antibody titers was observed for any conjugate as compared to the formulated monomer or dimer, except for the addition of the TLR9 agonist CPG7909. Clearly, enhancing the immunogenicity of a recombinant protein vaccine candidate by the formation of protein complexes must be established on an empirical basis

Insulin Gene Expression Is Regulated by DNA Methylation

BACKGROUND:Insulin is a critical component of metabolic control, and as such, insulin gene expression has been the focus of extensive study. DNA sequences that regulate transcription of the insulin gene and the majority of regulatory factors have already been identified. However, only recently have other components of insulin gene expression been investigated, and in this study we examine the role of DNA methylation in the regulation of mouse and human insulin gene expression. METHODOLOGY/PRINCIPAL FINDINGS:Genomic DNA samples from several tissues were bisulfite-treated and sequenced which revealed that cytosine-guanosine dinucleotide (CpG) sites in both the mouse Ins2 and human INS promoters are uniquely demethylated in insulin-producing pancreatic beta cells. Methylation of these CpG sites suppressed insulin promoter-driven reporter gene activity by almost 90% and specific methylation of the CpG site in the cAMP responsive element (CRE) in the promoter alone suppressed insulin promoter activity by 50%. Methylation did not directly inhibit factor binding to the CRE in vitro, but inhibited ATF2 and CREB binding in vivo and conversely increased the binding of methyl CpG binding protein 2 (MeCP2). Examination of the Ins2 gene in mouse embryonic stem cell cultures revealed that it is fully methylated and becomes demethylated as the cells differentiate into insulin-expressing cells in vitro. CONCLUSIONS/SIGNIFICANCE:Our findings suggest that insulin promoter CpG demethylation may play a crucial role in beta cell maturation and tissue-specific insulin gene expression

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure