Efficacy of hepatic transplantation in patients with primary sclerosing cholangitis

Controlled trials to assess the therapeutic benefit of orthotopic hepatic transplantation (OHTx) for primary sclerosing cholangitis (PSC) cannot be justified in view of improvement of patient survival after this operation since 1981. However, the actual patient survival with OHTx can be compared with the Mayo model estimated survival probabilities without OHTx. This model, which encompasses physical, biochemical and histopathologic parameters of PSC, was constructed from a study of 392 conservatively treated PSC patients at five international centers in England and North America. We compared the actual survival of 216 adult patients with the diagnosis of advanced PSC who underwent hepatic replacement with the expected survival estimated by the Mayo PSC natural history model, 'the simulated control technique.' OHTx was performed at the University of Pittsburgh and Mayo Medical Center between 5 December 1981 and 26 December 1990. The mean (plus or minus standard deviation) post-OHTx follow-up period was 34 ± 25 months (range of zero to 104 months). Before transplantation, biliary or portal hypertensive operation, or both, was performed upon 104 patients. At operation, the mean age of recipients was 42.1 ± 11.3 years and the mean value of total serum bilirubin was 13.3 ± 13.0 milligrams per deciliter. Extensive septal fibrosis and cirrhosis were histologically documented in 97 percent of the patients, with splenomegaly in 63 percent. Immunosuppressive therapy was based primarily on cyclosporin in 184 recipients and FK-506 in 32. Within six months, the Kaplan-Meier survival probability after OHTx (0.89) already was higher than predicted by the Mayo model (0.83). At five years, the Kaplan-Meier actual survival with OHTx was 0.73 compared with 0.28 expected Mayo model survival. The overall increased survival rate with transplantation was statistically significant (chi-square equals 126.6; p<0.001). At all risk stratifications, OHTx significantly improved survival with a p value of 0.031 (low risk), 0.001 (moderate risk) and <0.001 (high risk). Thus, OHTx is effective therapy for PSC. Disease gravity and unsuspected cholangiocarcinoma in the excised native liver adversely influenced short and long term survival rates after transplantation, respectively

Efficacy of Liver Transplantation in Patients with Primary Biliary Cirrhosis

No controlled trials have been performed to assess the efficacy of liver transplantation. Because of the marked improvement in survival after liver transplantation since 1981, random assignment of patients to a control group not undergoing transplantation is considered clinically inappropriate. To assess the efficacy of liver transplantation in patients with primary biliary cirrhosis, we compared survival in 161 patients with this diagnosis who had undergone a liver transplantation with survival in patients with the same diagnosis who had been treated conservatively. The comparison was performed with use of a recently developed statistical technique, the Mayo model. All patients had undergone liver transplantation between March 1980 and June 1987 and were followed for a median of 25 months. Three months after liver transplantation, the Kaplan–Meier survival probabilities in the recipients were substantially higher than the Mayo-model “simulated-control” survival probabilities (P<0.001). At two years, the Kaplan–Meier survival probability was 0.74, whereas the mean Mayo-model survival probability was 0.31. The patients who were at low risk according to the Mayo model had the best probability of survival after liver transplantation; however, patients at all risk levels who had undergone liver transplantation had higher probabilities of survival than those who had not. We conclude that liver transplantation is an efficacious treatment in patients with advanced primary biliary cirrhosis. (N Engl J Med 1989; 320:1709–13.), LIVER transplantation has been accepted clinically as a lifesaving treatment in various end-stage liver diseases, including primary biliary cirrhosis.1,2 However, no controlled trials have been performed to evaluate the efficacy of this procedure. Indeed, because there has been a marked improvement since 1981 in survival after transplantation, random assignment of patients with advanced liver disease to a nontransplantation control group is considered to be clinically inappropriate. At the Mayo Clinic, a Cox regression model for predicting the probability of survival in patients with conservatively treated primary biliary cirrhosis has been developed.3 To provide control data for assessing the efficacy of…. © 1989, Massachusetts Medical Society. All rights reserved

Does Deworming Improve Growth and School Performance in Children?

Background The World Bank ranks soil-transmitted helminth infection as causing more ill health in children aged 5–15 years than any other infection. In light of this ranking, global agencies recommend regular, mass treatment with deworming drugs to children in developing countries. The World Health Organization (WHO) argues that “deworming helps meet the Millennium Development Goals”, in particular the six health-related goals:eradicate extreme poverty and hunger;achieve universal primary education;promote gender equality and empower women;reduce child mortality and improve maternal health; and combat HIV/AIDS, malaria, and other diseases. However, deworming campaigns cost money to deliver, and so we must be clear that WHO statements about the impact of these programmes are based on reliable evidence. In 2000, we systematically reviewed the reliable evidence from relevant controlled trials about the effects of anthelminth drugs for soil-transmitted helminth infection on child growth and cognition. This systematic review, published in The Cochrane Database and the BMJ, demonstrated uncertainty around the assumed benefit and concluded that it may be a potentially important intervention, but needed better evaluation. The BMJ published a large number of letters that criticised the findings, including from authors at the World Bank, the WHO, the United States Centers for Disease Control and Prevention, and the Pan American Health Organization. We do not feel that these criticisms were scientifically substantive enough to undermine the method or the conclusion. For example, several critics commented on the fact that the systematic review could not make any conclusions about the long-term effects of treatment—but, as we argued in our reply to these criticisms, “we were unable to find any randomised controlled trials that evaluated long term benefit, and the evidence of short term benefit was not, for us, convincing.” The research community quite correctly carried out further randomised controlled trials (RCTs) of repeated doses in community trials with longer follow-up compared with no intervention or placebo. In light of this additional research, we have now updated the original Cochrane review. An author of one of the trials included in the 2000 review, Ed Cooper, criticised the review for not taking into account heterogeneity in parasite burdens. Therefore, in the recently updated review, we conducted an additional subgroup analysis at trial level stratified by worm intensity and prevalence

Exploring the behavioural drivers of veterinary surgeon antibiotic prescribing: a qualitative study of companion animal veterinary surgeons in the UK

Background: Multi-drug resistant bacteria are an increasing concern in both human and veterinary medicine. Inappropriate prescribing and use of antibiotics within veterinary medicine may be a contributory factor to antimicrobial resistance (AMR). The ‘One Health’ Initiative aims to work across species and environments to reduce AMR, however; little is currently known about the factors which influence antibiotic prescribing among veterinary surgeons in companion animal practice. This paper reports on qualitative data analysis of interviews with veterinary surgeons whose practice partially or wholly focuses on companion animals (N = 16). The objective of the research was to explore the drivers of companion animal veterinary surgeons’ antibiotic prescribing behaviours. The veterinary surgeons interviewed were all practising within the UK (England (n = 4), Scotland (n = 11), Northern Ireland (n = 1)). A behavioural thematic analysis of the data was undertaken, which identified barriers and facilitators to specific prescribing-related behaviours. Results: Five components of prescribing behaviours were identified: 1) confirming clinical need for antibiotics; 2) responding to clients; 3) confirming diagnosis; 4) determining dose, duration and type of antibiotic; and 5) preventing infection around surgery (with attendant appropriate and inappropriate antibiotic prescribing behaviours). Barriers to appropriate prescribing identified include: business, diagnostic, fear, habitual practice and pharmaceutical factors. Facilitators include: AMR awareness, infection prevention, professional learning and regulation and government factors. Conclusion: This paper uses a behavioural lens to examine drivers which are an influence on veterinary surgeons’ prescribing behaviours. The paper contributes new understandings about factors which influence antibiotic prescribing behaviours among companion animal veterinary surgeons. This analysis provides evidence to inform future interventions, which are focused on changing prescribing behaviours, in order to address the pressing public health concern of AMR

Bestrophin1: A Gene that Causes Many Diseases

Bestrophinopathies are a group of clinically distinct inherited retinal dystrophies that lead to the gradual loss of vision in and around the macular area. There are no treatments for patients suffering from bestrophinopathies, and no measures can be taken to prevent visual deterioration in those who have inherited disease-causing mutations. Bestrophinopathies are caused by mutations in the Bestrophin1 gene (BEST1), a protein found exclusively in the retinal pigment epithelial (RPE) cells of the eye. Mutations in BEST1 affect the function of the RPE leading to the death of overlying retinal cells and subsequent vision loss. The pathogenic mechanisms arising from BEST1 mutations are still not fully understood, and it is not clear how mutations in BEST1 lead to diseases with distinct clinical features. This chapter discusses BEST1, the use of model systems to investigate the effects of mutations and the potential to investigate individual bestrophinopathies using induced pluripotent stem cells

Alternative patterns of sex chromosome differentiation in Aedes aegypti (L).

BACKGROUND: Some populations of West African Aedes aegypti, the dengue and zika vector, are reproductively incompatible; our earlier study showed that divergence and rearrangements of genes on chromosome 1, which bears the sex locus (M), may be involved. We also previously described a proposed cryptic subspecies SenAae (PK10, Senegal) that had many more high inter-sex FST genes on chromosome 1 than did Ae.aegypti aegypti (Aaa, Pai Lom, Thailand). The current work more thoroughly explores the significance of those findings. RESULTS: Intersex standardized variance (FST) of single nucleotide polymorphisms (SNPs) was characterized from genomic exome capture libraries of both sexes in representative natural populations of Aaa and SenAae. Our goal was to identify SNPs that varied in frequency between males and females, and most were expected to occur on chromosome 1. Use of the assembled AaegL4 reference alleviated the previous problem of unmapped genes. Because the M locus gene nix was not captured and not present in AaegL4, the male-determining locus, per se, was not explored. Sex-associated genes were those with FST values ≥ 0.100 and/or with increased expected heterozygosity (H exp , one-sided T-test, p < 0.05) in males. There were 85 genes common to both collections with high inter-sex FST values; all genes but one were located on chromosome 1. Aaa showed the expected cluster of high inter-sex FST genes proximal to the M locus, whereas SenAae had inter-sex FST genes along the length of chromosome 1. In addition, the Aaa M-locus proximal region showed increased H exp levels in males, whereas SenAae did not. In SenAae, chromosomal rearrangements and subsequent suppressed recombination may have accelerated X-Y differentiation. CONCLUSIONS: The evidence presented here is consistent with differential evolution of proto-Y chromosomes in Aaa and SenAae

Measurement of the Relative Branching Fraction of Υ(4S)\Upsilon(4S) to Charged and Neutral B-Meson Pairs

We analyze 9.7 x 10^6 B\bar{B}$ pairs recorded with the CLEO detector to determine the production ratio of charged to neutral B-meson pairs produced at the Y(4S) resonance. We measure the rates for B^0 -> J/psi K^{(*)0} and B^+ -> J/psi K^{(*)+} decays and use the world-average B-meson lifetime ratio to extract the relative widths f+-/f00 = Gamma(Y(4S) -> B+B-)/Gamma(Y(4S) -> B0\bar{B0}) = = 1.04 +/- 0.07(stat) +/- 0.04(syst). With the assumption that f+- + f00 = 1, we obtain f00 = 0.49 +/- 0.02(stat) +/- 0.01(syst) and f+- = 0.51 +/- 0.02(stat) +/- 0.01(syst). This production ratio and its uncertainty apply to all exclusive B-meson branching fractions measured at the Y(4S) resonance.Comment: 11 pages postscript, also available through http://w4.lns.cornell.edu/public/CLN

First Observation of the Decays B0→D∗−ppˉπ+B^{0}\to D^{*-}p\bar{p}\pi^{+} and B^{0}\to D^{*-}p\bar{n}$

We report the first observation of exclusive decays of the type B to D^* N anti-N X, where N is a nucleon. Using a sample of 9.7 times 10^{6} B-Bbar pairs collected with the CLEO detector operating at the Cornell Electron Storage Ring, we measure the branching fractions B(B^0 \to D^{*-} proton antiproton \pi^+) = ({6.5}^{+1.3}_{-1.2} +- 1.0) \times 10^{-4} and B(B^0 \to D^{*-} proton antineutron) = ({14.5}^{+3.4}_{-3.0} +- 2.7) times 10^{-4}. Antineutrons are identified by their annihilation in the CsI electromagnetic calorimeter.Comment: 9 pages postscript, also available through http://w4.lns.cornell.edu/public/CLN

Study of the Decays B0 --> D(*)+D(*)-

The decays B0 --> D*+D*-, B0 --> D*+D- and B0 --> D+D- are studied in 9.7 million Y(4S) --> BBbar decays accumulated with the CLEO detector. We determine Br(B0 --> D*+D*-) = (9.9+4.2-3.3+-1.2)e-4 and limit Br(B0 --> D*+D-) < 6.3e-4 and Br(B0 --> D+D-) < 9.4e-4 at 90% confidence level (CL). We also perform the first angular analysis of the B0 --> D*+D*- decay and determine that the CP-even fraction of the final state is greater than 0.11 at 90% CL. Future measurements of the time dependence of these decays may be useful for the investigation of CP violation in neutral B meson decays.Comment: 21 pages, 5 figures, submitted to Phys. Rev.

A Search for B→τνB\to \tau\nu

We report results of a search for $B\to\tau\nu$ in a sample of 9.7 million charged $B$ meson decays. The search uses both $\pi\nu$ and $\ell\nu\bar\nu$ decay modes of the $\tau$, and demands exclusive reconstruction of the companion $\bar B$ decay to suppress background. We set an upper limit on the branching fraction ${\cal B}(B\to \tau\nu) < 8.4\times 10^{-4}$ at 90% confidence level. With slight modification to the analysis we also establish ${\cal B}(B^\pm\to K^\pm\nu\bar\nu) < 2.4\times 10^{-4}$ at 90% confidence level.Comment: 10 ages postscript, also available through http://w4.lns.cornell.edu/public/CLN