Transmission dynamics of the 2016-18 outbreak of hepatitis A among men who have sex with men in England and cost-effectiveness analysis of vaccination strategies to prevent future outbreaks.

Background: Despite being vaccine-preventable, hepatitis A virus (HAV) outbreaks occur among men who have sex with men (MSM). We modelled the cost-effectiveness of vaccination strategies to prevent future outbreaks. Methods: A HAV transmission model was calibrated to HAV outbreak data for MSM in England over 2016-2018, producing estimates for the basic reproduction number (R0) and immunity levels (seroprevalence) post-outbreak. For a hypothetical outbreak in 2023 (same R0 and evolving immunity), the cost-effectiveness of pre-emptive (vaccination between outbreaks among MSM attending sexual health services (SHS)) and reactive (vaccination during outbreak among MSM attending SHS and primary care) vaccination strategies were modelled. Effectiveness in quality-adjusted life-years (QALYs) and costs were estimated (2017 UK pounds) from a societal perspective (10-year time horizon; 3% discount rate). The incremental cost-effectiveness ratio (ICER) was estimated. Findings: R0 for the 2016-2018 outbreak was 3·19 (95% credibility interval (95%CrI) 2·87-3·46); seroprevalence among MSM increased to 70·4% (95%CrI 67·3-72·8%) post-outbreak. For our hypothetical HAV outbreak in 2023, pre-emptively vaccinating MSM over the preceding five-years was cost-saving (compared to no vaccination) if the yearly vaccine coverage rate among MSM attending SHS was 8%. If the pre-emptive yearly vaccination rate fell below this threshold, it became cost-saving to add reactive vaccination to pre-emptive vaccination. Interpretation: Although highly transmissible, existing immunity limited the recent HAV outbreak among MSM in England. Pre-emptive vaccination between outbreaks, with reactive vaccination if indicated, is the best strategy for limiting future HAV outbreaks. Funding: NIHR

Technical Design Report for the PANDA Solenoid and Dipole Spectrometer Magnets

This document is the Technical Design Report covering the two large spectrometer magnets of the PANDA detector set-up. It shows the conceptual design of the magnets and their anticipated performance. It precedes the tender and procurement of the magnets and, hence, is subject to possible modifications arising during this process.Comment: 10 pages, 14MB, accepted by FAIR STI in May 2009, editors: Inti Lehmann (chair), Andrea Bersani, Yuri Lobanov, Jost Luehning, Jerzy Smyrski, Technical Coordiantor: Lars Schmitt, Bernd Lewandowski (deputy), Spokespersons: Ulrich Wiedner, Paola Gianotti (deputy

Asteroseismology and Interferometry

Asteroseismology provides us with a unique opportunity to improve our understanding of stellar structure and evolution. Recent developments, including the first systematic studies of solar-like pulsators, have boosted the impact of this field of research within Astrophysics and have led to a significant increase in the size of the research community. In the present paper we start by reviewing the basic observational and theoretical properties of classical and solar-like pulsators and present results from some of the most recent and outstanding studies of these stars. We centre our review on those classes of pulsators for which interferometric studies are expected to provide a significant input. We discuss current limitations to asteroseismic studies, including difficulties in mode identification and in the accurate determination of global parameters of pulsating stars, and, after a brief review of those aspects of interferometry that are most relevant in this context, anticipate how interferometric observations may contribute to overcome these limitations. Moreover, we present results of recent pilot studies of pulsating stars involving both asteroseismic and interferometric constraints and look into the future, summarizing ongoing efforts concerning the development of future instruments and satellite missions which are expected to have an impact in this field of research.Comment: Version as published in The Astronomy and Astrophysics Review, Volume 14, Issue 3-4, pp. 217-36

Prime–boost vaccination with plasmid and adenovirus gene vaccines control HER2/neu(+ )metastatic breast cancer in mice

INTRODUCTION: Once metastasis has occurred, the possibility of completely curing breast cancer is unlikely, particularly for the 30 to 40% of cancers overexpressing the gene for HER2/neu. A vaccine targeting p185, the protein product of the HER2/neu gene, could have therapeutic application by controlling the growth and metastasis of highly aggressive HER2/neu(+ )cells. The purpose of this study was to determine the effectiveness of two gene vaccines targeting HER2/neu in preventive and therapeutic tumor models. METHODS: The mouse breast cancer cell line A2L2, which expresses the gene for rat HER2/neu and hence p185, was injected into the mammary fat pad of mice as a model of solid tumor growth or was injected intravenously as a model of lung metastasis. SINCP-neu, a plasmid containing Sindbis virus genes and the gene for rat HER2/neu, and Adeno-neu, an E1,E2a-deleted adenovirus also containing the gene for rat HER2/neu, were tested as preventive and therapeutic vaccines. RESULTS: Vaccination with SINCP-neu or Adeno-neu before tumor challenge with A2L2 cells significantly inhibited the growth of the cells injected into the mammary fat or intravenously. Vaccination 2 days after tumor challenge with either vaccine was ineffective in both tumor models. However, therapeutic vaccination in a prime–boost protocol with SINCP-neu followed by Adeno-neu significantly prolonged the overall survival rate of mice injected intravenously with the tumor cells. Naive mice vaccinated using the same prime–boost protocol demonstrated a strong serum immunoglobulin G response and p185-specific cellular immunity, as shown by the results of ELISPOT (enzyme-linked immunospot) analysis for IFNγ. CONCLUSION: We report herein that vaccination of mice with a plasmid gene vaccine and an adenovirus gene vaccine, each containing the gene for HER2/neu, prevented growth of a HER2/neu-expressing breast cancer cell line injected into the mammary fat pad or intravenously. Sequential administration of the vaccines in a prime–boost protocol was therapeutically effective when tumor cells were injected intravenously before the vaccination. The vaccines induced high levels of both cellular and humoral immunity as determined by in vitro assessment. These findings indicate that clinical evaluation of these vaccines, particularly when used sequentially in a prime–boost protocol, is justified

Genome-wide association study identifies PERLD1 as asthma candidate gene

10.1186/1471-2350-12-170BMC Medical Genetics12-BMGM

The role of neutral Rh(PONOP)H, free NMe2H, boronium and ammonium salts in the dehydrocoupling of dimethylamine-borane using the cationic pincer [Rh(PONOP)(η2-H2)]+ catalyst

The σ-amine-borane pincer complex [Rh(PONOP)(η1-H3B·NMe3)][BArF4] [2, PONOP = κ3-NC5H3-2,6-(OPtBu2)2] is prepared by addition of H3B·NMe3 to the dihydrogen precursor [Rh(PONOP)(η2-H2)][BArF4], 1. In a similar way the related H3B·NMe2H complex [Rh(PONOP)(η1-H3B·NMe2H)][BArF4], 3, can be made in situ, but this undergoes dehydrocoupling to reform 1 and give the aminoborane dimer [H2BNMe2]2. NMR studies on this system reveal an intermediate neutral hydride forms, Rh(PONOP)H, 4, that has been prepared independently. 1 is a competent catalyst (2 mol%, ∼30 min) for the dehydrocoupling of H3B·Me2H. Kinetic, mechanistic and computational studies point to the role of NMe2H in both forming the neutral hydride, via deprotonation of a σ-amine-borane complex and formation of aminoborane, and closing the catalytic cycle by reprotonation of the hydride by the thus-formed dimethyl ammonium [NMe2H2]+. Competitive processes involving the generation of boronium [H2B(NMe2H)2]+ are also discussed, but shown to be higher in energy. Off-cycle adducts between [NMe2H2]+ or [H2B(NMe2H)2]+ and amine-boranes are also discussed that act to modify the kinetics of dehydrocoupling

Current and prospective pharmacological targets in relation to antimigraine action

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon