Evidence-based interventions in dementia: A pragmatic cluster-randomised trial of an educational intervention to promote earlier recognition and response to dementia in primary care (EVIDEM-ED)

Background: The National Dementia Strategy seeks to enhance general practitioners' diagnostic and management skills in dementia. Early diagnosis in dementia within primary care is important as this allows those with dementia and their family care networks to engage with support services and plan for the future. There is, however, evidence that dementia remains under-detected and sub-optimally managed in general practice. An earlier unblinded, cluster randomised controlled study tested the effectiveness of educational interventions in improving detection rates and management of dementia in primary care. In this original trial, a computer decision support system and practice-based educational workshops were effective in improving rates of detecting dementia although not in changing clinical management. The challenge therefore is to find methods of changing clinical management. Our aim in this new trial is to test a customised educational intervention developed for general practice, promoting both earlier diagnosis and concordance with management guidelines.Design/Method: The customised educational intervention combines practice-based workshops and electronic support material. Its effectiveness will be tested in an unblinded cluster randomised controlled trial with a pre-post intervention design, with two arms; normal care versus the educational intervention. Twenty primary care practices have been recruited with the aim of gaining 200 patient participants. We will examine whether the intervention is effective, pragmatic and feasible within the primary care setting. Our primary outcome measure is an increase in the proportion of patients with dementia who receive at least two dementia-specific management reviews per year. We will also examine important secondary outcomes such as practice concordance with management guidelines and benefits to patients and carers in terms of quality of life and carer strain.Discussion: The EVIDEM-ED trial builds on the earlier study but the intervention is different in that it is specifically customised to the educational needs of each practice. If this trial is successful it could have implications for the implementation of the National Dementia Strategy

Preclinical Development of an In Vivo BCG Challenge Model for Testing Candidate TB Vaccine Efficacy

There is an urgent need for an immunological correlate of protection against tuberculosis (TB) with which to evaluate candidate TB vaccines in clinical trials. Development of a human challenge model of Mycobacterium tuberculosis (M.tb) could facilitate the detection of such correlate(s). Here we propose a novel in vivo Bacille Calmette-Guérin (BCG) challenge model using BCG immunization as a surrogate for M.tb infection. Culture and quantitative PCR methods have been developed to quantify BCG in the skin, using the mouse ear as a surrogate for human skin. Candidate TB vaccines have been evaluated for their ability to protect against a BCG skin challenge, using this model, and the results indicate that protection against a BCG skin challenge is predictive of BCG vaccine efficacy against aerosol M.tb challenge. Translation of these findings to a human BCG challenge model could enable more rapid assessment and down selection of candidate TB vaccines and ultimately the identification of an immune correlate of protection

Acute and Persistent Mycobacterium tuberculosis Infections Depend on the Thiol Peroxidase TPX

The macrophage is the natural niche of Mycobacterium tuberculosis infection. In order to combat oxidative and nitrosative stresses and persist in macrophages successfully, M. tuberculosis is endowed with a very efficient antioxidant complex. Amongst these antioxidant enzymes, TpX is the only one in M. tuberculosis with sequence homology to thiol peroxidase. Previous reports have demonstrated that the M. tuberculosis TpX protein functions as a peroxidase in vitro. It is the dominant antioxidant which protects M. tuberculosis against oxidative and nitrosative stresses. The level of the protein increases in oxidative stress. To determine the roles of tpx gene in M. tuberculosis survival and virulence in vivo, we constructed an M. tuberculosis strain lacking the gene. The characteristics of the mutant were examined in an in vitro stationary phase model, in response to stresses; in murine bone marrow derived macrophages and in an acute and an immune resistant model of murine tuberculosis. The tpx mutant became sensitive to H2O2 and NO compared to the wild type strain. Enzymatic analysis using bacterial extracts from the WT and the tpx mutant demonstrated that the mutant contains reduced peroxidase activity. As a result of this, the mutant failed to grow and survive in macrophages. The growth deficiency in macrophages became more pronounced after interferon-γ activation. In contrast, its growth was significantly restored in the macrophages of inducible nitric oxide synthase (iNOS or NOS2) knockout mice. Moreover, the tpx mutant was impaired in its ability to initiate an acute infection and to maintain a persistent infection. Its virulence was attenuated. Our results demonstrated that tpx is required for M. tuberculosis to deal with oxidative and nitrosative stresses, to survive in macrophages and to establish acute and persistent infections in animal tuberculosis models

The effect of emotion on interpretation and logic in a conditional reasoning task

The effect of emotional content on logical reasoning is explored in three experiments. The participants completed a conditional reasoning task (If p, then q) with emotional and neutral contents. In Experiment 1, existing emotional and neutral words were used. The emotional value of initially neutral words was experimentally manipulated in Experiments 1B and 2, using classical conditioning. In all experiments, participants were less likely to provide normatively correct answers when reasoning about emotional stimuli, compared with neutral stimuli. This was true for both negative (Experiments 1B & 2) and positive contents (Experiment 2). The participants' interpretations of the conditional statements were also measured (perceived sufficiency, necessity, causality, and plausibility). The results showed the expected relationship between interpretation and reasoning. However, emotion did not affect interpretation. Emotional and neutral conditional statements were interpreted similarly. The results are discussed in light of current models of emotion and reasoning. Copyright 2006 Psychonomic Society, Inc

Macrophage activation and resistance to pulmonary tuberculosis.

Mice were vaccinated with 300 micrograms of BCG cell walls (BCG-CW) in oil-in-water emulsion intravenously or with a high or low dose of living BCG by inhalation (BCG-HD or BCG-LD, respectively). The consequences of vaccination were evaluated in terms of the growth of BCG in the lungs and spleen, lung and spleen weight, resistance to intravenous and airborne challenge with Listeria monocytogenes, airborne challenge with virulent Mycobacterium tuberculosis H37Rv, and transfer of adoptive immunity. BCG-CW and BCG-HD mice developed increased lung weight, which was associated with transiet, low-level resistance to airborne L. monocytogenes and initial resistance to airborne H37Rv. Only BCG-CW mice developed splenomegaly, which was accompanied by high resistance to intravenous challenge with L. monocytogenes. The initial resistance of BCG-CW mice to H37Rv was not sustained, whereas that of BCG-HD mice persisted. There was no initial resistance to H37Rv in BCG-LD mice, but immunity was generated later. Overall, BCG-HD mice were most resistant to H37Rv, and BCG-CW and BCG-LD mice were less but equally resistant