The clinical effectiveness of individual behaviour change interventions to reduce risky sexual behaviour after a negative human immunodeficiency virus test in men who have sex with men: systematic and realist reviews and intervention development

Background: Men who have sex with men (MSM) experience significant inequalities in health and well-being. They are the group in the UK at the highest risk of acquiring a human immunodeficiency virus (HIV) infection. Guidance relating to both HIV infection prevention, in general, and individual-level behaviour change interventions, in particular, is very limited. Objectives: To conduct an evidence synthesis of the clinical effectiveness of behaviour change interventions to reduce risky sexual behaviour among MSM after a negative HIV infection test. To identify effective components within interventions in reducing HIV risk-related behaviours and develop a candidate intervention. To host expert events addressing the implementation and optimisation of a candidate intervention. Data sources: All major electronic databases (British Education Index, BioMed Central, Cumulative Index to Nursing and Allied Health Literature, EMBASE, Educational Resource Index and Abstracts, Health and Medical Complete, MEDLINE, PsycARTICLES, PsycINFO, PubMed and Social Science Citation Index) were searched between January 2000 and December 2014. Review methods: A systematic review of the clinical effectiveness of individual behaviour change interventions was conducted. Interventions were examined using the behaviour change technique (BCT) taxonomy, theory coding assessment, mode of delivery and proximity to HIV infection testing. Data were summarised in narrative review and, when appropriate, meta-analysis was carried out. Supplemental analyses for the development of the candidate intervention focused on post hoc realist review method, the assessment of the sequential delivery and content of intervention components, and the social and historical context of primary studies. Expert panels reviewed the candidate intervention for issues of implementation and optimisation. Results: Overall, trials included in this review (n = 10) demonstrated that individual-level behaviour change interventions are effective in reducing key HIV infection risk-related behaviours. However, there was considerable clinical and methodological heterogeneity among the trials. Exploratory meta-analysis showed a statistically significant reduction in behaviours associated with high risk of HIV transmission (risk ratio 0.75, 95% confidence interval 0.62 to 0.91). Additional stratified analyses suggested that effectiveness may be enhanced through face-to-face contact immediately after testing, and that theory-based content and BCTs drawn from ‘goals and planning’ and ‘identity’ groups are important. All evidence collated in the review was synthesised to develop a candidate intervention. Experts highlighted overall acceptability of the intervention and outlined key ways that the candidate intervention could be optimised to enhance UK implementation. Limitations: There was a limited number of primary studies. All were from outside the UK and were subject to considerable clinical, methodological and statistical heterogeneity. The findings of the meta-analysis must therefore be treated with caution. The lack of detailed intervention manuals limited the assessment of intervention content, delivery and fidelity. Conclusions: Evidence regarding the effectiveness of behaviour change interventions suggests that they are effective in changing behaviour associated with HIV transmission. Exploratory stratified meta-analyses suggested that interventions should be delivered face to face and immediately after testing. There are uncertainties around the generalisability of these findings to the UK setting. However, UK experts found the intervention acceptable and provided ways of optimising the candidate intervention. Future work: There is a need for well-designed, UK-based trials of individual behaviour change interventions that clearly articulate intervention content and demonstrate intervention fidelity

The Protective Effect of Minocycline in a Paraquat-Induced Parkinson's Disease Model in Drosophila is Modified in Altered Genetic Backgrounds

Epidemiological studies link the herbicide paraquat to increased incidence of Parkinson's disease (PD). We previously reported that Drosophila exposed to paraquat recapitulate PD symptoms, including region-specific degeneration of dopaminergic neurons. Minocycline, a tetracycline derivative, exerts ameliorative effects in neurodegenerative disease models, including Drosophila. We investigated whether our environmental toxin-based PD model could contribute to an understanding of cellular and genetic mechanisms of minocycline action and whether we could assess potential interference with these drug effects in altered genetic backgrounds. Cofeeding of minocycline with paraquat prolonged survival, rescued mobility defects, blocked generation of reactive oxygen species, and extended dopaminergic neuron survival, as has been reported previously for a genetic model of PD in Drosophila. We then extended this study to identify potential interactions of minocycline with genes regulating dopamine homeostasis that might modify protection against paraquat and found that deficits in GTP cyclohydrolase adversely affect minocycline rescue. We further performed genetic studies to identify signaling pathways that are necessary for minocycline protection against paraquat toxicity and found that mutations in the Drosophila genes that encode c-Jun N-terminal kinase (JNK) and Akt/Protein kinase B block minocycline rescue

\u3ci\u3edtorsin\u3c/i\u3e, the \u3ci\u3eDrosophila\u3c/i\u3e Ortholog of the Early-Onset Dystonia \u3ci\u3eTOR1A\u3c/i\u3e (\u3ci\u3eDYT1\u3c/i\u3e), Plays a Novel Role in Dopamine Metabolism

Dystonia represents the third most common movement disorder in humans. At least 15 genetic loci (DYT1-15) have been identified and some of these genes have been cloned. TOR1A (formally DYT1), the gene responsible for the most common primary hereditary dystonia, encodes torsinA, an AAA ATPase family protein. However, the function of torsinA has yet to be fully understood. Here, we have generated and characterized a complete loss-of-function mutant for dtorsin, the only Drosophila ortholog of TOR1A. Null mutation of the X-linked dtorsin was semi-lethal with most male flies dying by the prepupal stage and the few surviving adults being sterile and slow moving, with reduced cuticle pigmentation and thin, short bristles. Third instar male larvae exhibited locomotion defects that were rescued by feeding dopamine. Moreover, biochemical analysis revealed that the brains of third instar larvae and adults heterozygous for the loss-of-function dtorsin mutation had significantly reduced dopamine levels. The dtorsin mutant showed a very strong genetic interaction with Pu (Punch: GTP cyclohydrolase), the ortholog of the human gene underlying DYT14 dystonia. Biochemical analyses revealed a severe reduction of GTP cyclohydrolase protein and activity, suggesting that dtorsin plays a novel role in dopamine metabolism as a positive-regulator of GTP cyclohydrolase protein. This dtorsin mutant line will be valuable for understanding this relationship and potentially other novel torsin functions that could play a role in human dystonia