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Cytochrome P450 2D6 (CYP2D6) is a critical pharmacogene involved in the metabolism of ~20% of commonly used drugs across a broad spectrum of medical disciplines including psychiatry, pain management, oncology and cardiology. Nevertheless, CYP2D6 is highly polymorphic with single-nucleotide polymorphisms, small insertions/deletions and larger structural variants including multiplications, deletions, tandem arrangements, and hybridisations with non-functional CYP2D7 pseudogenes. The frequency of these variants differs across populations, and they significantly influence the drug-metabolising enzymatic function of CYP2D6. Importantly, altered CYP2D6 function has been associated with both adverse drug reactions and reduced drug efficacy, and there is growing recognition of the clinical and economic burdens associated with suboptimal drug utilisation. To date, pharmacogenomic clinical guidelines for at least 48 CYP2D6-substrate drugs have been developed by prominent pharmacogenomics societies, which contain therapeutic recommendations based on CYP2D6-predicted categories of metaboliser phenotype. Novel algorithms to interpret CYP2D6 function from sequencing data that consider structural variants, and machine learning approaches to characterise the functional impact of novel variants, are being developed. However, CYP2D6 genotyping is yet to be implemented broadly into clinical practice, and so further effort and initiatives are required to overcome the implementation challenges and deliver the potential benefits to the bedside. [ABSTRACT FROM AUTHOR]

Background: Patients continue to suffer from medically unexplained symptoms otherwise referred to as persistent physical symptoms (PPS). General practitioners (GPs) play a key role in the management of PPS and require further training. Patients are often frustrated with the care they receive. This study aims to assess the acceptability of an 'integrated GP care' approach which consists of offering self-help materials to patients with PPS and offering their GPs training on how to utilise cognitive behavioural skills within their consultations, as well as assessing the feasibility of conducting a future trial in primary care to evaluate its benefit. Methods: A feasibility cluster randomised controlled trial was conducted in primary care, South London, UK. GP practices (clusters) were randomly allocated to 'integrated GP care plus treatment as usual' or 'treatment as usual'. Patients with PPS were recruited from participating GP practices before randomisation. Feasibility parameters, process variables and potential outcome measures were collected at pre-randomisation and at 12- and 24-weeks post-randomisation at cluster and individual participant level. Results: Two thousand nine hundred seventy-eight patients were identified from 18 GP practices. Out of the 424 patients who responded with interest in the study, 164 fully met the eligibility criteria. One hundred sixty-one patients provided baseline data before cluster randomisation and therefore were able to participate in the study. Most feasibility parameters indicated that the intervention was acceptable and a future trial feasible. 50 GPs from 8 GP practices (randomised to intervention) attended the offer of training and provided positive feedback. Scores in GP knowledge and confidence increased post-training. Follow-up rate of patients at 24 weeks was 87%. However estimated effect sizes on potential clinical outcomes were small. Conclusions: It was feasible to identify and recruit patients with PPS. Retention rates of participants up to 24 weeks were high. A wide range of health services were used. The intervention was relatively low cost and low risk. This complex intervention should be further developed to improve patients'/GPs' utilisation of audio/visual and training resources before proceeding to a full trial evaluation. Trial registration: NCT02444520 (ClinicalTrials.gov). [ABSTRACT FROM AUTHOR]

The article offers information on the mass mortality of Notopthalmus viridescens (Eastern Newt). Topics discussed include estimate of the past work on herpeto-faunal mortality, susceptibility of this species to impacts from impervious surfaces that may interrupt migratory pathways, and the most plausible mechanism for this mortality event.

• A longitudinal survey of 233 Australian coal miners was conducted. • Participants' age was a significant negative predictor of reported risk-taking. • Poor safety norms at mine sites were a significant positive predictor. • Reverse causal paths were nonsignificant in the longitudinal analysis. The present study undertook an exploratory investigation of the causes of risk-taking among Australian coal miners. A range of safety culture and climate variables were measured in a survey of open-cut and underground coal miners from New South Wales and Queensland. A repeat survey of 233 of these miners was conducted an average of 10 months after the initial survey. Participants' age and perceived safety norms at their mine site were significant longitudinal predictors of reported frequency of risk-taking. These findings suggest that young miners and miners who perceive it to be normal for miners at their mine site to ignore safety procedures are more likely to report taking safety risks in the future. Suggestions for safety interventions are considered. [ABSTRACT FROM AUTHOR]

The aim of the research described in this paper is to reduce the vulnerability of New Zealand's built infrastructure to wind damage through provision of improved wind speed prediction procedures for wind flow over complex terrain that could ultimately be incorporated into the AS/NZS 1170.2 loading standard. This paper presents results from a specific experiment which compares measured wind speedups (neutral atmosphere) over the rugged Belmont Hill region with wind speedups estimated from AS/NZS 1170.2 by two organisations, and from six other international wind-loading standards, through Computational Fluid Dynamics (Gerris and WAsP) modelling, and through wind-tunnel modelling. It was found that computer modelling with the large-eddy simulation CFD code Gerris and wind-tunnel measurements, agree remarkably well with the observations and differentiate considerably better between areas exposed or sheltered by the local terrain features compared to applying the CFD code WAsP (4.1), or applying the AS/NZS 1170.2 wind-loading standard. Furthermore, it was found that the AS/NZS1170.2 predictions differed significantly when carried out by different organisations. The wind speedup prediction methods from the six other international standards all use similar approaches and thus the predictions from all of them were quite similar, and did not agree particularly well with the field measurements. • Multiple method speedup comparison: Full-scale, Wind Tunnel, CFD LES and CFD WAsP. • Full-scale wind speedup measurements over complex terrain. • Large Collaboration: University of Auckland, NIWA, GNS Science, WPS-Opus. • Detailed analysis of wind speedup results and comparison with many wind standards. • Useful data for developing improved wind speedup algorithms for wind standards. [ABSTRACT FROM AUTHOR]

The synthesis of callipeltosides A, B and C has been achieved in a highly convergent manner. Key to this was the synthesis of the common callipeltoside aglycon by means of an ambitious diastereoselective alkenyl metal addition of the entire bottom fragment to the pyran core, followed by Yamaguchi macrolactonisation. Following this, the endgame was in sight, with each callipeltoside picked off in turn by attachment of the appropriate sugar and unequivocal completion of the series. It’s the bullseye! For more information see the Full Paper by S. V. Ley, J. R. Frost, et al. on page 13261 ff. [ABSTRACT FROM AUTHOR]

The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers. [ABSTRACT FROM AUTHOR]

An abstract of the article "NFkB Activation Promotes Immune Activation in HTLV-I-associated Myelopathy / Tropical Spastic Paraparesis," Matthew McCormick and colleagues from 15th International Conference on Human Retroviruses held in Belgium from June 5-8, 2011 is presented.