New drug controls and reduced hospital presentations due to novel psychoactive substances in Edinburgh.

AIMS: Recreational use of novel psychoactive substance (NPS) has become increasingly common. We aimed to assess the association of national legislation and local trading standards activity with hospital presentations. METHODS: We established observational cohorts of patients with recreational drug toxicity presenting to Edinburgh Royal Infirmary and dying with detectable recreational drugs in Edinburgh. We assessed associations with two temporary class drug-orders (April 2015: methylphenidates, Nov 2015: methiopropamine), the Psychoactive Substances Act (June 2016), and trading standards forfeiture orders (October 2015). RESULTS: The methylphenidate temporary class drug-order was associated with rapid 46.7% (P = 0.002) and 21.0% (P = 0.003) reductions in presentations and admissions, respectively, for NPS drug toxicity, comparing 12 months before with 6 months after. The change was greatest for ethylphenidate toxicity (96.7% reduction in admissions, P < 0.001) that was partly offset by a tripling in synthetic cannabinoid receptor agonist cases (P < 0.001) over the next 6 months. This increase reversed following trading standards activity removing all NPS drugs from local shops in October 2015, associated with 64.3% (P < 0.001) and 83.7% (P < 0.001) reductions in presentations and admissions, respectively, for all NPS drugs over the next 12 months. The effect was sustained and associated with a reduced postmortem detection of stimulant NPS drugs. The two interventions prevented an estimated 557 (95% confidence interval 327-934) NPS admissions during 2016, saving an estimated £303 030 (£177 901-508 133) in hospital costs. CONCLUSIONS: We show here that drug legislation and trading standards activity may be associated with effective and sustained prevention. Widespread adoption of trading standards enforcement, together with focused legislation, may turn the tide against these highly-damaging drugs.

Human In Silico Drug Trials Demonstrate Higher Accuracy than Animal Models in Predicting Clinical Pro-Arrhythmic Cardiotoxicity.

Early prediction of cardiotoxicity is critical for drug development. Current animal models raise ethical and translational questions, and have limited accuracy in clinical risk prediction. Human-based computer models constitute a fast, cheap and potentially effective alternative to experimental assays, also facilitating translation to human. Key challenges include consideration of inter-cellular variability in drug responses and integration of computational and experimental methods in safety pharmacology. Our aim is to evaluate the ability of in silico drug trials in populations of human action potential (AP) models to predict clinical risk of drug-induced arrhythmias based on ion channel information, and to compare simulation results against experimental assays commonly used for drug testing. A control population of 1,213 human ventricular AP models in agreement with experimental recordings was constructed. In silico drug trials were performed for 62 reference compounds at multiple concentrations, using pore-block drug models (IC50/Hill coefficient). Drug-induced changes in AP biomarkers were quantified, together with occurrence of repolarization/depolarization abnormalities. Simulation results were used to predict clinical risk based on reports of Torsade de Pointes arrhythmias, and further evaluated in a subset of compounds through comparison with electrocardiograms from rabbit wedge preparations and Ca2+-transient recordings in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). Drug-induced changes in silico vary in magnitude depending on the specific ionic profile of each model in the population, thus allowing to identify cell sub-populations at higher risk of developing abnormal AP phenotypes. Models with low repolarization reserve (increased Ca2+/late Na+ currents and Na+/Ca2+-exchanger, reduced Na+/K+-pump) are highly vulnerable to drug-induced repolarization abnormalities, while those with reduced inward current density (fast/late Na+ and Ca2+ currents) exhibit high susceptibility to depolarization abnormalities. Repolarization abnormalities in silico predict clinical risk for all compounds with 89% accuracy. Drug-induced changes in biomarkers are in overall agreement across different assays: in silico AP duration changes reflect the ones observed in rabbit QT interval and hiPS-CMs Ca2+-transient, and simulated upstroke velocity captures variations in rabbit QRS complex. Our results demonstrate that human in silico drug trials constitute a powerful methodology for prediction of clinical pro-arrhythmic cardiotoxicity, ready for integration in the existing drug safety assessment pipelines.

Low-Active Male Adolescents: A Dose Response to High-Intensity Interval Training.

PURPOSE: High-intensity interval training (HIIT) is a potential alternative to traditionally recommended steady state exercise for providing health benefits in adolescents, yet its dose-response relationship in this cohort remains unclear, as does its translatability to real-world, nonclinical settings. The present study adopts a novel dose-response design to investigate the effects of undertaking 8 wk of HIIT on the cardiometabolic health of low-active male adolescents. METHODS: Twenty-six male adolescents (age 16 ± 1 yr), identified as low active by nonparticipation in structured sport and physical education classes, were randomly assigned to one of five treatment groups. Corresponding with their group numbers (1-5), participants completed a number of HIIT "sets," which consisted of 4 repeated bouts of 20-s near-maximal exertion interspersed with 10-s passive recovery. Participants performed two HIIT sessions and one resistance training session each week for 8 wk. Baseline and follow-up health measures consisted of peak oxygen uptake (V˙O2peak) with an incremental ramp test to volitional exhaustion; body composition (including visceral fat mass, body fat, and lean tissue mass) with dual-energy x-ray absorptiometry; and lipid profile, glucose, insulin, and interleukin-6 from blood analysis. All health outcomes were analyzed as percentage changes, and data were modeled using a quadratic function to explore dose-response relationships. RESULTS: Significant improvements were observed for V˙O2peak (∼6%), body fat percentage (∼4%), visceral fat mass (∼10%), and waist circumference-to-height ratio (∼3%), but there was no clear effect of dose across groups. CONCLUSIONS: Low-active adolescent males performing a single HIIT set twice weekly, in addition to one resistance training session, gained meaningful improvements in fitness and body composition. Performing additional HIIT sets provided no additional improvements to those of the lowest dose in this study.

Head shape measurement standards and cranial orthoses in the treatment of infants with deformational plagiocephaly.

This review aims to determine how head shape is measured and describes the use of orthoses in the management of deformational plagiocephaly. A systematic review was conducted and papers published in English up to and including 2006 were sourced from nine databases. After initial screening, 20 papers were included; three literature reviews and 17 original papers. Of the original papers, eight concerned the method of head shape measurement. Measurements are important in determining clinical classification and treatment modality of deformational plagiocephaly. All studies were appraised and assigned a level of evidence according to the Scottish Intercollegiate Guidelines Network. Methodological quality was inadequate. Publications involving the use of cranial orthoses used convenience samples, were not blinded, and used different measurement techniques. No comparison groups were included and participants were not randomized. Evidence suggests that conservative treatments might reduce skull deformity although the quality is poor. Clinical studies investigating the use of cranial orthoses reported beneficial effects. Further research is required to identify the efficacy of cranial orthoses in the treatment of deformational plagiocephaly based on a standardized measurement technique to facilitate classification of this condition.