Discovery of reversible and covalent TEAD 1 selective inhibitors MSC-1254 and MSC-5046 based on one scaffold.

The Transcriptional Enhanced Associated Domain (TEAD) family of transcription factors are key components of the Hippo signalling family which play a crucial role in the regulation of cell proliferation, differentiation and apoptosis. The identification of inhibitors of the TEAD transcription factors are an attractive strategy for the development of novel anticancer therapies. A HTS campaign identified hit 1, which was optimised using structure-based drug design, to deliver potent TEAD1 selective inhibitors with both a reversible and covalent mode of inhibition. The preference for TEAD1 could be rationalised by steric differences observed in the lower pocket of the palmitoylation-site between subtypes, with TEAD1 having the largest available volume to accommodate substitution in this region.

Substances and your senses: The sensory patterns of young people within an alcohol and drug treatment service.

Background: Substance use disorders (SUD) and trauma histories in adults have been linked with sensory processing patterns that are significantly different from the general population. Nevertheless, no studies have investigated sensory patterns, or the variables with which they are related, in youth with SUD. This study aimed to compare sensory patterns of this sample with normative data and consider associations between sensory patterns and: substance use, trauma, quality-of-life, mental and physical health. Methods: A cross-sectional quantitative research design was employed with a sample of 87 young people (mean age = 20.8 years) with SUD voluntarily attending a specialist youth outpatient alcohol and other drug (AOD) service. For participants, the Adolescent Adult Sensory Profile was added to measures routinely collected at the service. Results: Participants' sensory processing patterns for low registration, sensory sensitivity, and sensation avoiding were significantly higher than the normative population, while sensation seeking was both lower and higher. Ninety-one percent reported atypical scores on one or more sensory patterns. High rates of probable Post-Traumatic-Stress-Disorder (PTSD), psychological distress, and low quality-of-life were also reported, which were meaningfully related with sensory patterns. Conclusion: Young people reported complex combinations of sensory processing patterns, with comorbid probable PTSD, psychological distress, and low quality-of-life. Findings reflect studies with adult AOD, trauma, and other clinical conditions, and highlight the potential value of screening for sensory patterns and applying transdiagnostic approaches which simultaneously address substance use, mental health, trauma and sensory needs to optimize outcomes for young people with SUD.

Examination of a group entry model into alcohol and other drug (AOD) treatment: Improvements in attendance, retention, and clinical capacity.

Background: Nonattendance in alcohol and other drug (AOD) treatment has been a persistent issue for service provision. The study reports on the outcomes of implementing a group intervention, titled Getting Ready for Change (GRFC), as the default entry pathway into an AOD counseling service that aimed to improve initial attendance and retention through reduced wait days and improved clinical capacity. Methods: Clients of the service (N = 274) were offered either an individual appointment (baseline) between September 2015 and February 2016 or a group-based appointment (intervention) between September 2016 and February 2017. The samples were compared in terms of demographics, principal drug of concern, wait days to initial and follow-up appointments, and attendance. Results: The implementation of GRFC reduced wait days to initial appointment from 15 to 5 days and improved initial attendance rates by 24%. Wait days to follow-up were reduced from 10 to 8, retention rates improved by 24%. Further, there was an increased service capacity to meet community demand. Conclusions: A group entry model into AOD treatment is a novel intervention, is easy to implement, improves attendance and retention in treatment, reduces wait days, and enhances clinical capacity.

Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis.

Cystic fibrosis (CF) lung disease is characterized by chronic and exaggerated inflammation in the airways. Despite recent developments to therapeutically overcome the underlying functional defect in the cystic fibrosis transmembrane conductance regulator, there is still an unmet need to also normalize the inflammatory response. The prolonged and heightened inflammatory response in CF is, in part, mediated by a lack of intrinsic down-regulation of the proinflammatory NF-κB pathway. We have previously identified reduced expression of the NF-κB down-regulator A20 in CF as a key target to normalize the inflammatory response. Here, we have used publicly available gene array expression data together with a statistically significant connections' map (sscMap) to successfully predict drugs already licensed for the use in humans to induce A20 mRNA and protein expression and thereby reduce inflammation. The effect of the predicted drugs on A20 and NF-κB(p65) expression (mRNA) as well as proinflammatory cytokine release (IL-8) in the presence and absence of bacterial LPS was shown in bronchial epithelial cells lines (16HBE14o-, CFBE41o-) and in primary nasal epithelial cells from patients with CF (Phe508del homozygous) and non-CF controls. Additionally, the specificity of the drug action on A20 was confirmed using cell lines with tnfαip3 (A20) knockdown (siRNA). We also show that the A20-inducing effect of ikarugamycin and quercetin is lower in CF-derived airway epithelial cells than in non-CF cells.

Steering Clear of Driving After Drinking: a Tailored e-Health Intervention for Reducing Repeat Offending and Modifying Alcohol Use in a High-Risk Cohort.

PURPOSE: Digital interventions to reduce risk behaviours are emerging as effective public health measures; however, few have been applied to drink driving and associated alcohol use based on a harm reduction perspective. This paper reports on the design, development, and pilot of a novel intervention which aims to reduce repeat offending by first-time convicted drink driving offenders. It explores whether an online program is acceptable and user friendly and contains useful and relevant content, with a sample of first-time drink driving offenders recruited at the time of conviction. METHOD: Building upon existing research into interventions to reduce drink driving recidivism and problem alcohol use, a tailored program was designed to provide content specifically concerned with drink driving and with an additional component related to alcohol use. Following stakeholder and internal review, the 'Steering Clear First Offender Drink Driving Program' was subsequently piloted with 15 first-time drink driving offenders. Evaluative data was analysed both quantitatively and qualitatively. RESULTS: The pilot results indicate that the participants found the program to be user friendly, as demonstrated by high scores in relation to navigation, online delivery, engagement, avatar usage and straightforwardness. They reported that they found the content to be useful and relevant and that the key learning area was in relation to the consequences of drink driving. CONCLUSION: Online interventions for reducing risky behaviour such as drink driving may be useful and cost effective from a public health perspective. Potentially, they can directly address risky behaviours associated with alcohol use in high-risk cohorts that may not ordinarily receive intervention.

Methamphetamine and emerging drugs of concern: A training needs analysis of Australian alcohol and other drug helplines.

INTRODUCTION: Fielding greater than 100,000 calls annually, telephone helplines are an important point of entry to alcohol and other drug (AOD) support and services in Australia. Methamphetamine and emerging drugs can present a particular challenge for this workforce. We sought to identify training needs for these services, so that appropriate targeted resources can be developed. METHODS: We distributed an anonymous, online, cross-sectional survey to helpline staff from New South Wales, Queensland, South Australia, Victoria and Western Australia. Based on the WHO Hennessy-Hicks training needs analysis tool, participants were asked: to rate on a 7-point likert scale the importance of a topic to their practice and how well they perform in relation to the topic; open-ended questions specifying their own self-perceived training needs; and demographic data. RESULTS: Of 50 participants, 29 completed the full survey (median age 49 [IQR 30-57.5]; median time working in AOD sector 6 years [IQR 1-20]). The results identified a need for: practical community-informed population relevant information for culturally and linguistically diverse populations and Aboriginal and Torres Strait Islander peoples for calls relating to methamphetamine and emerging drugs of concern; training and resources with a particular focus on families and friends of people who use methamphetamine and emerging drugs; and readily accessible up-to-date information on new and emerging drugs and treatment of related disorders. DISCUSSION AND CONCLUSIONS: This training needs analysis provides a structured approach to supporting the first-line AOD counsellors to provide up-to-date and accurate information to assist Australians seeking information, support and advice.

Development and validation of the cannabis experiences questionnaire - Intoxication effects checklist (CEQ-I) short form.

OBJECTIVE: To develop and validate a short form of the Cannabis Experiences Questionnaire - Intoxication Effects (CEQ-I), a 42-item scale which measures the euphoric and paranoid-dysphoric effects of cannabis intoxication. METHOD: Exploratory and confirmatory factor analyses were conducted among 604 past-month cannabis users to develop the short form. The factor structure was replicated in a second sample of 146 past-month cannabis users. The concurrent validity of the scale was also examined. RESULTS: Consistent with previous research, two factors were identified (paranoid-dysphoric; euphoric), and were replicated with confirmatory factor analyses. The most parsimonious scale consisted of 13 items. Correlations of short-form subscales with corresponding original subscales were high. The paranoid-dysphoric subscale was also moderately positively correlated with measures of psychotic-like experiences (PLEs) and psychological distress. CONCLUSIONS: The revised and validated CEQ-I short form can be used to explore the euphoric and paranoid-dysphoric effects of cannabis intoxication in young cannabis users, and whether these experiences increase their risk of developing cannabis use and psychotic disorders. The CEQ-I short form has the potential to aid in the identification of young cannabis users at risk of the paranoid-dysphoric effects of cannabis intoxication and may assist in the development of early intervention strategies targeting cannabis users with PLEs.

Self-Efficacy, Planning, and Drink Driving: Applying the Health Action Process Approach.

OBJECTIVE: This study examines the constructs from the health action process approach (HAPA) theoretical model (Schwarzer, 1992) on future drink driving avoidance by first time drink driving offenders. This research presents an advance in health related theory by the novel application of the health model to predict risk avoidance. METHOD: Baseline interviews were conducted with 198 first time drink driving offenders at the time of court appearance, and offenders were followed up 6-8 months following the offense date. The key outcome variables used in 3 stages were behavioral expectation, planning, and self-reported avoidance of drink driving at follow-up. RESULTS: Bivariate and multivariate analyses were conducted for each stage. High task self-efficacy and female gender were significantly related to having no behavioral expectation of future drink driving. High maintenance self-efficacy was significantly related to high levels of planning to avoid future drink driving. Those with higher planning scores at baseline had significantly higher odds of reporting that they had avoided drink driving at follow up. CONCLUSION: Planning plays an important role in drink driving rehabilitation and should be a focus of early intervention programs aimed at reducing drink driving recidivism following a first offense. Self-efficacy is an important construct to consider for the behavior and could strengthen a planning focused intervention. (PsycINFO Database Record

The Quality and Accuracy of Mobile Apps to Prevent Driving After Drinking Alcohol.

BACKGROUND: Driving after the consumption of alcohol represents a significant problem globally. Individual prevention countermeasures such as personalized mobile app aimed at preventing such behavior are widespread, but there is little research on their accuracy and evidence base. There has been no known assessment investigating the quality of such apps. OBJECTIVE: This study aimed to determine the quality and accuracy of apps for drink driving prevention by conducting a review and evaluation of relevant mobile apps. METHODS: A systematic app search was conducted following PRISMA guidelines. App quality was assessed using the Mobile App Rating Scale (MARS). Apps providing blood alcohol calculators (hereafter "calculators") were reviewed against current alcohol advice for accuracy. RESULTS: A total of 58 apps (30 iOS and 28 Android) met inclusion criteria and were included in the final analysis. Drink driving prevention apps had significantly lower engagement and overall quality scores than alcohol management apps. Most calculators provided conservative blood alcohol content (BAC) time until sober calculations. None of the apps had been evaluated to determine their efficacy in changing either drinking or driving behaviors. CONCLUSIONS: This novel study demonstrates that most drink driving prevention apps are not engaging and lack accuracy. They could be improved by increasing engagement features, such as gamification. Further research should examine the context and motivations for using apps to prevent driving after drinking in at-risk populations. Development of drink driving prevention apps should incorporate evidence-based information and guidance, lacking in current apps.

Development and Validation of the User Version of the Mobile Application Rating Scale (uMARS).

BACKGROUND: The Mobile Application Rating Scale (MARS) provides a reliable method to assess the quality of mobile health (mHealth) apps. However, training and expertise in mHealth and the relevant health field is required to administer it. OBJECTIVE: This study describes the development and reliability testing of an end-user version of the MARS (uMARS). METHODS: The MARS was simplified and piloted with 13 young people to create the uMARS. The internal consistency and test-retest reliability of the uMARS was then examined in a second sample of 164 young people participating in a randomized controlled trial of a mHealth app. App ratings were collected using the uMARS at 1-, 3,- and 6-month follow up. RESULTS: The uMARS had excellent internal consistency (alpha = .90), with high individual alphas for all subscales. The total score and subscales had good test-retest reliability over both 1-2 months and 3 months. CONCLUSIONS: The uMARS is a simple tool that can be reliably used by end-users to assess the quality of mHealth apps.