Microbatch under-oil salt screening of organic cations: single-crystal growth of active pharmaceutical ingredients

Multicomponent solid forms of active pharmaceutical ingredients represent a modern method of tuning their physicochemical properties. Typically, salts are the most commonly used multicomponent solid form in the pharmaceutical industry. More than 38% are formulated as organic cations. Salt screening is an essential but demanding step when identifying the most appropriate formulation. The microbatch under-oil crystallization technique of proteins has been combined with the previously developed high-throughput vapour-diffusion screening for use as a novel method of primary salt screening of organic cations. The procedure allows the set up of about 100 crystallization experiments per 30 min. This requires between 17 and 564 mg of screened cationic active pharmaceutical ingredients, which were of moderate to very high water solublity. Five distinct organic salts, three of them diverse active pharmaceutical compounds or the other enantiomer thereof, in the form of chloride salts were tested. The screening was extremely successful; at least two new single-crystal structures could be obtained for each particular compound and many more salts as single crystals were formed compared with our previous vapour-diffusion method

Screening and brief interventions for hazardous and harmful alcohol use in primary care: a cluster randomised controlled trial protocol

A large number of randomised controlled trials in health settings have consistently reported positive effects of brief intervention in terms of reductions in alcohol use. However,although alcohol misuse is common amongst offenders, there is limited evidence of alcohol brief interventions in the criminal justice field. This factorial pragmatic cluster randomised controlledtrial with Offender Managers (OMs) as the unit of randomisation will evaluate the effectiveness and cost-effectiveness of different models of screening to identify hazardous and harmful drinkers in probation and different intensities of brief intervention to reduce excessive drinking in probation clients. Ninety-six OMs from 9 probation areas across 3 English regions (the NorthEast Region (n = 4) and London and the South East Regions (n = 5)) will be recruited. OMs will berandomly allocated to one of three intervention conditions: a client information leaflet control condition (n = 32 OMs); 5-minute simple structured advice (n = 32 OMs) and 20-minute brieflifestyle counselling delivered by an Alcohol Health Worker (n = 32 OMs). Randomisation will be stratified by probation area. To test the relative effectiveness of different screening methods all OMs will be randomised to either the Modified Single Item Screening Questionnaire (M-SASQ) orthe Fast Alcohol Screening Test (FAST). There will be a minimum of 480 clients recruited into the trial. There will be an intention to treat analysis of study outcomes at 6 and 12 months postintervention. Analysis will include client measures (screening result, weekly alcohol consumption,alcohol-related problems, re-offending, public service use and quality of life) and implementation measures from OMs (the extent of screening and brief intervention beyond the minimum recruitment threshold will provide data on acceptability and feasibility of different models of brief intervention). We will also examine the practitioner and organisational factors associated with successful implementation.The trial will evaluate the impact of screening and brief alcohol intervention in routine probation work and therefore its findings will be highly relevant to probation teams and thus the criminal justice system in the UK

Drug, nicotine, and alcohol use among exercisers: does substance addiction co-occur with exercise addiction?

Background: Scholastic works suggest that those at risk for exercise addiction are also often addicted to illicit drugs, nicotine, and/or alcohol, but empirical evidence is lacking. Aims: The aim of the present work was to examine the co-occurrence of illicit drug, nicotine, and alcohol use frequency (prevalence of users) and severity (level of problem in users) among exercisers classified at three levels of risk for exercise addiction: (i) asymptomatic, (ii) symptomatic, and (iii) at-risk. Methods: A sample of 538 regular exercisers were surveyed via the Qualtrics research platform. They completed the (i) Drug Use Disorder Identification Test, (ii) Fagerström Test for Nicotine Dependence, (iii) Alcohol Use Disorder Identification Test, and (iv) Exercise Addition Inventory. Results: A large proportion (n = 59; 10.97%) of the sample was found to be at risk for exercise addiction. The proportion of drug and alcohol users among these participants did not differ from the rest of the sample. However, the incidence of nicotine consumption was lowest among them. The severity of problematic substance use did not differ across the groups. Conclusions: These findings suggest that substance addiction and the risk for exercise addiction are unrelated. In fact, those at risk for exercise addiction exhibited the healthiest profile related to the prevalence of smoking

Characterization of the Escherichia coli pyridoxal 5'-phosphate homeostasis protein (YggS): Role of lysine residues in PLP binding and protein stability

The pyridoxal 5'-phosphate (PLP) homeostasis protein (PLPHP) is a ubiquitous member of the COG0325 family with apparently no catalytic activity. Although the actual cellular role of this protein is unknown, it has been observed that mutations of the PLPHP encoding gene affect the activity of PLP-dependent enzymes, B6 vitamers and amino acid levels. Here we report a detailed characterization of the Escherichia coli ortholog of PLPHP (YggS) with respect to its PLP binding and transfer properties, stability, and structure. YggS binds PLP very tightly and is able to slowly transfer it to a model PLP-dependent enzyme, serine hydroxymethyltransferase. PLP binding to YggS elicits a conformational/flexibility change in the protein structure that is detectable in solution but not in crystals. We serendipitously discovered that the K36A variant of YggS, affecting the lysine residue that binds PLP at the active site, is able to bind PLP covalently. This observation led us to recognize that a number of lysine residues, located at the entrance of the active site, can replace Lys36 in its PLP binding role. These lysines form a cluster of charged residues that affect protein stability and conformation, playing an important role in PLP binding and possibly in YggS function

Does social disadvantage over the life-course account for alcohol and tobacco use in Irish people? Birth cohort study

Medical Research Council (MRC) training fellowship awarded to J.D-M; Grant number: G0701595/

Development and implementation of a structured intervention for alcohol use disorders for telephone helpline services

A six-session intervention for harmful alcohol use was piloted via a 24-hour alcohol and other drug (AOD) helpline, assessing feasibility of telephone-delivered treatment. The intervention, involving practice elements from Motivational Interviewing, Cognitive-Behavioral Therapy, and node-link mapping, was evaluated using a case file audit (n D 30) and a structured telephone interview one month after the last session (n D 22). Average scores on the Alcohol Use Disorder Identification Test (AUDIT) dropped by more than 50%, and there were significant reductions in psychological distress. Results suggest that, even among dependent drinkers, a telephone intervention offers effective and efficient treatment for those unable or unwilling to access face-to-face treatment

Rumination, substance use, and self-harm in a representative Australian adult sample

Background: There are few data on self-harm in the general population, especially examining the roles of rumination and substance use. Objectives: To evaluate the inter-relationships of rumination, self-harm, and potential mediating variables. Method: A cohort with follow-up every 4 years involving a random sample of adults aged 20–24 and 40–44 years (at baseline) living in Australia. The survey included items on three common forms of self-harm. Other measures included rumination, Goldberg Anxiety and Depression scales, substance use, coping style (Brief COPE), and demographic risk factors. Results: The sample comprised 2,184 women and 1,942 men with 287 self-harm cases (7.0%). Depression and coping style were significant mediators of rumination on self-harm for men, with depression being the only robust mediator for women. For males, age and education were also significantly associated, while for women, age, smoking, trauma, and sexual abuse were significant. Conclusions: Men and women differ on mediators of self-harm

An Automated Mobile Game-based Screening Tool for Patients with Alcohol Dependence

Traditional methods for screening and diagnosis of alcohol dependence are typically administered by trained clinicians in medical settings and often rely on interview responses. These self-reports can be unintentionally or deliberately false, and misleading answers can, in turn, lead to inaccurate assessment and diagnosis. In this study, we examine the use of user-game interaction patterns on mobile games to develop an automated diagnostic and screening tool for alcohol-dependent patients. Our approach relies on the capture of interaction patterns during gameplay, while potential patients engage with popular mobile games on smartphones. The captured signals include gameplay performance, touch gestures, and device motion, with the intention of identifying patients with alcohol dependence. We evaluate the classification performance of various supervised learning algorithms on data collected from 40 patients and 40 age-matched healthy adults. The results show that patients with alcohol dependence can be automatically identified accurately using the ensemble of touch, device motion, and gameplay performance features on 3-minute samples (accuracy=0.95, sensitivity=0.95, and specificity=0.95). The present findings provide strong evidence suggesting the potential use of user-game interaction metrics on existing mobile games as discriminant features for developing an implicit measure to identify alcohol dependence conditions. In addition to supporting healthcare professionals in clinical decision-making, the game-based self-screening method could be used as a novel strategy to promote alcohol dependence screening, especially outside of clinical settings

Context and alcohol consumption behaviors affect inhibitory control

Contrasting the traditional focus on alcohol-related visual images, this study examined the impact of both alcohol-related auditory cues and visual stimuli on inhibitory control (IC). Fifty-eight participants completed a Go/No-Go Task, with alcohol-related and neutral visual stimuli presented with or without short or continuous auditory bar cues. Participants performed worse when presented with alcohol-related images and auditory cues. Problematic alcohol consumption and higher effortful control (EC) were associated with better IC performance for alcohol images. It is postulated that those with higher EC may be better able to ignore alcohol-related stimuli, while those with problematic alcohol consumption are unconsciously less attuned to these. This runs contrary to current dogma and highlights the importance of examining both auditory and visual stimuli when investigating IC