Computer-Based Training for Cognitive Behavioural Therapy for Substance Use Disorder: A Randomized Controlled Trial Including Quantitative and Qualitative Health and Economic Outcomes: Formation informatisée pour la thérapie cognitivo-comportementale pour les troubles liés à l'usage de substances : un essai randomisé contrôlé y compris les résultats quantitatifs et qualitatifs en matière de santé et d'économie.

OBJECTIVES: Heavy alcohol and drug use is reported by a substantial number of Canadians; yet, only a minority of those experiencing substance use difficulties access specialized services. Computer-Based Training for Cognitive Behavioural Therapy (CBT4CBT) offers a low-cost method to deliver accessible and high-quality CBT for substance use difficulties. To date, CBT4CBT has primarily been evaluated in terms of quantitative outcomes within substance use disorder (SUD) samples in the United States. A comparison between CBT4CBT versus standard care for SUDs in a Canadian sample is critical to evaluate its potential for health services in Canada. We conducted a randomized controlled trial of CBT4CBT versus standard care for SUD. METHODS: Adults seeking outpatient treatment for SUD (N = 50) were randomly assigned to receive either CBT4CBT or treatment-as-usual (TAU) for 8 weeks. Measures of substance use and associated harms and quality of life were completed before and after treatment and at 6-month follow-up. Qualitative interviews were administered after treatment and at follow-up, and healthcare utilization and costs were extracted for the entire study period. RESULTS: Participants exhibited improvements on the primary outcome as well as several secondary outcomes; however, there were no differences between groups. A cost-effectiveness analysis found lower healthcare costs in CBT4CBT versus TAU in a subsample analysis, but more days of substance use in CBT4CBT. Qualitative analyses highlighted the benefits and challenges of CBT4CBT. DISCUSSION: Findings supported an overall improvement in clinical outcomes. Further investigation is warranted to identify opportunities for implementation of CBT4CBT in tertiary care settings.Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03767907.

Evaluating a digital intervention targeting substance use difficultiesPlain Language SummaryWhy was the study done?Heavy alcohol and drug use is frequent in the Canadian population, although very few people have access to treatment. The digital intervention, Computer-Based Training for Cognitive Behavioural Therapy (CBT4CBT), may provide a low-cost, high-quality, and easily accessible method of treatment for substance use difficulties. Limited research on this digital intervention has been conducted in Canadian populations, and few studies thus far have evaluated participants' subjective experience using the intervention, along with the cost on the Canadian healthcare system.What did the researchers do?The research team recruited participants and provided access to either CBT4CBT or to standard care at a mental health hospital for 8 weeks. Participants were asked questions about their substance use and related consequences, quality of life, and thoughts on the treatment they received. Information regarding healthcare use and the cost to the healthcare system was also gathered.What did the researchers find?Participants in both groups improved with regards to their substance use, some related consequences, and psychological quality of life. Participants provided insight on the benefits and challenges of both types of treatment. It was also found that the CBT4CBT intervention was less costly.What do these findings mean?These findings support that adults receiving CBT4CBT and standard care both improved to a similar degree in this sample. Participant feedback may inform future studies of how best to implement this intervention in clinical studies. Future studies with larger samples are needed to further examine whether CBT4CBT can increase access to supports and be beneficial in the Canadian healthcare system.

Towards accountability-centred practices: governance in OSCEs subordinating patient and practitioner clinical experience.

New public management ideals and standards have become increasingly adhered to in health professions education; this is particularly apparent in high-stakes assessment, as a gateway to practice. Using an Institutional Ethnographic approach, we looked at the work involved in running high-stakes Objective Structured Clinical Exams (OSCEs) throughout an academic year including use of observations, interviews and textual analysis. In our results, we describe three types of 'work'-standardising work, defensibility work and accountability work-summarising these in the discussion as an Accountability Circuit, which shows the organising role of texts on people's work processes. We show how this form of governance mandates a shift towards accountability-centred practices, away from practices which are person-centred; this lens on accountability-centring during high-stakes assessments invites critique of the often-unquestioned emphasis of new public management in health professions education.

A selective small-molecule inhibitor of macrophage migration inhibitory factor-2 (MIF-2), a MIF cytokine superfamily member, inhibits MIF-2 biological activity.

Cytokine macrophage migration inhibitory factor-2 (MIF-2 or D-dopachrome tautomerase) is a recently characterized second member of the MIF cytokine superfamily in mammalian genomes. MIF-2 shares pro-inflammatory and tumorigenic properties with the clinical target MIF (MIF-1), but the precise contribution of MIF-2 to immune physiology or pathology is unclear. Like MIF-1, MIF-2 has intrinsic keto-enol tautomerase activity and mediates biological functions by engaging the cognate, common MIF family receptor CD74. Evidence that the catalytic site of MIF family cytokines has a structural role in receptor binding has prompted exploration of tautomerase inhibitors as potential biological antagonists and therapeutic agents, although few catalytic inhibitors inhibit receptor activation. Here we describe the discovery and biochemical characterization of a selective small-molecule inhibitor of MIF-2. An in silico screen of 1.6 million compounds targeting the MIF-2 tautomerase site yielded several hits for potential catalytic inhibitors of MIF-2 and identified 4-(3-carboxyphenyl)-2,5-pyridinedicarboxylic acid (4-CPPC) as the most functionally potent compound. We found that 4-CPPC has an enzymatic IC50 of 27 µm and 17-fold selectivity for MIF-2 versus MIF-1. An in vitro binding assay for MIF-1/MIF-2 to the CD74 ectodomain (sCD74) indicated that 4-CPPC inhibits MIF-2-CD74 binding in a dose-dependent manner (0.01-10 µm) without influencing MIF-1-CD74 binding. Notably, 4-CPPC inhibited MIF-2-mediated activation of CD74 and reduced CD74-dependent signal transduction. These results open opportunities for development of more potent and pharmacologically auspicious MIF-2 inhibitors to investigate the distinct functions of this MIF family member in vivo.

Titrating the Rig: How Paramedics Work in and on Their Ambulance.

In this article, I take readers inside of an ambulance and explore how paramedics work in and on their "apparatus unit" to make it a workable fit. This taken-for-granted work is important because much is at stake in the back of the ambulance, particularly in relation to quality of care and safety. I draw on data from an institutional ethnography into the socially organized work and work settings of paramedics, which included more than 200 hr of observations and more than 100 interviews with paramedics. The findings shed light on the situated work processes of paramedics as they orient and respond to their "apparatus unit" and enact quality and safety in practice. This article adds to the sociological literature on work and occupations as well as safety and quality in health care of an increasingly important group of health care and emergency services professional.

How mothers talk about placement of their child with autism outside the home.

In this article I use insights offered by the poststructural shift and linguistic turn in social scientific inquiry, specifically discourse analysis, to explore mothers' talk about the placement of their child with autism outside of the home. By viewing mothers' talk as data, I bring to light the discourses and interpretive practices that mothers drew on to organize their talk of placement. In doing so, I provide insights into how mothers gave meaning to processes of placement while also expanding on commonsensical discursive notions of "good" mothering, caregiving, and family. Implications of the findings are discussed.

Producing paramedicine: Case studies in the medical labor process.

How is medical labor power, that being the capacity to assemble, adjust, or arrange medical subjects, converted into medical practice? Drawing on three qualitative case studies in the United States, Canada, and the United Kingdom, we argue that this conversion is shaped by pressures channeled through the relations that medical workers enter into with patients "from below" and managers "from above." We demonstrate this by examining a common empirical object: ambulance labor. In addition to providing a unique window into the varieties of medical work, paramedicine offers a strategic venue for examining the kinds of productive relations that medical laborers enter into. Our research shows how the labor process is shaped by patient requests that can either conform or contradict workers' shared sense of vocation. We also detail how this same process is simultaneously pressured by managers who are generally focused on increasing both the flexibility and the visibility of their workers. Many of these pressures, we argue, can be linked to common forces of neoliberalism across our three nations. Our analysis of the medical labor process inspires some practical recommendations to reform ambulance-based care. However, our primary aim is to advance a labor-centric approach to studying medicine.

Peer support and online cognitive behavioural therapy for substance use concerns: protocol for a randomised controlled trial.

INTRODUCTION: Hazardous alcohol and drug use is associated with substantial morbidity, mortality and societal cost worldwide. Yet, only a minority of those struggling with substance use concerns receive specialised services. Numerous barriers to care exist, highlighting the need for scalable and engaging treatment alternatives. Online interventions have exhibited promise in the reduction of substance use, although studies to date highlight the key importance of patient engagement to optimise clinical outcomes. Peer support may provide a way to engage patients using online interventions. The goal of this study is to evaluate the efficacy and cost-effectiveness of Breaking Free Online (BFO), an online cognitive-behavioural intervention for substance use, delivered with and without peer support. METHODS AND ANALYSIS: A total of 225 outpatients receiving standard care will be randomised to receive clinical monitoring with group peer support, with BFO alone, or with BFO with individual peer support, in an 8-week trial with a 6-month follow-up. The primary outcome is substance use frequency; secondary outcomes include substance use problems, depression, anxiety, quality of life, treatment engagement and cost-effectiveness. Mixed effects models will be used to test hypotheses, and thematic analysis of qualitative data will be undertaken. ETHICS AND DISSEMINATION: The protocol has received approval by the Centre for Addiction and Mental Health Research Ethics Board. Results will help to optimise the effectiveness of structured online substance use interventions provided as an adjunct to standard care in hospital-based treatment programmes. Findings will be disseminated through presentations and publications to scholarly and knowledge user audiences. TRIAL REGISTRATION NUMBER: NCT05127733.

Why institutional ethnography? Why now? Institutional ethnography in health professions education.

This 'A Qualitative Space' article takes a critical look at Dorothy Smith's approach to inquiry known as institutional ethnography and its potentiality in contemporary health professions education research. We delve into institutional ethnography's philosophical underpinnings, setting out the ontological shift that the researcher needs to make within this critical feminist approach. We use examples of research into frontline healthcare, into the health work of patients and into education to allow the reader to consider what an institutional ethnography research project might offer. We lay out our vision for potential growth for institutional ethnography research within the health professions education field and explain why we see this as the opportune moment to adopt institutional ethnography to meet some of the challenges facing health professions education in a way that offers informed change.

2-aryloxy-4-alkylaminopyridines: discovery of novel corticotropin-releasing factor 1 antagonists.

An orally active clinical candidate of corticotropin-releasing factor 1 (CRF 1) antagonist 1 showed a significant positive food effect in dog and human after oral administration. Efforts to address the food effect issue led us to explore and discover compounds in series 2 as orally active CRF 1 receptor antagonists, in which some compounds showed improved physicochemical properties while retaining desired pharmacological properties. Compound 3a (CP-376395) was selected for further development, due not only to its reduced food effects but also its greater efficacy in CNS models. Compound 3a was advanced to the clinic. The synthesis of representative potential candidates and their in vitro, ex vivo, and in vivo data are described.

Design and discovery of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (PF-04447943), a selective brain penetrant PDE9A inhibitor for the treatment of cognitive disorders.

6-[(3S,4S)-4-Methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (PF-04447943) is a novel PDE9A inhibitor identified using parallel synthetic chemistry and structure-based drug design (SBDD) and has advanced into clinical trials. Selectivity for PDE9A over other PDE family members was achieved by targeting key residue differences between the PDE9A and PDE1C catalytic site. The physicochemical properties of the series were optimized to provide excellent in vitro and in vivo pharmacokinetics properties in multiple species including humans. It has been reported to elevate central cGMP levels in the brain and CSF of rodents. In addition, it exhibits procognitive activity in several rodent models and synaptic stabilization in an amyloid precursor protein (APP) transgenic mouse model. Recent disclosures from clinical trials confirm that it is well tolerated in humans and elevates cGMP in cerebral spinal fluid of healthy volunteers, confirming that it is a quality pharmacological tool for testing clinical hypotheses in disease states associated with impairment of cGMP signaling or cognition.

Discovery of a novel class of phosphodiesterase 10A inhibitors and identification of clinical candidate 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the treatment of schizophrenia.

By utilizing structure-based drug design (SBDD) knowledge, a novel class of phosphodiesterase (PDE) 10A inhibitors was identified. The structure-based drug design efforts identified a unique "selectivity pocket" for PDE10A inhibitors, and interactions within this pocket allowed the design of highly selective and potent PDE10A inhibitors. Further optimization of brain penetration and drug-like properties led to the discovery of 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920). This PDE10A inhibitor is the first reported clinical entry for this mechanism in the treatment of schizophrenia.

Identification of a brain penetrant PDE9A inhibitor utilizing prospective design and chemical enablement as a rapid lead optimization strategy.

By use of chemical enablement and prospective design, a novel series of selective, brain penetrant PDE9A inhibitors have been identified that are capable of producing in vivo elevations of brain cGMP.

Thiazole-diamides as potent gamma-secretase inhibitors.

The thiazole-diamide series (1) has been identified as highly potent gamma-secretase inhibitors. Several representative compounds showed IC(50) values of <0.3 nM. The synthesis and SAR, as well as a radiolabeled synthesis of [(3)H]-2a, are described.