Dlk1 is a novel adrenocortical stem/progenitor cell marker that predicts malignancy in adrenocortical carcinoma.

Disruption of processes involved in tissue development and homeostatic self-renewal is increasingly implicated in cancer initiation, progression, and recurrence. The adrenal cortex is a dynamic tissue that undergoes life-long turnover. Here, using genetic fate mapping and murine adrenocortical carcinoma (ACC) models, we have identified a population of adrenocortical stem cells that express delta-like non-canonical Notch ligand 1 (DLK1). These cells are active during development, near dormant postnatally but are re-expressed in ACC. In a study of over 200 human ACC samples, we have shown DLK1 expression is ubiquitous and is an independent prognostic marker of recurrence-free survival. Paradoxically, despite its progenitor role, spatial transcriptomic analysis has identified DLK1 expressing cell populations to have increased steroidogenic potential in human ACC, a finding also observed in four human and one murine ACC cell lines. Finally, the cleavable DLK1 ectodomain is measurable in patients' serum and can discriminate between ACC and other adrenal pathologies with high sensitivity and specificity to aid in diagnosis and follow-up of ACC patients. These data demonstrate a prognostic role for DLK1 in ACC, detail its hierarchical expression in homeostasis and oncogenic transformation and propose a role for its use as a biomarker in this malignancy.

Key benthic species are affected by predicted warming in winter but show resistance to ocean acidification.

The effects of climate change on coastal biodiversity are a major concern because altered community compositions may change associated rates of ecosystem functioning and services. Whilst responses of single species or taxa have been studied extensively, it remains challenging to estimate responses to climate change across different levels of biological organisation. Studies that consider the effects of moderate realistic near-future levels of ocean warming and acidification are needed to identify and quantify the gradual responses of species to change. Also, studies including different levels of biological complexity may reveal opportunities for amelioration or facilitation under changing environmental conditions. To test experimentally for independent and combined effects of predicted near-future warming and acidification on key benthic species, we manipulated three levels of temperature (winter ambient, +0.8 and +2°C) and two levels of pco 2 (ambient at 450 ppm and elevated at 645 ppm) and quantified their effects on mussels and algae growing separately and together (to also test for inter-specific interactions). Warming increased mussel clearance and mortality rates simultaneously, which meant that total biomass peaked at +0.8°C. Surprisingly, however, no effects of elevated pco 2 were identified on mussels or algae. Moreover, when kept together, mussels and algae had mutually positive effects on each other's performance (i.e. mussel survival and condition index, mussel and algal biomass and proxies for algal productivity including relative maximum electron transport rate [rETRmax], saturating light intensity [I k] and maximum quantum yield [F v/F m]), independent of warming and acidification. Our results show that even moderate warming affected the functioning of key benthic species, and we identified a level of resistance to predicted ocean acidification. Importantly, we show that the presence of a second functional group enhanced the functioning of both groups (mussels and algae), independent of changing environmental conditions, which highlights the ecological and potential economic benefits of conserving biodiversity in marine ecosystems.

Conservative Management and Postoperative Return to Sport in Endurance Athletes with Flow Limitations in the Iliac Arteries: A Scoping Review.

BACKGROUND: Flow limitations in the iliac arteries (FLIA) is a sport-related vascular condition increasingly recognised as an occupational risk for professional cyclists and other endurance athletes. Surgical reconstruction is the definitive treatment for athletes wishing to continue competition. However, less information has been published regarding conservative management options and return-to-sport (RTS) guidelines. OBJECTIVE: Our aim was to review the existing literature on conservative treatment of FLIA, identify knowledge gaps and propose an RTS framework for athletes returning to competition. METHODS: A comprehensive literature review was performed using the Ovid-MEDLINE, PubMed, Embase and PEDro databases for publications relevant to conservative management of FLIA. A scoping review was conducted following PRISMA-ScR guidelines. Original, peer-reviewed publications in English describing conservative or postoperative management for athletes with FLIA were included. Additional grey literature and clinical expertise were consulted to inform RTS guidelines. RESULTS: Overall, 62 studies were included in this review. In total, 11 categories of conservative modalities were extracted and presented qualitatively in terms of the information source (discussion or results statements) and perspective of the authors (positive, negative or mixed). We have proposed RTS guidelines covering pre-operative preparation and postoperative rehabilitation based on the available literature, clinical experience, and drawing from other areas of sports medicine research. CONCLUSION: There is insufficient literature evaluating the effectiveness of conservative management options for FLIA to establish best practices. Considering the importance of RTS for competitive athletes, we proposed practical guidelines to help with clinician and patient decision making. Future consensus should be sought for RTS best practices.

Using in silico methods to determine optimal tapering regimens for decanoate-based long-acting injectable psychosis drugs.

Background: Reducing the dose of psychosis drugs in a gradual hyperbolic manner may minimise withdrawal effects and risk of relapse. There is presently limited guidance on tapering decanoate-based long-acting injectable dopamine antagonists (LIDAs). Objectives: We aimed to apply hyperbolic principles of tapering to the decanoate-based LIDAs flupentixol, zuclopenthixol and haloperidol to develop withdrawal regimens. Design: We used in silico methodology to predict plasma drug levels and D2 occupancy for different LIDA regimens. Methods: Existing pharmacokinetic and receptor occupancy data from nuclear neuroimaging studies were used to power modelling. Abrupt discontinuation was examined as a potential strategy, and dose reduction was modelled with pre-defined constraints used in similar work of 10 (fast regimens), 5 (moderate) and 2.5 (slow) percentage points of D2 occupancy change per month. Results: Abrupt discontinuation of decanoate-based LIDAs leads to excessive change in D2 occupancy which violated our pre-defined constraints, potentially resulting in withdrawal symptoms and increased risk of relapse. Reduction of LIDA dose allowed hyperbolic reduction in plasma level consistent with imposed constraints on receptor occupancy reduction rate. For equivalent per-weekly LIDA dosing, more frequent administration allowed a more gradual reduction of D2 occupancy. However, switching to oral forms is required to continue hyperbolic tapering to full discontinuation; reduction to zero using only LIDA produces too large a reduction in D2 occupancy. Guidance for reduction and cessation of LIDAs according to slow, moderate and fast criteria is provided. Conclusion: Abrupt cessation of decanoate LIDAs is not consistent with gradual hyperbolic tapering, despite their longer half-lives compared with oral formulations. Reduction to the point of full discontinuation can only be achieved by switching to oral therapy to complete the taper. These results are limited by the in silico and theoretical nature of the study, and there is a need to confirm these findings through real-world observational and interventional studies.

Computer-based research on the best way to reduce the dose and eventually stop three depot antipsychotics What is the problem? Psychosis affects how someone experiences reality. Antipsychotics are used to treat psychosis. They work by blocking a chemical called dopamine. Stopping these too rapidly can cause psychosis to occur again. This might be because the dopamine block is removed suddenly. Sometimes antipsychotics are given by injection. Injections stay in the body for a longer time than tablets. The best way to reduce these injections is currently unknown. What did we do? We explored the best way to reduce and stop antipsychotic injections. We looked at three different types of psychosis injection. We used existing data to assess how these drugs affect the brain. We examined what would happen if an antipsychotic injection was suddenly stopped. We then evaluated the effect of reducing the dose gradually. What did we find? Stopping antipsychotic injections suddenly would lead to rapid changes at brain receptors. This might lead to symptoms of withdrawal and a high risk of psychosis recurring. Reducing the dose of injections leads to less change than stopping suddenly. Switching to a tablet allows for more control when reducing dose. Having injections more often also reduce the changes occurring between injections. We outline three different rates of dose reduction. What does this mean? Antipsychotic injections stay in the body longer than tablets. However, stopping injections suddenly may still not be safe. We recommend that people reduce the dose of their injection instead. We also recommend people switch to tablets or liquid before stopping. It should be noted that our research is computer-based. We would like to see our recommendations tested in the real world.

Evaluation of agreement of IOP measurements by Tono-Vera tonometer to Goldmann applanation tonometry.

Purpose: To evaluate the accuracy of the new Tono-Vera rebound tonometer (Reichert Inc, Buffalo, NY) compared to Goldmann Applanation Tonometry. Methods: This prospective, observational, cross-sectional study was designed in accordance with ANSI Z80.10-2014 and ISO 8612-2009 guidelines for tonometer comparison. Intraocular Pressure (IOP) was measured by Goldmann Applanation and Tono-Vera on 160 eyes of 160 subjects. Corneal Astigmatism and Central Corneal Thickness were also measured. A single investigator (CN) conducted all measurements. The average of two measurements from each tonometer was used in the analysis. Bland-Altman plots, total least squares regression analysis, and simple linear regression were used to evaluate agreement between the tonometers. Results: Average IOP values from Goldmann Applanation and Tono-Vera were not significantly different (19.17 and 19.03 respectively, p=0.40, paired t-test). The total least squares regression analysis indicated strong agreement between the two tonometers (slope +0.97, offset +0.49 mmHg, standard deviation 2.11 mmHg). There were 2 IOP measurement pairs that exceeded the ± 5 mmHg limits of agreement required in ANSI Z80.10-2014 and ISO 8612-2009, which is within the range of acceptability specified in the standards. Conclusion: We evaluated IOP measurements by Tono-Vera Rebound Tonometer vs Goldmann Applanation Tonometry for eyes with a wide range of IOP values and found no statistically significant differences in the results. Tono-Vera meets the requirements of ANSI Z80.10-2014 and ISO 8612-2009, demonstrating accuracy comparable to Goldmann tonometry.

Examination of a case of "treatment failure" in long-term psychoanalytic psychotherapy for treatment-resistant depression.

Randomized controlled trials have reported psychoanalytic psychotherapy to improve longer-term post-treatment outcomes in patients with treatment-resistant depression. In this case study, we examine the therapy process of a female trial participant diagnosed with treatment-resistant depression. Structured clinical assessments indicated that the patient's level of depression remained unchanged during and after treatment. Over the course of the therapy, she repeatedly broke away from important others and finally also from the therapy itself, which we linked to the impact of earlier experiences of abandonment on her internal world. In the discussion, we present a variety of reflections that were put forward by the authors during a series of case discussion meetings. Some of these reflections relate to how the inner world of this patient might have triggered a negative therapeutic reaction and a destructive pattern of repetition. The interpretative stance, in which the therapist interpreted this reaction as indicative of a psychic conflict and linked this conflict to the therapeutic relationship, seemed to be experienced by the patient as unhelpful and persecutory. Other elements that were brought up include basic distrust, lack of symbolization and trauma in the patient, as well as the constraints of the research context.

Preparing for Artificial General Intelligence (AGI) in Health Professions Education: AMEE Guide No. 172.

Generative Artificial Intelligence (GenAI) caught Health Professions Education (HPE) institutions off-guard, and they are currently adjusting to a changed educational environment. On the horizon, however, is Artificial General Intelligence (AGI) which promises to be an even greater leap and challenge. This Guide begins by explaining the context and nature of AGI, including its characteristics of multi-modality, generality, adaptability, autonomy, and learning ability. It then explores the implications of AGI on students (including personalised learning and electronic tutors) and HPE institutions, and considers some of the context provided by AGI in healthcare. It then raises the problems to address, including the impact on employment, social risks, student adaptability, costs, quality, and others. After considering a possible timeline, the Guide then ends by indicating some first steps that HPE institutions and educators can take to prepare for AGI.

Identifying clinically relevant agranulocytosis in people registered on the UK clozapine Central Non-Rechallenge Database: retrospective cohort study.

BACKGROUND: Clozapine is the most effective antipsychotic for treatment-resistant psychosis. However, clozapine is underutilised in part because of potential agranulocytosis. Accumulating evidence indicates that below-threshold haematological readings in isolation are not diagnostic of life-threatening clozapine-induced agranulocytosis (CIA). AIMS: To examine the prevalence and timing of CIA using different diagnostic criteria and to explore demographic differences of CIA in patients registered on the UK Central Non-Rechallenge Database (CNRD). METHOD: We analysed data of all patients registered on the UK Clozaril® Patient Monitoring Service Central Non-Rechallenge Database (at least one absolute neutrophil count (ANC) < 1.5 × 109/L and/or white blood cell count < 3.0 × 109/L) between May 2000 and February 2021. We calculated prevalence rates of agranulocytosis using threshold-based and pattern-based criteria, stratified by demographic factors (gender, age and ethnicity). Differences in epidemiology based on rechallenge status and clozapine indication were explored. The proportion of patients who recorded agranulocytosis from a normal ANC was explored. RESULTS: Of the 3029 patients registered on the CNRD with 283 726 blood measurements, 593 (19.6%) were determined to have threshold-based agranulocytosis and 348 (11.4%) pattern-based agranulocytosis. In the total sample (75 533), the prevalence of threshold-based agranulocytosis and pattern-based agranulocytosis was 0.8% and 0.5%, respectively. The median time to threshold-based agranulocytosis was 32 weeks (IQR 184) and 15 (IQR 170) weeks for pattern-based agranulocytosis. Among age groups, the prevalence of pattern-based agranulocytosis and threshold-based agranulocytosis was highest in the >48 age group. Prevalence rates were greatest for White (18%) and male individuals (13%), and lowest for Black individuals (0.1%). The proportion of people who were determined to have pattern-based agranulocytosis without passing through neutropenia was 70%. CONCLUSIONS: Threshold-based definition of agranulocytosis may over-diagnose CIA. Monitoring schemes should take into consideration neutrophil patterns to correctly identify clinically relevant CIA. In marked contrast to previous studies, CIA occurred least in Black individuals and most in White individuals.

Methods for detection of cardiac glycogen-autophagy.

Glycogen-autophagy ('glycophagy') is a selective autophagy process involved in delivering glycogen to the lysosome for bulk degradation. Glycophagy protein intermediaries include STBD1 as a glycogen tagging receptor, delivering the glycogen cargo into the forming phagosome by partnering with the Atg8 homolog, GABARAPL1. Glycophagy is emerging as a key process of energy metabolism and development of reliable tools for assessment of glycophagy activity is an important priority. Here we show that antibodies raised against the N-terminus of the GABARAPL1 protein (but not the full-length protein) detected a specific endogenous GABARAPL1 immunoblot band at 18kDa. A stable GFP-GABARAPL1 cardiac cell line was used to quantify GABARAPL1 lysosomal flux via measurement of GFP puncta in response to lysosomal inhibition with bafilomycin. Endogenous glycophagy flux was quantified in primary rat ventricular myocytes by the extent of glycogen accumulation with bafilomycin combined with chloroquine treatment (no effect observed with bafilomycin or chloroquine alone). In wild-type isolated mouse hearts, bafilomycin alone and bafilomycin combined with chloroquine (but not chloroquine alone) elicited a significant increase in glycogen content signifying basal glycophagy flux. Collectively, these methodologies provide a comprehensive toolbox for tracking cardiac glycophagy activity to advance research into the role of glycophagy in health and disease.

Development of the Guide to Disseminating Research (GuiDiR): A consolidated framework.

BACKGROUND: Less than one third of research evidence is translated into policy or practice. Knowledge translation requires effective dissemination, adoption and finally implementation. These three stages are equally important, however, existing knowledge translation models and frameworks provide little and disparate information about the steps and activities required for effective dissemination. OBJECTIVE: This study aimed to empirically develop a consolidated framework of evidence-based steps and activities for disseminating research evidence. METHODS: We identified models and frameworks from a scoping review and dissemination and implementation webtool. We synthesised them into a prototype dissemination framework. Models and frameworks were eligible to inform steps in our framework if they fulfilled at least one of three elements of dissemination: intending to generate awareness of a message, incorporates targeting an audience: tailoring communication. An initial coding framework was created to organise data into dissemination steps. Drawing on 'co-approach' principles, authors of the included models and frameworks (dissemination experts) and health service researchers (end users) were invited to test and refine the prototype framework at a workshop. RESULTS: From 48 models and frameworks reviewed, only 32 fulfilled one or more of the three dissemination elements. The initial coding framework, upon refinement, yielded the Guide to Disseminating Research (GuiDiR) comprising five steps. 1) Identify target audiences and dissemination partners. 2) Engage with dissemination partners. 3) Identify barriers and enablers to dissemination. 4) Create dissemination messages. 5) Disseminate and evaluate. Multiple activities were identified for each step and no single model or framework represents all steps and activities in GuiDiR. CONCLUSIONS: GuiDiR unifies dissemination components from knowledge translation models and frameworks and harmonises language into a format accessible to non-experts. It outlines for researchers, funders and practitioners the expected structure of dissemination and details the activities for executing an evidence-based dissemination strategy.

Medical education in Georgia.

Since 1991, there have been significant changes in medical education in Georgia. Key changes include adapting national legislation toward international standards, establishing the National Center for Education Quality Enhancement (NCEQE), which was recognized in 2018 by the World Federation for Medical Education (WFME) as an accrediting agency and opening the Association for Medical Education in Europe (AMEE) International Networking Center in 2019. Undergraduate medical education, regulated by the Ministry of Education, Science and Youth of Georgia, spans six years. MD graduates then have options for further career paths, including working as junior doctors, residency, and/or pursuing PhD research.The main challenges the country presently faces are: the need to reduce the increasing number of (mainly) private medical schools. Recent updates to the national standards for undergraduate medical education have imposed stricter accreditation requirements for MD programs, resulting in the closure of schools that fail to meet these standards;postgraduate medical education is governed by the Ministry of Internally Displaced Persons from the Occupied Territories, Labor, Health and Social Affairs of Georgia (MOH) and needs further reform due to limited and paid residency positions;continuous professional development (CPD) was optional until recently, which led to an increase in professional inaccuracy and malpractice cases. To address this, regulatory bodies, including the MOH and professional associations, are preparing the legal basis for introducing compulsory CPD.

The biomechanics of splitting hairs.

Splitting of hair, creating 'split ends', is a very common problem which has been extensively documented. However, the mechanics underlying the splitting phenomenon are poorly understood. This is partly owing to the lack of a test in which splitting can be generated and quantified under laboratory conditions. We developed three new tests, known as 'loop tensile', 'moving loop' and 'moving loop fatigue', aiming to simulate the mechanical environment of tangles of hair strands during combing. We tested straight strands of human hair, comparing low-quality hair (from a subject who experienced split ends) with hair from a control (non-splitting) subject. Significant differences were found, especially in the moving loop fatigue test where the low-quality hair failed in fewer cycles. Splitting occurred in both types of hair, but with the crucial difference that in the low-quality hair, splits originated inside the hair strand and propagated longitudinally over considerable distances, while in the control hair, splits originated at the strand surface and remained short. Bleaching of the control hair changed its behaviour, making it similar to that of the low-quality hair. Some simple calculations emphasized the role of longitudinal shear stress and shear stress intensity in generating microcracks which could then propagate within the moving loop, paving the way for a future theoretical model of the splitting mechanism.

Cas12a domain flexibility guides R-loop formation and forces RuvC resetting.

The specific nature of CRISPR-Cas12a makes it a desirable RNA-guided endonuclease for biotechnology and therapeutic applications. To understand how R-loop formation within the compact Cas12a enables target recognition and nuclease activation, we used cryo-electron microscopy to capture wild-type Acidaminococcus sp. Cas12a R-loop intermediates and DNA delivery into the RuvC active site. Stages of Cas12a R-loop formation-starting from a 5-bp seed-are marked by distinct REC domain arrangements. Dramatic domain flexibility limits contacts until nearly complete R-loop formation, when the non-target strand is pulled across the RuvC nuclease and coordinated domain docking promotes efficient cleavage. Next, substantial domain movements enable target strand repositioning into the RuvC active site. Between cleavage events, the RuvC lid conformationally resets to occlude the active site, requiring re-activation. These snapshots build a structural model depicting Cas12a DNA targeting that rationalizes observed specificity and highlights mechanistic comparisons to other class 2 effectors.

Severe neutropenia unrelated to clozapine in patients receiving clozapine.

BACKGROUND: Clozapine is known to cause agranulocytosis. Mandatory monitoring schemes are aimed at reducing the risk of agranulocytosis and of the consequences of agranulocytosis. All cases of agranulocytosis occurring in people prescribed clozapine are assumed to be caused by clozapine. METHODS: In a previous study, we examined a cohort of patients listed on our hospital database as having had clozapine-induced agranulocytosis and applied specific criteria to identify those with confirmed clozapine-related, life-threatening agranulocytosis. In this study, we examine the cases not meeting these specific criteria. RESULTS: In the original study, 9 of 23 cases met the criteria for clozapine-induced, life-threatening agranulocytosis. Of the 13 remaining cases for whom data were available, 5 were probably caused by clozapine but were not life-threatening. Three cases were the result of concomitant cancer chemotherapy. Three were anomalous results probably related to measurement error. For the remaining two cases, the cause was not identified. CONCLUSION: Not all cases of agranulocytosis occurring in people taking clozapine are caused by clozapine. The widely used threshold criterion-based diagnosis overestimates the risk of agranulocytosis. True clozapine-related agranulocytosis is best identified by pattern-based criteria: rapid fall in neutrophil counts over around 2 weeks to below 0.5 × 109/L for two consecutive days (unless clozapine is stopped very early or granulocyte colony stimulating factor is given) where other possible causes (benign ethnic neutropenia, cancer chemotherapy) can be ruled out.

Autophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress by D2-HG.

OBJECTIVES: Cachexia is a metabolic disorder and comorbidity with cancer and heart failure. The syndrome impacts more than thirty million people worldwide, accounting for 20% of all cancer deaths. In acute myeloid leukemia, somatic mutations of the metabolic enzyme isocitrate dehydrogenase 1 and 2 cause the production of the oncometabolite D2-hydroxyglutarate (D2-HG). Increased production of D2-HG is associated with heart and skeletal muscle atrophy, but the mechanistic links between metabolic and proteomic remodeling remain poorly understood. Therefore, we assessed how oncometabolic stress by D2-HG activates autophagy and drives skeletal muscle loss. METHODS: We quantified genomic, metabolomic, and proteomic changes in cultured skeletal muscle cells and mouse models of IDH-mutant leukemia using RNA sequencing, mass spectrometry, and computational modeling. RESULTS: D2-HG impairs NADH redox homeostasis in myotubes. Increased NAD+ levels drive activation of nuclear deacetylase Sirt1, which causes deacetylation and activation of LC3, a key regulator of autophagy. Using LC3 mutants, we confirm that deacetylation of LC3 by Sirt1 shifts its distribution from the nucleus into the cytosol, where it can undergo lipidation at pre-autophagic membranes. Sirt1 silencing or p300 overexpression attenuated autophagy activation in myotubes. In vivo, we identified increased muscle atrophy and reduced grip strength in response to D2-HG in male vs. female mice. In male mice, glycolytic intermediates accumulated, and protein expression of oxidative phosphorylation machinery was reduced. In contrast, female animals upregulated the same proteins, attenuating the phenotype in vivo. Network modeling and machine learning algorithms allowed us to identify candidate proteins essential for regulating oncometabolic adaptation in mouse skeletal muscle. CONCLUSIONS: Our multi-omics approach exposes new metabolic vulnerabilities in response to D2-HG in skeletal muscle and provides a conceptual framework for identifying therapeutic targets in cachexia.

The cardiovascular safety of tricyclic antidepressants in overdose and in clinical use.

Tricyclic antidepressants (TCAs) remain widely prescribed for depression and many other conditions. There may be important differences between individual TCA in regard to their overdose toxicity and their cardiac toxicity in clinical use. We conducted a systematic review to compare the toxicity of individual TCA in overdose and the risk of serious adverse cardiac events occurring with therapeutic doses. We used the fatal toxicity index (FTI) and case fatality ratio as markers of fatality in overdose, and hazard ratios or odds ratios for the risk of cardiovascular adverse events during normal clinical use. In all, 30 reports of mortality in overdose and 14 observational studies assessing the risk of cardiovascular adverse events in clinical use were included. FTI values were of the same order of magnitude (101-102) for all TCAs except lofepramine. Desipramine appears to be somewhat more likely than other TCAs to lead to death in overdose. Amitriptyline, clomipramine, dothiepin/dosulepin, doxepin, trimipramine and imipramine showed broadly similar toxicity and were usually reported to be less toxic than desipramine. Data on nortriptyline were contradictory. Lofepramine had the lowest risk of death in overdose. The rank order of overdose toxicity was broadly consistent between different FTI definitions and between markers used. With respect to the risk of cardiovascular events at clinically relevant exposure, amitriptyline, nortriptyline and lofepramine were associated with a greater risk of in-use cardiotoxicity. All measures of overdose toxicity were subject to external influences and confounding. The continued use of TCAs in depression and other conditions should be minimized when considering their undoubted toxicity in overdose and possible toxicity in normal clinical use.

Older tricyclic antidepressants and their toxicity in overdose and in clinical use Tricyclic antidepressants were first used in the 1950s. Their use for depression has gone down in the past 20 or so years. This is because newer antidepressants are better tolerated and less toxic in overdose. Certain tricyclics - dosulepin and amitriptyline - have been identified as being particularly toxic tricyclics and their use has been restricted. However many other tricyclics remain widely used for depression and many other conditions. We examined all the evidence we could find on tricyclic toxicity. We found that, with one exception, all tricyclics are toxic and dangerous when taken in overdose. The exception is lofepramine - a tricyclic used in the UK and some other countries. When looking at toxicity in clinical use, we found no consistent evidence of difference between individual tricyclics. It is possible that most or all tricyclics do not increase the risk of heart attack or sudden cardiac death when used at normal clinical doses.

Making assessment a team sport: a qualitative study of facilitated group feedback in internal medicine residency.

Purpose: Competency-based medical education relies on feedback from workplace-based assessment (WBA) to direct learning. Unfortunately, WBAs often lack rich narrative feedback and show bias towards Medical Expert aspects of care. Building on research examining interactive assessment approaches, the Queen's University Internal Medicine residency program introduced a facilitated, team-based assessment initiative ("Feedback Fridays") in July 2017, aimed at improving holistic assessment of resident performance on the inpatient medicine teaching units. In this study, we aim to explore how Feedback Fridays contributed to formative assessment of Internal Medicine residents within our current model of competency-based training. Method: A total of 53 residents participated in facilitated, biweekly group assessment sessions during the 2017 and 2018 academic year. Each session was a 30-minute facilitated assessment discussion done with one inpatient team, which included medical students, residents, and their supervising attending. Feedback from the discussion was collected, summarized, and documented in narrative form in electronic WBA forms by the program's assessment officer for the residents. For research purposes, verbatim transcripts of feedback sessions were analyzed thematically. Results: The researchers identified four major themes for feedback: communication, intra- and inter-personal awareness, leadership and teamwork, and learning opportunities. Although feedback related to a broad range of activities, it showed strong emphasis on competencies within the intrinsic CanMEDS roles. Additionally, a clear formative focus in the feedback was another important finding. Conclusions: The introduction of facilitated team-based assessment in the Queen's Internal Medicine program filled an important gap in WBA by providing learners with detailed feedback across all CanMEDS roles and by providing constructive recommendations for identified areas for improvement.

Objectif: La formation médicale fondée sur les compétences s'appuie sur la rétroaction faite lors de l'évaluation des apprentissages par observation directe dans le milieu de travail. Malheureusement, les évaluations dans le milieu de travail omettent souvent de fournir une rétroaction narrative exhaustive et privilégient les aspects des soins relevant de l'expertise médicale. En se basant sur la recherche ayant étudié les approches d'évaluation interactive, le programme de résidence en médecine interne de l'Université Queen's a introduit en juillet 2017 une initiative d'évaluation facilitée et en équipe (« Les vendredis rétroaction ¼), visant à améliorer l'évaluation holistique du rendement des résidents dans les unités d'enseignement clinique en médecine interne. Dans cette étude, nous visons à explorer comment ces « vendredis rétroaction ¼ ont contribué à l'évaluation formative des résidents en médecine interne dans le cadre de notre modèle actuel de formation axée sur les compétences. Méthode: Au total, 53 résidents ont participé à des séances d'évaluation de groupe facilitées et bi-hebdomadaires au cours de l'année universitaire 2017-2018. Chaque séance consistait en une discussion d'évaluation facilitée de 30 minutes menée avec une équipe de l'unité de soins, qui comprenait des étudiants en médecine, des résidents et le médecin superviseur. Les commentaires issus de la discussion ont été recueillis, résumés et documentés sous forme narrative dans des formulaires électroniques d'observation directe dans le milieu de travail par le responsable de l'évaluation du programme de résidence. À des fins de recherche, les transcriptions verbatim des séances de rétroaction ont été analysées de façon thématique. Résultats: Les chercheurs ont identifié quatre thèmes principaux pour les commentaires : la communication, la conscience intra- et interpersonnelle, le leadership et le travail d'équipe, et les occasions d'apprentissage. Bien que la rétroaction concerne un large éventail d'activités, elle met fortement l'accent sur les compétences liées aux rôles intrinsèques de CanMEDS. De plus, le fait que la rétroaction avait un rôle clairement formatif est une autre constatation importante. Conclusions: L'introduction de l'évaluation en équipe facilitée dans le programme de médecine interne à Queen's a comblé une lacune importante dans l'apprentissage par observation directe dans le milieu de travail en fournissant aux apprenants une rétroaction détaillée sur tous les rôles CanMEDS et en formulant des recommandations constructives sur les domaines à améliorer.

Systematic Review and Meta-Analysis of Policies and Interventions that Improve Health, Psychosocial, and Economic Outcomes for Young People Leaving the Out-of-Home Care System.

Young people who transition to adulthood from out-of-home care (OOHC) are more likely to experience a range of poorer outcomes relative to their same-age peers in the community. This systematic review assessed the effectiveness of policies or interventions (hereafter "interventions") aimed at improving housing, health, education, economic, and psychosocial outcomes for youth leaving OOHC (hereafter "care leavers"). Eleven databases of published literature were reviewed along with gray literature. Eligible studies used randomized or quasi-experimental designs and assessed interventions that provided support to care leavers prior to, during, or after they left OOHC. Primary outcomes were housing and homelessness, health and well-being, education, economic and employment, criminal and delinquent behavior, and risky behavior, while secondary outcomes were supportive relationships and life skills. Where possible, results were pooled in a meta-analysis. Certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation. Fourteen studies published in 27 reports were identified that examined independent living programs (ILPs) (n = 5), intensive support services (n = 2), coaching and peer support (C&PSP) (n = 2), transitional housing (n = 1), health information or coaching (n = 2), and extended care (n = 2). All but one study was conducted in the United States. Twenty small meta-analyses were undertaken encompassing ILPs and C&PSP, with two showing results that favored the intervention with certainty. The level of confidence in each meta-analysis was considered very low. A significant risk of bias was identified in each of the included studies. While some interventions showed promise, particularly extended care, the scope and strength of included evidence is insufficient to recommend any included approach.

Effects of a competence-based approach for clerkship teaching under alternating clinical placements: An explanatory sequential mixed-methods research.

BACKGROUND: It is unclear whether alternating placements during clinical clerkship, without an explicit emphasis on clinical competencies, would bring about optimal educational outcomes. METHODS: This is an explanatory sequential mixed-methods research. We enrolled a convenience sample of 41 eight-year programme medical students in Sun Yat-sen University who received alternating placements during clerkship. The effects of competence-based approach (n = 21) versus traditional approach (n = 20) to clerkship teaching were compared. In the quantitative phase, course satisfaction was measured via an online survey and academic performance was determined through final scores on summative assessment. Then, in the qualitative phase, students were invited for semi-structured interviews about their learning experiences, and the transcripts were used for thematic analysis. RESULTS: Quantitative findings showed that students in the study group rated high course satisfaction and performed significantly better in their final scores compared with those in the control group. Qualitative findings from thematic analysis showed that students were relatively neutral about their preference on placement models, but clearly perceived, capitalised, and appreciated that their competencies were being cultivated by an instructor who was regarded as a positive role model. CONCLUSION: A competence-based approach to clerkship teaching resulted in better course satisfaction and academic performance, and was perceived, capitalised, and appreciated by students.