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.

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.

Use of Nonhuman Sera as a Highly Cost-Effective Internal Standard for Quantitation of Multiple Human Proteins Using Species-Specific Tryptic Peptides: Applicability in Clinical LC-MS Analyses.

Quantitation of proteins using liquid chromatography-tandem mass spectrometry (LC-MS/MS) is complex, with a multiplicity of options ranging from label-free techniques to chemically and metabolically labeling proteins. Increasingly, for clinically relevant analyses, stable isotope-labeled (SIL) internal standards (ISs) represent the "gold standard" for quantitation due to their similar physiochemical properties to the analyte, wide availability, and ability to multiplex to several peptides. However, the purchase of SIL-ISs is a resource-intensive step in terms of cost and time, particularly for screening putative biomarker panels of hundreds of proteins. We demonstrate an alternative strategy utilizing nonhuman sera as the IS for quantitation of multiple human proteins. We demonstrate the effectiveness of this strategy using two high abundance clinically relevant analytes, vitamin D binding protein [Gc globulin] (DBP) and albumin (ALB). We extend this to three putative risk markers for cardiovascular disease: plasma protease C1 inhibitor (SERPING1), annexin A1 (ANXA1), and protein kinase, DNA-activated catalytic subunit (PRKDC). The results show highly specific, reproducible, and linear measurement of the proteins of interest with comparable precision and accuracy to the gold standard SIL-IS technique. This approach may not be applicable to every protein, but for many proteins it can offer a cost-effective solution to LC-MS/MS protein quantitation.

The impact of mitotane therapy on serum-free proteins in patients with adrenocortical carcinoma.

Introduction: Adrenocortical carcinoma (ACC) is a rare malignancy of the adrenal cortex. Whilst surgery is the preferred treatment, adjunctive therapy with mitotane may be offered post-surgically to minimise the risk of recurrence or, in the absence of surgery, to attenuate progression. Aim: The objective was to evaluate the effects of mitotane treatment on serum protein concentrations in patients treated for ACC with mitotane therapy and compare this to patients with other adrenal neoplasms and a normal pregnant cohort. Methods: Serum cortisol, thyroid function tests, adrenocorticotrophic hormone (ACTH), cortisol-binding globulin (CBG), thyroxine-binding globulin (TBG), gonadotrophins and androgens were measured on plasma and serum samples. Thirty-five patients with ACC were included, and mitotane levels were noted to be sub-/supra-therapeutic. Data were tested for normality, reported as mean ± s.d., and compared to other two cohorts using paired-sample t-test with a 5% P-value for significance and a 95% CI. Results: Patients on mitotane therapy had a higher mean serum CBG concentration compared to the adrenal neoplasm group (sub-therapeutic: 79.5 (95% CI: 33.6, 125.4 nmol/L), therapeutic: 85.3 (95% CI: 37.1-133.6 nmol/L), supra-therapeutic: 75.7 (95% CI: -19.3, 170.6 nmol/L) and adrenal neoplasm: 25.5 (95% CI: 17.5, 33.5 nmol/L). Negative correlations between serum cortisol and CBG concentration were demonstrated within the supra-therapeutic plasma mitotane and adrenal neoplasm groups. Conclusion: Patients with ACC and therapeutic plasma mitotane concentrations had higher serum CBG concentrations compared to those with adrenal neoplasms or pregnant women, and higher serum cortisol. Whilst there was no direct correlation with cortisol and mitotane level, the negative correlation of cortisol with CBG may suggest that the direct effect of mitotane in increasing cortisol may also reflect that mitotane has a direct adrenolytic effect.

Twelve tips to develop entrustable professional activities.

Entrustable professional activities (EPAs), units of professional practice that require proficient integration of multiple competencies and can be entrusted to a sufficiently competent learner, are increasingly being used to define and inform curricula of health care professionals. The process of developing EPAs can be challenging and requires a deep yet pragmatic understanding of the concepts underlying EPA construction. Based on recent literature and the authors' lessons learned, this article provides the following practical and more or less sequential recommendations for developing EPAs: [1] Assemble a core team; [2] Build up expertise; [3] Establish a shared understanding of the purpose of EPAs; [4] Draft preliminary EPAs; [5] Elaborate EPAs; [6] Adopt a framework of supervision; [7] Perform a structured quality check; [8] Use a Delphi approach for refinement and/or consensus; [9] Pilot test EPAs; [10] Attune EPAs to their feasibility in assessment; [11] Map EPAs to existing curriculum; [12] Build a revision plan.

Low Baseline but Not Delta Cortisol Relates to 28-Day Transplant-Free Survival in Acute and Acute-on-Chronic Liver Failure.

Background and Aims: The clinical, prognostic, and therapeutic impact of adrenal insufficiency in acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) remains controversial and exact diagnostic criteria are lacking. We sought to determine the diagnostic and therapeutic value of cortisol measurement and glucocorticoid (GC) treatment in ALF and ACLF. Methods: 28-day transplant-free survival (TFS) was studied in relation to absolute cortisol concentrations and to GC treatment in ALF (n = 30) and ACLF (n = 34) patients. Cortisol concentrations and short synacthen test were assessed by chemiluminescence immunoassay and liquid chromatography-mass spectrometry. Clinicians decided independently on GC treatment. In relation, phenotypic and functional characteristics of circulating monocytes were assessed. Results: In ALF, baseline cortisol concentrations <387 nmol/L predicted TFS (sensitivity 83%, specificity 53%). In ACLF, baseline cortisol <392 nmol/L correlated with TFS (sensitivity 80%, specificity 61%). In both, ALF and ACLF, GC treatment did not influence 28-day TFS in patients with low baseline cortisol. However, in patients with baseline cortisol exceeding 387 and 392 nmol/L, respectively, TFS was higher if they had been treated with GC. High baseline cortisol was associated with low HLA-DR expression on monocytes. Conclusion: Our data suggest a prognostic value of baseline cortisol measurement in ALF and ACLF. Overall, strong activation of the hypothalamic-pituitary-adrenal axis indicated poor prognosis. Furthermore, baseline cortisol deserves prospective evaluation as a guide for GC treatment decision-making.

The logic behind entrustable professional activity frameworks: A scoping review of the literature.

INTRODUCTION: Entrustable professional activities (EPAs), discrete profession-specific tasks requiring integration of multiple competencies, are increasingly used to help define and inform curricula of specialty training programmes. Although guidelines exist to help guide the developmental process, deciding what logic to use to draft a preliminary EPA framework poses a crucial but often difficult first step. The logic of an EPA framework can be defined as the perspective used by its developers to break down the practice of a profession into units of professional work. This study aimed to map dominant logics and their rationales across postgraduate medical education and fellowship programmes. METHODS: A scoping review using systematic searches within five electronic databases (Medline, Embase, Google Scholar, Scopus and Web of Science) was performed. Dominant logics of included papers were identified using inductive coding and iterative analysis. RESULTS: In total, 42 studies were included. Most studies were conducted in the United States (n = 22; 52%), Canada (n = 6; 14%) and the Netherlands (n = 4; 10%). Across the reported range of specialties, family medicine (n = 4; 10%), internal medicine (n = 4; 10%), paediatrics (n = 3; 7%) and psychiatry (n = 3; 7%) were the most common. Three dominant logics could be identified, namely, 'service provision', 'procedures' and/or 'disease or patient categories'. The majority of papers (n = 37; 88%) used two or more logics when developing EPA frameworks (median = 3, range = 1-4). Disease or patient groups and service provision were the most common logics used (39% and 37%, respectively). CONCLUSIONS: Most programmes used a combination of logics when trying to capture the essential tasks of a profession in EPAs. For each of the three dominant logics, the authors arrived at a definition and identified benefits, limitations and examples. These findings may potentially inform best practice guidelines for EPA development.

International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers.

Approximately 20% of patients diagnosed with a phaeochromocytoma or paraganglioma carry a germline mutation in one of the succinate dehydrogenase (SDHx) genes (SDHA, SDHB, SDHC and SDHD), which encode the four subunits of the SDH enzyme. When a pathogenic SDHx mutation is identified in an affected patient, genetic counselling is proposed for first-degree relatives. Optimal initial evaluation and follow-up of people who are asymptomatic but might carry SDHx mutations have not yet been agreed. Thus, we established an international consensus algorithm of clinical, biochemical and imaging screening at diagnosis and during surveillance for both adults and children. An international panel of 29 experts from 12 countries was assembled, and the Delphi method was used to reach a consensus on 41 statements. This Consensus Statement covers a range of topics, including age of first genetic testing, appropriate biochemical and imaging tests for initial tumour screening and follow-up, screening for rare SDHx-related tumours and management of elderly people who have an SDHx mutation. This Consensus Statement focuses on the management of asymptomatic SDHx mutation carriers and provides clinicians with much-needed guidance. The standardization of practice will enable prospective studies in the near future.

Biochemical abnormalities in COVID-19: a comparison of white versus ethnic minority populations in the UK.

AIMS: Public Health England has identified that in COVID-19, death rates among ethnic minorities far exceeds that of the white population. While the increase in ethnic minorities is likely to be multifactorial, to date, no studies have looked to see whether values for routine clinical biochemistry parameters differ between ethnic minority and white individuals. METHODS: Baseline biochemical data for 22 common tests from 311 SARS-CoV-2 positive patients presenting to hospital in April 2020 in whom ethnicity data were available was retrospectively collected and evaluated. Data comparisons between ethnic minority and white groups were made for all patient data and for the subset of patients subsequently admitted to intensive care. RESULTS: When all patient data were considered, the ethnic minority population had statistically significant higher concentrations of C reactive protein (CRP), aspartate aminotransferase and gamma-glutamyl transferase, while troponin T was higher in the white group. A greater proportion of ethnic minority patients were subsequently admitted to intensive care, but when the presenting biochemistry of this subset of patients was compared, no significant differences were observed between ethnic minority and white groups. CONCLUSION: Our data show for the first time that routine biochemistry at hospital presentation in COVID-19 differs between ethnic minority and white groups. Among the markers identified, CRP was significantly higher in the ethnic minority group pointing towards an increased tendency for severe inflammation in this group.

The recommended description of an entrustable professional activity: AMEE Guide No. 140.

Entrustable professional activities (EPAs) have received much attention in the literature since they were first proposed in 2005. Useful guidelines, workshops, courses, and conferences have supported faculty in developing programs and designing assessment procedures using EPAs and entrustment decision-making. Yet, the need for clarification remains, particularly as more programs make the step from design to implementation.Well-written EPAs provide a natural construct to establish the outcome of training. To be useful, EPAs require more than a suitable title. This AMEE Guide elaborates eight sections of a full EPA description, and provides explanations and justifications for each. These sections are: title; specification and limitations; risks in case of failure; most relevant competency domains; knowledge, skills, attitudes and experiences; information sources to assess progress and support summative entrustment; entrustment/supervision level expected at which stage of training; and time period to expiration if not practiced.Constructing fully elaborated EPAs creates a shared mental model amongst learners and programs, informs competency-based curriculum design, directs ad-hoc and formal entrustment decision-making, and provides standards for certifying bodies and boundaries for scope of practice. The framework intends to support curricular leaders looking to adopt new EPAs, or revise and define established EPAs for competency-based education.

Posaconazole-Induced Hypertension Masquerading as Congenital Adrenal Hyperplasia in a Child with Cystic Fibrosis.

BACKGROUND: Deficiency of 11ß-hydroxylase is the second most common cause of congenital adrenal hyperplasia (CAH), presenting with hypertension, hypokalaemia, precocious puberty, and adrenal insufficiency. We report the case of a 6-year-old boy with cystic fibrosis (CF) found to have hypertension and cortisol insufficiency, which were initially suspected to be due to CAH, but were subsequently identified as being secondary to posaconazole therapy. Case Presentation. A 6-year-old boy with CF was noted to have developed hypertension after administration of two doses of Orkambi™ (ivacaftor/lumacaftor), which was subsequently discontinued, but the hypertension persisted. Further investigations, including echocardiogram, abdominal Doppler, thyroid function, and urinary catecholamine levels, were normal. A urine steroid profile analysis raised the possibility of CAH due to 11ß-hydroxylase deficiency, and a standard short synacthen test (SST) revealed suboptimal cortisol response. Clinically, there were no features of androgen excess. Detailed evaluation of the medical history revealed exposure to posaconazole for more than 2 months, and the hypertension had been noted to develop two weeks after the initiation of posaconazole. Hence, posaconazole was discontinued, following which the blood pressure, cortisol response to the SST, and urine steroid profile were normalized. CONCLUSION: Posaconazole can induce a clinical and biochemical picture similar to CAH due to 11ß-hydroxylase deficiency, which is reversible. It is prudent to monitor patients on posaconazole for cortisol insufficiency, hypertension, and electrolyte abnormalities.

EQual Rubric Evaluation of the Association of American Medical Colleges' Core Entrustable Professional Activities for Entering Residency.

PURPOSE: To have subject matter experts evaluate the Core Entrustable Professional Activities for Entering Residency (Core EPAs) with the EQual rubric to determine if revisions were required and, if applicable, how to focus revision efforts. METHOD: Ten entrustable professional activity (EPA) experts were invited to evaluate the 13 Core EPAs. Experts had a 6-month window (December 2018-May 2019) to complete the evaluation, which contained the complete EQual rubric and 3 additional prompts, one of which-"Do you think this EPA requires revision?"-was limited to a "yes/no" response. Descriptive statistics for overall and domain-specific EQual rubric scores for each of the 13 Core EPAs were calculated. Free-text responses to why and/or how a Core EPA should be revised were summarized for any Core EPA that scored below a cutoff or for which the majority of experts recommended revision. RESULTS: Six experts completed the evaluation. Most Core EPAs' (9/13) overall score was above the cutoff, indicating that they align with the key domains of the EPA construct. The remaining 4 Core EPAs (2, 7, 9, and 13) scored below the overall cutoff, suggesting that they may require revision. A majority of experts felt that Core EPAs 6, 7, 9, and 13 required revision. With regard to domain-specific scores, Core EPAs 2, 3, 7, 9, and 13 were below the discrete units of work cutoff; Core EPAs 7, 9, and 13 were below the entrustable, essential, and important tasks of the profession of medicine cutoff; and Core EPA 9 was below the curricular role cutoff. CONCLUSIONS: The Core EPAs represent a promising initial framework of EPAs for undergraduate medical education. Some Core EPAs might benefit from revision. The process of improving the Core EPAs must continue if they are to standardize outcomes for medical school graduates.

Creating Entrustable Professional Activities to Assess Internal Medicine Residents in Training: A Mixed-Methods Approach.

Background: Competency-based medical education has not advanced residency training as much as many observers expected. Some medical educators now advocate reorienting competency-based approaches to focus on a resident's ability to do authentic clinical work. Objective: To develop descriptions of clinical work for which internal medicine residents must gain proficiency to deliver meaningful patient care (for example, "Admit and manage a medical inpatient with a new acute problem"). Design: A modified Delphi process involving clinical experts followed by a conference of educational experts. Setting: The Royal College of Physicians and Surgeons of Canada. Participants: In phase 1 of the project, members of the Specialty Committee for Internal Medicine participated in a modified Delphi process to identify activities in internal medicine that represent the scope of the specialty. In phase 2 of the project, 5 experts who were scholars and leaders in competency-based medical education reviewed the results. Measurements: Phase 1 identified important activities, revised descriptions to improve accuracy and avoid overlap, and assigned activities to stages of training. Phase 2 compared proposed activity descriptions with published guidelines for their development and application in medical education. Results: The project identified 29 activities that qualify as entrustable professional activities. The project also produced a detailed description of each activity and guidelines for using them to assess residents. Limitation: These activities reflect the practice patterns of the developers and may not fully represent internal medicine practice in Canada. Conclusion: Identification of these activities is expected to facilitate modification of training and assessment programs for medical residents so that programs focus less on isolated skills and more on integrated tasks. Primary Funding Source: Southeastern Ontario Academic Medical Organization Endowed Scholarship and Education Fund and Queen's University Department of Medicine Innovation Fund.