Hypoxia Inducible Factor pathway proteins in high-altitude mammals.

Humans and other mammals inhabit hypoxic high-altitude locales. In many of these species, genes under positive selection include ones in the Hypoxia Inducible Factor (HIF) pathway. One is PHD2 (EGLN1), which encodes for a key oxygen sensor. Another is HIF2A (EPAS1), which encodes for a PHD2-regulated transcription factor. Recent studies have provided insights into mechanisms for these high-altitude alleles. These studies have (i) shown that selection can occur on nonconserved, unstructured regions of proteins, (ii) revealed that high altitude-associated amino acid substitutions can have differential effects on protein-protein interactions, (iii) provided evidence for convergent evolution by different molecular mechanisms, and (iv) suggested that mutations in different genes can complement one another to produce a set of adaptive phenotypes.

Genomic structural variation contributes to evolved changes in gene expression in high-altitude Tibetan sheep.

Tibetan sheep were introduced to the Qinghai Tibet plateau roughly 3,000 B.P., making this species a good model for investigating genetic mechanisms of high-altitude adaptation over a relatively short timescale. Here, we characterize genomic structural variants (SVs) that distinguish Tibetan sheep from closely related, low-altitude Hu sheep, and we examine associated changes in tissue-specific gene expression. We document differentiation between the two sheep breeds in frequencies of SVs associated with genes involved in cardiac function and circulation. In Tibetan sheep, we identified high-frequency SVs in a total of 462 genes, including EPAS1, PAPSS2, and PTPRD. Single-cell RNA-Seq data and luciferase reporter assays revealed that the SVs had cis-acting effects on the expression levels of these three genes in specific tissues and cell types. In Tibetan sheep, we identified a high-frequency chromosomal inversion that exhibited modified chromatin architectures relative to the noninverted allele that predominates in Hu sheep. The inversion harbors several genes with altered expression patterns related to heart protection, brown adipocyte proliferation, angiogenesis, and DNA repair. These findings indicate that SVs represent an important source of genetic variation in gene expression and may have contributed to high-altitude adaptation in Tibetan sheep.

EPAS1, a hypoxia- and ferroptosis-related gene, promotes malignant behaviour of cervical cancer by ceRNA and super-enhancer.

Hypoxia and Ferroptosis are associated with the malignant behaviour of cervical cancer. Endothelial PAS domain-containing protein 1 (EPAS1) contributes to the progression of cervical cancer. EPAS1 plays important roles in hypoxia and ferroptosis. Using the GEO dataset, machine-learning algorithms were used to screen for hypoxia- and ferroptosis-related genes (HFRGs) in cervical cancer. EPAS1 was identified as the hub gene. qPCR and WB were used to investigate the expression of EPAS1 in normal and cervical cancer tissues. The proliferation, invasion and migration of EPAS1 cells in HeLa and SiHa cell lines were detected using CCK8, transwell and wound healing assays, respectively. Apoptosis was detected by flow cytometry. A dual-luciferase assay was used to analyse the MALAT1-miR-182-5P-EPAS1 mRNA axis and core promoter elements of the super-enhancer. EPAS1 was significantly overexpressed in cervical cancer tissues. EPAS1 could increase the proliferation, invasion, migration of HeLa and SiHa cells and reduce the apoptosis of HeLa and SiHa cell. According to the double-luciferase assay, EPAS1 expression was regulated by the MALAT1-Mir-182-5p-EPAS1 mRNA axis. EPAS1 is associated with super-enhancers. Double-luciferase assay showed that the core elements of the super-enhancer were E1 and E3. EPAS1, an HFRG, is significantly overexpressed in cervical cancer. EPAS1 promotes malignant behaviour of cervical cancer cells. EPAS1 expression is regulated by super-enhancers and the MALAT1-miR-182-5P- EPAS1 mRNA axis. EPAS1 may be a target for the diagnosis and treatment of cervical cancer.

Akkermansia muciniphila alleviates abdominal aortic aneurysms via restoring CITED2 activated by EPAS1.

Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease that has been linked to gut microbiome dysbiosis. Therefore, this study aims to investigate the effects of Akkermansia muciniphila (Am) on AAA mice and the biomolecules involved. AAA mice were generated using angiotensin II (Ang II), and 16sRNA sequencing was used to identify an altered abundance of microbiota in the feces of AAA mice. Vascular smooth muscle cell (VSMC) markers and apoptosis, and macrophage infiltration in mouse aortic tissues were examined. The abundance of Am was reduced in AAA mouse feces, and endothelial PAS domain-containing protein 1 (EPAS1) was downregulated in AAA mice and VSMC induced with Ang II. Am delayed AAA progression in mice, which was blunted by knockdown of EPAS1. EPAS1 was bound to the Cbp/p300-interacting transactivator 2 (CITED2) promoter and promoted CITED2 transcription. CITED2 reduced VSMC apoptosis and delayed AAA progression. Moreover, EPAS1 inhibited macrophage inflammatory response by promoting CITED2 transcription. In conclusion, gut microbiome dysbiosis in AAA induces EPAS1-mediated dysregulation of CITED2 to promote macrophage inflammatory response and VSMC apoptosis.

High-Altitude Andean H194R HIF2A Allele Is a Hypomorphic Allele.

For over 10,000 years, Andeans have resided at high altitude where the partial pressure of oxygen challenges human survival. Recent studies have provided evidence for positive selection acting in Andeans on the HIF2A (also known as EPAS1) locus, which encodes for a central transcription factor of the hypoxia-inducible factor pathway. However, the precise mechanism by which this allele might lead to altitude-adaptive phenotypes, if any, is unknown. By analyzing whole genome sequencing data from 46 high-coverage Peruvian Andean genomes, we confirm evidence for positive selection acting on HIF2A and a unique pattern of variation surrounding the Andean-specific single nucleotide variant (SNV), rs570553380, which encodes for an H194R amino acid substitution in HIF-2α. Genotyping the Andean-associated SNV rs570553380 in a group of 299 Peruvian Andeans from Cerro de Pasco, Peru (4,338 m), reveals a positive association with increased fraction of exhaled nitric oxide, a marker of nitric oxide biosynthesis. In vitro assays show that the H194R mutation impairs binding of HIF-2α to its heterodimeric partner, aryl hydrocarbon receptor nuclear translocator. A knockin mouse model bearing the H194R mutation in the Hif2a gene displays decreased levels of hypoxia-induced pulmonary Endothelin-1 transcripts and protection against hypoxia-induced pulmonary hypertension. We conclude the Andean H194R HIF2A allele is a hypomorphic (partial loss of function) allele.

EPAS1-mutated paragangliomas associated with haemoglobin disorders.

We report a large series of 40 patients presenting EPAS1-mutated paraganglioma (PGL) in whom we investigated a cause underlying chronic hypoxia. Four patients suffered from hypoxaemic heart disease. In patients with available haemoglobin electrophoresis results, 59% presented with a haemoglobin disorder, including six with sickle cell disease, five with sickle cell trait and two with heterozygous haemoglobin C disease. Histological and transcriptomic characterization of EPAS1 tumours revealed increased angiogenesis and high similarities with pseudohypoxic PGLs caused by VHL gene mutations. Sickle haemoglobinopathy carriers could thus be at increased risk for developing EPAS1-PGLs, which should be taken into account in their management and surveillance.

Exploring Interprofessional Development of Entrustable Professional Activities For Pediatric Intensive Care Fellows: A Proof-of-Concept Study.

Phenomenon: Entrustable professional activities (EPAs) delineate major professional activities that an individual in a given specialty must be "entrusted" to perform, ultimately without supervision, to provide quality patient care. Until now, most EPA frameworks have been developed by professionals within the same specialty. As safe, effective, and sustainable health care ultimately depends on interprofessional collaboration, we hypothesized that members of interprofessional teams might have clear and possibly additional insight into which activities are essential to the professional work of a medical specialist. Approach: We recently employed a national modified Delphi study to develop and validate a set of EPAs for Dutch pediatric intensive care fellows. In this proof-of-concept study, we explored what pediatric intensive care physicians' non-physician team members (physician assistants, nurse practitioners, and nurses) constitute as essential professional activities for PICU physicians and how they regarded the newly developed set of nine EPAs. We compared their judgments with the PICU physicians' opinions. Findings: This study shows that non-physician team members share a mental model with physicians about which EPAs are indispensable for pediatric intensive care physicians. Despite this agreement however, descriptions of EPAs are not always clear for non-physician team members who have to work with them on a daily basis. Insights: Ambiguity as to what an EPA entails when qualifying a trainee can have implications for patient safety and trainees themselves. Input from non-physician team members may add to the clarity of EPA descriptions. This finding supports the involvement of non-physician team members in the developmental process of EPAs for (sub)specialty training programs.

Defining a set of teaching EPAs tailored to an undergraduate medical curriculum using a modified Delphi approach.

BACKGROUND: The concept of entrustable professional activities (EPAs) has recently been extended to operationalize professional tasks in teacher training and faculty development in health professions education. The aim of this study is to report on the process and results of defining a set of teaching EPAs (t-EPAs) tailored to the local characteristics of a particular undergraduate medical program. METHODS: The undergraduate medical program at the Charité - Universitätsmedizin Berlin is competency-based, integrates thematic modules and spans 6 years. A writing team identified teaching EPAs based on the program's study regulations and drafted content descriptions with titles, specifications and knowledge, skills and attitudes. Content validation involved a modified Delphi procedure with a systematic, iterative interaction between a panel of content experts consisting of purposively selected educators and physicians from our faculty (n = 11) and the writing team. The threshold for a consensus was an agreement of 80% of the participants. RESULTS: After two Delphi rounds, a consensus was reached regarding the teaching activities to be included and their content descriptions. The response rate was 100% in both Delphi rounds. The Delphi results include the content descriptions of a total of 13 teaching EPAs, organized into the two overarching EPA domains of classroom-based (n = 10) and workplace-based (n = 3) activities. Tailoring the classroom EPAs to small group teaching and the workplace EPAs to supervising medical students led to several distinct EPAs. Another feature was the development of 2 teaching EPAs for interdisciplinary teaching. CONCLUSIONS: In systematic, Delphi-based process, we defined a set of 13 distinct teaching EPAs tailored to a specific undergraduate medical program that cover the core teaching tasks for faculty in this program. Our report on the principles of the process and the results may guide other medical schools and educators in defining and tailoring teaching EPAs according to their contexts.

Pilot Study on the Effect of Patient Condition and Clinical Parameters on Hypoxia-Induced Factor Expression: HIF1A, EPAS1 and HIF3A in Human Colostrum Cells.

Hypoxia-inducible factor 1 (HIF-1) may play a role in mammary gland development, milk production and secretion in mammals. Due to the limited number of scientific reports on the expression of HIF genes in colostrum cells, it was decided to examine the expression of HIF1A, HIF3A and EPAS1 in the these cells, collected from 35 patients who voluntarily agreed to provide their biological material for research, were informed about the purpose of the study and signed a consent to participate in it. The expression of HIF genes was assessed using qPCR. Additionally, the influence of clinical parameters (method of delivery, occurrence of stillbirths in previous pregnancies, BMI level before pregnancy and at the moment of delivery, presence of hypertension during pregnancy, presence of Escherichia coli in vaginal culture, iron supplement and heparin intake during pregnancy) on the gene expression was assessed, revealing statistically significant correlations. The expression of HIF1A was 3.5-fold higher in the case of patients with the presence of E. coli in vaginal culture (p = 0.041) and 2.5 times higher (p = 0.031) in samples from women who used heparin during pregnancy. Approximately 1.7-fold higher expression of the EPAS1 was observed in women who did not supplement iron during pregnancy (p = 0.046). To our knowledge, these are the first studies showing the relationship between HIF expression in cells from breast milk and the method of delivery and health condition of women giving birth. The assessment of HIF expression requires deeper examination in a larger study group, and the results of further studies will allow to determine whether HIF can become biomarkers in pregnancy pathology states.

Boosting Clear Cell Renal Carcinoma-Specific Drug Discovery Using a Deep Learning Algorithm and Single-Cell Analysis.

Clear cell renal carcinoma (ccRCC), the most common subtype of renal cell carcinoma, has the high heterogeneity of a highly complex tumor microenvironment. Existing clinical intervention strategies, such as target therapy and immunotherapy, have failed to achieve good therapeutic effects. In this article, single-cell transcriptome sequencing (scRNA-seq) data from six patients downloaded from the GEO database were adopted to describe the tumor microenvironment (TME) of ccRCC, including its T cells, tumor-associated macrophages (TAMs), endothelial cells (ECs), and cancer-associated fibroblasts (CAFs). Based on the differential typing of the TME, we identified tumor cell-specific regulatory programs that are mediated by three key transcription factors (TFs), whilst the TF EPAS1/HIF-2α was identified via drug virtual screening through our analysis of ccRCC's protein structure. Then, a combined deep graph neural network and machine learning algorithm were used to select anti-ccRCC compounds from bioactive compound libraries, including the FDA-approved drug library, natural product library, and human endogenous metabolite compound library. Finally, five compounds were obtained, including two FDA-approved drugs (flufenamic acid and fludarabine), one endogenous metabolite, one immunology/inflammation-related compound, and one inhibitor of DNA methyltransferase (N4-methylcytidine, a cytosine nucleoside analogue that, like zebularine, has the mechanism of inhibiting DNA methyltransferase). Based on the tumor microenvironment characteristics of ccRCC, five ccRCC-specific compounds were identified, which would give direction of the clinical treatment for ccRCC patients.

Structural basis for binding of the renal carcinoma target hypoxia-inducible factor 2α to prolyl hydroxylase domain 2.

The hypoxia-inducible factor (HIF) prolyl-hydroxylases (human PHD1-3) catalyze prolyl hydroxylation in oxygen-dependent degradation (ODD) domains of HIFα isoforms, modifications that signal for HIFα proteasomal degradation in an oxygen-dependent manner. PHD inhibitors are used for treatment of anemia in kidney disease. Increased erythropoietin (EPO) in patients with familial/idiopathic erythrocytosis and pulmonary hypertension is associated with mutations in EGLN1 (PHD2) and EPAS1 (HIF2α); a drug inhibiting HIF2α activity is used for clear cell renal cell carcinoma (ccRCC) treatment. We report crystal structures of PHD2 complexed with the C-terminal HIF2α-ODD in the presence of its 2-oxoglutarate cosubstrate or N-oxalylglycine inhibitor. Combined with the reported PHD2.HIFα-ODD structures and biochemical studies, the results inform on the different PHD.HIFα-ODD binding modes and the potential effects of clinically observed mutations in HIFα and PHD2 genes. They may help enable new therapeutic avenues, including PHD isoform-selective inhibitors and sequestration of HIF2α by the PHDs for ccRCC treatment.

The hypoxia-induced changes in miRNA-mRNA in RNA-induced silencing complexes and HIF-2 induced miRNAs in human endothelial cells.

The cellular adaptive response to hypoxia relies on the expression of hypoxia-inducible factors (HIFs), HIF-1 and HIF-2. HIFs regulate global gene expression changes during hypoxia that are necessary for restoring oxygen homeostasis and promoting cell survival. In the early stages of hypoxia, HIF-1 is elevated, whereas at the later stages, HIF-2 becomes the predominant form. What governs the transition between the two HIFs (the HIF switch) and the role of miRNAs in this regulation are not completely clear. Genome-wide expression studies on the miRNA content of RNA-induced silencing complexes (RISC) in HUVECs exposed to hypoxia compared to the global miRNA-Seq analysis revealed very specific differences between these two populations. We analyzed the miRNA and mRNA composition of RISC at 2 h (mainly HIF-1 driven), 8 h (HIF-1 and HIF-2 elevated), and 16 h (mainly HIF-2 driven) in a gene ontology context. This allowed for determining the direct impact of the miRNAs in modulating the cellular signaling pathways involved in the hypoxic adaptive response. Our results indicate that the miRNA-mRNA RISC components control the adaptive responses, and this does not always rely on the miRNA transcriptional elevations during hypoxia. Furthermore, we demonstrate that the hypoxic levels of the vast majority of HIF-1-dependent miRNAs (including miR-210-3p) are also HIF-2 dependent and that HIF-2 governs the expression of 11 specific miRNAs. In summary, the switch from HIF-1 to HIF-2 during hypoxia provides an important level of miRNA-driven control in the adaptive pathways in endothelial cells.

The entrustable professional activities of laparoscopic surgery: moving toward an integrated training model.

BACKGROUND: Entrustable Professional Activities (EPAs) provide the opportunity to integrate multiple competencies into meaningful units that facilitate curriculum development and assessment design. As part of the process of reviewing and enhancing the Fundamentals of Laparoscopic of Surgery (FLS) program, we used the concept of EPAs to create a framework of reference that articulates a contemporary definition of Laparoscopic Surgery (LS). METHODS: The framework of reference of LS was created with data gathered from a literature review and during series of educational retreats with subject matter experts (SMEs). Various activities were implemented during these retreats to develop the LS EPAs, their constitutive competencies, and related observable behaviors. RESULTS: Ten EPAs and associated competency descriptors (articulated as observable behaviors) specific to LS were identified. In addition, knowledge areas were associated to each EPA. DISCUSSION: A comprehensive list of EPAs for LS were identified. These EPAs will be used in the development and update of the FLS program. Further, they can be used to guide the development of curriculum, clinical teaching, and assessment in any surgical program with a laparoscopic training component. They are applicable to any level of training by defining the expected observable behaviors associated with a given level of expertise. These fundamental aspects of LS provide a common framework of reference across different surgical specialties.

Efficacy of electrophysical agents in fibromyalgia: A systematic review and network meta-analysis.

OBJECTIVE: To examine the effectiveness of electrophysical agents in fibromyalgia. DATA SOURCES: CINAHL, Cochrane Library, Embase, Medline, PEDro, and Web of Science were searched from their inceptions to March 27, 2023. METHODS: This study was registered in PROSPERO (CRD42022354326). Methodological quality of included trials was assessed using PEDro scale, and the quality of evidence was determined according to the Grading of Recommendations Assessment, Development, and Evaluation system. The primary outcomes were pain, functional status, and mood. RESULTS: Fifty-four studies involving 3045 patients with fibromyalgia were eligible for qualitative synthesis and 47 (pain), 31 (functional status), and 26 (mood) for network meta-analysis. The network consistency model revealed that, when compared with true control, transcutaneous electrical nerve stimulation and microcurrent improved pain symptoms (P = 0.006 and P = 0.037, respectively); repetitive transcranial magnetic stimulation improved patient functional status (P = 0.018); and microcurrent (P = 0.001), repetitive transcranial magnetic stimulation (P = 0.022), and no treatment (P = 0.038) significantly improved mood after intervention. Surface under the cumulative ranking indicated that microcurrent was most likely to be the best for managing pain and mood (surface under the cumulative ranking: 70% and 100%, respectively); low-level laser therapy for pain and mood (80% and 70%, respectively); and repetitive transcranial magnetic stimulation for improving functional status and mood (80% and 70%, respectively). CONCLUSION: This review found low to moderate quality evidence that microcurrent, laser therapy, and repetitive transcranial magnetic stimulation are the most effective electrophysical agents for improving at least one outcome in fibromyalgia.

Tibetan PHD2, an allele with loss-of-function properties.

Tibetans have adapted to the chronic hypoxia of high altitude and display a distinctive suite of physiologic adaptations, including augmented hypoxic ventilatory response and resistance to pulmonary hypertension. Genome-wide studies have consistently identified compelling genetic signatures of natural selection in two genes of the Hypoxia Inducible Factor pathway, PHD2 and HIF2A The product of the former induces the degradation of the product of the latter. Key issues regarding Tibetan PHD2 are whether it is a gain-of-function or loss-of-function allele, and how it might contribute to high-altitude adaptation. Tibetan PHD2 possesses two amino acid changes, D4E and C127S. We previously showed that in vitro, Tibetan PHD2 is defective in its interaction with p23, a cochaperone of the HSP90 pathway, and we proposed that Tibetan PHD2 is a loss-of-function allele. Here, we report that additional PHD2 mutations at or near Asp-4 or Cys-127 impair interaction with p23 in vitro. We find that mice with the Tibetan Phd2 allele display augmented hypoxic ventilatory response, supporting this loss-of-function proposal. This is phenocopied by mice with a mutation in p23 that abrogates the PHD2:p23 interaction. Hif2a haploinsufficiency, but not the Tibetan Phd2 allele, ameliorates hypoxia-induced increases in right ventricular systolic pressure. The Tibetan Phd2 allele is not associated with hemoglobin levels in mice. We propose that Tibetans possess genetic alterations that both activate and inhibit selective outputs of the HIF pathway to facilitate successful adaptation to the chronic hypoxia of high altitude.

A 14-bp deletion in bovine EPAS1 gene is associated with carcass traits.

EPAS1 (Endothelial PAS Domain Protein 1) gene is well-known for its function in plateau hypoxia adaptability. It encodes HIF-2α, which involved in the induction of genes regulated by oxygen and then affects multiple physiological processes such as angiogenesis and energy metabolism. All of these indicate it may affect the development of animals. In this study, a 14-bp deletion in EPAS1 gene was uncovered in Shandong black cattle population (n = 502). Two genotypes (II and ID) were found and the frequency of the homozygous II genotype is higher than the heterozygous ID genotype. This population is consisted with HWE (p > 0.05). And more importantly, the 14-bp deletion was associated with outside flat (p = 0.003), brisket (p = 0.001), and knuckle (p = 0.032). These findings suggested that the 14-bp deletion is significantly associated with carcass traits, which could be served as a molecular marker applied to cow breeding.

Congenital Cyanotic Heart Disease and the Association with Pheochromocytomas and Paragangliomas.

PURPOSE OF REVIEW: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that commonly produce excess catecholamines causing significant morbidity and mortality. Patients with cyanotic congenital heart disease (CCHD) develop PPGLs at a higher frequency than the general population. This review will summarize recent research in the association of PPGL and CCHD. RECENT FINDINGS: Advances in molecular genetics have provided new insights into a variety of germline mutations and somatic mutations related to PPGLs. In the CCHD population, mutations can occur in the hypoxia signaling pathway with gain-of-function somatic mutations in EPAS1, which prevent degradation of hypoxia-inducible factor-2 alpha. These mutations are implicated in oncogenesis. PPGLs associated with CCHD develop as early as age 15 years and have predominantly noradrenergic secretion. Surgical removal is considered the first line of therapy, although belzutifan, a HIF-2α inhibitor, is currently being tested as a potential therapy. Early screening with plasma metanephrines may assist in identifying PPGLs in patients with CCHD.

Viewing Readiness-for-Residency through Binoculars: Mapping Competency-Based Assessments to the AAMC's 13 Core Entrustable Professional Activities (EPAs).

Construct: The construct being assessed is readiness-for-residency of graduating medical students, as measured through two assessment frameworks. Background: Readiness-for-residency of near-graduate medical students should be but is not consistently assessed. To address this, the Association of American Medical Colleges (AAMC), in 2014, identified and described 13 core Entrustable Professional Activities (EPAs), which are tasks that all residents should be able to perform unsupervised upon entering residency. However, the AAMC did not initially provide measurement guidelines or propose standardized assessments. We designed Night-onCall (NOC), an immersive simulation for our near-graduating medical students to assess and address their readiness-for-residency, framed around tasks suggested by the AAMC's core EPAs. In adopting this EPA assessment framework, we began by building upon an established program of competency-based clinical skills assessments, repurposing competency-based checklists to measure components of the EPAs where possible, and designing new checklists, when necessary. This resulted in a blended suite of 14 checklists, which theoretically provide substantive assessment of all 13 core EPAs. In this paper, we describe the consensus-based mapping process conducted to ensure we understood the relationship between competency and EPA-based assessment lenses and could therefore report meaningful feedback on both to transitioning students in the NOC exercise. Approach: Between January-November 2017, five clinician and two non-clinician health professions educators at NYU Grossman School of Medicine conducted a rigorous consensus-based mapping process, which included each rater mapping each of the 310 NOC competency-based checklist items to lists of entrustable behaviors expected of learners according to the AAMC 13 core EPAs. Findings: All EPAs were captured to varying degrees by the 14 NOC checklists (overall Intraclass Correlation Coefficient (ICC) = 0.77). Consensus meetings resolved discrepancies and improved ICC values for three (EPA-9, EPA-10, EPA-12) of the four EPAs that initially showed poor reliability. Conclusions: Findings suggest that with some limitations (e.g., EPA-7 "form clinical questions/retrieve evidence") established competency-based assessments can be repurposed to measure readiness-for-residency through an EPA lens and both can be reported to learners and faculty.

How much is enough? Proposing achievement thresholds for core EPAs of graduating medical students in Canada.

PURPOSE: The transition towards Competency-Based Medical Education at the Cumming School of Medicine was accelerated by the reduced clinical time caused by the COVID-19 pandemic. The purpose of this study was to define a standard protocol for setting Entrustable Professional Activity (EPA) achievement thresholds and examine their feasibility within the clinical clerkship. METHODS: Achievement thresholds for each of the 12 AFMC EPAs for graduating Canadian medical students were set by using sequential rounds of revision by three consecutive groups of stakeholders and evaluation experts. Structured communication was guided by a modified Delphi technique. The feasibility/consequence models of these EPAs were then assessed by tracking their completion by the graduating class of 2021. RESULTS: The threshold-setting process resulted in set EPA achievement levels ranging from 1 to 8 across the 12 AFMC EPAs. Estimates were stable after the first round for 9 of 12 EPAs. 96.27% of EPAs were successfully completed by clerkship students despite the shortened clinical period. Feasibility was predicted by the slowing rate of EPA accumulation overtime during the clerkship. CONCLUSION: The process described led to consensus on EPA achievement thresholds. Successful completion of the assigned thresholds was feasible within the shortened clerkship.[Box: see text].

Relationship between epa level of supervision with their associated subcompetency milestone levels in pediatric fellow assessment.

BACKGROUND: Entrustable Professional Activities (EPA) and competencies represent components of a competency-based education framework. EPAs are assessed based on the level of supervision (LOS) necessary to perform the activity safely and effectively. The broad competencies, broken down into narrower subcompetencies, are assessed using milestones, observable behaviors of one's abilities along a developmental spectrum. Integration of the two methods, accomplished by mapping the most relevant subcompetencies to each EPA, may provide a cross check between the two forms of assessment and uncover those subcompetencies that have the greatest influence on the EPA assessment. OBJECTIVES: We hypothesized that 1) there would be a strong correlation between EPA LOS ratings with the milestone levels for the subcompetencies mapped to the EPA; 2) some subcompetencies would be more critical in determining entrustment decisions than others, and 3) the correlation would be weaker if the analysis included only milestones reported to the Accreditation Council for Graduate Medical Education (ACGME). METHODS: In fall 2014 and spring 2015, the Subspecialty Pediatrics Investigator Network asked Clinical Competency Committees to assign milestone levels to each trainee enrolled in a pediatric fellowship for all subcompetencies mapped to 6 Common Pediatric Subspecialty EPAs as well as provide a rating for each EPA based upon a 5-point LOS scale. RESULTS: One-thousand forty fellows were assessed in fall and 1048 in spring, representing about 27% of all fellows. For each EPA and in both periods, the average milestone level was highly correlated with LOS (rho range 0.59-0.74; p < 0.001). Correlations were similar when using a weighted versus unweighted milestone score or using only the ACGME reported milestones (p > 0.05). CONCLUSIONS: We found a strong relationship between milestone level and EPA LOS rating but no difference if the subcompetencies were weighted, or if only milestones reported to the ACGME were used. Our results suggest that representative behaviors needed to effectively perform the EPA, such as key subcompetencies and milestones, allow for future language adaptations while still supporting the current model of assessment. In addition, these data provide additional validity evidence for using these complementary tools in building a program of assessment.