Error Management Training and Adaptive Expertise in Learning Computed Tomography Interpretation: A Randomized Clinical Trial.

Importance: Adaptive expertise helps physicians apply their skills to novel clinical cases and reduce preventable errors. Error management training (EMT) has been shown to improve adaptive expertise with procedural skills; however, its application to cognitive skills in medical education is unclear. Objective: To evaluate whether EMT improves adaptive expertise when learning the cognitive skill of head computed tomography (CT) interpretation. Design, Setting, and Participants: This 3-arm randomized clinical trial was conducted from July 8, 2022, to March 30, 2023, in 7 geographically diverse emergency medicine residency programs. Participants were postgraduate year 1 through 4 emergency medicine residents masked to the hypothesis. Interventions: Participants were randomized 1:1:1 to a difficult EMT, easy EMT, or error avoidance training (EAT) control learning strategy for completing an online head CT curriculum. Both EMT cohorts received no didactic instruction before scrolling through head CT cases, whereas the EAT group did. The difficult EMT cohort answered difficult questions about the teaching cases, leading to errors, whereas the easy EMT cohort answered easy questions, leading to fewer errors. All 3 cohorts used the same cases. Main Outcomes and Measures: The primary outcome was a difference in adaptive expertise among the 3 cohorts, as measured using a head CT posttest. Secondary outcomes were (1) differences in routine expertise, (2) whether the quantity of errors during training mediated differences in adaptive expertise, and (3) the interaction between prior residency training and the learning strategies. Results: Among 212 randomized participants (mean [SD] age, 28.8 [2.0] years; 107 men [50.5%]), 70 were allocated to the difficult EMT, 71 to the easy EMT, and 71 to the EAT control cohorts; 150 participants (70.8%) completed the posttest. The difficult EMT cohort outperformed both the easy EMT and EAT cohorts on adaptive expertise cases (60.6% [95% CI, 56.1%-65.1%] vs 45.2% [95% CI, 39.9%-50.6%], vs 40.9% [95% CI, 36.0%-45.7%], respectively; P < .001), with a large effect size (η2 = 0.19). There was no significant difference in routine expertise. The difficult EMT cohort made more errors during training than the easy EMT cohort. Mediation analysis showed that the number of errors during training explained 87.2% of the difficult EMT learning strategy's effect on improving adaptive expertise (P = .01). The difficult EMT learning strategy was more effective in improving adaptive expertise for residents earlier in training, with a large effect size (η2 = 0.25; P = .002). Conclusions and Relevance: In this randomized clinical trial, the findings show that EMT is an effective method to develop physicians' adaptive expertise with cognitive skills. Trial Registration: ClinicalTrials.gov Identifier: NCT05284838.

Quantifying For-Profit Outcomes in GME: A Multispecialty Analysis of Board Certifying Examination Pass Rates in For-Profit Affiliated Residency Programs.

Background: The number of for-profit hospitals has increased in the United States, but their role in and outcomes for graduate medical education (GME) are unclear. Objectives: To describe for-profit involvement in internal medicine (IM), general surgery (GS), and pediatrics GME by quantifying change in for-profit affiliated residency programs and comparing for-profit and nonprofit affiliated program board certifying examination pass rates. Methods: We used Accreditation Council for Graduate Medical Education and Medicare data to quantify for-profit prevalence in IM, GS, and pediatrics GME from 2001 to 2021. We used public pass rate data from the American Board of Surgeons (2017-2019; n=242 programs; 6562 examinees), American Board of Internal Medicine (2018-2020; n=465 programs; 23 922 examinees), and American Board of Pediatrics (2018-2020; n=202 programs; 9819 examinees) to model the relationship between profit status and pass rate within each specialty and across specialties combined using linear regression. Results: The proportion of for-profit affiliated residency programs increased 400.0% in IM, 334.4% in GS, and 23.2% in pediatrics from 2001 to 2021. Bivariate linear regression revealed significantly lower pass rate in for-profit affiliated programs in IM ß =-7.73, P<.001), pediatrics (ß =-14.6, P<.001), and the 3 specialties combined (ß =-5.45, P<.001). Upon multiple regression with addition of program characteristic covariates, this relationship remained significant in pediatrics (ß =-10.04, P=.006). Conclusions: The proportion of for-profit affiliated residency programs has increased in IM, GS, and pediatrics from 2001 to 2021. After controlling for covariates, for-profit affiliated programs were associated with lower board examination pass rates in pediatrics with no association in IM, GS, or the combined measure.

A Systematic Review of Pain Management Education in Graduate Medical Education.

Background: Despite the importance of pain management across specialties and the effect of poor management on patients, many physicians are uncomfortable managing pain. This may be related, in part, to deficits in graduate medical education (GME). Objective: We sought to evaluate the methodological rigor of and summarize findings from literature on GME interventions targeting acute and chronic non-cancer pain management. Methods: We conducted a systematic review by searching PubMed, MedEdPORTAL, and ERIC (Education Resources Information Center) to identify studies published before March 2019 that had a focus on non-cancer pain management, majority of GME learners, defined educational intervention, and reported outcome. Quality of design was assessed with the Medical Education Research Study Quality Instrument (MERSQI) and Newcastle-Ottawa Scale-Education (NOS-E). One author summarized educational foci and methods. Results: The original search yielded 6149 studies; 26 met inclusion criteria. Mean MERSQI score was 11.6 (SD 2.29) of a maximum 18; mean NOS-E score was 2.60 (SD 1.22) out of 6. Most studies employed a single group, pretest-posttest design (n=16, 64%). Outcomes varied: 6 (24%) evaluated reactions (Kirkpatrick level 1), 12 (48%) evaluated learner knowledge (level 2), 5 (20%) evaluated behavior (level 3), and 2 (8%) evaluated patient outcomes (level 4). Interventions commonly focused on chronic pain (n=18, 69%) and employed traditional lectures (n=16, 62%) and case-based learning (n=14, 54%). Conclusions: Pain management education research in GME largely evaluated chronic pain management interventions by assessing learner reactions or knowledge at single sites.

The Graduate Medical Education Scholars Track: Developing Residents as Clinician-Educators During Clinical Training via a Longitudinal, Multimodal, and Multidisciplinary Track.

PROBLEM: Residency clinician-educator tracks have been created; however, they have generally been limited to a single discipline or program and experienced some challenges. The Graduate Medical Education Scholars Track (GMEST), an embedded longitudinal, multimodal, multidisciplinary clinician-educator track for residents, was piloted at the Pritzker School of Medicine, University of Chicago, in academic year 2014-2015. APPROACH: The GMEST is a two-year experience completed during residency training. The goal is to prepare trainees for academic careers as clinician-educators with a focus on medical education scholarship. This track is designed for residents from diverse training programs with variable clinical schedules and blends a live interactive program, asynchronous instruction and discussion, and overarching multimodal mentorship in medical education. Participants are expected to complete a capstone medical education project and submit it to institutional, regional, and/or national venues. OUTCOMES: Data gathered from the 2014-2016 and 2015-2017 cohorts demonstrated that 21/22 (95%) participants were satisfied with the GMEST curriculum, felt it was important to their development as future clinician-educators, and felt it would positively influence their ability to work in medical education. Further, 18/22 (82%) participants wished to pursue a career as a clinician-educator and in medical education leadership and/or scholarship. NEXT STEPS: The authors will longitudinally track graduates' future career positions, projects, publications, and awards, and cross-match and compare GMEST graduates with non-GMEST residents interested in medical education. Faculty mentors, program directors, and the Medical Education, Research, Innovation, Teaching, and Scholarship community will be asked for feedback on the GMEST.

Mastery Learning of Video Laryngoscopy Using the Glidescope in the Emergency Department.

INTRODUCTION: According to the Accreditation Council for Graduate Medical Education emergency medicine requirements established before the popularity of video laryngoscopy (VL) use, 35 intubations are necessary for graduation. Our study aimed to establish a mastery-learning model for a skill set very different (VL) from direct laryngoscopy (DL) and to determine the number of attempts needed to achieve mastery with VL. METHODS: With the use of a randomized, controlled crossover study design, two learner groups underwent baseline testing intubating a mannequin using VL. Afterward, the intervention group received a mastery training intervention. After training, learners were required to repeat the procedure until achievement of 100% on the checklist for two consecutive attempts was achieved. After 3 months, both groups returned for retesting, and the control group received the same mastery training as the intervention group. Both groups returned for final testing after another 3 months. RESULTS: The intervention arm had an improvement in performance versus the control arm at 3 months of total time (P < 0.05). Both groups had an improvement within their groups' checklist scores at 3 months after training (P < 0.05), and within the intervention arm, this effect was sustained at 6 months (P < 0.05). There was no significant difference in the mean required attempts to demonstrate mastery (overall, 2.5; intervention, 2.75; control 2.25; P = 0.28). CONCLUSIONS: Simulation-based mastery-learning produces skill enhancement with VL that is resistant to decay across 6 months. Furthermore, although a small number of attempts are needed to achieve mastery, clinical experience did not substitute as a proxy for skill acquisition. This mastery-learning model provides skill sets that are not otherwise obtained in the clinical curriculum in a 3-month period.

Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90.

Most cancers are characterized by multiple molecular alterations, but identification of the key proteins involved in these signaling pathways is currently beyond reach. We show that the inhibitor PU-H71 preferentially targets tumor-enriched Hsp90 complexes and affinity captures Hsp90-dependent oncogenic client proteins. We have used PU-H71 affinity capture to design a proteomic approach that, when combined with bioinformatic pathway analysis, identifies dysregulated signaling networks and key oncoproteins in chronic myeloid leukemia. The identified interactome overlaps with the well-characterized altered proteome in this cancer, indicating that this method can provide global insights into the biology of individual tumors, including primary patient specimens. In addition, we show that this approach can be used to identify previously uncharacterized oncoproteins and mechanisms, potentially leading to new targeted therapies. We further show that the abundance of the PU-H71-enriched Hsp90 species, which is not dictated by Hsp90 expression alone, is predictive of the cell's sensitivity to Hsp90 inhibition.

Design, synthesis, and evaluation of small molecule Hsp90 probes.

A number of compounds from different chemical classes are known to bind competitively to the ATP-pocket of Hsp90 and inhibit its chaperone function. The natural product geldanamycin was the first reported inhibitor of Hsp90 and since then synthetic inhibitors from purine, isoxazole and indazol-4-one chemical classes have been discovered and are currently or soon to be in clinical trials for the treatment of cancer. In spite of a similar binding mode to Hsp90, distinct biological profiles were demonstrated among these molecules, both in vitro and in vivo. To better understand the molecular basis for these dissimilarities, we report here the synthesis of chemical tools for three Hsp90 inhibitor classes. These agents will be useful for probing tumor-by-tumor the Hsp90 complexes isolated by specific inhibitors. Such information will lead to better understanding of tumor specific molecular markers to aid in their clinical development. It will also help to elucidate the molecular basis for the biological differences observed among Hsp90 inhibitors.

Design of a flexible cell-based assay for the evaluation of heat shock protein 70 expression modulators.

Heat shock protein 70 (Hsp70) is a chaperone protein that helps protect against cellular stress, a function that may be co-opted to fight human diseases. In particular, the upregulation of Hsp70 can suppress the neurotoxicity of misfolded proteins, suggesting possible therapeutic strategies in neurodegenerative diseases. Alternatively, in cancer cells where high levels of Hsp70 inhibit both intrinsic and extrinsic apoptotic pathways, a reduction in Hsp70 levels may induce apoptosis. To evaluate and identify, in a single assay format, small molecules that induce or inhibit endogenous Hsp70, we have designed and optimized a microtiter assay that relies on whole-cell immunodetection of Hsp70. The assay utilizes a minimal number of neuronal or cancer cells, yet is sufficiently sensitive and reproducible to permit quantitative determinations. We further validated the assay using a panel of Hsp70 modulators. In conclusion, we have developed an assay that is fast, robust, and cost efficient. As such, it can be implemented in most research laboratories. The assay should greatly improve the speed at which novel Hsp70 inducers and inhibitors of expression can be identified and evaluated.

HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans.

JAK2 kinase inhibitors were developed for the treatment of myeloproliferative neoplasms (MPNs), following the discovery of activating JAK2 mutations in the majority of patients with MPN. However, to date JAK2 inhibitor treatment has shown limited efficacy and apparent toxicities in clinical trials. We report here that an HSP90 inhibitor, PU-H71, demonstrated efficacy in cell line and mouse models of the MPN polycythemia vera (PV) and essential thrombocytosis (ET) by disrupting JAK2 protein stability. JAK2 physically associated with both HSP90 and PU-H71 and was degraded by PU-H71 treatment in vitro and in vivo, demonstrating that JAK2 is an HSP90 chaperone client. PU-H71 treatment caused potent, dose-dependent inhibition of cell growth and signaling in JAK2 mutant cell lines and in primary MPN patient samples. PU-H71 treatment of mice resulted in JAK2 degradation, inhibition of JAK-STAT signaling, normalization of peripheral blood counts, and improved survival in MPN models at doses that did not degrade JAK2 in normal tissues or cause substantial toxicity. Importantly, PU-H71 treatment also reduced the mutant allele burden in mice. These data establish what we believe to be a novel therapeutic rationale for HSP90 inhibition in the treatment of JAK2-dependent MPN.

Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models.

Triple-negative breast cancers (TNBCs) are defined by a lack of expression of estrogen, progesterone, and HER2 receptors. Because of the absence of identified targets and targeted therapies, and due to a heterogeneous molecular presentation, treatment guidelines for patients with TNBC include only conventional chemotherapy. Such treatment, while effective for some, leaves others with high rates of early relapse and is not curative for any patient with metastatic disease. Here, we demonstrate that these tumors are sensitive to the heat shock protein 90 (Hsp90) inhibitor PU-H71. Potent and durable anti-tumor effects in TNBC xenografts, including complete response and tumor regression, without toxicity to the host are achieved with this agent. Notably, TNBC tumors respond to retreatment with PU-H71 for several cycles extending for over 5 months without evidence of resistance or toxicity. Through a proteomics approach, we show that multiple oncoproteins involved in tumor proliferation, survival, and invasive potential are in complex with PU-H71-bound Hsp90 in TNBC. PU-H71 induces efficient and sustained downregulation and inactivation, both in vitro and in vivo, of these proteins. Among them, we identify downregulation of components of the Ras/Raf/MAPK pathway and G(2)-M phase to contribute to its anti-proliferative effect, degradation of activated Akt and Bcl-xL to induce apoptosis, and inhibition of activated NF-kappaB, Akt, ERK2, Tyk2, and PKC to reduce TNBC invasive potential. The results identify Hsp90 as a critical and multimodal target in this most difficult to treat breast cancer subtype and support the use of the Hsp90 inhibitor PU-H71 for clinical trials involving patients with TNBC.

Alterations in ribosome biogenesis cause specific defects in C. elegans hermaphrodite gonadogenesis.

Ribosome biogenesis is a cell-essential process that influences cell growth, proliferation, and differentiation. How ribosome biogenesis impacts development, however, is poorly understood. Here, we establish a link between ribosome biogenesis and gonadogenesis in Caenorhabditis elegans that affects germline proliferation and patterning. Previously, we determined that pro-1(+)activity is required in the soma--specifically, the sheath/spermatheca sublineage--to promote normal proliferation and prevent germline tumor formation. Here, we report that PRO-1, like its yeast ortholog IPI3, influences rRNA processing. pro-1 tumors are suppressed by mutations in ncl-1 or lin-35/Rb, both of which elevate pre-rRNA levels. Thus, in this context, lin-35/Rb acts as a soma-autonomous germline tumor promoter. We further report the characterization of two additional genes identified for their germline tumor phenotype, pro-2 and pro-3, and find that they, too, encode orthologs of proteins involved in ribosome biogenesis in yeast (NOC2 and SDA1, respectively). Finally, we demonstrate that depletion of additional C. elegans orthologs of yeast ribosome biogenesis factors display phenotypes similar to depletion of progenes. We conclude that the C. elegans distal sheath is particularly sensitive to alterations in ribosome biogenesis and that ribosome biogenesis defects in one tissue can non-autonomously influence proliferation in an adjacent tissue.