Artificial intelligence (AI) holds transformative potential for graduate medical education (GME), yet, a comprehensive exploration of AI’s applications, perceptions, and limitations in GME is lacking. To map the current literature on AI in GME, identifying prevailing perceptions, applications, and research gaps to inform future research, policy discussions, and educational practices through a scoping review. Following the Joanna Briggs Institute guidelines and the PRISMA-ScR checklist a comprehensive search of multiple databases up to February 2024 was performed to include studies addressing AI interventions in GME. Out of 1734 citations, 102 studies met the inclusion criteria, conducted across 16 countries, predominantly from North America (72), Asia (14), and Europe (6). Radiology had the highest number of publications (21), followed by general surgery (11) and emergency medicine (8). The majority of studies were published in 2023. Several key thematic areas emerged from the literature. Initially, perceptions of AI in graduate medical education (GME) were mixed, but have increasingly shifted toward a more favorable outlook, particularly as the benefits of AI integration in education become more apparent. In assessments, AI demonstrated the ability to differentiate between skill levels and offer meaningful feedback. It has also been effective in evaluating narrative comments to assess resident performance. In the domain of recruitment, AI tools have been applied to analyze letters of recommendation, applications, and personal statements, helping identify potential biases and improve equity in candidate selection. Furthermore, large language models consistently outperformed average candidates on board certification and in-training examinations, indicating their potential utility in standardized assessments. Finally, AI tools showed promise in enhancing clinical decision-making by supporting trainees with improved diagnostic accuracy and efficiency. This scoping review provides a comprehensive overview of applications and limitations of AI in GME but is limited with potential biases, study heterogeneity, and evolving nature of AI.

Practice questions are highly sought out for use as a study tool among medical students in undergraduate medical education. At the same time, it remains unknown how medical students use and incorporate practice questions and their rationales into their studies. To explore this heavily relied upon study strategy, semi-structured interviews were conducted with second-year medical students to assess how they approach using practice questions. Qualitative thematic analysis revealed several recurrent themes: (1) Medical students use practice questions for primary learning, (2) Medical students place more importance on the rationale of a practice question versus selecting the right answer, and (3) Medical students view practice questions as being designed to be used once or having a single-use. Together, these themes provide insight into how medical students use practice questions to study, which may guide medical educators in their creation of practice questions with appropriate rationales and provide foundational data for future mixed methods analyses seeking to generalize these findings.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract Context National licensing exams (NLEs) including the Comprehensive Osteopathic Medical Licensing Examination (COMLEX) Level 1 evaluate student achievement. Scores have historically been utilized to stratify medical student applicants for residency. Grade point average (GPA), number of practice questions completed, and performance on practice exams have been shown to be predictive of NLE performance. Test anxiety and acute stress have been shown to negatively impact NLE performance. The role of study behaviors and other nonacademic factors in COMLEX Level 1 performance is unknown. Objectives This study aims to evaluate academic and nonacademic factors and to correlate them with COMLEX Level 1 performance. Additional analysis is conducted to associate COMLEX Level 1 performance with academic and nonacademic factors when controlling for GPA. Methods An anonymous online survey was administered to third- (OMS III) and fourth-year (OMS IV) osteopathic medical students at Kansas City University that had completed the COMLEX Level 1 examination. In total, 72 students responded to the survey. Survey results were linked to student records of GPA and COMLEX Level 1 scores, resulting in 59 complete responses for analysis. Independent-sample t-tests and linear ordinary least squares regression were utilized to analyze the results. Results The majority of participants are male (62.7%) and OMS III (98.3%) with an average age of 27.14 ± 2.58 (mean ± standard deviation). Further demographic data reveal hours per week spent for personal time during dedicated study (n=46, 19.7 ± 18.53), hours of sleep per night during dedicated study (7.34 ± 0.92), and money spent on board preparation ($1,319.12 ± $689.17). High ($1,600–$3,000), average ($1,000–$1,500), and low ($100–$900) spenders do not statistically differ and COMLEX Level 1 performance is not related to the number of resources utilized (F statistics <1; p>0.05). Pearson correlations reveal a statistically significant relationship between COMLEX Level 1 scores with GPA (0.73, p<0.001), number of practice exams completed (0.39, p<0.001), number of questions completed (0.46, p<0.001), number of weeks of study (0.55, p<0.001), and preparation cost (0.28, p<0.05). The regression analysis revealed that money spent on board preparation, number of questions completed, and time spent studying accounted for 75.8% of the variance in COMLEX Level 1 scores after controlling for GPA. Conclusions The data show the association of money spent on board preparation, numbers of questions competed, and time spent studying with a student’s COMLEX Level 1 score. Additionally, these results highlight the amount of money students spend on extracurricular materials to prepare for COMLEX Level 1, yet the data show that the number of resources that students utilized is not related to a student’s COMLEX Level 1 performance.

Medical school presents a unique challenge to the average learner as the instructional strategies used in medical curricula are often different than what the student has experienced prior. The large volume of information taught in medical school is delivered with a variety of techniques. After the educational material has been delivered, it is the student's responsibility to study and learn the information for future exams and for their future patients. The current study aims to explore what learning activities and teaching strategies first (M1) and second year (M2) medical students use and prefer. Additionally, the study aims to determine if there are cohort differences in classroom and study habits. A group of 95 M1 students and 109 M2 students were recruited to participate in this online survey study. The analyses indicated statistical differences between M1 and M2 student cohorts with M1 students preferring group work and small group discussions more than M2 students. Classic didactic lecturing was preferred by 71.6% of students surveyed. M1 students reported a greater tendency for self-testing and group study versus M2 students. GPA and study technique preference were not correlated. These findings indicate that medical students are not using research-based learning and study strategies at the possible detriment of long-term knowledge retention. Modeling of research-based learning and study strategies by medical educators is one possible solution to encourage medical students to change their study practice. Future work should focus on how medical student learning preferences change as they progress through medical school.

Aryl hydrocarbon receptor (AHR) agonists such as dioxin have been associated with obesity and the development of diabetes. Whole-body Ahr knockout mice on high-fat diet (HFD) have been shown to resist obesity and hepatic steatosis. Tissue-specific knockout of Ahr in mature adipocytes via adiponectin-Cre exacerbates obesity while knockout in liver increases steatosis without having significant effects on obesity. Our previous studies demonstrated that treatment of subcutaneous preadipocytes with exogenous or endogenous AHR agonists disrupts maturation into functional adipocytes in vitro. Here, we used platelet-derived growth factor receptor alpha (Pdgfrα)-Cre mice, a Cre model previously established to knock out genes in preadipocyte lineages and other cell types, but not liver cells, to further define AHR's role in obesity. We demonstrate that Pdgfrα-Cre Ahr-floxed (Ahrfl/fl) knockout mice are protected from HFD-induced obesity compared to non-knockout Ahrfl/fl mice (control mice). The Pdgfrα-Cre Ahrfl/fl knockout mice were also protected from increased adiposity, enlargement of adipocyte size, and liver steatosis while on the HFD compared to control mice. On a regular control diet, knockout and non-knockout mice showed no differences in weight gain, indicating the protective phenotype arises only when animals are challenged by a HFD. At the cellular level, cultured cells from brown adipose tissue (BAT) of Pdgfrα-Cre Ahrfl/fl mice were more responsive than cells from controls to transcriptional activation of the thermogenic uncoupling protein 1 (Ucp1) gene by norepinephrine, suggesting an ability to burn more energy under certain conditions. Collectively, our results show that knockout of Ahr mediated by Pdgfrα-Cre is protective against diet-induced obesity and suggest a mechanism by which enhanced UCP1 activity within BAT might confer these effects.

Hyperactivated AKT/mTOR signaling is a hallmark of pancreatic neuroendocrine tumors (PNETs). Drugs targeting this pathway are used clinically, but tumor resistance invariably develops. A better understanding of factors regulating AKT/mTOR signaling and PNET pathogenesis is needed to improve current therapies. We discovered that RABL6A, a new oncogenic driver of PNET proliferation, is required for AKT activity. Silencing RABL6A caused PNET cell-cycle arrest that coincided with selective loss of AKT-S473 (not T308) phosphorylation and AKT/mTOR inactivation. Restoration of AKT phosphorylation rescued the G1 phase block triggered by RABL6A silencing. Mechanistically, loss of AKT-S473 phosphorylation in RABL6A-depleted cells was the result of increased protein phosphatase 2A (PP2A) activity. Inhibition of PP2A restored phosphorylation of AKT-S473 in RABL6A-depleted cells, whereas PP2A reactivation using a specific small-molecule activator of PP2A (SMAP) abolished that phosphorylation. Moreover, SMAP treatment effectively killed PNET cells in a RABL6A-dependent manner and suppressed PNET growth in vivo. The present work identifies RABL6A as a new inhibitor of the PP2A tumor suppressor and an essential activator of AKT in PNET cells. Our findings offer what we believe is a novel strategy of PP2A reactivation for treatment of PNETs as well as other human cancers driven by RABL6A overexpression and PP2A inactivation.

As new medical students start their journey to become the next generation of physicians, they are in awe of the wealth of knowledge at their fingertips as they begin medical school. Every student brings with them a unique story, and most bring with them a high tolerance for technology. The internet, smart phones, and the personal computer have shrunk the academic world and allowed students access to entire libraries that fit within their pockets. Medical school curricula continues to try to evolve to meet students in their increasingly technology filled world. How are medical schools evolving to integrate technology into their curricula? What follows is a review of the application of different technologies in medical education and a close look at the most efficient uses of technology within medical school curricula. This discussion is followed by perspectives from professors and a student on the use of a variety of different technologies for teaching and learning including podcasts, YouTube, Twitter, and varying online resources.

Abstract Introduction: A better molecular understanding of pancreatic neuroendocrine tumors (PNETs) is needed to improve patient diagnosis and treatment. Everolimus (mTOR inhibitor) is a standard-of-care therapy for PNET patients based on aberrant activation of the PI3K/Akt/mTOR kinase pathway in tumors. However, sustained mTOR inhibition paradoxically promotes Akt kinase hyperactivation due to loss of negative feedback regulation and tumors become drug resistant. Our data reveal that RABL6A, a novel oncoprotein amplified in PNETs, is a key regulator of this clinically relevant pathway. Methods: RABL6A and Akt protein levels were manipulated using viral shRNAs in BON1 PNET cells. Transcript levels were assayed by microarray and qRT-PCR, proteins assessed by western blotting, and cell proliferation and survival measured by cell counts, trypan blue exclusion and EdU incorporation. Effect of RABL6A expression on sensitivity to clinically relevant drugs, MK2206 (Akt inhibitor) and everolimus, were tested. Results: Silencing of RABL6A in PNET cells causes G1 and G2/M cell cycle arrest, and pathway analysis of microarray data suggested inactivation of Akt signaling in the arrested cells. Immunoblotting confirmed dramatic loss of Akt phosphorylation at Ser-473 along with impaired phosphorylation and activation of its targets, PRAS40 and FOXO-1/3. Phosphorylation of S6K, a downstream target of Akt-mTOR signaling, was also reduced by RABL6A deficiency. The mechanism by which RABL6A controls Akt-S473 phosphorylation is currently not known although we demonstrated that mTORC2 (the kinase that phosphorylates Akt at Ser473) remains active in RABL6A deficient cells since the phosphorylation of other mTORC2 substrates (SGK1 and PKCα) is unaffected. Given the central role of Akt1 in tumorigenesis, we hypothesized that reinstating its activity may rescue the arrest phenotype caused by RABL6A loss. Restoration of Akt1 in RABL6A-depleted cells partially rescued the G1 phase arrest and induced S phase entry but was insufficient to allow mitosis, suggesting RABL6A regulates other factors required for cell division. Finally, drug response assays showed that RABL6A loss desensitizes PNET cells to Akt and mTOR inhibitors. Conclusion: Our previous work showed RABL6A promotes G1 progression in PNET cells by inactivating Rb1, an established suppressor of PNET pathogenesis. We now show that RABL6A also controls Akt phosphorylation and is essential for Akt-mTOR activation. Thus, RABL6A controls multiple cancer pathways necessary for PNET cell cycle progression and survival. We are testing if RABL6A status in PNETs predicts responsiveness to combination therapies targeting Akt and mTOR. Overall, this work identifies RABL6A as a new essential activator of Akt1-mTOR signaling, suggesting it is a new potential biomarker and target for anticancer therapy in PNET patients. Citation Format: Shaik Amjad Ume Salma, Jussara Hagen, Jacki Reilly, Ryan Sheehy, Nitija Tiwari, Jackson Nteeba, Scott K. Sherman, Thomas M. O'Dorisio, James R. Howe, Andrew M. Bellizzi, Benjamin W. Darbro, Dawn E. Quelle. RABL6A, a novel critical regulator of Akt-mTOR signaling in pancreatic neuroendocrine tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1368. doi:10.1158/1538-7445.AM2017-1368

Schweinfurthins are intriguing natural products with anti-cancer activities and as yet incompletely understood mechanisms of action. We investigated whether inhibitors of P-glycoprotein (Pgp), in a manner analogous to other natural products, might enhance schweinfurthins' growth inhibitory actions by increasing intracellular schweinfurthin levels. Both the schweinfurthin-sensitive glioblastoma multiforme cell line SF-295 and relatively insensitive lung carcinoma cell line A549 were treated with 2 schweinfurthin analogs: 3-deoxyschweinfurthin B-p-nitro bis-stilbene (3dSB-PNBS) and 5'-methylschweinfurthin G (methyl-G). There was a synergistic enhancement of growth inhibition with the combination of the Pgp inhibitor verapamil and both analogs in SF-295 cells. Methyl-G, verapamil, and the combination did not result in alterations to intracellular calcium concentration. Verapamil increased the intracellular concentration of 3dSB-PNBS in both SF-295 and A549 cells in a Pgp-independent manner. Methyl-G, verapamil, and the combination do not result in increased ER stress. Methyl-G increased the intracellular concentration of a known Pgp substrate, Rhodamine 123 in SF-295 cells. Reduction of cellular cholesterol leads to the accumulation of Pgp substrates, as Pgp requires cholesterol for proper function. Since 3dSB enhances lovastatin-induced upregulation of the cholesterol efflux pump ABCA1, it is intriguing that co-treatment with cholesterol rescued the methyl-G-induced increase in Rhodamine 123 intracellular concentration. These studies support the hypothesis that verapamil potentiates the schweinfurthin growth inhibitory effect by increasing its intracellular concentration.

Abstract Schweinfurthins are intriguing natural product anti-cancer agents with incompletely defined mechanisms of action. Schweinfurthins increase ER stress and result in apoptosis in vitro. To augment schweinfurthins’ growth inhibitory activity we hypothesized that an inhibitor of P-glycoprotein (Pgp) may increase the intracellular concentration of the schweinfurthins and lead to synergistic growth inhibition. The schweinfurthin sensitive glioblastoma multiforme cell line SF-295 and the relatively schweinfurthin insensitive lung carcinoma cell line A549 were treated with two schweinfurthin isoforms: methyl-G and 3-deoxyschweinfurthin B P-nitro bis stilbene (3dSB-PNBS). Methyl-G and 3dSB-PNBS (1 nM - 1 μM) decreased MTT activity at 48 hours but not at 24-hour incubation in both cell lines. The addition of verapamil (1μM - 1 mM) strongly induced synergy at 24 hours in SF-295 cells, yet verapamil did not greatly potentiate the schweinfurthin effect at 48 hours. This pattern was not evident in A549 cells. Isobologram analysis revealed combination indices of 0.38 and 0.47 at 24 hours in SF-295 cells for methyl-G and 3dSB-PNBS respectively. Fluorescent detection of 3dSB-PNBS demonstrated that verapamil increased the intracellular concentration of 3dSB-PNBS 3-fold in SF-295 and 2-fold in A549 cells. This effect occurred in a Pgp-independent manner as the specific Pgp inhibitor, CP 100356, failed to increase the intracellular concentration of 3dSB-PNBS. Flow cytometric analysis of intracellular calcium release demonstrated that neither methyl-G, verapamil, nor the combination increased intracellular calcium. However, Western blotting revealed that verapamil enhanced the ER stress caused by methyl-G in that there was increased expression of glucose-regulated protein 78 and increased phosphorylation of eukaryotic initiation factor 2α. Pgp expression was increased by verapamil in SF-295 cells, yet this increase was not present when methyl-G was combined with verapamil. Methyl-G also increased the intracellular concentration of a known Pgp substrate, Rhodamine 123 (R123), in SF-295 cells. Pgp requires cholesterol to function properly as a reduction in cellular cholesterol leads to the accumulation of Pgp substrates. Interestingly, since 3dSB depletes intracellular cholesterol and up-regulates the cholesterol efflux pump ABCA1, add-back of cholesterol rescued the methyl-G induced increase in R123 intracellular concentration. These studies demonstrate verapamil is able to potentiate the schweinfurthin growth inhibitory effect by increasing its intracellular concentration and by enhancing schweinfurthin induced ER stress; cholesterol is also identified as a key component of schweinfurthin action. Citation Format: Ryan M. Sheehy, Zoe C. Bachman, Raymond J. Hohl. Schweinfurthin activity enhanced by verapamil. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 811. doi:10.1158/1538-7445.AM2014-811

Schweinfurthins are potent inhibitors of cancer cell growth, especially against human central nervous system tumor lines such as SF-295 cells. However, the mechanisms through which these compounds impede cell growth are not fully understood. In an effort to understand the basis for the effects of schweinfurthins, we present a fluorescent schweinfurthin, 3-deoxyschweinfurthin B-like p-nitro-bis-stilbene (3dSB-PNBS), which displays biological activity similar to that of 3-deoxyschweinfurthin B (3dSB). These two schweinfurthins retain the unique differential activity of the natural schweinfurthins, as evidenced by the spindle-like morphological changes induced in SF-295 cells and the unaltered appearance of human lung carcinoma A549 cells. We demonstrate that incubation with 3dSB or 3dSB-PNBS results in cleavage of poly-ADP-ribose polymerase (PARP) and caspase-9, both markers of apoptosis. Coincubation of 3dSB or 3dSB-PNBS with the caspase-9 inhibitor (Z)-Leu-Glu(O-methyl)-His-Asp(O-methyl)-fluoromethylketone prevents PARP cleavage. Therapeutic agents that induce apoptosis often activate cellular stress pathways. A marker for multiple stress pathways is the phosphorylation of eukaryotic initiation factor 2α, which is phosphorylated in response to 3dSB and 3dSB-PNBS treatment. Glucose-regulated protein 78 and protein disulfide isomerase, both endoplasmic reticulum chaperones, are up-regulated with schweinfurthin exposure. Using the fluorescent properties of 3dSB-PNBS and dimethoxyphenyl-p-nitro-bis-stilbene (DMP-PNBS), a control compound, we show that the intracellular levels of 3dSB-PNBS are higher than those of Rhodamine 123 or DMP-PNBS in SF-295 and A549 cells.