Developing culturally competent physicians: Empathy, inclusivity, moral distress training and ethical reflections during the Medicine Clerkship.

PURPOSE: We aimed to develop a tool that would allow assessment of ethics competency and moral distress during the Internal Medicine Clerkship and to introduce curricular changes that could empower students to better address ethical dilemmas and challenges encountered during the clerkship. MATERIALS AND METHODS: A structured ethics assignment was introduced where students could reflect on impactful stressful scenarios and address questions related to emotional responses, identified ethical issues, management themes, and professional obligations. A 4-tiered grading rubric and individual narrative feedback was provided for each assignment, and small-group debriefing sessions were introduced for reflective thought and future planning. De-identified assignments were analyzed and classified into subgroups according to 5 main ethical issue subgroups and 10 specific management themes. Assignments were also analyzed for the presence of moral distress. RESULTS: 357 students completed the reflective ethics activities. The most commonly identified ethical issues were related to Shared Medical Decision Making (>40%), Primary of Patient Welfare challenges, (>20%), and Social/Organizational dilemmas. Management themes often pertained to Patient Wishes/Legal Obligations, Professional Behaviors, and Limited Resources. 87% of assignments demonstrated moral distress. CONCLUSION: Medical school is a stressful time and challenges are augmented during clinical years. Our reflective activity demonstrated significant exposures to ethical dilemmas, reviewed earlier principles of ethics training, and provided a safe forum in which to discuss these important aspects of healthcare. We captured powerful images of challenging situations eliciting moral distress, and students greatly appreciated the activity. We encourage future investigations that support student well-being and enable smooth transitions into residency training.

Time Does Matter: Reduced Internal Medicine Clerkship Clinical Experiences Due to COVID-19.

Introduction The coronavirus disease 2019 (COVID-19) pandemic has affected medical education in many ways. The Association of American Medical Colleges (AAMC) temporarily suspended clinical student rotations, calling for a transition to remote learning. Unfortunately, due to the heavy impact of COVID-19 in our South Florida community, medical students were not able to return to in-person activities for a significant time. During this period, students had remote clerkship learning activities, didactic sessions, narrative projects, and small-group learning sessions, which were front-loaded using Zoom technology (Zoom Video Communications, Inc., San Jose, California, United States) and web-based learning tools. Once in-person clinical experiences resumed, the duration of all third-year clerkships for the remainder of the year was reduced to five weeks to allow for timely graduation. The Herbert Wertheim College of Medicine (HWCOM) Internal Medicine (IM) clerkship has traditionally been an eight-week-long rotation. Other clerkships that varied from six to eight weeks were similarly reduced to five weeks. We hypothesized that the shortened duration of the IM clerkship would have negative impacts on National Board of Medical Examiners (NBME) exam performance and clerkship clinical experiences would likely be affected. Methods We compared the NBME subject exam results and end of clerkship evaluations from the Class of 2021 (CO2021) which had the traditional eight weeks of patient care, with the CO2022, which had only five weeks of in-person patient care. A T-test analysis was performed comparing performance on the NBME medicine clinical subject exam between students who completed the usual eight-week rotation versus those who completed a five-week rotation. We also evaluated the IM clerkship course evaluation and analyzed student responses and ratings to assess any areas that were statistically significant when comparing the traditional eight-week IM clerkship to the shortened five-week clerkship. Results There was no statistically significant difference (t=0.68, p<0.4951) in mean NBME subject exam performance between cohorts. Students who completed the shortened five-week IM clerkship indicated there was limited volume and diversity of patients, which consequently affected their ability to complete all the required clinical experiences for the IM clerkship. These results indicated a statistically significant difference between the two cohorts (t =3.33, p<.001). Conclusion Students with shortened IM clerkship clinical care time (five weeks) were found to have no significant statistical differences in NBME subject exam performance compared to the traditional eight-week cohorts. However, students felt there was a decreased volume and diversity of patients, and they reported greater difficulties in completing the required clinical experiences, with diminished clinical confidence. Time does matter, and clinical time is very valuable for a student's undergraduate medical education. If another pandemic were to arise, the duration of different clerkships should be carefully assessed and individualized, and methods to assess and reclaim lost clinical time during the advanced clinical and postgraduate years should be considered.

Adenomatous polyposis coli interacts with flap endonuclease 1 to block its nuclear entry and function.

In previous studies, we found that adenomatous polyposis coli (APC) blocks the base excision repair (BER) pathway by interacting with 5'-flap endonuclease 1 (Fen1). In this study, we identify the molecular features that contribute to the formation and/or stabilization of the APC/Fen1 complex that determines the extent of BER inhibition, and the subsequent accumulation of DNA damage creates mutagenic lesions leading to transformation susceptibility. We show here that APC binds to the nuclear localization sequence of Fen1 (Lys(365)Lys(366)Lys(367)), which prevents entry of Fen1 into the nucleus and participation in Pol-ß-directed long-patch BER. We also show that levels of the APC/Fen1 complex are higher in breast tumors than in the surrounding normal tissues. These studies demonstrate a novel role for APC in the suppression of Fen1 activity in the BER pathway and a new biomarker profile to be explored to identify individuals who may be susceptible to the development of mammary and other tumors.

Amino acid Asp181 of 5'-flap endonuclease 1 is a useful target for chemotherapeutic development.

DNA alkylation-induced damage is one of the most efficacious anticancer therapeutic strategies. Enhanced DNA alkylation and weakened DNA repair capacity in cancer cells are responsible for the effectiveness of DNA-alkylating therapies. 5'-Flap endonuclease 1 (Fen1) is an important enzyme involved in base excision repair (BER), specifically in long-patch BER (LP-BER). Using the site-directed mutagenesis approach, we have identified an important role for amino acid Asp181 of Fen1 in its endonuclease activity. Asp181 is thought to be involved in Mg(2+) binding in the active site. Using structure-based molecular docking of Fen1 targeted to its metal binding pocket M2 (Mg(2+) site), we have identified a potent low-molecular weight inhibitor (LMI, NSC-281680) that efficiently blocks LP-BER. In this study, we have demonstrated that the interaction of this LMI with Fen1 blocked its endonuclease activity, thereby blocking LP-BER and enhancing the cytotoxic effect of DNA-alkylating agent Temozolomide (TMZ) in mismatch repair (MMR)-deficient and MMR-proficient colon cancer cells. The results further suggest that blockade of LP-BER by NSC-281680 may bypass other drug resistance mechanisms such as mismatch repair (MMR) defects. Therefore, our findings provide groundwork for the development of highly specific and safer structure-based small molecular inhibitors targeting the BER pathway, which can be used along with existing chemotherapeutic agents, like TMZ, as combination therapy for the treatment of colorectal cancer.

Structure/function analysis of the interaction of adenomatous polyposis coli with DNA polymerase beta and its implications for base excision repair.

Mutations in the adenomatous polyposis coli (APC) gene are associated with an early onset of colorectal carcinogenesis. Previously, we described a novel role for the APC polypeptide in base excision repair (BER). The single-nucleotide (SN) and long-patch (LP) BER pathways act to repair the abasic sites in DNA that are induced by stressors, such as spontaneous oxidation/reduction, alkylation, and hyperthermia. We have shown that APC interacts with DNA polymerase beta (Pol-beta) and flap endonuclease 1 (Fen-1) and blocks Pol-beta-directed strand-displacement synthesis. In this study, we have mapped the APC interaction site in Pol-beta and have found that Thr79, Lys81, and Arg83 of Pol-beta were critical for its interaction with APC. The Pol-beta protein (T79A/K81A/R83A) blocked strand-displacement DNA synthesis in which tetrahydrofuran was used as DNA substrate. We further showed that the APC-mediated blockage of LP-BER was due to inhibition of Fen-1 activity. Analysis of the APC-mediated blockage of SN-BER indicated that the interaction of APC with Pol-beta blocked SN-BER activity by inhibiting Pol-beta-directed deoxyribose phosphate lyase activity. Collectively, our findings indicate that APC blocked both Pol-beta-directed SN- and LP-BER pathways and increased sensitivity of cells to alkylation induced DNA damage.

Mechanism of adenomatous polyposis coli (APC)-mediated blockage of long-patch base excision repair.

Recently, we found an interaction between adenomatous polyposis coli (APC) and DNA polymerase beta (pol-beta) and showed that APC blocks strand-displacement synthesis of long-patch base excision repair (LP-BER) (Narayan, S., Jaiswal, A. S., and Balusu, R. (2005) J. Biol. Chem. 280, 6942-6949); however, the mechanism is not clear. Using an in vivo LP-BER assay system, we now show that the LP-BER is higher in APC-/- cells than in APC+/+ cells. In addition to pol-beta, the pull-down experiments showed that the full-length APC also interacted with flap endonuclease 1 (Fen-1). To further characterize the interaction of APC with pol-beta and Fen-1, we performed a domain-mapping of APC and found that both pol-beta and Fen-1 interact with a 138-amino acids peptide from the APC at the DRI-domain. Our functional assays showed that APC blocks pol-beta-mediated 1-nucleotide (1-nt) as well as strand-displacement synthesis of reduced abasic, nicked-, or 1-nt gapped-DNA substrates. Further studies demonstrated that APC blocks 5'-flap endonuclease as well as the 5'-3' exonuclease activity of Fen-1 resulting in the blockage of LP-BER. From these results, we concluded that APC can have three different effects on the LP-BER pathway. First, APC can block pol-beta-mediated 1-nt incorporation and strand-displacement synthesis. Second, APC can block LP-BER by blocking the coordinated formation and removal of the strand-displaced flap. Third, APC can block LP-BER by blocking hit-and-run synthesis. These studies will have important implications for APC in DNA damage-induced carcinogenesis and chemoprevention.