'We're like Spider-Man; with great power comes great responsibility': Coaches' experiences supporting struggling medical students.

BACKGROUND: Medical students can experience a range of academic and non-academic struggles. Coaching is a valuable strategy to support learners, but coaches describe working with struggling learners as taxing. Transformative learning theory (TLT) provides insights into how educators grow from challenging experiences to build resilience. This study explores how coaches evolve as educators through supporting struggling students. METHODS: This qualitative study grounded in an interpretivist paradigm used interviews of longitudinal medical student coaches at two academic institutions. Interviews, using TLT as a sensitizing concept, explored coaches' experience coaching struggling learners. We performed thematic analysis. RESULTS: We interviewed 15 coaches. Coaches described supporting students through multi-faceted struggles which often surprised the coach. Three themes characterized coaches' experiences: personal responsibility, emotional response, and personal learning. Coaches shouldered high personal responsibility for learners' success. For some, this burden felt emotional, raised parental instincts and questions about maintaining boundaries with learners. Coaches evolved their coaching approach, challenged biases, and built skills. Coaches learned to better appreciate the learner point of view and employ resources to support students. DISCUSSION: Through navigating learner struggles, educators can gain self-efficacy, learn to understand learners' perspectives, and evolve their coaching approach to lessen their personal emotional burden through time.

Beyond thinking fast and slow: Implications of a transtheoretical model of clinical reasoning and error on teaching, assessment, and research.

From dual process to a family of theories known collectively as situativity, both micro and macro theories of cognition inform our current understanding of clinical reasoning (CR) and error. CR is a complex process that occurs in a complex environment, and a nuanced, expansive, integrated model of these theories is necessary to fully understand how CR is performed in the present day and in the future. In this perspective, we present these individual theories along with figures and descriptive cases for purposes of comparison before exploring the implications of a transtheoretical model of these theories for teaching, assessment, and research in CR and error.

Addressing Atropisomerism in the Development of Sotorasib, a Covalent Inhibitor of KRAS G12C: Structural, Analytical, and Synthetic Considerations.

Nearly a century after its first description, configurationally stable axial chirality remains a rare feature in marketed drugs. In the development of the KRASG12C inhibitor sotorasib (LUMAKRAS/LUMYKRAS), an axially chiral biaryl moiety proved a critical structural element in engaging a "cryptic" protein binding pocket and enhancing inhibitor potency. Restricted rotation about this axis of chirality gave rise to configurationally stable atropisomers that demonstrated a 10-fold difference in potency. The decision to develop sotorasib as a single-atropisomer drug gave rise to a range of analytical and synthetic challenges, whose resolution we review here.Assessing the configurational stability of differentially substituted biaryl units in early inhibitor candidates represented the first challenge to be overcome, as differing atropisomer stability profiles called for differing development strategies (e.g., as rapidly equilibrating rotamers vs as single atropisomers). We relied on a range of NMR, HPLC, and computational methods to assess atropisomer stability. Here, we describe the various variable-temperature NMR, time-course NMR, and chiral HPLC approaches used to assess the configurational stability of axially chiral bonds displaying a range of rotational barriers.As optimal engagement of the "cryptic" pocket of KRASG12C was ultimately achieved with a configurationally stable atropisomeric linkage, the second challenge to be overcome entailed preparing the preferred (M)-atropisomer of sotorasib on industrial scale. This synthetic challenge centered on the large-scale synthesis of an atropisomerically pure building block comprising the central azaquinazolinone and pyridine rings of sotorasib. We examined a range of strategies to prepare this compound as a single atropisomer: asymmetric catalysis, chiral chromatographic purification, and classical resolution. Although chiral liquid and simulated moving bed chromatography provided expedient access to initial multikilo supplies of this key intermediate, a classical resolution process was ultimately developed that proved significantly more efficient on metric-ton scale. To avoid discarding half of the material from this resolution, this process was subsequently refined to enable thermal recycling of the undesired atropisomer, providing an even more efficient commercial process that proved both robust and green.While the preparation of sotorasib as a single atropisomer significantly increased both the analytical and synthetic complexity of its development, the axially chiral biaryl linkage that gave rise to the atropisomerism of sotorasib proved a key design element in optimizing sotorasib's binding to KRASG12C. It is hoped that this review will help in outlining the range of analytical techniques and synthetic strategies that can be brought to bear in addressing the challenges posed by such axially chiral compounds and that this account may provide helpful guidelines for future efforts aimed at the development of such single atropisomer, axially chiral pharmaceutical agents.

Understanding the role of placental pathophysiology in the development of bronchopulmonary dysplasia.

The associations between bronchopulmonary dysplasia (BPD) and the gestational pathologies of chorioamnionitis (CA) and hypertensive disorders of pregnancy (HDP) have become increasingly well recognized. However, the mechanisms through which these antenatal conditions cause increased risk of BPD remain less well characterized. The objective of this review is to discuss the role of the placenta in BPD predisposition as a primary driver of intrauterine alterations adversely impacting fetal lung development. We hypothesize that due to similarities in structure and function, placental disorders during pregnancy can uniquely impact the developing fetal lung, creating a unique placental-pulmonary connection. In the current review, we explore this hypothesis through analysis of clinical literature and preclinical model systems evaluating BPD predisposition, discussion of BPD phenotypes, and an overview on strategies to incorporate placental investigation into research on fetal lung development. We also discuss important concepts learned from research on antenatal steroids as a modulator fetal lung development. Finally, we propose that the appropriate selection of animal models and establishment of in vitro lung developmental model systems incorporating primary human placental components are key in continuing to understand and address antenatal predisposition to BPD.

Concordance of Narrative Comments with Supervision Ratings Provided During Entrustable Professional Activity Assessments.

BACKGROUND: Use of EPA-based entrustment-supervision ratings to determine a learner's readiness to assume patient care responsibilities is expanding. OBJECTIVE: In this study, we investigate the correlation between narrative comments and supervision ratings assigned during ad hoc assessments of medical students' performance of EPA tasks. DESIGN: Data from assessments completed for students enrolled in the clerkship phase over 2 academic years were used to extract a stratified random sample of 100 narrative comments for review by an expert panel. PARTICIPANTS: A review panel, comprised of faculty with specific expertise related to their roles within the EPA program, provided a "gold standard" supervision rating using the comments provided by the original assessor. MAIN MEASURES: Interrater reliability (IRR) between members of review panel and correlation coefficients (CC) between expert ratings and supervision ratings from original assessors. KEY RESULTS: IRR among members of the expert panel ranged from .536 for comments associated with focused history taking to .833 for complete physical exam. CC (Kendall's correlation coefficient W) between panel members' assignment of supervision ratings and the ratings provided by the original assessors for history taking, physical examination, and oral presentation comments were .668, .697, and .735 respectively. The supervision ratings of the expert panel had the highest degree of correlation with ratings provided during assessments done by master assessors, faculty trained to assess students across clinical contexts. Correlation between supervision ratings provided with the narrative comments at the time of observation and supervision ratings assigned by the expert panel differed by clinical discipline, perhaps reflecting the value placed on, and perhaps the comfort level with, assessment of the task in a given specialty. CONCLUSIONS: To realize the full educational and catalytic effect of EPA assessments, assessors must apply established performance expectations and provide high-quality narrative comments aligned with the criteria.

REACT: Rapid Evaluation Assessment of Clinical Reasoning Tool.

INTRODUCTION: Clinical reasoning encompasses the process of data collection, synthesis, and interpretation to generate a working diagnosis and make management decisions. Situated cognition theory suggests that knowledge is relative to contextual factors, and clinical reasoning in urgent situations is framed by pressure of consequential, time-sensitive decision-making for diagnosis and management. These unique aspects of urgent clinical care may limit the effectiveness of traditional tools to assess, teach, and remediate clinical reasoning. METHODS: Using two validated frameworks, a multidisciplinary group of clinicians trained to remediate clinical reasoning and with experience in urgent clinical care encounters designed the novel Rapid Evaluation Assessment of Clinical Reasoning Tool (REACT). REACT is a behaviorally anchored assessment tool scoring five domains used to provide formative feedback to learners evaluating patients during urgent clinical situations. A pilot study was performed to assess fourth-year medical students during simulated urgent clinical scenarios. Learners were scored using REACT by a separate, multidisciplinary group of clinician educators with no additional training in the clinical reasoning process. REACT scores were analyzed for internal consistency across raters and observations. RESULTS: Overall internal consistency for the 41 patient simulations as measured by Cronbach's alpha was 0.86. A weighted kappa statistic was used to assess the overall score inter-rater reliability. Moderate reliability was observed at 0.56. DISCUSSION: To our knowledge, REACT is the first tool designed specifically for formative assessment of a learner's clinical reasoning performance during simulated urgent clinical situations. With evidence of reliability and content validity, this tool guides feedback to learners during high-risk urgent clinical scenarios, with the goal of reducing diagnostic and management errors to limit patient harm.

Synthesis of Substituted Pyridines via Formal (3+3) Cycloaddition of Enamines with Unsaturated Aldehydes and Ketones.

An organocatalyzed, formal (3+3) cycloaddition reaction is described for the practical synthesis of substituted pyridines. Starting from readily available enamines and enal/ynal/enone substrates, the protocol affords tri- or tetrasubstituted pyridine scaffolds bearing various functional groups. This method was demonstrated on a 50 g scale, enabling the synthesis of 2-isopropyl-4-methylpyridin-3-amine, a raw material used for the manufacture of sotorasib. Mechanistic analysis using two-dimensional nuclear magnetic resonance (NMR) spectrometry revealed the transformation proceeds through the reversible formation of a stable reaction off-cycle species that precedes pyridine formation. In situ reaction progress kinetic analysis and control NMR studies were employed to better understand the role of FeCl3 and pyrrolidine hydrochloride in promoting the reaction.

Characterization of false positive, contaminant-driven mutagenicity in impurities associated with the sotorasib drug substance.

Sotorasib (Lumakras™) is a first-in-class, non-genotoxic, small molecule inhibitor of KRAS G12C developed as an anticancer therapeutic for treatment of patients that have a high unmet medical need. Anticancer therapeutics are considered out of scope of ICH M7 guidance for control of mutagenic impurities; however, based on ICH S9 Q&A, mutagenicity assessments are needed for impurities that exceed the qualification threshold, consistent with ICH Q3A/B, and non-mutagenic drugs. Here, we carried out hybrid-based mutagenicity assessment of sotorasib drug substance (DS) impurities using in silico quantitative structure-activity relationship (QSAR) modelling and Ames tests (for in silico positive mutagens). We encountered contradictive mutagenicity results for 2 impurities (Beta-Chloride and PAC). PAC was negative initially by QSAR but positive in a GLP full plate Ames test and Beta-Chloride was positive by QSAR, negative in a non-GLP micro-Ames but positive in a GLP full plate Ames assay. Root cause analyses identified and characterized mutagenic contaminants, 3-chloropropionic acid in batches of Beta-Chloride and 3-chloropropionic acid and Chloro-PAC in batches of PAC, used in initial GLP full-plate Ames tests. Significant reduction of these contaminants in re-purified batches resulted in no induction of mutagenicity in follow-up GLP micro-Ames tests. In summary, root-cause analyses led to accurate mutagenicity assessment for sotorasib DS-associated impurities.

Characterization of Clinical Skills Remediation: A National Survey of Medical Schools.

OBJECTIVES: Clinical skills instruction is a standard part of medical school curricula, but how institutions address learners who struggle in this area is less clear. Although recommendations for the remediation of clinical skills at an institutional level have been published, how these recommendations are being implemented on a national scale is unknown. In this descriptive study, we characterize current clinical skills remediation practices at US medical schools and US-accredited Caribbean medical schools. METHODS: We conducted a cross-sectional survey of medical educators who work with struggling students. From March 24, 2020 to April 9, 2020, the Directors of Clinical Skills Remediation Working Group conducted an e-mail survey incorporating four aspects of remediation program design and function: identification, assessment, active remediation, and ongoing evaluation. RESULTS: In total, 92 individuals representing 45 institutions provided descriptive information about their respective remediation programs. The majority of respondents have a formal process of identifying (75%) and assessing (86%) students who are identified as struggling with clinical skills, but lack a standardized method of categorizing deficits. Fewer institutions have a standardized approach to active remediation and ongoing evaluation of struggling learners. Fifty-two percent of institutions provide training to faculty involved in the remediation process. CONCLUSIONS: Although most institutions are able to identify struggling students, they lack a standardized approach to intervene. Remediation effectiveness is limited by a lack of student buy-in and institutional time, expertise, and resources. These findings highlight the need for more formalized structure and standardization in remediation program design and implementation.

A High-Value Care Curriculum Using Individual and Group Structured Reflection.

OBJECTIVE: One-third of all healthcare dollars are wasted, primarily in the form of clinician-ordered unnecessary diagnostic tests and treatments. Medical education has likely played a central role in the creation and perpetuation of this problem. We aimed to create a curriculum for medical students to promote their contribution to high-value care conversations in the clinical environment. METHODS: At a large university medical center between March 2017 and February 2018, we implemented a 3-phase curriculum combining multimodal educational initiatives with individual and group reflection for third-year medical students during their 12-week long Internal Medicine clerkship rotation. Students were asked to identify examples of clinical decision making that lacked attention to high-value care, propose solutions to the identified situation, and pinpoint barriers to the implementation of effective solutions using a structured reflection framework and then participate in a debrief debate with fellow students. To assess the curriculum, reflective narratives were coded by frequency and codes were compared with one another and with relevant high-value care literature to identify patterns and themes. RESULTS: In total, 151 medical students participated in phase 1 and 119 in phase 3. For phase 2, 126 reflective narratives (94.7% participation rate) comprised 226 problems, 280 solutions, and 179 barriers. CONCLUSIONS: When provided appropriate resources, medical students are able to identify relevant examples of low-value care, downstream solutions, and barriers to implementation through a structured reflection curriculum comprising written narratives and in-person debate.

Exploring Everyday Chemistry: The Effectiveness of an Organic Chemistry Massive Open Online Course as an Education and Outreach Tool.

A massive open online course (MOOC), Exploring Everyday Chemistry (eeDc), was delivered four times between 2017 and 2019, attracting a worldwide audience of over 15 000 learners from a wide range of backgrounds. This 4-week course was designed to show a variety of everyday applications of organic chemistry, targeted at high school students seeking to study a chemistry-related degree at university. A mix of video, text, polls, quizzes, and practical activities was incorporated with material designed to build on high school studies, highlighting aspects of university-level teaching and research, as well as showcasing some career opportunities for chemistry graduates. We monitored student attitudes toward this course, finding a consistent enthusiasm for the approach and selection of material. The impact of the course was evident from the significant number of students who mentioned it positively in their university applications.

Going Green in Process Chemistry: Optimizing an Asymmetric Oxidation Reaction To Synthesize the Antiulcer Drug Esomeprazole.

Sustainable practices in process chemistry are highlighted by a novel, 9 week team project of 8-12 students, in collaboration with AstraZeneca chemists, in an organic chemistry laboratory. Students synthesize the antiulcer medicine esomeprazole, which involves the asymmetric oxidation of pyrmetazole. To provide insight into the modern process chemistry industry, they propose environmentally friendly modifications to the asymmetric oxidation. Students first synthesize pyrmetazole and then follow a standard oxidation procedure and carry out modified, greener reactions of their choice. They investigate how a change in reaction conditions affects both the yield and enantioselectivity of esomeprazole. Positive student feedback was received and student postlab reports were analyzed over a 4 year period (2015-2018). Results consistently showed that the project provided students with the key tools to develop greener syntheses. This contextual approach not only offers the opportunity to develop valuable communication and team-working skills, but it also gives students creative input into their experimental work. It teaches the important research skills involved in sustainable process chemistry, from reproducing and modifying a literature procedure to identifying green metrics.

Enantioselective Synthesis of a γ-Secretase Modulator via Vinylogous Dynamic Kinetic Resolution.

Two efficient asymmetric routes to γ-secretase modulator BMS-932481, under investigation for Alzheimer's disease, have been developed. The key step for the first route involves a challenging enantioselective hydrogenation of an unfunctionalized trisubstituted alkene to establish the benzylic stereocenter, representing a very rare case of achieving high selectivity on a complex substrate. The second route demonstrates the first example of a vinylogous dynamic kinetic resolution (VDKR) ketone reduction, where the carbonyl and the racemizable stereocenter are not contiguous, but are conjugated through a pyrimidine ring. Not only did this transformation require both catalyst and substrate control to correctly establish the two stereocenters, but it also necessitated that the nonadjacent benzylic center of the ketone substrate be more acidic than that of the alcohol product to make the process dynamic. DFT computations aided the design of this novel VDKR pathway by reliably predicting the relative acidities of the intermediates involved.

Effects of a healthier snack on snacking habits and glycated Hb (HbA1c): a 6-week intervention study.

Dietary behaviour modification may change eating habits and reduce the impact of poor nutrition. This study aimed to evaluate the effects of daily consumption of a healthier snack bar on snacking habits and glycated Hb (HbA1c) within a 6-week intervention. In all, twenty-eight participants were randomly allocated to two groups to either consume the bars as the main snack for 6 weeks (n 14) or receipt of the bars was delayed for 6 weeks (n 14) following a stepped-wedge design. All participants had HbA1c concentrations measured at weeks -1, 0, 4, 6, 10 and 12. A short dietary habits questionnaire was self-completed at weeks 0, 6 and 12. Participants consumed the bars they received instead of other snacks, and found that the healthier snack bar was acceptable as part of their daily dietary pattern. Over the 12 weeks, there was a significant reduction in intake of biscuits, cakes and pies (approximately 2 servings/week, P<0·05) in both groups. Fruit juice intake was reduced (approximately 1 serving/week, P=0·029) in the first group. In all, twenty participants (71·4 %) experienced a decrease (n 15) or no change (n 5) in HbA1c (range 0-4 mmol/mol), whereas eight participants experienced an increase in HbA1c (range 0·5-2·5 mmol/mol). There was high compliance with the healthier snack intervention and a trend towards a favourable effect on glucose homoeostasis. Habitual snacking behaviour has the potential to be improved through changes in the food supply, and in the longer term may reduce the impact of poor nutrition on public health.

Lessons in clinical reasoning - pitfalls, myths, and pearls: a case of tarsal tunnel syndrome caused by an intraneural ganglion cyst.

OBJECTIVES: Intraneural ganglionic cysts are non-neoplastic cysts that can cause signs and symptoms of peripheral neuropathy. However, the scarcity of such cases can lead to cognitive biases. Early surgical exploration of space occupying lesions plays an important role in identification and improving the outcomes for intraneural ganglionic cysts. CASE PRESENTATION: This patient presented with loss of sensation on the right sole with tingling numbness for six months. A diagnosis of tarsal tunnel syndrome was made. Nerve conduction study revealed that the mixed nerve action potential (NAP) was absent in the right medial and lateral plantar nerves. The magnetic resonance imaging (MRI) found a cystic lesion measuring 1.4×1.8×3.8 cm as the presumed cause of the neuropathy. Surgical exploration revealed a ganglionic cyst traversing towards the flexor retinaculum with baby cysts. The latter finding came as a surprise to the treating surgeon and was confirmed to be an intraneural ganglionic cyst based on the histopathology report. CONCLUSIONS: Through integrated commentary by a case discussant and reflection by an orthopedician, this case highlights the significance of the availability heuristic, confirmation bias, and anchoring bias in a case of rare disease. Despite diagnostic delays, a medically knowledgeable patient's involvement in their own care lead to a more positive outcome. A fish-bone diagram is provided to visually demonstrate the major factors that contributed to the diagnostic delay. Finally, this case provides clinical teaching points in addition to a pitfall, myth, and pearl related to availability heuristic and the sunk cost fallacy.

Influence of a Large Language Model on Diagnostic Reasoning: A Randomized Clinical Vignette Study.

Importance: Diagnostic errors are common and cause significant morbidity. Large language models (LLMs) have shown promise in their performance on both multiple-choice and open-ended medical reasoning examinations, but it remains unknown whether the use of such tools improves diagnostic reasoning. Objective: To assess the impact of the GPT-4 LLM on physicians' diagnostic reasoning compared to conventional resources. Design: Multi-center, randomized clinical vignette study. Setting: The study was conducted using remote video conferencing with physicians across the country and in-person participation across multiple academic medical institutions. Participants: Resident and attending physicians with training in family medicine, internal medicine, or emergency medicine. Interventions: Participants were randomized to access GPT-4 in addition to conventional diagnostic resources or to just conventional resources. They were allocated 60 minutes to review up to six clinical vignettes adapted from established diagnostic reasoning exams. Main Outcomes and Measures: The primary outcome was diagnostic performance based on differential diagnosis accuracy, appropriateness of supporting and opposing factors, and next diagnostic evaluation steps. Secondary outcomes included time spent per case and final diagnosis. Results: 50 physicians (26 attendings, 24 residents) participated, with an average of 5.2 cases completed per participant. The median diagnostic reasoning score per case was 76.3 percent (IQR 65.8 to 86.8) for the GPT-4 group and 73.7 percent (IQR 63.2 to 84.2) for the conventional resources group, with an adjusted difference of 1.6 percentage points (95% CI -4.4 to 7.6; p=0.60). The median time spent on cases for the GPT-4 group was 519 seconds (IQR 371 to 668 seconds), compared to 565 seconds (IQR 456 to 788 seconds) for the conventional resources group, with a time difference of -82 seconds (95% CI -195 to 31; p=0.20). GPT-4 alone scored 15.5 percentage points (95% CI 1.5 to 29, p=0.03) higher than the conventional resources group. Conclusions and Relevance: In a clinical vignette-based study, the availability of GPT-4 to physicians as a diagnostic aid did not significantly improve clinical reasoning compared to conventional resources, although it may improve components of clinical reasoning such as efficiency. GPT-4 alone demonstrated higher performance than both physician groups, suggesting opportunities for further improvement in physician-AI collaboration in clinical practice.

Novel route to chaetomellic acid A and analogues: serendipitous discovery of a more competent FTase inhibitor.

A new practical route to chaetomellic acid A (ACA), based on the copper catalysed radical cyclization (RC) of (Z)-3-(2,2-dichloropropanoyl)-2-pentadecylidene-1,3-thiazinane, is described. Remarkably, the process entailed: (i) a one-pot preparation of the intermediate N-α-perchloroacyl-2-(Z)-alkyliden-1,3-thiazinanes starting from N-(3-hydroxypropyl)palmitamide, (ii) a two step smooth transformation of the RC products into ACA and (iii) only one intermediate chromatographic purification step. The method offers a versatile approach to the preparation of ACA analogues, through the synthesis of an intermediate maleic anhydride with a vinylic group at the end of the aliphatic tail, a function that can be transformed through a thiol-ene coupling. Serendipitously, the disodium salt of 2-(9-(butylthio)nonyl)-3-methylmaleic acid, that we prepared as a representative sulfurated ACA analogue, was a more competent FTase inhibitor than ACA. This behaviour was analysed by a molecular docking study.