Commentary on ICH guideline on genomic sampling and data management-enabling opportunities in drug development and patient treatment.

The ability to benefit from knowledge of human genomic data in medicine has been anticipated since the sequencing of the human genome. That promise has experienced some degree of realization, particularly in oncology where biomarker-specific clinical trials and patient treatment specific to the genetics of their tumours now occur. With whole genome sequencing and related technologies becoming more affordable, and the generation and management of vast amounts of data and information, more capable, new opportunities to benefit from these developments lie ahead. Already emerging are many studies describing the association of genomic variation with molecular underpinnings of disease, association with patient response to drugs and informing the nomination of new drug targets. These developments are accompanied by some ethical, legal and regulatory challenges, which we discuss in this article.

Unanswered clinical questions: a survey of specialists and primary care providers.

OBJECTIVE: With the myriad of cases presented to clinicians every day at our integrated academic health system, clinical questions are bound to arise. Clinicians need to recognize these knowledge gaps and act on them. However, for many reasons, clinicians might not seek answers to these questions. Our goal was to investigate the rationale and process behind these unanswered clinical questions. Subsequently, we explored the use of biomedical information resources among specialists and primary care providers and identified ways to promote more informed clinical decision making. METHODS: We conducted a survey to assess how practitioners identify and respond to information gaps, their background knowledge of search tools and strategies, and their usage of and comfort level with technology. RESULTS: Most of the 292 respondents encountered clinical questions at least a few times per week. While the vast majority often or always pursued answers, time was the biggest barrier for not following through on questions. Most respondents did not have any formal training in searching databases, were unaware of many digital resources, and indicated a need for resources and services that could be provided at the point of care. CONCLUSIONS: While the reasons for unanswered clinical questions varied, thoughtful review of the responses suggested that a combination of educational strategies, embedded librarian services, and technology applications could help providers pursue answers to their clinical questions, enhance patient safety, and contribute to patient-based, self-directed learning.

From the coliseum to the convention centre: a reflection on the current state of medical education conferences and conference-goers.

The advancement of knowledge and development of policy in the field of medical education require critical academic discourse among the most intelligent medical educators; and critical academic discourse requires coffee. In this essay, we reflect on the state of professional development conferences in the field of medical education and the rituals that surround their success. Having begun in ancient Greece, symposia were ripe with debauchery. Today, sedated by the light brown walls of hotel conference centres, symposia are more serious endeavours, engaging men and women in the sometimes turbulent waters of epistemological debate. The abstract submission process (summed up by: 'Yay! It was accepted for presentation' [Deep breath] 'Oh no…it was accepted for presentation'), the 'juggling act' of parent attendees, the acting prowess of abstract presenters and the unapologetic approach to buffet eating are all by-products of the collision of true intellects among medical education scholars. We hold these rituals in high regard and argue that they are required to advance the field of medical education. These rituals bind the walls supporting true progressive thought and innovative research, all fuelled by the glass of wine purchased with that one coveted drink ticket.

Cultivating Medical Education Research Mentorship as a Pathway Towards High Quality Medical Education Research.

The lack of effective and consistent research mentorship and research mentor training in both undergraduate medical education (UME) and graduate medical education (GME) is a critical constraint on the development of innovative and high quality medical education research. Clinical research mentors are often not familiar with the nuances and context of conducting education research. Clinician-educators, meanwhile, often lack the skills in developing and conducting rigorous research. Mentors who are not prepared to articulate potential scholarship pathways for their mentees risk limiting the mentee's progress in early stages of their career. In fact, the relative paucity of experienced medical education research mentors arguably contributes to the perpetuation of a cycle leading to fewer well-trained researchers in medical education, a lack of high quality medical education research, and relative stagnation in medical education innovation. There is a path forward, however. Integration of doctoral-level educators, structured inter-departmental efforts, and external mentorship provide opportunities for faculty to gain traction in their medical education research efforts. An investment in medical education research mentors will ensure rigorous research for high quality innovation in medical education and patient care.

Characterizing the PK/PD relationship for inhibition of capsaicin-induced dermal vasodilatation by MK-3207, an oral calcitonin gene related peptide receptor antagonist.

AIMS: Calcitonin gene related peptide (CGRP) receptor antagonists are effective acute migraine treatments. A capsaicin-induced dermal vasodilatation (CIDV) model has been developed to provide target-engagement information in healthy volunteers. In the model, CGRP release is provoked after dermal capsaicin application, by activating transient receptor potential vanilloid-type-1 (TRPV1) receptors at peripheral sensory nerves. Laser Doppler imaging is used to quantify CIDV and subsequent inhibition by CGRP receptor antagonists. We sought to evaluate a CGRP receptor antagonist, MK-3207, in the biomarker model and to assess the predictability of the CIDV response to migraine clinical efficacy. METHODS: An integrated population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the exposure-response relationship for CIDV inhibition by CGRP and TRPV1 receptor antagonists. MK-3207 dose-response predictions were made based on estimated potency from the PK/PD model and mean plasma concentrations observed at the doses investigated. RESULTS: The results suggested that a 20 mg dose of MK-3207 (EC50 of 1.59 nm) would be required to attain the peripheral CIDV response at a target level that was shown previously to correlate with 2 h clinical efficacy based on phase 3 telcagepant clinical data, and that a plateau of the dose-response would be reached around 40-100 mg. These predictions provided a quantitative rationale for dose selection in a phase 2 clinical trial of MK-3207 and helped with interpretation of the efficacy results from the trial. CONCLUSIONS: The integrated CIDV PK/PD model provides a useful platform for characterization of PK/PD relationships and predictions of dose-response relationships to aid in future development of CGRP and TRPV1 receptor antagonists.

Lost in the pandemic: COVID-19's impact on health professions educators.

BACKGROUND: Minimal research has explored the pandemic's impact on health professions educators (HPEs). Given that health professions educator academies provide centralised support and professional development to HPEs through communities of practice and promoting education at their institutions, it is important to examine how academies met HPEs' needs during the pandemic. This study investigates the COVID-19 pandemic's effects on HPEs and examines how academies supported HPEs' educational roles during the pandemic. METHODS: Using a mixed-methods approach, the authors surveyed United States educator academy members on changes in HPEs' activities, emphasising clinical and educational tasks and work-life integration. Participants shared their academies' innovations and support responses. Data were analysed using chi-square and content analyses. FINDINGS: Twenty percent of 2784 recipients (n = 559) completed the survey. Most respondents indicated the pandemic caused them to spend more time on clinical and education leadership/administration than before the pandemic. HPEs integrated innovative instructional strategies, yet many shifted away from teaching, mentoring and scholarship. Over half were dissatisfied with work-life integration during the pandemic. Females, especially, reported that professional work was compromised by personal caregiving. Academies increased their range of member services; however, they did not fully meet their members' needs, including providing expanded professional development and advocating on HPE's behalf for increased protected time dedicated to educator responsibilities. DISCUSSION: HPEs faced unprecedented challenges in their personal and professional lives during the COVID-19 pandemic. Neglecting the needs of HPEs amidst global crises poses a substantial threat to the quality of education for upcoming generations of health care professionals.

In vivo quantification of calcitonin gene-related peptide receptor occupancy by telcagepant in rhesus monkey and human brain using the positron emission tomography tracer [11C]MK-4232.

Calcitonin gene-related peptide (CGRP) is a potent neuropeptide whose agonist interaction with the CGRP receptor (CGRP-R) in the periphery promotes vasodilation, neurogenic inflammation and trigeminovascular sensory activation. This process is implicated in the cause of migraine headaches, and CGRP-R antagonists in clinical development have proven effective in treating migraine-related pain in humans. CGRP-R is expressed on blood vessel smooth muscle and sensory trigeminal neurons and fibers in the periphery as well as in the central nervous system. However, it is not clear what role the inhibition of central CGRP-R plays in migraine pain relief. To this end, the CGRP-R positron emission tomography (PET) tracer [(11)C]MK-4232 (2-[(8R)-8-(3,5-difluorophenyl)-6,8-[6-(11)C]dimethyl-10-oxo-6,9-diazaspiro[4.5]decan-9-yl]-N-[(2R)-2'-oxospiro[1,3-dihydroindene-2,3'-1H-pyrrolo[2,3-b]pyridine]-5-yl]acetamide) was discovered and developed for use in clinical PET studies. In rhesus monkeys and humans, [(11)C]MK-4232 displayed rapid brain uptake and a regional brain distribution consistent with the known distribution of CGRP-R. Monkey PET studies with [(11)C]MK-4232 after intravenous dosing with CGRP-R antagonists validated the ability of [(11)C]MK-4232 to detect changes in CGRP-R occupancy in proportion to drug plasma concentration. Application of [(11)C]MK-4232 in human PET studies revealed that telcagepant achieved only low receptor occupancy at an efficacious dose (140 mg PO). Therefore, it is unlikely that antagonism of central CGRP-R is required for migraine efficacy. However, it is not known whether high central CGRP-R antagonism may provide additional therapeutic benefit.

Curating a media-linked curriculum.

BACKGROUND: The COVID-19 pandemic motivated considerable educational innovation in technology-enhanced learning (TEL), and educators must now thoughtfully apply identified best practices to both in-person and virtual learning experiences through instructional design and reflective practice. This paper describes the development and evaluation of an innovation utilising TEL to enhance our core curriculum content and students' learning. APPROACH: The curriculum-linked media (CLM) was introduced as a part of a doctoring and clinical skills course for pre-clinical medical students as a structured curriculum that pairs audio and/or video-based content with reflection prompts designed to prime students for active, in-person learning upon arrival to their classrooms. The CLM aimed to help students (1) gain a deeper understanding of the course content, (2) partake in reflective practice and (3) explore diverse perspectives on a particular topic. EVALUATION: All students completed a survey at the end of their academic year to evaluate the activity. Some students found the innovation helpful in that it facilitated perspective taking and prepared them for their in-person class. The reflection questions that paired with the media prompted discussion in class and a deeper connection with the materials. Making the content relevant to the local community and highlighting regional issues made the activity more relatable. IMPLICATIONS: Our experience demonstrated that the CLM model can be a helpful and efficient tool to stretch the educational reach of the classroom. Future applications may consider the implementation and evaluation of the model with clinical students and postgraduate trainees.

The Impact of a Web-Based Preintubation Preparation Module on the Knowledge, Confidence, and Behavior of Critical Care Fellows: A Single-Center Pilot Study.

OBJECTIVES: The objectives of this study were to standardize airway management among critical care fellows and to evaluate whether the completion of a web-based preintubation airway preparation module improves their knowledge and behaviors in the identification and preparation of difficult airways. METHODS: Critical care experts used international guidelines to develop the module, which contained mandatory readings, brief lectures, and a case-based activity. We measured learner satisfaction, improvements in fellows' preintubation preparation knowledge, and safety-oriented behavior. The paired t-test was used to compare knowledge assessment scores and the chi-square test was used to compare the categorical variables in the evaluation of the behavior construct. RESULTS: All trainees (N = 14) completed the module and were satisfied with its contents and structure. Fellows logged 114 intubations during the study period. The mean score on the knowledge test increased (pre 79% vs post 90%, P = .02) postmodule and there was a significant increase in documentation of airway risk stratification in fellows' procedure notes (65.9% vs 72.9%, P = .049). All respondents were confident that they would be able to apply what they learned in the module into clinical practice and that their patients would likely benefit from their new knowledge. CONCLUSION: The implementation of an asynchronous web-based module on airway assessment and intubation preparation was feasible. The module was engaging, enhanced the knowledge of our trainees, and improved procedural documentation.

Evaluation of a Health Professions Teaching Academy Through the Lens of Social Capital.

INTRODUCTION: Academies of health professions educators can amplify members' social capital, promoting educational innovation and organizational change. However, research in this area is limited. This article attempts to close the gap in literature with the results of a program evaluation of our interprofessional teaching academy through the lens of social capital and organizational culture. METHODS: A program evaluation using a cross-sectional survey was conducted with all members of the Baystate Education Research and Scholarship of Teaching (BERST) Academy. The survey drew on a conceptual framework from previous literature on social capital, communities of practice, and faculty development evaluation. Data were analyzed with descriptive statistics and analysis of variance. RESULTS: Overall survey response rate was 54%. More than 90% of respondents have applied the skills learned through BERST Academy into their practice. Social capital was defined with five items (Cronbach alpha = 0.87), and we found no significant difference between profession and social capital, suggesting that perceptions of social capital did not significantly differ by membership in a specific profession. DISCUSSION: Our results showed that BERST Academy members were able to cultivate social capital through high-quality connections. An academy can serve as a unique culture within an institution to foster collaborative relationships that increase social capital, for members of different professions. In addition, an academy can also provide members with a community that benefits them in the greater organizational culture.

Applying Conceptual and Theoretical Frameworks to Health Professions Education Research: An Introductory Workshop.

Introduction: Literature suggests that the quality and rigor of health professions education (HPE) research can be elevated if the research is anchored in existing theories and frameworks. This critical skill is difficult for novice researchers to master. We created a workshop to introduce the practical application of theories and frameworks to HPE research. Methods: We conducted two 60- to 75-minute workshops, one in 2019 at an in-person national conference and another in 2021 during an online national education conference. After a brief role-play introduction, participants applied a relevant theory to a case scenario in small groups, led by facilitators with expertise in HPE research. The workshop concluded with a presentation on applying the lessons learned when preparing a scholarly manuscript. We conducted a postworkshop survey to measure self-reported achievement of objectives. Results: Fifty-five individuals participated in the in-person workshop, and approximately 150 people completed the online workshop. Sixty participants (30%) completed the postworkshop survey across both workshops. As a result of participating in the workshop, 80% of participants (32) indicated they could distinguish between frameworks and theories, and 86% (32) could apply a conceptual or theoretical framework to a research question. Strengths of the workshop included the small-group activity, access to expert facilitators, and the materials provided. Discussion: The workshop has been well received by participants and fills a gap in the existing resources available to HPE researchers and mentors. It can be replicated in multiple settings to model the application of conceptual and theoretical frameworks to HPE research.

The potent calcitonin gene-related peptide receptor antagonist, telcagepant, does not affect nitroglycerin-induced vasodilation in healthy men.

AIMS: To assess the effect of the calcitonin gene-related peptide (CGRP) receptor antagonist, telcagepant, on the haemodynamic response to sublingual nitroglycerin (NTG). METHODS: Twenty-two healthy male volunteers participated in a randomized, placebo-controlled, double-blind, two-period, crossover study. Subjects received 500 mg telcagepant or placebo followed, 1.5 h later, by 0.4 mg NTG. To assess the haemodynamic response the following vascular parameters were measured: blood pressure, aortic augmentation index (AIx) and brachial artery diameter (BAD). Data are presented as mean (95% confidence interval, CI). RESULTS: The aortic AIx following NTG decreased by -18.50 (-21.02, -15.98) % after telcagepant vs. -17.28 (-19.80, -14.76) % after placebo. The BAD fold increase following NTG was 1.14 (1.12, 1.17) after telcagepant vs. 1.13 (1.10, 1.15) after placebo. For both AIx and BAD, the hypothesis that telcagepant does not significantly affect the changes induced by NTG is supported (P < 0.0001). In addition, no vasoconstrictor effect of telcagepant could be demonstrated. CONCLUSIONS: Telcagepant did not affect NTG-induced haemodynamic changes. These data suggest that NTG-induced vasodilation is not CGRP dependent.

Effect of telcagepant on spontaneous ischemia in cardiovascular patients in a randomized study.

OBJECTIVE: The primary purpose of the study was to explore the safety and tolerability of telcagepant in patients with stable coronary artery disease. BACKGROUND: Triptans are effective acute anti-migraine drugs whose vasoconstrictive effects limit their use in patients at risk for adverse cardiovascular events. Telcagepant, a calcitonin gene-related peptide receptor antagonist, is being developed for the acute treatment of migraine. Antagonism of calcitonin gene-related peptide, which does not appear to cause vasoconstriction, may allow for treatment of migraine in patients with coronary artery disease. METHODS: In this randomized, double-blind, placebo-controlled, crossover study, patients with documented stable coronary artery disease were assigned to 1 of 2 treatment sequences: telcagepant then placebo, or placebo then telcagepant. In each treatment period, patients received 2 doses of telcagepant 300-mg or placebo 2 hours apart. They remained in the research center for 24 hours after receiving the first dose of each period, during which time continuous 12-lead ambulatory electrocardiographic (Holter) monitoring was performed. RESULTS: Twenty-eight patients were enrolled; all patients completed the study and were included in all analyses. Telcagepant was generally well tolerated. No laboratory or serious adverse experiences were reported, and no patient discontinued due to an adverse experience. There were no consistent treatment-related changes in laboratory, vital signs or electrocardiogram safety parameters. Three patients (2 after receiving placebo and 1 after receiving telcagepant) experienced ST segment depression during the study; none of these patients reported chest pain. CONCLUSIONS: Two doses of 300-mg telcagepant, administered 2 hours apart, did not appear to exacerbate spontaneous ischemia and were generally well tolerated in a small cohort of patients with stable coronary artery disease. Results of this study support further evaluation of telcagepant in patients with stable coronary artery disease.

Global Landscape of Clostridioides Difficile Phylogeography, Antibiotic Susceptibility, and Toxin Polymorphisms by Post-Hoc Whole-Genome Sequencing from the MODIFY I/II Studies.

INTRODUCTION: Clostridioides (Clostridium) difficile infection, the leading cause of healthcare-associated diarrhea, represents a significant burden on global healthcare systems. Despite being a global issue, information on C. difficile from a global perspective is lacking. The aim of this study is to model the global phylogeography of clinical C. difficile. METHODS: Using samples collected from the MODIFY I and II studies (NCT01241552, NCT01513239), we performed whole-genome sequencing of 1501 clinical isolates including 37 novel sequence types (STs), representing the largest worldwide collection to date. RESULTS: Our data showed ribotypes, multi-locus sequence typing clades, and whole-genome phylogeny were in good accordance. The clinical C. difficile genome was found to be more conserved than previously reported (61% core genes), and modest recombination rates of 1.4-5.0 were observed across clades. We observed a significant continent distribution preference among five C. difficile clades (Benjamini-Hochberg corrected Fisher's exact test P < 0.01); moreover, weak association between geographic and genetic distance among ribotypes suggested sources beyond healthcare-related transmission. Markedly different trends of antibiotic susceptibility among lineages and regions were identified, and three novel mutations (in pyridoxamine 5'-phosphate oxidase family protein: Tyr130Ser, Tyr130Cys, and a promoter SNP) associated with metronidazole-reduced susceptibility were discovered on a nim-related gene and its promotor by genome-wide association study. Toxin gene polymorphisms were shown to vary within and between prevalent ribotypes, and novel severe mutations were found on the tcdC toxin regulator protein. CONCLUSION: Our systematic characterization of a global set of clinical trial C. difficile isolates from infected individuals demonstrated the complexity of the genetic makeup of this pathogenic organism. The geographic variability of clades, variability in toxin genes, and mutations associated with antibiotic susceptibility indicate a highly complex interaction of C. difficile between host and environment. This dataset will provide a useful resource for validation of findings and future research of C. difficile.

Examining Shopping Patterns, Use of Food-Related Resources, and Proposed Solutions to Improve Healthy Food Access Among Food Insecure and Food Secure Eastern North Carolina Residents.

In the Southern United States (U.S.), food insecurity rates are higher in rural (20.8%) versus urban communities (15%). Food insecurity can exacerbate diet-related disease. Thus, the purpose of this study was to examine differences in the use of food-related community resources and potential solutions proposed among food insecure versus food secure residents. A community survey (n = 370) was conducted in rural eastern North Carolina, with questions pertaining to food security status and food-related resources. The IBM SPSS Statistics software and SAS software were used to examine differences in food-related resources, and qualitative data analysis was used to examine differences in solutions offered between food insecure and food secure participants. Of the 370 respondents, forty-eight-point-six percent were classified as food insecure. Food insecure participants were more likely to report shopping for groceries at a convenience/discount store, less likely to use their own vehicle for transportation, and less likely to purchase food from local producers. Food insecure participants were more likely to suggest solutions related to reducing the cost of healthy food, while food secure participants were more likely to suggest educational or convenience-related interventions.

Genetic Association Reveals Protection against Recurrence of Clostridium difficile Infection with Bezlotoxumab Treatment.

Bezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B, indicated to prevent recurrence of C. difficile infection (rCDI) in high-risk adults receiving antibacterial treatment for CDI. An exploratory genome-wide association study investigated whether human genetic variation influences bezlotoxumab response. DNA from 704 participants who achieved initial clinical cure in the phase 3 MODIFY I/II trials was genotyped. Single nucleotide polymorphisms (SNPs) and human leukocyte antigen (HLA) imputation were performed using IMPUTE2 and HIBAG, respectively. A joint test of genotype and genotype-by-treatment interaction in a logistic regression model was used to screen genetic variants associated with response to bezlotoxumab. The SNP rs2516513 and the HLA alleles HLA-DRB1*07:01 and HLA-DQA1*02:01, located in the extended major histocompatibility complex on chromosome 6, were associated with the reduction of rCDI in bezlotoxumab-treated participants. Carriage of a minor allele (homozygous or heterozygous) at any of the identified loci was related to a larger difference in the proportion of participants experiencing rCDI versus placebo; the effect was most prominent in the subgroup at high baseline risk for rCDI. Genotypes associated with an improved bezlotoxumab response showed no association with rCDI in the placebo cohort. These data suggest that a host-driven, immunological mechanism may impact bezlotoxumab response. Trial registration numbers are as follows: NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II).IMPORTANCEClostridium difficile infection is associated with significant clinical morbidity and mortality; antibacterial treatments are effective, but recurrence of C. difficile infection is common. In this genome-wide association study, we explored whether host genetic variability affected treatment responses to bezlotoxumab, a human monoclonal antibody that binds C. difficile toxin B and is indicated for the prevention of recurrent C. difficile infection. Using data from the MODIFY I/II phase 3 clinical trials, we identified three genetic variants associated with reduced rates of C. difficile infection recurrence in bezlotoxumab-treated participants. The effects were most pronounced in participants at high risk of C. difficile infection recurrence. All three variants are located in the extended major histocompatibility complex on chromosome 6, suggesting the involvement of a host-driven immunological mechanism in the prevention of C. difficile infection recurrence.

The Impact of an Institutional Grant Program on the Economic, Social, and Cultural Capital of Women Researchers.

Introduction: Early funding can have significant impact on a researcher's career. However, funding is not equal for men and women. Not only do female researchers apply for fewer grants than men, but they also experience a lower success rate when they do. The Zucker Grant Program (ZGP) was established in 2000 to promote the early success of women researchers. The purpose of this evaluation is to support other institutions hoping to grow the research careers of women scientists. Methods: This program evaluation reviewed the first 16 years of the program's history. Our mixed-methods, outcomes-based evaluation had four phases: (I) interviews with key stakeholders, (II) development and distribution of a survey to ZGP recipients, (III) focus groups and interviews with ZGP recipients, (IV) document analysis from the ZGP Center and the Tufts University School of Medicine (TUSM) Development Office. This article reports on the qualitative data collection and analysis. Results: Between 2000 and 2016, US$377,050 was awarded for 142 recipients. Qualitative data revealed how grant funding was critical to support pilot data in awardees' research to inform extramural grant applications. However, the program evaluation also identified effects on awardees' confidence as researchers and connection to a community. Conclusion: Outcomes are interpreted through the framework of Bourdieu's three forms of capital, including economic, social, and cultural capital. Viewed through this framework, they provide a critical infrastructure to the development and success of early career female investigators. This work offers other institutions a framework to consider when establishing intramural funding and support programs for their early career investigators.

Pharmacogenetic Analysis of OATP1B1, UGT1A1, and BCRP Variants in Relation to the Pharmacokinetics of Letermovir in Previously Conducted Clinical Studies.

The cytomegalovirus (CMV) viral terminase inhibitor letermovir is indicated for prevention of CMV infection in CMV-seropositive allogeneic hematopoietic stem cell transplant recipients. In this analysis, functional variants in solute carrier organic anion transporter family member 1B1 (SLCO1B1), uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1), and breast cancer resistance protein (BCRP) were assessed for effects on letermovir pharmacokinetics (PK) using pooled genetic information from 296 participants in 12 phase 1 studies. Letermovir area under the plasma concentration-time curve (AUC) was increased in carriers of the SLCO1B1 variant rs4149056 C allele relative to noncarriers with a geometric mean ratio (GMR) of 1.18 (95% confidence interval [CI], 1.06-1.30) for carriers of 1 copy and 1.42 (1.10-1.84) for carriers of 2 copies of the risk allele C compared with noncarriers. The SLCO1B1 variant rs4149032 T allele was associated with a decrease in letermovir AUC with GMR (95%CI) of 0.93 (0.85-1.02) and 0.82 (0.73-0.92) for carriers of 1 and 2 copies of the risk allele T, respectively, compared with noncarriers. The UGT1A1*6 variant rs4148323 A allele was present predominantly in Asian participants and was associated with an increase in letermovir AUC compared with noncarriers (GMR, 1.36; 95%CI, 1. 1.07-1.74). SLCO1B1 variant rs2306283, UGT1A1*28 TA promoter repeat, and BCRP variant rs2231142 had no effect on letermovir PK. Together, these data suggest that variants of enzymes and transporters that are involved in the disposition of letermovir in vitro may account for some variability in letermovir PK, but do not affect exposure to a clinically relevant extent.

Accuracy Screening for ST Elevation Myocardial Infarction in a Task-switching Simulation.

INTRODUCTION: Interruptions in the emergency department (ED) are associated with clinical errors, yet are important when providing care to multiple patients. Screening triage electrocardiograms (ECG) for ST-segment elevation myocardial infarction (STEMI) represent a critical interrupting task that emergency physicians (EP) frequently encounter. To address interruptions such as ECG interpretation, many EPs engage in task switching, pausing their primary task to address an interrupting task. The impact of task switching on clinical errors in interpreting screening ECGs for STEMI remains unknown. METHODS: Resident and attending EPs were invited to participate in a crossover simulation trial. Physicians first completed a task-switching simulation in which they viewed patient presentations interrupted by clinical tasks, including screening ECGs requiring immediate interpretation before resuming the patient presentation. Participants then completed an uninterrupted simulation in which patient presentations and clinical tasks were completed sequentially without interruption. The primary outcome was accuracy of ECG interpretation for STEMI during task switching and uninterrupted simulations. RESULTS: Thirty-five participants completed the study. We found no significant difference in accuracy of ECG interpretation for STEMI (task switching 0.89, uninterrupted 0.91, paired t-test p=0.21). Attending physician status (odds ratio [OR] [2.56], confidence interval [CI] [1.66-3.94], p<0.01) and inferior STEMI (OR [0.08], CI [0.04-0.14], p<0.01) were associated with increased and decreased odds of correct interpretation, respectively. Low self-reported confidence in interpretation was associated with decreased odds of correct interpretation in the task-switching simulation, but not in the uninterrupted simulation (interaction p=0.02). CONCLUSION: In our simulation, task switching was not associated with overall accuracy of ECG interpretation for STEMI. However, odds of correct interpretation decreased with inferior STEMI ECGs and when participants self-reported low confidence when interrupted. Our study highlights opportunities to improve through focused ECG training, as well as self-identification of "high-risk" screening ECGs prone to error during interrupted clinical workflow.