Discovery of a Novel Class of d-Amino Acid Oxidase Inhibitors Using the Schrödinger Computational Platform.

d-Serine is a coagonist of the N-methyl d-aspartate (NMDA) receptor, a key excitatory neurotransmitter receptor. In the brain, d-serine is synthesized from its l-isomer by serine racemase and is metabolized by the D-amino acid oxidase (DAO, DAAO). Many studies have linked decreased d-serine concentration and/or increased DAO expression and enzyme activity to NMDA dysfunction and schizophrenia. Thus, it is feasible to employ DAO inhibitors for the treatment of schizophrenia and other indications. Powered by the Schrödinger computational modeling platform, we initiated a research program to identify novel DAO inhibitors with the best-in-class properties. The program execution leveraged an hDAO FEP+ model to prospectively predict compound potency. A new class of DAO inhibitors with desirable properties has been discovered from this endeavor. Our modeling technology on this program has not only enhanced the efficiency of structure-activity relationship development but also helped to identify a previously unexplored subpocket for further optimization.

Association of Simulation Participation With Diagnostic Reasoning Scores in Preclinical Students.

PURPOSE: The aim of the study was to evaluate for an association between the number of voluntary mannequin simulation sessions completed during the school year with scores on a year-end diagnostic reasoning assessment among second-year medical students. METHOD: This is retrospective analysis of participation in 0 to 8 extracurricular mannequin simulation sessions on diagnostic reasoning assessed among 129 second-year medical students in an end-of-year evaluation. For the final skills assessment, 2 physicians measured students' ability to reason through a standardized case encounter using the Diagnostic Justification (DXJ) instrument (4 categories each scored 0-3 by raters reviewing students' postencounter written summaries). Rater scores were averaged for a total DXJ score (0-12). To provide additional baseline comparison, zero participation students were divided into 2 groups based on intent to participate: those who signed up for extracurricular sessions but never attended versus those who never expressed interest. Scores across the attendance groups were compared with an analysis of variance and trend analysis. RESULTS: The class DXJ mean equaled 7.56, with a standard deviation of 2.78 and range of 0 to 12. Post hoc analysis after a significant analysis of variance (F = 4.91, df = 8, 128, P < 0.001) showed those participating in 1 or more extracurricular sessions had significantly higher DXJ scores than those not participating. Students doing 7 extracurricular sessions had significantly higher DXJ scores than those doing 0 and 2 (P < 0.05). Zero attendance groups were not different. A significant linear trend (R = 0.48, F = 38.0, df = 1, 127, P < 0.001) was found with 9 groups. A significant quadratic effect, like a dose-response pattern, was found (F = 18.1, df = 2, 125, P < 0.001) in an analysis including both zero attendance groups, a low (1-4 extracurricular sessions) group and a high (5-8) group. CONCLUSIONS: Higher year-end diagnostic reasoning scores were associated with increased voluntary participation in extracurricular mannequin-based simulation exercises in an approximate dose-response pattern.

A Guide for Medical Educators: How to Design and Implement In Situ Simulation in an Academic Emergency Department to Support Interprofessional Education.

In situ simulation (ISS) put simulation training directly into the clinical practice environment. Although ISS creates opportunities to identify latent system threats, understand culture, and improve team dynamics, there are limited resources for medical educators to guide the development and implementation of ISS at academic (or community-based) emergency departments (EDs). We describe the implementation of ISS in a high-volume urban ED to help educators understand the requirements and limitations of successful program design. During an academic year, 66 individual learners participated in at least one of our 22 training sessions, a cohort that included 37 nurses, 17 physicians, eight physician assistants, and four allied health professionals. Feedback from these participants and case facilitators informed our iterative process of review and development of program guidelines and best practices. We share these key technical points and the themes we found to be essential to the successful implementation of an ISS program: consideration of session timing, participant buy-in, flexibility, and threats to professional identity. Overall, our report demonstrates the feasibility of implementing an ISS program in a high-volume urban ED and provides medical educators with a guide for creating an ISS program for interprofessional education.

Expansion of simulation and extended reality for undergraduate health professions education: A call to action.

In the spring of 2020, the COVID-19 pandemic limited access for many health professions students to clinical settings amid concerns about availability of appropriate personal protective equipment as well as the desire to limit exposure in these high-risk settings. Furthermore, the pandemic led to a need to cancel clinics and inpatient rotations, with a major impact on training for health professions and interprofessional health delivery, the long-term effects of which are currently unknown. While problematic, this also presents an opportunity to reflect on challenges facing the traditional clinical training paradigm in a rapidly changing and complex health care system and develop sustainable, high-quality competency-based educational models that incorporate rapidly progressing technologies. We call for pilot studies to explore specific simulation-based inpatient and outpatient clinical rotations for professional and interprofessional training.

Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites.

Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a tetrahydroquinolone, with increased sp3-character to improve parasite selectivity. Relative to other cytochrome b inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces Toxoplasma gondii tachyzoites and encysted bradyzoites in vitro, and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant Plasmodium falciparum in vitro. Causal prophylaxis and radical cure are achieved after P. berghei sporozoite infection with oral administration of a single dose (2.5 mg/kg) or 3 days treatment at reduced dose (0.625 mg/kg/day), eliminating parasitemia, and leading to 100% survival. Enzymatic, binding, and co-crystallography/pharmacophore studies demonstrate selectivity for apicomplexan relative to mammalian enzymes. JAG21 has significant promise as a pre-clinical candidate for prevention, treatment, and cure of toxoplasmosis and malaria.

Emergency Department Adult Fiberoptic Intubations: Incidence, Indications, and Implications for Training.

OBJECTIVE: The objective was to describe the frequency, indications, and outcomes of flexible fiberoptic intubations (FFI) performed in the emergency department (ED). METHODS: From the National Emergency Airway Registry (NEAR), we identified all encounters from July 1, 2002, through December 31, 2012, with the use of FFI. We determined patient, provider, and intubation characteristics; success and failure rates; and modes of intubation rescue. RESULTS: Among 17,910 intubations of patients > 15 years old at 13 EDs, FFI was used in 204 cases (1.1%, 95% confidence interval [CI] = 0.26%-2.0%). FFI was the first method chosen (primary FFI) in 180 encounters (1%, 95% CI = 0.2%-1.8%). The most common indication for FFI was airway obstruction (36.1%, 95% CI = 24.6%-47.7%). For primary FFI, first-attempt intubation success was 51.1% (95% CI = 43.6%-58.6%), and overall intubation success with FFI was 74.3% (95% CI = 65.7%-82.9%). FFI was used as a rescue airway strategy in 24 cases (0.1% of all encounters) and was successful in 17 of those (70.8%, 95% CI = 65.4%-85.2%). CONCLUSIONS: Emergency department FFI is uncommon and typically used as a nonsurgical alternative for airway obstruction. First-attempt ED FFI is successful in half of cases and in two-thirds of rescue attempts. These data provide an important baseline to help better characterize the nature of FFI as a rare critical procedure in the ED and offer an empiric basis for ongoing discussions on the optimal role of FFI in ED training and practice.

Simulation-based Education to Ensure Provider Competency Within the Health Care System.

The acquisition and maintenance of individual competency is a critical component of effective emergency care systems. This article summarizes consensus working group deliberations and recommendations focusing on the topic "Simulation-based education to ensure provider competency within the healthcare system." The authors presented this work for discussion and feedback at the 2017 Academic Emergency Medicine Consensus Conference on "Catalyzing System Change Through Healthcare Simulation: Systems, Competency, and Outcomes," held on May 16, 2017, in Orlando, Florida. Although simulation-based training is a quality and safety imperative in other high-reliability professions such as aviation, nuclear power, and the military, health care professions still lag behind in applying simulation more broadly. This is likely a result of a number of factors, including cost, assessment challenges, and resistance to change. This consensus subgroup focused on identifying current gaps in knowledge and process related to the use of simulation for developing, enhancing, and maintaining individual provider competency. The resulting product is a research agenda informed by expert consensus and literature review.

New Opportunities in the Structure-based Design of Anti-Protozoan Agents.

Since the recent renaissance of phenotypic screening in the field of protozoan drug discovery, is there still an opportunity for the structure-based design of new anti-protozoan agents? Target-based approaches should be used in parallel to phenotypic screening to strengthen the pipeline of anti-protozoan agents. We give an overview of the protozoan drug discovery landscape highlighting four protein targets of interest: cytochrome bc1, dihydroorotate dehydrogenase, dihydrofolate reductase and calcium-dependent protein kinase 1. We discuss recent structurebased design efforts to inhibit these targets, reviewing their crystal structures and their ability to accommodate potent and selective compounds. Finally, we discuss future opportunities to apply structure-based methods to promising molecular targets within protozoan parasites discovered using chemical genomics.

Characteristics and Core Curricular Elements of Medical Simulation Fellowships in North America.

Background In the past few years, there has been rapid growth in the number of simulation fellowships for physicians in the United States and Canada, with the objective of producing faculty with expertise and leadership training in medical simulation. Relatively little is known about the collective content and structure of these new fellowship opportunities. Objective We sought to identify a common set of core curricular elements among existing simulation fellowships and to obtain demographic background information on participants and leadership. Methods We designed a web-based survey and circulated it to simulation fellowship directors in the United States and Canada. The questions explored aspects of the fellowship curriculum. A grounded theory approach was used to qualitatively analyze fellowship goals and objectives. Results Of the 29 program directors surveyed, 23 responded (79%). The most commonly listed goals and objectives were to increase skills in simulation curriculum development, simulation operations and training environment setup, research, educational theory, administration, and debriefing. The majority of the responding fellowship directors (17 of 22, 77%) indicated that a set of consensus national guidelines would benefit their fellowship program. Conclusions Simulation fellowships are experiencing a period of rapid growth. Development of a common set of program guidelines is a widely shared objective among fellowship directors.

Satisfaction of Basic Psychological Needs, Self-Determined Exercise Motivation, and Psychological Well-Being in Mothers Exercising in Group-Based Versus Individual-Based Contexts.

We compared mothers who exercised predominantly in group settings, those who exercised predominantly in individual settings, and those who exercised equally in group and individual contexts among the following: (a) satisfaction of basic psychological needs (autonomy, competence, and relatedness); (b) self-determined exercise motivation; and (c) psychological well-being. With clear implications for mothers' exercise interventions we found that exercising either predominantly in group contexts or in mixed group and individual settings was associated with mothers having significantly higher satisfaction of basic psychological needs and self-determined exercise motivation than those exercising predominantly alone.

A simulation-based resident-as-teacher program: The impact on teachers and learners.

BACKGROUND: Residency training is charged with improving resident teaching skills. Utilizing simulation in teacher training has unique advantages such as providing a controlled learning environment and opportunities for deliberate practice. OBJECTIVE: We assessed the impact of a simulation-based resident-as-teacher (RaT) program. DESIGN: A RaT program was embedded in an existing 8-case simulation curriculum for 52 internal medicine (IM) interns. Residents participated in a workshop, then served as facilitators in the curriculum and received feedback from faculty. METHODS: Residents' teaching and feed back skills were measured using a pre- and post-program self-assessment and post-session and post-curriculum evaluations by intern learners. SETTING/PARTICIPANTS: Forty-one second- and third-year residents participated in the study August 2013 to October 2013 at a single center. RESULTS: Pre- and post-program teaching skills were assessed for 34 of 41 resident facilitators (83%) participating in 3.9 sessions on average. Partaking in the program led to improvements in resident facilitators' self-reported teaching and feedback skills across all domains. The most significant improvement was in teaching in a simulated environment (2.81 to 4.16, P < 0.001). Interns rated the curriculum highly (81% "excellent," 19% "good") and reported that resident facilitators frequently utilized debriefing techniques covered in the RaT program. CONCLUSIONS: Our simulation-based RaT program offered a unique opportunity for deliberate practice of teaching skills in a controlled environment and led to improvements in resident facilitators' teaching and feed back skills. The simulation curriculum, facilitated by residents, was well received by the intern learners. Our program design may serve as a model for the development of simulation curricula and RaT programs within IM residencies.

Simulation Improves Procedural Protocol Adherence During Central Venous Catheter Placement: A Randomized Controlled Trial.

BACKGROUND: Simulation training may improve proficiency at and reduce complications from central venous catheter (CVC) placement, but the scope of simulation's effect remains unclear. This randomized controlled trial evaluated the effects of a pragmatic CVC simulation program on procedural protocol adherence, technical skill, and patient outcomes. METHODS: Internal medicine interns were randomized to standard training for CVC insertion or standard training plus simulation-based mastery training. Standard training involved a lecture, a video-based online module, and instruction by the supervising physician during actual CVC insertions. Intervention-group subjects additionally underwent supervised training on a venous access simulator until they demonstrated procedural competence. Raters evaluated interns' performance during internal jugular CVC placement on actual patients in the medical intensive care unit. Generalized estimating equations were used to account for outcome clustering within trainees. RESULTS: We observed 52 interns placing 87 CVCs. Simulation-trained interns exhibited better adherence to prescribed procedural technique than interns who received only standard training (P = 0.024). There were no significant differences detected in first-attempt or overall cannulation success rates, mean needle passes, global assessment scores, or complication rates. CONCLUSIONS: Simulation training added to standard training improved protocol adherence during CVC insertion by novice practitioners. This study may have been too small to detect meaningful differences in venous cannulation proficiency and other clinical outcomes, highlighting the difficulty of patient-centered simulation research in settings where poor outcomes are rare. For high-performing systems, where protocol deviations may provide an important proxy for rare procedural complications, simulation may improve CVC insertion quality and safety.

Prospective analysis of an interprofessional team training program using high-fidelity simulation of contrast reactions.

OBJECTIVE: Successful management of a contrast reaction requires prompt recognition and treatment and effective team dynamics among radiologists, technologists, and nurses. A radiology department implemented a simulation program in which teams of nurses, technologists, and physicians managed simulated contrast reactions. The purpose of this study was to evaluate whether simulation improved the participants' abilities to manage a contrast reaction and work in a team during an emergency. SUBJECTS AND METHODS: Physicians, nurses, and technologists worked in inter-professional teams to manage two high-fidelity simulated adverse contrast reactions. Participants completed surveys before and after the simulation that included knowledge-based questions about the appropriate management of contrast reactions. Surveys also included questions for assessing participants' perceptions of their ability to manage adverse contrast reactions, measured with a 6-point Likert scale. Before and after comparisons were made with the McNemar test with a Bonferroni correction requiring p ≤ 0.003 for significance. For the other analyses, p ≤ 0.05 was considered significant. RESULTS: After completion of the simulation exercises, participants had significant improvement in knowledge (p < 0.001). After the simulation, participants reported significant improvement in their ability to manage an anaphylactoid reaction and their ability to work in a team (p < 0.00001). Participants requested repeat simulation exercises every 6-12 months. CONCLUSION: Simulation exercises improved the self-reported ability of radiology personnel to manage contrast reactions and work in a team during an emergency. Simulation should be incorporated into future educational initiatives to improve patient safety in radiology practices.

Intrinsic motivation of preclinical medical students participating in high-fidelity mannequin simulation.

Introduction: While medical schools strive to foster students' lifelong learning, motivational theories have not played an explicit role in curricular design. Self-determination Theory is a prominent motivational theory. It posits that perceived autonomy, competence and relatedness foster intrinsic motivation. This study explores the effects of autonomy on intrinsic motivation in medical students participating in high-fidelity mannequin simulation. Methods: A non-randomised crossover trial compared first-year medical students participating in (1) required simulation sessions with predetermined learning objectives and (2) extracurricular simulation sessions with student-directed learning objectives. An adapted Intrinsic Motivation Inventory (IMI) was used to assess intrinsic motivation, perceived autonomy, competence and relatedness. Each participant completed the IMI survey after each type of session. Variables were compared with signed-rank tests. Results: All 22 participants completed the IMI after both types of session. Perceived autonomy was significantly higher during extracurricular simulation (p<0.001), but intrinsic motivation, competence and relatedness were not. Intrinsic motivation correlated with autonomy (RS=0.57 and extracurricular simulation, ES=0.52), competence (RS=0.46 and ES=0.15) and relatedness (RS=0.51 and ES=0.64). The IMI subscales had good internal consistency (Cronbach's α=0.84, 0.90, 0.90 and 0.76 for intrinsic motivation, autonomy, competence and relatedness, respectively). Conclusions: Extracurricular sessions increased students' perceived autonomy, but they were highly intrinsically motivated in both settings. Further study is needed to understand the relationship between perceived autonomy and intrinsic motivation in medical education learning activities. The IMI shows promise as a measurement tool for this work.

Inspiring careers in STEM and healthcare fields through medical simulation embedded in high school science education.

The most effective ways to promote learning and inspire careers related to science, technology, engineering, and mathematics (STEM) remain elusive. To address this gap, we reviewed the literature and designed and implemented a high-fidelity, medical simulation-based Harvard Medical School MEDscience course, which was integrated into high school science classes through collaboration between medical school and K-12 faculty. The design was based largely on the literature on concepts and mechanisms of self-efficacy. A structured telephone survey was conducted with 30 program alumni from the inaugural school who were no longer in high school. Near-term effects, enduring effects, contextual considerations, and diffusion and dissemination were queried. Students reported high incoming attitudes toward STEM education and careers, and these attitudes showed before versus after gains (P < .05). Students in this modest sample overwhelmingly attributed elevated and enduring levels of impact on their interest and confidence in pursuing a science or healthcare-related career to the program. Additionally, 63% subsequently took additional science or health courses, 73% participated in a job or educational experience that was science related during high school, and 97% went on to college. Four of every five program graduates cited a health-related college major, and 83% offered their strongest recommendation of the program to others. Further study and evaluation of simulation-based experiences that capitalize on informal, naturalistic learning and promote self-efficacy are warranted.

How we implemented a resident-led medical simulation curriculum in a large internal medicine residency program.

Mannequin-based simulation in graduate medical education has gained widespread acceptance. Its use in non-procedural training within internal medicine (IM) remains scant, possibly due to the logistical barriers to implementation of simulation curricula in large residency programs. We report the Massachusetts General Hospital Department of Medicine's scale-up of a voluntary pilot program to a mandatory longitudinal simulation curriculum in a large IM residency program (n = 54). We utilized an eight-case curriculum implemented over the first four months of the academic year. An intensive care unit curriculum was piloted in the spring. In order to administer a comprehensive curriculum in a large residency program where faculty resources are limited, thirty second-year and third-year residents served as session facilitators and two senior residents served as chairpersons of the program. Post-session anonymous survey revealed high learner satisfaction scores for the mandatory program, similar to those of the voluntary pilot program. Most interns believed the sessions should continue to be mandatory. Utilizing residents as volunteer facilitators and program leaders allowed the implementation of a well-received mandatory simulation program in a large IM residency program and facilitated program sustainability.

Pilot testing of a model for insurer-driven, large-scale multicenter simulation training for operating room teams.

OBJECTIVE: To test the feasibility of implementing a standardized teamwork training program with full operating room teams in multiple institutions, driven by malpractice insurer support and incentives. BACKGROUND: Failures in intraoperative teamwork are among the leading causes of preventable patient injury and death in surgical patients. Teamwork training, particularly using simulation, can be an effective intervention but is difficult to scale. METHODS: A malpractice insurer convened a collaborative with 4 Harvard-affiliated simulation programs to develop a standardized operating room teamwork training curriculum, including principles of communication, assertiveness, and use of the World Health Organization Surgical Safety Checklist. Participant teams were compensated for lost operative time via malpractice premium discounts, continuing education credits, and compensation for lost wages. The course was delivered through a simulation program involving the management of intraoperative emergency scenarios. Participants were surveyed for their perceptions of the program and of its impact on clinical practice. RESULTS: A total of 221 active operating room staff members participated in the program. Each team contained at least 1 attending surgeon, 1 attending anesthesiologist, and 1 operating room nurse (mean size per team: 7 ± 2 participants). No study dates were cancelled because of lack of attendance. The survey response rate was 99% (218/221). Overall, the vast majority of participants found the scenarios realistic [94% (95% confidence interval: 90.9%, 97.2%)], appropriately challenging [95.4% (92.6%, 98.2%)], relevant to their practice [96.3% (93.8%, 98.8%)], and found the training would help them provide safer patient care [92.6% (89.1%, 96.1%)]. Surgeons reported their greatest personal deficit as communication skills. Operating room nurses and anesthesiologists reported a greater need than surgeons to work on personal assertiveness. CONCLUSIONS: A standardized multicenter team training program involving full operative teams is feasible with high-fidelity simulation and modest compensation for lost time. The vast majority of the multidisciplinary participants believed the course to have had a meaningful impact on their approach to clinical practice.

Reflections on the consensus process: a leadership role for emergency medicine in educational scholarship and practice across health care.

In just a few decades, emergency medicine (EM) has assumed a leadership role in medical education across many academic medical centers. This rapid evolution suggests medical education as a natural priority area for EM scholarship. This year's Academic Emergency Medicine consensus conference provides an ideal forum to focus on educational research as a core element of the specialty's academic portfolio.