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Abstract Background We present a compendium of N-ethyl-N-nitrosourea (ENU)-induced mouse mutations, identified in our laboratory over a period of 10 years either on the basis of phenotype or whole genome and/or whole exome sequencing, and archived in the Mutagenetix database. Our purpose is threefold: 1) to formally describe many point mutations, including those that were not previously disclosed in peer-reviewed publications; 2) to assess the characteristics of these mutations; and 3) to estimate the likelihood that a missense mutation induced by ENU will create a detectable phenotype. Findings In the context of an ENU mutagenesis program for C57BL/6J mice, a total of 185 phenotypes were tracked to mutations in 129 genes. In addition, 402 incidental mutations were identified and predicted to affect 390 genes. As previously reported, ENU shows strand asymmetry in its induction of mutations, particularly favoring T to A rather than A to T in the sense strand of coding regions and splice junctions. Some amino acid substitutions are far more likely to be damaging than others, and some are far more likely to be observed. Indeed, from among a total of 494 non-synonymous coding mutations, ENU was observed to create only 114 of the 182 possible amino acid substitutions that single base changes can achieve. Based on differences in overt null allele frequencies observed in phenotypic vs. non-phenotypic mutation sets, we infer that ENU-induced missense mutations create detectable phenotype only about 1 in 4.7 times. While the remaining mutations may not be functionally neutral, they are, on average, beneath the limits of detection of the phenotypic assays we applied. Conclusions Collectively, these mutations add to our understanding of the chemical specificity of ENU, the types of amino acid substitutions it creates, and its efficiency in causing phenovariance. Our data support the validity of computational algorithms for the prediction of damage caused by amino acid substitutions, and may lead to refined predictions as to whether specific amino acid changes are responsible for observed phenotypes. These data form the basis for closer in silico estimations of the number of genes mutated to a state of phenovariance by ENU within a population of G3 mice.

Objective: To characterize the association between number, timing, and type of Advanced Pharmacy Practice Experiences (APPEs) and likelihood of postgraduate year one (PGY1) residency match outcomes., Methods: A retrospective cohort study was performed among PGY1 residency-seeking pharmacy students from graduating years 2018-2021 as identified from the National Matching Services Inc. enrollee list. The number of APPEs of interest (AOI) most likely to align with general PGY1 residencies (acute care, ambulatory care, and elective rotations with significant direct patient care interactions) completed before January of the respective graduation year (GY) was compared between matched and unmatched students to a PGY1 program in any phase. Classification and regression tree (CART) analyses were performed to identify the AOI threshold associated with an increased likelihood of matching., Results: Among 155 students meeting inclusion criteria, 115 students (74%) matched during the study period. The probability of matching was 36%, 74%, and 83% for students completing two, three or four AOI, respectively. CART analyses identified three or more AOI completed prior to January of the GY as the threshold significantly associated with PGY1 residency matching., Conclusion: Completing at least three AOI before January of the GY was associated with a significantly increased probability of PGY1 residency matching. These findings may influence students' preferences for sequencing of APPEs to improve match results, but may be limited by institutional capacity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In response to the COVID-19 pandemic, most U.S. medical schools acutely transitioned from regimented in-person learning to highly flexible virtual asynchronous learning. This transition at our medical school provided a unique opportunity to evaluate if and how students adapted their academic and personal lives in response., Methods: Medical students in a single class that made this transition were retrospectively provided with 24-hour diaries for three periods - one shortly before the transition, a second early in the transition, and third several months into the transition - and asked to select the academic or personal activities done in each hour. The percentage of medical students performing each activity each hour was analyzed, as was the time spent on each activity per day, and per morning, afternoon, per evening within the day., Results: Overall study time did not change in either virtual period but shifted significantly to the morning (6 AM to 12 PM). Time spent studying in groups fell significantly during both virtual periods, concordant with a significant increase in alone study time in the early virtual period. Early in the transition to virtual learning, students replaced in-person didactics with online faculty lectures; several months later in virtual learning, they had replaced online faculty lectures with commercial products. There was no significant change in time spent on specific personal activities., Conclusions: Consistent with extensive constraints imposed by the heavy cognitive load of a medical school curriculum, students did not significantly change their overall study time and any self-care-related activities in the transition to virtual learning. However, transitioning to virtual learning allowed our students to adapt their study strategies, i.e. reducing group study time and increasing lone studying time. Furthermore, students shifted studying time to the morning to optimize the management of the cognitive task-load they faced.

This small-group activity provides two cases in cardiovascular pharmacology to engage students in a medical or other health professions curriculum. The goal of this activity is to apply students' basic knowledge of physiology and pharmacology to clinical case scenarios. Students were provided with the cases 1 week in advance and were encouraged to use their lecture notes and/or other references of their choosing to answer as many of the questions as possible and prepare to discuss the answers with their classmates at the session. Facilitators were provided with detailed notes and a video that explain the answers and provide suggestions for engaging and challenging the students. For the 2021 academic year, 201 students (139 first-year medical students and 62 second-year pharmacy students) at UC San Diego participated in the small-group activity. Eighteen facilitators were recruited to lead this 110-min session. Students' performance was assessed on the final exam of their integrated cardiovascular physiology-pharmacology course. Students achieved 84% (SD 17.54) on questions related to the small-group session compared to 78% (SD 15.60) on other cardiovascular pharmacology questions not related to the activity. Student perceptions of the facilitators leading the small-group activity were very positive (average of 4.7 on a 5-point Likert Scale). Using this approach, we demonstrate that a small-group activity with clinical scenarios helps students master the pharmacology content related to cardiovascular drugs. The small-group activity included constructed response questions to foster conceptual understanding., (© 2022 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

There is currently little guidance for medical school admissions committees regarding how to weigh postbaccalaureate program grades relative to undergraduate grades. This study was designed to address this issue. Admissions data, preclerkship course performance and United States Medical Licensing Exam (USMLE) Step 1 results were analyzed over three years for University of California, San Diego (UCSD) postbaccalaureate premedical (PBPM) students (n = 25), students who participated in other postbaccalaureate programs (n = 34), and for the remainder of the medical students who did not participate in any postbaccalaureate programs (n = 329). UCSD PBPM program alumni did not significantly differ in their cumulative academic performance on exams in preclerkship courses and USMLE Step 1 pass rates compared to the rest of the class despite their significantly lower GPA, lower Biology, Chemistry, Physics and Math (BCPM) GPA, and Medical College Admissions Test (MCAT) percentiles. For students who participated in the PBPM programs, PBPM program GPA was a significant predictor of preclerkship academic performance and USMLE Step 1 performance. When assessing academic readiness of applicants who have completed postbaccalaureate programs, admissions committees might closely consider the postbaccalaureate program GPA in addition to other academic metrices such as BCPM GPA and MCAT score., (© 2022. The Author(s).)

Doctor of Pharmacy (PharmD) students and faculty at University of California, San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences (SSPPS) were highly motivated to support local and regional COVID-19 vaccination efforts, which began in January 2021. A system was created to streamline requests for SSPPS volunteers, maximize opportunities for student learning and engagement, and ensure adherence to pharmacy practice standards and laws in the process of assisting with vaccination efforts in the community. An existing model for approving student organized events was modified to fit additional needs for COVID-19 vaccination efforts by SSPPS students and faculty. For each event, students completed a standardized form containing event details including location, date, time, pharmacist preceptors, and duties. All requests were screened by designated SSPPS faculty to ensure student safety, availability, and feasibility. After each event, students and faculty completed a unique online form designed to track volunteer hours. Students received course credit for volunteering and completing a standardized self-reflection. Comments from students' reflections ( n = 74) were analyzed to identify common challenges. Between 11 January 2021 and 31 May 2021, SSPPS faculty and students volunteered for 245 shifts, totaling 1346 h. Students encountered several logistical challenges, such as availability of vaccines. The system utilized allowed for SSPPS students and faculty to play an integral role in COVID-19 vaccination efforts throughout the region.

Complement receptor of immunoglobulin superfamily (CRIg) is expressed on liver macrophages and directly binds complement component C3b or Gram-positive bacteria to mediate phagocytosis. CRIg plays important roles in several immune-mediated diseases, but it is not clear how its pathogen recognition and phagocytic functions maintain homeostasis and prevent disease. We previously associated cytolysin-positive Enterococcus faecalis with severity of alcohol-related liver disease. Here, we demonstrate that CRIg is reduced in liver tissues from patients with alcohol-related liver disease. CRIg-deficient mice developed more severe ethanol-induced liver disease than wild-type mice; disease severity was reduced with loss of toll-like receptor 2. CRIg-deficient mice were less efficient than wild-type mice at clearing Gram-positive bacteria such as Enterococcus faecalis that had translocated from gut to liver. Administration of the soluble extracellular domain CRIg-Ig protein protected mice from ethanol-induced steatohepatitis. Our findings indicate that ethanol impairs hepatic clearance of translocated pathobionts, via decreased hepatic CRIg, which facilitates progression of liver disease., (© 2021. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: Sleep deprivation is associated with poor academic performance, although the impact on pharmacy students has been minimally reported. This study examined sleep quality in pharmacy students in the first (P1), second (P2), and third (P3) professional years during perceived low and high stress periods in a course. Individual sleep and environmental factors were also explored., Methods: This prospective cohort study used an 18-item survey adapted from the Pittsburgh Sleep Quality Index (PSQI) that included demographics, individual sleep components, and factors affecting sleep. Surveys were administered at the beginning of the quarter (low stress) and the week before final exams (high stress). Chi-square tests compared categorical variables; ANOVA/ANCOVA tests compared continuous variables., Results: During high stress, PSQI scores worsened among all classes and was significant for the P3s. Average sleep duration was 6.64 (SD 1.18) and 6.8 (SD 1.18) hours per night for P1s and P3s, respectively, at the beginning of the quarter; both groups had significant reduction in sleep duration at the end of the quarter. There were no significant correlations between PSQI and exam scores. Factors impacting sleep such as exercise, use of technology at bedtime, and work hours outside of school decreased during high times of stress, for P1s, P2s, and P3, respectively., Conclusions: Students demonstrated worsening sleep quality during high stress periods and less sleep than recommended. Academic performance was not adversely affected. Future research should use sleep logs and other performance measures to determine the impact of sleep quality on academic success and wellbeing., Competing Interests: Declaration of competing interest Dr. Lee is a consultant for Shire, Takeda Pharmaceuticals, Otsuka Pharmaceutical Co., Ltd, and TrueLearn., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality 1-3 . Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice 4 , but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin-a two-subunit exotoxin that is secreted by Enterococcus faecalis 5,6 -as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis.

Objective. To describe the revision of a pharmacology course series taught over three quarters within a Doctor of Pharmacy (PharmD) curriculum and assess changes in students' attitudes toward and performance after the revision. Methods. Based in part on students' dissatisfaction regarding a pharmacology course series, a course director was hired and tasked with teaching a major portion of the course content, rewriting course examinations, and facilitating active learning in the course series. Course evaluations and examination scores of students who completed the course series after the implementation of the redesigned curriculum (classes of 2015 and 2016) were assessed and compared with those of students who completed the course before the revisions were made (classes of 2013 and 2014). Results. Qualitative analysis of second-year pharmacy student evaluations identified a lack of integration and coordination within the pharmacology course sequence. Poor examination quality and the absence of active teaching methods were other frequently described shortcomings of the pharmacology curriculum. Course evaluations dramatically improved after shortcomings were addressed and students' performance in the subsequent therapeutics course also increased significantly. Conclusion. Adding additional structure to and oversight for a pharmacology course series by adding a course director improved student satisfaction with the course and improved performance in the subsequent therapeutics course. This study highlights the importance of a well-designed pharmacology curriculum for continued success in core courses in the PharmD curriculum., (© 2019 American Association of Colleges of Pharmacy.)

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that regulates glucose, lipid, and energy homeostasis. While gene expression of FGF21 is regulated by the nuclear hormone receptor peroxisome proliferator-activated receptor alpha in the fasted state, little is known about the regulation of trafficking and secretion of FGF21. We show that mice with a mutation in the Yip1 domain family, member 6 gene ( Klein - Zschocher [ KLZ ]; Yipf6 KLZ/Y ) on a high-fat diet (HFD) have higher plasma levels of FGF21 than mice that do not carry this mutation (controls) and hepatocytes from Yipf6 KLZ/Y mice secrete more FGF21 than hepatocytes from wild-type mice. Consequently, Yipf6 KLZ/Y mice are resistant to HFD-induced features of the metabolic syndrome and have increased lipolysis, energy expenditure, and thermogenesis, with an increase in core body temperature. Yipf6 KLZ/Y mice with hepatocyte-specific deletion of FGF21 were no longer protected from diet-induced obesity. We show that YIPF6 binds FGF21 in the endoplasmic reticulum to limit its secretion and specifies packaging of FGF21 into coat protein complex II (COPII) vesicles during development of obesity in mice. Levels of YIPF6 protein in human liver correlate with hepatic steatosis and correlate inversely with levels of FGF21 in serum from patients with nonalcoholic fatty liver disease (NAFLD). YIPF6 is therefore a newly identified regulator of FGF21 secretion during development of obesity and could be a target for treatment of obesity and NAFLD., Competing Interests: Conflict of interest statement: B.B. received salary support from Pfizer, Inc. B.S. is consulting for Ferring Research Institute.

Introduction and Background: In 2010, the UC San Diego School of Medicine launched a new curriculum, the integrated scientific curriculum. As part of this curricular redesign, the school instituted academic communities. This perspective article outlines our experience with the first 8 years of these academic communities., Single-Institution Experience: We initiated academic communities with the hope that this structure would cultivate enhanced student-student and student-faculty engagement, improve faculty-student mentoring, and create additional service-learning and student leadership opportunities. The communities would also provide an environment for small group learning throughout the 4-year curriculum. After 8 years of experience, a comparison of student survey data pre- and post establishment of academic communities demonstrated enhanced connectedness between students and faculty and higher scores for faculty mentoring and for career planning. Our own lived experience with the communities revealed several unanticipated outcomes. The community directors became a source of support and advice for one another. Some faculty and administrators whose previous roles were affected by start of the academic communities needed to adjust expectations., Conclusions: The establishment of academic communities was associated with improvement in student-faculty engagement, student assessment of faculty mentoring, and career planning., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Medical schools with a diverse student body face the challenge of ensuring that all students succeed academically. Many medical schools have implemented prematriculation programs to prepare students from diverse backgrounds; however, evidence on their impact is largely lacking. In this study, we analyzed participants' demographics as well as the impact of the prematriculation program on Year 1 performance. Predictive validity of the program was assessed and compared to other traditional predictors, including grade point average (GPA) and Medical College Admission Test (MCAT) scores and subscores. Linear mixed effect models determined the impact of the prematriculation program, and linear regression analysis assessed the predictive value of the overall score in the prematriculation program and other traditional predictors. Demographics of students participating in the prematriculation program from 2013 to 2015 (n = 75) revealed a significantly higher prevalence of academically disadvantaged students including older students, students with lower GPA and MCAT scores and students of racial and ethnic populations that are underrepresented in medicine, compared to non-participants (n = 293). Participants performed significantly better in Year 1 courses that were covered in the prematriculation program compared to courses that were not covered. The overall performance in the prematriculation program correlated significantly with Year 1 performance and was found to be a strong predictor for Year 1 performance. This study suggests that a prematriculation program can help students to succeed in the first year of medical school. The results have implications for medical schools seeking to implement or evaluate the effectiveness of their prematriculation program.

Background & Aims: The degree of cholestasis is an important disease driver in alcoholic hepatitis, a severe clinical condition that needs new biomarkers and targeted therapies. We aimed to identify the largely unknown mechanisms and biomarkers linked to cholestasis in alcoholic hepatitis., Methods: Herein, we analyzed a well characterized cohort of patients with alcoholic hepatitis and correlated clinical and histological parameters and outcomes with serum bile acids and fibroblast growth factor 19 (FGF19), a major regulator of bile acid synthesis., Results: We found that total and conjugated bile acids were significantly increased in patients with alcoholic hepatitis compared with controls. Serum FGF19 levels were strongly increased and gene expression of FGF19 was induced in biliary epithelial cells and ductular cells of patients with alcoholic hepatitis. De novo bile acid synthesis (CYP7A1 gene expression and C4 serum levels) was significantly decreased in patients with alcoholic hepatitis. Importantly, total and conjugated bile acids correlated positively with FGF19 and with disease severity (model for end-stage liver disease score). FGF19 correlated best with conjugated cholic acid, and model for end-stage liver disease score best with taurine-conjugated chenodeoxycholic acid. Univariate analysis demonstrated significant associations between FGF19 and bilirubin as well as gamma glutamyl transferase, and negative correlations between FGF19 and fibrosis stage as well as polymorphonuclear leukocyte infiltration, in all patients with alcoholic hepatitis., Conclusion: Serum FGF19 and bile acids are significantly increased in patients with alcoholic hepatitis, while de novo bile acid synthesis is suppressed. Modulation of bile acid metabolism or signaling could represent a promising target for treatment of alcoholic hepatitis in humans., Lay Summary: Understanding the underlying mechanisms that drive alcoholic hepatitis is important for the development of new biomarkers and targeted therapies. Herein, we describe a molecule that is increased in patients with alcoholic hepatitis. Modulating the molecular pathway of this molecule might lead to promising targets for the treatment of alcoholic hepatitis., (Published by Elsevier B.V.)

Seeded emulsion polymerizations of styrene are modeled on the basis of a detailed kinetic scheme accounting for the chain length and conversion dependence of termination rate coefficients. A holistic kinetic Monte Carlo approach was developed, which simulates the elemental reactions in the aqueous phase, the transfer of radicals into individual particles, and the radical polymerization in each particle based on a complete kinetic model. Experimentally-derived particle size distributions are used as input for the simulations. The required rate coefficients were taken from literature. Without any adjustment of this data a very good agreement between simulation results and experimental data is found. The validation of the model is performed based on monomer conversion - time data and full molar mass distributions.

In addition to online questionnaires, many medical schools use supplemental evaluation tools such as focus groups to evaluate their courses. Although some benefits of using focus groups in program evaluation have been described, it is unknown whether these in-person data collection methods provide sufficient additional information beyond online evaluations to justify them. In this study we analyze recommendations gathered from student evaluation team (SET) focus group meetings and analyzed whether these items were captured in open-ended comments within the online evaluations. Our results indicate that online evaluations captured only 49% of the recommendations identified via SETs. Surveys to course directors identified that 74% of the recommendations exclusively identified via the SETs were implemented within their courses. Our results indicate that SET meetings can provide information not easily captured in online evaluations and that these recommendations result in actual course changes.

Electrocatalysis for the oxygen evolution reaction (OER) is of great interest for improving the effectiveness of water splitting devices. Decreasing the anodic overpotential and simultaneously changing the anodic reaction selectively to produce valuable chemicals instead of O 2 would be a major improvement of the overall cost efficiency. Some amines, when present in aqueous electrolytes, were recently shown to change the selectivity of the anodic process to generate H 2 O 2 rather than O 2 on MnO x at pH 10. This results in unusually high apparent "anodic activities". In this work, industrially relevant OER catalysts, oxyhydroxides of cobalt (CoO x ), nickel-iron (NiFeO x ), and nickel (NiO x ) all show more pronounced effects. Moreover, as anodes they also selectively catalyzed the production of nbutyronitrile from n-butylamine at higher pH as an easily retrievable valuable product. The pH dependence of the activity was investigated at pH values closer those at which alkaline electrolyzers operate. The highest activities were observed for NiO x thin-film electrodes at pH 12 in the presence of 0.4 m n-butylammonium sulfate, without poisoning the active sites of Pt electrocatalysts at the hydrogen evolution electrode. 1 H NMR spectroscopy showed that n-butylamine is selectively oxidized to n-butyronitrile, an organic chemical with numerous applications. However, measurements using rotating ring-disk electrodes indicated that some H 2 O 2 is also generated at the surface of the oxide anodes., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The University of California, San Diego, School of Medicine implemented a curriculum change that included reduction of lectures, incorporation of problem-based learning and other small group activities. Six academic communities were introduced for teaching longitudinal curricular content and organizing extracurricular activities., Methods: Surveys were collected from 904 first- and second-year medical students over 6 years. Student satisfaction data with their sense of connectedness and community support were collected before and after the implementation of the new curriculum. In a follow-up survey, medical students rated factors that contributed to their sense of connectedness with faculty and students (n = 134)., Results: Students' perception of connectedness to faculty significantly increased following implementation of a curriculum change that included academic communities. Students ranked small group clinical skills activities within academic communities significantly higher than other activities concerning their sense of connectedness with faculty. Students' perception of connectedness among each other was high at baseline and did not significantly change. Small group activities scored higher than extracurricular activities regarding students' connectedness among themselves., Conclusions: The implementation of a new curriculum with more small group educational activities including academic communities enhanced connectedness between students and faculty and resulted in an increased sense of community.

Liver and intestine are tightly linked through the venous system of the portal circulation. Consequently, the liver is the primary recipient of gut-derived products, most prominently dietary nutrients and microbial components. It functions as a secondary "firewall" and protects the body from intestinal pathogens and other microbial products that have crossed the primary barrier of the intestinal tract. Disruption of the intestinal barrier enhances microbial exposure of the liver, which can have detrimental or beneficial effects in the organ depending on the specific circumstances. Conversely, the liver also exerts influence over intestinal microbial communities via secretion of bile acids and IgA antibodies. This mini-review highlights key findings and concepts in the area of host-microbial interactions as pertinent to the bilateral communication between liver and gut and highlights the concept of the gut-liver axis., (Copyright © 2017 the American Physiological Society.)

Purpose of Review: Nonalcoholic fatty liver disease (NAFLD) is a liver disease with high prevalence in western countries. Progression from NAFLD to nonalcoholic steatohepatitis (NASH) occurs in 10-20%. NASH pathogenesis is multifactorial including genetic and environmental factors. The gut microbiota is involved in disease progression and its role is complex., Recent Findings: NASH is associated with changes in the intestinal microbiota, although findings in recent studies are inconsistent. Dysbiosis can trigger intestinal inflammation and impair the gut barrier. Microbial products can now reach the liver, induce hepatic inflammation and contribute to NAFLD and NASH progression. As the gut microbiota is also involved in the regulation of metabolic pathways, metabolomic approaches identified unique metabolomic profiles in patients with NASH. Altered metabolite patterns can serve as biomarkers, whereas specific metabolites (such as ethanol) have been linked with disease progression. Modifying metabolic profiles might serve as new therapeutic microbiome-based approaches., Summary: In this review, we will highlight findings from the recent literature important to the gut-liver axis. We will predominantly focus on human studies with NASH.