Muscle cofilin alters neuromuscular junction postsynaptic development to strengthen functional neurotransmission.

Cofilin, an actin-severing protein, plays key roles in muscle sarcomere addition and maintenance. Our previous work found that Drosophila cofilin (DmCFL) knockdown in muscle causes progressive deterioration of muscle structure and function and produces features seen in nemaline myopathy caused by cofilin mutations. We hypothesized that disruption of actin cytoskeleton dynamics by DmCFL knockdown would impact other aspects of muscle development, and, thus, conducted an RNA-sequencing analysis that unexpectedly revealed upregulated expression of numerous neuromuscular junction (NMJ) genes. We found that DmCFL is enriched in the muscle postsynaptic compartment and that DmCFL muscle knockdown causes F-actin disorganization in this subcellular domain prior to the sarcomere defects observed later in development. Despite NMJ gene expression changes, we found no significant changes in gross presynaptic Bruchpilot active zones or total postsynaptic glutamate receptor levels. However, DmCFL knockdown resulted in mislocalization of GluRIIA class glutamate receptors in more deteriorated muscles and strongly impaired NMJ transmission strength. These findings expand our understanding of the roles of cofilin in muscle to include NMJ structural development and suggest that NMJ defects may contribute to the pathophysiology of nemaline myopathy.

Impact of COVID-19 pandemic on physician-scientist trainees to faculty one year into the pandemic.

PURPOSE: Physician-scientists play a crucial role in advancing biomedical sciences. Proportionally fewer physicians are actively engaged in scientific pursuits, attributed to attrition in the training and retention pipeline. This national study evaluated the ongoing and longer-term impact of the COVID-19 pandemic on stress levels, research productivity, and optimism for physician-scientists at all levels of training. METHODS: A multi-institutional cross-sectional survey of medical students, graduate students, and residents/fellows/junior faculty (RFJF) was conducted from April to August 2021 to assess the impact of COVID-19 on individual stress, productivity, and optimism. Multivariate regression analyses were performed to identify associated variables and unsupervised variable clustering techniques were employed to identify highly correlated responses. RESULTS: A total 677 respondents completed the survey, representing different stages of physician-scientist training. Respondents report high levels of stress (medical students: 85%, graduate students: 63%, RFJF: 85%) attributed to impaired productivity concerns, concern about health of family and friends, impact on personal health and impairment in training or career development. Many cited impaired productivity (medical students: 65% graduate students: 79%, RFJF: 78%) associated with pandemic impacts on training, labs closures and loss of facility/resource access, and social isolation. Optimism levels were low (medical students: 37%, graduate students: 38% and RFJF: 39%) with females less likely to be optimistic and more likely to report concerns of long-term effects of COVID-19. Optimism about the future was correlated with not worrying about the long-term effects of COVID-19. Since the COVID-19 pandemic, all respondents reported increased prioritization of time with family/friends (67%) and personal health (62%) over career (25%) and research (24%). CONCLUSIONS: This national survey highlights the significant and protracted impact of the COVID-19 pandemic on stress levels, productivity, and optimism among physician-scientists and trainees. These findings underscore the urgent need for tailored support, including mental health, academic, and career development assistance for this biomedical workforce.

Sociodemographic factors and research experience impact MD-PhD program acceptance.

The 2014 NIH Physician-Scientist Workforce Working Group predicted a future shortage of physician-scientists. Subsequent studies have highlighted disparities in MD-PhD admissions based on race, income, and education. Our analysis of data from the Association of American Medical Colleges covering 2014-2021 (15,156 applicants and 6,840 acceptees) revealed that acceptance into US MD-PhD programs correlates with research experience, family income, and research publications. The number of research experiences associated with parental education and family income. Applicants were more likely to be accepted with a family income greater than $50,000 or with one or more publications or presentations. Applicants were less likely to be accepted if they had parents without a graduate degree, were Black/African American, were first-generation college students, or were reapplicants, irrespective of the number of research experiences, publications, or presentations. These findings underscore an admissions bias that favors candidates from affluent and highly educated families, while disadvantaging underrepresented minorities.

Cooperation between Nodal and FGF signals regulates zebrafish cardiac cell migration and heart morphogenesis.

Asymmetric vertebrate heart development is driven by an intricate sequence of morphogenetic cell movements, the coordination of which requires precise interpretation of signaling cues by heart primordia. Here we show that Nodal functions cooperatively with FGF during heart tube formation and asymmetric placement. Both pathways act as migratory stimuli for cardiac progenitor cells (CPCs), but FGF is dispensable for directing heart tube asymmetry, which is governed by Nodal. We further find that Nodal controls CPC migration by inducing left-right asymmetries in the formation of actin-based protrusions in CPCs. Additionally, we define a developmental window in which FGF signals are required for proper heart looping and show cooperativity between FGF and Nodal in this process. We present evidence FGF may promote heart looping through addition of the secondary heart field. Finally, we demonstrate that loss of FGF signaling affects proper development of the atrioventricular canal (AVC), which likely contributes to abnormal chamber morphologies in FGF-deficient hearts. Together, our data shed insight into how the spatiotemporal dynamics of signaling cues regulate the cellular behaviors underlying organ morphogenesis.

Latinas in medicine: evaluating and understanding the experience of Latinas in medical education: a cross sectional survey.

BACKGROUND: The percentage of physicians identifying as Latina has not improved despite improvements in recruitment of Latina medical students, suggesting barriers to retention and career advancement. Discriminatory experiences and mental health inflictions throughout training may contribute to difficulties in recruitment, retainment, and advancement of Hispanic/Latinx trainees, a notably understudied population. METHODS: An anonymous, online survey was distributed to Latinas in the continental U.S. between June 22 to August 12, 2022. Eligibility criteria included: self-identifying as Hispanic/Latina, female/woman, and completing or have completed medical school, residency, or fellowship in the continental U.S. in the past 10 years. Recruitment was done via the Twitter account @LatinasInMed and outreach to Latino Medical Student Association chapters. Descriptive statistics summarized the self-reported experiences. RESULTS: The survey included 230 Hispanic/Latinx women, mostly medical students (46.9%). A majority (54.5%) reported negative ethnicity-based interactions from patients and/or patients' families; 71.8%, from others in the medical field. High rates of depression (76.2%) and anxiety (92.6%) during training were reported by Latinas, especially medical students. Feelings of imposter syndrome and burnout were high at 90.7% and 87.4%, respectively. CONCLUSIONS: This is the first study evaluating the unique experiences of Latinas in medicine, who reported discrimination and mental health struggles, specifically during medical school, at alarmingly high rates. Our findings could aid in creating the needed interventions to support Latinas in medical training to reduce the existing exodus of Latinas from medicine.

Muscle cofilin alters neuromuscular junction postsynaptic development to strengthen functional neurotransmission.

Cofilin, an actin severing protein, plays critical roles in muscle sarcomere addition and maintenance. Our previous work has shown Drosophila cofilin (DmCFL) knockdown causes progressive deterioration of muscle structure and function and produces features seen in nemaline myopathy (NM) caused by cofilin mutations. We hypothesized that disruption of actin cytoskeleton dynamics by DmCFL knockdown would impact other aspects of muscle development, and, thus, conducted an RNA sequencing analysis which unexpectedly revealed upregulated expression of numerous neuromuscular junction (NMJ) genes. We found that DmCFL is enriched in the muscle postsynaptic compartment and that DmCFL deficiency causes F-actin disorganization in this subcellular domain prior to the sarcomere defects observed later in development. Despite NMJ gene expression changes, we found no significant changes in gross presynaptic Bruchpilot active zones or total postsynaptic glutamate receptor levels. However, DmCFL knockdown results in mislocalization of glutamate receptors containing the GluRIIA subunit in more deteriorated muscles and neurotransmission strength is strongly impaired. These findings expand our understanding of cofilin's roles in muscle to include NMJ structural development and suggest that NMJ defects may contribute to NM pathophysiology.

Impact of COVID-19 Pandemic on Physician-Scientist Trainees to Faculty One Year into the Pandemic.

Purpose: Physician-scientists play a crucial role in advancing biomedical sciences. Proportionally fewer physicians are actively engaged in scientific pursuits, attributed to attrition in the training and retention pipeline. This national study evaluated the ongoing and longer-term impact of the COVID-19 pandemic on research productivity for physician-scientists at all levels of training. Methods: A survey of medical students, graduate students, and residents/fellows/junior faculty (RFJF) was conducted from April to August 2021 to assess the impact of COVID-19 on individual stress, productivity, and optimism. Multivariate regression analyses were performed to identify associated variables and unsupervised variable clustering techniques were employed to identify highly correlated responses. Results: A total 677 respondents completed the survey, representing different stages of physician-scientist training. Respondents report high levels of stress (medical students: 85%, graduate students: 63%, RFJF: 85%) attributed to impaired productivity concerns, concern about health of family and friends, impact on personal health and impairment in training or career development. Many cited impaired productivity (medical students: 65% graduate students: 79%, RFJF: 78%) associated with pandemic impacts on training, labs closures and loss of facility/resource access, and social isolation. Optimism levels were low (medical students: 37%, graduate students: 38% and RFJF: 39%) with females less likely to be optimistic and more likely to report concerns of long-term effects of COVID-19. Optimism about the future was correlated with not worrying about the long-term effects of COVID-19. Since the COVID-19 pandemic, all respondents reported increased prioritization of time with family/friends (67%) and personal health (62%) over career (25%) and research (24%). Conclusions: This national survey highlights the significant and protracted impact of the COVID-19 pandemic on stress levels, productivity, and optimism among physician-scientists and trainees. These findings underscore the urgent need for tailored support, including mental health, academic, and career development assistance for this biomedical workforce.

Interventions Associated With Racial and Ethnic Diversity in US Graduate Medical Education: A Scoping Review.

Importance: Racially and ethnically minoritized individuals remain underrepresented in graduate medical education relative to their proportion in the population. While many programs and initiatives have been developed to address this problem, there is little consensus regarding strategies that work to improve representation across specialties. Objective: To examine and synthesize evidence-based practices that have been used to increase the proportions of underrepresented in medicine (URiM) trainees at US residency and fellowship programs. Evidence Review: The authors searched PubMed, Google Scholar, Embase, PsycInfo, ERIC, Cochrane Reviews, Cochrane Trials, CINAHL, Scopus, and PROSPERO electronic databases to identify relevant studies published through January 2022. They screened all titles and abstracts for relevance and read full-text articles to identify articles reporting reliable data describing the outcomes of interventions to improve racial and ethnic diversity among trainees. Findings: Twenty-seven articles were included in this review. Two studies reported on fellowship programs. The most common interventions included holistic review (48%), decreased emphasis on United States Medical Licensing Examination Step 1 scores (48%), and explicit institutional messaging regarding the importance of diversity (37%). A combination of interventions was associated with an increased number of URiM applicants, interviewees, and matriculants across various medical and surgical specialties. Conclusions and Relevance: In this scoping review, approaches and interventions associated with increased diversity in residency and fellowship programs were identified. Continued efforts are necessary to sustain such efforts and assess long-term outcomes.

The Virtual Summer Research Program: supporting future physician-scientists from underrepresented backgrounds.

Introduction: Physician-scientist training programs expect applicants to have had extensive research experience prior to applying. Even at the best of times, this leaves individuals from underserved and underrepresented backgrounds at a competitive disadvantage, especially those remote from major academic centers. The COVID-19 pandemic exacerbated that disadvantage by closing research laboratories and suspending summer research opportunities. Methods: The Virtual Summer Research Program (VSRP) was designed to combat this shortfall by helping participating students become better informed and better prepared for applying to MD/DO-PhD programs. 156 participants were recruited from historically black colleges and universities and from national organizations for underrepresented trainees. Participants were paired with medical school faculty members and current MD/DO-PhD students from 35 participating institutions. The program lasted for at least 4 weeks and included a short research project, interactive sessions, journal clubs, social events, and attendance at a regional American Physician Scientists Association conference. Results: In follow-up surveys, participants reported improvements in their science-related skills and in their confidence in becoming a physician-scientist, applying to training programs, and navigating mentorship relationships. A follow-up study completed one year later indicated that participants felt they had benefited from an enhanced skill set, long-term relationships with their mentors, and connections to the physician-scientist community at large. Discussion: The results suggest that VSRP met its primary goals, which were to provide a diverse group of trainees with mentors, provide skills and resources for MD/DO-PhD application and matriculation and to support the development of longitudinal relationships between VSRP mentees and APSA. VSRP provides an approach that can be applied at an even larger scale when the constraints caused by a global pandemic have lifted.

The Impact of COVID-19 on Physician-Scientist Trainees and Faculty in the United States: A National Survey.

PURPOSE: Physician-scientists have long been considered an endangered species, and their extended training pathway is vulnerable to disruptions. This study investigated the effects of COVID-19-related challenges on the personal lives, career activities, stress levels, and research productivity of physician-scientist trainees and faculty. METHOD: The authors surveyed medical students (MS), graduate students (GS), residents/fellows (R/F), and faculty (F) using a tool distributed to 120 U.S. institutions with MD-PhD programs in April-June 2020. Chi-square and Fisher's exact tests were used to compare differences between groups. Machine learning was employed to select variables for multivariate logistic regression analyses aimed at identifying factors associated with stress and impaired productivity. RESULTS: The analyses included 1,929 respondents (MS: n = 679, 35%; GS: n = 676, 35%; R/F: n = 274, 14%; F: n = 300, 16%). All cohorts reported high levels of social isolation, stress from effects of the pandemic, and negative impacts on productivity. R/F and F respondents were more likely than MS and GS respondents to report financial difficulties due to COVID-19. R/F and F respondents with a dual degree expressed more impaired productivity compared with those without a dual degree. Multivariate regression analyses identified impacted research/scholarly activities, financial difficulties, and social isolation as predictors of stress and impaired productivity for both MS and GS cohorts. For both R/F and F cohorts, impacted personal life and research productivity were associated with stress, while dual-degree status, impacted research/scholarly activities, and impacted personal life were predictors of impaired productivity. More female than male respondents reported increased demands at home. CONCLUSIONS: This national survey of physician-scientist trainees and faculty found a high incidence of stress and impaired productivity related to the COVID-19 pandemic. Understanding the challenges faced and their consequences may improve efforts to support the physician-scientist workforce in the postpandemic period.

Social Media: Flattening Hierarchies for Women and Black, Indigenous, People Of Color (BIPOC) to Enter the Room Where It Happens.

Social media platforms are widely used to connect people across multiple settings, including country of origin, profession, race/ethnicity, sexual orientation, gender identity, seniority, and training. Groups that have been marginalized or historically excluded from decision-making encounters may lack formal mentors/sponsors because of a lack of representation of women and Black, Indigenous, People Of Color (BIPOC) in senior leadership positions. This can serve as a barrier to professional advancement at all stages of career development. Identifying and connecting with these potential mentors/sponsors outside of one's institutional space can be challenging. For this reason, leveraging social media to develop these professional relationships through flattened hierarchies can allow for professional networking beyond traditional mechanisms. Here we aim to describe how individuals can connect through social media to advance their careers and scientific and clinical expertise, advocate for communities, and provide high-quality communication to the public.

Pediatric Nemaline Myopathy: A Systematic Review Using Individual Patient Data.

Nemaline myopathy is a skeletal muscle disease that affects 1 in 50 000 live births. The objective of this study was to develop a narrative synthesis of the findings of a systematic review of the latest case descriptions of patients with NM. A systematic search of MEDLINE, Embase, CINAHL, Web of Science, and Scopus was performed using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines using the keywords pediatric, child, NM, nemaline rod, and rod myopathy. Case studies focused on pediatric NM and published in English between January 1, 2010, and December 31, 2020, in order to represent the most recent findings. Information was collected about the age of first signs, earliest presenting neuromuscular signs and symptoms, systems affected, progression, death, pathologic description, and genetic changes. Of a total of 385 records, 55 case reports or series were reviewed, covering 101 pediatric patients from 23 countries. We review varying presentations in children ranging in severity despite being caused by the same mutation, in addition to current and future clinical considerations relevant to the care of patients with NM. This review synthesizes genetic, histopathologic, and disease presentation findings from pediatric NM case reports. These data strengthen our understanding of the wide spectrum of disease seen in NM. Future studies are needed to identify the underlying molecular mechanism of pathology, to improve diagnostics, and to develop better methods to improve the quality of life for these patients.

Trends in clinical presentation of children with COVID-19: a systematic review of individual participant data.

BACKGROUND: There are sparse patient-level data available for children with novel coronavirus disease (COVID-19). Therefore, there is an urgent need for an updated systematic literature review that analyzes individual children rather than aggregated data in broad age groups. METHODS: Six databases (MEDLINE, Scopus, Web of Science, CINAHL, Google Scholar, medRxiv) were searched for studies indexed from January 1 to May 15, 2020, with MeSH terms: children, pediatrics, COVID-19, SARS-CoV-2. 1241 records were identified, of which only unique papers in English with individual patient information and documented COVID-19 testing were included. This review of 22 eligible studies followed Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data guidelines. RESULTS: A total of 123 patients from five countries were identified. 46% were females. The median age was 5 years (IQR = 8). At presentation, 62% had a fever, 32% had a cough, 58% had a single symptom, and 21% were asymptomatic. Abnormal chest imaging was seen in 62% (65/105) of imaged and 76.9% (20/26) of asymptomatic children. A minority of children had elevated platelets, CRP, lactate dehydrogenase, and D-dimer. CONCLUSION: Data from this independent participant data systematic review revealed that the majority of children with COVID-19 presented with either no symptoms or a single, non-respiratory symptom. IMPACT: This systematic review revealed that the majority of children with COVID-19 presented with either no symptoms or a single, non-respiratory symptom. By using an independent participant data approach, this analysis underscores the challenge of diagnosing COVID-19 in pediatric patients due to the wide variety of symptoms and seemingly poor correlation of imaging findings with symptomatic disease. The data presented from individual patients from case series or cohort studies add more granularity to the current description of pediatric COVID-19.

The Role and Impact of Social Media in Cardio-oncology During the COVID-19 Pandemic.

PURPOSE OF REVIEW: To give an overview of the role of social media (SoMe) in cardio-oncology during the COVID-19 pandemic. RECENT FINDINGS: SoMe has been critical in fostering education, outreach, awareness, collaboration, dissemination of information, and advocacy in cardio-oncology. This has become increasingly evident during the COVID-19 pandemic, during which SoMe has helped share best practices, community, and research focused on the impact of COVID-19 in cardiology and hematology/oncology, with cardio-oncology at the interface of these two subspecialty fields. A strength of SoMe is the ability to amplify a message in real-time, globally, with minimal investment of resources. This has been particularly beneficial for the emerging field of cardio-hematology/cardio-oncology, a field focused on the interplay of cancer and cardiovascular disease. SoMe field especially during the COVID-19 pandemic. We illustrate how social media has supported innovation (including telemedicine), amplification of healthcare workers' voice, and illumination of pre-existing and continued health disparities within the field of cardio-oncology during the pandemic.