Commitment to inclusion: The importance of collaboration in gender equity work.

Despite decades of faculty professional development programs created to prepare women for leadership, gender inequities persist in salary, promotion, and leadership roles. Indeed, men still earn more than women, are more likely than women to hold the rank of professor, and hold the vast majority of positions of power in academic medicine. Institutions demonstrate commitment to their faculty's growth by investing resources, including creating faculty development programs. These programs are essential to help prepare women to lead and navigate the highly matrixed, complex systems of academic medicine. However, data still show that women persistently lag behind men in their career advancement and salary. Clearly, training women to adapt to existing structures and norms alone is not sufficient. To effectively generate organizational change, leaders with power and resources must commit to gender equity. This article describes several efforts by the Office of Faculty in the Johns Hopkins University School of Medicine to broaden inclusivity in collaborative work for gender equity. The authors are women and men leaders in the Office of Faculty, which is within the Johns Hopkins University School of Medicine dean's office and includes Women in Science and Medicine. Here, we discuss potential methods to advance gender equity using inclusivity based on our institutional experience and on the findings of other studies. Ongoing data collection to evaluate programmatic outcomes in the Johns Hopkins University School of Medicine will be reported in the future.

Bone-marrow-homing lipid nanoparticles for genome editing in diseased and malignant haematopoietic stem cells.

Therapeutic genome editing of haematopoietic stem cells (HSCs) would provide long-lasting treatments for multiple diseases. However, the in vivo delivery of genetic medicines to HSCs remains challenging, especially in diseased and malignant settings. Here we report on a series of bone-marrow-homing lipid nanoparticles that deliver mRNA to a broad group of at least 14 unique cell types in the bone marrow, including healthy and diseased HSCs, leukaemic stem cells, B cells, T cells, macrophages and leukaemia cells. CRISPR/Cas and base editing is achieved in a mouse model expressing human sickle cell disease phenotypes for potential foetal haemoglobin reactivation and conversion from sickle to non-sickle alleles. Bone-marrow-homing lipid nanoparticles were also able to achieve Cre-recombinase-mediated genetic deletion in bone-marrow-engrafted leukaemic stem cells and leukaemia cells. We show evidence that diverse cell types in the bone marrow niche can be edited using bone-marrow-homing lipid nanoparticles.

Cascade genetic testing for hereditary cancer syndromes: a review of barriers and breakthroughs.

Germline genetic sequencing is now at the forefront of cancer treatment and preventative medicine. Cascade genetic testing, or the testing of at-risk relatives, is extremely promising as it offers genetic testing and potentially life-saving risk-reduction strategies to a population exponentially enriched for the risk of carrying a cancer-associated pathogenic variant. However, many relatives do not complete cascade testing due to barriers that span individual, relationship, healthcare community, and societal/policy domains. We have reviewed the published research on cascade testing. Our aim is to evaluate barriers to cascade genetic testing for hereditary cancer syndromes and explore strategies to mitigate these barriers, with the goal of promoting increased uptake of cascade genetic testing.

Staying Virtual: A Survey Study of the Virtual Lecture Experience in Academic Medicine.

BACKGROUND: Increasing clinical demands can adversely impact academic advancement, including the ability to deliver lectures and disseminate scholarly work. The virtual lecture platform became mainstream during the height of the coronavirus-19 pandemic. Lessons learned from this period may offer insight into supporting academic productivity among physicians who must balance multiple demands, including high clinical workloads and family care responsibilities. We evaluated perceptions on delivering virtual lectures to determine whether virtual venues merit continuation beyond the pandemic's initial phase and whether these perceptions differ by gender and rank. METHODS: In a survey study, faculty who spoke in 1 of 3 virtual lecture programs in the Departments of Anesthesiology and Critical Care Medicine, Otolaryngology, and Radiology at a university hospital in 2020 to 2022 were queried about their experience. Speakers' motivations to lecture virtually and the perceived advantages and disadvantages of virtual and in-person lectures were analyzed using descriptive statistics and qualitative analyses. RESULTS: Seventy-two of 95 (76%) faculty members responded (40% women, 38% men, and 22% gender undisclosed). Virtual lectures supported the speakers "a lot" to "extremely" with the following goals: enhancing one's reputation and credibility (76%), networking (70%), receiving feedback (63%), and advancing prospects for promotion (59%). Virtual programs also increased the speakers' sense of accomplishment (70%) and professional optimism (61%) by at least "a lot," including instructors and assistant professors who previously had difficulty obtaining invitations to speak outside their institution. Many respondents had declined prior invitations to speak in-person due to clinical workload (66%) and family care responsibilities (58%). Previous opportunities to lecture in-person were also refused due to finances (39%), teaching (26%), and research (19%) requirements, personal medical conditions or disabilities (9%), and religious obligations (5%). Promotion was a stronger motivating factor to lecture virtually for instructors and assistant professors than for associate and full professors. By contrast, disseminating work and ideas was a stronger motivator for associate and full professors. Associate and full professors also reported greater improvement in work-related well-being than earlier career faculty from the virtual lecture experience. Very few differences were found by gender. CONCLUSIONS: Virtual lecture programs support faculty who might not otherwise have the opportunity to lecture in-person due to multiple constraints. To increase the dissemination of scholarly work and expand opportunities to all faculty, virtual lectures should continue even as in-person venues are reestablished.

Allied Health Clinicians' Uptake of Evidence in Stroke Rehabilitation: A Systematic Review of Determinants Targeted in Implementation Studies.

OBJECTIVE: This study aimed to determine whether targeting specific implementation determinants is associated with allied health clinicians' uptake of evidence when implemented within stroke rehabilitation settings. DATA SOURCES: 7 key databases were searched to identify articles published between 1990 and 2022 for inclusion. Reference lists of relevant articles were hand searched. STUDY SELECTION: Studies were independently screened by 2 authors and included if the implementation intervention targeted allied health clinical practice in any stroke rehabilitation context and reported at least 1 quantitative measure of evidence uptake. Thirty studies met inclusion criteria. DATA EXTRACTION: Data were independently extracted by the first and second author. Implementation outcomes for each study were categorized as either mostly successful, partially successful, or not successful based on the degree of evidence uptake achieved. Determinants targeted were categorized using the Consolidated Framework for Implementation Research (CFIR). DATA SYNTHESIS: Patterns between the degree of evidence uptake and determinants targeted across studies were analyzed by the first and second authors in 1 of 3 groups: A (pre-post statistical analysis), B (pre-post descriptive analysis), or C (post-only descriptive analysis). Patterns between evidence uptake and determinants targeted were first identified within groups A and B, with group C consulted to support findings. All studies categorized as "mostly successful" targeted facilitation in combination with establishing face-to-face networks and communication strategies. Conversely, no studies rated "not successful" targeted either of these determinants. Studies rated "partially successful" targeted either 1, but seldom both, of these determinants. CONCLUSIONS: This review has provided descriptive evidence of determinants which may be important to target for allied health clinicians' uptake of evidence within stroke rehabilitation settings.

Gender Bias and Ophthalmology Accreditation Council for Graduate Medical Education Milestones Evaluations.

Importance: Women remain underrepresented in ophthalmology and gender-based disparities exist in salary, grant receipt, publication rates, and surgical volume throughout training and in practice. Although studies in emergency medicine and general surgery showed mixed findings regarding gender differences in Accreditation Council for Graduate Medical Education (ACGME) Milestones ratings, limited data exist examining such differences within ophthalmology. Objective: To examine gender differences in ophthalmology ACGME Milestones. Design, Setting, and Participants: This was a retrospective cross-sectional study of postgraduate year 4 (PGY-4) residents from 120 ophthalmology programs graduating in 2019. Main Outcomes and Measures: PGY-4 midyear and year-end medical knowledge (MK) and patient care (PC) ratings and Written Qualifying Examination (WQE) scaled scores for residents graduating in 2019 were included. Differential prediction techniques using Generalized Estimating Equations models were performed to identify differences by gender. Results: Of 452 residents (median [IQR] age, 30.0 [29.0-32.0] years), 275 (61%) identified as men and 177 (39%) as women. There were no differences in PC domain average between women and men for both midyear (-0.07; 95% CI, -0.11 to 0; P =.06) and year-end (-0.04; 95% CI, -0.07 to 0.03; P =.51) assessment periods. For the MK domain average in the midyear assessment period, women (mean [SD], 3.76 [0.50]) were rated lower than men (mean [SD], 3.88 [0.47]; P = .006) with a difference in mean of -0.12 (95% CI, -0.18 to -0.03). For the year-end assessment, however, the average MK ratings were not different for women (mean [SD], 4.10 [0.47]) compared with men (mean [SD], 4.18 [0.47]; P = .20) with a difference in mean of -0.08 (95% CI, -0.13 to 0.03). Conclusions and Relevance: Results suggest that ACGME ophthalmology Milestones in 2 general competencies did not demonstrate major gender bias on a national level at the time of graduation. There were, however, differences in MK ratings at the midyear mark, and as low ratings on evaluations and examinations may adversely affect career opportunities for trainees, it is important to continue further work examining other competencies or performance measures for potential biases.

Potent and uniform fetal hemoglobin induction via base editing.

Inducing fetal hemoglobin (HbF) in red blood cells can alleviate ß-thalassemia and sickle cell disease. We compared five strategies in CD34+ hematopoietic stem and progenitor cells, using either Cas9 nuclease or adenine base editors. The most potent modification was adenine base editor generation of γ-globin -175A>G. Homozygous -175A>G edited erythroid colonies expressed 81 ± 7% HbF versus 17 ± 11% in unedited controls, whereas HbF levels were lower and more variable for two Cas9 strategies targeting a BCL11A binding motif in the γ-globin promoter or a BCL11A erythroid enhancer. The -175A>G base edit also induced HbF more potently than a Cas9 approach in red blood cells generated after transplantation of CD34+ hematopoietic stem and progenitor cells into mice. Our data suggest a strategy for potent, uniform induction of HbF and provide insights into γ-globin gene regulation. More generally, we demonstrate that diverse indels generated by Cas9 can cause unexpected phenotypic variation that can be circumvented by base editing.

Ex vivo prime editing of patient haematopoietic stem cells rescues sickle-cell disease phenotypes after engraftment in mice.

Sickle-cell disease (SCD) is caused by an A·T-to-T·A transversion mutation in the ß-globin gene (HBB). Here we show that prime editing can correct the SCD allele (HBBS) to wild type (HBBA) at frequencies of 15%-41% in haematopoietic stem and progenitor cells (HSPCs) from patients with SCD. Seventeen weeks after transplantation into immunodeficient mice, prime-edited SCD HSPCs maintained HBBA levels and displayed engraftment frequencies, haematopoietic differentiation and lineage maturation similar to those of unedited HSPCs from healthy donors. An average of 42% of human erythroblasts and reticulocytes isolated 17 weeks after transplantation of prime-edited HSPCs from four SCD patient donors expressed HBBA, exceeding the levels predicted for therapeutic benefit. HSPC-derived erythrocytes carried less sickle haemoglobin, contained HBBA-derived adult haemoglobin at 28%-43% of normal levels and resisted hypoxia-induced sickling. Minimal off-target editing was detected at over 100 sites nominated experimentally via unbiased genome-wide analysis. Our findings support the feasibility of a one-time prime editing SCD treatment that corrects HBBS to HBBA, does not require any viral or non-viral DNA template and minimizes undesired consequences of DNA double-strand breaks.

"I never should have been a doctor": a qualitative study of imposter phenomenon among internal medicine residents.

INTRODUCTION: Imposter phenomenon is common among medical trainees and may influence learning and professional development. The authors sought to describe imposter phenomenon among internal medicine residents. METHODS: In 2020, using emailed invites we recruited a convenience sample of 28 internal medicine residents from a teaching hospital in Baltimore, Maryland to participate in an exploratory qualitative study. In one-on-one interviews, informants described experiences of imposter phenomenon during residency training. Using thematic analysis to identify meaningful segments of text, the authors developed a coding framework and iteratively identified and refined themes. Informants completed the Clance Imposter Phenomenon Scale. RESULTS: Informants described feelings and thoughts related to imposter phenomenon, the contexts in which they developed and the impact on learning. Imposter phenomenon has profound effects on residents including: powerful and persistent feelings of inadequacy and habitual comparisons with others. Distinct contexts shaping imposter phenomenon included: changing roles with increasing responsibilities; constant scrutiny; and rigid medical hierarchy. Learning was impacted by inappropriate expectations, difficulty processing feedback, and mental energy diverted to impression management. DISCUSSION: Internal medicine residents routinely experience imposter phenomenon; these feelings distort residents' sense of self confidence and competence and may impact learning. Modifiable aspects of the clinical learning environment exacerbate imposter phenomenon and thus can be acted upon to mitigate imposter phenomenon and promote learning among medical trainees.

Drama Training as a Tool to Teach Medical Trainees Communication Skills: A Scoping Review.

PURPOSE: Recognizing the similarities between the skills an actor needs and those required of a physician in clinical communication, medical educators have begun to create drama-based interventions to teach communication skills. The purpose of this scoping review was to summarize existing educational interventions that use drama training to teach medical trainees communication skills. METHOD: The authors searched PubMed, CINAHL Plus, Embase, ERIC, and Web of Science Core Collection multiple times beginning in March 2020 through March 2022. Articles were included if they (1) described components of an educational intervention, (2) used an active intervention based on drama training, (3) stated a curricular goal of improving learners' communication skills, and (4) included medical trainee learners. Data extracted included the details of the targeted learners and educational interventions, assessment tools, and outcomes. The quality of each study was assessed. RESULTS: Thirty articles met the inclusion criteria. Twenty-five (83%) articles included acting and improvisation exercises, 9 (30%) used some or all of the conventions of forum theater, and 3 (10%) used dramatic performance. The interventions included undergraduate, graduate, and continuing medical education learners. Most were elective and involved a member of the theatrical community. Although low overall study quality (average MERSQI score was 8.5) limited the strength of the evidence, of the 8 articles that evaluated learners' knowledge, skills, and/or behaviors, the majority showed an initial improvement in communication skills post-intervention. CONCLUSIONS: This review is the first, to the authors' knowledge, to focus on the curricular goal of improving communication skills and to include a broader scope (beyond medical improv) of drama trainings. While the included articles represent a diverse group of interventions, generally they reported an outcome of improved communication skills in their learners. More high-quality studies are needed to determine best practices and the generalizability of drama-based initiatives.

Editing human hematopoietic stem cells: advances and challenges.

Genome editing of hematopoietic stem and progenitor cells is being developed for the treatment of several inherited disorders of the hematopoietic system. The adaptation of CRISPR-Cas9-based technologies to make precise changes to the genome, and developments in altering the specificity and efficiency, and improving the delivery of nucleases to target cells have led to several breakthroughs. Many clinical trials are ongoing, and several pre-clinical models have been reported that would allow these genetic therapies to one day offer a potential cure to patients with diseases where limited options currently exist. However, there remain several challenges with respect to establishing safety, expanding accessibility and improving the manufacturing processes of these therapeutic products. This review focuses on some of the recent advances in the field of genome editing of hematopoietic stem and progenitor cells and illustrates the ongoing challenges.

Limitations of mouse models for sickle cell disease conferred by their human globin transgene configurations.

We characterized the human ß-like globin transgenes in two mouse models of sickle cell disease (SCD) and tested a genome-editing strategy to induce red blood cell fetal hemoglobin (HbF; α2γ2). Berkeley SCD mice contain four to 22 randomly arranged, fragmented copies of three human transgenes (HBA1, HBG2-HBG1-HBD-HBBS and a mini-locus control region) integrated into a single site of mouse chromosome 1. Cas9 disruption of the BCL11A repressor binding motif in the γ-globin gene (HBG1 and HBG2; HBG) promoters of Berkeley mouse hematopoietic stem cells (HSCs) caused extensive death from multiple double-strand DNA breaks. Long-range sequencing of Townes SCD mice verified that the endogenous Hbb genes were replaced by single-copy segments of human HBG1 and HBBS including proximal but not some distal gene-regulatory elements. Townes mouse HSCs were viable after Cas9 disruption of the HBG1 BCL11A binding motif but failed to induce HbF to therapeutic levels, contrasting with human HSCs. Our findings provide practical information on the genomic structures of two common mouse SCD models, illustrate their limitations for analyzing therapies to induce HbF and confirm the importance of distal DNA elements in human globin regulation. This article has an associated First Person interview with the first author of the paper.