Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34+ cell therapy to induce fetal hemoglobin for sickle cell disease.

Sickle cell disease (SCD) is a common, severe genetic blood disorder. Current pharmacotherapies are partially effective and allogeneic hematopoietic stem cell transplantation (HSCT) is associated with immune toxicities. Genome editing of patient hematopoietic stem cells (HSCs) to reactivate fetal hemoglobin (HbF) in erythroid progeny offers an alternative potentially curative approach to treat SCD. Although the FDA released guidelines for evaluating genome editing risks, it remains unclear how best to approach pre-clinical assessment of genome-edited cell products. Here we describe rigorous pre-clinical development of a therapeutic γ-globin gene promoter editing strategy that supported an investigational new drug (IND) application cleared by the FDA. We compared γ-globin promoter and BCL11A enhancer targets, identified a potent HbF-inducing lead candidate, and tested our approach in mobilized CD34+ HSPCs from SCD patients. We observed efficient editing, HbF induction to predicted therapeutic levels, and reduced sickling. With single-cell analyses, we defined the heterogeneity of HbF induction and HBG1/HBG2 transcription. With CHANGE-seq for sensitive and unbiased off-target discovery followed by targeted sequencing, we did not detect off-target activity in edited HSPCs. Our study provides a blueprint for translating new ex vivo HSC genome editing strategies towards clinical trials for treating SCD and other blood disorders.

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.

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.

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.

"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.

Twelve tips for mindful teaching and learning in medical education.

Mindfulness practice has been shown to have many positive benefits for patients, clinicians, and trainees. Mindfulness fosters compassion, connection, and enhanced clinical reasoning and can reduce burnout among clinicians. A primary focus of mindfulness is present-moment awareness and may be achieved through openness, curiosity, perspective-taking, and letting go of judgment. We propose that the core principles of mindfulness can be harnessed by educators to enhance their teaching skills specifically around creating a supportive and safe learning environment, using questions effectively, providing feedback, and serving as role models. Mindful teaching promotes mindful learning, which focuses on context, openness to new possibilities, reflection, and critical thinking, as opposed to rote repetition and memorization. This article describes core mindfulness principles and strategies that can be used to become a more mindful teacher.

"It's a Little Different for Men"-Sponsorship and Gender in Academic Medicine: a Qualitative Study.

BACKGROUND: Women remain underrepresented in top leadership positions in academic medicine. In business settings, a person with power and influence actively supporting the career advancement of a junior person is referred to as a sponsor and sponsorship programs have been used to diversify leadership. Little is known about how sponsorship functions in academic medicine. OBJECTIVE: To explore perceptions of sponsorship and its relationship to gender and career advancement in academic medicine. DESIGN: Qualitative study using semi-structured, one-on-one interviews with sponsors and protégés. PARTICIPANTS: Twelve sponsors (clinical department chairs) and 11 protégés (participants of a school of medicine executive leadership program [N = 23]) at the Johns Hopkins School of Medicine. KEY RESULTS: All sponsors were men and all were professors, six of the 11 protégés were women, and four of the 23 participants were underrepresented minorities in medicine. We identified three themes: (1) people (how and who): women seek out and receive sponsorship differently; (2) process (faster and further): sponsorship provides an extra boost, especially for women; and (3) politics and culture (playing favorites and paying it forward): sponsorship and fairness. Informants acknowledge that sponsorship provides an extra boost for career advancement especially for women. Sponsors and protégés differ in their perceptions of how sponsorship happens. Informants describe gender differences in how sponsorship is experienced and specifically noted that women were less likely to actively seek out sponsorship and be identified as protégés compared to men. Informants describe a tension between sponsorship and core academic values such as transparency, fairness, and merit. CONCLUSION: Sponsorship is perceived to be critical to high-level advancement and is experienced differently by women. Increased understanding of how sponsorship works in academic medicine may empower individual faculty to utilize this professional relationship for career advancement and provide institutions with a strategy to diversify top leadership positions.

Microbial Transformation of A Sulfonamide Antibiotic Under Various Background Nutrient Conditions.

Certain microbes can biotransform antibiotics. Little is known about these microbes or the biotransformation processes. The objective of this study was to determine the effects of background nutrient conditions on a sulfonamide degrading culture and on its biotransformation of sulfadiazine (SDZ) with respect to transformation kinetics and transformation products. The mixed culture capable of degrading SDZ consisted primarily of three genera, Brevibacterium, Castellaniella and Leucobacter. The maximum biotransformation rate was 4.55 mg L-1 d-1 in the absence of background nutrients. Among the three background nutrient conditions tested, diluted R2A medium lead to the highest maximum SDZ biotransformation rates, followed by humic acid and glucose. 2-aminopyrimidine was the major SDZ biotransformation product under the background nutrient conditions tested, while another previously reported biotransformation product, sulfanilic acid, was further degraded by the mixed culture. The findings from this study can help improve our estimation of the fate of antibiotics in the environment.

Pennsylvania State Core Competencies for Education on Opioids and Addiction.

OBJECTIVE: The objective of this project was to develop core competencies for education on opioids and addiction to be used in all Pennsylvania medical schools. METHODS: The Pennsylvania Physician General created a task force that was responsible for the creation of the core competencies. A literature review was completed, and a survey of graduating medical students was conducted. The task force then developed, reviewed, and approved the core competencies. RESULTS: The competencies were grouped into nine domains: understanding core aspects of addiction; patient screening for substance use disorder; proper referral for specialty evaluation and treatment of substance use disorder; proper patient assessment when treating pain; proper use of multimodal treatment options when treating acute pain; proper use of opioids for the treatment of acute pain (after consideration of alternatives); the role of opioids in the treatment of chronic noncancer pain; patient risk assessment related to the use of opioids to treat chronic noncancer pain, including the assessment for substance use disorder or increased risk for aberrant drug-related behavior; and the process for patient education, initiation of treatment, careful patient monitoring, and discontinuation of therapy when using opioids to treat chronic noncancer pain. Specific competencies were developed for each domain. CONCLUSIONS: These competencies will be incorporated into the educational process at all Pennsylvania medical schools. It is hoped that these curriculum changes will improve student knowledge and attitudes in these areas, thus improving patient outcomes.

Burned Out at the Bedside: Patient Perceptions of Physician Burnout in an Internal Medicine Resident Continuity Clinic.

BACKGROUND: Burnout is high among resident physicians and may be associated with suboptimal patient care and reduced empathy. OBJECTIVE: To investigate the relationship between patient perceptions of empathy and enablement and physician burnout in internal medicine residents. DESIGN: Cross-sectional, survey-based observational study between December 2012 and March 2013 in a resident continuity clinic located within a large urban academic primary care practice in Baltimore, Maryland. PARTICIPANTS: Study participants were 44 PGY1-3 residents and a convenience sample of their English-speaking adult primary care patients (N = 244). MAIN MEASURES: Patients rated their resident physicians using the Consultation and Relational Empathy Measure (CARE) and the Patient Enablement Instrument (PEI). Residents completed the Maslach Burnout Inventory (MBI). We tested for associations between resident burnout and patients' perceptions of resident empathy (CARE) and enablement (PEI) using multilevel regression analysis. KEY RESULTS: Multilevel regression analyses indicated significant positive associations between physician depersonalization scores on the MBI and patient ratings of empathy (B = 0.28, SE = 0.17, p < 0.001) and enablement (B = 0.11, SE = 0.11, p = 0.02). Emotional exhaustion scores on the MBI were not significantly related to either patient outcome. CONCLUSIONS: Patients perceived residents who reported higher levels of depersonalization as more empathic and enabling during their patient care encounters. The relationship between physician distress and patient perceptions of care has important implications for medical education and requires further study.

Chaplains on the Medical Team: A Qualitative Analysis of an Interprofessional Curriculum for Internal Medicine Residents and Chaplain Interns.

Improved collaboration between physicians and chaplains has the potential to improve patient experiences. To better understand the benefits and challenges of learning together, the authors conducted several focus groups with participants in an interprofessional curriculum that partnered internal medicine residents with chaplain interns in the clinical setting. The authors derived four major qualitative themes from the transcripts: (1) physician learners became aware of effective communication skills for addressing spirituality. (2) Chaplain interns enhanced the delivery of team-based patient-centered care. (3) Chaplains were seen as a source of emotional support to the medical team. (4) The partnership has three keys to success: adequate introductions for team members, clear expectations for participants, and opportunities for feedback. The themes presented indicate several benefits of pairing physicians and chaplains in the setting of direct patient care and suggest that this is an effective approach to incorporating spirituality in medical training.

A national survey of eating disorder training.

OBJECTIVE: Eating disorders (EDs) result in the highest mortality rate of all psychiatric disorders, and in the United States, approximately one in twenty females suffers from an eating disorder. However, training provided within residency programs to address the needs of these patients is sparse. The objective of this study was to conduct a national survey that assesses the amount of EDs training for trainees across five ACGME accredited specialties: internal medicine, pediatrics, family medicine, psychiatry, and child and adolescent psychiatry. The results of the survey will be used to develop strategies to improve eating disorder education among residents. METHOD: Eight hundred eighty training coordinators were contacted using information available on the ACGME website and asked to complete the survey. RESULTS: Of the 637 responding programs, 514 did not offer any scheduled or elective rotations for EDs. Of the 123 programs offering rotations, only 42 offered a formal, scheduled rotation. Child and adolescent psychiatry offered the most clinical experiences, and pediatric programs offered the greatest number of didactic hours on EDs. DISCUSSION: Training in EDs is limited. Simulated patient encounters, massive open online courses, web-based curricula, dedicated rotations and clinical experiences, didactic curricula, and brief-training programs may help to improve eating disorder diagnostic and treatment skills among trainees.

Detection, Occurrence and Fate of Emerging Contaminants in Agricultural Environments.

A total of 43 papers published in 2014 were reviewed ranging from detailed descriptions of analytical methods, to fate and occurrence studies, to measuring and predicting biological effects for a wide variety of emerging contaminants likely to occur in agricultural environments. New methods and studies on veterinary pharmaceuticals, natural and synthetics steroids, and antibiotic resistance genes in agricultural environments continue to expand our knowledge base on the occurrence and potential impacts of these compounds. This review is divided into the following sections: Introduction, Analytical Methods, Occurrence and Fate, Antibiotic Resistance Genes, and Risk Assessment.