Microglia regulate GABAergic neurogenesis in prenatal human brain through IGF1.

GABAergic neurons are an essential cellular component of neural circuits. Their abundance and diversity have enlarged significantly in the human brain, contributing to the expanded cognitive capacity of humans. However, the developmental mechanism of the extended production of GABAergic neurons in the human brain remains elusive. Here, we use single-cell transcriptomics, bioinformatics, and histological analyses to uncover microglial regulation of the sustained proliferation of GABAergic progenitors and neuroblasts in the human medial ganglionic eminence (hMGE). We show that insulin-like growth factor 1 (IGF1) and its receptor IGR1R as the top ligand-receptor pair underlying microglia-progenitor communication in the prenatal human brain. Using our newly developed neuroimmune hMGE organoids, which mimics hMGE cytoarchitecture and developmental trajectory, we demonstrate that microglia-derived IGF1 promotes progenitor proliferation and the production of GABAergic neurons. Conversely, IGF1-neutralizing antibodies and IGF1 knockout human embryonic stem cells (hESC)-induced microglia (iMG) completely abolished iMG-mediated progenitor proliferation. Together, these findings reveal a previously unappreciated role of microglia-derived IGF1 in promoting proliferation of neural progenitors and the development of GABAergic neurons.

Pathogenesis of Germinal Matrix Hemorrhage: Insights from Single-Cell Transcriptomics.

The germinal matrix harbors neurogenic niches in the subpallium of the prenatal human brain that produce abundant GABAergic neurons. In preterm infants, the germinal matrix is particularly vulnerable to developing hemorrhage, which disrupts neurogenesis and causes severe neurodevelopmental sequelae. However, the disease mechanisms that promote germinal matrix hemorrhage remain unclear. Here, we review recent advances using single-cell transcriptomics to uncover novel mechanisms that govern neurogenesis and angiogenesis in the germinal matrix of the prenatal human brain. These approaches also reveal the critical role of immune-vascular interaction that promotes vascular morphogenesis in the germinal matrix and how proinflammatory factors from activated neutrophils and monocytes can disrupt this process, leading to hemorrhage. Collectively, these results reveal fundamental disease mechanisms and therapeutic interventions for germinal matrix hemorrhage.

Disability inclusion in national surveys.

National surveys are important for understanding the disparities that disabled people experience across social determinants of health; however, limited research has examined the methods used to include disabled people in these surveys. This study reviewed nationally representative surveys administered by the Centers for Disease Control and Prevention (CDC) and the US Census Bureau that collected data in the past 5 years and sampled adults ≥18 years. Data from both publicly available online survey documents and a questionnaire emailed to survey administrators were used to determine whether surveys (1) oversampled disabled people, (2) had a data-accessibility protocol to support data collection, and (3) provided multiple data-collection modalities (eg, phone, paper). Of the 201 surveys identified, 30 met the inclusion criteria for the study. Of these 30 surveys, 1 oversampled disabled people, none had a data-collection accessibility protocol, and 21 provided multiple data-collection modalities. This study highlights barriers and opportunities to including disabled people in national surveys, which is essential for ensuring survey data are generalizable to the US population.

Proinflammatory immune cells disrupt angiogenesis and promote germinal matrix hemorrhage in prenatal human brain.

Germinal matrix hemorrhage (GMH) is a devastating neurodevelopmental condition affecting preterm infants, but why blood vessels in this brain region are vulnerable to rupture remains unknown. Here we show that microglia in prenatal mouse and human brain interact with nascent vasculature in an age-dependent manner and that ablation of these cells in mice reduces angiogenesis in the ganglionic eminences, which correspond to the human germinal matrix. Consistent with these findings, single-cell transcriptomics and flow cytometry show that distinct subsets of CD45+ cells from control preterm infants employ diverse signaling mechanisms to promote vascular network formation. In contrast, CD45+ cells from infants with GMH harbor activated neutrophils and monocytes that produce proinflammatory factors, including azurocidin 1, elastase and CXCL16, to disrupt vascular integrity and cause hemorrhage in ganglionic eminences. These results underscore the brain's innate immune cells in region-specific angiogenesis and how aberrant activation of these immune cells promotes GMH in preterm infants.

Idiopathic Granulomatous Mastitis: Imaging Findings and Outcomes with Nonsteroidal Treatment in a Predominantly Hispanic Population.

OBJECTIVE: We describe the demographics, clinical presentation, imaging findings, and treatment response among 235 cases of biopsy-proven idiopathic granulomatous mastitis (IGM) at a single institution. METHODS: An institutional review board-approved retrospective search of the breast imaging database was performed to select patients with biopsy-proven IGM between 2017 and 2022. Retrospective review evaluated clinical presentation, imaging findings with US and mammography, and treatment recommendations (antibiotics, nonsteroidal anti-inflammatory drugs [NSAIDs], warm compresses, or observation only). Response to treatment was evaluated on follow-up US. A favorable treatment response was a decrease in size or resolution of disease on follow-up imaging. Statistical analysis using Poisson regression was performed to evaluate the clinical outcomes associated with each treatment. RESULTS: A total of 235 patients met the selection criteria with a mean age of 38 years (18 to 68). The majority of patients were Hispanic (95%, 223/235). Of all patients, 75.3% (177/235) received treatment (consisting of 1 or any combination of antibiotics, NSAIDs, warm compresses), 24.7% (58/235) were treated with observation, 78.7% (185/235) returned for follow-up imaging, and 21.3% (50/235) were lost to follow-up. Of those with follow-up imaging, disease improvement was seen in 70.3% (102/145) of patients who received treatment compared with 72.5% (29/40) of patients treated by observation alone. Multivariate analysis further showed no difference in clinical outcomes among the treatment of unifocal, multifocal, or recurrent IGM. CONCLUSION: Nonsteroidal treatment of IGM showed no significant improvement on follow-up imaging compared to treatment with observation alone in a predominantly Hispanic patient population.

Mucocutaneous toxicities from MEK inhibitors: a scoping review of the literature.

BACKGROUND: MEK inhibitors cause a wide spectrum of mucocutaneous toxicities which can delay or interrupt life-saving therapy. PURPOSE: To summarize the morphology, incidence, and clinical presentation of mucocutaneous toxicities from MEK inhibitors via a scoping review of the literature. METHODS: We conducted a scoping review of the published literature, including clinical trials, retrospective and prospective studies, reviews, and case reports and series. All included literature was analyzed by a panel of pediatric and adult oncodermatologists. RESULTS: Of 1626 initial citations, 227 articles met final inclusion criteria. Our review identified follicular reactions, ocular toxicities, xerosis, eczematous dermatitis, edema, and paronychia as the most common mucocutaneous side effects from MEK inhibitor therapy. Grade 1 and 2 reactions were the most prevalent and were typically managed while continuing treatment; however, grade 3 toxicities requiring dose reductions or treatment interruptions were also reported. CONCLUSION: Mucocutaneous toxicities to MEK inhibitor therapy are common and most often mild in severity. Early recognition and treatment can mitigate disruptions in oncologic therapy.

Treatment of oral graft-versus-host disease with intraoral nbUVB phototherapy.

PURPOSE: There are limited treatment options available for hematopoietic stem-cell transplant patients (HSCT) with oral graft-versus-host disease (GVHD). Intraoral phototherapy is a novel, yet promising therapeutic regimen. RESEARCH QUESTION: To assess the safety and effectiveness of intraoral narrowband UVB (nbUVB) phototherapy in the treatment of oral GVHD. METHODS: This case series evaluated 10 patients with refractory oral GVHD, who were treated at Northwestern Memorial Hospital with nbUVB between July 2019 and October 2023. Primary outcomes were to evaluate the safety and efficacy of phototherapy. Efficacy was measured by objective improvement in symptom scores and subjective improvement in patient reported symptoms. Safety was determined by the withdrawal due to adverse events. Total nbUVB exposure, number of treatments, and change in systemic immunosuppressive medications were also examined. RESULTS: The study cohort comprised 10 patients who developed oral GVHD at a median of 9.5 months after HSCT. The total median dose of nbUVB was 36 J/cm2, and the median number of sessions was 55. All 10 patients demonstrated some degree of improvement in symptoms. Notably, there was a reduction in the number of patients who reported symptoms of oral pain (83%), bleeding (67%), xerostomia (50%), and oral sensitivity (78%) after initiating phototherapy. There was also a statistically significant decrease in the levels of pain, erythema, and edema (p ≤ 0.001, < 0.001, 0.01, respectively). Most patients tolerated phototherapy well, but 1 patient withdrew from treatment due to adverse effects. Seventy-five percent of patients who were on immunosuppressive medications were able to decrease or stop these medications. CONCLUSION: This case series suggests that nbUVB phototherapy is well tolerated and efficacious in patients with oral GVHD.

Using ACGME General Surgery Milestones to Define the Competent Foundational Surgical Resident.

OBJECTIVE: In transitioning to competency-based surgical training, the need to clearly define competency is paramount. The purpose of this study is to define the well-prepared foundational resident using the ACGME General Surgery Milestones as our conceptual framework. DESIGN: Participants reflected on their expectations of a well-prepared resident at the end of PGY1, then assigned milestone levels reflecting this level of competence for General Surgery Milestones 1.0 and 2.0. Subcompetency scores were averaged among residents and faculty. The level of the well-prepared foundational resident was determined based on the highest level within one standard deviation of faculty, resident, and total group averages. SETTING: This took place during a dedicated education retreat at a single, large academic general surgery residency program. PARTICIPANTS: Key faculty stakeholders and a representative sample of residents (PGY 1-5) within our institution participated. RESULTS: Eight faculty and five residents completed Milestones 1.0 and 2.0 scoring. Mean scores between faculty and residents were compared. For 1.0, mean scores for Practice-Based Learning and Improvement 3 (PBLI 3) and Interpersonal Communication Skills 3 (ICS 3) were discernably lower for residents than for faculty (PBLI 3 1.3 (0.3) v 0.9 (0.2), p = 0.01; ICS3 1.6 (0.6) v 1.1 (1), p = 0.01). Scores of 2.0 were comparable across all subcompetency domains. With this broad agreement, Milestone-based competency standards were determined. Descriptive narratives of the KSAs were created for each subcompetency, combining the determined Milestones 1.0 and 2.0 levels. CONCLUSIONS: We were able to clearly define the competent foundational resident using the ACGME Milestones as a conceptual framework. These Milestone levels reflect the culture and expectations in our department, providing a foundation upon which to build a program of assessment. This methodology can be readily replicated in other programs to reflect specific expectations of the program within the larger ACGME frameworks of competency.

Defining D-irAEs: consensus-based disease definitions for the diagnosis of dermatologic adverse events from immune checkpoint inhibitor therapy.

With an increasing number of patients eligible for immune checkpoint inhibitors, the incidence of immune-related adverse events (irAEs) is on the rise. Dermatologic immune-related adverse events (D-irAEs) are the most common and earliest to manifest, often with important downstream consequences for the patient. Current guidelines lack clarity in terms of diagnostic criteria for D-irAEs. The goal of this project is to better define D-irAE for the purposes of identification, diagnosis, and future study of this important group of diseases.The objectives of this project were to develop consensus guidance for an approach to D-irAEs including disease definitions and severity grading. Knowing that consensus among oncologists, dermatologists, and irAE subspecialists would be critical for usability, we formed a Dermatologic irAE Disease Definition Panel. The panel was composed of 34 experts, including oncologists, dermatologists, a rheumatologist, and an allergist/immunologist from 22 institutions across the USA and internationally. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two virtual meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness, and accuracy on 9-point scales in electronic surveys and provided free text comments. A working group aggregated survey responses and incorporated them into revised definitions. Consensus was based on numeric ratings using the RAND/UCLA Appropriateness Method with prespecified definitions.Following revisions based on panelist feedback, all items received consensus in the second round of ratings. Consensus definitions were achieved for 10 core D-irAE diagnoses: ICI-vitiligo, ICI-lichen planus, ICI-psoriasis, ICI-exanthem, ICI-bullous pemphigoid, ICI-Grover's, ICI-eczematous, ICI-eruptive atypical squamous proliferation, ICI-pruritus without rash, and ICI-erosive mucocutaneous. A standard evaluation for D-irAE was also found to reach consensus, with disease-specific exceptions detailed when necessary. Each disorder's description includes further details on disease subtypes, symptoms, supportive exam findings, and three levels of diagnostic certainty (definite, probable, and possible).These consensus-driven disease definitions standardize D-irAE classification in a useable framework for multiple disciplines and will be the foundation for future work. Given consensus on their accuracy and usability from a representative panel group, we anticipate that they can be used broadly across clinical and research settings.

Anatomic Subtype Differences in Extramammary Paget Disease: A Meta-Analysis.

Importance: Extramammary Paget disease (EMPD) is a rare, highly recurrent cutaneous malignant neoplasm of unclear origin. EMPD arises most commonly on the vulvar and penoscrotal skin. It is not presently known how anatomic subtype of EMPD affects disease presentation and management. Objective: To compare demographic and tumor characteristics and treatment approaches for different EMPD subtypes. Recommendations for diagnosis and treatment are presented. Data Sources: MEDLINE, Embase, Web of Science Core Collection, and Cochrane Reviews CENTRAL from December 1, 1990, to October 24, 2022. Study Selection: Articles were excluded if they were not in English, reported fewer than 3 patients, did not specify information by anatomic subtype, or contained no case-level data. Metastatic cases on presentation were also excluded. Data Extraction and Synthesis: Abstracts of 1295 eligible articles were independently reviewed by 5 coauthors, and 135 articles retained. Reporting was in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. The analysis was cunducted in August 2019 and updated in November 2022. Findings: Most vulvar EMPD cases were asymptomatic, and diagnosis was relatively delayed (mean, 25.1 months). Although most vulvar EMPD cases were intraepidermal (1247/1773 [70.3%]), radical surgeries were still performed in almost one-third of cases. Despite this aggressive surgical approach, 481 of 1423 (34%) recurred, commonly confined to the skin and mucosa (177/198 [89.4%]). By contrast, 152 of 1101 penoscrotal EMPD cases (14%) recurred, but more than one-third of these recurrences were regional or associated with distant metastases (54 of 152 [35.5%]). Perianal EMPD cases recurred in one-third of cases (74/218 [33.9%]), with one-third of these recurrences being regional or associated with distant metastasis (20 of 74 [27.0%]). Perianal EMPD also had the highest rate of invasive disease (50% of cases). Conclusions and Relevance: The diagnosis and treatment of EMPD should differ based on anatomic subtypes. Considerations for updated practice may include less morbid treatments for vulvar EMPD, which is primarily epidermal, and close surveillance for local recurrence in vulvar EMPD and metastatic recurrence in perianal EMPD. Recurrences in penoscrotal subtype were less common, and selective surveillance in this subtype may be considered. Limitations of this study include the lack of replication cohorts and the exclusion of studies that did not stratify outcomes by anatomic subtype.

Peritoneal dialysis-associated peritonitis: A case first for Aquamicrobium.

Aquamicrobium is an aerobic gram-negative rod which until recently had only been isolated from wastewater and contaminated soil. In 2021, two cases of Aquamicrobium infection in humans were reported. Both were cases of endophthalmitis following cataract surgery. In this manuscript, we describe the presentation and treatment of a 56-year-old immunocompetent male who has peritoneal dialysis-associated peritonitis caused by Aquamicrobium lusatiense. To our knowledge, this is the third reported case of Aquamicrobium infection in humans and the first example of this agent causing peritonitis.

A randomized Phase I pre-operative window trial of transdermal endoxifen in women planning mastectomy: Evaluation of dermal safety, intra-mammary drug distribution, and biologic effects.

Breast cancer prevention only requires local exposure of the breast to active drug. However, oral preventive agents entail systemic exposure, causing adverse effects that limit acceptance by high-risk women. Drug-delivery through the breast skin is an attractive option, but requires demonstration of dermal safety and drug distribution throughout the breast. We formulated the tamoxifen metabolite (E/Z)-endoxifen for transdermal delivery and tested it in a placebo-controlled, double-blinded Phase I trial with dose escalation from 10 to 20 mg daily. The primary endpoint was dermal toxicity. Thirty-two women planning mastectomy were randomized (2:1) to endoxifen-gel or placebo-gel applied to both breasts for 3-5 weeks. Both doses of endoxifen-gel incurred no dermal or systemic toxicity compared to placebo. All endoxifen-treated breasts contained the drug at each of five sampling locations; the median per-person tissue concentration in the treated participants was 0.6 ng/g (IQR 0.4-1.6), significantly higher (p < 0.001) than the median plasma concentration (0.2 ng/mL, IQR 0.2-0.2). The median ratio of the more potent (Z)-isomer to (E)-isomer at each breast location was 1.50 (IQR 0.96-2.54, p < 0.05). No discernible effects of breast size or adiposity on tissue concentrations were observed. At the endoxifen doses and duration used, and the tissue concentration achieved, we observed a non-significant overall reduction of tumor proliferation (Ki67 LI) and significant downregulation of gene signatures known to promote cancer invasion (FN1, SERPINH1, PLOD2, PDGFA, ITGAV) (p = 0.03). Transdermal endoxifen is an important potential breast cancer prevention agent but formulations with better dermal penetration are needed.

Impact of Preference Signals on Interview Selection Across Multiple Residency Specialties and Programs.

Background Program signaling is an innovation that allows applicants to express interest in specific programs while providing programs the opportunity to review genuinely interested applicants during the interview selection process. Objective To examine the influence of program signaling on "selected to interview" status across specialties in the 2022 Electronic Residency Application Service (ERAS) application cycle. Methods Dermatology, general surgery-categorical (GS), and internal medicine-categorical (IM-C) programs that participated in the signaling section of the 2022 supplemental ERAS application (SuppApp) were included. Applicant signal data was collected from SuppApp, applicant self-reported characteristics collected from the MyERAS Application for Residency Applicants, and 2020 program characteristics collected from the 2020 GME Track Survey. Applicant probability of being selected for interview was analyzed using logistic regression, determined by the selected to interview status in the ERAS Program Director's WorkStation. Results Dermatology had a 62% participation rate (73 of 117 programs), GS a 75% participation rate (174 of 232 programs), and IM-C an 86% participation rate (309 of 361 programs). In all 3 specialties examined, on average, signaling increased the likelihood of being selected to interview compared to applicants who did not signal. This finding held across gender and underrepresented in medicine (UIM) groups in all 3 specialties, across applicant types (MDs, DOs, international medical graduates) for GS and IM-C, and after controlling for United States Medical Licensing Examination Step 1 scores. Conclusions Although there was variability by program, signaling increased likelihood of being selected for interview without negatively affecting any specific gender or UIM group.

INDIVIDUAL ARTICLE: USCOM Algorithm for the Prevention and Management of Cutaneous Immunotherapy-Related Adverse Events.

BACKGROUND: In 2023, nearly 2 million patients will be diagnosed with cancer in the United States and at least 40% will be eligible for treatment with an immune checkpoint inhibitor (ICI). Cutaneous immune related adverse events (cirAEs) from ICIs are common and include pruritus as well as maculopapular, eczematous, bullous, lichenoid, and psoriasiform reactions. All clinicians interfacing with cancer patients must expedite proper evaluation and diagnosis, treatment, and/or consultation that supports the need for evidence-directed guidelines. MATERIALS AND METHODS: A panel of advisors was selected, and a systematic literature review generated foundational evidence to develop a treatment algorithm for cirAEs via a modified Delphi process. Iterations of the algorithm were performed until the group met consensus. RESULTS: An algorithm that tailors the management of cirAEs was developed based on the CTCAE v.5 grading of skin disorders. Representative clinical images and suggested diagnostic measures, supplement the algorithm. CONCLUSION: Recognition and treatment of cirAEs guided through a multidisciplinary, physician-developed algorithm will limit disruption of immunotherapy, optimize quality of life, and enhance overall outcomes in patients treated with ICIs. J Drugs Dermatol. 2023;22:11(Suppl 1):s3-10.

Protocol for a feasibility trial (EXPRESS-C-GVHD) for an expressive helping intervention within a support group for cutaneous graft-versus-host-disease.

BACKGROUND: Cutaneous graft-versus-host disease (cuGVHD) is a complication of allogeneic hematopoietic stem cell transplantation that presents with varying severity and can significantly affect one's quality of life (QOL). No trials have yet tested nonpharmacologic interventions to improve the QOL of patients with cuGVHD. The primary objective of the Expressive Helping in Support Groups for Cutaneous GVHD (EXPRESS-C-GVHD) Trial is to evaluate the effect of a support group that employs expressive writing on cutaneous and systemic GVHD symptoms, general distress, and QOL immediately after the intervention. Secondary objectives include evaluating the impact of the intervention on QOL at 1 month post intervention, as well as willingness to participate, compliance, feasibility, and satisfaction. METHODS: The EXPRESS-C-GVHD Trial will include patients with chronic cuGVHD who are at least 18 years old and able to use a writing utensil, have access to Zoom, an online video conference platform, and attend all four live support group sessions. Subjects will be recruited from the Department of Dermatology, Northwestern University, Chicago, IL and will participate in a 4 week program via Zoom. Program activities will be 1 h long and consist of 40 min of participant-led verbal reflection and discussion in a group setting in response to prompts, and 20 min of expressive writing. Participants will fill out a baseline willingness survey, follow-up surveys after every session, and post-intervention surveys at 2 weeks and 1 month after intervention. DISCUSSION: The EXPRESS-C-GVHD Trial is a pilot trial and will assess whether a Zoom-based expressive writing intervention within the framework of a support group is feasible and can improve QOL outcomes among individuals with cuGVHD. TRIAL REGISTRATION: The trial is registered under number NCT05694832.

Neuropsychological Differences Between Surgery Interns and Age-Matched Adults.

OBJECTIVE: The purpose of this study was to assess how neuropsychological factors differ between general surgery interns and normative data from age-matched adults in the general population. DESIGN: Participants completed a comprehensive neuropsychological assessment battery. Neuropsychological factors assessed included: executive function (Behavioral Rating Inventory of Executive Function, BRIEF), working memory (Wechsler Adult Intelligence Scale, or WAIS, digit span), psychomotor speed (WAIS coding, Trails A and B), selective attention (D2 Test of Attention), and problem solving (Tower of London, TOL). Data for all measures was compared to previously published normative data for age-matched, healthy adults in the general population using one-sample t-tests. SETTING: This study was completed at Indiana University School of Medicine in Indianapolis, IN, which is a large academic healthcare training institution. PARTICIPANTS: Postgraduate year 1 general surgery residents (PGY1s) voluntarily participated in this study. RESULTS: Twenty-six general surgery PGY1s completed all measures. We found that PGY1s had significantly better behavioral inhibition, working memory, selective attention, problem solving, and psychomotor speed than their counterparts in the general population (Table 1). Conversely, we found that PGY1s had significantly lower cognitive flexibility (p = 0.02) and ability to monitor task progress (p = 0.006) than the general population. CONCLUSIONS: The results from this study indicate that there are several neuropsychological factors that may help explain the high achievement of general surgery PGY1s. Assessment of these factors could aid general surgery programs in the selection and training of high-caliber residents. However, there are indicators that PGY1s struggle from cognitive inflexibility and task monitoring compared to the general population. These skills are needed to manage the complex and dynamic nature of surgical performance, so educators should consider methods to enhance junior residents' development of these characteristics.

Skin Infiltrate Composition as a Telling Measure of Responses to Checkpoint Inhibitors.

Checkpoint inhibitors treat a variety of tumor types with significant benefits. Unfortunately, these therapies come with diverse adverse events. Skin rash is observed early into treatment and might serve as an indicator of downstream responses to therapy. We studied the cellular composition of cutaneous eruptions and whether their contribution varies with the treatment applied. Skin samples from 18 patients with cancer and 11 controls were evaluated by mono- and multiplex imaging, quantification, and statistical analysis. T cells were the prime contributors to skin rash, with T cells and macrophages interacting and proliferating on site. Among T cell subsets examined, type 1 and 17 T cells were relatively increased among inflammatory skin infiltrates. A combination of increased cytotoxic T cell content and decreased macrophage abundance was associated with dual checkpoint inhibition over PD1 inhibition alone. Importantly, responders significantly separated from nonresponders by greater CD68+ macrophage and either CD11c+ antigen-presenting cell or CD4+ T cell abundance in skin rash. The microenvironment promoted epidermal proliferation and thickening as well. The combination of checkpoint inhibitors used affects the development and composition of skin infiltrates, whereas the combined abundance of two cell types in cutaneous eruptions aligns with responses to checkpoint inhibitor therapy.

See One, Do One, Improve One's Wellness: Resident Autonomy in US General Surgery Programs, A Mixed-methods Study.

OBJECTIVE: We sought to examine the factors associated with resident perceptions of autonomy and to characterize the relationship between resident autonomy and wellness. BACKGROUND: Concerns exist that resident autonomy is decreasing, impacting competence. METHODS: Quantitative data were collected through a cross-sectional survey administered after the 2020 ABSITE. Qualitative data were collected through interviews and focus groups with residents and faculty at 15 programs. RESULTS: Seven thousand two hundred thirty-three residents (85.5% response rate) from 324 programs completed the survey. Of 5139 residents with complete data, 4424 (82.2%) reported appropriate autonomy, and these residents were less likely to experience burnout [odds ratio (OR) 0.69; 95% CI 0.58-0.83], suicidality (OR 0.69; 95% CI 0.54-0.89), and thoughts of leaving their programs (OR 0.45; 95% CI 0.37-0.54). Women were less likely to report appropriate autonomy (OR 0.81; 95% CI 0.68-0.97). Residents were more likely to report appropriate autonomy if they also reported satisfaction with their workload (OR 1.65; 95% CI 1.28-2.11), work-life balance (OR 2.01; 95% CI 1.57-2.58), faculty engagement (OR 3.55; 95% CI 2.86-4.35), resident camaraderie (OR 2.23; 95% CI, 1.78-2.79), and efficiency and resources (OR 2.37; 95% CI 1.95-2.88). Qualitative data revealed that (1) autonomy gives meaning to the clinical experience of residency, (2) multiple factors create barriers to autonomy, and (3) autonomy is not inherent to the training paradigm, requiring residents to learn behaviors to "earn" it. CONCLUSION: Autonomy is not considered an inherent part of the training paradigm such that residents can assume that they will achieve it. Resources to function autonomously should be allocated equitably to support all residents' educational growth and wellness.