Trainee Autonomy and Supervision in the Modern Clinical Learning Environment: A Mixed-Methods Study of Faculty and Trainee Perspectives.

Background: Balancing autonomy and supervision during medical residency is important for trainee development while ensuring patient safety. In the modern clinical learning environment, tension exists when this balance is skewed. This study aimed to understand the current and ideal states of autonomy and supervision, then describe the factors that contribute to imbalance from both trainee and attending perspectives. Methods: A mixed-methods design included surveys and focus groups of trainees and attendings at three institutionally affiliated hospitals between May 2019-June 2020. Survey responses were compared using chi-square tests or Fisher's exact tests. Open-ended survey and focus group questions were analyzed using thematic analysis. Results: Surveys were sent to 182 trainees and 208 attendings; 76 trainees (42%) and 101 attendings (49%) completed the survey. Fourteen trainees (8%) and 32 attendings (32%) participated in focus groups. Trainees perceived the current culture to be significantly more autonomous than attendings; both groups described an "ideal" culture as more autonomous than the current state. Focus group analysis revealed five core contributors to the balance of autonomy and supervision: attending-, trainee-, patient-, interpersonal-, and institutional-related factors. These factors were found to be dynamic and interactive with each other. Additionally, we identified a cultural shift in how the modern inpatient environment is impacted by increased hospitalist attending supervision and emphasis on patient safety and health system improvement initiatives. Conclusions: Trainees and attendings agree that the clinical learning environment should favor resident autonomy and that the current environment does not achieve the ideal balance. There are several factors contributing to autonomy and supervision, including attending-, resident-, patient-, interpersonal-, and institutional-related. These factors are complex, multifaceted, and dynamic. Cultural shifts towards supervision by primarily hospitalist attendings and increased attending accountability for patient safety and systems improvement outcomes further impacts trainee autonomy.

Designing and Implementing a Novel Virtual Rounds Curriculum for Medical Students' Internal Medicine Clerkship During the COVID-19 Pandemic.

Introduction: During the COVID-19 pandemic, third-year medical students were temporarily unable to participate in onsite clinical activities. We identified the curricular components of an internal medicine (IM) clerkship that would be compromised if students learned solely from online didactics, case studies, and simulations (i.e., prerounding, oral presentations, diagnostic reasoning, and medical management discussions). Using these guiding principles, we created a virtual rounds (VR) curriculum to provide IM clerkship students with clinical exposure during a virtual learning period. Methods: Held three times a week for 2 weeks, VR consisted of three curricular components. First, clerkship students prerounded on an assigned hospitalized patient by remotely accessing the electronic health record and calling into hospital rounds. Second, each student prepared an oral presentation on their assigned patient. Third, using videoconferencing, students delivered these oral presentations to telemedicine VR small groups consisting of three to four students and three tele-instructors. Tele-instructors then provided feedback on oral presentations and taught clinical concepts. We assessed the effectiveness of VR by anonymously surveying students and tele-instructors. Results: Twenty-nine students and 34 volunteer tele-instructors participated in VR over four blocks. A majority of students felt VR improved their prerounding abilities (86%), oral presentation abilities (93%), and clinical reasoning skills (62%). All students found small group to be useful. Discussion: VR allowed students to practice rounding skills in a supportive team-based setting. The lessons learned from its implementation could facilitate education during future pandemics and could also supplement in-person clerkship education.

Advocacy in action: Medical student reflections of an experiential curriculum.

INTRODUCTION: Patient advocacy is a core value in medical education. Although students learn about social determinants of health (SDH) in the pre-clinical years, applying this knowledge to patients during clerkship rotations is not prioritized. Physicians must be equipped to address social factors that affect health and recognize their roles as patient advocates to improve care and promote health equity. We created an experience-based learning curriculum called Advocacy in Action (AiA) to promote the development and application of health advocacy knowledge and skills during an Internal Medicine (IM) clerkship rotation. METHODS: Sixty-six students completed a mandatory curriculum, including an introductory workshop on SDH and patient advocacy using tools for communication, counselling and collaboration skills. They then actively participated in patient advocacy activities, wrote about their experience and joined a small group debriefing about it. Forty-nine written reflections were reviewed for analysis of the impact of this curriculum on student perspectives. RESULTS: Written reflections had prominent themes surrounding advocacy skills development, meaningful personal experiences, interprofessional dynamics in patient advocacy and discovery of barriers to optimal patient care. DISCUSSION: AiA is a novel method to apply classroom knowledge of SDH to the clinical setting in order to incorporate advocacy in daily patient care. Students learned about communication with patients, working with interprofessional team members to create better health outcomes and empathy/compassion from this curriculum. It is important to utilize experiential models of individual patient-level advocacy during clerkships so that students can continuously reflect on and integrate advocacy into their future careers.

Successful Use of Interventions in Combination to Improve Human Papillomavirus Vaccination Coverage Rates Among Adolescents-Chicago, 2013 to 2015.

In 2013, National Immunization Survey-Teen data indicated that >40% of female adolescents had not initiated the human papillomavirus (HPV) vaccine series and >60% had not completed the series, documenting vaccination rates much lower than those for other vaccines recommended for adolescents. The Chicago Department of Public Health (CDPH) was 1 of 22 jurisdictions nationwide to receive a Prevention and Public Health Fund award through the Centers for Disease Control and Prevention to improve HPV vaccination rates among adolescents. The CDPH implemented 5 interventions targeting the public, clinicians and their staff, and diverse immunization and cancer prevention stakeholders. Compared with 2013 jurisdiction-specific HPV vaccination rates among all adolescents, Chicago's HPV vaccination rates were increased significantly in 2014 and 2015. This article details the methods and results of Chicago's successful interventions, the particular strengths as well as barriers encountered, and future steps necessary for sustaining improvement.

Early Antibody Lineage Diversification and Independent Limb Maturation Lead to Broad HIV-1 Neutralization Targeting the Env High-Mannose Patch.

The high-mannose patch on HIV Env is a preferred target for broadly neutralizing antibodies (bnAbs), but to date, no vaccination regimen has elicited bnAbs against this region. Here, we present the development of a bnAb lineage targeting the high-mannose patch in an HIV-1 subtype-C-infected donor from sub-Saharan Africa. The Abs first acquired autologous neutralization, then gradually matured to achieve breadth. One Ab neutralized >47% of HIV-1 strains with only ∼11% somatic hypermutation and no insertions or deletions. By sequencing autologous env, we determined key residues that triggered the lineage and participated in Ab-Env coevolution. Next-generation sequencing of the Ab repertoire showed an early expansive diversification of the lineage followed by independent maturation of individual limbs, several of them developing notable breadth and potency. Overall, the findings are encouraging from a vaccine standpoint and suggest immunization strategies mimicking the evolution of the entire high-mannose patch and promoting maturation of multiple diverse Ab pathways.

A structural hierarchy mediated by multiple nuclear factors establishes IgH locus conformation.

Conformation of antigen receptor gene loci spatially juxtaposes rearranging gene segments in the appropriate cell lineage and developmental stage. We describe a three-step pathway that establishes the structure of the 2.8-Mb immunoglobulin heavy chain gene (IgH) locus in pro-B cells. Each step uses a different transcription factor and leads to increasing levels of structural organization. CTCF mediates one level of compaction that folds the locus into several 250- to 400-kb subdomains, and Pax5 further compacts the 2-Mb region that encodes variable (VH) gene segments. The 5' and 3' domains are brought together by the transcription factor YY1 to establish the configuration within which gene recombination initiates. Such stepwise mechanisms may apply more generally to establish regulatory fine structure within megabase-sized topologically associated domains.

Genome-wide CIITA-binding profile identifies sequence preferences that dictate function versus recruitment.

The class II transactivator (CIITA) is essential for the expression of major histocompatibility complex class II (MHC-II) genes; however, the role of CIITA in gene regulation outside of MHC-II biology is not fully understood. To comprehensively map CIITA-bound loci, ChIP-seq was performed in the human B lymphoblastoma cell line Raji. CIITA bound 480 sites, and was significantly enriched at active promoters and enhancers. The complexity of CIITA transcriptional regulation of target genes was analyzed using a combination of CIITA-null cells, including a novel cell line created using CRISPR/Cas9 tools. MHC-II genes and a few novel genes were regulated by CIITA; however, most other genes demonstrated either diminished or no changes in the absence of CIITA. Nearly all CIITA-bound sites were within regions containing accessible chromatin, and CIITA's presence at these sites was associated with increased histone H3K27 acetylation, suggesting that CIITA's role at these non-regulated loci may be to poise the region for subsequent regulation. Computational genome-wide modeling of the CIITA bound XY box motifs provided constraints for sequences associated with CIITA-mediated gene regulation versus binding. These data therefore define the CIITA regulome in B cells and establish sequence specificities that predict activity for an essential regulator of the adaptive immune response.

B cell differentiation is associated with reprogramming the CCCTC binding factor-dependent chromatin architecture of the murine MHC class II locus.

The transcriptional insulator CCCTC binding factor (CTCF) was shown previously to be critical for human MHC class II (MHC-II) gene expression. Whether the mechanisms used by CTCF in humans were similar to that of the mouse and whether the three-dimensional chromatin architecture created was specific to B cells were not defined. Genome-wide CTCF occupancy was defined for murine B cells and LPS-derived plasmablasts by chromatin immunoprecipitation sequencing. Fifteen CTCF sites within the murine MHC-II locus were associated with high CTCF binding in B cells. Only one-third of these sites displayed significant CTCF occupancy in plasmablasts. CTCF was required for maximal MHC-II gene expression in mouse B cells. In B cells, a subset of the CTCF regions interacted with each other, creating a three-dimensional architecture for the locus. Additional interactions occurred between MHC-II promoters and the CTCF sites. In contrast, a novel configuration occurred in plasma cells, which do not express MHC-II genes. Ectopic CIITA expression in plasma cells to induce MHC-II expression resulted in high levels of MHC-II proteins, but did not alter the plasma cell architecture completely. These data suggest that reorganizing the three-dimensional chromatin architecture is an epigenetic mechanism that accompanies the silencing of MHC-II genes as part of the cell fate commitment of plasma cells.

CTCF and ncRNA Regulate the Three-Dimensional Structure of Antigen Receptor Loci to Facilitate V(D)J Recombination.

At both the immunoglobulin heavy and kappa light chain loci, there are >100 functional variable (V) genes spread over >2 Mb that must move into close proximity in 3D space to the (D)J genes to create a diverse repertoire of antibodies. Similar events take place at the T cell receptor (TCR) loci to create a wide repertoire of TCRs. In this review, we will discuss the role of CTCF in forming rosette-like structures at the antigen receptor (AgR) loci, and the varied roles it plays in alternately facilitating and repressing V(D)J rearrangements. In addition, non-coding RNAs, also known as germline transcription, can shape the 3D configuration of the Igh locus, and presumably that of the other AgR loci. At the Igh locus, this could occur by gathering the regions being transcribed in the VH locus into the same transcription factory where Iµ is being transcribed. Since the Iµ promoter, Eµ, is adjacent to the DJH rearrangement to which one V gene will ultimately rearrange, the process of germline transcription itself, prominent in the distal half of the VH locus, may play an important and direct role in locus compaction. Finally, we will discuss the impact of the transcriptional and epigenetic landscape of the Igh locus on VH gene rearrangement frequencies.

Deep sequencing of the murine IgH repertoire reveals complex regulation of nonrandom V gene rearrangement frequencies.

A diverse Ab repertoire is formed through the rearrangement of V, D, and J segments at the IgH (Igh) loci. The C57BL/6 murine Igh locus has >100 functional VH gene segments that can recombine to a rearranged DJH. Although the nonrandom usage of VH genes is well documented, it is not clear what elements determine recombination frequency. To answer this question, we conducted deep sequencing of 5'-RACE products of the Igh repertoire in pro-B cells, amplified in an unbiased manner. Chromatin immunoprecipitation-sequencing results for several histone modifications and RNA polymerase II binding, RNA-sequencing for sense and antisense noncoding germline transcripts, and proximity to CCCTC-binding factor (CTCF) and Rad21 sites were compared with the usage of individual V genes. Computational analyses assessed the relative importance of these various accessibility elements. These elements divide the Igh locus into four epigenetically and transcriptionally distinct domains, and our computational analyses reveal different regulatory mechanisms for each region. Proximal V genes are relatively devoid of active histone marks and noncoding RNA in general, but having a CTCF site near their recombination signal sequence is critical, suggesting that being positioned near the base of the chromatin loops is important for rearrangement. In contrast, distal V genes have higher levels of histone marks and noncoding RNA, which may compensate for their poorer recombination signal sequences and for being distant from CTCF sites. Thus, the Igh locus has evolved a complex system for the regulation of V(D)J rearrangement that is different for each of the four domains that comprise this locus.

Multiple histone methyl and acetyltransferase complex components bind the HLA-DRA gene.

Major histocompatibility complex class II (MHC-II) genes are fundamental components that contribute to adaptive immune responses. While characterization of the chromatin features at the core promoter region of these genes has been studied, the scope of histone modifications and the modifying factors responsible for activation of these genes are less well defined. Using the MHC-II gene HLA-DRA as a model, the extent and distribution of major histone modifications associated with active expression were defined in interferon-γ induced epithelial cells, B cells, and B-cell mutants for MHC-II expression. With active transcription, nucleosome density around the proximal regulatory region was diminished and histone acetylation and methylation modifications were distributed throughout the gene in distinct patterns that were dependent on the modification examined. Irrespective of the location, the majority of these modifications were dependent on the binding of either the X-box binding factor RFX or the class II transactivator (CIITA) to the proximal regulatory region. Importantly, once established, the modifications were stable through multiple cell divisions after the activating stimulus was removed, suggesting that activation of this system resulted in an epigenetic state. A dual crosslinking chromatin immunoprecipitation method was used to detect histone modifying protein components that interacted across the gene. Components of the MLL methyltransferase and GCN5 acetyltransferase complexes were identified. Some MLL complex components were found to be CIITA independent, including MLL1, ASH2L and RbBP5. Likewise, GCN5 containing acetyltransferase complex components belonging to the ATAC and STAGA complexes were also identified. These results suggest that multiple complexes are either used or are assembled as the gene is activated for expression. Together the results define and illustrate a complex network of histone modifying proteins and multisubunit complexes participating in MHC-II transcription.

Regulation of major histocompatibility complex class II genes.

The major histocompatibility complex class II (MHC-II) genes are regulated at the level of transcription. Recent studies have shown that chromatin modification is critical for efficient transcription of these genes, and a number of chromatin modifying complexes recruited to MHC-II genes have been described. The MHC-II genes are segregated from each other by a series of chromatin elements, termed MHC-II insulators. Interactions between MHC-insulators and the promoters of MHC-II genes are mediated by the insulator factor CCCTC-binding factor and are critical for efficient expression. This regulatory mechanism provides a novel view of how the entire MHC-II locus is assembled architecturally and can be coordinately controlled.