Holistic Review in Family Medicine Residency Programs: A CERA Study.

BACKGROUND AND OBJECTIVES: Interest in using holistic review for residency recruitment as a strategy to improve the diversity of the physician workforce has increased. However, no data are published on the prevalence of holistic review in the selection process for family medicine residency programs. We designed this study to assess programs' knowledge, skills, and attitudes; prevalence; barriers to implementation; and program characteristics associated with the use of holistic review. METHODS: Data for this study were elicited as part of a 2023 survey conducted by the Council of Academic Family Medicine Educational Research Alliance. The nationwide, web-based survey was sent to 739 family medicine residency program directors. RESULTS: A total of 309 program directors completed the holistic review portion of the survey. Programs that understood and agreed with holistic review used it more in their selection process. Holistic review was more common in programs with higher rates of residents, faculty, and patients that are underrepresented in medicine. Barriers to holistic review utilization were increased number of applicants, increased resources associated with holistic review, and lack of consensus on the holistic review approach. CONCLUSIONS: The holistic review process is an area of growing interest to diversify the physician workforce, especially among residencies caring for underresourced communities. Further discussions on the specific scoring rubrics of family medicine residency programs that use holistic review are needed and could help programs that are facing barriers. Widespread use of holistic review to diversify the physician workforce has the potential to improve patient care access and health.

Loss of the stress sensor GADD45A promotes stem cell activity and ferroptosis resistance in LGR4/HOXA9-dependent AML.

ABSTRACT: The overall prognosis of acute myeloid leukemia (AML) remains dismal, largely because of the inability of current therapies to kill leukemia stem cells (LSCs) with intrinsic resistance. Loss of the stress sensor growth arrest and DNA damage-inducible 45 alpha (GADD45A) is implicated in poor clinical outcomes, but its role in LSCs and AML pathogenesis is unknown. Here, we define GADD45A as a key downstream target of G protein-coupled receptor (LGR)4 pathway and discover a regulatory role for GADD45A loss in promoting leukemia-initiating activity and oxidative resistance in LGR4/HOXA9-dependent AML, a poor prognosis subset of leukemia. Knockout of GADD45A enhances AML progression in murine and patient-derived xenograft (PDX) mouse models. Deletion of GADD45A induces substantial mutations, increases LSC self-renewal and stemness in vivo, and reduces levels of reactive oxygen species (ROS), accompanied by a decreased response to ROS-associated genotoxic agents (eg, ferroptosis inducer RSL3) and acquisition of an increasingly aggressive phenotype on serial transplantation in mice. Our single-cell cellular indexing of transcriptomes and epitopes by sequencing analysis on patient-derived LSCs in PDX mice and subsequent functional studies in murine LSCs and primary AML patient cells show that loss of GADD45A is associated with resistance to ferroptosis (an iron-dependent oxidative cell death caused by ROS accumulation) through aberrant activation of antioxidant pathways related to iron and ROS detoxification, such as FTH1 and PRDX1, upregulation of which correlates with unfavorable outcomes in patients with AML. These results reveal a therapy resistance mechanism contributing to poor prognosis and support a role for GADD45A loss as a critical step for leukemia-initiating activity and as a target to overcome resistance in aggressive leukemia.