Family Medicine Resident Perceptions on Racial Justice Training in Residency: A CERA Study.

Introduction: Structural racism is a root cause of health disparities. While family medicine residency programs recognize the importance of addressing race in medicine, it is unclear how many programs have established racial justice training (RJT). This study examines residents\u27 views on the current state of RJT in their respective programs. Methods: This survey was part of the Council of Academic Family Medicine Educational Research Alliance (CERA) 2021 national survey of family medicine residents. Questions addressed RJT, resident reported barriers to implementing such training, and recommendations for change. Results: Of the family medicine residents who responded (n=266), the majority of individuals (91.5%) and their residency programs (65.0%) stated that addressing racism in medicine is an educational priority. Residents reported a minority of their programs (17.3%) have a longitudinal curriculum. Residents who received RJT in residency are more likely to be in communities of color (P=.03). The top requests included recruiting faculty and residents of color, and establishing community-based partnerships. Conclusions: Few residencies have been able to implement RJT to the extent that residents\u27 desire. Lack of curricular time and faculty training were commonly cited barriers. Strategies to address these barriers and implement RJT across residencies are needed to combat structural racism

Interferon regulatory factor-5 deficiency ameliorates disease severity in the MRL/lpr mouse model of lupus in the absence of a mutation in DOCK2.

Interferon regulatory factor 5 (IRF5) polymorphisms are strongly associated with an increased risk of developing the autoimmune disease systemic lupus erythematosus. In mouse lupus models, IRF5-deficiency was shown to reduce disease severity consistent with an important role for IRF5 in disease pathogenesis. However these mouse studies were confounded by the recent demonstration that the IRF5 knockout mouse line contained a loss-of-function mutation in the dedicator of cytokinesis 2 (DOCK2) gene. As DOCK2 regulates lymphocyte trafficking and Toll-like receptor signaling, this raised the possibility that some of the protective effects attributed to IRF5 deficiency in the mouse lupus models may instead have been due to DOCK2 deficiency. We have therefore here evaluated the effect of IRF5-deficiency in the MRL/lpr mouse lupus model in the absence of the DOCK2 mutation. We find that IRF5-deficient (IRF5-/-) MRL/lpr mice develop much less severe disease than their IRF5-sufficient (IRF5+/+) littermates. Despite markedly lower serum levels of anti-nuclear autoantibodies and reduced total splenocyte and CD4+ T cell numbers, IRF5-/- MRL/lpr mice have similar numbers of all splenic B cell subsets compared to IRF5+/+ MRL/lpr mice, suggesting that IRF5 is not involved in B cell development up to the mature B cell stage. However, IRF5-/- MRL/lpr mice have greatly reduced numbers of spleen plasmablasts and bone marrow plasma cells. Serum levels of B lymphocyte stimulator (BLyS) were markedly elevated in the MRL/lpr mice but no effect of IRF5 on serum BLyS levels was seen. Overall our data demonstrate that IRF5 contributes to disease pathogenesis in the MRL/lpr lupus model and that this is due, at least in part, to the role of IRF5 in plasma cell formation. Our data also suggest that combined therapy targeting both IRF5 and BLyS might be a particularly effective therapeutic approach in lupus

Less severe renal disease in IRF5-deficient MRL/lpr mice.

<p>A and B, Kidneys from IRF5^+/+ (n = 13), IRF5^+/− (n = 10) and IRF5^−/− (n = 10) female MRL/lpr littermates were analyzed at 16 weeks of age. Renal disease was quantified by measuring the percentage of glomeruli in each mouse showing evidence of mesangial expansion (A), and the percentage of glomeruli in each mouse with crescents or necrosis (B). C, Serum BUN levels in IRF5^+/+ (n = 12), IRF5^+/− (n = 12) and IRF5^−/− (n = 12) female MRL/lpr littermates at 16 weeks of age. Bars represent mean ± SEM. *p<0.05; **p<0.01.</p

IRF5-deficient MRL/lpr mice have greatly reduced numbers of spleen plasmablasts and bone marrow plasma cells.

<p>A. Spleen cells from IRF5^+/+ and IRF5^−/− MRL/lpr mice at 4 months of age were stained with antibodies against CD19, CD3, B220, CD22, CD44 and CD138. Plasmablasts (B220^lowCD22^lowCD44⁺CD138⁺) were identified within the splenic B cell (CD19⁺CD3⁻) population. Bone-marrow cells from IRF5^+/+ and IRF5^−/− MRL/lpr mice were stained with antibodies against CD4, CD8, F4/80, Gr-1, B220 and CD138. CD4⁻CD8⁻F4/80⁻Gr-1⁻ cells were gated to analyze plasma cells (B220⁻CD138⁺). B. Numbers and percentages of spleen plasmablasts and bone marrow plasma cells of IRF5^+/+ (filled circles) and IRF5^−/− (open circles) MRL/lpr mice at 2, 3 and 4 months of age are shown. Each dot represents an individual mouse. Bars represent mean ± SEM. *p<0.05; **p<0.01.</p

The experimental mice used in this study did not have the DOCK2 mutation.

<p>PCR to detect the DOCK2 mutation was performed on tail DNA of all mice used in this study. Experimental mice are indicated by number. DNA from a mouse with the DOCK2 mutation (Mu) was used as a positive control and gave a PCR product for the DOCK2 mutation (305 bp). DNA from a mouse without the DOCK2 mutation (WT) was used as a negative control. CD19 PCR (477 bp) was used as an internal control to verify the adequacy of DNA preparation in each sample.</p

Lymphadenopathy, splenomegaly and splenic CD4⁺ T cell numbers are reduced in IRF5-deficient MRL/lpr mice.

<p>A. Lymph node weight and B. Spleen weight and splenocyte number in IRF5^+/+, IRF5^+/− and IRF5^−/− female MRL/lpr littermates. C. Percentages (upper panels) and total number (lower panels) of splenic B cells and T cell populations in IRF5^+/+, IRF5^+/− and IRF5^−/− female MRL/lpr littermates analyzed by flow cytometry. Mice were analyzed at 16 weeks of age. Bars represent mean ± SEM. *p<0.05; **p<0.01.</p

B cell development in IRF5^+/+ and IRF5^−/− MRL/lpr mice.

<p>Bone marrow (A) and spleen cells (B) from 2, 3, and 4-month-old IRF5^+/+ (filled circles) and IRF5^−/− (open circles) MRL/lpr mice were stained with antibodies against B220, AA4.1, IgM, CD19, CD21 and CD23. A. In bone marrow, percentages of B220⁺AA4.1⁺ (pro-B, pre-B and immature B) and B220⁺AA4.1⁻ (mature B) cells, percentages of Hardy fractions B-D (pro-B and pre-B; B220⁺IgM⁻), fraction E (immature B; B220^intermediateIgM⁺), and fraction F (mature or re-circulating B; B220^highIgM⁺) were determined. B. In spleen, percentages and cell numbers of B cells (CD19⁺), immature B cells (B220⁺AA4.1⁺) and mature B cells (B220⁺AA4.1⁻) were determined. Mature B cells were further classified as marginal zone (MZ) B cells (CD21⁺CD23^low) and follicular (FO) B cells (CD23⁺) based on CD21 and CD23 expression. Each dot represents an individual mouse. Bars represent mean ± SEM. *p<0.05; **p<0.01.</p

Decreased autoantibody production in IRF5-deficient MRL/lpr mice.

<p>Sera from IRF5^+/+, IRF5^+/− and IRF5^−/− female MRL/lpr littermates were analyzed at 16 weeks of age. Anti-nuclear antibody (ANA) titers were measured by HEp2 cell immunofluorescence (left-hand panel) and anti-double stranded DNA (dsDNA) antibodies were measured by Crithidia lucillae luminescence (right-hand panel). Bars represent mean ± SEM. *p<0.05; **p<0.01.</p

Serum BLyS levels are elevated in MRL/lpr mice but are not affected by IRF5 deficiency.

<p>A and B. BLyS levels in the sera of IRF5^+/+ MRL/lpr mice and IRF5^−/− MRL/lpr mice (A), and C57BL/6 mice (B) at several ages were measured by ELISA. C. BLyS levels in the sera of sixteen week old IRF5^+/+ (n = 11), IRF5^+/− (n = 6) and IRF5^−/− (n = 11) female MRL/lpr mice were measured by ELISA. The BLyS serum levels of the C57BL/6 mice (n = 10) shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0103478#pone-0103478-g007" target="_blank">figure 7B</a> (age range 13–32 weeks) are included for data comparison. Bars represent mean ± SEM. No significant differences were found between any of the MRL/lpr experimental groups.</p

Increased survival in IRF5-deficient MRL/lpr mice.

<p>IRF5^+/+ (n = 12), IRF5^+/− (n = 14) and IRF5^−/− (n = 14) female MRL/lpr littermates were observed until they met the criteria for euthanasia based on predetermined humane endpoints. ** p<0.01.</p