BACKGROUND: Black patients are disproportionately affected by COVID-19. The purpose of this study was to compare risks of hospitalization of Black and non-Black COVID-19 patients presenting to the emergency department and, of those hospitalized, to compare mortality and acute kidney injury. METHODS: A retrospective cohort of 831 adult COVID-19 patients (68.5% Black) who presented to the emergency departments of four academic hospitals, March 1, 2020-May 31, 2020. The primary outcome was risk of hospitalization among Blacks vs. non-Blacks. Secondary outcomes were mortality and acute kidney injury, among hospitalized patients. RESULTS: The crude odds of hospitalization were not different in Black vs. non-Black patients; however, with adjustment for age, Blacks had 55% higher odds of hospitalization. Mortality differed most in the model adjusted for age alone. Acute kidney injury was more common in the Black hospitalized patients, regardless of adjustment. Stratified analyses suggested that disparities in the risk of hospitalization and of in-hospital acute kidney injury were highest in the youngest patients. CONCLUSIONS: Our report shows that Black and non-Black patients presenting to the emergency department with COVID-19 had similar risks of hospitalization and, of those who were hospitalized, similar mortality when adjusted for multiple factors. Blacks had higher risk of acute kidney injury. Our results suggest that examination of disparities without exploration of the individual effects of age and comorbidities may mask important patterns. While stratified analyses suggest that disparities in outcomes may differ substantially by age and comorbid conditions, further exploration among these important subgroups is needed to better target interventions to reduce disparities in COVID-19 clinical outcomes.

Purpose

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by an extensive fibroinflammatory stroma, which includes abundant cancer-associated fibroblast (CAF) populations. PDAC CAFs are heterogeneous, but the nature of this heterogeneity is incompletely understood. The Hedgehog pathway functions in PDAC in a paracrine manner, with ligands secreted by cancer cells signaling to stromal cells in the microenvironment. Previous reports investigating the role of Hedgehog signaling in PDAC have been contradictory, with Hedgehog signaling alternately proposed to promote or restrict tumor growth. In light of the newly discovered CAF heterogeneity, we investigated how Hedgehog pathway inhibition reprograms the PDAC microenvironment.

Experimental design

We used a combination of pharmacologic inhibition, gain- and loss-of-function genetic experiments, cytometry by time-of-flight, and single-cell RNA sequencing to study the roles of Hedgehog signaling in PDAC.

Results

We found that Hedgehog signaling is uniquely activated in fibroblasts and differentially elevated in myofibroblastic CAFs (myCAF) compared with inflammatory CAFs (iCAF). Sonic Hedgehog overexpression promotes tumor growth, while Hedgehog pathway inhibition with the smoothened antagonist, LDE225, impairs tumor growth. Furthermore, Hedgehog pathway inhibition reduces myCAF numbers and increases iCAF numbers, which correlates with a decrease in cytotoxic T cells and an expansion in regulatory T cells, consistent with increased immunosuppression.

Conclusions

Hedgehog pathway inhibition alters fibroblast composition and immune infiltration in the pancreatic cancer microenvironment.