Sepsis-induced myeloid-derived suppressor cells (MDSCs) increase mortality risk. We previously identified that long non-coding RNA Hotairm1 supports myeloid precursor shifts to Gr1<sup>+</sup>CD11b<sup>+</sup> MDSCs during mouse sepsis. A major unanswered question is what molecular processes control Hotairm1 expression. In this study, we found by a genetic deletion that a specific PU.1-binding site is indispensable in controlling Hotairm1 transcription. We then identified H3K4me3 and H3K27me3 at the PU.1 site on the Hotairm1 promoter. Controlling an epigenetic switch of Hotairm1 transcription by PU.1 was histone KDM6A demethylase for H3K27me3 that derepressed its transcription with possible contributions from Ezh2 methyltransferase for H3K27me3. KDM6A knockdown in MDSCs increased H3K27me3, decreased H3K4me3, and inhibited Hotairm1 transcription activation by PU.1. These results enlighten clinical translation research of PU.1 epigenetic regulation as a potential sepsis immune-checkpoint treatment site.
Background Currently, there is limited literature on the impact of the COVID-19 infection on medications and medical conditions in COVID-19 intensive care unit (ICU) survivors. Our study is, to our knowledge, the first multicenter study to describe the prevalence of new medical conditions and medication changes at hospital discharge in COVID-19 ICU survivors. Objective To determine the number of medical conditions and medications at hospital admission compared to at hospital discharge in COVID-19 ICU survivors. Methods Retrospective multicenter observational study (7 ICUs) evaluated new medical conditions and medication changes at hospital discharge in patients with COVID-19 infection admitted to an ICU between March 1, 2020, to March 1, 2021. Patient and hospital characteristics, baseline and hospital discharge medication and medical conditions, ICU and hospital length of stay, and Charlson comorbidity index were collected. Descriptive statistics were used to describe patient characteristics and number and type of medical conditions and medications. Paired t-test was used to compare number of medical conditions and medications from hospital discharge to admission. Results Of the 973 COVID-19 ICU survivors, 67.4% had at least one new medical condition and 88.2% had at least one medication change. Median number of medical conditions (increased from 3 to 4, P < .0001) and medications (increased from 5 to 8, P < .0001) increased from admission to discharge. Most common new medical conditions at discharge were pulmonary disorders, venous thromboembolism, psychiatric disorders, infection, and diabetes. Most common therapeutic categories associated with medication change were cardiology, gastroenterology, pain, hematology, and endocrinology. Conclusion and Relevance Our study found that the number of medical conditions and medications increased from hospital admission to discharge. Our results provide additional data to help guide providers on using targeted approaches to manage medications and diseases in COVID-19 ICU survivors after hospital discharge.
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