Association Between Transfusion of RBCs and Subsequent Development of Delirium in Critically Ill Children.

OBJECTIVES: To determine the temporal relationship between the transfusion of RBCs and the subsequent development of delirium in a cohort of critically ill children. DESIGN: Nested retrospective cohort study within prospective cohort study. SETTING: Urban academic tertiary care PICU. PATIENTS: All consecutive admissions from September 2014 through August 2015. INTERVENTIONS: Children were screened twice daily for delirium during their PICU admission. MEASUREMENTS AND MAIN RESULTS: Among 1,547 independent admissions screened for delirium, 166 (10.7%) were transfused RBCs. Children who were transfused RBCs were more than twice as likely to be delirious during their admission compared with children who were never transfused, after controlling for known predictors of delirium development (adjusted odds ratio, 2.16; 95% CI, 1.38-3.37; p = 0.001). Among transfused children, a temporal relationship was observed between receipt of RBCs and the subsequent development of delirium. For each additional 10 mL/kg of RBCs transfused, the recipients were 90% more likely to develop delirium or coma in the 72 hours following the transfusion, after controlling for confounders (adjusted odds ratio, 1.90; 95% CI, 1.14-3.17; p = 0.01). Anemia (represented by nadir hemoglobin prior to transfusion) was not associated with delirium development. CONCLUSIONS: In this cohort of critically ill children, there is an independent association between the receipt of an RBC transfusion and the subsequent development of delirium. Further prospective studies are warranted to replicate this finding and investigate possible pathophysiologic mechanisms for this association.

miR-30 Family Controls Proliferation and Differentiation of Intestinal Epithelial Cell Models by Directing a Broad Gene Expression Program That Includes SOX9 and the Ubiquitin Ligase Pathway.

Proliferation and differentiation of intestinal epithelial cells (IECs) occur in part through precise regulation of key transcription factors, such as SOX9. MicroRNAs (miRNAs) have emerged as prominent fine-tuners of transcription factor expression and activity. We hypothesized that miRNAs, in part through the regulation of SOX9, may mediate IEC homeostasis. Bioinformatic analyses of the SOX9 3'-UTR revealed highly conserved target sites for nine different miRNAs. Of these, only the miR-30 family members were both robustly and variably expressed across functionally distinct cell types of the murine jejunal epithelium. Inhibition of miR-30 using complementary locked nucleic acids (LNA30bcd) in both human IECs and human colorectal adenocarcinoma-derived Caco-2 cells resulted in significant up-regulation of SOX9 mRNA but, interestingly, significant down-regulation of SOX9 protein. To gain mechanistic insight into this non-intuitive finding, we performed RNA sequencing on LNA30bcd-treated human IECs and found 2440 significantly increased genes and 2651 significantly decreased genes across three time points. The up-regulated genes are highly enriched for both predicted miR-30 targets, as well as genes in the ubiquitin-proteasome pathway. Chemical suppression of the proteasome rescued the effect of LNA30bcd on SOX9 protein levels, indicating that the regulation of SOX9 protein by miR-30 is largely indirect through the proteasome pathway. Inhibition of the miR-30 family led to significantly reduced IEC proliferation and a dramatic increase in markers of enterocyte differentiation. This in-depth analysis of a complex miRNA regulatory program in intestinal epithelial cell models provides novel evidence that the miR-30 family likely plays an important role in IEC homeostasis.