Impact of timing of multimodal analgesia in enhanced recovery after cesarean delivery protocols on postoperative opioids: A single center before-and-after study.

STUDY OBJECTIVE: Enhanced recovery after cesarean delivery (ERAC) programs aim to decrease maternal morbidity and aid in maternal recovery and return to baseline. Multimodal analgesia is an important element of ERAC protocols, but no consensus exists on the timing of medication administration. We compared maternal pain outcomes following scheduled cesarean delivery with modification of the timing of administration of multimodal analgesia with non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. DESIGN: Before-and-after study. SETTING: Labor and delivery unit at a single academic institution. INTERVENTION: NSAIDs and acetaminophen were administered as a fixed-interval alternating regimen every 3 h for the initial ERAC group (ERAC 1) and fixed-interval combined regimen every 6 h for the modified ERAC group (ERAC 2). ERAC 1 and ERAC 2 groups were compared to historical controls (Pre-ERAC). PATIENTS: 520 women undergoing scheduled cesarean delivery (Pre-ERAC n = 179, ERAC 1 n = 179, and ERAC 2 n = 162). MEASUREMENTS: The primary outcomes were postoperative total and daily opioid utilization as measured in morphine milligram equivalents (MME). Secondary outcomes included postoperative length of stay, maximum pain scores, and racial disparities in care. MAIN RESULTS: The modified schedule of non-opioid analgesics involving combined administration (ERAC 2) versus alternating administration (ERAC 1) of multimodal analgesia resulted in decreased total postoperative opioid utilization (median = 26.3 vs 52.5 MME, Bonferroni corrected P = 0.002). Total postoperative opioid utilization among the ERAC 2 group was also significantly reduced compared to the Pre-ERAC group (median = 26.3 vs 105.0 MME, Bonferroni corrected P < 0.0001). CONCLUSIONS: Multidisciplinary teams developing or modifying ERAC protocols for scheduled cesarean delivery should consider a combined administration at fixed intervals of NSAIDs and acetaminophen throughout the hospital stay to optimize postoperative pain management.

ADAR1 controls apoptosis of stressed cells by inhibiting Staufen1-mediated mRNA decay.

Both p150 and p110 isoforms of ADAR1 convert adenosine to inosine in double-stranded RNA (dsRNA). ADAR1p150 suppresses the dsRNA-sensing mechanism that activates MDA5-MAVS-IFN signaling in the cytoplasm. In contrast, the biological function of the ADAR1p110 isoform, which is usually located in the nucleus, is largely unknown. Here, we show that stress-activated phosphorylation of ADAR1p110 by MKK6-p38-MSK MAP kinases promotes its binding to Exportin-5 and its export from the nucleus. After translocating to the cytoplasm, ADAR1p110 suppresses apoptosis in stressed cells by protecting many antiapoptotic gene transcripts that contain 3'-untranslated-region dsRNA structures primarily comprising inverted Alu repeats. ADAR1p110 competitively inhibits binding of Staufen1 to the 3'-untranslated-region dsRNAs and antagonizes Staufen1-mediated mRNA decay. Our study reveals a new stress-response mechanism in which human ADAR1p110 and Staufen1 regulate surveillance of a set of mRNAs required for survival of stressed cells.

Functions of the RNA Editing Enzyme ADAR1 and Their Relevance to Human Diseases.

Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double-stranded RNA (dsRNA). Among the three types of mammalian ADARs, ADAR1 has long been recognized as an essential enzyme for normal development. The interferon-inducible ADAR1p150 is involved in immune responses to both exogenous and endogenous triggers, whereas the functions of the constitutively expressed ADAR1p110 are variable. Recent findings that ADAR1 is involved in the recognition of self versus non-self dsRNA provide potential explanations for its links to hematopoiesis, type I interferonopathies, and viral infections. Editing in both coding and noncoding sequences results in diseases ranging from cancers to neurological abnormalities. Furthermore, editing of noncoding sequences, like microRNAs, can regulate protein expression, while editing of Alu sequences can affect translational efficiency and editing of proximal sequences. Novel identifications of long noncoding RNA and retrotransposons as editing targets further expand the effects of A-to-I editing. Besides editing, ADAR1 also interacts with other dsRNA-binding proteins in editing-independent manners. Elucidating the disease-specific patterns of editing and/or ADAR1 expression may be useful in making diagnoses and prognoses. In this review, we relate the mechanisms of ADAR1's actions to its pathological implications, and suggest possible mechanisms for the unexplained associations between ADAR1 and human diseases.