Post-transcriptional Regulation of De Novo Lipogenesis by mTORC1-S6K1-SRPK2 Signaling.

mTORC1 is a signal integrator and master regulator of cellular anabolic processes linked to cell growth and survival. Here, we demonstrate that mTORC1 promotes lipid biogenesis via SRPK2, a key regulator of RNA-binding SR proteins. mTORC1-activated S6K1 phosphorylates SRPK2 at Ser494, which primes Ser497 phosphorylation by CK1. These phosphorylation events promote SRPK2 nuclear translocation and phosphorylation of SR proteins. Genome-wide transcriptome analysis reveals that lipid biosynthetic enzymes are among the downstream targets of mTORC1-SRPK2 signaling. Mechanistically, SRPK2 promotes SR protein binding to U1-70K to induce splicing of lipogenic pre-mRNAs. Inhibition of this signaling pathway leads to intron retention of lipogenic genes, which triggers nonsense-mediated mRNA decay. Genetic or pharmacological inhibition of SRPK2 blunts de novo lipid synthesis, thereby suppressing cell growth. These results thus reveal a novel role of mTORC1-SRPK2 signaling in post-transcriptional regulation of lipid metabolism and demonstrate that SRPK2 is a potential therapeutic target for mTORC1-driven metabolic disorders.

Increased health care costs associated with new persistent opioid use after major surgery in opioid-naive patients.

BACKGROUND: Opioid use after surgery is associated with increased health care utilization and costs. Although some studies show that surgical patients may later become persistent opioid users, data on the association between new persistent opioid use after surgery and health care utilization and costs are lacking. OBJECTIVE: To compare health care utilization and costs after major inpatient or METHODS: The IBM MarketScan Research databases were used to identify opioid-naive patients with major inpatient or outpatient surgeries and at least 1 year of continuous enrollment before and after this index surgery. Cohorts were stratified by new persistent opioid utilization status, setting of surgery (inpatient, outpatient), and payer (commercial, Medicare, Medicaid). Patients were considered new persistent opioid users if they had at least 1 opioid claim 4-90 days after index surgery and at least 1 opioid claim 91-180 days after index surgery. Patients with opioid prescription claims between 1 year and 15 days before their index event were excluded. Health care utilization and costs (excluding index surgery) were measured in the 1-year period after surgery. Predicted costs and cost ratios were estimated using multivariable log-linked gamma-family generalized linear models. RESULTS: In the inpatient cohorts, 827,583 commercial, 186,154 Medicare, and 104,734 Medicaid patients were included in the study, and the incidence of new persistent opioid use in these cohorts was 4.1%, 5.6%, and 7.1%, respectively. In the outpatient cohorts, 1,542,565 commercial, 390,876 Medicare, and 94,878 Medicaid patients were selected, with 2.0%, 1.5%, and 6.4% new persistent opioid use, respectively. Across all 3 payers in both surgical settings, patients with new persistent opioid use had a higher comorbidity burden and more use of concomitant medications in the baseline period. In the 1-year period after index surgery, patients with new persistent opioid use had more inpatient admissions, emergency department visits, and ambulance/paramedic service use than patients without persistent use, regardless of payer and setting. Patients with new persistent opioid use had approximately 5 times more opioid prescriptions and also had more nonopioid pharmacy claims than those without persistent use across all cohorts. After covariate adjustment, predicted 1-year total health care costs were significantly higher for patients with new persistent opioid use compared with those without persistent use for all comparisons (commercial inpatient: $29,499 vs. $11,798; Medicare inpatient: $34,455 vs. $21,313; Medicaid inpatient: $14,622 vs. $6,678; commercial outpatient: $18,751 vs. $7,517; Medicare outpatient ($26,411 vs. $13,577; Medicaid outpatient: $12,381 vs. $6,784; all P < 0.001). CONCLUSIONS: New persistent opioid use after major surgery in opioid-naive patients is associated with increased health care utilization and costs in the year after surgery across all surgical settings and payers. DISCLOSURES: Funding for this study was provided by Heron Therapeutics, which participated in analysis and interpretation of data, drafting, reviewing, and approving the publication. All authors contributed to the analysis and interpretation of the data and development of the publication and maintained control over the final content. England and Evans-Shields are employees of Heron Therapeutics. Kong, Lew, Zimmerman, and Henriques are employees of IBM Watson Health, which was compensated by Heron Therapeutics for conducting this research. Brummett is a paid consultant for Heron Therapeutics, Vertex Pharmaceuticals, and Alosa Health and provides expert testimony. He further reports receipt of research funding from MDHHS (Sub K Michigan Open), NIDA (Centralized Pain Opioid Non-Responsiveness R01 DA038261-05), NIH0DHHS-US-16 PAF 07628 (R01 NR017096-05), NIH-DHHS (P50 AR070600-05 CORT), NIH-DHHS-US (K23 DA038718-04), NIH-DHHS-US-16-PAF06270 (R01 HD088712-05), NIH-DHHS-US-17-PAF02680 (R01 DA042859-05), and UM Michigan Genomics Initiative and holds a patent for peripheral perineural dexmedetomidine. Sun reports funding from the National Institute on Drug Abuse (K08DA042314) as well as consulting fees from the Mission Lisa Foundation that are unrelated to this work.

Health Care Burden Associated with Outpatient Opioid Use Following Inpatient or Outpatient Surgery.

BACKGROUND: The treatment of postsurgical pain with prescription opioids has been associated with persistent opioid use and increased health care utilization and costs. OBJECTIVE: To compare the health care burden between opioid-naive adult patients who were prescribed opioids after a major surgery and opioidnaive adult patients who were not prescribed opioids. METHODS: Administrative claims data from the IBM Watson Health MarketScan Research Databases for 2010-2016 were used. Opioid-naive adult patients who underwent major inpatient or outpatient surgery and who had at least 1 year of continuous enrollment before and after the index surgery date were eligible for inclusion. Cohorts were defined based on an opioid pharmacy claim between 7 days before index surgery and 1 year after index surgery (opioid use during surgery and inpatient use were not available). To ensure an opioid-naive population, patients with opioid claims between 365 and 8 days before surgery were excluded. Acute medical outcomes, opioid utilization, health care utilization, and costs were measured during the post-index period (index surgery hospitalization and day of index outpatient surgery not included). Predicted costs were estimated from multivariable log-linked gamma-generalized linear models. RESULTS: The final sample consisted of 1,174,905 opioid-naive patients with an inpatient surgery (73% commercial, 20% Medicare, 7% Medicaid) and 2,930,216 opioid-naive patients with an outpatient surgery (74% commercial, 23% Medicare, and 3% Medicaid). Opioid use after discharge was common among all 3 payer types but was less common among Medicare patients (63% inpatient/43% outpatient) than patients with commercial (80% inpatient/75% outpatient) or Medicaid insurance (86% inpatient/81% outpatient). Across all 3 payers, opioid users were younger, were more likely to be female, and had a higher preoperative comorbidity burden than nonopioid users. In unadjusted analyses, opioid users tended to have more hospitalizations, emergency department visits, and pharmacy claims. Adjusted predicted 1-year post-period total health care costs were significantly higher (P< 0.001) for opioid users than nonopioid users for commercial insurance (inpatient: $22,209 vs. $14,439; outpatient: $13,897 vs. $8,825), Medicare (inpatient: $31,721 vs. $26,761; outpatient: $24,529 vs. $15,225), and Medicaid (inpatient: $13,512 vs. $9,204; outpatient: $11,975 vs. $8,212). CONCLUSIONS: Filling an outpatient opioid prescription (vs. no opioid prescription) in the 1 year after inpatient or outpatient surgery was associated with increased health care utilization and costs across all payers. DISCLOSURES: Funding for this study was provided by Heron Therapeutics, which participated in analysis and interpretation of data, drafting, reviewing, and approving the publication. All authors contributed to the development of the publication and maintained control over the final content. Brummett is a paid consultant for Heron Therapeutics and Recro Pharma and reports receipt of research funding from MDHHS (Sub K Michigan Open), NIDA (Centralized Pain Opioid Non-Responsiveness R01 DA038261-05), NIH0DHHS-US-16 PAF 07628 (R01 NR017096-05), NIH-DHHS (P50 AR070600-05 CORT), NIH-DHHS-US (K23 DA038718-04), NIH-DHHS-US-16-PAF06270 (R01 HD088712-05), NIH-DHHS-US-17-PAF02680 (R01 DA042859-05), and UM Michigan Genomics Initiative and holding a patent for peripheral perineural dexmedetomidine. Oderda is a paid consultant for Heron Therapeutics. Pawasauskas is a paid consultant to Heron Therapeutics and Mallinckrodt Pharmaceuticals. England and Evans-Shields are employees of Heron Therapeutics. Kong, Lew, Zimmerman, and Henriques are employees of IBM Watson Health, which was compensated by Heron Therapeutics for conducting this research. Portions of this work were presented as a poster at the AMCP Managed Care and Specialty Pharmacy Annual Meeting 2019; March 25-28, 2019; San Diego, CA.