Limitations on Postoperative Opioid Prescriptions and Effects on Health Care Resource Use Following Elective Anterior Cervical Discectomy and Fusion.

OBJECTIVE: To curb the misuse of postoperative prescription opioids, the state of North Carolina enacted the Strengthen Opioid Misuse Prevention (STOP) Act of 2017 limiting the duration of initial postoperative opioid prescriptions. The purpose of this study was to evaluate the STOP Act's effect on health care resource use by comparing patient outcomes and opioid prescribing practices following elective anterior cervical discectomy and fusion (ACDF). METHODS: Outcomes and opioid prescribing data were retrospectively evaluated for Pre-Law (January 1, 2017, to December 31, 2017) and Post-Law (January 1, 2018, to December 31, 2018) elective 1- to 4-level anterior cervical discectomy and fusion patient cohorts. Outcome measures included hospital and clinic resource use in the form of emergency department visits, readmissions, major postoperative complications, number of clinic visits, or number of clinic phone calls by patients reporting uncontrolled pain or requesting new opioid prescriptions. Opioid-prescribing practices in the form of discharge prescription number of pills and total morphine milliequivalents also were recorded. RESULTS: Surrounding the STOP Act's implementation, there was no significant difference (P > 0.05) in emergency department visits, readmissions, major complications, number of postoperative clinic visits, or number of clinic phone calls for uncontrolled pain or new prescription requests. There was a significant decline in mean discharge prescription number of pills (89.7 vs. 67.0, P < 0.001), and average morphine milliequivalents (683.4 vs. 509.6, P < 0.001). CONCLUSIONS: This may reflect overprescribing in this population, where larger opioid prescriptions were likely not needed to manage pain that would otherwise require a return to care.

ABC Transporter Inhibition Plus Dexamethasone Enhances the Efficacy of Convection Enhanced Delivery in H3.3K27M Mutant Diffuse Intrinsic Pontine Glioma.

BACKGROUND: An impermeable blood-brain barrier and drug efflux via ATP-binding cassette (ABC) transporters such as p-glycoprotein may contribute to underwhelming efficacy of peripherally delivered agents to treat diffuse intrinsic pontine glioma (DIPG). OBJECTIVE: To explore the pharmacological augmentation of convection-enhanced delivery (CED) infusate for DIPG. METHODS: The efficacy of CED dasatinib, a tyrosine kinase inhibitor, in a transgenic H3.3K27M mutant murine model was assessed. mRNA expression of ABCB1 (p-glycoprotein) was analyzed in 14 tumor types in 274 children. In Vitro viability studies of dasatinib, the p-glycoprotein inhibitor, tariquidar, and dexamethasone were performed in 2 H3.3K27M mutant cell lines. Magnetic resonance imaging (MRI) was used to evaluate CED infusate (gadolinium/dasatinib) distribution in animals pretreated with tariquidar and dexamethasone. Histological assessment of apoptosis was performed. RESULTS: Continuous delivery CED dasatinib improved median overall survival (OS) of animals harboring DIPG in comparison to vehicle (39.5 and 28.5 d, respectively; P = .0139). Mean ABCB1 expression was highest in K27M gliomas. In Vitro, the addition of tariquidar and dexamethasone further enhanced the efficacy of dasatinib (P < .001). In Vivo, MRI demonstrated no difference in infusion dispersion between animals pretreated with dexamethasone plus tariquidar prior to CED dasatinib compared to the CED dasatinib. However, tumor apoptosis was the highest in the pretreatment group (P < .001). Correspondingly, median OS was longer in the pretreatment group (49 d) than the dasatinib alone group (39 d) and no treatment controls (31.5 d, P = .0305). CONCLUSION: ABC transporter inhibition plus dexamethasone enhances the efficacy of CED dasatinib, resulting in enhanced tumor cellular apoptosis and improved survival in H3.3K27M mutant DIPG.

Comparison of the adolescent and adult mouse prefrontal cortex proteome.

Adolescence is a developmental period characterized by unique behavioral phenotypes (increased novelty seeking, risk taking, sociability and impulsivity) and increased risk for destructive behaviors, impaired decision making and psychiatric illness. Adaptive and maladaptive adolescent traits have been associated with development of the medial prefrontal cortex (mPFC), a brain region that mediates regulatory control of behavior. However, the molecular changes that underlie brain development and behavioral vulnerability have not been fully characterized. Using high-throughput 2D DIGE spot profiling with identification by MALDI-TOF mass spectrometry, we identified 62 spots in the PFC that exhibited age-dependent differences in expression. Identified proteins were associated with diverse cellular functions, including intracellular signaling, synaptic plasticity, cellular organization and metabolism. Separate Western blot analyses confirmed age-related changes in DPYSL2, DNM1, STXBP1 and CFL1 in the mPFC and expanded these findings to the dorsal striatum, nucleus accumbens, motor cortex, amygdala and ventral tegmental area. Ingenuity Pathway Analysis (IPA) identified functional interaction networks enriched with proteins identified in the proteomics screen, linking age-related alterations in protein expression to cellular assembly and development, cell signaling and behavior, and psychiatric illness. These results provide insight into potential molecular components of adolescent cortical development, implicating structural processes that begin during embryonic development as well as plastic adaptations in signaling that may work in concert to bring the cortex, and other brain regions, into maturity.