Inpatient Buprenorphine Induction for Opioid Use Disorder in Pregnancy.

Objective Buprenorphine is a commonly used medication to manage opioid use disorder, however there is limited data to guide induction protocols specifically during pregnancy. Similar to non-pregnant patients the Clinical Opiate Withdrawal Scale (COWS) is often used to guide induction and titration of buprenorphine in pregnancy. The objective of this retrospective descriptive study is to assess the inpatient buprenorphine induction patterns, treatment retention, and pregnancy outcomes among obstetric patients with opioid use disorder seeking treatment.  Study design This was a retrospective study of obstetric patients with opioid use disorder admitted for inpatient buprenorphine induction at a large academic center between May 2015 to 2020. A descriptive analysis of the cohort, induction patterns, and dose retention after discharge were evaluated in addition to obstetric and neonatal outcomes. Results Sixty patients were admitted for inpatient buprenorphine induction at a median gestational age of 16.7 weeks. The median COWS score on presentation was 9. The starting dose for half of the patients (30 out of 60 patients) was 8 mg of buprenorphine, while 24 patients were started at 4 mg. The median duration of hospitalization was three days (range 2-12). The median buprenorphine dose upon discharge was 10 mg (range 4-20). Only 13 of the 35 patients (37%) who desired prenatal care at our institution returned to receive routine prenatal care. Of the 12 (20%) patients who delivered at our institution, nine were live births (75%). Among the live births, the median gestational age at delivery was 37.4 weeks, birth weight 3085 grams, and only one (8%) developed neonatal abstinence syndrome. Conclusion When using the Clinical Opiate Withdrawal Scale to guide inpatient buprenorphine titration for pregnant patients with opioid use disorder it takes approximately three days to establish a satisfactory maintenance dose with the median dose at discharge in this population being 10 mg. The majority of patients who followed up after hospital discharge did not need dose adjustments.

Uptake of postplacental intrauterine device placement at cesarean delivery.

BACKGROUND: Several studies have investigated the effectiveness of intrauterine device placement at cesarean delivery as a contraceptive method. However, national-level use and outcomes of a postplacental intrauterine device at cesarean delivery are currently understudied in the United States. OBJECTIVE: This study aimed to examine the trends, characteristics, and outcomes of patients who received a postplacental intrauterine device at cesarean delivery. STUDY DESIGN: This retrospective cohort study used the National Inpatient Sample. The study cohort included patients who underwent cesarean delivery from October 2015 to December 2018. The exclusion criteria included hemorrhage, chorioamnionitis, uterine anomaly, hysterectomy, and permanent surgical sterilization. Eligible cases were grouped on the basis of the use of a postplacental intrauterine device at cesarean delivery. The primary outcome measures were temporal trends and characteristics associated with the use of a postplacental intrauterine device at cesarean delivery, assessed using the generalized estimating equation model in multivariable analysis. The secondary outcome measure was perioperative morbidity (leukocytosis, endometritis, myometritis, and sepsis). Propensity score matching was used to balance the baseline characteristics. RESULTS: Among 2,983,978 patients who met the inclusion criteria, 10,145 patients (0.3%) received a postplacental intrauterine device at cesarean delivery. The use of a postplacental intrauterine device increased from 0.1% in the fourth quarter of 2015 to 0.6% in the fourth quarter of 2018 (P<.001). In a multivariable analysis, the use of a postplacental intrauterine device increased by 14% every quarter-year (adjusted odds ratio, 1.14; 95% confidence interval, 1.13-1.15). In addition, (1) patient characteristics of young age, non-White race, obesity, tobacco use, lowest quartile median household income, and insured with Medicaid; (2) hospital characteristics of large bed capacity and urban teaching setting in Northeast region; and (3) pregnancy characteristics of early gestational age at cesarean delivery, hypertensive disease, previous cesarean delivery, multifetal pregnancy, grand multiparity, placenta previa, and nonelective cesarean delivery represented the independent characteristics associated with the use of a postplacental intrauterine device (all P<.05). A regression tree model identified 35 discrete patterns of the use of a postplacental intrauterine device based on 8 factors (time, race or ethnicity, primary expected payer, obesity, hospital bed capacity, hospital teaching status, hospital region, and previous cesarean delivery). There were 9 patterns, representing 8.8% of the study population, exhibiting a use rate of ≥1.0%, whereas there were 7 patterns, representing 16.0% of the study population, exhibiting no use of a postplacental intrauterine device (absolute rate difference from the highest group to the lowest group, 4.7%). In a propensity score-matched model, postplacental intrauterine device placement at cesarean delivery was not associated with increased risk of measured morbidity (any, 1.8% vs 1.7%; odds ratio, 1.06; 95% confidence interval, 0.66-1.69; P=.812), including postpartum endometritis (1.2% vs 1.0%; odds ratio, 1.19; 95% confidence interval, 0.67-2.14; P=.554). CONCLUSION: The use of a postplacental intrauterine device at cesarean delivery increased significantly in recent years in the United States.

Patient characteristics of contraception and sterilization selection at vaginal delivery.

Objective: To examine patient characteristics among those who selected the long-acting reversible contraception (LARC) and surgical sterilization methods at vaginal delivery. Design: Retrospective cohort study. Setting: The National Inpatient Sample. Patients: A total of 8,013,785 vaginal deliveries from October 2016 to December 2019. Interventions: Exposure assignment per LARC (subdermal contraceptive implant [implants] or intrauterine device [IUD]) or surgical sterilization (bilateral salpingectomy [BS] or bilateral tubal ligation [BTL]) type. Main Outcome Measures: Utilization trends of LARC or surgical sterilization, assessed with linear segmented regression with log-transformation, and differences in patient characteristics per the exposure strata (implants vs. IUD in the LARC group and BS or BTL in the surgical sterilization group), assessed using the multivariate binary logistic regression model. Results: In a comparison between LARC and surgical sterilization, surgical sterilization use decreased from 1.90% to 1.55% (18.4% relative decrease), whereas LARC use increased from 0.35% to 1.02% (191% relative increase). In the LARC group, implant use (from 0.12% to 0.50%) increased more compared with IUD use (from 0.22% to 0.52%): relative increase, 317% vs. 136%. In the surgical sterilization group, BTL use decreased from 0.66% to 0.18% (72.7% relative decrease), whereas BS use was statistically unchanged (from 1.24% to 1.37%). In a multivariate analysis, recent year remained an independent characteristic for implant use in the LARC group and BS use in the surgical sterilization group. Moreover, in both LARC and surgical sterilization strata, procedure choices significantly differed on the basis of patient, pregnancy, hospital, and delivery factors. Conclusions: Immediate postpartum contraception choice has evolved in recent years in the United States with an increasing demand for the LARC methods with implants at the time of vaginal delivery.

Association of severe maternal morbidity and post-traumatic stress disorder.

BACKGROUND: Severe maternal morbidity refers to the most serious complications of pregnancy. Whether severe maternal morbidity is associated with post-traumatic stress disorder is currently under active investigation. OBJECTIVE: This study aimed to examine the association between severe maternal morbidity and post-traumatic stress disorder at delivery. STUDY DESIGN: This was a retrospective cohort study querying the Healthcare Cost and Utilization Project's National Inpatient Sample, which included 12,857,721 patients for national estimates who had vaginal or cesarean deliveries between January 2016 and December 2019. Patients with mental health conditions other than post-traumatic stress disorder and substance use disorder were excluded. Severe maternal morbidity was defined according to the Centers for Disease Control and Prevention definition (a total of 21 indicators). Main outcomes were trends and characteristics related to post-traumatic stress disorder, assessed with a multivariable binary logistic regression model. Sensitivity analysis included subcohort assessment restricted to patients per clinical and obstetrical demographics. RESULTS: A total of 8880 patients had a diagnosis of post-traumatic stress disorder during the hospital admission for delivery (prevalence rate, 6.9 per 10,000). The prevalence rate of post-traumatic stress disorder increased from 5.0 to 8.8 per 10,000 deliveries between 2016 and 2019. This increasing trend remained independent in multivariable analysis. The adjusted odds ratio, compared with 2016, was 1.26 (95% confidence interval, 1.19-1.35) for 2017, 1.50 (95% confidence interval, 1.41-1.60) for 2018, and 1.73 (95% confidence interval, 1.63-1.84) for 2019. Severe maternal morbidity occurred in 210,605 (1.6%) patients. Patients who had severe maternal morbidity were more likely to have a diagnosis of post-traumatic stress disorder than those without severe maternal morbidity (12.8 vs 6.8 per 10,000 deliveries; adjusted odds ratio, 1.57; 95% confidence interval, 1.39-1.78) in multivariable analysis. This association remained robust in several subcohort analyses including (1) participants aged ≤35 years (adjusted odds ratio, 1.62; 95% confidence interval, 1.41-1.86), (2) those aged ≤35 years without medical comorbidity (adjusted odds ratio, 2.01; 95% confidence interval, 1.70-2.37), and (3) those aged <35 years without medical comorbidity, cesarean delivery, and preterm delivery (adjusted odds ratio, 4.52; 95% confidence interval, 3.56-5.74). CONCLUSION: There has been a gradual increase in the number of patients with a diagnosis of post-traumatic stress disorder at delivery in recent years among those without other mental health or substance use conditions. These data suggest that there is a possible association between severe maternal morbidity and post-traumatic stress disorder.

Comprehensive Metabolic Profiling of MYC-Amplified Medulloblastoma Tumors Reveals Key Dependencies on Amino Acid, Tricarboxylic Acid and Hexosamine Pathways.

Reprograming of cellular metabolism is a hallmark of cancer. Altering metabolism allows cancer cells to overcome unfavorable microenvironment conditions and to proliferate and invade. Medulloblastoma is the most common malignant brain tumor of children. Genomic amplification of MYC defines a subset of poor-prognosis medulloblastoma. We performed comprehensive metabolic studies of human MYC-amplified medulloblastoma by comparing the metabolic profiles of tumor cells in three different conditions-in vitro, in flank xenografts and in orthotopic xenografts in the cerebellum. Principal component analysis showed that the metabolic profiles of brain and flank high-MYC medulloblastoma tumors clustered closely together and separated away from normal brain and in vitro MYC-amplified cells. Compared to normal brain, MYC-amplified medulloblastoma orthotopic xenograft tumors showed upregulation of the TCA cycle as well as the synthesis of nucleotides, hexosamines, amino acids and glutathione. There was significantly higher glucose uptake and usage in orthotopic xenograft tumors compared to flank xenograft tumors and cells in culture. In orthotopic tumors, glucose was the main carbon source for the de novo synthesis of glutamate, glutamine and glutathione through the TCA cycle. In vivo, the glutaminase II pathway was the main pathway utilizing glutamine. Glutathione was the most abundant upregulated metabolite in orthotopic tumors compared to normal brain. Glutamine-derived glutathione was synthesized through the glutamine transaminase K (GTK) enzyme in vivo. In conclusion, high MYC medulloblastoma cells have different metabolic profiles in vitro compared to in vivo, and key vulnerabilities may be missed by not performing in vivo metabolic analyses.

Unbiased Proteomic and Phosphoproteomic Analysis Identifies Response Signatures and Novel Susceptibilities After Combined MEK and mTOR Inhibition in BRAFV600E Mutant Glioma.

The mitogen-activated protein kinase pathway is one of the most frequently altered pathways in cancer. It is involved in the control of cell proliferation, invasion, and metabolism, and can cause resistance to therapy. A number of aggressive malignancies, including melanoma, colon cancer, and glioma, are driven by a constitutively activating missense mutation (V600E) in the v-Raf murine sarcoma viral oncogene homolog B (BRAF) component of the pathway. Mitogen-activated protein kinase kinase (MEK) inhibition is initially effective in targeting these cancers, but reflexive activation of mammalian target of rapamycin (mTOR) signaling contributes to frequent therapy resistance. We have previously demonstrated that combination treatment with the MEK inhibitor trametinib and the dual mammalian target of rapamycin complex 1/2 inhibitor TAK228 improves survival and decreases vascularization in a BRAFV600E mutant glioma model. To elucidate the mechanism of action of this combination therapy and understand the ensuing tumor response, we performed comprehensive unbiased proteomic and phosphoproteomic characterization of BRAFV600E mutant glioma xenografts after short-course treatment with trametinib and TAK228. We identified 13,313 proteins and 30,928 localized phosphosites, of which 12,526 proteins and 17,444 phosphosites were quantified across all samples (data available via ProteomeXchange; identifier PXD022329). We identified distinct response signatures for each monotherapy and combination therapy and validated that combination treatment inhibited activation of the mitogen-activated protein kinase and mTOR pathways. Combination therapy also increased apoptotic signaling, suppressed angiogenesis signaling, and broadly suppressed the activity of the cyclin-dependent kinases. In response to combination therapy, both epidermal growth factor receptor and class 1 histone deacetylase proteins were activated. This study reports a detailed (phospho)proteomic analysis of the response of BRAFV600E mutant glioma to combined MEK and mTOR pathway inhibition and identifies new targets for the development of rational combination therapies for BRAF-driven tumors.

Novel Glutamine Antagonist JHU395 Suppresses MYC-Driven Medulloblastoma Growth and Induces Apoptosis.

Medulloblastoma is the most common malignant pediatric brain tumor. Amplification of c-MYC is a hallmark of a subset of poor-prognosis medulloblastoma. MYC upregulates glutamine metabolism across many types of cancer. We modified the naturally occurring glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) by adding 2 promoeities to increase its lipophilicity and brain penetration creating the prodrug isopropyl 6-diazo-5-oxo-2-(((phenyl (pivaloyloxy) methoxy) - carbonyl) amino) hexanoate, termed JHU395. This prodrug was shown to have a 10-fold improved CSF-to-plasma ratio and brain-to-plasma ratio relative to DON. We hypothesized that JHU395 would have superior cell penetration compared with DON and would effectively and more potently kill MYC-expressing medulloblastoma. JHU395 treatment caused decreased growth and increased apoptosis in multiple human high-MYC medulloblastoma cell lines at lower concentrations than DON. Parenteral administration of JHU395 in Nu/Nu mice led to the accumulation of micromolar concentrations of DON in brain. Treatment of mice bearing orthotopic xenografts of human MYC-amplified medulloblastoma with JHU395 increased median survival from 26 to 45 days compared with vehicle control mice (p < 0.001 by log-rank test). These data provide preclinical justification for the ongoing development and testing of brain-targeted DON prodrugs for use in medulloblastoma.

MEK Inhibition Suppresses Growth of Atypical Teratoid/Rhabdoid Tumors.

Atypical teratoid/rhabdoid (AT/RT) tumors are the most common malignant brain tumor of infancy and have a poor prognosis. We have previously identified very high expression of LIN28A and/or LIN28B in AT/RT tumors and showed that AT/RT have corresponding increased expression of the mitogen-activated protein (MAP) kinase pathway. Binimetinib is a novel inhibitor of mitogen-activated protein kinase (MAP2K1 or MEK), and is currently in pediatric phase II clinical trials for low-grade glioma. We hypothesized that binimetinib would inhibit growth of AT/RT cells by suppressing the MAP kinase pathway. Binimetinib inhibited AT/RT growth at nanomolar concentrations. Binimetinib decreased cell proliferation and induced apoptosis in AT/RT cells and significantly reduced AT/RT tumor growth in flank xenografts. Our data suggest that MAP kinase pathway inhibition could offer a potential avenue for treating these highly aggressive tumors.

Inhibition of hyaluronan synthesis attenuates pulmonary hypertension associated with lung fibrosis.

BACKGROUND AND PURPOSE: Group III pulmonary hypertension (PH) is a highly lethal and widespread lung disorder that is a common complication in idiopathic pulmonary fibrosis (IPF) where it is considered to be the single most significant predictor of mortality. While increased levels of hyaluronan have been observed in IPF patients, hyaluronan-mediated vascular remodelling and the hyaluronan-mediated mechanisms promoting PH associated with IPF are not fully understood. EXPERIMENTAL APPROACH: Explanted lung tissue from patients with IPF with and without a diagnosis of PH was used to identify increased levels of hyaluronan. In addition, an experimental model of lung fibrosis and PH was used to test the capacity of 4-methylumbeliferone (4MU), a hyaluronan synthase inhibitor to attenuate PH. Human pulmonary artery smooth muscle cells (PASMC) were used to identify the hyaluronan-specific mechanisms that lead to the development of PH associated with lung fibrosis. KEY RESULTS: In patients with IPF and PH, increased levels of hyaluronan and expression of hyaluronan synthase genes are present. Interestingly, we also report increased levels of hyaluronidases in patients with IPF and IPF with PH. Remarkably, our data also show that 4MU is able to inhibit PH in our model either prophylactically or therapeutically, without affecting fibrosis. Studies to determine the hyaluronan-specific mechanisms revealed that hyaluronan fragments result in increased PASMC stiffness and proliferation but reduced cell motility in a RhoA-dependent manner. CONCLUSIONS AND IMPLICATIONS: Taken together, our results show evidence of a unique mechanism contributing to PH in the context of lung fibrosis.