Identifying Optimal Methods for Addressing Confounding Bias When Estimating the Effects of State-level Policies.

BACKGROUND: Policy evaluation studies that assess how state-level policies affect health-related outcomes are foundational to health and social policy research. The relative ability of newer analytic methods to address confounding, a key source of bias in observational studies, has not been closely examined. METHODS: We conducted a simulation study to examine how differing magnitudes of confounding affected the performance of 4 methods used for policy evaluations: (1) the two-way fixed effects difference-in-differences model; (2) a 1-period lagged autoregressive model; (3) augmented synthetic control method; and (4) the doubly robust difference-in-differences approach with multiple time periods from Callaway-Sant'Anna. We simulated our data to have staggered policy adoption and multiple confounding scenarios (i.e., varying the magnitude and nature of confounding relationships). RESULTS: Bias increased for each method: (1) as confounding magnitude increases; (2) when confounding is generated with respect to prior outcome trends (rather than levels), and (3) when confounding associations are nonlinear (rather than linear). The autoregressive model and augmented synthetic control method had notably lower root mean squared error than the two-way fixed effects and Callaway-Sant'Anna approaches for all scenarios; the exception is nonlinear confounding by prior trends, where Callaway-Sant'Anna excels. Coverage rates were unreasonably high for the augmented synthetic control method (e.g., 100%), reflecting large model-based standard errors and wide confidence intervals in practice. CONCLUSIONS: In our simulation study, no single method consistently outperformed the others, but a researcher's toolkit should include all methodologic options. Our simulations and associated R package can help researchers choose the most appropriate approach for their data.

Prevalence of Buprenorphine Providers Requiring Cash Payment From Insured Women Seeking Opioid Use Disorder Treatment.

CONTEXT: Medications for opioid use disorder (OUD) are known to be effective, especially in reducing the risk of overdose death. Yet, many individuals suffering from OUD are not receiving treatment. One potential barrier can be the patient's ability to access providers through their insurance plans. DATA AND METHODS: We used an audit (simulated patient) study methodology to examine appointment-granting behavior by buprenorphine prescribers in 10 different US states. Trained callers posed as women with OUD and were randomly assigned Medicaid or private insurance status. Callers request an OUD treatment appointment and then asked whether they would be able to use their insurance to cover the cost of care, or alternatively, whether they would be required to pay fully out-of-pocket. FINDINGS: We found that Medicaid and privately insured women were often asked to pay cash for OUD treatment--40% of the time over the full study sample. Such buprenorphine provider requests happened more than 60% of the time in some states. Areas with more providers or with more generous provider payments were not obviously more willing to accept the patient's insurance benefits for OUD treatment. Rural providers were less likely to require payment in cash in order for the woman to receive care. CONCLUSIONS: State-to-state variation was the most striking pattern in our field experiment data. The wide variation suggests that women of reproductive age with OUD in certain states face even greater challenges to treatment access than perhaps previously thought; however, it also reveals that some states have found ways to curtail this problem. Our findings encourage greater attention to this public health challenge and possibly opportunities for shared learning across states.

County-level Factors and Treatment Access Among Insured Women With Opioid Use Disorder.

BACKGROUND: An over 40% increase in overdose deaths within the past 2 years and low levels of engagement in treatment call for a better understanding of factors that influence access to medication for opioid use disorder (OUD). OBJECTIVE: To examine whether county-level characteristics influence a caller's ability to secure an appointment with an OUD treatment practitioner, either a buprenorphine-waivered prescriber or an opioid treatment program (OTP). RESEARCH DESIGN AND SUBJECTS: We leveraged data from a randomized field experiment comprised of simulated pregnant and nonpregnant women of reproductive age seeking treatment for OUD among 10 states in the US. We employed a mixed-effects logistic regression model with random intercepts for counties to examine the relationship between appointments received and salient county-level factors related to OUD. MEASURES: Our primary outcome was the caller's ability to secure an appointment with an OUD treatment practitioner. County-level predictor variables included socioeconomic disadvantage rankings, rurality, and OUD treatment/practitioner density. RESULTS: Our sample comprised 3956 reproductive-aged callers; 86% reached a buprenorphine-waivered prescriber and 14% an OTP. We found that 1 additional OTP per 100,000 population was associated with an increase (OR=1.36, 95% CI: 1.08 to 1.71) in the likelihood that a nonpregnant caller receives an OUD treatment appointment from any practitioner. CONCLUSIONS: When OTPs are highly concentrated within a county, women of reproductive age with OUD have an easier time securing an appointment with any practitioner. This finding may suggest greater practitioners' comfort in prescribing when there are robust OUD specialty safety nets in the county.

Trends in Neonatal Extracorporeal Membrane Oxygenation During a Venovenous Cannula Shortage.

OBJECTIVES: To report temporal trends in venovenous extracorporeal membrane oxygenation (ECMO) use for neonatal respiratory failure in U.S. centers before and after functional venovenous cannula shortage due to withdrawal of one dual lumen venovenous cannula from the market in 2018. DESIGN: Retrospective cohort study. SETTING: ECMO registry of the Extracorporeal Life Support Organization. PATIENTS: Infants who received neonatal (cannulated prior to 29 d of age) respiratory ECMO at a U.S. center and had a record available in the ECMO registry from January 1, 2010 to July 20, 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome was receipt of venovenous ECMO (vs venoarterial or other), and secondary outcomes were survival to hospital discharge and adverse neurologic outcomes. Using an interrupted time series design, we fit multivariable mixed effects logistic regression models with receipt of venovenous ECMO as the dependent variable, treatment year modeled as a piecewise linear variable using three linear splines (pre shortage: 2010-2014, 2014-2018; shortage: 2018-2021), and adjusted for center clustering and multiple covariates. We evaluated trends in venovenous ECMO use by primary diagnosis including congenital diaphragmatic hernia, meconium aspiration, pulmonary hypertension, and other. Annual neonatal venovenous ECMO rates decreased after 2018: from 2010 to 2014, adjusted odds ratio (aOR) for yearly trend 0.98 (95% CI 0.92-1.04), from 2014 to 2018, aOR for yearly trend 0.90 (95% CI 0.80-1.01), and after 2018, aOR for yearly trend 0.46 (95% CI 0.37-0.57). We identified decreased venovenous ECMO use after 2018 in all diagnoses evaluated, and we failed to identify differences in temporal trends between diagnoses. Survival and adverse neurologic outcomes were unchanged across the study periods. CONCLUSIONS: Venovenous ECMO for neonatal respiratory failure in U.S. centers decreased after 2018 even after accounting for temporal trends, coincident with withdrawal of one of two venovenous cannulas from the market.

Family Care Plans for Infants with Prenatal Substance Exposure.

The federal Child Abuse Prevention and Treatment Act (CAPTA) requires that a plan of safe care, called a family care plan (FCP) in Connecticut, be developed for all newborns identified as being affected by substance abuse and their caregivers. In Connecticut, FCPs are developed in treatment or hospital settings, not by child protective services. Analyzing data from Connecticut from 2019-2021, we found robust yet uneven implementation of FCPs that may have resulted in inadequate support for some affected caregiver-infant dyads. Additional implementation strategies may be needed to ensure that all dyads receive comprehensive FCPs.

"The Problem's Bigger than We Are": Understanding How Local Factors Influence Child Welfare Responses to Substance Use in Pregnancy, A Qualitative Study.

State eligibility for certain federal child welfare funding requires a gubernatorial assurance that infants affected by substances receive plans of safe care (POSC). We conducted 18 interviews with state and county child welfare staff to understand how POSC has been implemented and found variability in practice driven by vague policy, challenges of cross-system collaboration, and a lack of knowledge about substance use disorder. Policy improvements should align requirements with POSC practice and create shared accountability with key partners.

APOBEC3F Constitutes a Barrier to Successful Cross-Species Transmission of Simian Immunodeficiency Virus SIVsmm to Humans.

Simian immunodeficiency virus infecting sooty mangabeys (SIVsmm) has been transmitted to humans on at least nine occasions, giving rise to human immunodeficiency virus type 2 (HIV-2) groups A to I. SIVsmm isolates replicate in human T cells and seem capable of overcoming major human restriction factors without adaptation. However, only groups A and B are responsible for the HIV-2 epidemic in sub-Saharan Africa, and it is largely unclear whether adaptive changes were associated with spread in humans. To address this, we examined the sensitivity of infectious molecular clones (IMCs) of five HIV-2 strains and representatives of five different SIVsmm lineages to various APOBEC3 proteins. We confirmed that SIVsmm strains replicate in human T cells, albeit with more variable replication fitness and frequently lower efficiency than HIV-2 IMCs. Efficient viral propagation was generally dependent on intact vif genes, highlighting the need for counteraction of APOBEC3 proteins. On average, SIVsmm was more susceptible to inhibition by human APOBEC3D, -F, -G, and -H than HIV-2. For example, human APOBEC3F reduced infectious virus yield of SIVsmm by ∼80% but achieved only ∼40% reduction in the case of HIV-2. Functional and mutational analyses of human- and monkey-derived alleles revealed that an R128T polymorphism in APOBEC3F contributes to species-specific counteraction by HIV-2 and SIVsmm Vifs. In addition, a T84S substitution in SIVsmm Vif increased its ability to counteract human APOBEC3F. Altogether, our results confirm that SIVsmm Vif proteins show intrinsic activity against human APOBEC3 proteins but also demonstrate that epidemic HIV-2 strains evolved an increased ability to counteract this class of restriction factors during human adaptation. IMPORTANCE Viral zoonoses pose a significant threat to human health, and it is important to understand determining factors. SIVs infecting great apes gave rise to HIV-1. In contrast, SIVs infecting African monkey species have not been detected in humans, with one notable exception. SIVsmm from sooty mangabeys has crossed the species barrier to humans on at least nine independent occasions and seems capable of overcoming many innate defense mechanisms without adaptation. Here, we confirmed that SIVsmm Vif proteins show significant activity against human APOBEC3 proteins. Our analyses also revealed, however, that different lineages of SIVsmm are significantly more susceptible to inhibition by various human APOBEC3 proteins than HIV-2 strains. Mutational analyses suggest that an R128T substitution in APOBEC3F and a T84S change in Vif contribute to species-specific counteraction by HIV-2 and SIVsmm. Altogether, our results support that epidemic HIV-2 strains acquired increased activity against human APOBEC3 proteins to clear this restrictive barrier.

Standardizing the Clinical Definition of Opioid Withdrawal in the Neonate.

OBJECTIVE: To standardize the clinical definition of opioid withdrawal in neonates to address challenges in clinical care, quality improvement, research, and public policy for this patient population. STUDY DESIGN: Between October and December 2020, we conducted 2 modified-Delphi panels using ExpertLens, a virtual platform for performing iterative expert engagement panels. Twenty clinical experts specializing in care for the substance-exposed mother-neonate dyad explored the necessity of key evidence-based clinical elements in defining opioid withdrawal in the neonate leading to a diagnosis of neonatal abstinence syndrome (NAS)/neonatal opioid withdrawal syndrome (NOWS). Expert consensus was assessed using descriptive statistics, the RAND/UCLA Appropriateness Method, and thematic analysis of participants' comments. RESULTS: Expert panels concluded the following were required for diagnosis: in utero exposure (known by history, not necessarily by toxicology testing) to opioids with or without the presence of other psychotropic substances, and the presence of at least two of the most common clinical signs characteristic of withdrawal (excessive crying, fragmented sleep, tremors, increased muscle tone, gastrointestinal dysfunction). CONCLUSIONS: Results indicate that both a known history of in utero opioid exposure and a distinct set of withdrawal signs are necessary to standardize a definition of neonatal withdrawal. Implementation of a standardized definition requires both patient engagement and a mother-neonate dyadic approach mindful of program and policy implications.

Leftover Opioid Analgesics and Disposal Following Ambulatory Pediatric Surgeries in the Context of a Restrictive Opioid-Prescribing Policy.

BACKGROUND: Opioid analgesics are commonly prescribed for postoperative analgesia following pediatric surgery and often result in leftover opioid analgesics in the home. To reduce the volume of leftover opioids and overall community opioid burden, the State of Tennessee enacted a policy to reduce initial opioid prescribing to a 3-day supply for most acute pain incidents. We aimed to evaluate the extent of leftover opioid analgesics following pediatric ambulatory surgeries in the context of a state-mandated restrictive opioid-prescribing policy. We also aimed to evaluate opioid disposal rates, methods of disposal, and reasons for nondisposal. METHODS: Study personnel contacted the parents of 300 pediatric patients discharged with an opioid prescription following pediatric ambulatory surgery. Parents completed a retrospective telephone survey regarding opioid use and disposal. Data from the survey were combined with data from the medical record to evaluate proportion of opioid doses prescribed that were left over. RESULTS: The final analyzable sample of 185 patients (62% response rate) were prescribed a median of 12 opioid doses (interquartile range [IQR], 12-18), consumed 2 opioid doses (IQR, 0-4), and had 10 opioid doses left over (IQR, 7-13). Over 90% (n = 170 of 185) of parents reported they had leftover opioid analgesics, with 83% of prescribed doses left over. A significant proportion (29%, n = 54 of 185) of parents administered no prescribed opioids after surgery. Less than half (42%, n = 71 of 170) of parents disposed of the leftover opioid medication, most commonly by flushing down the toilet, pouring down the sink, or throwing in the garbage. Parents retaining leftover opioids (53%, n = 90 of 170) were most likely to keep them in an unlocked location (68%, n = 61 of 90). Parents described forgetfulness and worry that their child will experience pain in the future as primary reasons for not disposing of the leftover opioid medication. CONCLUSIONS: Despite Tennessee's policy aimed at reducing leftover opioids, a significant proportion of prescribed opioids were left over following pediatric ambulatory surgeries. A majority of parents did not engage in safe opioid disposal practices. Given the safety risks related to leftover opioids in the home, further interventions to improve disposal rates and tailor opioid prescribing are warranted after pediatric surgery.

Risk of Death at 1 Year Following Postpartum Opioid Exposure.

OBJECTIVE: Opioids are commonly prescribed to women for acute pain following childbirth. Postpartum prescription opioid exposure is associated with adverse opioid-related morbidities but the association with all-cause mortality is not well studied. This study aimed to examine the association between postpartum opioid prescription fills and the 1-year risk of all-cause mortality among women with live births. METHODS: In a retrospective cohort study of live births among women enrolled in Tennessee Medicaid (TennCare) between 2007 and 2015, we compared women who filled two or more postpartum outpatient opioid prescriptions (up to 41 days of postdelivery discharge) to women who filled one or fewer opioid prescription. Women were followed from day 42 postdelivery discharge through 365 days of follow-up or date of death. Deaths were identified using linked death certificates (2007-2016). We used Cox's proportional hazard regression and inverse probability of treatment weights to compare time to death between exposure groups while adjusting for relevant confounders. We also examined effect modification by delivery route, race, opioid use disorder, use of benzodiazepines, and mental health condition diagnosis. RESULTS: Among 264,135 eligible births, 216,762 (82.1%) had one or fewer maternal postpartum opioid fills and 47,373 (17.9%) had two or more fills. There were 182 deaths during follow-up. The mortality rate was higher in women with two or more fills (120.5 per 100,000 person-years) than in those with one or fewer (57.7 per 100,000 person-years). The risk of maternal death remained higher in participants exposed to two or more opioid fills after accounting for relevant covariates using inverse probability of treatment weighting (adjusted hazard ratio: 1.46 [95% confidence interval: 1.01, 2.09]). Findings from stratified analyses were consistent with main findings. CONCLUSION: Filling two or more opioid prescriptions during the postpartum period was associated with a significant increase in 1-year risk of death among new mothers. KEY POINTS: · Opioid prescribing in the postpartum period is common.. · Prior studies show that >1 postnatal opioid fill is associated with adverse opioid-related events.. · > 1 opioid fill within 42 days of delivery was associated with an increase in 1-year risk of death..

Impact of stigmatizing language describing opioid-exposed mother infant dyads: A randomized case vignette study.

Background: Existing literature suggests that using stigmatizing language may promote negative attitudes and result in more punitive views toward individuals with addiction. It is unclear how the commonly used colloquial terms to describe opioid-exposed mother infant dyads impacts public opinion of pregnant women with opioid use disorder (OUD). We sought to examine the extent to which language such as "opioid addict" and "born addicted" influences the perception of pregnant women with OUD. Methods: We conducted a randomized case-based vignette study using a population-weighted sample of parents living in Tennessee, varying in the language used to describe an opioid-exposed mother infant dyad. Participant demographics, views on opioid prescribing, and opinions on criminal justice and child welfare responses following delivery were obtained. Ordinal logistic regression was used to examine the association between vignette type and punitive responses. Results: Eleven hundred participants completed the survey. Overall, 30.6% felt the mother should be arrested and 68.6% felt the mother should lose custody of her infant. There was insufficient evidence to suggest a difference in punitive response selection based on the vignette language (p = 0.27). In the adjusted model, the odds of answering a more punitive response among parents who received non-stigmatizing language was 0.8 (95% CI 0.59-1.08) compared to parents who received stigmatizing language in the vignette. Conclusions: Many parents hold punitive views toward mothers receiving OUD treatment that was not altered by using less value-laden language. Broader stigma-reduction interventions may be more effective.

Disparities in receipt of medications for opioid use disorder among pregnant women.

Background: Medications for opioid use disorder (MOUD) improve outcomes for pregnant women and infants. Our primary aim was to examine disparities in maternal MOUD receipt by family sociodemographic characteristics. Methods: This retrospective cohort study included mother-infant dyads with Medicaid-covered deliveries in Tennessee from 2009 to 2016. First, we examined family sociodemographic characteristics - including race/ethnicity, rurality, mother's primary language and education level, and whether paternity was recorded in birth records - and newborn outcomes by type of maternal opioid use. Second, among pregnant women with OUD, we used logistic regression to measure disparities in receipt of MOUD by family sociodemographic characteristics including interactions between characteristics. Results: Our cohort from Medicaid-covered deliveries consisted of 314,965 mother-infant dyads, and 4.2 percent were exposed to opioids through maternal use. Among dyads with maternal OUD, MOUD receipt was associated with lower rates of preterm and very preterm birth. Logistic regression adjusted for family sociodemographic characteristics showed that pregnant women with OUD in rural versus urban areas (aOR: 0.66; 95% CI: 0.60-0.72) and who were aged ≥35 years versus ≤25 years (aOR: 0.75; 95% CI: 0.64-0.89) were less likely to have received MOUD. Families in which the mother's primary language was English (aOR: 2.47; 95% CI: 1.24-4.91) and paternity was recorded on the birth certificate (aOR: 1.30; 95% CI: 1.19-1.42) were more likely to have received MOUD. Regardless of high school degree attainment, non-Hispanic Black versus non-Hispanic White race was associated with lower likelihood of MOUD receipt. Hispanic race was associated with lower likelihood of MOUD receipt among women without a high school degree. Conclusions: Among a large cohort of pregnant women, we found disparities in receipt of MOUD among non-Hispanic Black, Hispanic, and rural pregnant women. As policymakers consider strategies to improve access to MOUD, they should consider targeted approaches to address these disparities.

Development and Validation of a Model to Predict Neonatal Abstinence Syndrome.

OBJECTIVES: To develop and validate clinical risk prediction tools for neonatal abstinence syndrome (NAS). STUDY DESIGN: We developed prediction models for NAS based on a set of 30 demographic and antenatal exposure covariates collected during pregnancy. Data (outpatient prescription, vital, and administrative records), were obtained from enrollees in the Tennessee Medicaid Program from 2009 to 2014. Models were created using logistic regression and backward selection based on improvement in the Akaike information criterion, and internally validated using bootstrap cross-validation. RESULTS: A total of 218 020 maternal and infant dyads met inclusion criteria, of whom 3208 infants were diagnosed with NAS. The general population model included age, hepatitis C virus infection, days of opioid used by type, number of cigarettes used daily, and the following medications used in the last 30 day of pregnancy: bupropion, antinausea medicines, benzodiazepines, antipsychotics, and gabapentin. Infant characteristics included birthweight, small for gestational age, and infant sex. A high-risk model used a smaller number of predictive variables. Both models discriminated well with an area under the curve of 0.89 and were well-calibrated for low-risk infants. CONCLUSIONS: We developed 2 predictive models for NAS based on demographics and antenatal exposure during the last 30 days of pregnancy that were able to risk stratify infants at risk of developing the syndrome.

Moving beyond the classic difference-in-differences model: a simulation study comparing statistical methods for estimating effectiveness of state-level policies.

BACKGROUND: Reliable evaluations of state-level policies are essential for identifying effective policies and informing policymakers' decisions. State-level policy evaluations commonly use a difference-in-differences (DID) study design; yet within this framework, statistical model specification varies notably across studies. More guidance is needed about which set of statistical models perform best when estimating how state-level policies affect outcomes. METHODS: Motivated by applied state-level opioid policy evaluations, we implemented an extensive simulation study to compare the statistical performance of multiple variations of the two-way fixed effect models traditionally used for DID under a range of simulation conditions. We also explored the performance of autoregressive (AR) and GEE models. We simulated policy effects on annual state-level opioid mortality rates and assessed statistical performance using various metrics, including directional bias, magnitude bias, and root mean squared error. We also reported Type I error rates and the rate of correctly rejecting the null hypothesis (e.g., power), given the prevalence of frequentist null hypothesis significance testing in the applied literature. RESULTS: Most linear models resulted in minimal bias. However, non-linear models and population-weighted versions of classic linear two-way fixed effect and linear GEE models yielded considerable bias (60 to 160%). Further, root mean square error was minimized by linear AR models when we examined crude mortality rates and by negative binomial models when we examined raw death counts. In the context of frequentist hypothesis testing, many models yielded high Type I error rates and very low rates of correctly rejecting the null hypothesis (< 10%), raising concerns of spurious conclusions about policy effectiveness in the opioid literature. When considering performance across models, the linear AR models were optimal in terms of directional bias, root mean squared error, Type I error, and correct rejection rates. CONCLUSIONS: The findings highlight notable limitations of commonly used statistical models for DID designs, which are widely used in opioid policy studies and in state policy evaluations more broadly. In contrast, the optimal model we identified--the AR model--is rarely used in state policy evaluation. We urge applied researchers to move beyond the classic DID paradigm and adopt use of AR models.

Neonatal Abstinence Syndrome and Maternal Opioid-Related Diagnoses in the US, 2010-2017.

Importance: Substantial increases in both neonatal abstinence syndrome (NAS) and maternal opioid use disorder have been observed through 2014. Objective: To examine national and state variation in NAS and maternal opioid-related diagnoses (MOD) rates in 2017 and to describe national and state changes since 2010 in the US, which included expanded MOD codes (opioid use disorder plus long-term and unspecified use) implemented in International Classification of Disease, 10th Revision, Clinical Modification. Design, Setting, and Participants: Repeated cross-sectional analysis of the 2010 to 2017 Healthcare Cost and Utilization Project's National Inpatient Sample and State Inpatient Databases, an all-payer compendium of hospital discharge records from community nonrehabilitation hospitals in 47 states and the District of Columbia. Exposures: State and year. Main Outcomes and Measures: NAS rate per 1000 birth hospitalizations and MOD rate per 1000 delivery hospitalizations. Results: In 2017, there were 751 037 birth hospitalizations and 748 239 delivery hospitalizations in the national sample; 5375 newborns had NAS and 6065 women had MOD documented in the discharge record. Mean gestational age was 38.4 weeks and mean maternal age was 28.8 years. From 2010 to 2017, the estimated NAS rate significantly increased by 3.3 per 1000 birth hospitalizations (95% CI, 2.5-4.1), from 4.0 (95% CI, 3.3-4.7) to 7.3 (95% CI, 6.8-7.7). The estimated MOD rate significantly increased by 4.6 per 1000 delivery hospitalizations (95% CI, 3.9-5.4), from 3.5 (95% CI, 3.0-4.1) to 8.2 (95% CI, 7.7-8.7). Larger increases for MOD vs NAS rates occurred with new International Classification of Disease, 10th Revision, Clinical Modification codes in 2016. From a census of 47 state databases in 2017, NAS rates ranged from 1.3 per 1000 birth hospitalizations in Nebraska to 53.5 per 1000 birth hospitalizations in West Virginia, with Maine (31.4), Vermont (29.4), Delaware (24.2), and Kentucky (23.9) also exceeding 20 per 1000 birth hospitalizations, while MOD rates ranged from 1.7 per 1000 delivery hospitalizations in Nebraska to 47.3 per 1000 delivery hospitalizations in Vermont, with West Virginia (40.1), Maine (37.8), Delaware (24.3), and Kentucky (23.4) also exceeding 20 per 1000 delivery hospitalizations. From 2010 to 2017, NAS and MOD rates increased significantly for all states except Nebraska and Vermont, which only had MOD increases. Conclusions and Relevance: In the US from 2010 to 2017, estimated rates of NAS and MOD significantly increased nationally and for the majority of states, with notable state-level variation.

Medications for opioid use disorder among pregnant women referred by criminal justice agencies before and after Medicaid expansion: A retrospective study of admissions to treatment centers in the United States.

BACKGROUND: Criminal justice involvement is common among pregnant women with opioid use disorder (OUD). Medications for OUD improve pregnancy-related outcomes, but trends in treatment data among justice-involved pregnant women are limited. We sought to examine trends in medications for OUD among pregnant women referred to treatment by criminal justice agencies and other sources before and after the Affordable Care Act's Medicaid expansion. METHODS AND FINDINGS: We conducted a serial, cross-sectional analysis using 1992-2017 data from pregnant women admitted to treatment facilities for OUD using a national survey of substance use treatment facilities in the United States (N = 131,838). We used multiple logistic regression and difference-in-differences methods to assess trends in medications for OUD by referral source. Women in the sample were predominantly aged 18-29 (63.3%), white non-Hispanic, high school graduates, and not employed. Over the study period, 26.3% (95% CI 25.7-27.0) of pregnant women referred by criminal justice agencies received medications for OUD, which was significantly less than those with individual referrals (adjusted rate ratio [ARR] 0.45, 95% CI 0.43-0.46; P < 0.001) or those referred from other sources (ARR 0.51, 95% CI 0.50-0.53; P < 0.001). Among pregnant women referred by criminal justice agencies, receipt of medications for OUD increased significantly more in states that expanded Medicaid (n = 32) compared with nonexpansion states (n = 18) (adjusted difference-in-differences: 12.0 percentage points, 95% CI 1.0-23.0; P = 0.03). Limitations of this study include encounters that are at treatment centers only and that do not encompass buprenorphine prescribed in ambulatory care settings, prisons, or jails. CONCLUSIONS: Pregnant women with OUD referred by criminal justice agencies received evidence-based treatment at lower rates than women referred through other sources. Improving access to medications for OUD for pregnant women referred by criminal justice agencies could provide public health benefits to mothers, infants, and communities. Medicaid expansion is a potential mechanism for expanding access to evidence-based treatment for pregnant women in the US.

Antenatal Admissions Among Women with Opioid-Affected and Non-Opioid-Affected Deliveries.

OBJECTIVES: (1) To compare the prevalence of antenatal admissions and mean length of stay among women with opioid-affected and non-opioid-affected deliveries; (2) examine predictors of admission; and (3) describe the most common discharge diagnoses in each group. METHODS: Using data from seven states in the State Inpatient Databases for varying years between 2009 and 2014, delivery hospitalizations among women 18 years of age and older were identified and classified as opioid-affected or non-opioid-affected. Antenatal admissions were linked to deliveries. The antenatal admission ratio and mean length of stay for each group were calculated; the percentage of deliveries in each group with no, any, one, two, or three or more antenatal admissions were compared with t-tests. Logistic regression models estimated odds of any antenatal admission, stratified by opioid-affected and non-opioid-affected deliveries. Frequencies were tabulated for the ten most common discharge diagnoses in each group. RESULTS: Of 2,684,970 deliveries, 14,765 were opioid-affected. Admissions among women with opioid-affected deliveries were more prevalent (26.4 per 100 deliveries) compared to 6.7 among women with non-opioid-affected deliveries and were associated with a 1.5-day longer mean length of stay. The presence of a behavioral health condition was associated with higher odds of antenatal admission in both groups, with a particularly strong association among women with opioid-affected deliveries. Six of the ten most common diagnoses for admissions prior to opioid-affected deliveries were behavioral health-related. CONCLUSIONS FOR PRACTICE: These results highlight the importance of addressing the large burden of behavioral health conditions among pregnant women, especially those with opioid dependence and abuse.

Enzymatic and Structural Characterization of the Naegleria fowleri Glucokinase.

Infection with the free-living amoeba Naegleria fowleri leads to life-threatening primary amoebic meningoencephalitis. Efficacious treatment options for these infections are limited, and the mortality rate is very high (∼98%). Parasite metabolism may provide suitable targets for therapeutic design. Like most other organisms, glucose metabolism is critical for parasite viability, being required for growth in culture. The first enzyme required for glucose metabolism is typically a hexokinase (HK), which transfers a phosphate from ATP to glucose. The products of this enzyme are required for both glycolysis and the pentose phosphate pathway. However, the N. fowleri genome lacks an obvious HK homolog and instead harbors a glucokinase (Glck). The N. fowleri Glck (NfGlck) shares limited (25%) amino acid identity with the mammalian host enzyme (Homo sapiens Glck), suggesting that parasite-specific inhibitors with anti-amoeba activity can be generated. Following heterologous expression, NfGlck was found to have a limited hexose substrate range, with the greatest activity observed with glucose. The enzyme had apparent Km values of 42.5 ± 7.3 µM and 141.6 ± 9.9 µM for glucose and ATP, respectively. The NfGlck structure was determined and refined to 2.2-Å resolution, revealing that the enzyme shares greatest structural similarity with the Trypanosoma cruzi Glck. These similarities include binding modes and binding environments for substrates. To identify inhibitors of NfGlck, we screened a small collection of inhibitors of glucose-phosphorylating enzymes and identified several small molecules with 50% inhibitory concentration values of <1 µM that may prove useful as hit chemotypes for further leads and therapeutic development against N. fowleri.

Umbilical Cord Tissue and Meconium May Not Be Equivalent for Confirming in Utero Substance Exposure.

In a retrospective study of 501 neonates with potential in utero substance exposure, the drug detection performance of a commercially available umbilical cord tissue toxicology test was evaluated against a commercially available gold standard meconium toxicology test. Drugs detected in paired meconium and umbilical cord tissue samples were often discordant.