Prenatal Substance Exposure and Neonatal Abstinence Syndrome: State Estimates from the 2016-2020 Transformed Medicaid Statistical Information System.

INTRODUCTION: Estimating Neonatal Abstinence Syndrome (NAS) and prenatal substance exposure rates in Medicaid can help target program efforts to improve access to services. METHODS: The data for this study was extracted from the 2016-2020 Transformed Medicaid Statistical Information System (T-MSIS) Analytic Files (TAF) Research Identifiable Files (RIF) and included infants born between January 1, 2016 and December 31, 2020 with a either a NAS diagnosis or prenatal substance exposure. RESULTS: Between 2016 and 2020, the estimated national rate of NAS experienced a 18% decline, while the estimated national rate of prenatal substance exposure experienced a 3.6% increase. At the state level in 2020, the NAS rate ranged from 3.2 per 1000 births (Hawaii) to 68.0 per 1000 births (West Virginia). Between 2016 and 2020, 28 states experienced a decline in NAS births and 20 states had an increase in NAS rates. In 2020, the lowest prenatal substance exposure rate was observed in New Jersey (9.9 per 1000 births) and the highest in West Virginia (88.1 per 1000 births). Between 2016 and 2020, 38 states experienced an increase in the rate of prenatal substance exposure and 10 states experienced a decline. DISCUSSION: Estimated rate of NAS has declined nationally, but rate of prenatal substance exposure has increased, with considerable state-level variation. The reported increase in prenatal substance exposure in the majority of US states (38) suggest that substances other than opioids are influencing this trend. Medicaid-led initiatives can be used to identify women with substance use and connect them to services.

What is already known about the topic? Neonatal Abstinence Syndrome (NAS) and prenatal substance exposure are significant risk factors for poor neurodevelopmental and mental health outcomes in early childhood. NAS birth rates have been increasing in the US since 2000 and the majority of NAS births are covered by Medicaid.What this article adds? This article estimates national and state-level prenatal substance exposure and NAS rates among Medicaid-covered infants born between 2016-2020 using data from the Transformed Medicaid Statistical Information System. This is the first study using post-2017 data to estimate national NAS rates. The findings can inform future federal and state policy efforts to improve access to screening, diagnosis and treatment among pregnant women with substance use disorder and infants with NAS.

Evaluation of State-Led Surveillance of Neonatal Abstinence Syndrome - Six U.S. States, 2018-2021.

Opioid use disorder (OUD) is a significant public health problem in the United States, which affects children as well as adults. During 2010-2017, maternal opioid-related diagnoses increased approximately 130%, from 3.5 to 8.2 per 1,000 hospital deliveries, and neonatal abstinence syndrome (NAS) increased 83%, from 4.0 to 7.3 per 1,000 hospital deliveries (1). NAS, a withdrawal syndrome, can occur among infants following in utero exposure to opioids and other psychotropic substances (2). In 2018, a study of six states with mandated NAS case reporting for public health surveillance (2013-2017) found that mandated reporting helped quantify NAS incidence and guide programs and services (3). To review surveillance features and programmatic development in the same six states, a questionnaire and interview with state health department officials on postimplementation efforts were developed and implemented in 2021. All states reported ongoing challenges with initial case reporting, limited capacity to track social and developmental outcomes, and no requirement for long-term follow-up in state-mandated case reporting; only one state instituted health-related outcomes monitoring. The primary surveillance barrier beyond initial case reporting was lack of infrastructure. To serve identified needs of opioid- or other substance-exposed mother-infant dyads, state health departments reported programmatic successes expanding education and access to maternal medication for opioid use disorder (MOUD), community and provider education or support services, and partnerships with perinatal quality collaboratives. Development of additional infrastructure is needed for states aiming to advance NAS surveillance beyond initial case reporting.

MAP4K4 regulates integrin-FERM binding to control endothelial cell motility.

Cell migration is a stepwise process that coordinates multiple molecular machineries. Using in vitro angiogenesis screens with short interfering RNA and chemical inhibitors, we define here a MAP4K4-moesin-talin-ß1-integrin molecular pathway that promotes efficient plasma membrane retraction during endothelial cell migration. Loss of MAP4K4 decreased membrane dynamics, slowed endothelial cell migration, and impaired angiogenesis in vitro and in vivo. In migrating endothelial cells, MAP4K4 phosphorylates moesin in retracting membranes at sites of focal adhesion disassembly. Epistasis analyses indicated that moesin functions downstream of MAP4K4 to inactivate integrin by competing with talin for binding to ß1-integrin intracellular domain. Consequently, loss of moesin (encoded by the MSN gene) or MAP4K4 reduced adhesion disassembly rate in endothelial cells. Additionally, α5ß1-integrin blockade reversed the membrane retraction defects associated with loss of Map4k4 in vitro and in vivo. Our study uncovers a novel aspect of endothelial cell migration. Finally, loss of MAP4K4 function suppressed pathological angiogenesis in disease models, identifying MAP4K4 as a potential therapeutic target.

Assessment of the hepatic CYP reductase null mouse model and its potential application in drug discovery.

CYP Oxidoreductase (Por) is the essential electron donor for all CYP enzymes and is responsible for the activation of CYP. The Taconic Hepatic CYP Reductase Null (HRN) mouse model possesses a targeted mutation that results in liver-specific deletion of the Por gene thereby resulting in a disruption of CYP metabolism in the liver. The objectives of these studies were to further characterize the HRN mouse using probe drugs metabolized by CYP. In addition, tumor exposure in xenograft tumor bearing HRN immune-compromised (nude) mice was also determined. In HRN mice following intravenous (iv) administration of midazolam, clearance (CL) was reduced by ∼ 80% compared to wild-type mice (WT). After oral administration, the AUC of midazolam was increased by ∼ 20-fold in HRN mice compared to WT mice; this greater effect suggests that hepatic first pass plays a role in the oral CL of midazolam. A 50% and an 80% decrease in CL were also observed in HRN mice following iv administration of docetaxel and theophylline, respectively, compared to WT mice. In addition, a 2- to 3-fold increase in tumor concentrations of G4222, a tool compound, were observed in tumor bearing HRN nude mice compared to tumor bearing nude WT mice. The observations from these experiments demonstrate that, for compounds that are extensively metabolized by hepatic CYP, the HRN mouse model could potentially be valuable for evaluating in vivo efficacy of tool compounds in drug discovery where high hepatic CL and low exposure may prevent in vivo evaluation of a new chemical entity.

Discovery of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine inhibitors of Erk2.

The discovery and optimization of a series of tetrahydropyridopyrimidine based extracellular signal-regulated kinase (Erks) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent and selective inhibition of Erk2 and knockdown of phospho-RSK levels in HepG2 cells and tumor xenografts.

Psychotropic Medication and Psychosocial Service Use Among Transition Age Youth With Autism Spectrum Disorder.

People with autism spectrum disorder (ASD) experience high rates of psychotropic medication utilization and barriers to psychosocial services, yet limited literature explores use of these services and the association between a mental health condition (MH) and use. Using national multipayer claims data, this study estimates a multinomial logistic regression model to discern psychotropic medication and psychosocial service use among transition age youth (TAY) with ASD (12-26 years; N = 52,083) compared to a matched cohort of those without ASD (12-26 years; N = 52,083). Approximately one-third of TAY with ASD and no MH condition receive only psychotropic medication and the likelihood of using both psychosocial services and medication is higher only when TAY with ASD have a co-occurring MH condition.

Health Services Use Among Children With Prenatal Substance Exposure or Neonatal Abstinence Syndrome.

OBJECTIVE: Infants with prenatal substance exposure or neonatal abstinence syndrome (NAS) use health services more often than other children; however, little is known about their use of mental health services and psychotropic medication. METHODS: The sample (N=1,004,085) consisted of infants born in 2016 in 38 states who were followed through the fifth year of life and enrolled each year in Medicaid or the Children's Health Insurance Program. Infants with prenatal substance exposure or NAS were identified with ICD-10 diagnosis codes; procedure and revenue codes documented their service use. RESULTS: Rates of any mental health visit and of psychotropic medication use were higher among infants with prenatal substance exposure or NAS compared with infants without either condition; these patterns persisted during most years of the 5-year study. CONCLUSIONS: Infants' elevated mental health services use through their first 5 years of life highlights the importance of early screening and subsequent engagement in school-based mental health interventions.

Telepsychiatry Use Before and During the COVID-19 Pandemic Among Children Enrolled in Medicaid.

OBJECTIVE: This study examined telepsychiatry use among children enrolled in Medicaid before and during the COVID-19 pandemic. METHODS: A retrospective analysis was conducted of claims data from the Transformed Medicaid Statistical Information System for children (ages 3-17) with any mental health service use in 2019 (N=5,606,555) and 2020 (N=5,094,446). RESULTS: The number of children using mental health services declined by 9.1% from 2019 to 2020. Mental health services in all care settings (inpatient, outpatient, residential, emergency department, intensive outpatient/partial hospitalization) declined except for telehealth, which increased by 829.6%. In 2020, 44.5% of children using telehealth were non-Hispanic White, 16.1% were non-Hispanic Black, and 19.7% were Hispanic. Attention-deficit hyperactivity disorder, trauma, anxiety, depression, and behavior/conduct disorder were the most prevalent psychiatric diagnoses among children using telehealth services. CONCLUSIONS: Although telehealth use increased substantially in 2020, overall mental health service use declined among Medicaid-enrolled children. Telehealth may not fully address unmet mental health service needs.

Substance Use Disorder Treatment, Perceived Need for Treatment, and Barriers to Treatment Among Parenting Women With Substance Use Disorder in US Rural Counties.

OBJECTIVE: Higher rates of substance use in rural counties compared to urban counties have been well documented. Low perceived need for treatment among those with substance use disorder (SUD) has also been documented in the literature. However, not much is known about SUD treatment among parenting women in rural counties and the impact of perceived need for treatment in seeking care. Little research has also examined barriers to SUD treatment among parenting women in rural communities. METHODS: Using a large nationally representative dataset, the study utilizes multivariable logistic regression models to estimate the differences in utilizing SUD treatment among parenting women with SUD in rural and urban counties in the United States. Role of perceived need for SUD treatment and barriers related to finance, access, and stigma are also examined. RESULTS: Parenting women in rural counties with SUD who perceive a need for treatment have more than 90% lower odds of receiving treatment compared to those in urban counties. In addition, parenting women with SUD in rural counties have more than 50% higher odds of identifying access-related issues such as lack of openings in programs, unavailability of treatment facilities, and lack of transportation as barriers to care compared to parenting women in urban counties. CONCLUSION: Diagnosis of SUD among parenting women is steadily increasing in rural communities. While many resources in combatting maternal SUD are being utilized, policy and programmatic responses tailored for mothers with SUD in rural communities might help increase utilization of treatment and reduce barriers to treatment.

Psychotropic Medication Utilization Among Children Diagnosed With Fetal Alcohol Spectrum Disorder.

BACKGROUND AND OBJECTIVES: To date, there has been no large, population-based study estimating the prevalence of psychotropic medication use and cooccurring medical conditions among children with fetal alcohol syndrome disorder (FASD). In addition, it is not known how psychotropic medication use varies by mental health status of the children with FASD and their health insurance coverage. This study attempts to fill this gap by analyzing a large health insurance claims database covering Medicaid and private insurance. METHODS: The study used the 2017 IBM Watson Health MarketScan Multistate Medicaid and Commercial Claims databases. The sample for the analysis includes children between the ages of 0 and 17 with either an FASD diagnosis or a mental health diagnosis (N = 848 721 Medicaid; N = 511 061 private insurance). RESULTS: More than half of the children with an FASD diagnosis were prescribed psychotropic medications (63% Medicaid; 57% private). Utilization rates of psychotropic medication among children with cooccurring FASD and a mental health condition (79% Medicaid; 71% private) were higher compared to children with a mental health diagnosis but no FASD (57% Medicaid; 57% private). Stimulants were the most commonly prescribed. Encephalopathy, attention deficit hyperactivity disorder, and epilepsy were the 3 most common cooccurring diagnosis among children with FASD using psychotropic medication under Medicaid compared to encephalopathy, attention deficit hyperactivity disorder, and anxiety with private insurance. CONCLUSIONS: These results exemplify the complexity of the neurobehavioral profile of children with FASD and the challenge of treatment. Future studies may determine how supportive services for these children will affect psychotropic medication use.

Preclinical assessment of novel BRAF inhibitors: integrating pharmacokinetic-pharmacodynamic modelling in the drug discovery process.

The objective of these studies were to determine the preclinical disposition of the two BRAF inhibitors, G-F and G-C, followed by pharmacokinetic (PK)-pharmacodynamic (PD) modelling to characterize the concentration-efficacy relationship of these compounds in the Colo205 mouse xenograft model. With G-F, the relationship of pERK inhibition to concentration was also characterized. Compounds G-F and G-C were administered to mice, rats and dogs and the pharmacokinetics of G-F and G-C was determined. In addition, using indirect response models the concentration-efficacy relationship was described. The clearance of G-F was low; 0.625 and 4.65 mL/min/kg in rat and dog respectively. Similarly, the clearance of G-C was low in rat and dog, 0.490 and 4.43 mL/min/kg, respectively. Both compounds displayed low volumes of distribution (0.140-0.267 L/kg), resulting in moderate half-lives across species (~2.5 to 4 h). Bioavailability was formulation dependent and decreased with increasing dose. Using the indirect response models, the KC(50) (50% K(max); maximal response) value for tumor growth inhibition for G-F and G-C were 84.5 and 19.2 µM, respectively. The IC(50) for pERK inhibition in Colo205 tumors by G-F was estimated to be 29.2 µM. High exposures of G-F and G-C were required for efficacy. Despite good PK properties of low CL and moderate half-life, limitations in obtaining exposures adequate for safety testing in rat and dog resulted in development challenges.

Medical Marijuana Laws, Marijuana Use, and Opioid-Related Outcomes among Women in the United States.

BACKGROUND: In the context of the opioid epidemic, a limited but growing body of literature has found state medical marijuana laws (MMLs) to be associated with lower levels of opioid prescribing. However, robust evidence linking state MMLs with individual-level opioid-related outcomes is lacking, particularly among women. This finding is especially true for pregnant and parenting women, who have been disproportionately affected by the opioid crisis. METHODS: Using data drawn from the 2002-2014 National Survey on Drug Use and Heath, the study uses a difference-in-differences estimation strategy to compare opioid-related outcomes (opioid misuse initiation, opioid misuse in the past month and past year, and opioid use disorder) among all women, pregnant women, and parenting women in states with and without MMLs (before and after implementation). The study also investigates the impact of MMLs on marijuana use and marijuana use disorder. RESULTS: The findings indicate that MMLs were not associated with opioid misuse, opioid misuse initiation, or opioid use disorder among all women, pregnant women, and parenting women. These laws were, however, positively correlated with marijuana use and marijuana use disorder among all women and women with children. In addition, MMLs were associated with an increase in the frequency of opioid misuse for pregnant women and a decrease in the frequency of opioid misuse for parenting women. CONCLUSIONS: This finding suggests that, although medical marijuana may be viewed by some as a substitute for opioid analgesics, MMLs may not be an effective policy tool to tackle the opioid epidemic among women, especially pregnant and parenting women.

X chromosome-linked inhibitor of apoptosis regulates cell death induction by proapoptotic receptor agonists.

Proapoptotic receptor agonists cause cellular demise through the activation of the extrinsic and intrinsic apoptotic pathways. Inhibitor of apoptosis (IAP) proteins block apoptosis induced by diverse stimuli. Here, we demonstrate that IAP antagonists in combination with Fas ligand (FasL) or the death receptor 5 (DR5) agonist antibody synergistically stimulate death in cancer cells and inhibit tumor growth. Single-agent activity of IAP antagonists relies on tumor necrosis factor-alpha signaling. By contrast, blockade of tumor necrosis factor-alpha does not affect the synergistic activity of IAP antagonists with FasL or DR5 agonist antibody. In most cancer cells, proapoptotic receptor agonist-induced cell death depends on amplifying the apoptotic signal via caspase-8-mediated activation of Bid and subsequent activation of the caspase-9-dependent mitochondrial apoptotic pathway. In the investigated cancer cell lines, induction of apoptosis by FasL or DR5 agonist antibody can be inhibited by knockdown of Bid. However, knockdown of X chromosome-linked IAP (XIAP) or antagonism of XIAP allows FasL or DR5 agonist antibody to induce activation of effector caspases efficiently without the need for mitochondrial amplification of the apoptotic signal and thus rescues the effect of Bid knockdown in these cells.

Utilization of Mental Health Services in Educational Setting by Adolescents in the United States.

BACKGROUND: Schools play an important role as providers of mental health services for adolescents; however, information on the broader picture of utilization of mental health services in educational versus other settings is limited because of the lack of national-level data. METHODS: Using multinomial logistic regression models based on national-level data from the 2012-2015 National Survey on Drug Use and Health, we explore the characteristics of adolescents who received mental health treatment in educational and other settings. In addition, the study examines the reasons for seeking services in various treatment settings. RESULTS: The analysis finds that while the majority of adolescents who access mental health services receive care at noneducational settings, slightly more than one-third of them received services only in an educational setting. Adolescents who had public insurance, were from low-income households, and were from racial/ethnic minority groups were more likely to access services in an educational setting only. Common reasons for accessing services in educational settings included problems with schools, friends, and family members. CONCLUSIONS: Despite increased access to treatment in outpatient settings in the last decade, schools play an important role in providing access to mental health services for disadvantaged populations.

Psychotropic Medication and Psychotropic Polypharmacy Among Children and Adolescents in the US Child Welfare System.

This cross-sectional study evaluates rates of psychotropic medication and polypharmacy use among youths in the US child welfare system compared with other youths with Medicaid coverage in 2019.

Medications for Opioid Use Disorder During the Prenatal Period and Infant Outcomes.

This cross-sectional study explores the association between mothers' receipt of opioid use disorder treatment during pregnancy and their infants' health services use in the first year of life.

Racial and Ethnic Differences in Encounters Related to Suicidal Behavior Among Children and Adolescents With Medicaid Coverage During the COVID-19 Pandemic.

This cohort study evaluates rates of encounters for suicidal behavior by race and ethnicity among children with Medicaid coverage during vs before the COVID-10 pandemic.