Society for Maternal-Fetal Medicine Position Statement: Access to abortion care.

POSITION: The Society for Maternal-Fetal Medicine supports the right of all individuals to access the full spectrum of reproductive health services, including abortion care. Reproductive health decisions are best made by each individual with guidance and support from their healthcare providers. The Society opposes legislation and policies that limit access to abortion care or criminalize abortion care and self-managed abortion. In addition, the Society opposes policies that compromise the patient-healthcare provider relationship by limiting a healthcare provider's ability to counsel patients and provide evidence-based, medically appropriate treatment.

Association of Patient Sex and Pregnancy Status With Naloxone Administration During Emergency Department Visits.

OBJECTIVE: To evaluate the association of sex and pregnancy status with rates of naloxone administration during opioid overdose-related emergency department (ED) visits by using the Nationwide Emergency Department Sample. METHODS: A retrospective cohort study was conducted using the Nationwide Emergency Department Sample 2016 and 2017 data sets. Eligible records included men and women, 15-49 years of age, with an opioid overdose-related ED visit; records for women were stratified by pregnancy status (International Classification of Diseases, Tenth Revision O codes). A multivariable logistic regression model was used to assess the primary outcome of naloxone administration (Current Procedural Terminology code: J2310). Secondary outcomes included subsequent admission and mortality. A subgroup analysis compared pregnant women who did receive naloxone compared with those who did not receive naloxone. RESULTS: Records from 443,714 men, 304,364 nonpregnant women, and 25,056 pregnant women were included. Nonpregnant women had lower odds for naloxone administration (1.70% vs 2.10%; adjusted odds ratio [aOR] 0.86 [95% CI 0.83-0.89]) and mortality (2.21% vs 2.99%; aOR 0.71 [95% CI 0.69-0.73]) but higher odds of subsequent admission (30.22% vs 27.18%; aOR 1.04 [95% CI 1.03-1.06]) compared with men. Pregnant women had lower odds for naloxone administration (0.27% vs 1.70%; aOR 0.16 [95% CI 0.13-0.21]) and mortality (0.41% vs 2.21%; aOR 0.28 [95% CI 0.23-0.35]) but higher odds of subsequent admission (40.50% vs 30.22%; aOR 2.04 [95% CI 2.00-2.10]) compared with nonpregnant women. Pregnant women who received naloxone had higher odds of mortality (14% vs 0.39%; aOR 6.30 [95% CI 2.11-18.78]) compared with pregnant women who did not receive naloxone. Pregnant women who did not receive naloxone were more likely to have Medicaid as their expected insurance payer, be in the lowest quartile of median household income for residence ZIP codes, and have a concurrent mental health diagnosis compared with pregnant women who did receive naloxone. CONCLUSION: Reproductive-aged women who are nonpregnant and pregnant were less likely to receive naloxone during opioid overdose-related ED visits compared with reproductive-aged men. Naloxone administration for reproductive-aged women should be prioritized in the efforts to reduce opioid- and pregnancy-related morbidity and mortality in the United States.

Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia.

Dysregulated gene expression contributes to most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of MYB transcriptional co-activator complex. By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB, but not CREB or MLL1, we find that the leukemic functions of MYB are mediated by CBP/P300 co-activation of a distinct set of transcription factor complexes. These MYB complexes assemble aberrantly with LYL1, E2A, C/EBP family members, LMO2, and SATB1. They are organized convergently in genetically diverse subtypes of AML and are at least in part associated with inappropriate transcription factor co-expression. Peptidomimetic remodeling of oncogenic MYB complexes is accompanied by specific proteolysis and dynamic redistribution of CBP/P300 with alternative transcription factors such as RUNX1 to induce myeloid differentiation and apoptosis. Thus, aberrant assembly and sequestration of MYB:CBP/P300 complexes provide a unifying mechanism of oncogenic gene expression in AML. This work establishes a compelling strategy for their pharmacologic reprogramming and therapeutic targeting for diverse leukemias and possibly other human cancers caused by dysregulated gene control.

Influence of maternal aerobic exercise during pregnancy on fetal cardiac function and outflow.

BACKGROUND: Risk factors for cardiovascular disease, the leading cause of death, have been documented in children as young as 3 years of age. Maternal environment (eg, exercise) influences fetal development and long-term health. Thus, the development of the fetal cardiovascular system during pregnancy is likely a preliminary indicator of cardiac health at birth and a proxy for the future risk of cardiovascular disease throughout life. OBJECTIVE: The purpose of this study was to assess the effects of supervised prenatal aerobic exercise at recommended levels on fetal cardiac function and outflow in the third trimester of pregnancy. We hypothesized that fetuses of aerobically trained women compared with fetuses of nonexercising women would exhibit increased cardiac function and greater cardiac output. STUDY DESIGN: Secondary data analyses of a 20-week, randomized controlled exercise intervention trial in pregnant women between 2015 and 2018 in Eastern North Carolina were performed. Eligibility criteria included pregnant women <16 weeks gestation, singleton pregnancy, aged 18-40 years, body mass index of 18.5-34.99 kg/m2, physician clearance letter for exercise participation, reliable transportation, and method of communication. Exclusion criteria included the presence of chronic conditions (eg, type 1 or 2 diabetes mellitus), current medications known to adversely affect fetal growth (eg, antidepressants), alcohol, smoking, or illicit drug use. The patient cohort consisted of 133 eligible pregnant women who were assigned randomly to either an aerobic exercise (n=66) group that participated in 150 minutes of supervised, moderate-intensity (40-59% VO2peak; 12-14 on Borg Rating of Perceived Exertion) aerobic exercise per week or a nonexercising group (n=61) that consisted of 150 minutes per week of light (<40% VO2peak) stretching and relaxation breathing techniques. Between 34 and 36 weeks gestation, a fetal echocardiogram was performed to assess fetal cardiac function, which included fetal heart rate, right- and left-ventricular stroke volume, stroke volume index, cardiac output, cardiac output index, and cardiac outflow that included pulmonary and aortic valve diameters, peak flow velocity, and peak flow velocity-time integral. Fetal activity state (quiet vs active) during the echocardiogram and maternal aerobic capacity served as covariates. Intention-to-treat and per-protocol (participants who attended ≥80% of exercise sessions) analysis of covariance regression models were performed. RESULTS: Of the 127 randomly assigned participants, 66 and 50 participants were included in the intention-to-treat and per-protocol analyses, respectively. Prenatal aerobic exercise significantly increased fetal right-ventricular cardiac measures of right ventricular stroke volume (P=.001) and stroke index via velocity-time integral (P=.003), right ventricular cardiac output (P=.002), cardiac index via velocity-time integral (P=.006), pulmonary artery diameter (P=.02), and pulmonary valve velocity-time integral (P=.03). Only in the intention-to-treat analysis was a significant difference in fetal left ventricular cardiac outflow observed; there was a greater aortic valve peak velocity (P=.04) found among fetuses of aerobically trained pregnant women. No other statistically significant between-group differences were found. CONCLUSION: The findings of this study demonstrate that participation in prenatal aerobic exercise at recommended levels may improve fetal cardiac function and outflow parameters. Follow-up cardiovascular measures in the postnatal period are needed to determine potential long-term effects on the offspring's cardiac function and outflow.

Screening for Opioid and Stimulant Exposure In Utero Through Targeted and Untargeted Metabolomics Analysis of Umbilical Cords.

BACKGROUND: Neonatal abstinence syndrome is an array of signs and symptoms experienced by a newborn due to abrupt discontinuation of intrauterine exposure to certain drugs, primarily opioids. In the United States, the incidence of neonatal abstinence syndrome has tripled over the past decade. The current standard of care for drug testing includes the analysis of infant urine and meconium. Sample collection is associated with several limitations, including diaper media interferences, limited sample amount, sample heterogeneity, and the need for professional staff for collection. Umbilical cord tissue has emerged as a convenient sample matrix for testing owing to its universal availability. The purpose of this study was to examine umbilical cords using an untargeted metabolomics approach to determine the detected drugs and validate an analytical method to confirm and quantify the identified drugs. METHODS: A metabolomics analysis was performed with 21 umbilical cords to screen for drugs and drug metabolites by liquid chromatography-mass spectrometry. Drugs were identified using the National Institute of Standards and Technology database, and an analytical method was developed and validated using secondary liquid chromatography-mass spectrometry instrument for positive confirmation and quantitative analysis. RESULTS: Twenty-one random umbilical cords from women were tested: 4 were positive for cocaine and the primary and secondary metabolites; one was positive for methadone, the primary metabolite; 3 were positive for cotinine, the metabolite of nicotine; and 5 were positive for acetyl norfentanyl. CONCLUSIONS: Our research is a prospective method development study using untargeted and targeted approaches to characterize steady-state drug metabolite levels in the umbilical cord matrix at the time of delivery. By characterizing drug type and concentration, this methodology can be used to develop a reliable complementary testing method for meconium toxicology screens.

MYB-activated models for testing therapeutic agents in adenoid cystic carcinoma.

OBJECTIVE: There are no effective systemic therapies for adenoid cystic cancer (ACC) and lack of tumor lines and mouse models have hindered drug development.We aim to develop MYB-activated models for testing new therapeutic agents. MATERIALS AND METHODS: We studied new ACC patient-derived xenograft (PDX) models and generated a matched cell line from one patient. In addition, we generated a genetically-engineered MYB-NFIB mouse model (GEMM) that was crossed with Ink4a+/-/Arf+/- mice to study tumor spectrum and obtain tumor lines. Using human and murine ACC-like tumor lines, we analyzed MYB expression by RNA-Seq and immunoblot and tested efficacy of new MYB inhibitors. RESULTS: We detected MYB-NFIB transcripts in both UFH1 and UFH2 PDX and observed tumor inhibition by MYB depletion using shRNA in vivo. We observed rapid loss of MYB expression when we cultured UFH1 in vitro, but were able to generate a UFH2 tumor cell line that retained MYB expression for 6 months. RNA-Seq expression detected an ACC-like mRNA signature in PDX samples and we confirmed an identical KMT2A/MLL variant in UFH2 PDX, matched cell line, and primary biopsy. Although the predominant phenotype of the MYB-NFIB GEMM was B-cell leukemia, we also generated a MYB-activated ACC-like mammary tumor cell line. We observed tumor inhibition using a novel MYB peptidomimetic in both human and murine tumor models. CONCLUSIONS: We generated and studied new murine and human MYB-activated tumor samples and detected growth inhibition with MYB peptidomimetics. These data provide tools to define treatment strategies for patients with advanced MYB-activated ACC.

Peptidomimetic blockade of MYB in acute myeloid leukemia.

Aberrant gene expression is a hallmark of acute leukemias. MYB-driven transcriptional coactivation with CREB-binding protein (CBP)/P300 is required for acute lymphoblastic and myeloid leukemias, including refractory MLL-rearranged leukemias. Using structure-guided molecular design, we developed a peptidomimetic inhibitor MYBMIM that interferes with the assembly of the molecular MYB:CBP/P300 complex and rapidly accumulates in the nuclei of AML cells. Treatment of AML cells with MYBMIM led to the dissociation of the MYB:CBP/P300 complex in cells, its displacement from oncogenic enhancers enriched for MYB binding sites, and downregulation of MYB-dependent gene expression, including of MYC and BCL2 oncogenes. AML cells underwent mitochondrial apoptosis in response to MYBMIM, which was partially rescued by ectopic expression of BCL2. MYBMIM impeded leukemia growth and extended survival of immunodeficient mice engrafted with primary patient-derived MLL-rearranged leukemia cells. These findings elucidate the dependence of human AML on aberrant transcriptional coactivation, and establish a pharmacologic approach for its therapeutic blockade.

Evaluation of Diabetic Retinal Screening and Factors for Ophthalmology Referral in a Telemedicine Network.

Importance: Retinal telescreening for evaluation of diabetic retinopathy (DR) in the primary care setting may be useful in reaching rural and underserved patients. Objectives: To evaluate telemedicine retinal screenings for patients with type 1 or 2 diabetes and identify factors for ophthalmology referral in the North Carolina Diabetic Retinopathy Telemedicine Network. Design, Setting, and Participants: A preimplementation and postimplementation evaluation was conducted from January 6, 2014, to November 1, 2015, at 5 primary care clinics serving rural and underserved populations in North Carolina among 1787 adult patients with type 1 or 2 diabetes who received primary care at the clinics and obtained retinal telescreening to determine the presence and severity of DR. A total of 1661 patients with complete data were included in the statistical analysis. Intervention: Nonmydriatic fundus photography with remote interpretation by an expert. Main Outcomes and Measures: Number of patients recruited, level of detected DR, change in rates of screening, rate of ophthalmology referral, percentage of completed referrals, and patient characteristics associated with varying levels of DR. Results: Of the 1661 patients (1041 women and 620 men; mean [SD] age, 55.4 [12.7] years), 1323 patients (79.7%) had no DR, 183 patients (11.0%) had DR without a need for an ophthalmology referral, and 155 patients (9.3%) had DR with a need for an ophthalmology referral. The mean rate of screening for DR before implementation of the program was 25.6% (1512 of 5905), which increased to 40.4% (1884 of 4664) after implementation. A total of 93 referred patients (60.0%) completed an ophthalmology referral visit within the study period. Older patients (odds ratio [OR], 1.28; 95% CI, 1.11-1.48) and African American patients (OR, 1.84; 95% CI, 1.24-2.73) or other racial/ethnic minorities (OR, 2.19; 95% CI, 1.16-4.11) had greater odds of requiring an ophthalmology referral compared with white and/or younger patients. Patients with higher hemoglobin A1c levels (OR, 1.19 per unit change; 95% CI, 1.13-1.25 per unit change) and longer duration of diabetes (OR, 1.76 per decade; 95% CI, 1.53-2.02 per decade) had greater odds of DR requiring an ophthalmology referral. History of stroke (OR, 1.65; 95% CI, 1.10-2.48) and kidney disease (OR, 1.59; 95% CI, 1.10-2.31) were strongly associated with DR and ophthalmology referral. Conclusions and Relevance: When implemented in the primary care setting, retinal telescreening increased the rate of evaluation for DR for patients in rural and underserved settings. This strategy may also increase access to care for minorities and patients with DR requiring treatment.

Geographic Information Systems Mapping of Diabetic Retinopathy in an Ocular Telemedicine Network.

Importance: Minimal information exists on the use of geographic information systems mapping for visualizing access barriers to eye care for patients with diabetes. Objective: To use geographic information systems mapping techniques to visualize (1) the locations of patients participating in the North Carolina Diabetic Retinopathy Telemedicine Network, (2) the locations of primary care clinicians and ophthalmologists across the state, and (3) the travel times associated with traveling to the 5 primary care clinics in our study. Design, Setting, and Participants: Cross-sectional study conducted from January 6, 2014, to November 1, 2015, at 5 Area Health Education Center primary care clinics that serve rural and underserved populations in North Carolina. In total, 1787 patients with diabetes received retinal screening photographs with remote expert interpretation to determine the presence and severity of diabetic retinopathy. Participants included patients 18 years or older with type 1 or type 2 diabetes who presented to these 5 clinics for their routine diabetes care. Main Outcomes and Measures: Development of qualitative maps illustrating the density of patients with diabetes and their distribution around the 5 North Carolina Diabetic Retinopathy Telemedicine Network sites by zip code and the density of ophthalmologists and primary care clinicians by zip code relative to US Census Urban Areas. A travel time map was also created using road network analysis to determine all areas that can be reached by car in a user-specified amount of time. Results: Mean (SD) age of patients was 55.4 (12.7) years. Women made up 62.7% of the study population. The study included more African American patients (55.4%) compared with white (35.5%) and Hispanic (5.8%) patients. The mean (SD) hemoglobin A1c level was 7.8% (2.4%) (to convert to proportion of total hemoglobin, multiply by 0.01), and the mean (SD) duration of diabetes was 9.2 (8.2) years. Whereas the clinics located in Greensboro, Asheville, and Fayetteville screened patients from more immediate surrounding areas, the Greenville site had the widest distribution of zip codes, suggesting that patients travel from greater distances to reach this facility. Primary care clinicians were spread somewhat uniformly across the state, whereas ophthalmologists were concentrated around urban centers. Also, the number and type of surface roads surrounding the clinics determined the distance and time patients must travel to receive care. Conclusions and Relevance: Geographic information systems mapping is a useful technique for visualizing geographic access barriers to eye care for patients with diabetes and may help to identify underserved areas that would benefit from the expansion of retinal screening programs via telemedicine.

Conceptualizing and Measuring Safe, Stable, Nurturing Relationships and Environments in Educational Settings.

Most children and adolescents older than five years spend at least six hours of their day in school settings. Like parents, education professionals can promote health and protect youth from harm by providing safe, stable, nurturing relationships and environments. The Centers for Disease Control and Prevention (CDC) has developed a framework which posits that safe, stable, nurturing relationships and environments are Essentials for Childhood and are fundamental to promoting health and well-being; protecting youth from maltreatment and other violence and victimization; and ensuring optimal, healthy development. In this paper, the authors propose an approach to applying safe, stable, nurturing relationships and environments to the school ecology; review select survey measures to examine these constructs within educational settings; and suggest available indicators to measure safety, stability, and nurturance within the school context.

A High Throughput Screening Assay for Anti-Mycobacterial Small Molecules Based on Adenylate Kinase Release as a Reporter of Cell Lysis.

Mycobacterium tuberculosis (Mtb) is well-established to be one of the most important bacterial pathogens for which new antimicrobial therapies are needed. Herein, we describe the development of a high throughput screening assay for the identification of molecules that are bactericidal against Mycobacteria. The assay utilizes the release of the intracellular enzyme adenylate kinase into the culture medium as a reporter of mycobacterial cell death. We demonstrate that the assay is selective for mycobactericidal molecules and detects anti-mycobacterial activity at concentrations below the minimum inhibitory concentration of many molecules. Thus, the AK assay is more sensitive than traditional growth assays. We have validated the AK assay in the HTS setting using the Mtb surrogate organism M. smegmatis and libraries of FDA approved drugs as well as a commercially available Diversity set. The screen of the FDA-approved library demonstrated that the AK assay is able to identify the vast majority of drugs with known mycobactericidal activity. Importantly, our screen of the Diversity set revealed that the increased sensitivity of the AK assay increases the ability of M. smegmatis-based screens to detect molecules with relatively poor activity against M. smegmatis but good to excellent activity against Mtb.

Repurposing the antihistamine terfenadine for antimicrobial activity against Staphylococcus aureus.

Staphylococcus aureus is a rapidly growing health threat in the U.S., with resistance to several commonly prescribed treatments. A high-throughput screen identified the antihistamine terfenadine to possess, previously unreported, antimicrobial activity against S. aureus and other Gram-positive bacteria. In an effort to repurpose this drug, structure-activity relationship studies yielded 84 terfenadine-based analogues with several modifications providing increased activity versus S. aureus and other bacterial pathogens, including Mycobacterium tuberculosis. Mechanism of action studies revealed these compounds to exert their antibacterial effects, at least in part, through inhibition of the bacterial type II topoisomerases. This scaffold suffers from hERG liabilities which were not remedied through this round of optimization; however, given the overall improvement in activity of the set, terfenadine-based analogues provide a novel structural class of antimicrobial compounds with potential for further characterization as part of the continuing process to meet the current need for new antibiotics.